285 | P a g e International Standard Serial Number (ISSN ...

285 | P a g e International Standard Serial Number (ISSN): 2319-8141

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International Journal of Universal Pharmacy and Bio Sciences 3(2): March-April 2014

INTERNATIONAL JOURNAL OF UNIVERSAL

PHARMACY AND BIO SCIENCES IMPACT FACTOR 1.89***

ICV 5.13***

Pharmaceutical Sciences RESEARCH ARTICLE……!!!

DESIGN AND DEVELOPMENT OF SELF-MICROEMULSIFYING DRUG

DELIVERY SYSTEM OF FEBUXOSTAT

Paresh K. Patel*, DR.M.R.Patel, DR.K.R.Patel

Department of Pharmaceutics, B. M. Shah College of Pharmaceutical Education and Research,

Modasa, Gujarat, India.

KEYWORDS:

SMEDDs, Febuxostat,

bioavailability, In-vitro

release study. Droplet size.

For Correspondence:

Paresh K. Patel*

Address:

Shri B. M. Shah College

of Pharmaceutical

Education and Research,

College Campus,

Modasa -383315,

Gujarat, India

Mobile- +91-9429250426

E-mail ID:

[email protected]

om

ABSTRACT

Purpose: Febuxostat is poorly water soluble drug. It should be come

into the BCS Class II drug. Hence oral Bioavailability of Febuxostat

is less (49%). To develop novel dosage foam of the self-

Microemulsifying drug delivery systems (SMEDDS) for the

Febuxostat for enhancing its solubility. Method: Before the

formulation of SMEDDS solubility study was performed in different

excipients and select excipients on basis of solubility of Febuxostat.

Microemulsion region was decided by preparing ternary phase

diagram. Drug excipients interaction study performed FTIR. After

preliminary study, SMEDDS formulation was prepared in Capmul

PG 8 NF(oil), Acrysol k-160(surfactant), Transcutol P(co-surfactant)

by simple mixing at 40°C. Parameters evaluated included:

macroscopic evaluation, visual assessment, self-emulsification,

transmittance test, particle size distribution, zeta potential and

polydespersity index and In vitro dissolution. In vitro dissolution was

carried in USP apparatus II using phosphate buffer pH 6.0 at

37±0.5°C with 75 rpm rotating speed, drug release measured by

spectroscopic method. Result: From the solubility study, better

solubility was seen in Capmul PG 8 NF(oil), Acrysol k-

160(surfactant), Transcutol P(co-surfactant). No any drug excipients

interaction seen. Optimized formulation P4 of SMEDDS was

observed with smaller droplet size 17.08nm, PDI 0.230 and zeta

potential -14.5mV. Formulation was clear after dilution with water.

SMEDDS formulation showed complete release in 60 minutes as

compared with Furic (40mg) tablet. Conclusion: SMEDDS

Febuxostat oral formulation was prepared that provides excellent

drug solubilisation and improved in vitro release of Febuxostat.



INTRODUCTION:

Oral route still remains the favorite route of drug administration in many diseases and till today it is the

first way investigated in the development of new dosage forms. The major problem in oral drug

formulations is low bioavailability, which mainly results from poor aqueous solubility. This may lead to

high inter and intra subject variability, lack of dose proportionality and therapeutic failure. It is estimated

that 40% of active substances are poorly soluble in water. The improvement of bio-availability of drugs

with such properties presents one of the greatest challenges in drug formulations. Various technological

strategies are reported in the literature including micronization, solid dispersions or cyclodextrines complex

formation and different technologies of drug delivery systems. Among various approach self

Microemulsifying drug delivery system has gained more attention due to enhanced oral bio-availability

enabling reduction in dose, more consistent temporal profiles of drug absorption, selective targeting of

drug(s) toward specific absorption window in GIT, and protection of drug(s) from the hostile environment

in gut.

Self-Microemulsifying drug delivery systems (SMEDDS) is isotropic mixtures of oils and surfactants, co-

surfactants and drug which emulsify spontaneously to produce fine oil-in-water emulsions when introduced

into aqueous phase under gentle agitation.

Oral delivery of poorly water-soluble compounds is to pre-dissolve the compound in a suitable solvent and

fill the formulation into capsules. The main benefit of this approach is that pre-dissolving the compound

overcomes the initial rate limiting step of particulate dissolution in the aqueous environment within the GI

tract. However, a potential problem is that the drug may precipitate out of solution when the formulation

disperses in the GI tract, particularly if a hydrophilic solvent is used (e.g. Polyethylene glycol). If the drug

can be dissolved in a lipid vehicle there is less potential for precipitation on dilution in the GI tract, as

partitioning kinetics will favor the drug remaining in the lipid droplets.

Hyperuricemia is defined as a serum urate concentration exceeding the limit of solubility (about 6.8 mg per

deciliter). The clinical manifestations of gout (acute gouty arthritis, gouty arthropathy, chronic tophaceous

gout, uric acid urolithiasis, and gouty nephropathy) result from deposition of monosodium urate or uric

acid crystals from supersaturated body fluids. The most frequently used pharmacologic urate-lowering

strategies involve reducing urate production with a xanthine oxidase inhibitor and enhancing urinary

excretion of uric acid with a uricosuric agent. The average dose is 300 mg per day, although dosing

recommendations range from 100 to 800 mg per day, titrated to serum urate and creatinine clearance. The



side effects of allopurinol, although uncommon, may be severe or life-threatening and occur more often in

patients with renal insufficient.

Febuxostat is a potent xanthine oxidase inhibitor, has minimal effects on other enzymes involved in purine

and pyrimidine metabolism, and is metabolized mainly by glucuronide formation and oxidation in the liver.

Febuxostat is poorly soluble and aqueous solubility. Rapid onset of action is desirable to provide fast relief

in treatment of gout. Therefore, it is necessary to enhance the aqueous solubility and dissolution rate of

Febuxostat to obtain faster on set of action, minimize the variability in absorption and improve its oral

bioavailabity.1, 2

MATERIAL AND METHODS

Materials

Febuxostat was gifted by Cadila pharmaceutical Ltd. Acrysol K-160 was gifted by Corel Chemical Ltd,

Ahmedabad. Capmul PG 8 NF and Capmul MCM NF was gifted from Abitec Corporation, USA.

Transcutol P and Transcutol CG was gifted from gattefosse, Mumbai

Solubility study of Febuxostat in various excipients

Unknown amount of selected vehicles was added to each cap vial containing an excess of Febuxostat. After

sealing, the mixture was heated at 40˚C in a water bath to facilitate the solubilization. Mixing of the

systems was performed using a vortex mixer. Formed suspensions were then shaken with a shaker at 25˚C

for 48 h. After reaching equilibrium, each vial was centrifuged at 3000 r/min for 5 min, and excess

insoluble LOV was discarded by filtration using a membrane filter (0.45 μm, 13 mm, Whatman, India).

The concentration of Febuxostat was then quantified by UV spectrophotometer. Solubility study was

performed at three times and standard deviation was calculated.

Physicochemical compatibility of Febuxostat to excipients

An FTIR-8400s spectrophotometer (Shimadzu, Japan) equipped with attenuated total reflectance (ATR)

accessory was used to obtain the infrared spectra of drug in the isotropic mixture of excipients, analysis of

pure drug, physical mixtures of the drug with the excipients (Capmul PG 8 NF, Acrysol K-160, Transcutol

P) were carried out using diffuse reflectance spectroscopy (DRS)-FTIR with KBr disc. for the preparation

of solid SMEDDS, the selected liquid SMEDDS (Febuxostat 40mg) formulation was mixed with solid

carrier Aerosil 200.briefly,the SMEDDS was added drop wise over the solid adsorbent contained in a

porcelain dish. After each addition the mixture was homogenized using glass rod to ensure uniform

distribution of the formulation the resultant damp mass passed through sieve no.120 dried ambient



temperature and stored until further use, for each the spectrum, 8 scans were obtained at a resolution of 4

cm-1

from a frequency range of 4000-400cm-1

Pseudo-ternary phase diagram study

Surfactant (Acrysol k-160) and co-surfactant(Transcutol P) were mixed (Smix)in different volume ratios

(1:1, 2:1, 2.5:1)for each phase diagram, oil(Capmul PG 8 NF) and specific surfactant/co-

surfactant(Smix)ratio were mixed thoroughly in different volume ratios from 1:9 to

9:1(1;9,2:8,3:7,4:6,5:5,6:4.7:3,8:2,9:1)in different glass vials. Pseudo-ternary phase diagram was developed

using aqueous titration method. Slow titration with aqueous phase was performed for each combination of

oil and Smix separately. The amount of aqueous phase added was varied to produce a water concentration

in the range of 5% to 95% of total volume at around 5% time intervals. This system is that scale-up of the

proportions is easy, as the system is thermodynamically stable. After each 5% addition of the aqueous

phase to the oil:Smix mixture, visual observation was made and recorded.in a similar manner, calculations

for the other ratio of oil and Smix were also done. For each Smix ratio, a separate phase diagram was

constructed, and for each phase diagram visual observations were recorded. The pseudo ternary phase

diagram was constructed using CHEMIX software based on the visual observations noted.in figure only

microemulsion points are plotted(shaded area),so that there is no overcrowding of the phases in the

diagram, as for formulation development only the microemulsion area is of interest.

FORMULATION OF SMEDDS

The formulation was prepared by initially dissolving required quantity of Febuxostat in oil. Then surfactant

and co-surfactant mixer were added and final mixture was mixed by vortexing until a clear solution was

obtained. The formulation was equilibrated at ambient temperature for at least 48 hrs, and examined for

signs of turbidity or phase separation, self-emulsification and particle size studies. Final formulation in

hard gelatin capsule (size 00).

Table 1: SMEDDS formulation of Febuxostat

Ingredient Batch (in mg)

F1 F2 F3 F4 F5 F6 F7

Capmul PG 8 NF 200 250 150 200 250 150 200

Acrysol k 160 400 375 566 533 500 604 570

Transcutol P 400 375 284 267 250 246 228

Febuxostat 80 80 80 80 80 80 80

*Amount of drug in 1gm SMEDDS Formulation



Visual assessment

Febuxostat SMEDDS concentration (approximately 0.2ml) was diluted with purified water (100) and

gently stirred with magnetic stirrer. Temperature should 37°C.These were shown in table 2, Result

shown in Table no.3

Table: 2 visual assessments

Grade Dispersibility and appearances Time of self-micro

emulsification

I Rapid forming microemulsion which is clear

or slightly bluish in appearance

< 1 min

II Rapid forming, slightly less clear emulsion,

which has a bluish white appearance

< 2 min

III Bright white emulsion (similar to milk) < 3 min

IV Dull, grayish white emulsion with a slightly

oily appearance that is slow to emulsify

>3min

V Exhibit poor or minimal emulsification with

large oil droplets present on the surface

>3 min

Transmission test

Stability of optimized microemulsion formulation with respect to dilution was checked by measuring

transmittance through UV spectrophotometer (UV 1800, Shimadzu).transmittance of samples was

measured at 650nm. Result shown in Table no.4

Determination of self-emulsification time

The efficiency of self-emulsification of oral SMEDDS was assessed using a standard USP dissolution

apparatus -II. The time needed for a pre-concentrate to form homogeneous mixture upon dilution, was

monitored by both visual observation .One ml of each formulation was added to 500 ml of water at 37 ±

0.5°C. A standard stainless steel dissolution paddle rotating at 50 rpm provided mild agitation. Result

shown in Table no. 5

Drug Content

Febuxostat from SMEDDS formulation was extracted in methanol using sonication technique. The

solutions were filtered, using wattman filter paper. The methanolicextract was analyzed for the

Febuxostat content spectrophotometrically (UV-1800, Shimadzu, japan) at 315 nm using standard

curve. Result shown in Table no.6

Robustness to dilution

These systems when diluted with excess of water, standard phosphate buffer pH 6.8 and 0.1N HCl (500-

900 ml) and were stored for 12 hrs give no precipitation or phase separation. Result shown in Table no.7



Droplet size analysis and poly dispersibility index (PDI)

Formulations (P1 to P7) each of 1ml were diluted with 100ml of water in a volumetric flask. The

volumetric flask was inverted twice to ensure complete dispersion of the formulation. After ensuring

complete dispersion of the formulation the droplet size of resultant microemulsion was determined by

photon correlation spectroscopy that analyze the fluctuation in light scattering due to the Brownian

motion of the droplets as function of time using a zetasizer nano series (Malvern instruments) light

scattering was monitored at 25°C at 90° angle value of droplet size and PDI.

Zeta potential measurement

Zeta potential of the formulations (P1 to P7) with deylamine, without oleylermine was measured by

using Malvern zetasizer (Malvern instruments) equipped with a 4.0mw He-Ne red laser (633nm)

zetasizer measures the potential ranged from -120 to 120 for measurement of zeta potential 2gm of each

formulations were diluted with 100 zeta potential values are mentioned in table 8

In Vitro Dissolution Studies

The quantitative in vitro release test was performed in 900 mL of phosphate buffer pH 6.0 using USP

dissolution apparatus-II paddle type (TDT 08L, Electrolab, Mumbai, India). The paddles were rotated at

75 rpm. The SMEDDS formulations were put into hard gelatin capsules (00 sizes) and used for drug

release studies; results were compared with Furic (40 mg) tablet. During the release studies, a 5 ml

Samples were withdrawn at pre-determined time intervals (05, 10, 15, 20, 25,30 and 40 min) and

filtered using a 0.45 μm filter. An equal volume of the respective dissolution medium was added to

maintain the volume constant. The drug content of the samples was assayed at 315nm drug release.

Thermodynamic Stability

1.Heating cooling cycle: Six cycles between refrigerator temperature 4°C and 45°C with storage at

each temperature of not less than 48 h was studied .stable formulations at these temperatures, were

subjected to centrifugation test.

2. Centrifugation: passed formulations were centrifuged at 3500 rpm for 30min.

Formulations that did not show any phase separation was taken for the freeze thaw stress test. Result

shown in Table no.9 and 10

RESULT AND DISCUSSION

Solubility of Febuxostat in various excipients

Solubility studies were carried in different surfactant, co-surfactant, oils and co-solvents. The results of

these studies are mentioned in figure 1, 2, 3. On the basis of solubility studies, amongst the different



surfactant the drug has high solubility in Acrysol K160. Whereas Capmul PG 8 NF provided higher

solubility than other lipids. Transcutol P has a higher solubility than oils and co-surfactant.

Figure 1 : Schematic diagram of drug solubility in different oils

Figure 2: Schematic diagram of drug solubility in different surfactant

Figure 3: Schematic diagram of drug solubility in different Co-surfactant

0

50

100

Sun

flow

er o

il

Cas

tor

oil

Corn

oil

Cap

ryol

90

Cap

mul G

MO

Oli

c ac

id

Oli

ve

oil

Soya

bea

n o

il

Cott

on

seed

oil

Sea

sam

oil

Lin

seed

oil

Pen

ut oil

Cap

mu

l …

Cap

tex 2

00P

Capm

ul …

Lab

rafa

c

Capm

ul …

Solubility (mg/gm)

Solubility …

050

100150200250300350400

Solubility (mg/gm)

Solubility (mg/gm)

050

100150200250300350

Transcutol CG

PEG 400 Propylene glycol

Transcutol P

Solubility(mg/gm)

Solubility(mg/gm)



Physicochemical compatibility of drug to polymer

Functional Group Frequency of Pure Drug (cm-1

) Frequency of

formulation

O-H stretch 3072.71,2816.16,2548.05 3074.76,2823.25,2550.09

C-H stretch 2875.96 2875.91

C=O 1678.13 1678.13

N-H 1518.03 1520.13

The FTIR spectra of pure drug and overlapping spectra of formulation show in Figure there is no

significant change in characteristic peaks of pure drug and formulation. So, it indicates that formulation

was compatible with excipients.

Construction of ternary phase diagram

After performing solubility studies, components in which drug showed more solubility put forwarded for

phase behavior study. In present study, combinations of surfactant (Smix) with high and low HLB value

were used. Capmul PG 8 NF has low HLB value and Acrysol k-160 having higher HLB value.

Combination of low and high HLB surfactant leads to more rapid dispersion and finer emulsion droplet

size on addition to aqueous phase. Capmul PG 8 NF and Acrysol k-160 in the ratio of 2:1 should wider

microemulsion existence area and rapid emulsification compared with 1:1, thus 2:1 Smix selected for

formulation development.



Figure 4: Pseudo-Ternary Phase diagram of Surfactant (Acrysol K-160)/Co-surfactant (Transcutol

P) ratio: (2:1) and Oil (Capmul PG 8 NF)

VISUAL ASSESSMENT

Table 3: visual assessment of various formulations

GRADE- I Transmission test

%Transmittance was measured by directly taking the absorbance of the diluted SMEDDS.no significant

was observed among the percentage transmittance of formulations P1 to P7 and formulation P4 was found

to have the highest percentage transmittance A value of percentage transmittance closer to 100% signifying

that all of the formulations were clear and transparent. Besides signifying clarity of the formulation, a

percentage transmittance closer to 100% also indicates that the size of the globules in the formulation is in

Formulation code Grade

P1 I

P2 I

P3 I

P4 I

P5 I

P6 I

P7 I



the nanometer range. This in turn indicates that the drug in the formulation has a large surface area for

release.

Table 4: %transmission test of SMEDDS formulation in water

Determination of self-emulsification time

The efficiency of self-emulsification could be estimated primarily by determining the rate of emulsification

which is an important index for the assessment of the efficiency of emulsification that is the SMEDDS

should disperse completely and quickly when subjected to aqueous dilution under mild agitation. The

emulsification time of these formulations were in the range of 17.08 – 30.3sec.

Table 5: Emulsification times of formulations

Formulation Code Emulsification Time (sec)

P1 17±0.81

P2 25.3±0.4

P3 20±0.81

P4 17±0.81

P5 27±0.8

P6 28±0.81

P7 30.3±0.41

*values are expressed as mean ± S.D, n=3

Drug Content

Difference in composition the drug content of formulations P1 and P7 was found in range of 98.3% -

101.2%.

Table 6: %drug content of P1 to P7 Formulation

Formulation code %drug content

P1 101.2

P2 99.3

P3 99.5

P4 99.7

P5 98.4

P6 100.7

P7 99.3

Formulation code Transmittance (%)

P1 98.3±0.21

P2 98.1±0.45

P3 98.6±0.18

P4 99.4±0.29

P5 99.2±0.16

P6 99.0±0.08

P7 97.76±0.12



Robustness to dilution

Robustness to dilution was performed diluted with excess of water, standard phosphate buffer pH 6.8 and

0.1N HCl 900 ml and was stored for 12 hours gives no precipitation or phase separation was found and

result were shown in table 7

Table 7: Robustness to dilution

Vehicles P1 P2 P3 P4 P5 P6 P7

Distilled

water

√ √ √ √ √ √ √

0.1N HCl √ √ √ √ √ √ √

Phosphate

buffer pH 6.8

√ √ √ √ √ √ √

Droplet size measurement

The mean droplet size and polydispersity index (PI) were calculated from intensity, volume and bimodal

distribution assuming spherical particles. PI is a measure of particle homogeneity and it varies from 0.0 to

1.0. The closer to zero the Polydispersity value the more homogenous are the particles. It may be seen that

optimized SMEDDS show very small particle size and upon 100 fold dilution with water. This suggests

that upon dilution with gastric fluid in body, optimized microemulsion formulation will remain stable and

will not convert into macro emulsion. Droplet size and PI was mentioned in Table 8

Droplet size of microemulsion is generally between 10 to 200 nm. Formulations P2, P3, P4, P5, P6 and P7

have droplet size in between17.08-167.8 nm; PI is also near to zero. It indicates all particles in SMEDDS

are more homogeneous.

Figure 5: Droplet size Distribution of Batch P4

Zeta potential measurement

Zeta potential results of all SMEDDS formulations and it’s 100 times diluted with water. Results are shown

in Table 8 Zeta potential of all SMEDDS formulation was found between –10.7 to -36.8 mV in the 100



times diluted. SMEDDS formulation consist of non-ionic components which show relatively neutral charge

it means it will not affected by body membrane charge during absorption.

Figure 6: Zeta Potential Determination of Batch P4

Table 8: Droplet size, PDI, Zeta potential of P1 to P7 Formulation

Formulation

code

Average droplet size

(water)

PDI Zeta potential

P1 210.5 nm 0.312 -10.7 mV

P2 161.4 nm 0.346 -36.8 mV

P3 69.29 nm 0.454 -12.1 mV

P4 17.08 nm 0.230 -14.5 mV

P5 138.4 nm 0.106 -13.6 mV

P6 49.12 nm 0.376 -11.7 mV

P7 167.8 nm 0.366 -32.5 mV

In Vitro Dissolution Studies

In-Vitro dissolution studies were performed to compare SMEDDS formulation of Febuxostat and marketed

formulation 40mg Febuxostat tablet, formulation releases more than 85% drug within 30min while release

rate is very slow in case marketed formulation.

Dissolution studies were performed for the SMEDDS formulation in 6.0 pH phosphate buffer solution. The

quantitative release of the Febuxostat from the SMEDDS is droplet size dependent. This suggests that large

interfacial area present in Microemulsions with smaller drops promotes rapid drug was increased by

decreasing the Microemulsions droplet size. Suggesting that release rate of poorly water soluble drug like

Febuxostat could be controlled by selecting the mean droplet size in the carrier emulsion generated from

SMEDDS.

SMEDDS formulation resulted in spontaneous formulation of a microemulsion with a small droplet size

which permitted a faster rate of Febuxostat release in dissolution media. Formulation P4 give release in



40minute due to smallest particle size (17.08nm) and less PDI value (0.230). On the basis ofin-vitro release

study formulation P4 is optimize with give 99.49% release in 40min.

SMEDDS formulations were found to be significantly higher as compared with that of Febuxostat tablet

(Feburic, 40mg)

Figure 7: Dissolution profile of SMEDDS Formulation and Marketed formulation

(Furic 40mg Febuxostat Tablet)

Thermodynamic Stability

SMEDDS are thermodynamically stable system and are formed at a particular concentration of oil,

surfactant, co-surfactant and water with no phase separation, creaming, or cracking. It is the thermo

stability which differentiates microemulsion from emulsions that have kinetic stability and will eventually

phase separation, thus the selected formulations were subjected to different thermodynamic stability by

using heating cooling cycle and centrifugation stress tests.

Table 9: Temperature stability study of P1 to P7 Formulation

Formulation Code Phase Separation Flocculation Precipitation

P1 Not Seen Not Seen Not Seen






P7 Not Seen Not Seen Seen



Table 10: Centrifugation Stability of P1 to P7 Formulation

Formulation code Phase separation

P1 Not Seen

P2 Not Seen

P3 Not Seen

P4 Not Seen

P5 Not Seen

P6 Not Seen

P7 Seen

CONCLUSION

Febuxostat is a potent xanthine oxidase inhibitor (Anti-hyperuricemia). It is a lipophilic drug (log P 3.52),

poorly water soluble drug with absolute bioavailability of 49%.SMEDDS of Febuxostat was prepared and

optimized by using in vitro parameters like particle size, polydespersity index, zeta potential and in vitro

release studies. Optimal SMEDDS contains Capmul PG 8 NF as oil phase, Acrysol k-160 as a surfactant,

and Transcutol P as a co-surfactant were selected on the basis of solubility and emulsification ability.

Febuxostat was formulated as a SMEDDS in an attempt to increase its solubility.an optimized formulation

of SMEDDS containing Febuxostat was development through the construction of pseudo-ternary phase

diagram. The combination of all three components i.e. oil/surfactant/co-surfactant formulates P4 SMEDDS

with lower particle size17.08nm, PDI 0.230 and zeta potential -14.5mV

This optimized SMEDDS showed good in vitro release which is increased. When compared with marketed

formulation Furic (40mg) tablet. SMEDDS offers a promising approache to increase solubility and

bioavailability of poorly water soluble Febuxostat.

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3. Rao P.B, Beny B and Durgaprasad Y, “Formulation and Evaluation of SMEDDS with Capmul MCM

for Enhanced Dissolution Rate of Valsartan” Journal Pharmaceutical Science, Apr–June 2013, pp.34-

40.



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