FORMULATION AND EVALUATION OF ORAL SUPERSATURABLE …
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FORMULATION AND EVALUATION OF ORAL SUPERSATURABLE
SELF MICRO EMULSIFYING DRUG DELIVERY SYSTEM
ITRACONAZOLE
Pooja Dave1*, Brahmdutta Raval
2, Naisarg Pujara
3 and Tushar Gohil
4
1Assistant Professor, Parul Institute of Pharmacy and Research, Parul University, Vadadora,
Gujarat 391760, India.
2Supretendent Pharmacist, Government of Gujarat, Gujarat, India.
3School of Pharmacy, The University of Queensland, Brisbane, QLD 4102, Australia.
4Professor, Smt. Champaben Vasantbhai Gajera Pharmacy Mahila College, Amerli,
Gujarat 365601, India.
ABSTRACT
The present investigation was to formulate and evaluate of oral
Supersaturable self-micro emulsifying drug delivery system of
itraconazole for the treatment of fungal infection. Supersaturable self-
micro emulsifying drug delivery system was prepared by selecting oil,
surfactant and cosolvent ratio with HPMC as crystal growth inhibitor.
To enhance the dissolution, oral absorption and inhibit the crystal
growth of poorly water- soluble itraconazole, Supersaturable self-
micro emulsifying drug delivery system (SMEDDS) composed of oil,
surfactant and cosurfactant for oral administration of itraconazole was
formulated, and various evaluation tests were evaluated. Among the
surfactants and oils studies, castor oil, tween 20 and PEG400 were
selected that showed the maximal solubility of itraconazole. Phase diagrams were constructed
at different ratios of surfactant/co- surfactant (Smix) to determine microemulsion existence
region. Supersaturable Self micro emulsifying drug delivery system of Itraconazole may
provide a useful dosage form for oral water-insoluble drug without food effect, inhibit crystal
growth and reduces GI toxicity. Results of preformulation study were satisfactory as no
interaction was observed between itraconazole and various excipients by FTIR and DSC. All
the evaluation parameters were tested. In vitro drug release profiles were examined, and
compared with marketed product. The drug release of F12 batch is extended up to 95.66% in
WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES
SJIF Impact Factor 7.632
Volume 10, Issue 2, 1903-1921 Research Article ISSN 2278 – 4357
*Corresponding Author
Pooja Dave
Assistant Professor, Parul
Institute of Pharmacy and
Research, Parul University,
Vadadora, Gujarat 391760,
India.
Article Received on
19 Dec. 2020,
Revised on 09 Jan. 2021,
Accepted on 30 Jan. 2021
DOI: 10.20959/wjpps20212-18347
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120min. The droplet size of F12 is 42.20nm and zeta potential is negative (-28.51). SMEDDS
formulation significantly improved oral absorption of itraconazole, improve the solubility and
inhibit the crystal growth.
KEYWORDS: Supersaturable SMEDDS, Itraconazole, HPMC.
INTRODUCTION
Itraconazole is an orally active antifungal agent that acts primarily by inhibiting the
biosynthesis of ergosterol with broad-spectrum activity. It is weakly basic with a pka of 3.7,
and highly lipophilic, lop P>5 (m-octanol-aqueous buffer, pH 6). An oil-in-water emulsion
system formulation of ITC also effectively provided an improved absorption profile;
however, it still has limitations including poor physical stability and the requirement of large
volume intake.[1,38]
Self-microemulsifying drug delivery system (SMEDDS) are able to form microemulsion with
droplet size of less than 100nm under mild agitation, such as in the gastrointestinal tract.[1,2,3]
This property renders SMEDDS as good candidates for oral delivery of lipophilic drugs with
adequate solubility in oil/surfactant mixture.[9,10,11,12]
Additionally, SMEDDS has been
identified as a prominent technology for drug delivery, because the formulations have great
solubilization capacity, ease of production, enhanced the solvent capacity, increased stability
and potential to orally administer the final product as soft or hard gelatine capsules.[4,5,6,7]
Supersaturable SMEDDS formulations are SMEDDS formulations having decreases amount
of surfactant, and crystal growth inhibitor.[25]
The high concentration of surfactant (60% w/v)
in the formulation could show the way to severe GI Irritation.[25]
The Supersaturable
SMEDDS formulations generally contain a lower concentration of surfactant and a polymeric
precipitation inhibitor to yield and stabilize the drug in a provisional supersaturated
state.[28,31]
In an attempt to reduce the side effects of surfactants and maximize the intestinal
absorption of poorly soluble drugs, a Supersaturable self-emulsifying drug delivery system
was proposed.[28,31]
The precipitation inhibitors thermodynamically and/or kinetically prolong
the supersaturated state of active molecules in aqueous medium by reducing the rate of drug
nucleation and crystal growth through physical interactions with drug compounds or by
changing the medium properties. Supersaturable systems provide higher oral absorption and
fewer side effects as compared to that of the conventional SMEDDS. e.g., HPMC, PVP.[28,32]
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S-SMEDDS is developed by incorporating SMEDDS into inter solid pharmaceutical
excipients.[13,36]
Solidification methods for preparing S-SMEDDS include absorption to solid
carriers, spray drying, freeze drying, rotary evaporation, melt extrusion-spheronization, and
melt granulation. Among these methods, adsorption to solid carriers is a simple and easy
technique for small-scale preparation, offering a stable free-flowing S-SMEDDS. Water-
insoluble carriers and water-soluble carriers have been used to formulate drugs with poor
water solubility.[28,32]
However, the comparison of solidification capacity between water-
soluble carriers and water-insoluble carriers has not been studied extensively.[14,15,16,17]
In the present study, develop a novel Supersaturable solid self-microemulsifying drug
delivery system as micro crystalline cellulose as a solid carrier and evaluate the
Supersaturable S-SMEDDS improved the solubility.[18,19,20,21,22,23]
Reconstitution properties
of the formulation were investigate and compared to solid state characterization of the
powder using a scanning electron microscope (SEM), differential scanning calorimeter
(DSC), powder X-ray diffraction (PXRD), and Fourier transform infrared (FTIR)
spectrophotometer. Comparative dissolution, stability studies were also performed.[28,32]
MATERIALS AND METHODS
Materials
Itraconazole was purchased from Metrochem API PVT. LTD. (Hyderabad, India). Castor oil,
Tween 80, PEG 400, HPMC, Micro Crystalline Cellulose were obtained from Loba Chemie
Pvt. Ltd. (Mumbai, India). All other chemicals and solvents were of reagent grade and were
used without further purification.
Solubility Study
The select suitable components for the development of SMEDDS formulation, solubility
studies were conduct for a variety of oils and surfactants.[18]
A known amount of excess drug
(approximately 50 mg) was added to contain 3 mL of pure oils or 10% (w/v) aqueous
surfactant solutions. It was mix in cyclon mixer and kept at 25°C for 48 hours. After getting
equilibrium, each vial was centrifuged at 5000 rpm for 10 min furthermore excess insoluble
drug was separated by filtration using Whatman filter paper. Solubilized drug concentration
was quantified by UV spectroscopy along with Insoluble drug was weighed to confirm the
mass balance.[29,30]
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Construction of pseudo-ternary phase diagram
The Pseudo Ternary Phase Diagram is constructed by using expert systems to predict the
phase behaviour of multi-component Micro emulsion forming systems.[28]
To find out the
appropriate component in the formulation of o/w and w/o micro emulsions, safe and non-
toxic surfactants plus co-surfactants were used.[40]
The pseudo ternary phase diagram of oil,
surfactant, cosurfactant as well as water were constructed using water titration method to
obtain the components and their concentration ranges that can results in large existence area
of microemulsion.[28]
Surfactant was blended with co surfactant in predetermined weight
ratios (1:1, 2:1, 3:1, 4:1). Aliquots of every surfactant and co-surfactant mixture (Smix) were
then mixed with oil at room temperature (25⁰ C). For every phase diagram, the ratio of oil to
Smix was varied as 1:9, 2:8, 3:7, 4:6, 5:5, 6:4, 7:3, 8:2 and 9:1 (w/w). Water was added drop
wise to all mixture under vigorous stirring by using magnetic stirrer. Subsequently each
mixture was visually observed for clarity and flowability. No heating was applied during the
preparation; conversely well covered magnetic stirring was performed throughout the titration
process for a thorough mixing. Afterwards the data was plotted using Microsoft Excel and
phase diagram was obtained. Subsequent to the identification of micro emulsion region in the
phase diagram, the microemulsion formations were selected at desired component ratios. The
preparation of selected microemulsion was simply performed by adding up the weighed
components together and stirring to form a clear microemulsion.[40,41]
Preparation of liquid and solid SMEDDS
Determined amount of the itraconazole was dissolved in the obligatory quantity of oil,
Surfactant and cosurfactant in a fixed ratio. Ultimately, mixture was vortexed to obtain a
clear solution.[35]
The self- emulsification and particle size analysis were concluded after
examining the formulations for phase separation or signs of turbidity.[35]
Afterwards, 0.5 g of
the solid carrier (micro crystalline cellulose) was well dissolved in 100 mL of ethanol by
magnetic stirring; then 1 mL of liquid SMEDDS (equivalent to 100 mg of Itraconazole) was
magnetically stirred constantly.
Characterization of Supersaturable S-SMEDDS
Visual Inspection
This method is for self-emulsification assessment. In this method fix quantity of liquid self-
emulsifying mixture can mix with distilled water in presence of absence of mild agitation.[26]
Generally agitation represents the movement of gastrointestinal tract. Approximately 0.5 mL
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to 1 mL of liquid self-emulsifying formulation can mix with 200-500 mL of purified water
which is placed in USP type-II apparatus, at with lowest possible rotating paddle speed. Self-
emulsification is then evaluated by visual inspection for development of fine transparent
emulsion (dispersion) as well as time required for development of uniform dispersion.[30]
Determination of emulsification time
This process of self-emulsification was observed using light microscopy. It was clear that the
mechanism of emulsification involved erosion of a fine cloud of small particles from the
surface of large droplets, rather than a progressive decrease in droplet size.[26]
Dilution Test
Dilution test describe the type of emulsion and also give indication concerning the stability of
prepared microemulsion.[26]
Liquid SMEDDS equivalent to 10mg of Itraconazole was diluted
with both media 0.1 N HCl and distilled water (500 mL), individually. Both were kept as it is
for 24hr to see any sign of separation.
Dispersibility Test
Liquid SMEDDS was dispersed in distilled water also visually checked for its ability to form
microemulsion was checked.[26]
Various grades are given below, depending upon the ability
of Liquid SEDDS to form microemulsion. The grades are assigned:
Grade A: Rapidly forming (within 1 min) nanoemulsion, having a clear or bluish
appearance.
Grade B: Speedily forming, slightly clear emulsion, having a bluish white appearance.
Grade C: Fine milky emulsions this is less than 2 min.
Grade D: Dull, greyish white emulsion having faintly oily appearance that is slow to
emulsify (longer than2min).
Grade E: Formulation, exhibiting either poor or minimal emulsification through large oil
globules present on the surface.
Drug Content
Liquid SMEDDS (1 mL) was withdrawn and diluted with 0.1 N HCl to 100 mL. From that
solution, 0.1 mL was taken and added to 10 mL volumetric flask. Finally, volume was made
up to 10 mL with methanol and absorbance of the same was measured by using UV
spectrophotometer at 262nm.
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Turbidity measurement
This identifies efficient self-emulsification by establishing whether the dispersion reaches
equilibrium rapidly and in reproducible time. These measurements are carried out on
turbidity meters, generally the Hach turbidity meter as well as the Orbeco-Helle turbidity
meter.[26,28]
This apparatus is connected to a dissolution apparatus and optical clarity of
formulation is taken in every 15 second to determine clarity of nano or microemulsion
formed and also to emulsification time.
Droplet Size
This is a crucial factor in self-emulsification performance asit determines the rate and extent
of drug release, as well as the stability of the emulsion. Photon correlation spectroscopy,
microscopic techniques or else a Coulter Nanosizer[26]
are mainly used for the determination
of the emulsion droplet size.[28]
Approximately small amount, i.e. 0.5 to 1 mL of liquid
SEDDS is diluted with 100, 500 and 1000 mL of purified water. Then samples from different
dilutions at different time interval (freshly diluted, after 24 hours, and after one week) are
taken for droplet size evaluation. These will determine effect of dilution on droplet size and
stability (precipitation of drug).
Zeta Potential Measurements
Zeta Potential is used to identify the charge of droplets, in conventional SEDDS, the charge
on an oil droplet is negative because of presence of free fatty acids.[26,28,30]
Differential scanning calorimetry
Identification was done using differential scanning calorimetry. It was performed on pure
drug and on final formulation.[26,28,30]
The data were recorded and compatibility was observed
by endothermic and exothermic peaks.[26,28,30]
Viscosity measurement
The rheological properties of micro emulsion can be measured by using Brookfield
viscometer which is used to find out the type of system whether it is o/w or w/o. If the
system represents less viscous nature it is regarded as o/w type and if it is high viscous in
nature it is regarded as w/o type.
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Characterization of Solid-SMEDDS
Outer macroscopic structure of solid SMEDDS can be investigated by scanning electron
microscopy (SEM). Physical state of the drug in solid SMEDDS must be check as it may
affect drug release as well bioavailability of drug. Drug must be present in dissolved state
throughout product’s self-life. Differential Scanning Calorimetric method as well as X-
Ray diffraction can be used for this purpose.[26, 30]
Reconstitution from S-SMEDDS
Micro emulsion must be released without any interference from S-SEDDS. Solid self-
emulsifying formulation (powder, beads, pallets, Tablet, etc.) are placed in approximately
200 to 500 mL of purified water and allow to discharge the micro emulsion. Sample is then
evaluated for globule size and polydispersibility index.[26,30]
Sample should also be evaluated
for several kind of precipitation of drug after constitution.
In vitro Drug Release from S-SEDDS
Every solid dosage form must be evaluated for release of drug form that dosage form.
Usually in vitro dissolution is used for determination of drug release form solid self-
emulsifying formulation.[26,30]
USP-II type dissolution apparatus containing accurate
dissolution media should be used for conducting drug release study.[26, 30]
Stability Study
The optimized formulation was charged for the accelerated stability studies according to ICH
guidelines. Prepared Solid SEDDS was kept at 25℃/60% Relative Humidity and 40℃/75%
Relative Humidity.[26,30]
After one-month formulation was evaluated for its self-micro
emulsification ability and drug content.
RESULT AND DISCUSSION
Solubility of Itraconazole in Oils
Table 1: Solubility of Itraconazole in Oils.
Oils Solubility (mg/mL)
Castor oil 1.43
Corn oil 0.15
Sunflower oil 0.10
Olive oil 0.56
Oleic acid 0.67
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Itraconazole solubility in various oils is obtainable in Table 1. As mentioned, Castor oil has
higher solubility (1.43 mg/mL) as compared with other oils of itraconazole. Thus, Castor oil
was selected as oil phase for present work.
Solubility of Itraconazole in surfactants
Table 2: Solubility of Itraconazole in surfactants.
Oils Solubility (mg/mL)
Tween 80 1.35
Span 20 1.18
Propelyene glycole 1.01
Tween 20 2.38
Span 80 1.11
The solubility of itraconazole in a choice of surfactants is shown in Table 2. Amongst all the
surfactants, Tween 20 showed highest solubilization capacity (2.38 mg/mL) for Itraconazole.
Thus tween 80 was selected as surfactant.
Solubility of itraconazole in co-solvents
Table 3: Solubility of itraconazole in co-solvents.
Oils Solubility (mg/mL)
PEG 400 1.05
Glycerol 0.73
The solubility of itraconazole in co-solvents is shown in Table 3. Among all the surfactants,
PEG400 showed highest solubilization capacity (1.05 mg/mL) for itraconazole. Thus PEG
400 was selected as co-solvent.
PSEUDO-TERNARY PHASE DIAGRAM
Figure 1: Pseudo-Ternary Phase Diagram.
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Pseudo Ternary Phase Diagram (Fig. 1) was constructed in the absence of Itraconazoleto
identify optimized concentrations of the oil, surfactant, and co-surfactant. It was concluded
that formed microemulsion was o/w type. Also 1:1 maximum region for microemulsion
formation.
FTIR Spectra of Itraconazole
Figure 2: FTIR Spectra of Itraconazole.
Comparison of reference and observed FTIR frequency of Itraconazole
Table 4: Comparison of reference and observed FTIR frequency of Itraconazole.
Functional group Standard frequency
(cm-1
)
Observed frequency
(cm-1
)
Alkane, Aromatic CH &
Amine Groups 2800-3200
2819.93, 2964.59 and
3138.18
C=N Bond 1609 1583.56
C=O Bond 1699 1697.36
C-N Bond 1425 1450.47
The comparison of reference and observed FTIR frequency of Itraconazole is shown in Table
4. Table indicates that, observed frequency and Standard frequency of Itraconazole was
nearly the same. This proves that sample obtained from supplier was pure and authentic.
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Drug excipient compatibility study by FTIR
Figure 3: Drug excipient compatibility study by FTIR.
Interpretation of IR Spectra
Table 5: Interpretation of IR Spectra.
Functional group Standard frequency (cm-1) Observed frequency (cm
-1)
Alkane, Aromatic CH &
Amine Groups 2800-3200 3340.71 and 2870.08
C=N Bond 1609 1567.67
C=O Bond 1699 1645.28
C-N Bond 1425 1450.47
Drug excipient compatibility study by FTIR is shown in Figure 3. From the above graphs all
the necessary peaks were observed and do not show any kind of interaction. From the
comparison of FTIR data of drug and final formulation shown in Table 5, it can conclude
that the drug and excipients have no interaction with each other.
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Zeta potential, Droplet size and Viscosity measurement
Figure 4: Zeta potential for F12 batch.
The droplet size of emulsion and zeta potential are crucial factors in supersaturable self-micro
emulsification performance as it determines the rate and extent of drug release as well as
absorption. Zeta potential can be defined as the difference in potential between surfaces of
the tightly bound layer (shear plane) along with the electro neutral region of an emulsion. If
zeta potential governs the degree of repulsion between adjacent, similarly charged, dispersed
droplets. If zeta potential is reduced below a certain value (which depends on particular
system being used), the attractive forces exceed the repulsive forces, and the particles come
together leading to flocculation. The zeta potential value of ±30mVis sufficient for the
stability of microemulsion. All the formulation complies with the requirement of the zeta
potential for stability. Optimize formulation gives best result among all the batches - 42.20
nm droplet size it means increase in absorption, -28.51 zeta potential which means stable
emulsion and 0.8090 cp viscosity.
In-vitro drug release
Dissolution studies were performed for the SMEDDS and Supersaturable SEMDDS
formulation in gastric fluid (0.1N HCl without pepsin) and further in phosphate buffer pH
6.8. Upon contact with gastric fluid, formulation rapidly formed a fine emulsion and over
77%-94% the drug release after 10 min. However, time elapsed, the drug release from the
batches rapidly decreases to 29-59% at 120min. In the next study, precipitation inhibitors
were incorporated in SMEDDS formulations to stabilize the supersaturated state of
itraconazole and establish the S-SMEDDS formulations. Upon contact with gastric fluid,
Supersaturable SMEDDS formulation rapidly formed a fine emulsion and over 78%-96% the
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drug release after 10 min. However, time elapsed, the drug release from the SMEDDS
formulation rapidly decreases to 30-63% at 120 min. It means, Supersaturable SMEDDS was
stabilized the formulation and enhance % drug release.
Figure 5: Dissolution studies.
In-vitro drug release study of selected batch and marketed formulation
From the above evaluation test, it can be concluded that, Supersaturable SMEDDS gives best
% drug release as compare to (canditral capsule) marketed preparation. Thus, Supersaturable
SMEDDS is an effective approach for increasing solubility and inhibit the crystal growth of
itraconazole.
Figure 6: Comparison of release profile of batch F12 and marketed formulation.
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Scanning Electron Microscopy Analysis.
The scanning electron microscopy of F-12 sample is shown in Figure 7. SEM analysis
demonstrating that the liquid Supersaturable SMEDDS was either adsorbed or else coated
inside the pores of adsorbent powder mixture.
Figure 7: SEM studies of F12 batch.
DSC of itraconazole pure drug
The DSC profile of pure itraconazole is shown in Figure 8. The sharp peak at 166.51⁰ C
indicates endothermic peak of itraconazole.
Figure 8: DSC profile of pure drug.
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DSC of drug with excipients
Figure 9: DSC profile of drug with excipients.
The DSC profile of F-12 batch shown in Figure 9. The sharp peak at 166.51⁰ C indicates
endothermic peak of itraconazole, while the peak at 167.48°C is of the final F-12 batch. Final
formulation (F-12) indicates that there was no interaction between drug and excipient.
Accelerated stability study
The stability study was performed in accordance with ICH guideline. The samples were
analyzed for various evaluating parameters such as were observed before and after storage at
room temperature. The results obtained for all parameter were in good proximity with that of
before evaluated parameters as shown in Table 6.
Table 6: Evaluation parameter of selected batch after stability study.
Evaluation
parameter
Storage for one month
Before 1 month After 1 month
Visual inspection Transparent bluish tinge Transparent bluish tinge
Dilution test
Robust (diluted in both
media distilled water and
0.1N HCl)
Robust (diluted in both
media distilled water and
0.1N HCl)
Dispersibility test Grade A Grade A
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In-vivo drug release profile of selected batch after accelerated short term Stability study
Figure 10: Comparison of %CDR of batch before and after accelerated short term
stability study.
The Comparison of %CDR of batch before and after accelerated short term stability study is
shown in Figure 10. It indicates that the drug release profile of itraconazole from optimize
batch before and after accelerated short term stability study. There is no significant change in
drug release was observed. It indicates good stability of product and product is stable.
CONCLUSION
Novel itraconazole Supersaturable SMEDDS formulation was effectively prepared with
incorporating HPMC as a precipitation inhibitor to SMEDDS composed of Castor oil as oil,
Tween 20 as a surfactant, and PEG 400 as a co-solvent. The in vitro dissolution tests in a
non-sink condition revealed that a small amount of HPMC effectively slowed down drug
precipitation and played a critical role in maintaining a supersaturated state of Itraconazole.
Drug dissolution from Supersaturable SMEDDS was pH-independent. The in-vitro drug
release of Supersaturable SMEDDS of itraconazole was 95.66%, droplet size was 42.20nm.
Supersaturable SMEDDS formulation significantly improved oral absorption of itraconazole,
improve the solubility and also inhibit the crystal growth. Study of S-SMEDDS demonstrates
the potential use of the S-SMEDDS formulation in development of poorly water-soluble oral
drugs.
REFERENCES
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