PREPARATION OF CETIRIZINE DIHYDROCHLORIDE ORAL FAST DISINTEGRATING TABLET

By Mr. Prachya Katewongsa

A Thesis Submitted in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy Program in Pharmaceutical Technology

Graduate School, Silpakorn University Academic Year 2014

Copyright of Graduate School, Silpakorn University

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PREPARATION OF CETIRIZINE DIHYDROCHLORIDE ORAL

FAST DISINTEGRATING TABLETS

By

Mr. Prachya Katewongsa

A Thesis Submitted in Partial Fulfillment of the Requirements for the Degree

Doctor of Philosophy Program in Pharmaceutical Technology

Graduate School, Silpakorn University

Academic Year 2014

Copyright of Graduate School, Silpakorn University

The Graduate School, Silpakom University has approved and accredited the Thesis title of "Preparation of cetirizine dihydrochloride oral fast disintegrating tablet" submitted by MR. Prachya Katewongsa as a partial fulfillment of the requirements for the degree of Doctor of Philosophy in Pharmaceutical Technology

(Associate Professor Panjai Tantatsanawong, Ph.D.)

Dean of Graduate School ... l .~ ... .1 ... av~ \1;-}.t ..... .1 .. 9. n~. s:

The Thesis Advisor

C:f/c£: ............ ~---················· (Associate Professor Thawatchai Phaechamud, Ph.D.)

The Thesis Examination Committee

... ~.~.~~.~~~ ...... ~~~~ .......... Chairman (Assistant Professor Warisada Sila-on, Ph.D.) ...... ~r. ....... ./ ... ?.01> .. .

... .& ................... !!&~ ....... Member (Professor Katsuhide Terada, Ph.D.) ..... ~ ..... ./ .... Jv0vs.t ...... ./ ... ~o .15 .. .

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.................................................... Member

(Assistant Professor Sarayut Janmahasatian, Ph.D.) (Associate Professor Thawatchai Phaechamud, Ph.D.)

.... .t .... .! ... A~~ . ! ........ .! .. ?.0.\5.... . ..... ! .... .! .... J~~~.t. ..... .t .. 1Q.I.f.. ..

53354801: MAJOR: PHARMACEUTICAL TECHNOLOGY KEY WORDS: CETIRIZINE DIHYDROCHLORIDE ORAL FAST DISINTEGRATING TABLET I

BET ACYCLODEXTRIN I COMPLEXATION I LUBRICANT PRACHYA KATEWONGSA: PREPARATION OF CETIRIZINE DIHYDROCHLORIDE

ORAL FAST DISINTEGRATING TABLET. THESIS ADVISOR: ASSOC.PROF. THAWATCHAI PHAECHAMUD, Ph.D. 98 pp.

Cetirizine dihydrochloride (CD), an antihistamine agent which is described as a long acting non-sedation with some mast-cell stabilizing activity. It is a bitter taste drug. The present work was carried out to study the application of inclusion complex for taste masking of bitter CD. ~-cyclodextrin (~-CyD) was used as the host for inclusion complexation, and kneading method was used to prepare the CD/~-CyD inclusion complex using ethanol as kneading solvent. The formation of inclusion complexes with P-CyD was confirmed by Fourier transform infrared spectroscopy (FT -IR), differential scanning calorimetry (DSC), powder X-ray diffractometry (PXRD), thermogravimetric analysis (TGA), simultaneous XRD-DSC measurement and 1H-nuclear magnetic resonance spectroscopy ( 1H-NMR). FT­IR, powder x-ray and DSC data indicated the inclusion complex formation . TGA and simultaneous XRD­DSC measurements revealed the transformation of the crystalline form of P-CyD by removing of water

molecules due to complex formation. 1H NMR spectroscopy indicated an intermolecular interaction of CD protons with the cavity of P-CyD. Furthermore, an unstructured line scale was used for the quantification of the taste sensory study by human volunteers. The taste evaluation by human volunteers showed that the CD!p-CyD had no bitter taste. Lubricants could effect on disintegration time (DT), hardness and dissolution of FDT. Therefore this study investigated the effect of amount and type of lubricants (magnesium stearate and sodium stearyl fumarate) as well as compression force on characteristics of the CD FDT. The spatial distribution of lubricants in tablets had been analyzed using Raman mapping and scanning electron microscopy-energy dispersive x-ray spectroscopy (SEM-EDX). The more concentration of lubricant, the more distribution of lubricants on tablet surface was detected. From the Raman mapping, the high compression force resulted in more distribution of lubricant. In addition, CD FDT was prepared by direct compression method. A 32 full factorial design was applied for the optimization of CD FDT. By adopting a systematic formulation approach, the closeness between predicted and observed values (DT, WT, contact angle, SFE, hardness) indicated the validity of derived equations for the dependent variables. Sodium stearyl fumarate had less impact on hardness and disintegration time than magnesium stearate. Therefore, FDT containing sodium stearyl fumarate as lubricant showed higher drug dissolution than that containing magnesium stearate. Finally, the disintegration time of fast disintegrating tablet (FDT) comprising CDI~-CyD inclusion complex prepared with direct compression was less than 60 sec in immersion fluid and 33 sec in the mouth of volunteers with fast drug dissolution and good taste with an average rating of0.28 (SD=0.26).

Program of Pharmaceutical Technology Student's signature .P..MC.Hf~ .. .Kn~~OOI.iSA Thesis Advisor's signatur~. :.F .. ~ ...... ........... .

iv

Graduate School, Silpakorn University Academic Year 2014

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ACKNOWLEDGEMENTS

First and foremost I offer my sincerest gratitude to my thesis advisor, Assoc. Prof. Dr.

Thawatchai Phaechamud for giving me the great opportunity to be a part of graduated school students. This thesis would not have been completed or written without his supervision. I would like to thank him for his kindness support, encouragement and valuable suggestion throughout my study at Faculty of Pharmacy, Silpakorn University. He has been supported me in diverse way that considerably help me to improve my skills in doing research and also for daily living. Mr. Peeracha Thanawattanawanich and Dr. Napasinee Aksornkoae for their kindness and precious support, valuable comments and sharing the great attitude in my research work. My sincere gratitude also goes to Assoc. Prof. Dr. Sontaya Limmatvapirat, Asst. Prof. Dr. Warisada Sila-on, and Asst. Prof. Dr. Sarayut Janmahasatian for the creative guidance encouragement and valuable comments to this work.

My grateful gratitude also goes to Prof. Dr. Katsuhide Terada and Assist. Prof. Dr. Yasuno Yoshihashi for giving me the great opportunity in doing part of my research in his laboratory; Department ofPharmaceutics, Faculty of Pharmaceutical Sciences, Toho University, Japan. I would like to thank him for his kindness and precious support, valuable comments and sharing the great attitude in my research work and also in my living in Japan.

I gratefully acknowledge the Thailand Research Funds through the Golden Jubilee Ph.D. Program (Grant No. PHD/0052/2552) and Faculty of Pharmacy, Silpakorn University, for the scholarship, laboratory equipment and other facilities to conduct my research and publications.

I would also like to show my grateful towards all of my instructors, faculty's staffs, and all my friends in Faculty of Pharmacy Silpakorn University for kindly support, encouragement and friendship over the years. Special thanks to my lovely laboratory partners, the Prirnpri Island members: Dr.Jongjan Mahadlek, Dr.Kodchamon Yodkham, Miss Sununta Srisopon, Miss Pitikarn Karnjanapruk, Miss Sasiprapa Chitrattha, , Miss Sumantana Anuchatkidcharoen, Mr.Chaieak Chonchewa who willingly

shared their precious time together and supporting me during the study. Special thanks to Mr kritamorn jitrangsri for his kind helping about HPLC method for me.

Special thanks to all of my beloved family especially mom, dad and my brother for their invaluable love, encouragement, care, and always beside me, understand and support me in everything. I love you all. Finally, an apology is offered to those whom I cannot mention personally one by one here.

vi

Table of Contents

English Abstract .............................................................................................................................. .

Thai Abstract ................................................................................................................................... .

Acknowledgments ........................................................................................................................... .

List of Tables ................................................................................................................................. .

List of Figures ................................................................................................................................. .

List of Abbreviation ........................................................................................................................ . Chapter

1 Introduction ................................................................................................................... .

2 Review of related literature ........................................................................................... .

3 Materials and Methods .................................................................................................. . 4 Results and Discussion .................................................................................................. .

Page

IV

v vi

viii

ix XII

1 6

31 44

5 Conclusions ............................................................................................................ ........ 79

Bibliography..................................................................................................................................... 80 Appendices . .. . . . .. .. . .. . . . .. .. . . . .. . . . . . . . . . . . . .. . . . . . . .. .. . . . . . . . .. . . . . . . . .. . . . .. .. .. . . . . . .. . . . . ... . .. .. . . . .. .. .. .. .. ... .. . . .. .. .. .. . . . . . . . .. . . . 93

Biography.................................................................................................................................... ..... 97

vii

List of Tables Tables Page

Change of chemical shift (~1>, ppm) for protons of P-CyD and complexation . . . 52

2 Physical properties of tablets containing disintegrant . . ... ..... . . ... . . . . .. . .. . .... . 55

3 Physical properties of tablets containing xylitol and other materials . ... .... .. . . . 56

4 Formulation for preparation of CD FDT .. . . .. .. . . . ..... . ..... . . .. . . .. . ... . .. ..... . . . 59

5 Full factorial design layout ... . . . . . ..... ......... ... . ....... . .. ..... ..... . . . . . .. ... . .. . . 59

6 Full factorial design of9 runs for identifying active formula and process

variables influencing dependent variables <mg-st) . . ... . . .. ...... . . ... . . . .... 65

7 Polynomial equation and the coefficients for DT, WT, Hardness, contact

angle and SFE .... .. .... . ..... . .. . . ........ . .. ............. . . .. . . .. .. . . ...... .. . 65

8 Full factorial design of9 runs for identifying the active formulation and

process variables influencing the dependent variables (SSF) . . . . ........ . 69

9 Polynomial equation and the coefficients for DT, WT, Hardness, contact

angle and SFE ..... . .... . .... . . . . ........... ....... . .... .... . . . .. . ...... . . .. ... . 69

IO Evaluation properties of check point formulation of tablet containing mg-st

(Ct) ... ........ .... .............. .. ... .... ................. ...... ........ .... .. .... . 74

II Evaluation properties of check point formulation of tablet containing SSF

(Cz) .. . .... ... . ....... . ... . ...... . .... . . . . . . .. . ... . . . . .. . .. .. .. ... .. . ... . . . . . . .... .. . 74

I2 Formulation of CD FDT . .. . . . . ... . . . . ............. . . ... ... .. . . . . .. . . ... .... . .. . ..... . 76

13 Evaluation of CD FDT . . .. . ............. .... . ... ... .. . ..... . .... . . .. . .. . .......... . . . 76

I4 Raw data of percentage CD release from CD FDT . ....... . . . .. . . . . . . . . .... . ... . 93

15 Raw data of percentage CD release from commercial product .......... . . .. . .. . 94

I6 Raw data of assay .... . . ................... . .. .... . . . ..... . .... . ....... .. . . . .......... . 94

I7 Raw data of content uniformity . .. . ..... . . . . . .. . ... . . . .. ... . . . . .. ..... . . ... ...... . . . 94

I8 Evaluation of bitterness score by volunteer .... .... . . . . . ....... . . .... . . . ... .. .... . 95

viii

List of Figures Figures Page

Structure of magnesium stearate (mg-st)(left) and sodium stearyl fumarate

(SSF, Alubra®)(right).... ... ........................ ..... ...... ....... .......... ............... ...... 18

2 Structure of CD ...... . .. . ............ . . . . .. ... . ... .. .......... . ..... . . . . .. . .. ............ . 19

3 Experiments in a design with three variables . . ... ............ .. . . . .. ....... . . . .... . 22

4 FT-IR spectra of CD,~- CyD, physical mixture of CD and~- CyD (PM), and

inclusion complex of CD and~- CyD. . . ... . .. .. . ... ... ... . . . . . . . . . . . . . . . .. . .. . 45

5 X-ray diffractograms of CD, ~-CyD, physical mixture of CD and ~-CyD (PM),

and inclusion complex of CD and ~-CyD. ... .. . .. . . . . .. ... ... ... . .. ... . . . . .... . 46

6 DSC curves of CD, ~- CyD, physical mixture of CD and ~-CyD (PM), and

inclusion complex of CD and~- CyD. .. . . . . . . ... .. . .. . . .. ... ... ... . . . . .. .. .. 47

7 XRD-DSC ofCD .. ... .. . . . . . .. . . . . . . . . . . .... . . . . . .... . . . . ... ..... . .. . . . . . . . . . . .. ..... . . 48

8 XRD-DSC of~-CyD ...... .. . . ... .. . ... . . .. . ..... ...... . . .. . ... . ....... . ..... . ... . ... . 49

9 XRD-DSC of PM . . . . . . . . . . ... . . .. . . ... . . .. .. . . . . . .... ... ... . .. . ..... . ... .. . . .... . . . . .. . 49

10 XRD-DSC of inclusion complex .. . . ..... ...... . . . ... .... . ... . . . . .. ........ . .. .. . .. . . 49

I I TGA of (A) CD, (B) ~-CyD, (C) physical mixture and (D) inclusion complex 50

12 1H NMR spectra (300 MHz) of CD, ~-CyD and complex of CD/ ~-CyD .. ... . 51

13 1H NMR spectra of ~-CyD and complex ................................... . . . . . ... . 52

14 SEM images of CD (A), ~-CyD (B) and inclusion complex (C) at 500x

magnification .... . .... .. . ....... . . . . . . . . . .... . ... ...... . . .. .. . . . .... . ... . . . .. . .. .. 53

15 Taste panel evaluation of (A) pure CD (B) physical mixture of CD/~-CyD and

(C) complexation ofCD/~-CyD by healthy volunteers (n=6) ...... . .. . . . .. . 54

16 Comparison of bitterness level which (*) indicated significantly difference

from the other samples (analyzed by R-stat p-value<0.05) . . . . . . . . . . . .. .... . 54

17 Contact angle of the tablets (n=6) .. . . . . . . . . . . .. . . . .. . ... . . . ... . .. . . . . . . . .... . .. . . . . . .. . 56

ix

Figures I8

19

20

21

List of Figures Page

SFE of the tablets (n=6)..... .. ............ . . ... . ... ... . .. ... . . . . . .. ... . . .. ... . . . . . . ..... 57 Scanning electron micrographs of (a) xylitol powder (magnification of I OOX);

(b) xylitol powder (magnification of 500X); (c) Avice! PH 10I

(magnification of IOOX); (d) Avice! PH 10I (magnification of 500X ); (e) tablet containing xylitoi :Avicel PH IOI 9:1 (magnification of IOOX);

(f) tablet containing xylitol:A vice! PH 10 I 9: I (magnification of 500X) 58 Spatial distribution of mg-st in tablet compressed at I ton/cm2 at magnification

of I Ox and 5 11m step size. The amount ofmg-st in tablets: (a) 0.25% w/w, (b) 2.5% w/w and (c) 5%

w/w. .. .. . . . . . . . . . .. ... . ... .. . . . . . ...... . .... .. . . . . . . .. . ... . ... .. ... . . ... . . . . .. . . .. . .. 60 EDX mapping for distribution ofmg-st at (a) 0.25% w/w, (b) 2.5% w/w, (c) 5%

wlw in FDT. . . .. . ..... . .. ..... . . .. . .. . . ..... . .. . . . . . . . ... ..... . . . . . . ...... . . . ... .. .. 6I 22 Spatial distribution ofSSF in surface of tablets prepared with compression force

23

24

25

of I ton/cm2 from Raman maps at magnification of I Ox and 5 11m step size. The amount ofSSF in tablets: (a) 0.25% w/w, (b) 2.5% w/w and (c)

5% w/w .... . .... ......... . . . . .......... . . . .. ... . .. . .. .. . . ... . .. . . . . . . ....... .. .......... .

EDX mapping for distribution ofSSF at (a) 0.25% w/w, (b) 2.5% w/w, (c) 5% w/w in FDT . .. . .. ..... . . . . ..... .. . . . . . . . . . . . . . . . . . . . .. . . . . . . . .......... ... . .... .. . .

Raman mapping for mg-st distribution on tablets containing 2.5% w/w mg-st

prepared (a) at compression force of I ton/cm2 (b) 5 ton/cm2 and tablets containing 5% w/w mg-st prepared (c) at compression force of I ton/cm2

and (d) 5 ton/cm2 and tablets containing 2.5% w/w SSF prepared (e) at compression force of 1 ton/cm2 (f) 5 ton/cm2 and tablets containing 5% wlw SSF prepared (g) at compression force of 1 ton/cm2 (h) 5 ton/cm2 . . . . . . . .. . .. • . .. . ....... . ..... . . .. .•.• .... . ... . .. • . . . . . . .. . . .. .... . ... .

SEM of CD surface tablets containing 0.25% w/w mg-stprepared (a) at compression force of 1 ton/cm2 (b) 5 ton/cm2 and tablets containing 2.5% w/w mg-st prepared (c) at compression force of 1 ton/cm2 (d) 5 ton/cm2

and tablets containing 5% w/w mg-st prepared (e) at compression force of I ton/cm2 (f) 5

62

63

64

ton/cm2.. . . . .. . . . . . .•.. . . . . . . . .. . . ..... •.•.. . . . . . .. .. . . . ..... . . . . ...... . . . .. . . .. ... . .. 67

26 Polar and dispersive component of mg-st of tablets containing 0.25% w/w SSF

27

prepared (A) at compression force of I ton/cm2 (B) 5 ton/cm2 and tablets containing 2.5% w/w mg-st prepared (C) at compression force of 1 ton/cm2 (D) at compression force of 5 ton/cm2 and tablets containing 5% w/w mg-st (E) at compression force of I ton/cm 2 and (F) 5 ton/cm2 . . . . . .. . . . . . . . .. . . . ... . .. ... . . . . . . . . . . .. .. . ...... . . ..... . .. . .. . .. .. . . .... . .

SEM of CD surface tablets containing 0.25% w/w SSF prepared (a) at

compression force of I ton/cm2 (b) 5 ton/cm2 and tablets containing 2.5%

w/w SSF prepared (c) at compression force of I ton/cm 2 (d) 5 ton/cm2

and tablets containing 5% w/w SSF prepared (e) at compression force of

I ton/cm2 (f) 5

68

ton/cm2. .. . . . . . • .. . . . . . . . . . . . . . .. . . . . . . . .. . . . . . . . ... •. . ... . . . . . . . . . . . . . . . .. . . . . ...... 7I

X

Figures

28

29

30

31

32

33 34

List of Figures

Polar and dispersive component of SFE of tablets containing 0.25% w/w SSF prepared (A) at compression force of 1 tonlcm 2 (B) 5 ton/cm2 and tablets containing 2.5% w/w SSF prepared (C) at compression force of I ton/cm 2

(D) at compression force of 5 ton/cm2 and tablets containing 5% w/w SSF

(E) at compression force of 1 ton/cm 2 and (F) 5 ton/cm2 . . . .... . . . ......... . . . . . . . .. . .................. •. . . .... . .. •.• . •... .. . . .. . ..

Effect of amount and type of lubricant of tablets prepared at compression force of 1 ton/cm2 on : (A) hardness and (B) DT (n=10) .. . . . . . . .. ... . . . . . . .. . .. . .. .

Comparative dissolution profiles of check point tablets prepared at compression force of 1 ton/cm2

: tablets containing I% w/w mg-st and tablets contammg 1% w/w SSF

(n=6) .. . .. . ... . .. . . . . ........ . . ... ..... ...... . . .. ........ · · · · · · · · · · · · · · · · · · · · · · · · · ···· Evaluation of the bitterness of CD/~-CyD FDT by the healthy volunteers

(n=6) .. . ....... . .. . . . . . . .. .... . . ... . . . . . . . . . . . .. . . ... ... . · · · · · · · · · · · · · · · · · · · · · · · · · · ·· Comparison of bitterness level which(*) indicated significantly difference

from the other samples (analyzed by R-stat p-value<0.05) .... ...... . .. ... . Dissolution study of CD FDT (n=6) .. . ..... ... . . . . . . ..... .. .. . . .......... . ........... . Calibration curve of CD .. .. . . .. .. ... . . . . . .. ... . ..... . . . . . . . . . . . .... . .. . . . . . ........... . .

xi

Page

72

73

75

77

77

77

93

%w/v

%w/w

%

[3

® ± oc llg

IlL llm mg

M

28 A Abs

AR grade

atm

C18

em

mm cm-1

cm2

CO., LTD.

et al. g

Hz HPLC

kg

Log

KeV

kPa m2

mg

mm

mL

mm

List of Abbreviations

percent weight by volume

percent weight by weight

percentage

beta

trademark

plus per minus

degree Celsius

microgram

microliter(s)

micrometer( s)

milligram

Molar

two theta

angstrom

absorbance

analytical reagent grade

atmospheric pressure

18 carbon atoms

centimeter( s)

millimeter( s)

wavenumber

square centimeter

Company Limited

and others

gram(s)

hertz High Performance Liquid Chromatography

kilogram(s)

logarithm

kiloelectron volt( s)

kilo pascal

square meter(s)

milligram( s)

minute(s)

milliliter( s)

millimeter( s)

xii

mJ/m2

Mw ng nm

No. N pH

rpm SD sec UV/vis v

List of Abbreviations

millijoule per square meter molecular weight nanogram(s) nanometer( s) number newton hydrogen ion concentration rounds per minute standard deviation second(s) Ultraviolet-visible volt(s)

xiii

CHAPTER!

INTRODUCTION

1. Statement and significance of the research problem

Solid dosage forms are widely used in the patients especially, tablet formulation. Appropriate tablet should provide a suitable hardness with rapid disintegration and promote the drug dissolution. However, the development and formulation are always challenged with major problems of unaccepted physical properties, particularly disintegration and dissolution of tablet. To overcome these problems, the recent developments in the fast disintegrating tablet (FDT) provide a convenient solution for patients who have difficulties in swallowing tablets (Bhowmik et al., 2009; S. Late et al., 201 0). FDT also offers all advantages of solid dosage forms and liquid dosage forms along with special advantages, such as easy administration and no risk of suffocation resulting from physical obstruction by a dosage form. The main target patients for using FDT are pediatric, geriatric, and bedridden or developmentally disabled patients; patients with persistent nausea; and patients who have difficulty to access or drink a water. FDT can be formulated using various methods such as lyophilization and direct compression. Superdisintegrants are commonly used in FDT prepared with compression because of their notable swelling or rapid water absorption for disintegrating the tablet (Biradar et al., 2006b; Chang et al., 2000). Therefore, the rapid and high drug absorption of the drug into the body could be attained (Mohanachandran et al., 2011; Rudnic et al., 1982; Zhao et al., 2005). Most of the techniques aim for lowering the disintegration time (DT), however the appropriate mechanical strength of tablet should be considered and controlled. (Madgulkar et al., 2009). The key properties of FDT are fast absorption of water into the core tablets and disintegration of associated particles into individual components for fast dissolution (Fu et al., 2005). The challenges to develop FDT are rapid disintegration of tablets, minimization of tablet size, sufficient mechanical strength and minimum or no residue in mouth (Y. Bi et al., 1996).

In the recent past, several new advanced technologies have been introduced for FDT fabrication with very interesting features, like extremely low disintegration time, exceptional taste masking ability, pleasant mouth feel and sugar free tablets for diabetic patients. The technologies utilized for fabrication of FDT include lyophilization, moulding, direct compression, cotton candy process, spray drying, sublimation, mass extrusion, nanonization and quick dissolve film formation (Shukla et al., 2009). However, direct compression is the most convenient to produce tablet with sufficient structural integrity (Jinichi Fukami et al., 2006; Kandu et al., 2008). Therefore, direct

1

2

compression has appropriate for large scale manufacturing because it could minimize the production cost since it uses the conventional equipment, commonly available excipients, high dose accommodation, and limited number of process steps.

Cetirizine dihydrochloride (CD) is described as a long acting non-sedative antihistamine with some mast-cell stabilizing activity (Demoly et al., 2003; Spencer et al., 1993). CD preparations available in the market are in the form oftablet and syrup for oral administration. Regarding liquid dosage form, the major problem is poor stability. Although, the oral administration is the most popular route, many patients find its difficulty to swallow a solid dosage form. Therefore, it results in high incident of patient non-compliance. To overcome these problems, cetirizine dihydrochloride fast disintegtrating tablet (CD FDT) has been prepared as recommended to enhance the fast dissolution and pleasant mouth feeling to the patients. Such a dosage form is beneficial to the geriatric and pediatric patients who are bedridden and do not access to water. Moreover, CD FDT is suitable for patients who have an acute allergy during travel such as: hay fever, angioedema and urticaria.

Practically, the basic tablet excipients include binders, diluents, disintegrants, glidants and lubricants. Lubricants are added in the final steps of mixing formulation components prior to compression. Lubricants practically prevent adhesion of compacts to the surface of the punches and dies during compression and ejection from the die cavity. Due to hydrophobic of lubricants which hinders the penetration of water in the tablet, it can influence on disintegration time (DT), hardness and dissolution of prepared tablets (Iyad et al., 201 0; Joshi et al., 2004). The excess lubricant could cause the powder to form into globules and to resist the proper cohesion. Over the years, there have been many reports that extending this film, through either an increase in the amount of magnesium stearate (mg-st) or a longer mixing time, has a negative effect on the hardness, friability, and DT of the tablet (Aly, 2006; Bolhuis et al., 1975; Bossert et al., 1980). Along with a decrease in tablet hardness, most authors reported that an increase in the amount of mg~st led to an increase in DT of tablet (Lindberg, 1972).

There have been numerous attempts to detect the lubricants by chemical or physical methods in order to get a better understanding of the nature of these lubricant films. However, most of these investigations have relied on the indirect techniques. The use of chemical imaging based on vibrational spectroscopy (Raman spectroscopy) has been rapidly increasing in the field of pharmaceutical technology during past few years. The spatial distribution of components in tablets had been analyzed using Raman imaging and mapping. Moreover, energy dispersive X-ray spectroscopy (EDX) is a non-destructive technique for chemical characterization using scanning electron microscopy (SEM). In previous study (Lakio et al., 2013), Raman chemical imaging was used in order to detect distribution of mg -st in tablet at different blending time. The

3

resulted found that if the optimal blending time is exceeded, overlubrication happens. Nevertheless, this study Raman spectroscopy and SEM/EDX had been applied to create

the maps of lubricant distribution and to investigate the effect of compression force on lubricant distribution. Raman spectra of lubricant were measured by Raman spectroscopy to examine a lubricant distribution after compression of tablet.

The traditional approach to develop a formulation was to change one variable at time. By this method it was difficult to develop an optimized formulation. Traditional experimental methods involves significant amount oftime and efforts to get meaningful of results for a complex system. It is very much desirable to obtain an acceptable formulation using minimum amount of time and material. From disadvantage of

traditional way of experimental, optimization is a rational approach to the selection of the several excipients and the manufacturing steps for formulated FDT. After investigation of lubricants on the surface of tablets, it is important to optimize the concentration of lubricants and compression force in formulation. Previous study reported that factorial design was used to optimize the concentrations of disintegrating

agent and lubricant. A two factor, three levels (32) full factorial design was used and nine experimental runs were performed to optimize the FDT (Late et al., 2009). Furthermore, knowledge of the wettability and surface free energy of pharmaceutical solids is very important in the design of pharmaceutical formulation. Since lubricants form a hydrophobic film on the surface of the powder particle, the wettability and

surface free energy of tablets were assessed by contact angle measurement. The method of assessing the surface free energy indirectly from wettability measurement was widely used. Moreover, to investigate the polar and dispersive component, the liquid penetration rate ofthe tablets was measured. The solutions with which the value of the surface free energy was known were used in order to evaluate surface free energy of tablets. Therefore, the purpose of this study was to determine the distribution of

lubricant and evaluate the effect of lubricant on the tablet characteristics of FDT prepared by direct compression. The lubricants used in this study were mg-st and sodium stearyl fumarate (SSF). To develop model for predict formulation, a 32 full factorial design was applied for the optimization of CD FDT. The concentration of

lubricant (XI) and compression force (X2) were taken as independent variables. The selected dependent variables were disintegration time, wetting time, hardness, contact angle and surface free energy (SFE) to find out the effect of independent variables on dependent variables.

Considering patient quality of life, the developments in the FDT provide a convenient solution for patients who have difficulties in swallowing tablets and other dosage forms (Fu et al., 2004). FDT dissolves or disintegrates in the saliva within a matter of seconds when places upon the tongue and then it was swallowed to the

4

stomach (Jinichi Fukami et al., 2006; Sunada et al., 2002; Wilson et al., 1987). In the

case ofFDT, however, it often encounters the problem of bitter taste of the drug due to disintegration of the active compound in the mouth (Ishikawa et al., 1999). After FDT disintegration/dissolution in the saliva, the drug in FDT remains in the oral cavity until it is swallowed. If the drug has a bitter taste, taste masking is critically important in the formulation for maximal patient acceptability. More than 50% of pharmaceutical are administered orally for several reason and undesirable taste is one of the formulation problem encountered with such oral products (Sheth et al., 2010). Therefore, the bitterness of pharmaceutical medicine should be masked for patient compliance (Madgulkar et al., 2009).

Unfortunately, CD is accompanied with a very unpleasant bitter taste. CD preparations available in the market are in the form of tablet and syrup for oral administration. Regarding liquid dosage form, the major problem is poor stability. Although, the oral administration is the most popular route, many patients find it difficult to swallow solid dosage form. Therefore, it results in high incident of patient non-compliance. To overcome such problems, CD FDT should be prepared as recommended to enhance the fast dissolution and pleasantness of a mouth feel to the patients.

To mask the unpleasant taste, various techniques have been used including flavoring, polymeric coatings, microencapsulation, complexation with ion exchange resins, complexation with cyclodextrins etc. Cyclodextrins are cyclic oligosaccharides which its glucose units of the cyclodextrins form a cyclic structure with hydrophilic outer surface and inner less polar cavity. Beta-cyclodextrin (p-CyD) is a family of cyclic oligosaccharides which it is safety to develop as taste masking agent. It is widely used in many industrial products, technologies and analytical methods. Moreover, P­CyD shows low hygroscopicity, less toxicity, excellent compatibility and compressibility. P-CyD appears to be the most useful complexing agent because of its cavity size, and ease with which it could be obtained on the industrial scale leading to reasonably cheaper price of the compound. Therefore, P-CyD is suitable for taste masking agent in pharmaceutical products.

There have been numerous attempts to form inclusion complex but the kneading method is the method which is also effective and simple for developing for scale up and industrial scale. Due to hardly removing of water from complex, therefore this study used ethanol as solvent for kneading. In addition, ethanol is widely used for wet granulation process in industry thus it is possibly used as solvent for kneading method in large scale. The present work was conducted to investigate the application of P-CyD for taste masking of CD, and kneading method which using ethanol as solvent was used to prepare the cetirizine dihydrochloride/beta-cyclodextrin inclusion complex (CD/P­CyD). If achievement for inclusion complex was attained, it continued to be used for

5

taste masking CD FDT because ~-CyD was safety to develop as taste masking agent and could be applied on the industrial scale leading to reasonably cheaper price of the

compound (Del Valle, 2004). Therefore, CD was used to develop into FDT in this study. Direct compression

was chosen to manufacture FDT. To detect the effect oflubricant on properties ofFDT, Raman spectroscopy and SEM/EDX were applied to create the maps of lubricant distribution and the developed FDTs were evaluated for their physical properties. The lubricants used in this study were mg-st and SSF. To develop model for predict

formulation, a 32 full factorial design was applied for the optimization of CD FDT. Additionally, this present work was conducted to investigate the application of ~-CyD for taste masking of CD and using ethanolic kneading method to prepare the CD/~-CyD inclusion complex and CD FDT.

2. Objective of this study

1. To prepare the CD FDT with direct compression and to investigate the effect of

lubricant distribution on tablet properties

2. To mask a bitter taste ofCD by ~-CyD

3. HYPOTHESIS:

1. CD FDT could be fabricated with direct compression and could disintegrate within 1

min with other appropriated properties.

2. ~-CyD could be used for masking a bitter taste of CD by inclusion complex.

CHAPTER2

REVIEW OF RELATED LITERATURE

1. Fast Disintegrating Tablet (FDT)

Recent developments in the fast disintegrating tablets (FDTs) provide a convenient solution for patients who have difficulties in swallowing tablets and other dosage forms (Bhowmik et al., 2009; S.G. Late et al., 2010). Fast disintegrating tablet are also called as orodispersible tablets, quick disintegrating tablets, mouth dissolving tablet, fast disintegrating tablets, fast dissolving tablets, rapid dissolving tablets, porous tablets and rapimelts. However, of all the above term, United States pharmacopoeia (USP) approved these dosage forms as ODTs. Recently, European Pharmacopoeia has used the term orodispersible tablet for tablet disperses readily and within 3 min in mouth before swallowing. United States Food and Drug Administration (FDA) defined FDT as a solid dosage form containing medical substance or active ingredient which disintegrates rapidly usually within a matter of seconds when placed upon the tongue. The disintegration time for FDT generally ranges from several second to about a minute (Hirani et al., 2009; S. H. Jeong et al., 2008). FDT can be formulated using various methods. Some of them involve increasing the porosity of the tablet and decreasing the disintegration time (DT) (Biradar et al., 2006a). Superdisintegrants swell or absorb water rapidly to disintegrate the tablet (Chang et al., 2000). Such a tablet disintegrates into smaller granules or melts in the mouth from a hard solid to a gel-like structure, allowing easy swallowing by patients. The disintegration time for appropriate FDTs varies from several seconds to about a minute. The FDT showed good bioavailability. During the last decade, FDT technologies have been progressed for making tablets disintegrate in the mouth without chewing.

1.1 The advantages of FDT

FDT also offers all advantages of solid dosage forms and liquid dosage forms along with special advantages, such as easy administration and no risk of suffocation resulting from physical obstruction by a dosage form. The primary patients for FDT are pediatric, geriatric, and bedridden or developmentally disabled patients; patients with persistent nausea; and patients who have little or no access to water. Because the tablets disintegrate inside the mouth, drugs may be absorbed in the buccal, pharyngeal, and gastric regions. Thus, rapid drug therapy intervention and increased bioavailability of drugs are possible. Because the pregastric drug absorption avoids the first pass metabolism (Fu et al., 2004; Roger Reig et al., 2006), the drug dose can be reduced if a significant amount of the drug is lost through the hepatic metabolism (Bandari et al., 2008; Dobetti, 2001; Habib et al., 2000; Seager, 1998). Furthermore, FDT has all the advantages of solid dosage forms, such as good stability, accurate dosing, easy

6

7

manufacturing, small packaging size, and easy handling by patient (Brown, 2003; Dobetti, 2001; Habib et al., 2000; Seager, 1998). FDT also have the advantages of liquid formulations, such as easy administration and no risk of suffocation resulting

from physical obstruction by a dosage form.

1.2 The need for development of FDT

Patient factors: (Chang et al., 2000; Slawson et al., 1985):

Fast dissolving dosage form is suitable for those patients (particularly pediatric and geriatric patients) who are not able to swallow traditional tablets and capsules.

These include the following:

• The patients have difficulty in swallowing or chewing solid dosage forms.

• The elderly patients of depression may not be able to swallow the solid dosage forms.

• Patient with allergies desires a more convenient dosage form than

antihistamine syrup.

• The middle-aged patient using radiation therapy for breast cancer may be too nauseous to swallow her H2- blocker

• The schizophrenic patient may try to hide a conventional tablet under

his or her tongue to avoid their daily dose of an atypical antipsychotic.

• The patient with persistent nausea may be journey or has little or no access to water (Siddiqui et al., 201 0).

Effectiveness factor: Dispersion in saliva in oral cavity causes pre-gastric absorption of drug which

dissolves. Buccal, pharyngeal and gastric regions are all areas of absorption for many drugs. Any pre-gastric absorption avoids first pass hepatic metabolism which increase the bioavailability. Furthermore, safety profiles may be improved for drugs that produce significant amounts of toxic metabolites mediated by first-pass liver metabolism and gastric metabolism and for drugs that have a substantial fraction of absorption in the oral cavity and pre-gastric segments of gastrointestinal tract.

1.3 Ideal properties of FDT (Hirani et al., 2009)

The properties ofFDT depend on the technology used during their manufacture. The necessary property of such tablets is the ability to disintegrate rapidly and disperse or dissolve in saliva. Various technologies have been developed FDT to perform this

unique function. An ideal FDT should show the following criteria: • It does not require water for oral administration yet disintegrates and dissolves

in oral cavity within a few seconds.

8

• It has sufficient strength to withstand the rigors of the manufacturing process

and post-manufacturing handling. • It allows high drug loading.

• It has a pleasant mouth feel. • It is insensitive to environmental conditions such as humidity and temperature. • It is adaptable to existing processing and packaging machineries.

1.4 Challenges in development of FDT

Because the administration of FDT is different from conventional tablets, the FDT should maintain several properties, as listed below (Chang et al., 2000; Dobetti, 2001; Seager, 1998).

Fast disintegration

FDT should disintegrate in the mouth without additional water or with a very small amount of water. The disintegration fluid is provided by the saliva of the patient. The disintegrated tablet should become a soft paste or liquid suspension, which can provide good mouth feel and smooth swallowing. The fast disintegration usually means disintegration of tablets in less than 1 min.

Taste of active ingredients

Because FDT disintegrates in the mouth, the drug will be partially dissolved in close proximity to the taste buds. After swallowing, there should be minimal or no residue in the mouth. A pleasant taste inside the mouth becomes critical for patient acceptance. As most drugs are unpalatable, orally disintegrating drug delivery systems usually contain the medicament in a taste-masked form (Brown, 2003; Reddy et al., 2002). Unless the drug is tasteless or does not have an undesirable taste, taste masking techniques should be used. An ideal taste-masking technology should provide drugs without grittiness and with good mouth feel. The taste masking technology should also be compatible with FDT formulations. For example, if drug particles are coated to minimize unpleasant taste, the coating should not be broken during compression or dissolved during wet granulation. Taste masking of bitter tasting drugs is critical to the success ofthe FDT formulations.

Tablet strength and porosity

Because FDT is designed to have a quick disintegration time, the tablet porosity is usually maximized to ensure fast water absorption into the tablets. The key properties of the tablets are fast absorption or wetting of water into the tablets and disintegration of associated particles into individual components for fast dissolution. This requires that excipients should have high wettability, and the tablet structure should also have a highly porous network. Because the strength of a tablet is related to compression pressure, and porosity is inversely related to compression pressure, it is important to find the porosity that allows fast water absorption while maintaining high mechanical strength. In addition, low compression pressure causes fast dissolving dosage forms to be soft, friable, and unsuitable for packaging in conventional blisters

9

or bottles. A strategy to increase tablet mechanical strength without sacrificing tablet porosity or requiring a special packaging to handle fragile tablets should be provided. It is obvious that increasing the mechanical strength will delay the disintegration time. So a good compromise between these two parameters is always essential. FDTs are formulated to obtain disintegration time usually less than a minute. While doing so, maintaining a good mechanical strength is a prime challenge (Bhandari et al., 2008).

Moisture sensitivity

FDT should have a low sensitivity to humidity. This problem can be especially challenging because many highly water-soluble excipients are used in formulation to enhance the fast dissolving properties as well as to create a good mouth feel. Those highly water-soluble excipients are susceptible to moisture; some will even deliquesce at high humidity. A good package design or other strategy should be created to protect FDT from various environmental conditions (Chang et al., 2000; Van Campen et al., 1980). The FDT product should have appropriately packaging because FDT which is produced by various technologies is porous in nature, has less physical resistance, sensitive to moisture, and may degrade at higher humidity conditions. Peelable backing foil and dome-shaped blister, which prevent vertical movement of tablet within the depression and protect tablets from breaking during storage and transportation are used for FDT. Some of the products have sufficient mechanical strength to withstand the transport and handling shock thus they are generally packed in push through blisters or in bottles (Kannuri et al., 2011; Yadav et al., 2012).

1.5 Techniques for preparing FDT

The property of FDT is fast absorption and wetting of water into the tablets and disintegration of associated particles into the individual component for fast dissolution. One of the more common strategies to achieve a rapid disintegration is to maintain

highly porous tablet structure, which will ensure a fast water absorption in the matrix. However, the porosity is inversely related to the compression pressure, which is in turn related to the strength of a tablet. Thus, it is important to find the optimum porosity that

allows both fast absorption and high mechanical strength. Moreover, a low compression pressure causes FDT to become too fragile for packaging in conventional blister or bottle (Seong Hoon Jeong et al., 2008).

In the recent past, several new advanced technologies have been introduced for the formulation ofFDT with very interesting features, like extremely low disintegration time, exceptional taste masking ability, pleasant mouth feel and sugar free tablets for

diabetic patients. The technologies utilized for fabrication of FDTs include lyophilization, molding, direct compression, cotton candy process, spray drying, sublimation, mass extrusion and quick dissolve film formation. These techniques are

based on the principles of increasing porosity and/or addition of superdisintegrants and water soluble excipients in the tablets. The formulations prepared from these techniques differ from each other on the basis of the factors like mechanical strength of final

10

product, drug and dosage form stability, mouth feel, taste, rate of dissolution of the formulation in saliva, rate of absorption from saliva and overall drug bioavailability (Shukla et al., 2009).

Freeze drying

Freeze drying (lyophilization) is a process in which solvent is removed from a frozen drug solution or a suspension containing structure-forming excipients. The resulting tablets are usually very light and have highly porous structures that allow rapid dissolution or disintegration. Freeze-dried forms offer more rapid dissolution than other available solid products. When placed on the tongue, the freeze dried unit dissolves almost instantly to release the incorporated drug. The main advantage being that pharmaceutical substances can be processed at non elevated temperatures, thereby eliminating adverse thermal effects, and stored in a dry state with relatively few shelf­life stability problems. The freeze-drying process may result in a glassy amorphous structure of excipients as well as the drug substance, leading to the enhanced dissolution rate. Freeze drying, however, is a relatively expensive manufacturing process, and the formulation has poor stability at higher temperature.

Moulding The major components of molded tablets typically are water-soluble

ingredients. The powder mixture is moistened with a solvent (usually ethanol or water), and then the mixture is molded into tablets under pressures lower than those used in conventional tablet compression. Then the solvent can be removed by air-drying. Because molded tablets are usually compressed at a lower pressure than are conventional compressed tablets, a higher porous structure is created to enhance the dissolution. To improve the dissolution rate, the powder blend usually has to be passed through a very fine screen. Recently, moulded forms also have been prepared directly from a molten matrix in which the drug is dissolved or dispersed (heat moulding) or by evaporating the solvent from a drug solution or suspension at ambient pressure (no­vacuum lyophilization) (Dobetti, 2001). Tablets produced by moulding are solid dispersions. The drug can exist as discrete particles or microparticles dispersed in the matrix. It can dissolve totally in the molten carrier to form a solid solution, or dissolve partially in the molten carrier while the remaining particles stay undissolved and dispersed in the matrix. The characteristics of the tablets (such as disintegration time, drug dissolution rate, and mouth feel) vary based on the type of the dispersion or dissolution. Because the dispersion matrix is, in general, made from water-soluble sugars, moulded tablets disintegrate more rapidly and offer improved taste. These properties are enhanced when tablets with porous structures are produced or when components that are physically modified by the moulding process are used. Unfortunately, moulded tablets typically do not possess great mechanical strength.

11

Erosion and breakage of the moulded tablets often occurs during tablet handling and

when blister pockets are opened. Hardness agents can be added to the formulation, but

then the rate of tablet solubility usually decreases.

Compaction Using compression to make FDT is a very attractive method because of the low

manufacturing cost and ease in technology transfer. When making conventional tablets,

maintaining high tablet porosity is not a primary concern, and high compression force

is used to ensure the tablet strength. Many strategies have been tried to achieve high

porosity and adequate tablet strength using a tablet press. F1rst, several granulation

methods have been tried to obtain granules suitable for making FDT. Wet granulation,

dry granulation and spray drying have been tried. The second approach is to select the

special types of excipients as the main component for FDT. The third approach is to

compress tablets at low pressure and apply various after treatments to the soft tablets.

I. Granulation method

1. Wet Granulation The formulation includes polyalcohols (e.g., mannitol, xylitol, sorbitol)

and an active ingredient as the dry mixture. This mixture is mixed with an aqueous

solution of a water-soluble or water-dispersible polymer (polyethylene glycols,

carrageenan, and ethylcellulose ). Granules with high porosity and low apparent density

were obtained, and the tablets made by such granules had rapid disintegration times

ranging from 3 to 30 seconds in the saliva.

2. Dry granulation Low-density alkali earth metal salts and water soluble carbohydrates are

also difficult to compress and caused inadequate content uniformity. For these reasons,

low-density alkali earth metal salts or water-soluble carbohydrates were precompacted,

and the resulting granules were compressed into tablets that could dissolve fast. In this

process, a powdered material with a density of 0.2-0.55 g/mL was precompacted to

increase the density to 0.4-0.75 g/mL by applying a force ranging from 1 to 9 kN/cm.

The resulting granules were compressed into tablets (Fu et al., 2004).

3. Melt granulation

Melt granulation technique is a process by which pharmaceutical

powders are efficiently agglomerated by a meltable binder, involving the use of a

hydrophilic waxy binder (Superpolystate®, PEG-6-stearate) by melt granulation or wet

granulation. Because Superpolystate® is a waxy material with a melting point of 33-3 7 oc and a hydrophilic to lipid balance (HLB) value of9, it will not only act as a binder

and increase the physical strength of tablets but also help the disintegration of the

tablets. The melt granulation FDTs had better hardness results than the wet granulation

FDTs. The disintegration times of melt granulation tablets, however, was more than 1

12

minute (Abdelbary eta!., 2004). Moreover, the advantage of this technique compared to a conventional granulation is that no water or organic solvents is needed. Because there is no drying step, the process is less time consuming and uses less energy than wet granulation. It is a useful technique to enhance the dissolution rate of poorly water­soluble drugs, such as griseofulvin (Yang et al., 2007).

4. Spray drying Spray drying is used for the preparation of the microspheres. Spray

drying is widely used in pharmaceutical processing because it requires only a one-step process and can be easily controlled and scaled up. Spray drying is widely used in pharmaceutical and biochemical fields and the final particle size is controlled by a number of factors including the size of the nozzle used in the processing (Giunchedi et a!., 2001; Lieberman eta!., 2005; Rattes et al., 2007). The previous study (Fu et al., 2004) reported that produced a particulate support matrix for use in making FDTs by a spray-drying technique. The mixtures of components were spray dried to obtain porous granules.

II. Direct compression Direct compression is the simplest and most cost-effective tablet

manufacturing procedure. This method can be applied to manufacturing FDT by choosing appropriate combinations of excipients, which can provide fast disintegration and good physical resistance. Sugar-based excipients have been widely used as bulking agents because of their high aqueous solubility and sweetness, pleasing mouth-feel and good taste masking (Chang eta!., 2000). FDT can be prepared by using this technique because of the availability of improved excipients especially superdisintegrants and sugar based excipients. Zolmitriptan FDT, anagainst migraine attacks, showed that 46.9% of the patients preferred it and the 6.3% patients opposed for zolmitriptan conventional tablet (Dowson et al., 2007). Patients with gastro-oesophageal reflux disease showed 47% preference in favor of FDT lansoprazole formulation while 33% preferred the capsule (Blanco et al., 2009). Many drugs have unpleasant taste which could lead to reducing patients' compliance and preference for FDT. Various techniques have been successfully applied like hot melt extrusion of ibuprofen (Gryczke eta!., 2011 ), spray drying for famotidine (Xu et al., 2008) or fluid bed coating of clindamycin hydrochloride (Cantor eta!., 2015) and showed to be easily feasible with the process of tableting. A retrospective study comparing the amount of ingested paracetamol by children younger than 6 years showed that 59% more paracetamol was ingested when using an FDT compared to conventional tablet (p=0.085) (Ceschi eta!., 2011).

III. Compaction and subsequent treatments 1. Sublimation method Sublimation has been used to produce FDTs with high porosity. When

volatile materials are compressed into tablets using the conventional method, they can

13

be removed v1a sublimation, resulting in highly porous structures. Inert solid ingredients with high volatility (e.g., ammonium bicarbonate, ammonium carbonate, benzoic acid, camphor, hexamethylene- tetramine, naphthalene, phthalic anhydride,

urea and urethene) have been used for this purpose (Kumaresan, 2008). 2. Humidity treatment It is also known that certain types of sugar change from the amorphous

to the crystalline state when their solution is spray dried or used as a binder solution.

Further investigations have shown that when an amorphous sugar is treated to go through the humidification and drying process, it changes to a crystalline state. This change increases the tablet strength substantially. The increase is known to be due to the formation of liquid bridges in the presence of moisture and then formation of solid bridges after drying ges in the presence of moisture and then formation of solid bridges after drying. (Sugimoto et al., 2001 ).

However, direct compression is the most convenient to produce tablet with sufficient structural integrity (Jinichi Fukami et al., 2006; Kandu et al., 2008;

Verley et al., 1990). Therefore, direct compression has appropriate for large scale. Direct compression is the easiest way to manufacture tablet in low manufacturing cost. It uses conventional, commonly available excipients, high dose accommodation, and limited number of process steps. The disintegration time in general satisfactory, although the disintegration efficacy is strongly affected by tablet size and hardness. Breakage of tablet edges during handling, the presence of deleterious powder in the blistering phase, and tablet rapture during the opening of the blister alveolus all result from insufficient physical strength (Dobetti, 2001)

1.6 Evaluation of FDT Twenty tablets were selected randomly from the lot and weighted individually

to check for weight variation. Ten tablets of CD tablet are accurately weighed and transferred into a 1 00 ml volumetric flask. The content uniformity was determined by the HPLC which mentioned in assay (United States Pharmacopoeia and National Formulary (USP 37-NF 32), 2015). Twenty tablets were powdered. The HPLC equipped with a UV /vis detector was used throughout the procedures. The acceptance criteria was 90.0%-110% (United States Pharmacopoeia and National Formulary (USP 37-NF 32), 2015). Hardness of tablet is defined as the force applied across the

diameter of the tablet in the order to break the tablet. The resistance of the tablet to chipping, abrasion or breakage under condition of storage transformation and handling before usage depends on its hardness. Hardness of the tablet of each formulation was determined using Monsanto Hardness tester.

Additionally, there are other evaluation for FDT including:

14

Wetting time: Wetting time of dosage form is related to the contact angle. It needs to be

assessed to give an insight into the disintegration properties of the tablets; a lower

wetting time implies a quicker disintegration of the tablet. The wetting time of the

prepared tablet was conducted after exposure to 10 mL simulated saliva fluid in 10 em

diameter of glass petri dish. The time required for the simulated saliva fluid to appear

on the upper surface of tablet was noted as wetting time (Gohel et al., 2004).

Contact angle and surface free energy: Knowledge of the wettability and surface free energy of pharmaceutical solids

is very important in the design of pharmaceutical formulation. The method of assessing

the surface free energy indirectly from wettability measurement is widely used.

The previous study (Katewongsa et al., 2012) reported the wettability and SFE

of tablets were determined by contact angle measurement which was carried out by the

liquid drop on the tablet surface using the drop shape analysis method on the

goniometer (FTA 1000, First Ten Angstroms, USA). A stainless tube packed with the

mixture was lowered into liquid and the recording of the contact angle was started when

the liquid contacted with the tablet at 1 second (n=6). Distilled water, formamide,

ethylene glycol were used as test solvents which had the different polarities. The SFE of tablets was calculated by Wu harmonic method (Chowhan et al., 1986). In the

method of Wu, the surface free energy is taken as the sum of the dispersive (Y·ct) and

the polar (YP) components. The surface free energies of solid materials can be

determined by means of contact angle measurements, using two liquids (water and formamide were used as the solvent in this study) with known polarities. They can be

assessed by solving an equation (1) with two unknowns:

(l cos e)~ .~ *~ I J

where 8 is the contact angle, Ys is the solid surface free energy and y, is the liquid

surface free energy (Baki et al., 2010). The result ofwettability and surface free energy

studies were to understand the formation of the surface tablets which related to the

disintegration and wetting time ofFDT containing various lubricant.

Moreover, to investigate the polar and dispersive component, the liquid

penetration rate of the tablets was measured by using Tensiometer Kruss K12 (Kruss GmbH, Hamburg, Germany) at 25°C. The solutions with which the value of the surface

free energy is known were used in order to evaluate a surface free energy of tablets.

The tablet was lowered into liquid, and time zero was recorded when the liquid

15

contacted with the tablet. The weight of liquid penetrated into the tablet was recorded against time. The penetration rate constants for various liquids were calculated by Washburn equation (Washburn, 1921). The mean of five measurements for each liquid

were used to calculate the penetration rate constants. The contact angle between liquid and tablet surface was evaluated from the penetration rate constants. The surface free energy of tablets was evaluated and polar and dispersion components of the solid were obtained (J. Fukami eta!., 2005). The surface free energy of tablet was evaluated from Owens, Wendt, Rabie, and Kaelble's equation (Abdelbary eta!., 2004) using the values of the contact angle and the known surface free energy of liquids .

.......... (2)

where 8 is contact angle, YL and vs are the surface free energy of the liquid and the solid

respectively and p and d represent polar and dispersion component of the surface free energy, respectively. From Eq. 2, polar and dispersion component of the solid are obtained. Polar and dispersive component were used to investigate polarity of the tablet containing talc. The result was reported that the polar part of talc was increased by

grinding (Katsuhide Terada eta!., 2004). Moreover, FDT was formulated using amino acids which behaviors were well analyzed by the introduction of surface free energy. When the polar component of amino acid was large value or the dispersion component was small value, faster wetting of tablet was observed (J. Fukami eta!., 2005). The effect of lubricants on the characteristics of FDT manufactured using phase transition of sugar alcohol. The result displayed that the polarity of the tablet components containing talc was remarkably increased by heating (Kuno eta!., 2008).

In vitro disintegration time time (DT): The time for disintegration of FDT is generally less than one minute. The

standard procedure of performing disintegration test for these dosage forms has several limitations. The method needs to be modified for FDT as disintegration is required without water; thus the test should mimic disintegration in salivary contents. The disintegration time is determined when the tablet has completely disintegrated and passed through the screen of the sinker (Y.X. Bi et a!., 1999). Furthermore, the

simulated saliva fluid (comprising 2.38 g Na2HP04, 0.19 g KH2P04 and 8.00 g NaCl

per liter of distilled water which pH was adjusted to 6.76 with phosphoric acid) was

used as immersion fluid for disintegration testing in previous study (Late et a!., 2009; Peh et a!., 1999).

Various scientists (El-Arini eta!., 2002) have developed new in vitro methods that allow an accurate determination of disintegration test. The disintegration test is performed using a texture analyzer instrument. In this test, a flat-ended cylindrical

16

probe penetrates into the disintegrating tablet immersed in water. As the tablet

disintegrates, the instrument is set to maintain a small force for a determined period of time. The plots of some distance traveled by the probe generated with the instrument's software provide disintegration profile of the tablets as a function of time. The plot facilitates calculation of the start and end-point of the tablet disintegration. Moreover, other study need to be modified for FDT as disintegration is required without water;

thus the test should mimic disintegration in salivary contents. A modified dissolution apparatus is applied to an FDT with a disintegration time that is too fast to distinguish differences between tablets when the compendia! method is used. A basket sinker containing the tablets is placed just below the water surface in a container with 900 mL of water at 3 7 °C, and a paddle rotating at 1 00 rpm is used. The disintegration time is determined when the tablet has completely disintegrated and passed through the screen

of the sinker (El-Arini et al., 2002).

In vitro dissolution test: Dissolution conditions for drugs listed in a pharmacopoeia monograph, is a

good place to start with scouting runs for a bioequivalent FDT which use water as medium for dissolutioin test. Other media such as 0.1 M HCl and buffer (pH 4.5 and 6.8) are used as media for evaluated FDT in the same way. It has been suggested that USP 2 paddle apparatus is the most suitable and common choice for orally disintegrating tablets, with a paddle speed of 50 rpm commonly used (Kraemer et al., 2012).

In vivo disintegration time and taste masking palatability In vivo disintegration tests of FDT can be conducted on volunteers who are

trained to test for In vivo disintegration time (Dor et al., 2000). Tablets are placed on

their tongues, and the time for disintegration is measured by immediately starting a stopwatch. The volunteers are allowed to move FDT against the upper roof of the mouth with their tongue and to cause a gentle tumbling action on the tablet without biting on it or tumbling it from side to side. Immediately after the last noticeable granule has disintegrated, the stopwatch is stopped and the time recorded.

Taste evaluation is done using healthy human which informed consent is approved by the ethics committee. Bitterness, mouth feeling and disintegration time were recorded immediately. (Lawless et al., 1998; Meilgaard et al., 2007; Stone et al., 2004)

1.7 Investigation of lubricant distribution in FDT (Lakio et al., 2013; Scoutaris et al., 20 14; Zuurman et al., 1999)

Practically, the basic tablet excipients include binder, diluents, disintegrant, glidant and lubricant. Lubricant is added in the final steps of mixing formulation components prior to compression. Lubricants practically prevent an adhesion of

17

compacts to the surface of the punches and dies during compression and ejection from the die cavity. Lubricants prevent ingredients from clumping together and from sticking to the tablet punches or capsule filling machine. Lubricants also ensure that tablet formation and ejection can occur with low friction between the solid and die wall.

Common minerals like talc or silica, and fats, e.g. vegetable stearin, magnesium stearate (mg-st) or stearic acid are the most frequently used lubricants in tablets or hard gelatin capsules. Lubricants are usually added in the final stages of mixing of the formulation components, prior to compression or encapsulation. Both tablets and capsules require lubricants in their formulations in order to reduce the friction between the powder and

metal surfaces. The main function of lubricants is to prevent the adhesion of compacts to the surface of the punches, dyes or encapsulating tools used in pharmaceutical manufacture. Mg-st is the most widely used lubricant during tablet compaction and capsule filling operations in the pharmaceutical industry. It is preferred because of its low cost, high lubrication potential, relatively high melting point and chemical stability. In industry, a number of problems arise in this context. It is important to investigate and resolve these problems. This is especially important in case of relatively new drug delivery systems, because there is not too much experience about their formulation. Medicated chewing gum has recently been included in the Pharmacopeias as a separate drug dosage form. New method of its production is not widespread yet.

In general, there are four lubrication mechanisms: hydrodynamic lubrication, elastohydrodynamic lubrication, mixed lubrication, and boundary lubrication. In the pharmaceutical industry, boundary lubrication is the most common mechanism functioning in unit operations (J. Wang et al., 2010). For boundary lubrication, a lubricant typically forms layers/film between surfaces or at interfaces to reduce friction, where the penetration of the lubricant into surface asperities occurs. Structurally, the lubricants commonly used for boundary lubrication are long chain molecules with active end-groups such as stearic acid and its metallic salts. The typical end-groups include: (1) -OH (long chain alcohol); (2) -NHz (long chain amine); (3) -COOH (long chain fatty acids); and ( 4) metal ions such as Mg2+. The molecules with these end­

groups can be readily adsorbed on the surfaces of metals or other particles to form an oriented monolayer or multilayers. The layers formed prevent further contact between the intended surfaces and powder particles. The efficiency of a boundary lubricant is

measured by the extent to which these films can mask the field of force of the

underlying surface. In other words, a lubricant film such as the film of mg-st needs to be sufficiently thick to cover the surface, typically a few layers. In addition, the breaking down of the lubricant film plays a significant role so that the motion of lubricated surface is facilitated. This will be illustrated by our discussion on the dihydrate of mg-st, which in general gives the best lubrication efficiency due to its layered structure.

18

Lubricants can influence on disintegration time (DT), hardness and dissolution of prepared tablets (Iyad eta!., 2010; Joshi eta!., 2004). Too much lubricant, however, will cause the powder to form globules and to resist the proper cohesion. Magnesium stearate (mg-st) has been widely used as the lubricant in tablet production. Over the years, there have been many reports that extending this film, through either an increase in the amount of mg-st or a longer mixing time, has a negative effect on the hardness, friability, and DT of the tablets. Because the bonds between mg-st particles are weaker than those between non lubricated excipient particles, a more extensive coverage of the excipient particles by mg-st will lead to a decrease in tablet hardness. This decrease in hardness may also lead to an increase in tablet friability (Aly, 2006; Bolhuis et a!., 1975; Bossert et a!., 1980). Along with a decrease in tablet hardness, most authors report that an increase in the amount of mg-st leads to an increase in tablet DT (Lindberg, 1972). This is due to the hydrophobic nature of the mg-st molecule and, by extension, of the lubricant film, which hinders the penetration of water in the tablet. Structure ofmg-st is depicted in Fig 1. Sodium stearyl fumarate (SSF, Alubra®) is the fatty acid esters. Compared to mg-st, this lubricant shows less interference with tablet strength and has a less negative effect on tablet disintegration and dissolution because of its hydrophilic nature (J. Wang eta!., 201 0). Structures ofmg-st and SSF are depicted in Fig 1.

0

o· 0

Mg2+ 0

o· o· Na+

0 0

Fig. 1 Structure of magnesium stearate (mg-st)(left) and sodium stearyl fumarate

(SSF, Alubra®)(right)

There have been numerous attempts to detect the lubricants by chemical or physical methods in order to get a better understanding of the nature of these films. However, most of these investigations have relied on the indirect techniques. The use of chemical imaging based on vibrational spectroscopy (near infrared and Raman spectroscopy) has been rapidly increasing in the field of pharmaceutical technology during past few years. Raman imaging is a non-destructive method, and it gives information about the chemical composition, structure and morphology of solid pharmaceuticals. The spatial distribution of components in tablets had been analyzed

19

using Raman imaging and mapping. Previous study reported the method could be used to measure the uniformity of blending, the existence of agglomerates and the migration of material during aging. Raman spectroscopy enabled the detection of mg-st on the surfaces of the tablets and powder. Raman directly measures hydrophobic CH2 groups in mg-st. Determination of low dose tablets using Raman mapping that revealed information about the distributions of the drug and, roughly, even the particle size ntioned in previous study (Henson et al., 2006). The distribution of mg-st in imipramine tablet could be properly visualized using high spatial and optical resolution of Raman imaging (Vajna et al., 201 0).

Energy dispersive X-ray spectroscopy (EDX) 1s a non-destructive technique for chemical characterization using scanning electron microscopy (SEM). The atoms in the sample are stimulated by an electron beam of uniform energy which generates the x-rays with specific energies for each element such that the energy of the emitted radiation provides information about the elemental composition of the sample. Energy, in the form ofx-rays, is released that corresponds to the difference in energy states of the two shells. The energies of the x-rays are characteristic of the elements from which they were emitted; this allows the elemental composition of the specimen to be determined. Effect of blending time on behavior and distribution of lubricants had been reported (Abe et al., 2012; Lakio et al., 2013) Raman spectroscopy detection mg-st distribution in tablet surface was evident after mixing 2-5 min. Furthermore, SEM/EDX was used to investigate the drug distribution in the surface tablet which the detection of carbon, nitrogen, oxygen interpreted as a mixture of the drug (paracetamol) (Scoutaris et al., 2014). Consequently, the results from the SEM/EDX and Raman spectroscopy confirmed that the higher amount of lubricants, the more distribution of lubricants was detected.

2. Cetirizine dihydrochloride

Cl

Fig. 2 Structure of CD

20

Cetirizine dihydrochloride (CD) is the selective histamine (H-1)-receptor antagonist in Fig. 2. It is used in the treatment of hay fever, allergies, angioedema, and urticaria. Because the symptoms of itching and redness in these conditions are caused by histamine acting on the HI receptor, blocking those receptors temporarily relieves those symptoms. Cetirizine is also commonly prescribed to treat acute and (in particular cases) chronic urticaria, more efficiently than any other second-generation antihistamine. Onset of action is 15-30 min. The half-life elimination is 8 hours (Demoly et al., 2003; Spencer et al., 1993). CD is a water soluble drug (pKa 8.3) (Balasubramaniam et al., 2008). CD is very bitter drug. Cetirizine crosses the blood­brain barrier only slightly, reducing the sedative side-effect common with older antihistamines (A. Gupta et al., 2006). Unlike many other antihistamines, cetirizine does not exhibit anticholinergic properties (Orzechowski et al., 2005).

Overdosage has been reported with cetirizine. In one adult patient who took 150 mg of cetirizine, the patient was somnolent but did not display any other clinical signs or abnormal blood chemistry ofhematology results. In an 18 month old pediatric patient who took an overdose of cetirizine (approximately 180 mg), restlessness and irritability

were observed initially; this was followed by drowsiness. The acute minimal lethal oral doses were 237 mg/kg in mice (approximately 95 times the maximum recommended

daily oral dose in adults on a mg/m2 basis, or approximately 40 times the maximum recommended daily oral doses in infants on a mg/m2 basis) and 562 mg/kg in rats

(approximately 460 times the maximum recommended daily oral doses in adults on a

mg/m2 basis, or approximately 190 times the maximum recommended daily oral doses in infant on a mg/m2 basis) (Balasubramaniam et al., 2008; A. Gupta et al., 2006;

Orzechowski et al., 2005).

CD preparations available in the market are in the form of tablet and syrup for oral administration. Regarding liquid dosage form, the major problem is poor stability. Although, the oral administration is the most popular route, many patients find its difficulty to swallow a solid dosage form. Therefore, it results in high incident of patient non-compliance. To overcome these problems, CD FDT has been prepared as recommended to enhance the fast dissolution and pleasant mouth feeling to the patients. Such a dosage form is beneficial to the geriatric and pediatric patients who are bedridden and do not access to water. Moreover, CD FDT is suitable for patients who have an acute allergy during travel such as: hay fever, angioedema and urticaria.

Furthermore, researcher prepare CD FDT with high porosity by using water soluble material (mannitol) along with a subliming material (camphor). Tablets prepared with drug, mannitol and camphor in ratio 1:16:3 showed least disintegration time (less than lmin. without shaking) and short in vivo mouth disintegration time

21

(17.58 sec) (A.K. Gupta et al., 2011). Moreover, cyclodextrin and its derivatives were used as taste masking agents for the preparation of rapidly dissolving films of cetirizine hydrochloride. A 32 full factorial design was utilized to study the effect of 2 independent variables i.e. amount ofHPMC (Xt) and amount of PEG 400 (X2) on responses in-vitro disintegration time and mechanical properties of rapidly dissolving films. Optimized batch possessed in-vitro disintegration time was 67.5 s (Mishra et al. , 2013). 3. Experimental design

In the past, research techniques depend on experience, trial and error and change one separate factor at a time (COST). In order to find optimal conditions, experimental design (DoE) is used in the research and development steps. Therefore, experimental

design (DoE) is a structured, organized method that is used to determine the

relationship between the different factor (X) affecting a process and the output of that process (Y). When the results of these experiments are analyzed, they help to identify optimal conditions, the factors that most influence the results. And those that do not, as well as details such as the existence of interactions and synergies between factors (G.E.P. Box, 1952; G.E.P Box et al., 1992; G.E.P Box et al., 1955). DoE is used in research and development to find optimization, to save cost and time.

Experimental design and optimization are tools that are used to systematically examine different types of problems that arise within, e.g., research, development and production. It is obvious that if experiments are performed randomly the result obtained will also be random. Therefore, it is a necessity to plan the experiments in such a way that the interesting information will be obtained. In the following pages, experimental design and optimization are presented to give the experimentalist useful tools in the real experimental situation (Lundstedt et al., 1998).

3.1 Full Factorial Design The traditional approach to develop a formulation was to change one variable

at time. By this method it was difficult to develop an optimized formulation.

•

• •

Full factorial design is used: To identify the factors that the most influence the response; moreover, it can show interactions and synergies between factors This method can study several factors in the same time This method gives first order regression model. The equation was presented in Eq. 1

Y = bo+b1Xt+b2X2+bt2XtX 2+bt1Xt2+b22Xl ... . . ... .. . .... . ...... . ... .. . . (3) For equation 3, Y was dependent variable, bo was arithmetic mean response of

nine batches, and b1 was estimated coefficient for factor Xt. The main effects (X1 and

22

X2) represented the average results of changing one factor at a time from its low to high

value. The interaction term (X1X2) showed how the response changes when two

factors were simultaneously changed. The polynomial terms X12 and Xl were included

to investigate non-linearity. Each variable (factor) has a set number of possible levels or values. The levels of the factors are given by minus for low level and plus for high

level. A zero-level is also included, a center, in which all variables are set at their mid

value.

If there are k variables, each set at 2 possible levels ('high' and 'low') then there are 2k possible combinations. These designs are called two-level factorial designs. If all

combinations are used, they are called full factorial designs (Fig. 3)

B c

c +

+

+

c +

+

+ +

+

Fig. 3 Experiments in a design with three variables

Therefore, the equation 4 showed the number of run for a full factorial design

N = number of run L = number of level

N=LK ............... (4)

K = number of independent variable

Example: 22 = 4 runs 23 = 8 runs 24 = 16 runs 22 = 4 runs; 1, a, b, ab (2 levels and 2 factors) 23 = 8 runs; 1, a, b, ab, c, ac, be, abc (2 levels and 3 factors)

24 = 16 runs; I, a, b, ab, c, ac, be, abc, d, ad, bd, abd, cd, acd, bed, abed (2 levels

and 4 factors).

The domperidone FDT was prepared by direct compressionusing Plantago ovata mucilage (2-10% w/w) as natural superdisintegrant and microcrystalline

23

cellulose (0-30% w/w) as diluent, along with directly compressible mannitol to enhance a mouth feel. The validity of the generated mathematical model was tested by preparing two extra-design check point formulations. The optimized tablet formulation was compared with conventional commercial tablet formulation for drug release profiles. This formulation showed nearly four-fold faster drug release (tso% 2.85 min) compared to the conventional commercial tablet formulation (tso% 7.85 min) (Shahidulla et al., 2015). Moreover, 32 full factorial design was used to optimize the amounts of mg-st and calcium silicate as mentioned previous study (Late et al., 2009). Multiple linear regression analysis revealed that concentration of calcium silicate had no effect; however, concentration of mg-st was found to be important for tablet disintegration and hardness. 4. Taste and taste masking

4.1 Taste perception The tongue is like a kingdom divided into principalities by sensory talent. The

sweet sensations are easily detected at the tip whereas bitterness is most readily detected at the back of the tongue. Sour sensation occurs at the side of the tongue. Western civilization recognizes only four basic taste: Sweet, Sour, Salty and Bitter. The Japanese add a fifth taste called Umami for monosodium glutamate. The high acuity for bitterness may be an evolutionary defense mechanism that keeps us from swallowing the poisions (Sharma et al., 2007; Smith et al., 2001).

Taste is an important parameter in administering drugs orally. Undesirable taste is one of the important formulation problems that are encountered with many drugs. Administration of bitter drugs orally with acceptable level of palatability is a key issue for health providers. Proven methods for bitterness reduction and inhibition have resulted in improved palatability of oral pharmaceutical (Jeong et al., 2005; Puttewar et al., 2010). Taste masking is an essential requirement for tablet for commercial success.

It is estimated that there are about 10,000 taste buds on the tongue, roof of the mouth, cheeks, and throat, and each bud has 60-1 00 receptor cells. These receptor cells interact with molecules dissolved in the saliva and produce a positive or negative taste sensation. Many drugs are unpalatable and unattractive in their natural state. Physiological and physicochemical approaches have been used to prevent drugs from interacting with taste buds, and thus to eliminate or reduce negative sensory response (Reo et al., 2002). There is often a correlation between the chemical structure of a compound and its taste. Low molecular weight salts tend to taste salty where higher molecular weight salts tend toward bitterness. Nitrogen containing compounds, such as the alkaloids, tend to be quite bitter.

After FDT disintegrate in the saliva, the drug in FDT remains in the oral cavity until it is swallowed. If the drug has a bitter taste, taste masking is critically important in the formulation for maximal patient acceptability. Unfortunately, cetirizine dihydrochloride (CD) is accompanied with a very unpleasant bitter taste.

24

4.2 Taste masking method Current taste masking in FDT is achieved by

4.2.1. Using sweet-tasking substances as diluents, adding flavors Sweeteners are commonly used in taste masking of drugs. These are

commonly used in combination with other taste masking technologies. These can be mixed with bitter drugs so as to improve the taste of the core material. Sweeteners are classified into natural and synthetic, based on the origin. Synthetic sweeteners such as sucralose, aspartame, saccharin are showing their prominence in taste masking than the natural ones. These sweeteners are used in combination with sugar alcohols like lactitol,

maltitol and sorbitol to decrease their aftertaste perception. Sucralose can be used with acids (citric acid) to increase the taste masking efficiency ofthe sweetener (Vummaneni et al., 2012). Flavours are also commonly used in taste masking of drugs in solids and liquid dosage forms. Selection of suitable flavouring agent to be added depends on the original sensation of drug substance. The cooling effect of some flavours aids in reducing after,.. taste perception. Eucalyptus oil is a major constituent of many mouth washes and cough syrup formulations.

4.2.2. Impeding its interaction with taste buds Prodrug approach is used for change the taste receptor adsorption reaction. Hence if any alteration is done in molecular geometry, it lowers the adsorption rate constant.

Thus taste masking can be achieved through prodrug approach. Microencapsulation is a process by which very tiny droplets or particles of liquid or solid material are surrounded or coated with a film or polymeric material. (Tripathi et al., 2011). Solid dispersion has been defined as dispersion of one or more active ingredients in an inert carrier or matrix at solid state prepared by melting (fusion) solvent or melting solvent method. Recently solid dispersions were introduced as a taste masking technology. (Tripathi et al., 2011 ). Coating is the method which polymers should be such that it prevents the release of active agent in the oral cavity, following per oral intake, but allows it in stomach or small intestine where the drug is expected to be absorbed.

Polymers, which mainly insoluble at salivary pH 6.8 but readily, dissolve at gastric fluid pH 1.2 could be a good candidate for taste masking (Ayenew et al., 2009; Dhakane, 2011; Nanda et al., 2002). Moreover, a bitter tasting drugs can be absorbed onto ion exchange resins, thus effectively removing them from solution during the

transit through the mouth, at salivary pH 6.8, remains in intact form making the drug unavailable for the taste sensation. (Tripathi et al., 2011 ).

Taste masking by inclusion complexes Inclusion complexation is a process in which the guest molecule is

included in the cavity of a host or complexing agent. The complexing agent is capable of masking bitter taste of drug by either decreasing its oral solubility on ingestion or

25

decreasing the amount of drug particles exposed to taste buds. Cyclodextrin is most widely used complexing agent for inclusion type complexes. It is sweet, non toxic,

cyclic oligosaccharide obtained from starch. The following are the examples of drugs that the bitter taste can be suppressed by making inclusion complexes.

5. Cyclodextrin Cyclodextrins are non-reducingcyclic oligosaccharides comprised of oo-1 ,4

glycosidic-linked glucopyranose units. The family of cyclodextrins is very large, including the three major cyclodextrins, oo-cyclodextrin with 6 glucose units, ~­

cyclodextrin with 7 glucose units, and y-cyclodextrin with 8 glucose units (Szejtli, 1998) and several rare minor cyclic oligosaccharides with 9, 10, 11, or12 glucose units.

Cyclodextrins are cyclic oligosaccharides which its glucose units of the cyclodextrins form a cyclic structure with hydrophilic outer surface and inner less polar cavity. Because cyclodextrins have hydrophobic interior, this special feature allows them to form the inclusion complexes with various drugs of proper size and polarity by

non-covalent interaction force (hydrophobic bonds, hydrogen bonds or van der vaals forces) (Malik et al., 2011 ). This structure of cyclodextrins makes them both soluble in water and capable of including other apolar molecules of the appropriate size, also calledguest molecules, in the axial open cavity forming inclusion complexes (Biwer et al., 2002; Szejtli, 1998). The volume of the hydrophobic cavity of cyclodextrins varies due to the number of glucose units (Szejtli, 1998). For the formation of such complexes, the presence of water is an important factor. Water is not only a medium for dissolution of cyclodextrins, but also is required as a driving force for the hydrophobic interaction of the guest molecule with the cavity of the cyclodextrin (Hedges, 1998).

Cyclodextrins are derived from starch via enzymatic processes. The cyclodextrin glucosyl transferase enzymes (CGT-ases) are amylolytic enzymes produced naturally by a large number of microorganisms like Bacillus macerans, Klebsiella oxytoca, Bacillus circulans, and Alkalophylic bacillus. The CGT -ases act on pre-hydrolyzed starch by catalyzing several transglycosylation steps (Biwer et al., 2002). Cyclodextrin glucosyl transferases cleave helical amylose molecules at regular intervals of 6, 7, or 8 glucose units and, at the same time, form a ring by an intermolecular glucosyltransferase reaction (Lina et al. , 2004). Following the

transglycosylation steps, intramolecular cyclisation in theabsence of water leads to cyclodextrins (Szejtli, 1998). After these reactions, a mixture oo-, ~-, and y-cyclodextrin are synthesized.

Because cyclodextrins are linked by oo-1 ,4 bonds, oo-amylases are capable of hydrolyzing them. However, oo-amylases act slowly on cyclodextrins (Szejtli, 1998). The rate and extent of digestion by amylases depend on the type of cyclodextrin and the isoform of oo-amylases. Ingested y-cyclodextrin appears to be more readily digested

26

by salivary and pancreatic amylases. In contrast, ~-cyclodextrin is resistant to the action of these enzymes (Koutsou et al., 1999). y-cyclodextrin is hydrolyzed by oo-amylases of fungal and bacterial origin.

5.1 Applications of cyclodextrins Cyclodextrins were considered as interesting and promising molecules, but very

expensive and with very limited availability. Once production and use increased, the price decreased to levels where they became acceptablefor most industrial purposes (Szejtli, 1998). Because complexation changes the physical and chemical properties of the hydrophobic molecule, cyclodextrins are currently used by many industries, including the pharmaceutical, cosmetic, household and toiletry, and food industries. When complexed drugs are consumed, the physiological conditions of the gastrointestinal tract promote a rapid dissociation of the substance from the cyclodextrins, thus allowing the absorptiop of the drug. Other benefits of complexed drugs are the reduction of irritation to tissues and the masking of bitterness or undesirable odors ofthe uncomplexed drugs (Hedges, 1998).

Cyclodextrins are able to bind the cholesterol molecule and form a complex. This feature is being used in the dairy industry to produce low-cholesterol milk and butter (Alonso et al., 2009). Another use in the food industry is as vitamin carriers, enhancing bioavailability and protecting the vitamins from light, temperature, and oxygen degradation.

In environmental sciences, cyclodextrins play an important role immobilizing organic contaminants and heavy metals from soil and water. Cyclodextrins also are used in water treatment to encapsulate and adsorb contaminants (Del Valle, 2004).

~-cyclodextrin is most widely used complexing agent for inclusion type complexes. It is sweet, nontoxic, cyclic oligosaccharide obtained from starch. Strong bitter taste of carbapentane citrate syrup was reduced to approximately 50% by preparing a 1:1 complex with cyclodextrin. ~-cyclodextrin good compression characteristics as it good compressibility index (Wade et al., 1994 ). It is considered to be a promising direct compression material because of its favorable compactibility and dilution potential. It may get harder tablets at lower compression force using ~­

cyclodextrin, which is very essential for fast disintegrating tablets formulations (Late et al., 2009)

Adults generally swallow the bitter drug containing coated tablet without chewing them, but there are cases when for some reasons the dissolution of the active ingredient in the saliva is inevitable. If rapid (and eventually first pass metabolism avoiding) absorption is wanted, the tablet is administered as a sublingual or chewable tablet. In such cases the disgusting bitter, astringent taste is a real problem

27

Cyclodextrin is used as a debittering agents. There are only two theoretical possibilities (Szejtli et al., 2005).

• The CD enwraps the bad tasting molecule (inclusion complex formation), impeding its interact with the taste buds, or

• The CD interact with the gate-keeper proteins of the taste buds Cyclodextrin inclusion is a stoichiometric molecular which usually only one

guest molecule interacts with the cavity of the cyclodextrin molecule to become entrapped. A variety of non-covalent forces, such as van der Waals forces, hydrophobic interactions and other forces, are responsible for the formation of a stable complex. Generally, one guest molecule is included in one cyclodextrin molecule, although in the case of some low molecular weight molecules, more than one guest molecule may fit into the cavity, and in the case of some high molecular weight molecules, more than one cyclodextrin molecule may bind to the guest.

Complexes stabilized by non-covalent interactions:

• Hydrophobic complexation

• Hydrogen bonding

• Aromatic interactions: n-n and edge-face

• Ion-ion and dipolar interactions

5.2 Preparation method of inclusion complex Several techniques are used to form cyclodextrin complexes (Loftsson et al.,

1996) 5.2.1 Co-precipitation Cyclodextrin is dissolved in water and the guest is added while stirring

the cyclodextrin solution. Cyclodextrin is dissolved in water and the guest is added while stirring the cyclodextrin solution. In many cases, the solution of cyclodextrin and guest must be cooled while stirring before a precipitate is formed. The precipitate can be collected by decanting, centrifugation or filtration. The precipitate may be washed with a small amount of water or other water-miscible solvent such as ethyl alcohol, methanol or acetone. The main disadvantage of this method lies in the scale-up. Because of the limited solubility of the cyclodextrin, large volumes of water have to be used. Tank capacity, time and energy for heating and cooling may become important cost factors

5.2.2 Slurry complexation It is not necessary to dissolve the cyclodextrin completely to form a

complex. Cyclodextrin can be added to water as high as 50-60% solids and stirred. The aqueous phase will be saturated with cyclodextrin in solution. Guest molecules will complex with the cyclodextrin in solution and, as the cyclodextrin complex saturates the water phase, the complex will crystallise or precipitate out of the aqueous phase.

28

and the complex can be collected in the same manner as with the co-precipitation

method. 5.2.3 Kneading complexation Only a small amount of water or ethanol is added to form a paste, which

is mixed with the cyclodextrin using a mortar and pestle, or on a large scale using a

kneader. The resulting complex can be dried directly or washed with a small amount of water or ethanol and collected by filtration or centrifugation. Pastes will sometimes dry forming a hard mass instead of a fine powder. Generally, the hard mass can be dried thoroughly and milled to obtain a powdered form of the complex.

5.3 Characterization of inclusion complex 5.3.1. Determination of guest content: Quantitative determination can be performed by analytical methods such

as Ultraviolet Spectroscopy, Gas Liquid Chromatography (GLC) and High Pressure Liquid Chromatography (HPLC).

5.3.2. Thermal analytical methods: Thermal analytical methods determine whether the guest substance

undergoes some change before the thermic degradation of cyclodextrin. The change of the guest substance may be melting, evaporation or polymorphic transition. The change of the guest substance indicates the complex formation. The effect of cyclodextrins on the thermogram obtained by Thermogravimetric analysis (TGA) and Differential scanning calorimetry (DSC) were observed for broadening, shifting and appearance of new peaks or disappearance of certain peaks. Changes in the weight loss were evaluated to provide supporting evidence for the formation of inclusion complexes. If the interaction between the drug and the excipient is weak, the shift in the endothermic

peak is very small. (Al-Marzouqi et al., 2006; Jadhav et al. , 2008; Maestrelli et al. , 2005; Scalia et al., 2006; L. Wang et al. , 2007)

5.3.3 Scanning Electron Microscopy (SEM) Scanning Electron Microscopy(Maestrelli et al., 2005) (Franco et al. ,

2009; Scalia et al., 2006) is used to study the microscopic aspects of the raw material and the product. The difference in crystallization state of the raw material and the product seen under electron microscope indicates the formation of the inclusion complexes (Glomot et al., 1988; Patil et al., 2009; Sinha et al. , 2005). This method is inadequate to

confirm inclusion complex formation (Didja et al., 1989; Jadhav et al. , 2008).

5.3.4 Fourier transform infrared spectroscopy (FT -IR) FT-IR is used to estimate the interaction between cyclodextrin and the

guest molecules in the solid state (Jadhav et al., 2008; Maestrelli et al., 2005).

29

Cyclodextrin bands often change only slightly upon complex formation and if the fraction of the guest molecules encapsulated in the complex is less than 25%, bands which could be assigned to the included part of the guest molecules are easily masked by the bands of the spectrum of cyclodextrin (Chow et a!. , 1986; K et al., 1982; Kedzierewicz et al., 1990). FT -IR spectral studies give information regarding the involvement of hydrogen in various functional groups. This generally shifts the absorbance bands to the lower frequency, increases the intensity and widens the band caused by stretching vibration of the group involved in the formation of the hydrogen bonds. Hydrogen bond at the hydroxyl group causes the largest shift of the stretching vibration band. It has been observed that cleavage of the hydrogen bonding due to inclusion complexation results in the shift of absorbance bands to higher frequency.

5.3.5 Powder X-ray diffractometry (PXRD) Powder X-ray diffractiometry (Al-Marzouqi et al., 2006; L. Wang et

al., 2007) may be used to detect inclusion complexation in the solid state. When the guest molecules are liquid since liquid have no diffraction pattern of their own, then the diffraction pattern of a newly formed substance clearly differs from that of uncomplexed cyclodextrin. This difference of diffraction pattern indicates the complex formation (Sinha eta!., 2005). Freeze drying and grinding may change the crystallinity of the pure substances and this may lead to different diffraction patterns (Didja et a!. , 1989). A diffraction pattern of a physical mixture is often the sum of those of each component, while the diffraction pattern of cyclodextrin complexes are apparently different from each constituent and lead to a new solid phase with different diffractograms (Hassan et al., 1990; K et al., 1982; Uekama et a!., 1985). Diffraction peaks for a mixture of compounds are useful in determining the chemical decomposition and complex formation. The complex formation of drug with cyclodextrin alters the diffraction patterns and also changes the crystalline nature of the drug. The complex formation leads to the sharpening of the existing peaks, appearance of a few new peaks and shifting of certain peaks.

5.3.6 Nuclear magnetic resonance spectroscopy (NMR) The 1H-NMR spectroscopy is the most direct evidence for the inclusion

of a guest into a cyclodextrin cavity(Franco et al., 2009; Jadhav et al. , 2008; Sinha et al., 2005). 1H-NMR may also be used to determine the direction of penetration of guest molecules into the cyclodextrin cavity (Patil eta!., 2009).The H-3 and H-5 atoms of cyclodextrin, which are directed towards the interior of the cyclodextrin will show a significant upfield shift if inclusion does indeed occur and the H-1, H-2 and H-4 atoms, located on the exterior of the cavity will show only marginal upfield shifts. The spectrum of the guest molecule may also be changed upon inclusion complex formation

30

(Dahlheim et al., 2005; Duan et al. , 2005; Fukuda et al., 2008; Larsen et al. , 2005 ; L. Ribeiro et al., 2005; L.S. Ribeiro et al., 2007; Rodgers et al. , 2011; Sun et al., 2006).

5.3. 7 Taste evaluation of inclusion complex

Gustatory sensation test is carried out by panel of human volunteers which informed consent is approved by the ethics committee. Healthy human volunteers are selected out of about 20 volunteers based on taste sensitivity test from training. The healthy human volunteers are trained to recognize level of bitter taste. The caffeine is used as the standard of bitter taste to compare and recognize a bitter taste level. When the volunteers pass the training, they will be accepted for testing the bitter taste of sample. After expectoration, the bitterness level is recorded thereafter the samples are spitted out. The oral cavity is rinsed with distilled water twice. The time between the testing of each sample is 10 min (Lawless et al., 1998; Meilgaard et al., 2007; Stone et al., 2004).

CHAPTER3

MATERIALS AND METHODS

Materials

Equipment

Methods

1. Preparation and evaluation of cetirizine dihydrochloride (CD)/beta­cyclodextrin (fl-CyD) inclusion complex for taste masking

1.1. Preparation inclusion complex by kneading method 1.2. Characterization for inclusion complex

1.2.1. Fourier Transform Infrared Spectrophotometer (FT -IR)

1.2.2. X-ray powder diffraction (XRPD) 1.2.3. Differential scanning calorimetry (DSC)

1.2.4. Simultaneous XRD-DSC measurement 1.2.5. Thermogravimetric analysis (TGA) 1.2.6. Nuclear magnetic resonance study (NMR) 1.2.7. Scanning electron microscope (SEM) 1.2.8. Taste evaluation of inclusion complex

2. Preparation of cetirizine dihydrochloride fast disintegrating tablets (CD FDT) 2.1. Study and screening the effect of type of disintegrant on properties of tablets

2.1.1. Preparation of tablet containing different disintegrant

design

2.2. Evaluation of tablets containing different disintegrant 2.2.1. Hardness tester 2.2.2. Disintegration time (DT) 2.2.3. Wetting time (WT) 2.2.4. Contact angle and surface free energy (SFE) 2.2.5. Scanning electron microscope (SEM)

2.3. Formulation of CD FDT by direct compression method using factorial

2.4. Study of distribution and effect of lubricants on characteristics of CD FDT 2.4.1. Raman Chemical Imaging

2.4.2. Scanning electron microscope (SEM) 2.4.3. Scanning electron microscopy-energy dispersive x-ray

spectroscopy (SEM-EDX)

2.5. Evaluation of the prepared tablets properties

31

2.5.1. Hardness tester 2.5.2. Wetting time (WT) 2.5.3 Disintegration time (DT) 2.5.4. Contact angle and surface free energy (SFE) 2.5.5. In- vitro dissolution profile of prepared CD FDTs.

32

3 Preparation of CD FDT containing taste masked CD/p-CyD inclusion complex 3 .1. Preparation inclusion complex by kneading method at suitable ratio for

industrial product 3.2. Formulation of CD FDT by direct compression method containing

inclusion complex 3.3. Evaluation of CD FDT containing inclusion complex

3.3 .1. Weight variation 3.3.2. Assay

3.3.3. Content Uniformity 3.3.4. Disintegration time (DT) 3.3.5. In vivo disintegration time and taste masking palatability 3.3.6. In- vitro dissolution profile

4. Statistical analysis

Materials

Acetonitrile (SK chemicals Co., Ltd., Ulsan, Korea) Aspartame (Food Chern International Corporation, China) Beta-cyclodextrin (Lot No. 70P360, Sigma-Aldrich Co., Missouri, USA) Brilliant blue (Cayman Chemical, Michigan, USA) Caffeine anhydrous (Lot No. 58082, Sigma-Aldrich Co., Missouri, USA)

33

Cetirizine dihydrochloride (Lot No. 9022420541, Sigma-Aldrich Co., Missouri, USA) Chitin (Kyowa, Technos Co., Japan) Chitosan (Aqua premier, Chonburi, Thailand, having 97% deacetylation degrees with 70 kDa molecular weight) Di-sodium hydrogen orthophosphate (Na2HP04) (B/No. AF405300, Ajax finechem

Pty. LTD., New South Wales, Australia) Deuterium oxide (D20 99.9%, Batch No. MKBB6317, Sigma-Aldrich Co., Missouri,

USA) Ethanol (Absolute, AR grade, B/No. 10C240514, VWR international S.A.S., France) Formamide (HCONH2) (B/No. 0907280, Ajax finechem Pty. LTD., New South Wales,

Australia) Lemon flavour (Silesia Co., Ltd., Singapore) Ludiflash® (BASF, Bangkok, Thailand) Magnesium stearate (Sigma-Aldrich Co., Missouri, USA) Methanol (B/No. 0000019710, Avantor Performance materials Inc., Pennsylvania,

USA) Menthol (P. C. Drug Center Co., Ltd., Bangkok, Thailand) Microcrystalline cellulose (Avice}® PH101 and PH102) (Asahi Chemical Industry,

Japan) Phosphoric acid 85% (Merck KGaA, Darmstadt, Germany) Potassium dihydrogen phosphate (KH2P04) (AR grade, Lot No. P51 04-1-1000, QREC

Chemical CO., LTD., Chonburi, Thailand) Potassium bromide (KBr) (spectrograde, Fisher Scientific UK limited, UK) Silicon dioxide (Aerosil® 200) (Wacker-Chemie GmBH, Germany) Sodium carbonate (Na2C03) (AR grade, Lot No. SG28621111, Loba Chemie Pyt.

LTD., Mumbai, India) Sodium chloride (NaCl) (AR grade, Lot No. SG28621111, Loba Chemie Pyt. LTD.,

Mumbai, India) Sodimn hydroxide (QReC, New Zealand) Sodium stearyl fumarate (Alubra®;FMC Corporation, Co., Ltd., Philadelphia, U.S.A) Tetrahydrofuran (THF) (Lot no. 1340753, Fisher Scientific UK, UK) White bentonite (Ashapura, China Clay Company, China) Xylitol (Anhui Elite Industrial Co., Ltd., China)

Equipments

Aluminium covers (Perkins, PIN SSCOOOOE030 open sample pan, Japan) Aluminium crimping (Perkins, PIN SSCOOOOE032 crimping cover, Japan)

34

Analytical balance (CP2245 Satorious, Germany and PA214 Oharus, Oharus Corporation, USA)

Desiccator (Biologix Research company, USA) Differential scanning calorimetry (DSC) (Pyris Sapphire DSC, Standard 115V, Perkin

Elmer instruments, Japan) Disintegration apparatus (Erweka GmbH ZT31, Milford, Germany) Disintegration apparatus (Sotax DT3, Switzerland) Fourier Transform Infrared Spectrophotometer (FT-IR) (Nicolet 4700, Becthai, USA) Goniometer (FTA 1000, First Ten Angstroms, USA) Hardness tester (Erweka® TBH 225 Heusenstamm, German) High performance liquid chromatography (HPLC) (1100 series, Agilent technology,

Germany) Hot air oven (UT6760, Heraeus, Kendro Laboratory Products, Germany) HPLC column Phenomenex® C18 (4.6 mm x 25 em, USA) HPLC column Mightysil® C18 (4.6 mm x 25 em, Japan) Hydraulic press (SPECAC 15011, A Cambridge Electronic Industries Company, Kent

England) Magnetic stirrer and Magnetic bar (Becthai Bangkok Equipment and Chemical Co.,

Ltd, Thailand) Micropipette (2-20 !J.L, 20-200 !J.L, 100-1000 !J.L, 1-5 mL) and micropipette tip

(Eppendorf Co., Ltd. Hamburg, Germany) pH meter (Ultra BASIC, UB-10, Denver instrument GmbH, Goettingen, Germany) Powder x-ray diffractometer (PXRD) (Miniflex II, Rigaku Corp. Tokyo, Japan) Raman spectroscopy (Keiser Optical System; Inc., MI, USA) Scanning electron microscope (SEM) (Maxim 200 Cam scan, Cambridge, England) Scanning electron microscopy-energy dispersive x-ray spectroscopy (SEM-EDX)

(Bucks, England) Simultaneous measurements of X-ray diffraction (XRD) and differential scannmg

calorimetry (DSC) (Riguku Corporation, Tokyo, Japan) Sonication bath (Transsonic T890/H, Elma, New South Wales, Australia) Syringe filter nylon 13 mm 0.45 !J.m (Lubitech, Fortune Scientific Co., Ltd., Bangkok,

Thailand) Tensiometer Kruss K12 (Kruss GmbH, Hamburg, Germany) Thermogravimetric analyzer (TGA) (Pyris/TGA, PerkinElmer, USA) UV-Vis spectrophotometer (Perkin-Elmer, Germany) Vortex mixer (Gibthai VX-100, Thailand) Water bath (Julabo, Japan)

Methods

1. Preparation and evaluation of CD/fl-CyD taste masked inclusion complex 1.1. Preparation inclusion complex by kneading method

35

This study used CD to ~-CyD at 1:10 M ratio (1 0:260 mg) as has been reported in previous work (Lee et al., 201 0). Both compounds were mixed at 1:10 M ratio and ground in a mortar with a pestle for 1 min. The 1 mL of ethanol was added to the mixture and the obtained paste was further kneaded for 3 min. After mixing, the end product was dried in hot air oven at 50 oc for 30 min. The obtained precipitate was placed in desiccator for drying at room temperature for 1 days. The physical mixture as the same ratio was also prepared by mixing without ethanol.

1.2. Characterization for inclusion complex 1.2.1. Fourier Transform Infrared Spectrophotometer (FT -IR) Approximately 2 mg of inclusion complex was mixed and grinded with

100 mg KBr before compressed into pellet using KBr die kit. The chemical reaction was investigated by using FT-IR spectrometer (Nicolet 4700, Becthai, USA) between the wave number ranges of 400- 4000 cm-1 with 32 scans at 4 cm-1 resolution.

1.2.2. X-ray powder diffraction (XRPD) The samples were analyzed under the X-ray powder diffractometer

(Miniflex Iyl, Rigaku Corp. Tokyo, Japan). The x-ray source was Cu-Ka which

employed the x-radiation of wavelength (A-) of 1.5418 A o between a 28 angle ranges of

4° to 60° with voltage of 30 kV and current of 15 rnA. The samples were filled and compressed into a glass sample holder with 0.2 mm depth before test.

1.2.3. Differential scanning calorimetry (DSC) The 5 mg inclusion complex powder was added into aluminum pan.

Thermogram of the samples was recorded using differential scanning calorimetry (Pyris Sapphire DSC, Standard 115V, Perkin Elmer instruments, Japan) operated under atmosphere of nitrogen gas. Analyzing temperature was set at the ranges of30 oc -300 oc and heating rate of 1 0°C/min.

1.2.4. Simultaneous XRD-DSC measurement XRD-DSC measurement was carried out using a Rigaku XRD-DSC II

system (Riguku Corporation, Tokyo, Japan). Briefly, 5 mg of samples were weighted into opened aluminium pans. The heating rate of DSC was 10 °C/min purging by nitrogen gas at flow rate of 1 00 mL/min. X -ray diffraction was then measured simultaneously at 40 kV and 40 rnA.

1.2.5. Thermogravimetric analysis (TGA) Weight loss under heating condition was carried out by using a

thermogravimetric analyzer (TG8120, Rigaku, Tokyo, Japan). Samples of 10 mg were weighed into an open alumina crucible under the purging nitrogen gas. The dynamic experiment was carried out with the temperature ranges of 20 °C to 400 °C under the purging nitrogen gas at heating rate of 10 °C/min.

1.2.6. Nuclear magnetic resonance (NMR) study

36

One-dimensional spectra eH NMR, 500 MHz) were recorded on a nuclear magnetic resonance instrument (Bruker A vance 300, Karlsruhe, Germany) equipped with a 5 mm probe with actively shielded z-field gradient capability. All experiments were conducted using D20 (99.95% isotopic purity) as solvent. The probe temperature was regulated to 300 K.

1.2.7. Scanning electron microscope (SEM) Morphology of the samples was observed using SEM with 15 Ke V of

an accelerating voltage. The sample was strewed onto the carbon double adhesive tape that adhered on metal stub and then sputter-coated with gold. Images of the samples at magnification of 500 were taken using secondary electron image (SEI) mode.

1.2.8. Taste evaluation of inclusion complex Gustatory sensation test was carried out by panel of human volunteers

from whom informed consent was first obtained (approved by the ethics committee of Faculty of Pharmacy, Silpakorn University, 6/2557). For this purpose, the 6 healthy human volunteers, of either sex, in the age group of 20-35 years were selected out of about 20 volunteers based on taste sensitivity test from training. The 6 healthy human volunteers were trained to recognize level of bitter taste of CD. The caffeine was used as the standard of bitter taste to compare and recognize the bitter taste level of CD. Determination ofthreshold bitterness concentration of CD was determined. A series of caffeine standard solutions of different concentrations (0.05, 0.15 and 0.2 mg/mL) were prepared. The threshold value was selected from standard solutions of caffeine as that produced the sensation of bitter taste in human volunteers. When the volunteers could pass the training, they would be accepted for tasting the bitter taste of sample. CD powder was placed in mouth for 15 sec to compare with inclusion complex equivalent to 1 0 mg CD and compared with its physical mixture. After expectoration, the bitterness level was recorded and thereafter the samples were spitted out. Distilled water about 200 mL was used for rinsed oral cavity. The time between the tasting of each sample was 1 0 min. The scaling technique for this study was unstructured line scale for grading of the bitterness as following levels: 0= no bitterness and 12=strongly bitter (Lawless et a!., 1998; Mei1gaard et a!., 2007; Stone et a!., 2004). After taste evaluation by volunteer, the result was calculated for median and standard deviation. Significant differences among the test scores were analyzed using the R-stat test version 3.0.1; a value ofP<0.05 was accepted as index of a significant difference.

2. Preparation of CD FDT 2.1. Screening of effect of type of disintegrant on properties of tablets

2.1.1. Preparation of tablet containing different disintegrants The tablets were fabricated by direct compression with the compression

force of 1.5 tons using the different disintegrants (chitin, chitosan, xylitol, microcrystalline cell uloses, white bentonite). The single or the mixture materials were ground for 10 min with mortar and pestle. Then the components were compressed into

37

the 400 mg flat-faced tablet of 400 mg with 13 mm in diameter with compression force

of 1.5 tons using a hydraulic press by direct compression method. 2.2. Evaluation of tablets containing different disintegrants

2.2.1. Hardness tester The crushing strength of tablets was measured using a hardness tester

(Pharmatest, USA) (n=10).

2.2.2. Disintegration time (DT) Six tablets were placed individually m each tube of disintegration

apparatus and the discs were placed. The distilled water was maintained at a temperature of 37±0.5°C and the time taken for all tablets to disintegrate completely was recorded (n=6). The disintegration time of tablets was determined using standard USP testing method without disk by a disintegration apparatus (Erweka GmbH ZT31, Milford, Germany).

2.2.3. Wetting time (WT) The tablet was placed in a petri dish of 5.5 em in diameter, containing 2

mL of 0.5%wlv brilliant blue solution at room temperature, and the time for complete wetting was recorded (n=6).

2.2.4. Contact angle and surface free energy (SFE) The contact angle of a distilled water droplet on tablets was measured

using the goniometer. Contact angle at t = 0 was measured and estimated from the first automatic image of droplet. The surface free energy of the each sample was determined by means of contact angle measurements. Distilled water and formamide were used as test solvents having the different polarities. The surface free energy was calculated by

the Wu harmonic method (Wu, 1971) that was taken as the sum of the dispersive (yd)

and the polar (yP) components (n=6). They could be assessed by solving an equation 1:

(1 +COS 8) YI = 4 {(Yid Ysd I (yid + Ysd)) +(yiP Ysp I (yiP+ YsP))} ........ (1)

2.2.5. Scanning electron microscope (SEM) Morphology of the tablets was observed using SEM with 15 Ke V of an accelerating voltage as mentioned in 1.2.7.

2.3. Formulation of CD FDT fabricated by direct compression method using factorial design

The 5% wlw CD FDT formulation was used in this study. All ingredients were accurately weighed. Direct compression method was used to prepare the tablet which

drug and all the excipients except lubricant were mixed in mortar and pestle by geometric dilution for 10 min. Finally, the lubricant was added into this blend and

mixed properly again for 3 min. The blend was compressed using hydraulic press (SPECAC 15011, A Cambridge Electronic Industries Company, Kent England) to produce the tablets of200 mg with a diameter of9.53 mm with the compression force

of 1, 3, 5 ton/cm2. Full factorial design model with 2 factors, 3 levels and 9 runs was

selected for the optimized study. The polynomial equation generated by this experimental design using the software, Statistica 1 0; Stat Soft Inc. The three levels

38

were selected (high, intermediate and low) for both the independent variables. The concentration of lubricant (XI) and compression force (X2) were taken as independent

variables for different levels.

Full Factorial Design A32 full factorial design was used in the present study. The equation for this

study was presented in Eq. 5 Y = bo+biX I+b2X 2+b12XIX2+biiXI2+b22Xi ................ (5)

For equation 5, Y was dependent variable, bo was arithmetic mean response of nine batches, and bi was estimated coefficient for factor XI. The main effects (XI and X2) represented the average results of changing one factor at a time from its low to high value. The interaction term (XI X2) showed how the response changes when two factors were simultaneously changed. The polynomial terms XI 2 and X22

were included to investigate non-linearity. In this design, 2 factors , each at 3 levels were performed at all 9 possible combinations. The concentration of lubricant (mg-st or SSF

as XI) and compression force (X2) were taken as independent variable. The dependent variables selected were disintegration time, wetting time, hardness, contact angle and surface free energy (SFE) to find out influence of independent variables on dependent variables. Mean values of responses were used to generate the equations for each dependent variable which the estimated equation for the response variables were discussed separately. Finally, the model was validated by preparing and testing the new formulations.

2.4. Distribution and effect of lubricants on properties of CD FDT 2.4.1. Effect of compression force on lubricant distribution on the

surface of CD FDT by using Raman Chemical Imaging To investigate the effect of compression force on lubricant distribution,

Raman mapping spectra were recorded by Raman spectrometer (Keiser Optical System; Inc., MI, USA) at room temperature. A 1,000 nm excitation wavelength with a 400 MW laser power source and Inc AAS array detectors were used. A lOX objective lens (DM2500; Leica: Microsystems; Tokyo; Japan) with a 145 MW laser power and 16 ~m laser sampling diameter was utilized to acquire a point mapping with 5 ~m step size. Each spectrum was collected from 200-2400 cm-I with a resolution of 5 cm-I and a 5 sec exposure time while naphthalene was used to calibrate the wave number. The measured spectral range was 200-2000 cm-I. Spatial step size was 5x5 ~m which the measured area was 49x49 points (pixels) and target area was 250x250 ~m. Moreover, to study the effect of compression force on distribution of lubricants in tablets, the measured spectral range was 200-2000 cm-I. The sample was divided as nine parts. Spatial step size was 1 Ox 1 0 ~m and use point was 20x20 ~m in each part. Raman spectra were prepared using chemical imaging analysis software version Isys® 5.0.0.11 (Malvern; Instruments; Inc. MD, USA).

2.4.2. Scanning electron microscope (SEM) Morphology of the samples was observed using SEM with 15 Ke V of

an accelerating voltage as mentioned in 1.2.7.

39

2.4.3. Scanning electron microscopy-energy dispersive x-ray spectroscopy (SEM-EDX)

The spatial distribution of chemical phases was evaluated usmg scanning electron microscope and the elemental distribution on the surface of tablets was investigated using energy dispersive x-ray spectroscopy (SEM-EDX) (Oxford instruments x-max (50 mm2), Bucks, England). The applied accelerating voltage and working distance were 15 kV and 10 mm, respectively. The elemental mapping the intensity of the detected X-ray radiation was greater than 5000 counts/s.

2.5. Evaluation of the prepared tablets properties 2.5.1. Hardness tester The hardness of tablets was measured using a hardness tester (Erweka®

TBH 225 Heusenstamm, German) and the data reported was the mean often individual determinations (n= 1 0).

2.5.2. Wetting time (WT) The wetting time of the prepared tablet was conducted after exposure to

1 0 mL simulated saliva fluid in 1 0 em diameter of glass petri dish. The time required

for the simulated saliva fluid (2.38 g Na2HP04, 0.19 g KH2P04 and 8.00 g NaCl per

liter of distilled water, pH adjusted to 6.76 with phosphoric acid) to appear on the upper

surface of tablet was noted as wetting time (n=6)(Gohel et al., 2004). 2.5.3 Disintegration time (DT) The disintegration time of tablets was determined using standard USP

testing method as mentioned in 2.2.2 but this study used simulated saliva fluid as medium.

2.5.4. Contact angle and surface free energy (SFE) The contact angle of a distilled water droplet on tablets was measured

using the goniometer as mentioned in 2.2.4. Moreover, to investigate the polar and dispersive component, the liquid

penetration rate of the tablets was measured by using KRUSS K12 (KRUSS GmbH) at 25°C. The solutions with which the value of the surface free energy is known were used in order to evaluate a surface free energy of tablets (water 72.8 mJ/m2, ethanol 22.1 mJ/m2, hexane 18.4 mJ/m2). The tablet was lowered into liquid, and time zero was recorded when the liquid contacted with the tablet. The penetration rate constants for various liquids were calculated by Washburn equation (Washburn, 1921). The mean of five measurements for each liquid were used to calculate the penetration rate constants. The contact angle between liquid and tablet surface was evaluated from the penetration rate constants. The surface free energy of tablets was evaluated and polar and dispersion components of the solid were obtained (J. Fukami et al., 2005). The surface free energy of tablet was evaluated from Owens, Wendt, Rable, and Kaelble's equation (Abdelbary et al., 2004) using the values of the contact angle and the known surface free energy of liquids.

40

( ·\r_d.t1· d"i0 ·5 + (-..rP'v.Y'l; ·0 -5 := 0.5-.·11".1 + CC)S®)·-• ........... . ........ (2) -~ Si I ..;.i ~- t 5.< j T .)i - I ' ....

where 8 is contact angle, YL and ys are the surface free energy of the liquid and the solid respectively and p and d represent polar and dispersion component of the surface free energy, respectively. From Eq. 2, polar and dispersion component of the solid are obtained.

2.5.5. In- vitro dissolution of prepared CD FDT. The dissolution test was carried out with the dissolution apparatus type

II (paddle method) using 900 mL artificial saliva (pH 6.8), at 37±0.5 °C and 50 rpm modified (Jaber et al., 2004). An aliquot of 5 mL was collected at predetermined time intervals and replaced with fresh dissolution medium. Samples were analyzed by HPLC method using method as previously reported with slightly modified. The chromatographic system used as equipped with Luna C18, 5 1-lm column ( 4.6x250 mm) and a detector set at 230 nrn in a conjunction with a mobile phase of0.05 M dihydrogen phosphate: acetonitrile: methanol: tetrahydrofuran ( 60:25:10:5 by volume) with a pH of 5.5 was used as the mobile phase. Cumulative percentage of drug release was calculated using an equation obtained from a standard curve (n=6).

3. Preparation of CD FDT containing taste masking of drug by inclusion complex 3.1. Preparation inclusion complex by kneading method This study used CD to P-CyD at 10:60 mg for inclusion complex. Both

compounds were mixed by method as mentioned in 1.1. 3.2. Formulation of CD FDT by direct compression method containing

inclusion complex Direct compression method was used to prepare the tablets of CD. Complex

equivalent to 10 mg of drug was taken along with diluent. Ludiflash®, Aerosil 200, Alubra®, aspartame, menthol and lemon flavor were used as diluent, glidant, lubricant, sweetening and flavoring agent respectively. All the ingredients except lubricant were weighed and passed through sieve #30. And then, the powders were mixed geometrically in bottle. Finally, Alubra® was added and mixed in plastic bag. Tablets were compressed on single punch tablet machine using round concave punch of 9 mm diameter. The hardness of the tablet was maintained at 2-3 kPa. The commercial tablet was rectangle (rounded-off rectangular biconvex tablet) shape, size 9 mm and the total weight was 200 mg.

3.3. Evaluation of CD FDT containing inclusion complex 3.3.1. Weight variation

The weight variation test was performed on 20 randomly collected tablets from a batch. The procedure described in USP 37 NF 32 was followed for this test. Weight variation test was done by weighing 20 tablets individually (United States Pharmacopoeia and National Formulary (USP 37-NF 32), 2015)

3.3.2. Assay

41

Twenty tablets were powdered, and 20 mg equivalent weight of obtained powder was accurately weighed and transferred into a 100 ml volumetric flask. Initially, Diluent (Acetonitrile, 2 N HzS04 and water (2:33), water at ratio 100:1:1 00) was added

and shaken for 15 min. Then, the solution in the volumetric flask was filtered and

analyzed by HPLC method. The HPLC equipped with a UV /vis detector was used throughout the procedures. A symmetry C18 column (5 f.!m, 4.6 mm x 25 em column) was used as a stationary phase. The mobile phase was a 3/7 (v/v) mixture of acetonitrile and buffer (2.9 mLIL of phosphoric acid in water). The flow rate was set at 0.75 mL/min, the injection volume was 10 f.!L and the detection wavelength was 230 nm. The acceptance criteria was 90.0%-110% (United States Pharmacopoeia and National

Formulary (USP 37-NF 32), 2015).

3.3.3. Content Uniformity Ten tablets of CD tablet are accurately weighed and transferred into a

100 ml volumetric flask. Initially, diluent (Acetonitrile, 2 N HzS04 and water (2:33), water at ratio 1 00: 1: 1 00) was added and shaken for 15 min. Then, the solutions in the volumetric flask were filtered and analyzed by HPLC method. The HPLC equipped with a UV /vis detector was used throughout the procedures. A symmetry C 18 column (5 f.!m, 4.6 mm x 25 em column) was used as a stationary phase. The mobile phase was a 3/7 (v/v) mixture of acetonitrile and buffer (2.9 mLIL of phosphoric acid in water). The flow rate was set at 0.75 mL/min, the injection volume was 10 f.!L and the detection

wavelength was 230 nm (United States Pharmacopoeia and National Formulary (USP 37-NF 32), 2015).

3.3.4. Disintegration time (DT) The disintegration time of tablets was determined using standard USP

testing method as mentioned in 2.5.3.

3.3.5. In vivo disintegration time and taste masking palatability Taste evaluation was done using the intensity method on panel of 6

healthy human volunteers with informed consent approved by the ethics committee of Faculty ofPharmacy, Silpakorn University, 6/2557. Prior to the test the volunteers were instructed to rinse their oral cavity with distilled water. Each volunteer was asked to place one FDT on the tongue. Volunteers were strictly informed not to chew or swallow the tablets, though licking was allowed. The end point for disintegration was recorded when there was no lump left in the oral cavity. After the test was finished, volunteers

were informed to rinse their mouth properly. The oral cavity was rinsed with distilled water twice (200 mL per each time). Bitterness, mouth feeling and disintegration time were recorded immediately. The scaling technique for this study was unstructured line scale for grading of the bitterness as following levels: 0= no bitterness and 12=strongly

bitter (Lawless et al., 1998; Meilgaard et al., 2007; Stone et al., 2004).

3.3.6. In- vitro dissolution profile The dissolution of cetirizine dihydrochloride from FDT was determined

by USP dissolution testing apparatus II (paddle method). The dissolution test was

42

carried out using 900 rnL of water, at 37±0.5 oc and 50 rpm. A sample (10 rnL) of the solution was withdrawn from the dissolution apparatus at different time interval. An aliquot of 1 0 rnl was collected at predetermined time intervals and replaced with fresh dissolution medium. Samples were analyzed by HPLC method. The HPLC equipped with a UV /vis detector was used throughout the procedures. A symmetry C 18 column (5 !liD, 4.6 rnrn x 25 ern column) was used as a stationary phase. The mobile phase used was a 2/3 (v/v) mixture of acetonitrile and buffer (2.9 rnLIL of phosphoric acid in water). The rate of flow was set at 0.8 rnL/rnin, the injection volume was 50 11L and the detection wavelength was 230 nrn. The standard solution was 11 rncg/rnL of CD in water (United States Pharmacopoeia and National Formulary (USP 37-NF 32), 2015).

Moreover, the dissolution of the commercial CD (Zyrtec® tablet) and developed 10 rng CD FDT were investigated (n=6) using the USP dissolution apparatus II (paddle)

(RC-6, Minhua Pharmaceutical Machinery CO.,Ltd., China) at 50 rpm, 37 ± 0.5°C. The 900 rnL distilled water was used as medium (United States Pharmacopeia and National Formulary (USP 32-NF 27), 2009). The Zyrtec® tablet and developed CD FDT were investigated to compare the dissolution profile. The sampling time intervals were 1, 5, 10, 15, 20, 25, 30, 45 and 60 min. The sampling volume was 10 rnl and equal volume of a fresh medium was replaced. The amount of dissolved CD was measured using the high performance liquid chromatography (HPLC) method as mention in 4.3.5. The similarity factor (f2) (equation 6) and difference factor (fl) (equation 7) of CD and CD FDT was investigated as equations following:

........... (6)

........... (7)

When Rt and Tt are the cumulative percentage dissolved at each of the selected n time points of the reference and test product, respectively.

n is number of time points.

The similarity factor (f2) between 50-100 and the difference factor (fl)

between 0-15 indicated the sameness of two dissolution profiles (V Abbirarni et al., 2013).

4. Statistical analysis Values are expressed as mean± standard deviation (SD). Statistical significance

of samples was examined by using one-way analysis of variance (ANOVA). The significance level was set at p < 0.05. The analysis was performed by using SPSS for

43

windows (version 11.5). Taste evaluation by volunteer, the result was calculated for mean and standard deviation. Significant differences among the test scores were analyzed using the R-stat test version 3.0.1; a value ofP<0.05 was accepted as index of a significant difference.

CHAPTER4

RESULTS AND DISCUSSION

1. Preparation and evaluation of cetirizine dihydrochloride/beta-cyclodextrin

(CD/p-CyD) taste masked inclusion complex 1.1. Preparation the inclusion complex by kneading method

This study used CD to ~-CyD at 1:10 M ratio ( 10:260 mg) as has been reported in previous work (Lee et al., 201 0). Ethanol was added to the mixture and the obtained paste was further kneaded for 3 min. After mixing, the end product was dried in hot air oven at 50 °C for 30 min. The obtained precipitate was placed in desiccator for drying at room temperature for 1 days. The prepared inclusion complex was white and fine without stickiness. Moreover, rizatriptan benzoate and ~-CyD prepared by kneading with distilled water demonstrated an effective taste masking as previous study (Birhade, 201 0). However, due to hardly removing of water from complex, this study used ethanol as solvent for kneading because ethanol is widely used for wet granulation process in industry therefore it is possibly used as solvent for kneading method in large scale.

1.2. Characterization for inclusion complex 1.2.1. Fourier Transform Infrared Spectrophotometer (FT -IR) The prepared inclusion complex was white and fine without stickiness.

Fig. 4 shows the FT-IR spectra for CD, ~-CyD, physical mixture of CD and ~-CyD (PM)

and also inclusion complex of CD and ~-CyD. The carbonyl group of CD exhibited an intense absorption peak between 1500 and 1700 em -!due to its stretching vibration. CD exhibited the strong absorption peak at 1700 em -I of the carbonyl stretching vibration. In the physical mixture, as compared to pure CD, the spectrum showed a less intense absorption peak at 1700 cm-1• Moreover, the spectrum of the inclusion complex displayed almost similar to the pure ~-CyD which indicated the formation of the inclusion complex which CD was included into the cavity of~-CyD. Therefore FT-IR analysis demonstrated the interaction and complex formation between CD and ~-CyD. Previous study reported that cetirizine showed the strong absorption peak at 1 7 41 em -I and the spectra of inclusion complexes were similar to that of ~-CyD (Lee et al., 201 0).

44

45

CD

JJ-CyD

~--~~~------------P:l\-1

Co1nplex -2500 2000 1500 1000 500

Fig. 4 FT-IR spectra of CD, ~-CyD, physical mixture of CD and ~-CyD (PM), and inclusion complex of CD and ~-CyD

1.2.2. X-ray powder diffraction (XRPD) The formation of inclusion complex was identified by powder X-ray

diffraction as presented in Fig. 5. CD showed the sharp peaks at 8.46°, 15.04°, 15.06°, 15.08°, 18.26°, 18.3°, 18.84°, 20.84°, 20.86°, 23.18°, 23.2°, 23.94°, 24.5°and 25.06° 29 positions indicating crystalline nature of this drug. The XRD of~-CyD exhibited the sharppeakat9.2°, 10.8°, 10.82°, 12.62°, 12.64°, 12.66°, 15.54°, 15.56°, 16.12°, 16.14°, 16.88°, 16.9°, 17.34°, 17.36°, 19.64°, 19.66°, 21.04°, 21.06°, 22.92°,22.94° and 24.36° 29 positions. The powder X-ray diffraction pattern of the PM was the superposition of the patterns of each component, but the intensity was decreased. From the X-ray diffraction of inclusion complex, it showed a significant reduction of crystallinity. Loss of crystallinity in the complexes may signify the presence of reciprocal interactions between drug and ~-CyD (Laura Ribeiro et al., 2003; Zarif et al., 2012). Moreover, the x-ray pattern of the inclusion complex displayed almost similar to the ~-CyD powder. Therefore, these results confirmed that CD was included in the ~-CyD cavity.

46

~-CyD

Complex

Fig. 5 X-ray diffractograms of CD, ~-CyD, physical mixture of CD and ~-CyD (PM), and inclusion complex of CD and ~-CyD

1.2.3. Differential scanning calorimetry (DSC)

The DSC thermogram of CD (Fig. 6) exhibited an endothermic peak at 220 ac corresponding to its melting point. This result was in agreement with previous study which reported that DSC thermogram of cetirizine hydrochloride showed a sharp endothermic peak indicating melting at 220.4°C (Sovizi et a!., 2013). The endothermic peak of ~-CyD showed a broad peak about 90°C which attributed to a dehydration process. Previous study reported that endothermic peak of ~-CyD showed a broad peak about 91.82°C (Chandrakant et al., 2011). The physical mixture showed the two endothermic peaks, one for the ~-CyD at 90°C and another for the CD at 220 °C. Moreover, the DSC curves of the inclusion complex displayed almost similar to that of the ~-CyD indicated that CD was included into the cavity of ~-CyD.

CD A----m ·--------------~

PM

.-...........

Complex ,___.----------------.. __..-·

___..,.,... --__ ....--_.,._---50 166 150 2i5i} ~50

Temperature (0 C)

47

Fig. 6 DSC curves of CD, ~- CyD, physical mixture of CD and ~-CyD (PM), and inclusion complex of CD and ~- CyD

1.2.4. Simultaneous XRD-DSC measurement Parallel measurements of separate specimens using DSC and XRD and

a combination of both results are one of the popular methods for studying thermal reactions of solids. Simultaneous XRD and DSC measurement were used to prove the result of XRD and DSC of CD and inclusion complex as shown in Figs. 7-10. The

characteristic peaks of CD in Fig. 7 were at 8.5°, 15.04°, 15.06°, 15.08°, 18.84°, 20.84°, 20.86°, 23.18°, 23.2°, 23.94°, 24.5°, 25.06° 28 positions that exhibited at the same position as previous powder X-ray measurement. Moreover, DSC thermogram showed the characteristic peak of CD at around 180-220°C which previous study showed at

220°C (Arii et al., 1999; Sovizi et al., 2013). Figs. 8-10 displayed the simultaneous

XRD-DSC data of ~-CyD, PM and inclusion complex, respectively. There were three crystalline peaks of inclusion complex at around 10.85°, 13.58, 19.64° 28 positions. The first stage of inclusion complex showed a characteristic peak of X-ray pattern at

10.85° 28 position and showed the loss of water molecules of ~-CyD from DSC

thermogram around 70°C. Inclusion complex started to loss water from ~-CyD cavity at 71 °C (Laura Ribeiro et al., 2003; K. Sambasevam et al., 2013). Consequently, the

second stage of inclusion complex showed X-ray pattern at 13.58° 28 and the

exothermic peak of inclusion complex from a decomposed ~-CyD was found around

230°C. Some research reported the second decomposition of inclusion complex at 225°

(K. Sambasevam et al., 2013). And the third stage at 19.64° 28 was probably owing to

the melting point of CD which showed the endothermic peak around 220°C (Sovizi et

48

al., 2013 ). Additionally, XRD pattern of the inclusion complex was similar to that of (3-CyD indicated that CD was included into cavity.

Moreover, the physical mixture exhibited the characteristic peak of X­ray pattern at 9.1 °, 11.6°,13.84, 19.64° 29 positions whereas the inclusion complex showed at 10.85°, 13.58 °, 19.64° 29 positions. The changes in profile clearly indicated the transformation of the crystalline form to another by removal of water molecules. When the hydrate water molecules were released from the cavity of (3-CyD, the crystallinity of complexes was deteriorated. The main driving force of complex formation was the release of enthalpy-rich water molecules form the cavity. Water molecules were displaced by more hydrophobic guest or partially functional group of guest. Furthermore, the bindings of CD within (3-CyD cavity decreased the ring strain as well as the increased number of hydrogen bonds formed as the displaced water returned to the larger pool resulting in the changing 29 positions of inclusion complex compared with physical mixture. Therefore, water molecules played an important role for formation of inclusion complex. Ethanol has been used as solvent for kneading method because it could dissolve CD (soluble in ethanol) and (3-cyclodextrin (slightly soluble in ethanol) (Del Valle, 2004; Kawasaki eta!., 2007; Yoshii eta!., 1998).

l{,(H)OO

1~0000

11'10001)

1 _}0000

1..?0000

- llOOtX)

<1. 100000 v ~~noon '!":"! 8000C c ... ~

2 T h e td [de~ ]

Fig. 7 XRD-DSC of CD

850000

800000

750000

700000

650000

600000 --"---"--'"'--~----------1

550000 ~-"--"--'"'---_,.,...._------~ 500000 450000 ~--..A___. . .___ _ _,.,..._ ______ --i

~ 400000

j 350000~~""'---------1 300000

250000~~ 200000 ----''--.....-''~------------150000

100000

Humidity ( % ) 1 .0 0 .8 0.4 0 .2' 0 0 .7 0 .4 0 .6 0 .8 t

1100

100

u

100

,_...'!"', ~7-:--~-~..,,---,--8,_..,9-J"'=o..J ;' -~ ')

Heat rtow/rnW

1.0 0.8 0 .6

H umidity (%)

0 .4 0.2 0 -0.2 -0 .4 -0.6 -0.8 - 1.0

/

lOO.O

280.0

260.0

2 40.0

220.0

200.0 u

180.0 'OJ

160.0 ~ 140.0 ~ 120.0 ~

100.0

80 .0

60.0

40.0

28 .0

8.0 10.0 12.0 14.0 16.0 18.0 20.0 22.0 2 4 0 2 6 .0 28.0 30.0 32.0 3S.O :-. . .o !GO t~o too • • l'\o' 4 .,~ f-"0 t.,.o lnO ,.,o 10 '~ 0

2 Thet a [Des] Heat Flow/mW

Fig. 8 XRD-DSC of(3-CyD

::~:~c= - j 220000

200000 ~

80000

60000

4oooo I 20000

~

/ /

(

280.0

260.0 240.0

49

220.0

200.0

180.0 ~ :l

160.0;!

140.0 ~ 120.0~

100.0

80.0

60.0

40.0

8 10 12 14 16 18 20 22 24 26 28 30 32 34 - 1.0 -2.0 -3 .0 -4 .0 -5 .0 -6.0 -7 .0 -8 .0 -9 .0 -10.0 IO.S

2 Theta [Oeg] Heat Flow/mW

Fig. 9 XRD-DSC ofPM

650000

600000

550000

500000

450000

400000 L - M A--. -

'§: 350000 ---~

300000

250000

2oooooL - ~-------lsooooL ___ ~~-------100000

50000

8 10 12 14 16 18 20 22 24 26 28 30 32

2 Theta [Deg]

Fig. 10 XRD-DSC of inclusion complex

Humidity (%)

1.0 0.8 0.6 0.4 0.2 0 -0.2 -0.4 -0.6 -0.8 -1.0

/

} 1100

320.0

300.0

280.0 u

260.0 ~

240.0 .=:! 220.0 ~ 200.0 E 180.0 ~ 160.0 140.0

120.0

100.0 80.0

60.0 43.4

-1 -2 3 -4 -5 -6 -7 -8 -9 -10 '"'

Heat Flow/mW

1.2.5. Thermogravimetric analysis (TGA) Thermogravimetric analysis (TGA) was done on samples to identify the

change in weight percentange with respect to temperature change. Fig. 11 shows the TGA thermograms of pure CD, ~-CyD, PM and inclusion complex. ~-CyD exhibited two stages of weight loss. The first stage was due to the loss of water molecules at 50 oc which was located in the cavity of ~-CyD. Consequently, the weight loss found at 300 °C related to the decomposition of ~-CyD structure. ~-CyD decomposition has been reported previously at 307 °C (Giordano et al. , 2001 ). Moreover, weight loss found at 220 °C related to the endothermic peak of DSC corresponding to its thermal decomposition. For the inclusion complex it showed the weight losses in three stages. The first stage was the dehydration of water molecules, the second stage was due to the decomposition of CD and the third stage was the decomposition of ~-CyD. In comparison, to confirm the formation of the inclusion complex, the first weight loss for the inclusion complex started around 30 oc whereas the first weight loss for the PM

50

started around 50 oc which was almost similar to the water loss of ~-CyD. In addition, the second weight loss for the inclusion complex started at 250 oc whereas it started at 200 oc for the PM but for the ~(Ali et al., 2007)-CyD it occurred at 310 °C. Previous study mentioned that the formation of inclusion complex decreased the thermal stability

of ~-CyD (Chen et al. , 2006).

\Veight {mg)

0.5

~1.0

~1 .5

-2.0

-2.5 -

-:4.0 -

-3.5

-4.0 J

50 100 150 200 250 300 350 400

Tem perature/<>C

Fig. 11 TGA of (A) CD, (B) ~-CyD, (C) physical mixture and (D) inclusion complex

1.2.6. Nuclear magnetic resonance study (NMR)

Insertion of a guest molecule into the hydrophobic cavity of the ~­

cyclodextrin resulted in the chemical shift (~o) of guest and host molecules in the NMR spectra. In general, the large chemical shifts were observed at H3 and Hs which were located in the inner cavity of ~-cyclodextrin (Djedaini et al., 1990; Fernandes et al. , 2003). 1H NMR spectroscopy of CD, ~-CyD, PM, CD/ ~-CyD inclusion complex prepared by kneading method is showed in Fig. 12 and the chemical shift together with assignments were presented in Table 1. In this study only ~-CyD and inclusion complex protons were discussed because too many peaks were overlapped in 7.4-7. 7 ppm region of CD which related to the aromatic ring resonance (Lee et al. , 201 0; Stojanov et al. , 2011). From Table 1 and Fig. 13, some chemical shifts were observed for H1 , H2, H3, H4, Hs and H6. The largest chemical shift changes of CD were investigated for H3 and Hs cavity protons, resulting from intermolecular interactions with guest protons residing in the CD cavity. Chemical shift changes were determined to some extent for all CD protons, and the highest change was observed at the phenyl and chlorophenyl ring protons. Therefore, this shift provided the indication for the formation of the

51

inclusion complex between ~-CyD and CD (Harata, 1977; Saenger, 1984; Youming et

al. , 2008)

.......;;_P-_C.::...yD _ ___, _____ ~··l

7

Fig. 12 1H NMR spectra (300 MHz) of CD, ~-CyD and complex of CD/ ~-CyD

52

Table 1 Change of chemical shift (~o, ppm) for protons of ~-CyD and complex

orro I . . H..; ~l ~l

13-cyn 5.089 3.683 3.979 3.638 3.864 3.893

complex 5.089 3.690 3.950 3.646 3.842 3.888

1!:.6 0.000 0.007 -0.029 0.006 -0.022 -0.005

!!:. r t! t ~ ~ !.f !~~,!'!1.!

\i i iiHii \\\i/11 H.

"· B-eyD

n . :0

\i 1

Complrx

ppm uuuuuu~u«uouuuuuuu

Fig. 13 1H NMR spectra of ~-CyD and complex

53

1.2.7. Scanning electron microscope (SEM) CD particles were irregular-shaped crystals, while ~-CyD particles were

large and irregular in shape (Fig. 14). The SEM image of inclusion complex displayed almost similar to the pure ~-CyD. Moreover, a relatively compact and homogeneous structure was obtained in Fig. 14 (C) compared with Fig. 14 (A) and Fig. 14 (B).

(B)

(C)

Fig. 14 SEM images of CD (A), ~-CyD (B) and inclusion complex (C) at 500x magnification

1.2.8. Taste evaluation of inclusion complex Precisely, an unstructured line scale was used for the quantification of

the results from taste sensory study. The results from the bitterness evaluation using healthy volunteers (n=6) were presented in Fig. 15. Generally, all examiners demonstrated overall same pattern of bitterness perception for the CD. The overall ratings for various samples were obtained and the mean± SD rating was used to qualify the taste masking efficiency. It was found that inclusion complex showed an average rating of 1.75 (SD=0.22) as compared to 11.55 (SD=0.09), 8.4 (SD=0.28) in case of CD powder and CD/~-CD physical mixtures, respectively. From Fig. 16, the bitterness of complex displayed significantly different from CD powder, PM and inclusion complex (p < 0.05). CD was notably bitter and additionally it had sour taste due to its dihydrochloride salt form (Stojanov et al., 2012). Based on the average ratings it could be concluded that CD was successfully complexed in the cavity of ~-CyD using kneading method, which prevented a contact of CD with taste bud receptors. Taste evaluation of cefixime-~-CyD by kneading method was evaluated by six human volunteers. It was observed that there was no bitter taste perception when compared with the pure drug as mentioned in previous study (Madhavi eta!., 2014). Furthermore, rizatriptan benzoate and ~-CyD 1:10 was done by simple complexation approach using kneading mixture methods. The efficiency oftaste masking was evaluated by six human volunteers. It was observed that there was no bitter taste perception by kneading mixture when compared with the drug powder (Birhade, 2010).

54

II no bitterness (A) strongly bitter

I no bitterness (B) strongly bitter

I no bitterness (C) strongly bitter

Fig. 15 Taste panel evaluation of (A) CD powder (B) physical mixture of CD/p-CyD and (C) complex of CD/p-CyD by healthy volunteers (n=6)

~ e 0 > 0 ~

14

12

6

4

2

0 CDvsPlVI CD vs Complex

Formub

Pl\'l YS Complex

Fig. 16 Comparison ofbittemess level where(*) indicates significantly difference from the other samples (analyzed by R-stat at p value< 0.05) (n=6)

2. Preparation of cetirizine dihydrochloride fast disintegrating tablets

2.1. Study and screening of effect of type of disintegrants on properties of tablets

2.1.1. Preparation of tablet containing different disintegrants 2.2. Evaluation of tablets containing different disintegrants

55

From review research, chitin and chitosan were used as disintegrants in ondansetron FDT (H. Goel et al. , 2011), Avicel® could adsorb water into the tablet, xylitol showed apparent high solubility in water and good mouth feel. They were appropriate as disintegrants for FDT. The hardness of A vicel® PH 102 tablet was greater than that of the others. The hardness of A vicel® tablets resulted from hydrogen bonding between the plastically deformed, large surface area cellulose particles. Indeed, A vicel® tablet could be described as a cellulose fibril in which the microcrystals were compressed closely enough together so that hydrogen bonding between them occurs. A vicel® is recognized as the most compressible of any direct compression excipient, in that less compression force was required to produce a tablet of a given hardness than was required for other direct compression materials (Inghelbrecht et al. , 1998; Ishikawa et al. , 2001 ; J.Z. Li et al. , 1996; Thoorens et al., 2014). Tablets containing Avicel® PH 101, Avicel® PH 102, chitin had no significant difference on WT; however, the xylitol tablets were rapidly dissolved and disintegrated within 7±1 seconds due to its apparent high solubility in water ofxylitol (Z. Wang et al. , 2013), whereas, those of the others were longer than 30 min. Nevertheless, the hardness of the xylito1 tablet was very poor as presented in Table 2. Therefore, the tablets containing the mixture ofxylitol and other materials were subsequently fabricated. An incorporation of the other excipients could enhance the hardness of the xylitol tablet, especially, an addition of white bentonite as presented in Table 3. However, an addition of these two compounds prolonged the DT and WT of prepared tablets. The tablets containing xylitol and chitin at the ratio of 7:3 exhibited the high hardness and low DT. Previous study reported that chitin decreased the DT with an increase in tablet porosity and swelling (Bala et al. , 2012; H. Goel et al., 2011). Moreover, chitin had been widely acknowledged as effective tablet disintegrants due to their high water absorption capacity therefore tablet containing this polymer showed fast DT and WT (Badwan et al., 2015; Kumar et al. , 2002). With respect to chitin, their tablets showed acceptable mechanical properties as mentioned previous study. This could be attributed to the irregular particle shape, the external surface area, and the rough surface texture of chitin; all contributed to the high surface bonding between the particles (Karehill et al. , 1990).

Table 2 Physical properties of tablets containing disintegrants

Tablet Weight Hardness DT (s) WT (s)

(mg) (kPa) Avicel PH101 406.5±2.4 15.15±1.1 0 1830±177 7.2±0.2 A vicel PH 1 02 402.6+3.2 23.20+0.77 4990+241 15.7±2.9 Chitin 404.3+4.2 20.41+1.47 5460+281 11 .8±1 .8 Chi to san 400.8±3.1 15.35+ 1.28 5347±175 318.3±24.5 White bentonite NF 402.7+2.5 6.05±0.95 2400±306 1131.2±35.4 Xylito1 401.4+3.3 1.49±0.20 7+1 21 .3±2.3

56

Table 3 Physical properties of tablets containing xylitol and other materials

Tablet Weight (mg) Hardness DT (s) WT(s)

(kPa)

Xylitol: Chitin 7:3 400.5±2.9 2.44±0.31 13 .67±0.82 15.67±0.52 Xylitol : Chitin 8:2 401.4±2.7 1.73±0.27 12.33±0.82 17.17± 1.33 Xylitol: Chitin 9:1 403.3±5.2 1.12±0.28 8.17±0.41 18.50±1.38 Xylitol: Chitosan 9:1 401.3±2.1 1.39±0.24 10.33±1.21 5.67±0.52 Xylitol:Avicel PH101 9:1 399.4±2.7 1.83±0.38 6.67±0.82 5.17±0.75 Xylitoi:Avicel PH102 9:1 400.4±2.4 1.09±0.23 12.00±1.26 35.50±4.42 Xylitol : White bentonite NF 9: l 403.5±3.1 5.04±0.96 154.50±12.19 1318.83±61 .50

2.2.1. Contact angle and surface free energy (SFE)

The wettability of tablets could be described by the contact angle and

SFE. From Fig. 17 and Fig. 18 respectively, the results displayed that the tablets

containing mixture of 9:1 xylitol:A vicel PH 101 dembnstrated the lowest contact angle and the SFE. It could refer that the tablets containing mixture of 9: 1 xylitol and A vicel

PH 101 exhibited the best wettability its apparent high solubility of xylitol (Z. Wang et al. , 2013). Although Avicel® had hydrophobic property, it could adsorb water into the

tablet. The increased entrance of water by capillary action through the cellulose molecules resulted in the disruption of hydrogen bonds holding the molecules together thereby breaking up the tablets (Steele et al. , 2008).

--~ 70 ~ bll60 QJ

2.-so ~40 ; 30 -~ 20 -= 10 0 u 0

Formula

Fig. 17 Contact angle of the tablets (n=6)

57

N-100

s 90 -~ 80 s '-" » 70 ell 60 ~ ~

50 = ~

~ 40 ~

~ 30 ~ 20 ~

c.S 10 ~

= 0 rJJ

Fig. 18 SFE of the tablets (n=6) 2.2.2. Scanning electron microscope (SEM) The scanning electron micrographs revealed that xylitol was in form of

the crystal as shown in Fig 19. Moreover, tablets containing 9:1 xylitol: Avice}® PHI 01 showed disordered arrangement therefore it could promote the tablets disintegration as shown in Figs. 19 e-f. A vicel® PH 101 is water insoluble excipient, but it has the ability to draw fluid into the tablet lattice by capillary action (H Goel et al., 2008). The tablet then swells on contact with water and hence, microcrystalline cellulose acts as disintegrating agent. Besides xylitol shows good water solubility, it will facilitate the disintegration and dissolution (Seong Hoon Jeong et al., 2008). When xylitol was combined with A vice}® PH 101, they presented the synergic effect to rapidly disperse the tablets. In addition A vicel®PH 101 could also enhance the tablet hardness. Therefore they exhibited as suitable material for FDT. This revealed that the tablets containing xylitol or sugar alcohol and A vicel® could be employed as disintegrants for FDT.

58

(c)

(d) (e) (f)

Fig. 19 Scanning electron micrographs of(a) xylitol powder (magnification of 100X); (b) xylitol powder (magnification of 500X); (c) A vice I PH 101 (magnification of 1 OOX); (d) Avice! PH 102 (magnification of 500X ); (e) tablet containing xylitol:Avicel PH 101 9:1 (magnification of 100X); (f) tablet containing xylitol:Avicel PH 101 9:1 (magnification of 500X)

2.3. Formulation of CD FDT by direct compression method using factorial design

The composition of prepared tablets was shown in Table 4. The 5% w/w CD FDT formulation was used in this study. According to the formula given in Table 4, all ingredients were accurately weighed. Direct compression method was used to prepare the tablet which drug and all the excipients except lubricant were mixed in mortar and pestle by geometric dilution for 10 min. Finally, lubricant was added into this blend and mixed properly again for 3 min. The blend was compressed using hydraulic press (SPECAC 15011, A Cambridge Electronic Industries Company, Kent England) to produce the 200 mg tablets with a diameter of9.53 mm using the compress force of 1, 3, 5 ton/cm2

.

59

Table 4 Formulation for preparation of CD FDT

Formulations FI F2 FJ F4 Fs F6 F1 Fs F9 c

CD 10 10 10 10 10 10 10 10 10 10

Aerosil200 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2

Lubricant 0.5 5 10 0.5 5 10 0.5 5 10 2

Ludiflash® 189.3 184.8 179.8 189.3 184.8 179.8 189.3 184.8 179.8 187.8

Total wt. <mg) 200 200 200 200 200 200 200 200 200 200

Selection of levels for independent variables Full factorial design model with 2 factors, 3 levels and 9 runs was selected

for the optimized study. The polynomial equation generated by this experimental design using the software, Statistica 1 0; Stat Soft Inc. The three levels were selected (high, intermediate and low) for both the independent variables as sumarised in Table 5. The concentration of lubricant and compression force (X2) were taken as independent variables for different levels.

Table 5 Full factorial design layout

Batch code

FJ

F2

F3

F4

Fs

F6

F1

Fs

F9

0.25

2.5

5

0.25 3

2.5 3

5 3

0.25 5

2.5 5

5 5

2.4. Study of distribution and effect of lubricants on characteristics of cetirizine dihydrochloride fast disintegrating tablets

Distribution of lubricants in tablets and effect of compression force on lubricant distribution

The Raman maps in Fig. 20 provided the information about the spatial distribution of mg-st within the FDT. High spectral concentration for lubricant was shown with red colors, while blue colors correspond to low concentration of lubricant.

60

The distribution of 0.25% w/w mg-st in the FDT was showed in Fig. 20a and low concentration of mg-st in FDT (red colors) was evident. In addition, Fig. 2lc showed the most distribution of mg-st in tablet compared with Fig. 21 a and Fig. 21 b which SEMIEDX could detect the concentration ofmg-st at 0.18% w/w, 0.82% w/w, 1.65% w/w in Figs. 2la, b, c, respectively

~0

15

20

"' 25 <l> X 30 0:

35 40

45

5 0

10

15

20

~ 25 X 30 a:

35

40

45

5 0

Pixels

Pixe l s

b

Pixels C

O.C5·1

O.C~-6

o c.:a O.CcO

O.Cc-1

(J.Cce

O.C 7 0

O.C ..,..~

o.c ..,. ~•

Fig. 20 Spatial distribution of mg-st in tablet compressed at 1 ton/cm2 at magnification of lOx and 5 J.lffi step size. The amount ofmg-st in tablets: (a) 0.25% w/w, (b) 2.5% w/w and (c) 5% w/w.

61

a b c Fig. 21 EDX mapping for distribution (a) 0.25% w/w, (b) 2.5% w/w and (c) 5% w/w mg-st in FDT

The more amount of SSF was used in tablet, the higher distribution of SFF on tablet surface was detected as shown in Fig. 22. These results could be also confirmed by SEM/EDX in Fig. 23 . Fig. 23a showed the less distribution of SSF than Fig. 23b and Fig. 23c. SEM/EDX could detect the SSF at 0.20% w/w, 0.65% w/w, 1.86% w/w in Figs. 23a, 23b and 23c, respectively. From Raman spectroscopy detection mg-st distribution in tablet surface was evident after mixing 2-5 min (Lakio et al.,

2013). Furthermore, SEM/EDX was used to investigate the drug distribution in the surface tablet which the detection of carbon, nitrogen, oxygen interpreted as a mixture of the drug (paracetamol) (Scoutaris eta/. , 2014). Consequently, the results from the SEM/EDX and Raman spectroscopy confirmed that the higher amount of lubricants, the more distribution of lubricants was detected.

62

10 0.02 l!i

2 0 0.015

"' ?5 0.010 --a)

30 X 0.005 0.::

3S

4 0>

45

5(1

10 20 30

Pixe ls a

,07

.06

.05

"' 1:) 04 X a: 03

02

10 20 30 110

Pixels

b

10 20 30 40 50 r~xels

c Fig. 22 Spatial distribution ofSSF in surface of tablets prepared with compression force

of 1 tonlcm2 from Raman maps at magnification of 1 Ox and 5 Jlm step size. The amount ofSSF in tablets: (a) 0.25% w/w, (b) 2.5% w/w and (c) 5% w/w SSF

63

a b c

Fig. 23 EDX mapping for distribution of SSF at (a) 0.25% w/w, (b) 2.5% w/w, (c) 5% w/w in FDT

Typically, the hydrophobic nature of the lubricant film could hinder the penetration of water in the tablet. Therefore, this study investigated a distribution of lubricant to understand the effect of compression force on lubricant distribution. The measured spectral range was 200-2000 cm·1 which each tablet surface was divided into nine parts. The tablet containing 2.5% w/w mg-st prepared with compression force of 5 ton/cm2 (Fig. 24b) displayed more distribution of mg-st (red dots) than prepared at compression force of 1 ton/cm2 (Fig. 24a). Moreover, the tablet containing 5% w/w mg­st prepared at compression force of 5 ton/cm2 (Fig. 24d) showed more distribution of mg-st at the edge of tablets than distribution at the center, unlike tablet containing 5% w/w mg-st prepared at compression force of 1 ton/cm2 (Fig. 24c) which mg-st located toward the middle of tablets . Likewise, the distribution ofSSF (Fig. 24e-h) was similar to that of mg-st. Therefore, the higher compression force was used, the more distribution of SSF was detected. Consequently, the application of high compression force promoted more distribution of lubricant than using low compression force. The high compression force resulted in delamination of lubricant leading to large surface area of lubricant on the tablet surface (Shah et a!. , 1977). Moreover, the higher compression forces resulted in tablets with higher density and longer DT (Johansson, 1986; Rotthauser et al. , 1998).

64

a b c d

e f g h Fig. 24 Raman mapping for mg-st distribution on tablets containing 2.5% w/w mg-st prepared (a) at compression force of 1 ton/cm2 (b) 5 ton/cm2 and tablets containing 5% w/w mg-st prepared (c) at compression force of 1 ton/cm2 and (d) 5 ton/cm2 and tablets containing 2.5% w/w SSP prepared (e) at compression force of 1 ton/cm2 (f) 5 ton/cm2

and tablets containing 5% w/w SSP prepared (g) at compression force of 1 ton/cm2 (h) 5 ton/cm2

2.5. Evaluation of the prepared tablets Additionally, to overcome the problem of difficulty in swallowing

which resulted in non-compliance and ineffective therapy, developing CD PDT were prepared by direct compression method. A 32 full factorial design was applied for the optimization of CD PDT. The values ofDT, WT, hardness, contact angle and SFE of the 9 runs were listed in Table 6. All the dependent variables were strongly dependent on the selected independent variables (F, to F9). Mean values of responses were used to generate the equations for each dependent variable which the estimated equation for the response variables were discussed separately. Finally, the model was validated by preparing and testing the new formulations.

65

Table 6 Full factorial design of 9 runs for identifying active formula and process variables influencing dependent variables (mg-st)

Formula Independent variable

mg-st Force DT (sec) WT (sec)

(%w/w) (ton/em')

F, 0.25 91.50±3.94 55.83±2.56

F, 2.5 103.50±4.72 I 05.67±1.63

F, 5 275.17±3.19 473.83±3.76

F" 0.25 3 162.33±4.03 123.67±4.27

F, 2.5 3 205.83±6.08 227.67±1.86

F6 5 3 347.67±5.92 492.83±2.32

F1 0.25 5 172.33±2.25 147.00±2.83

Fs 2.5 5 247.00±3.35 234.00±3.58

F9 5 5 293.17±2.48 497.17±2.32

Dependent variables

Hardness

(N)

149.57±4.86

143.38±3.20

97.13±9.08

165.63±7.89

163.88±2.90

141.71±3.55

173.29±4.19

169.93±8.53

150.17±3 .87

Contact

angle (0)

7.44±0.39

39.49±0.24

41.87±1.53

14.81±1.11

43.03±1.61

43.45±2.79

21.05±0.58

48.03±1.60

43.33±1.60

SFE

(mJ/m')

66.92±14.15

55.16±8.91

55.22± 15.97

65.27±13.68

53.59±9.56

52.15±15.37

71.10±2.63

51.20±6.95

52.64±16.43

The terms of polynomial equation showed significant different if p-value displayed less than 0.05 at 95% level confidence in Table 7. However, the interaction

terms and second order quadratic terms revealed no significant difference (p>0.05)

which reported in previous study (Late et al., 2009). In addition, the independent factors

affecting the output might be discussed subsequently in the equations. Table 7 Polynomial equation and the coefficients for DT, WT, Hardness,

contact angle and SFE

DT WT Hardness contact angle SFE Term p- p- p- p- p-

coefficient value coefficient value coefficient value coefficient value coefficient value

bo 212.38 0.0003 265.29 0.0001 150.23 0.0000 33.86 0.0000 58.01 0.0000

b, 163.28 0.0092 379.11 0.0005 -33.16 0.0069 28.45 0.0000 -14.43 0.0038

b, 80.20 0.0601 80.33 0.0422 34.70 0.0061 7.76 0.0006 -0.84 0.6635

b., -33.04 0.3943 -35.13 0.3102 14.85 0.0927 -6.09 0.0521 -3 .29 0.2229

bll -33.95 0.2453 99.3 0.0166 11.94 0.0697 15.61 0.0000 -7.61 0.0153

b, 41.5 0.1763 29.14 0.0249 9.83 0.1070 0.23 0.6311 -1.7 0.3441

66

Y was dependent variable, bo was arithmetic mean response of nine batches, b 1 was estimated coefficient for factor X1, and b2 was estimated coefficient for factor X2. The interaction term (b12) showed the coefficient of response changes when two factors were simultaneously changed. The polynomial terms b11 and b12 were the coefficient of non-linearity.

Factorial equation for DT and WT From the response of 9 runs, the DT and WT were performed for creating the

equation. Concerning disintegration time, the results of multiple linear regression analysis showed that the coefficients ofb1 and b2 were a positive sign DT=212.38+ 163.28XI+80.20X2-33.04XIX2-33.95X,2+41.50Xi (R2=0.9450) .... . (8)

WT = 265.29+379.11XI+80.33X2-35.13XIX2+99.30X2,+29.14X2 2 (R2=0.9902) ... (9)

From the equations 8 and 9, increasing the concentration of mg-st displayed a notable impact on slowing of the DT and WT because the higher order (X1 2) was significantly difference. The hydrophobic lubricants increased the DT, however the hydrophilic lubricants (L-leucine) decreased in a DT as reported previously (Late et al., 2009). Furthermore, increasing the compression force increased in the DT and WT. These results could be explained by the formation of more condensed compacts with increasing the compression force (Late et al., 2009; Rotthauser et al., 1998; Y oshihashi et al., 1998).

Factorial equation for hardness From the response of 9 runs, the equation of hardness was generated for

prediction of tablet. Hardness= 150.23-33.16X,+34.70X2+ 14.85XIX2+ 11.94XI2+9.83Xl (R2=0.9740) ... (10)

The results of multiple linear regression analysis showed that the coefficients b 1 was a negative sign and b2 was a positive sign in equation 10. Therefore, increasing the concentration of mg-st minimized the tablet hardness. These results were in agreement with the results of previous study. The fine mg-st particles created a waxy covering and prohibited inter-particulate forces from bonding resulting in the decreasing in hardness of tablets (J. Wang et al., 2010). The surface topography of tablets fabricated with increasing compression forces (Fig. 25 b, d, f) was smoother than that fabricated with low compression forces (Fig. 25 a, c, e). Therefore the smoothest surface was evident for the tablets compressed with the highest compression force as previously reported (Riippi et al., 1998).

67

c

e £

Fig. 25 SEM of CD surface tablets containing 0.25% w/w mg-st prepared (a) at compression force of 1 ton/cm2 (b) 5 ton/cm2 and tablets containing 2.5% w/w mg-st prepared (c) at compression force of 1 ton/cm2 (d) 5 ton/cm2 and tablets containing 5% w/w mg-st prepared (e) at compression force of 1 ton/cm2 (f) 5 ton/cm2

Factorial equation for contact angle and SFE Typically, the wettability of tablets could be described from the contact angle

and SFE values (Kuno et al., 2008; K Terada et al., 2004). The equation of contact angle and SFE were generated for prediction of tablet. Contact angle=33.86+28.45X,+ 7. 76X2-6.09X,X2+ 15.61X,2+0.23Xi (R2=0.9994) .. . (11)

From the equation 11, an increasing amount of mg-st remarkably increased in the contact angle as the higher order (X1 2) was significantly different. The hydrophilicity of the tablets was changed with increasing amount ofmg-st. The higher the concentration of mg -st, the poorer the wettability of the tablet surface owing to poor wetting of mg-st (Late et al., 2009; J. Wang et al., 2010). In addition, an increasing compression force increased in the contact angle of tablets. The higher compression force led to large surface area of lubricant which related to the results of SEM in Fig. 25 and Raman mapping and hindering the water penetration into tablet. Moreover, an increasing the compression force resulted to increase in the hardness. The result was explained by the formation of more condensed compacts with increasing compression force. Therefore, the wetting of tablets was hindered (Late et al., 2009).

In addition to SFE, the results of multiple linear regression analysis showed that both coefficients b, and b2 were negative signs.

68

SFE = 58.01-14.43XJ -0.84X2 -3.29XtX2-7.61Xt2 -l.?OX22 (R2=0.9691) . . . (12) From the equation 12, the SFE strongly decreased with increasing the

concentration of mg-st because of hydrophobic nature of the film of mg-st (Lindberg, 1972; Perrault eta!. , 2011; J. Wang eta!., 201 0). Moreover, increasing compression force decreased the SFE of tablets. Furthermore, to investigate the polar and dispersive components, the liquid penetration rate of the tablets was measured. Fig. 26 showed a comparison of polar and dispersive components of SFE of tablet. More polar tablets had a stronger affinity to water because water was regarded as a polar solvent. The tablet composed of0.25% w/w mg-st prepared with compression force of 1 ton/cm2 had the largest polar surface free energy (Fig. 26A). On the other hand, the tablet comprising of 5% w/w mg-st prepared with compression force of 1 ton/cm2 (Fig. 26F) exhibited the largest dispersion surface free energy with low WT and DT. Polar and dispersive component had been used to investigate the polarity of the tablet containing talc which the polar part of talc was increased by grinding (K Terada eta!. , 2004).

50

>-. 40 ell I. QJ

= 30 QJ --N

QJ 8 QJ-~~ 20

QJ 8 eJ --~ 10 I.

= ri:J 0 A B c D E F

Formula

Fig. 26 Polar and dispersive components of surface free energy of tablet containing 0.25% w/w mg-st prepared (A) at compression force of 1 ton/cm2 (B) 5 ton/cm2 and tablets containing 2.5% w/w mg-st (C) at compression force of 1 ton/cm2 (D) 5 ton/cm2

and tablets containing 5% w/w mg-st (E) at compression force of 1 ton/cm2 and (F) 5 ton/cm2

To compare with mg-st, SSF was used as lubricant in the tablets with the same conditions. Table 8 clearly indicated that all the dependent variables were strongly dependent on the selected independent variables when SSF was used (F 1 to F9) . Mean values of responses were used to generate the equations for each dependent variable which the estimated equation for the response variables were discussed separately. And then, the model was validated by preparing and testing with new formulations.

69

Table 8 Full factorial design of9 runs for identifying the active formulation and process variables influencing the dependent variables (SSF)

Formula Independent Dependent variables

variables

SSF Force DT (sec) WT (sec) Hardness Contact SFE

(N) angle(0 ) (mJ/m2)

(%w/w) (ton/cm2)

Ft 0.25 57.00±2.10 92.00±1.90 141.33±1.75 6.23±0.10 67.08±13.73

F2 2.5 86.50±2.07 94.33±2.88 136.00±3.92 22.59±2.35 62.59±17.95

F3 5 114.17±3.19 146.17±4.67 138.00±3.85 45 .66±3.49 50.99± 15.10

F4 0.25 3 116.67±1.75 191.33±1.97 171.00±6.08 11.78±0.78 65.36±14.60

Fs 2.5 3 121.50± 1.52 218.00±2.61 157. 71±4.82 43 .65±2.12 52.28±8.20

F6 5 3 190.83±3.19 229.67±1.37 144.29±3.09 50.88±0.95 46.92±12.83

F1 0.25 5 122.67±2.50 213.67±2.73 180.40±4.62 15.03±0.53 64.31±16.20

Fs 2.5 5 179.00±0.89 229.83±2.32 150.29±3.30 47.68±2.58 49.40±8.21

F9 5 5 210.17±2.14 245 .33±3.78 145.50±3.51 51.87±1.18 46.43±12.91

From Table 9, the terms of polynomial equation showed significant different if p-value displayed less than 0.05 at 95% level confidence. The terms of polynomial equation showed significant different if p-value displayed less than 0.05 at 95% level confidence. However, the interaction terms and second order quadratic terms revealed no significant influence (p>0.05). In addition, the independent factors affecting the output might be discussed subsequently in the equations.

Table 9 Polynomial equation and the coefficients for DT, WT, Hardness, contact angle and SFE

DT WT Hardness contact angle SFE Term p- p- p- p- p-

coefficient value coefficient value coefficient value coefficient value coefficient value

bo 133.81 0.0001 184.84 00000 151.42 0.0000 33.16 0.0006 56.00 0.0000

bl 72.94 0.0105 41.39 0.0204 -21.65 0.0147 38.46 0.0052 -17.47 0.0080

b2 84.99 0.0069 118.57 0.0010 20.01 0.0182 13.34 0.0843 -6.85 0.0893

bl2 14.95 0.4081 -11.68 0.3750 -15.61 0.0578 -1.60 0.8189 -0.73 0.8435

bll -4.33 0.7206 -4.55 0.6072 -5 .99 0.2027 8.74 0.1498 -2.55 0.3646

bn 14.75 0.2732 42.78 0.0126 9.08 0.0905 3.93 0.4505 ·1.95 0.4754

70

Factorial Equation for DT and WT The fitted full equations relating the DT and WT to the transformed factors were

as: DT=133.81 +72.94XI+84.99X2+ 14.95XIX2-4.33XI2+ 14.75Xi (R2=0.9640) ... (13) WT = 184.84+41.39XJ+118.57X2-11.68XIX2-4.55XI2+42.78Xi (R2=0.9864) ... (14)

From the equations 13 and 14, increasing the concentration of SSF caused a

slowing of the DT and wetting time. However, owing to the more hydrophilicity ofSSF than mg-st the tablets containing SSF showed shorter DT (De Boer et al., 1978; Kanugo et al., 2013; Perrault et al., 2011) as well as an increase in the compression force increase in the DT and WT due to greater condensed compactness of tablets (Late et al., 2009).

Factorial equation for hardness. Hardness=151.42-21.65XI+ 20.01X2-15.61XIX2-5.99XI2+9.08Xi (15)

(R2=0.9564) ... .

For the tablets containing SSF, from equation 15, the hardness of the tablets decreased

with increasing amount of SSF due to reduction of interparticle bonding (J. Wang et al., 2010; Zuurman et al., 1999). Moreover, increasing the compression force also increased the hardness due to high density of tablets (Rotthiiuser et al., 1998). These results could be confirmed by SEM study which the results of surface topography were similar to the tablet containing mg-st. The SEM photographs displayed that the formulation with increasing compression force (Fig. 27b, d, f) was smoother than the formulation at low compression force (Fig. 27a, c, e).

71

c d

Fig. 27 SEM of CD surface tablets contammg 0.25% w/w SSF prepared (a) at compression force of 1 ton/cm2 (b) 5 ton/cm2 and tablets containing 2.5% w/w SSF prepared (c) at compression force of 1 ton/cm2 (d) 5 ton/cm2 and tablets containing 5% w/w SSF prepared (e) at compression force of 1 ton/cm2 (f) 5 ton/cm2

Factorial Equation for contact angle and SFE Contact angle= 33.16+38.46Xt+13.34X2-1.60XIX2+8.74XI2+ 3.93Xi (R2=0.9553) .. (16)

From equation 16, the contact angle increased with increasing amount of SSF and compression force. It related to the result of Raman mapping and SEM studies. The high compression force led to large surface area of lubricant which retarded the wetting of tablets. Besides, increasing the compression force also increased the hardness of tablets.

SFE = 56.00-17.47XI-6.85X2-0.73XIX2-2.55XI2-1.95Xi (R2=0.9407) ..... (17) The equation 17 showed that SFE decreased with the increase the concentration

of SSF and compression force. The tablet composed of0.25% w/w SSF at compression force of 1 ton/cm2 (Fig.

28A) displayed a larger polar surface free energy; on the other hand, the tablet containing 5% w/w SSF prepared at compression force 1 ton/cm2 showed a larger dispersion of surface free energy (Fig. 28F) relating with its slow WT and DT. Linear correlation between WT of tablets and the polar component has been previously reported (Riippi et al., 1998; Rotthauser et al., 1998; Yoshihashi et al., 1998).

72

60

;;;..... 50 bll l-o 40 ~

= ~ ,-... 30 N

~ e ~-~~ 20 ~ E c:J

,_, 10 ~

l-o

= 0 rLJ

A B c D E F

Formula

Fig. 28 Polar and dispersive component of SFE of tablets containing 0.25% w/w SSF prepared (A) at compression force of 1 ton/cm2 (B) 5 ton/cm2 and tablets containing 2.5% w/w SSF prepared (C) at compression force of 1 ton/cm2 (D) at compression force of 5 ton/cm2 and tablets containing 5% w/w SSF (E) at compression force of 1 ton/cm2

and (F) 5 ton/cm2

Although, the hardness of tablets containing mg-st and SSF was decreased when increasing the concentration of lubricants (Fig. 29A), the tablets containing SSF exhibited a minute impact on hardness. In general, the energy consumption was involved in the powder bed compaction. This event could be regarded as endothermal process whereas the bond formation was an exothermal event. When the mechanical stress was applied, the hardness of tablets depended on different factors such as, the elasticity and plastic characteristics of the material, changes in porosity, density and anisotropic force distribution within the compacted tablet. Moreover, lubricant at appropriate levels could enhance and normalize the relative transmission of forces within the die cavity as previously reported (Dlirig et al., 1997). Moreover, the brittle material caused a formation of new surface due to fragmentation, extensive and strong interparticulate bonding and formation of solid bridges during compaction (Hiestand et al., 1984). In addition, the increased hardness with increasing levels of SSF could be explained on the basis of an improved volume reduction, and consolidation behavior. It is involved in the formation of new surfaces and denser compacts by bridging the particle surface areas into closer proximity, and an increasing compression force results in more cohesive compacts (Late et al., 2009; Rotthauser et al., 1998). Increasing the concentration of mg-st within tablets decreased the tablet hardness because this enhanced volume reduction and ability to consolidate by greater particle surface interfering with in the bonding formation (Late et al., 2009). SSF had less effect on

73

disintegration time when the concentration of SSF is increased (Fig. 29B) because of

the more hydrophilic property of SSF.

160

z14o ._, ~ ~

~ 120 "'0 :0. = 100

-*-mg-st _.SSF

80 ._-------.--------~------~ 0

290

250

210 ,-.., CJ

~ 170 ._, ~ ~ 130

90

50 0 1

2 4

Lubricant (0/ow/w)

A

2 3 4

Lubricant (0/o w/w)

B

6

-+-mg-st

-+-SSF

5 6

Fig. 29 Effect of amount and type of lubricant of tablets prepared at compression

force of 1 ton/cm2 on: (A) hardness and (B) DT (n=l 0)

Besides, the validity of the above equation was verified by designing the check

point formulation (C1 and C2) and determining the DT, WT, hardness, contact angle,

SFE and dissolution profile. The dependent variables predicted from the derived

equation and those observed from experimental results are summarized in Table 10 and

Table 11 . The closeness of the predicted and observed values for formulation C in the

74

method indicated the validity of derived equations for the dependent variables as previously mentioned (Swamy et al., 2008) which the equation of FDT of

carbamazepine were verified by designing two check point formulations. The closeness

of the predicted and observed values indicated validity of derived equations for the dependent variable. In our research, the closeness of the predicted and observed values for check point formulation in the method indicated a good validity of derived equations for the dependent variables.

Table 10 Evaluation properties of check point formulation of tablet containing mg-st

(CI)

Dependent variables Predicted value Observed value

DT (sec) 94.59 100.33

WT (sec) 53.84 59.44

Hardness (N) 148.42 139.47

Contact angle (0) 21.21 18.20

SFE (mJ/m2) 61.30 66.61

Table 11 Evaluation properties of check point formulation of tablet containing SSF

(Cz)

Dependent variables Predicted value Observed value

DT (sec) 65.69 69.50

WT (sec) 92.23 89.33

Hardness (N) 139.26 134.87

Contact angle (0) 13.22 16.15

SFE (mJ/m2) 65.29 63.93

75

2.5.5. In- vitro dissolution profile of prepared CD FDT The tablets of check point formulation using SSF as lubricant showed

greater amount of drug released than that containing mg-st; therefore, SSF displayed less effect of the drug dissolution (Fig. 30). Structurally, the lubricants commonly used for boundary lubrication are long chain molecules with active end groups such as stearic acid and its metallic salts such as mg-st. The lubricant film formation could

prevent further contact between the intended surfaces and powder particles which mg-st needs to be sufficiently thick to cover the surface, typically a few layers (Bowden et al., 2001; J. Li et al., 2014). Accordingly, mg-st could cover the area larger than SSF

which mg-st resulted in obstruction ofwetting of prepared tablet.

120

100 - i,.....:i-•-• i i

80 .... ,-! ! ! ! ! • .L

-+-mg-st '"0 60 - .•-SSF ~

> -0 40 'I] 'I] ·-~ 20

'S. 0 0 ·1!!1

0 20 40 60 Time (min)

Fig. 30 Comparative dissolution profiles of check point tablets prepared at compression force of 1 ton/cm2

: +tablets containing 1% w/w mg-st, • tablets containing 1% w/w SSF (n=6)

3. Preparation of CD FDT containing taste masking of drug by inclusion complex Direct compression method was used to prepare the tablets of CD. Complex

equivalent to 10 mg of drug was taken along with diluent. Ludiflash®, Aerosil 200,

Alubra®, aspartame, menthol and lemon flavor were used as fast disintegrating diluent, glidant, lubricant, sweetening and flavoring agent, respectively. All the ingredients (as given in the Table 12) except lubricant were weighed and passed through 30 mesh. And then, the powders were mixed geometrically in plastic bottle. Finally, Alubra® was added and mixed in plastic bottle. Tablets were compressed on single punch tablet

machine using round concave punch of 9 mm diameter. The hardness of the tablet was maintained at 2-3 kPa.

76

Table 12 Formula of CD FDT

Formula mg/tab

CD/~-CyD complex equivalent to 10 mg of CD 70.17

Alubra® 4

Aerosil200 0.2

Aspartame 4

Menthol 0.4

Lemon flavor 2.4

Ludiflash® 138.83

Total 220

3.1. Evaluation of CD FDT containing inclusion complex The percentage of weight variation was within the prescribed official limits.

Assay was found to be in the range of 97-98% (Table 13) within the acceptable limit.

Content uniformity was shown in the 13. The low value of standard deviation indicated

the uniformity drug content. The disintegration time of tablets was less than 60 sec. The disintegration time of the FDT in the mouth of the volunteers was 33 sec (Table 13) thus a fast disintegration had been successfully achieved.

Table 13 Evaluation of CD FDT

Properties of FDTs

Assay(%) (n=20)

Content uniformity(%) (n=IO)

Disintegration time (sec) (n=6)

Oral disintegration time (sec) (n=6)

Results

97.67±0.38

98.69±1.34

31.33±1.37

33.83±4.49

3.1.1. In vivo disintegration time and taste masking palatability FDT was evaluated for its taste by the panel with 6 volunteers informing

that CD/~-CyD FDT showed good taste and tasteless ofbitter. CD/~-CyD FDT showed an average rating of 0.28 (SD=0.26) as showed in Fig. 31 and had significantly

77

difference from CD in Fig. 32 (p-value < 0.05). Moreover, all the volunteers experienced a good feeling in the mouth when FDT dissolved in the mouth with a minimum of grit. FDT had the fragrance of lemon and mint with sweet taste of aspartame. In conclusion, FDT ofCD/p-CyD exhibited good palatability.

II no bitterness strongly bitter

Fig. 31 Evaluation ofthe bitterness ofCD/p-CyD FDT by the healthy volunteers (n=6)

14

12 "" 0 10 .... i: 0 ~ 8 ..c "- 6 e Q > 4 0

......:;

2

0

* 0 .28

CDvsCDFDT

Formula

Fig. 32 Comparison of bitterness level where(*) indicates significantly difference from the other samples (analyzed by R-stat at p value< 0.05) (n=6)

3.1.2. In- vitro dissolution profile The in vitro drug dissolution of tablets was 99.5% within 10 min (Fig.

33). The standard equation of cetirizine dihydrochloride in range of 1.1-22 !J,g/ml using HPLC analysis was y = 92,105 .49x + 71.16 with r2 = 0. 9991. The in vitro drug release from tablets was 99.5% within 10 min. The drug dissolution profile of tablets was shown in Fig. 30.

120 "'0 100 Q)

> 80 -0 t"l.l 60 t"l.l ·-~ 40

'S. e 20 0

0 5 10 15 20 25 30 45 60

Time (min) Fig. 33 Dissolution study of CD FDT (n=6)

-+-CDFDT -A- Commercial

78

Moreover, the standard equation of commercial tablet in range of 1.1-22 ).lg/ml using HPLC analysis was y = 18,869.22x + 1.45 with r2 = 0.9993. The release profiles ofthe CD FDT and commercial CD tablet were 92.16% and 49.16% at 10 min of dissolution test, respectively, and both of CD FDT and commercial CD tablet were completely dissolved within 10 min and 20 min, respectively. The f2 value was 28.21 and fl was 23.31 which the dissolution profile of CD FDT and commercial CD tablet were different (V; Abbirami et al. , 2013). This result indicated that the CD FDT was the fast disintegrating formulation.

Therefore, ~-CyD could be used as the host for inclusion complexation, and kneading method was used to prepare the CD/~-CyD inclusion complex. Ethanol was used as solvent for kneading method because it dissolved both CD and ~-cyclodextrin.

Complex occurerd more rapidly when the guest compound was in the soluble form. Moreover, the more soluble the cyclodextrin in the solvent, the more molecules become available for complex. Furthermore, the solvent should not complex well with cyclodextrin and be easily removed by evaporation (K.P. Sambasevam et al., 2013). Ethanol was good example of such solvent.

Chapter 5

Conclusion

CD/~-CyD inclusion complex was attained successfully with kneading method using ethanol as solvent. All the data obtained from the FT-IR, DSC, X-ray diffraction, TGA, simultaneous XRD-DSC measurement, 1 H NMR spectroscopy and SEM studies confirmed the formation of an inclusion complex. In addition, inclusion complex reduced a bitter taste of CD after tested with an unstructured line scale. The taste evaluation by human volunteers showed that the CD/~-CyD FDT had good taste, good perception in the mouth and tasteless of bitter.

Consequently, Avicel®, xylitol, chitin and chitosan were tested to use as disintegrant in FDT. From evaluation properties of tablet, the tablets containing the mixture of xylitol and other materials were subsequently fabricated. An incorporation of the other excipients could enhance the hardness of the xylitol tablet. Therefore they exhibited as suitable material for FDT. This revealed that the tablets containing xylitol or sugar alcohol and Avice!® could be employed as disintegrant for FDT.

Spatial distribution of mg-st and SSF obtained from Raman mapping and SEM/EDX showed that the higher distribution of lubricants in CD FDT was evident when the more amount of lubricants or higher compression force were used. Therefore, the increasing compression force affected the distribution of lubricant in the tablet. Consequently, the application of high compression force promoted more distribution of lubricant than using low compression force. To compare with mg-st, SSF was used as lubricant in the tablets with the same conditions. The 32 full factorial design and evaluation of CD FDT signified that SSF was the more suitable lubricant for FDT than mg-st owing to its less impact on tablet properties especially DT and drug dissolution.

Finally, CD/~-CyD FDT was fabricated and investigated for their tablet properties. The disintegration time of tablets was less than 60 sec with fast drug dissolution. FDT was evaluated for its taste by the panel which 6 volunteers who informed that CD/~-CyD FDT exhibited the good taste without bitterness. Moreover, all the volunteers experienced a good feeling in the mouth when FDT dissolved in the mouth with only a minimum of grit.

79

80

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Appendix I

HPLC and Drug release data

Calibration curve of CD

Standard curve of CD 1800.00 .-----------------------------,

1600.00

Gl 1400.00

:g 1200.00 0 ~1000 00 2! 'E 800.00

~ 600.00

lij 400.00 en 200.00

y = 921 05.4922x + 71.1571 R2 = 0.9991

0.00 t__ _ ___, __ _.... __ __,_ __ _,_ __ _._ __ _,__ __ ....__---''------1

93

0.0000 0.0020 0.0040 0.0060 0.0080 0.0100 0.0120 0.0140 0.0160 0.0180

Concentration (mg/ml)

Fig. 34 Calibration curve of CD

Table 14 Raw data of percentage CD release from CD FDT Time

1 2 3 4 5 6 SD %RSD (min) mean

0 0 0 0 0 0 0 0 0 0

5 34.21 48.6 51.95 53.4 42.94 53.04 47.36 7.53 15.91

10 83.6 101.47 94.02 97.38 80.88 95.6 92.16 8.12 8.81

15 99.6 101.46 94.95 107.6 97.9 99.91 100.24 4.23 4.22

20 95.14 99.15 94.05 99.04 98.08 95.83 96.88 2.16 2.23

25 96.91 92.98 97.05 93.57 101.52 101.59 97.27 3.71 3.82

30 98.79 101.64 96.91 94.26 102.04 103.49 99.52 3.51 3.53

45 98.47 102.11 97.47 95.31 100.83 100.84 99.17 2.55 2.57

60 96.2 100.25 96.74 102.38 100.09 101.01 99.45 2.45 2.46

94

Table 15 Raw data of percentage CD release from commercial product Time

1 2 3 4 5 6 SD %RSD (min)

mean

0 0 0 0 0 0 0 0 0 0 5 12.48 11.35 17.66 15 .31 18.09 18.41 15 .55 3.04 19.55 10 40.88 48.03 53.52 47.61 51.22 53 .72 49.16 4.82 9.81 I5 77.71 84.62 85 .II 77.32 82 .16 82 .71 81.61 3.36 4.12 20 104.4 I00.43 104.54 100.07 I 01.35 105.3I 102.68 2.32 2.26 25 104.65 100.46 104.8 98.81 I03.63 103.67 102.67 2.46 2.39 30 103.62 96.36 I03.76 99.08 102.15 105.I6 I 01.69 3.33 3.28 45 102.8 99.66 I03.94 97.29 IOO.I5 I03.43 10 1.2I 2.60 2.57 60 I01.8 96.68 I 02 .I9 96.42 98.38 100.54 99.34 2.54 2.55

Table 16 Raw data of assay

Sample AUC %CD A 4563.8 98.1 B 4523.4 97.38 c 4523.4 97.54

mean 97.67 SD 0.378

%RSD 0.387

Table 17 Raw data of content uniformity

Sample AUC 0/o

CD 1 4234 100.5 2 4112 97.56 3 4220 100.1 4 4160 98.69 5 4096 97.18 6 4235 100.5 7 4131 98 8 4141 98.25 9 4084 96.9 10 4184 99.27

Mean 98.69 SD 1.338

%RSD 1.356

95

Appendix II

In vivo disintegration time and taste masking palatability

Table 18 Evaluation of bitterness score by volunteer

Volunteer CD PM Com[!lex 1 11.60 8.20 1.50

2 11.40 8.00 1.80 ,.,

11.60 8.60 1.40 .)

4 11.40 8.80 2.00 5 11 .50 8.40 1.70

6 11.60 8.40 1.80

mean 11.52 8.40 1.70

SD 0.10 0.28 0.22

median 11.55 8.40 1.75

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96

Name

Date of Birth

Place of Birth

Nationality /Religion

E-mail address

Education

2009-2013

2004-2008

Scholarship

2010-2015

Publications

97

Biography

Prachya Katewongsa, Mr.

May 23, 1987

Ratchburi, Thailand

Thai/Buddhism

billkatemedpharm498@gmail.com

Doctor of Philosophy, Ph.D. in Pharmaceutical Technology Silpakorn University, Thailand

Bachelor of Pharmacy Silpakorn University, Thailand

Thailand Research Funds through the Golden Jubilee Ph.D. Program (Grant No. PHD/0052/2552)

1. Prachya Katewongsa and Thawatchai Phaechamud. 2012. Influence of disintegrant on properties of fast disintegrating tablet containing xylitol. Advanced Materials Research. 581-582: 1141-1144.

2. Prachya Katewongsa and Thawatchai Phaechamud. 2012. Cetirizine dihydrochloride tablets comprising two different lubricants with highly loaded colloidal silicon dioxide. Journal ofMetals, Materials and Minerals. 22(2): 13-18.

3. Prachya Katewongsa, Thawatchai Phaechamud and Lawan Sratthaphut. 2014. Artificial neural network for solid dosage form applications. Thai Pharmaceutical and Health Science Journal. 7(3): 143-147.

98

Presentation (Poster)

1. Prachya Katewongsa and Thawatchai Phaechamud. 2012. Cetirizine dihydrochloride tablets comprising two different lubricants with highly loaded colloidal silicon dioxide. The 7'11 International Conference on Materials Science and Technology (MSAT-7) , National Metal and Materials Technology Center (MTEC), Miracle Grand Convention, Bangkok, Thailand, 4-5 June 2012. (poster)

Name

Date of Birth

Place of Birth

Nationality /Religion

E-mail address

Education

2009-2013

2004-2008

Scholarship

2010-2015

Publications

97

Biography

Prachya Katewongsa, Mr.

May 23, 1987

Ratchburi, Thailand

Thai/Buddhism

billkatemedpharm498@gmail.com

Doctor of Philosophy, Ph.D. in Pharmaceutical Technology

Silpakom University, Thailand

Bachelor of Pharmacy Silpakom University, Thailand

Thailand Research Funds through the Golden Jubilee Ph.D. Program (Grant No. PHD/0052/2552)

1. Prachya Katewongsa and Thawatchai Phaechamud. 2012. Influence of disintegrant on properties of fast disintegrating tablet containing xylitol. Advanced Materials Research. 581-582: 1141-1144.

2. Prachya Katewongsa and Thawatchai Phaechamud. 2012. Cetirizine

dihydrochloride tablets comprising two different lubricants with highly loaded colloidal silicon dioxide. Journal of Metals, Materials and Minerals. 22(2): 13-18.

3. Prachya Katewongsa, Thawatchai Phaechamud and Lawan Sratthaphut. 2014.

Artificial neural network for solid dosage form applications. Thai Pharmaceutical and Health Science Journal. 7(3): 143-147.

98

Presentation (Poster)

1. Prachya Katewongsa and Thawatchai Phaechamud. 2012. Cetirizine dihydrochloride tablets comprising two different lubricants with highly loaded colloidal silicon dioxide. The ?" International Conference on Materials Science and Technology (MSAT-7), National Metal and Materials Technology Center (MTEC), Miracle Grand Convention, Bangkok, Thailand, 4-5 June 2012. (poster)