International Journal of Innovative Pharmaceutical ... · Drug - Excipient Compatibility Study ......

RESEARCH ARTICLE B.Sumadeepthi et.al / IJIPSR / 2 (10), 2014, 2425-2437

Department of Pharmaceutics ISSN (online) 2347-2154

Available online: www.ijipsr.com October Issue 2425

IN-VITRO EVALUATION OF NEWLY FORMULATED

METAXOLONE TABLETS FOR IMMEDIATE RELEASE BY

WET GRANULATION TECHNIQUE

1B.Sumadeepthi*,

2G.Nagaraju,

3M.Ramakotaiah,

4M.Prasad Rao

Department Of Pharmaceutics, MAM College of Pharmacy, Narasaraopet, Guntur Dt., Andhra

Pradesh, India-522601, INDIA

Corresponding Author:

B.Sumadeepthi

Department of Pharmaceutics,

MAM College of Pharmacy,

Narasaraopet, Guntur Dist.,

Andhra Pradesh – 522601, INDIA

Email: [email protected]

Mobile: +919441502505

International Journal of Innovative

Pharmaceutical Sciences and Research www.ijipsr.com

Abstract

This dissertation work was done with an aim to design an immediate release oral dosage of

Metaxalone and evaluation of the tablets including in vitro drug release studies. Metaxalone tablets were

formulated by using corn starch (diluents & disintegrant), alginic acid (binder), ammonium calcium

alginate (disintegrant) and magnesium stearate (lubricant). The granules were compressed into tablets

and were analyzed for the parameters such as average weight, disintegration time, friability, thickness,

weight variation, hardness, moisture content and drug content. The formulation F5 and F8 showed

improved disintegration time when compared to innovator product. The dissolution profile of the

formulation F8 was found to have equivalent percentage drug release with that of the innovator product

(f2=.70.8% and 96.79%)The formulation F8 and process can be easily scaled up and can be easily

employed in large scale production because the process is simple, cost effective and precise and also

yields reproducible good tablets.

Keywords: Metaxalone, Immediate Release, Skeletal Muscle Relaxant, Wet granulation




INTRODUCTION

The goal of any drug delivery system is to provide a therapeutic amount of drug in the proper site

in the body to achieve promptly and then to maintain the desired drug concentration. That is, the

drug delivery system should deliver drug at a rate dedicated by the needs of the body over a

specified period of treatment [1]. Difficulty in swallowing (Dysphagia) is a common problem in

all age groups, especially the elderly and pediatrics, because of physiological changes associated

with these age groups. It is common to see those afflicted carrying a small device with them,

which is used for crushing tablets, enabling easy ingestion. Other categories that experience

problems using conventional oral dosage forms include are the mentally ill, uncooperative and

nauseated patients, those with conditions of motion sickness, sudden episodes of allergic attack

and coughing. Sometimes, it may be difficult to swallow conventional products due to

unavailability of water. These problems led to the development of a novel type of solid oral

dosage form called mouth-dissolving tablets, which disintegrate and dissolve rapidly in saliva

without the need of the water. They are also known as fast dissolving tablets, melt-in-mouth

tablets, rapimelts, porous tablets, oro-dispersible, quick dissolving or rapidly disintegrating

tablets. Since 1986 when the Zydis® lyophilized, fast-dissolving dosage forms were first

introduced, a number of other fast-dissolving formulations were developed, and the technology is

still improving. Using the concept of Gregory et al [2], Scherer has patented the Zydis

technology. Using the freeze-drying process, this technology converts the mixture of active

ingredient and water dispersible carrier materials into open matrix network that disintegrates

rapidly [2-4].

MATERIAL AND METHODS

Metaxalone is Skeletal muscle relaxant it was obtained as a gift sample from Richer

Pharmaceuticals,. Corn starch, Ammonium calcium alginate Alginic acid, obtained as gift sample

from FMC, Norway, Mumbai., Magnesium stearate, purified water as gift sample from

universal chemicals from,Hyderabad. all the chemicals and reagents used were analytical

grade.Infrared spectra were recorded for pure drug and optimized formulation using a shimadzu

FTIR 8300 spectrophotometer and the spectrum was recorded in the region of 4000 to 400.

Pre-Formulation Studies [7,8]

Drug - Excipient Compatibility Study

The objective of drug/excipient compatibility considerations and practical studies is to delineate,

as quickly as possible, real and possible interactions between potential formulation excipients and




the API. This is an important risk reduction exercise early in formulation development.

Homogenous mixtures of drug and excipients were prepared and filled in glass vials and self-seal

LDPE (Low Density Poly Ethylene) bags.

Conditions:

a) Samples packed in glass vials were maintained at 60 2°C for 2 weeks.

b) Those packed in LDPE bags were maintained at 40 2°C / 75 5% RH for 1 month.

The Results of particle size distribution of Metaxalone was tabulated in Table.

Remaining all the pre formulation studies like( Solubility Loss on Drying, Melting point, Bulk

density, Tapped density, Carr’s Index, Hausner’s Ratio, Angle of repose, Moisture content)

are conducted.

Formulation of Metaxalone Immediate Release Tablets Wet Granulation Method [9-12]

Sifting: Sift Metaxalone, alginic acid, ammonium calcium alginate and corn starch through mesh

#40 separately. Sifted materials of Step no.1 are mixed together and re-sifted through #40 Dry

mixing: Metaxalone was divided into two parts. To the first part, dry mix materials were added

and taken in a poly bag, mixed well. Then second part was added and blend for 5 min.

Binder solution Purified water was taken in a suitable stainless vessel and pre-heated to 55°C-

65°C and then corn starch was added to form a paste. Mixing was continued till all the particles

formed a consistent dispersion. Remainder quantity of purified water was added to form a smooth

corn starch paste and cooled below 30°C. The paste was mixed for 20minutes.

Granulation Granulate the dry mix of Step no.2.1 by adding binder paste of Step no.3 to obtain

wet granules.

Drying & Sifting Loaded the wet mass into rapid dryer at temperature of 60°C ± 5°C. Seived the

dried granules through mesh #16.

Extra granular sifting Corn starch and magnesium stearate are sifted separately through the

mesh#40.

Pre-Lubrication Loaded the sifted materials of step no.5 and sifted material of corn starch into a

suitable blender and blend for 10 minutes.

Lubrication Loaded the sifted Magnesium Stearate of step no.6 and step no.7 into polythene bag

and mixed for 10 minutes.

Compression The lubricated blend of step no.8 was compressed using following parameters:




Compression parameters

Tooling: 19.1 x 7.9 mm caplet shaped punches embossed “8667” on upper punch and “S” on

lower punch. Average weight: 930 mg .all the formulation key ingradents was shown in in the

table.1.

Table 1: Composition Different Formulations

Evaluation of prepared tablets

Mainly performed the fallowing evaluation tests like (Physical appearance, Hardness test,

Tablet size and Thickness, Weight variation of Tablets).

S. No

Ingredients

(mg)

F1

F2

F3

F4

F5

F6

F7

F8

Dry mix

1. Metaxalone 800 800 800 800 800 800 800 800

2. Corn starch 64.90 32.26 32.26 34.63 36.63 15.63 26.63 12.63

3. Ammonium

calcium

alginate

15.00 0.00 10.72 10.72 8.72 10.72 10.72 10.72

4. Alginic acid 36.87 13.87 0.00 12.00 12.00 12.00 12.00 40.63

Binder solution

5. Corn starch 0.00 45.00 45.00 45.00 45.00 45.0 35.00 43.00

6. Purified

Water

Q.S Q.S Q.S Q.S Q.S Q.S Q.S Q.S

Pre lubrication

7. Corn starch 0.00 23.50 23.50 23.00 23.00 42.00 43.00 27.00

8. Ammonium

calcium

alginate

0.00 10.72 0.00 0.00 0.00 0.00 0.00 0.00

9. Alginic acid 0.00 0.00 13.87 0.00 0.00 0.00 0.00 0.00

Lubrication

8. Magnesium stearate 10.00 4.65 4.65 4.65 4.65 4.65 4.65 4.65




Disintegration test:

Disintegration time is considered to be one of the important criteria in selection the best

formulation. To achieve correlation between disintegration time in-vitro and in-vivo, several

methods were proposed, developed and followed at their convenience. One tablet was placed into

each tube and the assembly was suspended into the 1000ml beaker containing water maintained at

37±0.5oc and operated the apparatus for 15 minutes. The assembly was removed from the liquid

and the tablets were observed. If one or two tablets fail to disintegrate completely, repeat the test

on 12 additional tablets. The requirement is met if not less than 16 of the total of 18 tablets tested

are disintegrated.

Dissolution test:

Dissolution parameters: Medium: Purified water+0.5%SLS, Volume: 900ml, Apparatus: USP

type II (Paddle type),Speed: 100 rpm,Temperature: 37 ± 0.5°C,Sampling intervals: 15, 30, 45, 60,

90 & 120 min (for profile

ASSAY: The assay of Metaxalone tablets was carried out by using HPLC method

Stability Studies [5, 12]:

FDA and ICH specifies the guidelines for stability testing of new drug products, as a technical

requirement for the registration of pharmaceuticals for human life. The ICH tripartite guidelines

have established long term stability testing to be done at 250C/60%RH for 12 months. Accelerated

stability testing should be done at 400

C/75%RH for 6 months stability testing at intermediate

storage condition should be done at 300C/65%RH the following table shows different storage

conditions and period of stability testing.

Comparision of Dissolution Profiles

Model independent approach:

According to US FDA guidance for dissolution data equivalence, model independent approach is

recommended. This involves the use of similarity (f2) and dissimilar factor (f1) which provides

simple means to compare the dissolution data.

Similarity factor (f2):

The similarity factor f2 was defined as a logarithmic reciprocal square root transformation of the

sum of squared error and is a measurement of the similarity in the percent (%) dissolution

between the two curves. This was calculated to compare the test product and reference product

with respect to the drug release or dissolution profiles. It was calculated data according to the

following equation:




f2 = 50 × log {[1+ (1/n) ∑t=1 n (Rt - Tt)2]-0.5

×100}

Where, n = number of full time points

Rt = The reference profile at the time point t

Tt = the test profile at the same point t

The method is more adequate to compare the dissolution profiles when more than three or four

dissolution time points are available and can be applied if average difference between Rt and Tt is

>100.

Dissimilarity factor (f1):

It is also called as Difference factor. It describes the relative percentage error between two

dissolution profiles. The percent error is zero when the test and reference profiles are identical and

increases the proportionality with the dissimilarity between the two profiles.

f1 = {[∑t=1 n (Rt-Tt)] / ∑t=1 n Rt]} ×100.

RESULTS

Bulk density and tapped density values were found to be within limits. Compressibility index has

been proposed as an indirect measure of bulk density, size and shape, surface area and

cohesiveness of material. The powdered blend has required flow property. Hausner’s ratio [the

quotient of bulk and tapped density] express the relative mechanical compression of granules.

With the help of Hausner’s ratio, attempts can be made at predicting both extent of compression

and the flow problems.Visually examined tablets from each formulation batch showed caplet

shaped concave punches embossed “8667” on upper punch and “S” on lower punch Hardness of

each formulation was analyzed. The formulations F2, F3, F4, F5, F6, F7, and F8 were found to

have good hardness so they were taken for further studies. The measured hardness of tablets of

each batch range between 135 to 150 N.Tablets mean thickness were almost uniform in all

formulations and were found to be in the range of 6.9mm to 7.2mm.Friability values are found to

be less than 0.06% in all the cases and considered to be satisfactory.

The total weight of each formulation was maintained constant and the weight variation of the

tablets was within limits of 5%.

Drug-excipient compatibility studies [6]

Appropriate quantities of the drug and excipients were weighed. The weighed drug and excipients

were blended physically and transferred to glass vials and sealed. The sealed mixture blend were

then kept at 25C/60%RH, 30C/70%RH and 40C/75%RH for a period of 4 weeks and tested for




various parameters at predetermined intervals as shown in Table 2. DSC thermo graphes are

shown in figure 1,2,.

Table 2: Drug and Excipient compatibility blend ratio

Name of the ingredient Drug : Excipient blend

ratio

Metaxalone 80

Ammonium Calcium alginate 1

Alginic acid 5

Corn starch 13.0

Magnesium stearate 1

Fig. 1: DSC Thermogram of Metaxalone (API)

Figure 2: DSC Thermogram of compatibility blend

In vitro dissolution profile of the innovator (SKELAXIN 800mg) in various medium were

shown in the following table 3.and figure 3.




Table 3: In vitro dissolution profile of the innovator (SKELAXIN 800mg) in various

medium

Time

(mins)

% Drug dissolved (900ml, USP II apparatus, 37 ± 0.50C)

Purified water

with 0.5% SLS

SGF without

Enzyme with 0.5%

SLS

pH 4.5 acetate

buffer with

0.5% SLS

0.05M Sodium

dihydrogen phosphate

(pH 6.8) buffer with

0.5% SLS

0 0 0 0 0

15 18.0 ± 9.1 1.0 ± 19.1 19 ± 7.98 15.1 ± 8.36

30 43.0 ± 2.9 1.7 ± 21.6 42.95 ± 3.27 35.27± 7.98

45 65.6 ± 2.3 2.5 ± 23.6 67.19 ± 5.30 54.01 ± 7.23

60 81.1 ± 1.7 3.4 ± 25.9 81.4 ± 4.16 71.77 ± 5.24

90 92.9 ± 4.2 5.0 ± 32.3 93.99 ± 2.92 89.5 ± 2.9

120 95.9 ± 1.3 6.3 ± 35.8 101.14 ± 1.57 94.6 ± 3.56

Figure 3: Dissolution Profile of Skelaxin in different dissolution medium

Invitro Dissolution study of all the formulations:




The first trial was performed using direct compression and it was observed that the flow of the

blend was poor; weight variation of tablets was observed. In order to overcome this problem next

trial were planned using wet granulation process by incorporating the following changes.

1. Distributing corn starch both in intra and extra granular portions to improve the flow of

the blend by keeping the same tablet weight i.e. 930mg.

2. Ammonium calcium alginate was added extra granularly (we assumed that it acts as

disintegrant)

3. Magnesium stearate concentration was decreased to 0.5%.

In the second trial the physical parameters were found to be satisfactory, but drying stage is

difficult. Drying time and LOD need to be optimized. In vitro dissolution release was decreased

than first trail. As per Innovator`s specification the release in the acidic medium should be less

than 10% and in purified water should be 96-99%. Hence we have planned to check the release in

both the mediums. Next trial was planned by incorporating alginic acid extra granularly.

In the third trial the compression parameters were found to be satisfactory and no manufacturing

issues were observed. Dissolution of the test product in both the mediums was observed to be on

lower side when compared to the innovator and disintegration time was found to be within the

limits. In order to improve the dissolution of the test product, the next trial was planned with the

following changes:

1. Alginic acid was added intragranularly.

2. Ammonium calcium alginate and alginic acid was added at 1:1.2 ratios.

In the fourth trial compression parameters were found to be satisfactory and no manufacturing

issues were observed. Dissolution of the test product was on the higher side when compared to the

innovator in water medium but in 0.1N HCl medium release was not good. Disintegration time

was found to be similar as the reference. Drying time & LOD was optimized here. Next trail was

planned to carry out by decreasing intra granular starch.

In the fifth trial no manufacturing issues were observed and the compression parameters were

found to be satisfactory. Since the dissolution and disintegration of the test product is similar to

reference, the next trial was planned to know the effect of increasing extra granular starch.

In the sixth trial compression parameters were found to be satisfactory and no manufacturing

issues were observed. Dissolution of the test product was on the higher side in 0.1N HCl medium.

In order to match the dissolution of the test product with the innovator at all the time points, the

next trial was planned by incorporating the following change:




Increasing the concentration of corn starch in intra granular portion from 15.63 mg to 26.63 mg.

In the seventh trial all the physical parameters were found to be satisfactory. The dissolution in

0.1N HCl is not achieved. The next trial was planned by incorporating the following changes:

1. Ammonium calcium alginate to alginic acid concentration was taken at 1:4 ratio.

2. Extra granular starch was decreased to 27 mg.

In the eighth trial all the parameters were found to be satisfactory and the dissolution

profile and DT of the test product was also matching with the innovator. Both F5 & F8 batches

are producing close results. Reproducibility batches carried out for both batches. Among two

optimized batches produced better results. Hence the formula of this batch was finalized for

further process optimization studies with same qualitative and quantitative composition. The

same samples were loaded for stability studies at different conditions. All the trails of drug

release were shown in table 4.and figure 4.

Table 4: In vitro dissolution studies of the formulations in Purified water + 0.5% SLS and

0.1N HCl ±0.5%SLS

S No

Trials

Medium

Mean percentage of Drug dissolved ± RSD

0

min

15

min

30

min

45

min

60

min

90

min

120

min

1.. F1 Water ND ND 45±1.5 65±1.2 81±2.3 92±1.6 96±1.8

pH1.2 - - - - - - -

2. F2 Water 0.0 8.2±1.2 17±1.8 22±3.2 27±2.6 35±.9 41±1.3

pH1.2 - - - - - - -

3. F3 Water 0.0 11±1.0 20±1.6 32±1.6 40±1.7 58±2.3 74±2.5

pH1.2 0.0 1.8±0.2 2.2±0.6 3.2±1.0 3.8±0.9 5.4±10 6.8±0.6

4. F4 Water 0.0 22±1.3 45±1.4 62±1.8 78±2.3 92±1.2 95±2.0

pH1.2 0.0 3.5±0.2 8.2±1.2 12±0.3 16±.9 22±1.4 26±1.5

5. F5 Water 0.0 15±0.0 41±0.9 58±2.1 73±1.5 89±3.2 94±2.5

pH1.2 0.0 1.0±0.5 1.7±0.1 2.4±0.9 2.8±1.5 3.6±15 4.4±2.2

6. F6 Water 0.0 27±3.0 60±1.5 81±1.5 92±1.8 96±3.5 96±2.1

pH1.2 0.0 ND ND ND ND 6.2±0.6 7.3±1.2

7. F7 Water 0.0 20±0.5 48±0.4 71±2.2 86±2.5 88±1.2 92 ±1.6

pH1.2 0.0 ND ND ND 2.8±0.1 3.6±0.3 8.9±0.6

8. F8 Water 0.0 17±0.7 45±2.5 68±1.6 84±2.3 99±2.0 99±1.2

pH1.2 0.0 1.2±0.2 2.3±0.6 3.5±0.2 4.0±0.3 4.9±0.3 5.8±0.9




Fig.4: Comparison of in-vitro dissolution profiles of all formulations (f1 to f8) to the

innovator in purified water+0.5%SLS medium

Fig. 5: Comparison of in-vitro dissolution profile of formulation (f8) and innovator in

Purified water+0.5% SLS medium

Stability study

From the below data shown in table 5, it was observed that, there is no much variation in all the

above data when stored at different storage conditions for 1 month.

Table 5: Data showing various physico- chemical parameters of optimized formulation F8

after one month stability study.

Conditions Parameter Initial data Data after one month

Room temperature

Hardness (N) 135 134

Friability (%) 0.04 0.05

Assay (%) 101.2 99.82

Intermediate

(30°C ± 2°C/ 70%

RH ± 5 % RH)

Hardness( N) 135 133


Assay (%) 101.2 99.37

Accelerated (40°C

± 2°C/ 75% RH ±

5 % RH)

Hardness (N) 135 134


Assay (%) 101.2 99.16




CONCLUSION

Metaxalone is a CNS depressant which is used as a skeletal muscle relaxant. In the present study,

Metaxalone tablets were prepared by wet granulation technique by using corn starch as a

disintegrant. Out of eight formulations, F8 formulation was found to be the best formulation

showing the drug release matched with that of the innovator (f2=70.8%).

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