FORMULATION AND EVALUATION OF ORAL SUPERSATURABLE …

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1903

Dave et al. World Journal of Pharmacy and Pharmaceutical Sciences

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/cosurfactant (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


1904


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.


1908


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.


1909


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.


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.


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.


1912


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.


1913


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


1914


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.


1915


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.


1916


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


1917


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.

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