DESIGN, DEVELOPMENT, AND CHARACTERIZATION OF …

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Munde et al. World Journal of Pharmacy and Pharmaceutical Sciences

DESIGN, DEVELOPMENT, AND CHARACTERIZATION OF

CLOTRIMAZOLE LOADED MICROSPONGE

V. P. Munde*, J. V. Shinde and R. K. Gaikwad

Pdea’s Seth Govind Raghunath Sable College of Pharmacy, Saswad, Pune 412301.

ABSTRACT

Conventional drug delivery systems require periodic doses of the

therapeutic agent to produce a maximum therapeutic effect. To

minimize its sustainable or extended delivery is the prime aim in the

era. Clotrimazole, a broad-spectrum imidazole antifungal agent is

widely used to treat fungal infections. Conventional formulations of

clotrimazole are intended to treat infections by effective penetration of

drugs into the stratum corneum. However, drawbacks such as poor

dermal bioavailability, poor penetration, very less aqueous solubility, a

shorter half-life (2.5-3 hr.) and certain side effects like earthman,

edema and skin irritation. So, encapsulation of Clotrimazole into

microsponge would modify the release rate and also reduce side effects and variable drug

levels limit the efficiency. In this study, Clotrimazole microsponge was prepared by the

emulsion solvent diffusion technique by using Eudragit RS100 and evaluated for % Practical

yield, % Entrapment efficiency and In vitro drug release study. Drug- excipients

compatibility was performed by the FTIR and DSC study. To control the delivery rate of

active agents to a predetermined rate in the any conventional formulation has been one of the

biggest challenges faced by the industry. Microsponge releases its active ingredient in a time

mode and also in response to other stimuli (rubbing, temperature, pH, etc.). Microsponge

technology offers entrapment of ingredients and is believed to contribute towards reduced

side effects, improved stability, increased elegance, and enhanced formulation flexibility.

Also, numerous studies have confirmed that Microsponge systems are nonirritating, Non-

mutagenic, non-allergenic, and non-toxic. Microsponge technology is being used currently in

a wide range of formulations.

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

SJIF Impact Factor 7.632

Volume 9, Issue 4, 651-668 Research Article ISSN 2278 – 4357

Article Received on

24 Jan. 2020,

Revised on 14 Feb. 2020,

Accepted on 04 March 2020

DOI: 10.20959/wjpps20204-15794

*Corresponding Author

V. P. Munde

Pdea’s Seth Govind

Raghunath Sable College of

Pharmacy, Saswad, Pune

412301.


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KEYWORDS: Fungal infections, Clotrimazole microsponge, formulation flexibility, fungal

infections, practical application.

INTRODUCTION

Numerous drug delivery systems have been developed for the drugs as a transdermal delivery

system to follow the controlled and predetermined drug release by using the skin as a

doorway for entrance. Despite of improved efficacy of drug delivery the active agent passes

the skin layers and gets into the systemic circulation while its final target is the skin itself.[1]

Drug controlled release onto epidermis asserts that the drug remains primarily localized and

does not enter the systemic circulation in significant amounts. Many conventional

formulations such as ointments, gels, etc. require high concentrations of drugs for effective

therapy, which results in a great number of side effects. Thus, it becomes essential to boost

the amount of time that a drug remains on skin surface or epidermis and simultaneously

decreasing its transdermal penetration into the body.[2]

So the given research is carried out to

use a microsponge novel drug delivery as a carrier system to provide controlled and

predetermined release of the antifungal drug. The invention of microsponges has become a

significant step toward overcoming these problems. These tiny sponges give the action at a

specific target site and stick on the surface and begin to release the drug in a controlled and

predictable manner for drugs with poor solubility.[3]

They enhance stability, reduced side

effects and modify drug release. It consists of micro-porous beads, typically 10-25 microns in

diameter, loaded with active agents. Besides, they may enhance stability, modify drug release

and reduce side effects favorably.[4]

The superficial cutaneous fungal infections involve the outer most layers of skin and its

appendages like hair and nails and are prevalent in most parts of the world. These are caused

by a group of filamentous fungi, closely related to each other antigenically, taxonomically,

morphologically and physiologically; with a capacity to invade keratinized tissues of the skin

and its appendages and are collectively known as dermatophytes. Other frequently used terms

like tinea and ringworm infections are synonyms of dermatophytoses. The infections caused

by non-dermatophytic fungi involving the skin are called as dermatomycoses whereas

involving hair and nail are called piedra and onychomycosis respectively. The dermatophytes

are assigned to three main genera namely Trichophyton, Microsporum, and

Epidermophyton.[5]


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Clotrimazole, a broad spectrum less toxic imidazole antifungal agent is widely used to treat

Candidiasis. It acts by inhibiting cytochrome 14α-demethylase enzyme of the fungal cells

responsible for cell wall synthesis. Chemically, clotrimazole is 1-((2-chlorophenyl)

diphenylmethyl)-1H-imidazole, insoluble in water (0.49 mg/L) with Log P of 6.1 and pKa

6.7. It is the first oral azole approved for fungal infections; however, it is not used as an oral

agent due to its limited oral absorption and systemic toxicity. Currently, clotrimazole is

available as conventional topical formulations such as cream (Lotrimin AF and Gyne-

Lotrimin), solution (Lotrimin AF), and lotion (Lotrimin AF). The topical bioavailability of

clotrimazole is very low ranging from 0.5% to 10% due to its poor aqueous solubility.

Therefore, clotrimazole must be loaded into a suitable drug delivery system to enhance its

topical bioavailability at the infection site. The clotrimazole has been loaded into various

novel drug delivery systems such as nanogels, microemulsions, solid lipid nanoparticles,

nanocapsules, and ethosomes with a main aim of control release but fail apart due to

limitations of this systems. On the other hand, microsponge drug delivery systems have

become more popular in recent times due to their advantages such as prolonged drug release,

improved drug penetration, targeted delivery to the site of infection, and improved physical

stability. Recently the use of microsponge drug delivery arises as a potential topical drug

delivery vehicle. Loading of clotrimazole into microsponge can result in enhanced release

time if we incorporate into any dosage form like topicals, orals, and solutions which enhance

the bioavailability of clotrimazole.[6]

Thus, the present investigation aims to develop a clotrimazole loaded microsponge delivery

system to reduce the dose and dosing frequency associated with conventional topical, vaginal

drug delivery system and achieve the therapeutic objective. The fabricated microsponges will

be characterized concerning particle size, surface morphology, drug entrapment efficiency, in

vitro diffusion studies, in vitro antifungal studies, release kinetics and stability studies.

MATERIALS AND METHODS

Materials

Clotrimazole was procured from Yarrow Chem Products, Mumbai. Eudragit RS-100 was

obtained from Research-Lab Fine Chem Industries Mumbai. Polyvinyl Alcohol,

Dichloromethane was purchased from Loba Chemie Pvt. Ltd., Mumbai and Cosmo chem

respectively. All other reagents used were of analytical grade. The microsponges were

prepared by the quasi emulsion solvent diffusion method.


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Method of preparation

Clotrimazole microsponge was prepared by the quasi emulsion solvent diffusion method. The

quasi emulsion solvent diffusion method seemed to be promising for the preparation of

Clotrimazole microsponges as it is easy, reproducible, and rapid and has the advantage of

avoiding solvent toxicity. To prepare the internal phase, Eudragit RS 100 is dissolved in

dichloromethane (DCM) and ethanol (1:1). The drug can be then added to the solution and

dissolved under ultra-sonication for 20 minutes. Dibutyl phthalate is added 1% to provide the

plasticity to the formulation. The internal phase containing clotrimazole 100mg and 5ml

DCM: Ethanol (1:1) was gradually added into a 100 ml distilled external phase, containing

polyvinyl alcohol as an emulsifying agent. The mixture was stirred on a magnetic stirrer at

1000 rpm for 8hrs at 40 °C to remove DCM. During the stirring process, the aluminum foil

with minute pores on the surface is covered on top of a mixture containing beaker which

provides impenetrability to moisture, oxygen and other gases, as well as micro-organisms.

Aluminum foil helps to keep safe formulation mixture from environmental impacts in perfect

condition for longer. The nitrogen purging is provided to the formulation to keep it in an inert

atmosphere to prevent exposure to oxygen and subsequent spoilage that results from

oxidation. The nitrogen gas is used as a blanketing and purging gas. The formed

microsponges were filtered through Whatman filter paper no. 41 (Whatman, UK), washed

with distilled water, dried at 40 °C for 12 h and weighed.[7,8]

Evaluation of clotrimazole microsponges

Production yield: The production yield of the microsponges is calculated by the given

formula Production yield (PY) = Practical mass of microsponges/Theoretical mass (polymer

+ drug) × 100

Drug‑excipient interaction study: The drug‑excipient interaction was investigated by

FT‑IR and DSC studies. IR spectra were recorded to check the compatibility of the drug with

excipients. DSC gives an idea regarding the physical properties of the sample nature

(crystalline or amorphous) and indicates any probable interaction among drug and excipients.

Thermal analysis: Differential scanning calorimetry (DSC) is a widely used technique to

understand the melting and recrystallization behavior of drug molecules. It is a thermo-

analytical technique that determines the thermodynamic properties of materials by providing

information about the polymorphic changes when subjected to a controlled heat flux. The


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thermogram of clotrimazole microsponge formulation was obtained using differential

scanning calorimeter (METTLER TOLEDO, Star SW 920). Outfitted with an intercooler. For

calibrating DSC enthalpy and temperature scale, the indium standard was implied. Micro

sponge samples were kept in aluminum pan hermetically and heated at a constant rate of

10°C/min over a temperature range of 40–200°C. By purging nitrogen with a flow rate of 10

ml/min inert atmosphere was maintained.

Fourier transform‑infrared spectroscopy: Using FT‑IR spectrophotometer (FTIR 8400S,

Shimadzu) implying Kbr pellet method, spectra of Clotrimazole, physical mixtures of

Clotrimazole and Eudragit RS‑100, and microsponge formulation were recorded in the

wavelength range of 4000–400 cm‑1.

Entrapment efficiency (EE) and actual drug content: 100 mg of microsponges were

accurately weighted. They were powdered and extracted with 100 ml of the method. Further,

it was serially diluted with pH 7.4 phosphate buffer. The resulting solution was analyzed for

clotrimazole drug content by measuring absorbance in a UV spectrophotometer at 261nm

using pH 7.4 phosphate buffer as blank. The studies were carried out in triplicate. The actual

drug content and entrapment efficiency were deliberate as

Actual drug content (%) = (Mact/Mms)*100

Entrapment efficiency (%) =Mact/Mthe)*100

Where Mact is the actual amount of clotrimazole in the weighed quantity of microsponges,

Mms is the weighed quantity of microsponges and Mthe is the theoretical amount of

fluconazole in microsponges.

The particle size of microsponge: Particle size of all the prepared batches of microsponge

was determined using optical microscopy at 10X and 40X. The microsponges were placed on

glass and observe under an optical microscope. The size of 50-100 microsponges was

measured using an optical microscope. Then the particle size, shape and surface was

calculated.


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Scanning Electron Microscopy

Scanning electron microscopy is an electron-optical imaging technology that confers

photographic pictures and elemental knowledge. SEM is useful for characterizing the

morphology and size of microscopic specimens with a particle size as low as nanometer to

decameter, the sample is installed in an evacuated chamber and check in a controlled pattern

by an electron beam. Interaction of the electron beam with the sample originates a kind of

physical phenomenon that when discover are used to form pictures and confer elemental

information about the sample. Microsponge was fixed on aluminum stubs and coated with

gold using a sputter coater SC 502, under vacuum [0.1 mm Hg]. The microsponge was then

analyzed by scanning electron microscopy (SEM).

In vitro dissolution studies: The release of clotrimazole from microsponge was investigated

in pH 7.4 phosphate buffer as dissolution medium (900ml) using the USP type I apparatus. A

sample of microsponge equivalent to 100mg of clotrimazole was taken in the basket. A speed

of 75 rpm and a temperature of 37± 0.5 °c was maintained throughout the experiment. At

fixed intervals, aliquots (5ml) were withdrawn and replaced with fresh dissolution media. The

concentration of drug released at different time intervals was then determined by measuring

the absorbance using Double beam UV spectrophotometer at 261 nm against a blank. The

studies were carried out in triplicate.[9,10]

Kinetic modelling

Data obtained from the in-vitro release studied were evaluated to check the goodness of fit to

various kinetics equations for quantifying the phenomena controlling the release from

microspheres. The kinetic models were used like zero order, first order, and Higuchi and

Korsmeyer - Peppas model. The goodness of fit was evaluated using the correlation

coefficient value (R2)

The results of in-vitro release profile obtained for all the formulations were plotted in kinetic

models as follows,

1. Cumulative of drug released versus time (zero-order kinetic models).

2. Log cumulative percent drug remaining to be absorbed versus time (First order model)

3. The cumulative amount of drug release versus square root of time (Higuchi model)

4. Log of cumulative drug release versus log time (Korsmeyer – Peppas model)


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Kinetic equations

1. Zero-order (% release = Kt)

2. First-order (log % unreleased = Kit)

3. Higuchi’s model (%release = Kt 0.5)

4. Pappas Korsmeyer equation (% release = Ktn)

(Or) an empirical equation of Mt/ Mμ =Ktn

Where, Mt/ Mμ = fractional drug release,

K = constant characteristics, and

n. diffusional exponential

if

n=0.5 indicates Fickian diffusion mechanism (Higuchi matrix)

n=0.5 to 1 indicates anomalous transport or non Fickian transport

n = 1 indicate case II transport (Zero-order release)

n >1 indicates super case – II transport.

The coefficient of correlation (R2) values was calculated for the linear curves obtained by

regression analysis of the above plots.[11,12]

Effect of Formulation Variables on the Formation of Microsponges

Effect of the drug: polymer ratio

To evaluate the effect of the drug on the formation of microsponge, different Eudragit

polymer to clotrimazole ratios (1:1, 1:2, 1:3, 1:4 and 1:5) were used to prepare microsponges.

The formed microsponges were evaluated for their appearance, drug content, particle size,

and entrapment Efficiency.

Effect of stirring speed on the formation of microsponges

To evaluate the effect of stirring speed on the formation of microsponges, were prepared with

different RPM of 500, 1000, 1200, 1500 and 2000, the formed microsponges were evaluated

for their drug content and particle size.[13, 14, 15]

RESULTS AND DISCUSSION

Production yield: The production yield of all batches of microsponges ranged from 34.35%

to 74.75% [Table 2]. Drug: Polymer ratio and stirring speed were found to affect the

production significantly. In the case of the drug: Polymer ratio 1:1 (F1), production yield was

very low, i.e. 34.35% while for a drug: Polymer ratio 1:5 (F5), it was 74.75%. It reflected that


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the higher the drug: Polymer ratio, the higher the production yield. Further, with low stirring

speed (500 RPM, F6), production yield was quite low, i.e., 44.33% and as the stirring speed

was increased from 500 mg to 2000 RPM the production yield was also found to be increased

which may the result of reduction I particle size. The reason for the increase in production

yield at an elevated drug: Polymer ratio was abridged dichloromethane diffusion rate from

concentrated solutions to the aqueous phase, which provides additional time for the formation

of droplet following improved yield.

Table 1: Composite design of microsponge formulation.

Formulation

code

Clotrimazole:

Eudragit

RS‑100 (mg)

Ethanol:

dichloromethane

(ml)

Dibutyl

phthalate

(% w/v)

Polyvinyl

alcohol

(mg)

Stirring

Speed(RPM)

Water

(ml)

F1 1:1 5 1 50 1000 100

F2 1:2 5 1 50 1000 100

F3 1:3 5 1 50 1000 100

F4 1:4 5 1 50 1000 100

F5 1:5 5 1 50 1000 100

F6 1:3 5 1 50 500 100

F7 1:3 5 1 50 1200 100

F8 1:3 5 1 50 1500 100

F9 1:3 5 1 50 2000 100

Table 2: Summary of results.

Formulation

code

Drug:

polymer

ratio

Stirring

speed

(RPM)

Actual

drug

content.

(%)

Entrapment

Efficiency.

(%)

Production

yield. (%)

Particle

size (%)

F1 1:1 1000 55.28±0.01 90.56±0.02 34.35±0.02 34.35±0.02

F2 1:2 1000 51.47±0.02 92.41±0.01 35.76±0.05 39.76±0.05

F3 1:3 1000 53.50±0.03 88.82±0.02 42.25±0.02 42.25±0.02

F4 1:4 1000 45.86±0.01 84.57±0.20 48.10±0.11 48.10±0.11

F5 1:5 1000 37.32±0.01 88.09±0.00 74.33±0.28 74.33±0.28

F6 1:3 500 28.25±0.02 78.57±0.03 44.33±0.02 70.44±0.02

F7 1:3 1200 34.25±0.15 90.75±0.04 54.33±0.49 54.33±0.49

F8 1:3 1500 39.78±0.02 89.50±0.02 57.66±0.47 57.66±0.47

F9 1:3 2000 41.01±0.01 92.30±0.04 61.10±0.61 30.10±0.61

Fourier transform‑infrared spectroscopy: The infrared spectrum of the drug sample was

recorded (Fig.1 (A)) and spectral analysis was done.


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Fig. 1: FTIR spectra of (a) clotrimazole.

The characteristics IR absorption peaks of clotrimazole at 3055.35 C–H stretch (aromatic),

1589.40 C=N stretch of imidazole ring (aromatic), 1589.40 C=N stretch of imidazole ring

(aromatic), 1435.09 C=C stretch of imidazole ring (aromatic), 1080.17, 1041.60 C–N stretch

of imidazole ring (aromatic), 1273.06, 1211.34 C–H bend (in-plane), 902.72, 817.85, 763.84

C–H bend (out-of-plane) were present in procured drug sample spectrum; which confirmed

the purity. The peaks obtain from Eudragit RS100 (Fig.2 (B)) at 3541, 3258, 2952,841, 1103.

Fig. 2: FTIR spectra of (b) eudragit Rs 100.

The characteristic IR absorption peaks of clotrimazole were present in the physical mixture

while traces of Eudragit RS100 peaks are also found in (fig.3.(C)). The FT-IR spectra of the

pure drug and formulation indicated that characteristics peaks of Clotrimazole were not

altered without any change in their position after mixture with polymer, indicating no

chemical interactions between the drug and carriers.


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Fig. 3: FTIR spectra of (c) physical mixture.

FT‑IR spectroscopic study results discovered no any new peak appearance or disappearance

of existing peaks, discarding any chemical interaction probability among drug and polymer

used. All characteristic peaks of clotrimazole have appeared in figure C and microsponge

formulation spectrum (fig,4 (D)). Thus, IR spectroscopy results depicted that the, excipients

and possess good stability in all microsponge formulations.it It also indicated the process

suitability of drug and excipient to formulation methodology.

Fig. 4: FTIR spectra of (d) microsponge formulation.

Thermal analysis: Compatibility study was carried out to check for any possible interaction

between drug and excipients used. In DSC studies, a pure clotrimazole thermogram reflected

an endothermic peak at 149.00°C corresponding to its standard melting point range depicted

in [Figure 5 and Figure 6(A)]. Physical mixture showed similar thermal behavior as that of

the pure drug but with lower intensity 148.25oC [Figure 6(C)]. However, the melting

endotherm of microsponge formulation was suppressed due to the partial protection of

clotrimazole and its encapsulation in the polymer system that's why it shows a sharp peak at


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145.25o

as depicted in [Figure 6(D) and Figure-7]. It was also observed that drug crystallinity

altered significantly in microsponge formulation confirming its dispersion in the system.

Clotrimazole is entrapped in Eudragit RS 100 is concluded from the above study as well as it

is compatible with Eudragit RS 100 as no any significant changes are seen in thermograms.so

it’s clear that it doesn’t hamper the physicochemical property of drug, polymer and

formulation mixture.

Fig. 5: DSC thermogram of pure clotrimazole.

Fig. 6: Overlay of thermograms.


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Fig. 7: DSC thermograms of microsponge formulation.

Drug‑excipient interaction study: FTIR study clearly indicated that no interaction occurred

between the drug and the polymer. It also indicated that the drug was loaded in the

microsponges as it showed desired peaks of both drug and polymer while the DSC study

shows that no significant deviation in the peaks was observed. It indicates that the drug

having compatibility with the components of Microsponge formulation as shown in fig. 2.

These results indicate the method used to prepare microsponge does not affect the

physicochemical properties of the systems.

Actual drug content: The actual drug content of all formulation is shown in Table no 2. The

% actual drug content was influenced by the Eudragit RS 100 polymer concentration and

stirring speed. Improved by a greater proportion of polymer concerning the amount of drug

available, hence more polymer can entrap more drug particles, i.e. more amount of polymer

present per unit. While the increase in the stirring speed leads to slightly less actual drug

content in results. This may occur as stirring speed increases the drug is insoluble in the given

solvent and polymer gets solidify without the drug.whie some other reason we can say that

drug is not fully solidified and gets out through the solvent during filtration.


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Entrapment efficiency: The mean amount of drug entrapped in fabricated microsponges was

found to be lesser than the theoretical value for every drug: Polymer ratio, because drug

encapsulation efficiency did not attain 100%. It was because of some drug dissolution in

aqueous phase or solvent used. Encapsulation efficiency outcomes reflected that higher drug:

Polymer ratios led to superior drug loadings. An elevated drug: Polymer ratio caused a slight

increase in dispersed phase viscosity. On the diffusion of solvents from the inner phase,

almost all of the dispersed phase was transformed into solid microsponges and estranged

particles emerged. The utmost drug loading efficiencies of these formulations could be

attributed to the availability of maximum polymer amount to each drug unit in contrast to the

rest of the formulations. The encapsulation efficiencies were in the range of 84.57–92.56% as

quoted in Table 2.

Particle size analysis: The average particle size of microsponges should be in the range of

5–300. The visual inspection of all batches using the optical microscope for particle size

revealed that particle size has increased with an increase in drug: Polymer ratio. It was

because of the fact that polymer available at a higher drug: Polymer ratio was in more amount

thereby increasing polymer wall thickness which led to the greater size of microsponges in

high drug: polymer ratio, the amount of polymer per microsponges is more. When

dichloromethane and ethanol diffuse out nearly all of the dispersed phases are converted to

the form of solid microsponges and separated particles appear. Therefore, in high drug:

polymer ratio more polymer surrounded the drug and increases the particle sizes of

microsponges. As shown in table no. 2 increase in polymer shows an increase in particle size

from 34.35 – 74.33 (F1-F5). While as stirring speed increases the size of microsponge was

reduced e.g. when the rate of stirring increased from 500-2000rpm the mean particle size was

decreased from 70.44 μm - 30.10 μm (F6 –F9).

Scanning electron microscopy: Prepared microsponges were subjected to scanning electron

microscopy (SEM) analysis for assessing their morphology and surface topography. The

captured SEMimages of microsponges are shown in Figure 8(A, B, C, D).


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Fig. 8: (A) Fig. 8:(B)

Fig. 8: (C) Fig. 8: (D)

Fig. 8: SEM images of microsponge.

SEM photomicrographs reflected that microsponges formed were highly porous,

predominantly spherical. By the diffusion of solvent from the surface of microsponges, pores

were induced. Moreover, it was exposed that the distinctive internal structure comprised of a

spherical cavity enclosing a stiff shell assembled of drug and polymer. The microsponges

were also observed under a fluorescence microscope [Figure 3c and d], which revealed that

formed microsponges were spherical as every single entity and had porous nature.

Release kinetics

The in vitro release data were subjected to various release models namely, zero order, first

order, Higuchi, Peppas and Hixson–Crowell, and the best fit model was decided by the

highest r2 value. The in vitro drug release showed the highest regression value for the zero-

order model (0.999 for F6). Based on the maximum regression value, zero-order was found to

be the best fit model for most of the formulations [Table 3].

Effect of formulation variables

Effect of the drug: Polymer ratio: Increased Production yield & article size is the due fact

that the amount of polymer is increased with an increased ratio of drug to polymer while


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actual drug content, entrapment efficiency, and cumulative drug release were found to be

decreased [Table 2]. This is because as a drug: Polymer ratio went on increasing, the polymer

amount available for each microsponge to encapsulate the drug was more, thus rising

polymer matrix wall thickness which led to extended diffusion path and ultimately to lesser

drug release. As a result, the amount of drug diffused and flux of the formulations was

decreased at a higher drug: Polymer ratio. It was also observed that as a drug to polymer ratio

increases the particle size increased; this is probably due to fact that at higher relative drug

content; the amount of polymer available per microsponge to encapsulate the drug become

more, thus increases the thickness of the polymer wall and hence larger the size of

microsponges. The in vitro drug release shows that as the drug: polymer ratio gets increases

the release rate is getting decreases. as table no.3 indicates above the F5 formulation shows

slower drug release.

Effect of stirring speed on the formulation

By changing the stirring speed from 500 to 2000 RPM and the effect of variables was

assessed for formulations F6-F9. It was observed that on increasing the stirring speed

increases, production yield, entrapment efficiency while the particle size was get decreased.

A slight decrease in drug release was observed as stirring speed increases. [Table 2]. From

the result given in Table no .3. We can conclude that as the stirring speed increases the

particle size is gets reduced and therefore the release of drugs is also reduced. The batch F6-

F9 clearly indicates that the increase in the stirring speed leads to slower drug release. F9

(78.87) shows the delayed-release up to 12 hrs. As compared to other batches where stirring

speed was higher.

Table 3: In vitro drug release study of clotrimazole loaded microsponges.

TIME (HRS) F1 F2 F3 F4 F5 F6 F7 F8 F9

0 0 0 0 0 0 0 0 0 0

1 22.51 13.19 9.36 15.12 11.62 6.7 11.63 8.9 5.91

2 31.17 22.24 13.8 20.45 16.01 10.8 13.43 10.12 7.63

3 56.61 34.51 15.34 28.38 23.11 11.2 15.84 14.56 8.21

4 71.52 39.48 17.64 37.54 28.23 17.69 25.01 18.87 11.26

5 83.66 57.03 36.13 48.64 33.43 24.18 24.98 21.3 15.07

6 95.58 76.52 67.04 60.73 35.06 26.34 36.66 26.74 18.42

7 89.96 72.28 66.8 45.78 43.44 48.2 30.11 23.54

8 99.01 95.32 81.21 58.71 52.83 53.19 37.24 34.1

9 96.99 79.50 66.75 71.47 44.91 41.35

10 94.93 78.11 62.6 57.52 46.79

11 81.76 84.99 69.91 54.66

12 96.51 89.78 76.83 78.87


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Table 4: Release kinetics data of microsponge formulations.

Formulation

code

Zero-

order

First-

order Higuchi Peppas

Hixson

Crowell

Best fitting

model

F1 0.996 0.980 0.991 0.956 0.956 Zero order

F2 0.976 0.983 0.967 0.967 0.981 First order

F3 0.964 0.944 0.935 0.954 0.922 Zero order

F4 0.914 0.911 0.905 0.962 0.965 Hixson–Crowell

F5 0.999 0.995 0.970 0.994 0.989 First order

F6 0.997 0.994 0.964 0.995 0.981 Zero order

F7 0.971 0.992 0.980 0.967 0.967 Zero order

F8 0.983 0.993 0.969 0.986 0.975 First order

F9 0.979 0.969 0.956 0.980 0.981 Zero order

Future perspectives-The formulated Microsponges of clotrimazole shows release at a

predetermined rate so we can conclude that the incorporation of these microsponges into any

gel base prolongs its release kinetics and may give sustain release to the upper layers of skin

which minimize further side effects.

DISCUSSION

Polymeric microsponge based system of Clotrimazole was developed successfully using

quasi‑emulsion solvent diffusion method to provide a controlled and sustained drug release

and thereby reducing the side effects of it. Also reduces the application frequency,

hypersensitive reactions allied to the conventional marketed formulation, and to improve

bioavailability and safety. The implemented method was found to be simple, reproducible

and rapid. Which led to the formation of highly porous, spherical microsponges with good

flow. Varied drug-polymer ratio reflected a remarkable effect on drug content, encapsulation

efficiency, particle size, and drug release. Thus, a microsponge based delivery system

developed and investigated in the present research approach was seems to be promising

concerning the sustainable and controlled release of active drug in various formulation and

helps to eradication of face fungus, candidiasis, and numerous other fungal infections, along

with the practical application in pharmaceuticals and cosmeceuticals.

ACKNOWLEDGEMENTS

I am grateful to all of those with whom I have had the pleasure to work during this and other

related projects. Each of the members of my Dissertation Committee has provided me

extensive personal and professional guidance and taught me a great deal about both scientific

research and life in general.


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