Nagesh C et al. IRJP 2 (8) 2011 100-104

IRJP 2 (8) August 2011 Page 100-104

INTERNATIONAL RESEARCH JOURNAL OF PHARMACY ISSN 2230 – 8407 Available online http://www.irjponline.com Research Article

IMPROVING THE SOLUBILITY OF ANTIHELMINTIC DRUG BY SOLID DISPERSIONS

AND INCLUSION COMPLEXES Kumar Vijay1, Venkatesh JS1, Shankaraiah MM1, Kant Aman1, Nagesh C*2

1S.C.S. College of Pharmacy, Harapanahalli-583131, Karnataka, India 2Maratha mandal’s College of Pharmacy, Belgaum, Karnataka, India

Article Received on: 02/07/11 Revised on: 01/08/11 Approved for publication: 16/08/11

*Dr. C. Nagesh, Professor, Department of Pharmaceutics, Maratha Mandal’s College of Pharmacy, Belgaum, Karnataka, India Email: nagesh_73@rediffmail.com ABSTRACT Fenbendazole is an Antihelmintic drug (BCS class 2) and poorly soluble in water. Fenbendazole is used as a model drug. This study was conducted to enhance the bioavailability by increasing the aqueous solubility of Fenbendazole. The solid dispersions were prepared with polyvinylpyrrolidone K-25 (PVP K25) and Urea, Inclusion complexes with beta-cyclodextrin (BCD). Solid dispersions and inclusion complexes are prepared by Kneading and Solvent evaporation methods using different drug-polymer ratio like 1:2, 1:4and 1:6. The prepared formulations were characterized for FTIR, drug content, Phase solubility, percent yield and in vitro release studies followed by various release kinetics. The drug content uniformity was found to be good in all formulations. Kinetic profile showed good linearity with first order i.e. exhibiting concentration dependent release of drug. The result indicated that the solubility and dissolution rates of all formulation were significantly increased by solid dispersions and cyclodextrin complexes when compare to pure drug. Dissolution of the pure drug more with beta cyclodextrin complexes than solid dispersion (PVPK25) and Urea. Among all the formulations, VA3 drug-beta-cyclodextrin ratio was found to be better. The result confirmed that beta-cyclodextrin (BCD) showed better solubility and dissolution characteristics when compared to polyvinylpyrrolidone K-25 (PVP K25) and Urea. Key words: Fenbendazole (FBz), beta-cyclodextrin, PVPK25, Urea and In-vitro drug release. INTRODUCTION Oral drug delivery is the simplest and easiest way of administering drugs. Because of the greater stability, smaller bulk, accurate dosage and easy production, solid oral dosages forms have many advantages over other types of oral dosage forms. Therefore, most of the new chemical entities (NCE) under development these days are intended to be used as a solid dosage form that originate an effective and reproducible in vivo plasma concentration after oral administration. In fact, most NCEs are poorly water soluble drugs, not well-absorbed after oral administration, which can detract from the drug’s inherent efficacy. Moreover, most promising NCEs, despite their high permeability, are generally only absorbed in the upper small intestine, absorption being reduced significantly after the ileum, showing, therefore, that there is a small absorption window. Consequently, if these drugs are not completely released in this gastrointestinal area, they will have a low bioavailability. Therefore, one of the major current challenges of the pharmaceutical industry is related to strategies that improve the water solubility of drugs1. Lipophilic molecules, especially those belonging to the biopharmaceutics classification system (BCS) class II

and IV, dissolve slowly, poorly and irregularly, and hence pose serious delivery challenges, like incomplete release from the dosage form, poor bioavailability, increased food effect, and high inter-patient variability2. Different kinds of techniques have been used to enhance the solubility and dissolution rate of poorly water soluble drugs or lipophilic drugs. Out of them, the solid dispersion technique3–5 and the inclusion complexes with cyclodextrins6–8 are used very commonly. Hydrophilic polymers have been widely accepted carriers for solid dispersion technique; Polyvinylpyrrolidone (PVP) and urea have been used very commonly due to their low cost and high aqueous solubility. Both polymers are freely soluble in water and are available in various molecular weights (10,000 to 700,000 for PVP). The molecular size of polymers helps in the formation of interstitial solid solutions 9–11. Cyclodextrins is pharmaceutical excipients and mainly used to increase the aqueous solubility and dissolution rate of drugs. Number of molecules is solubilized in cyclodextrin solutions through formation of an inclusion complex12. Cyclodextrin can also be used to prevent drug-drug and drug-additive interaction, convert liquid drugs into microcrystalline powder, and decrease the

Nagesh C et al. IRJP 2 (8) 2011 100-104

IRJP 2 (8) August 2011 Page 100-104

volatility, and modify gastrointestinal or ocular irritation and to mask the unpleasant taste or odor of drugs13. FBz is poorly water soluble drug (BCS class 2). It makes a suitable candidate for solid dispersion and inclusion complexes. The main objective of this work was to investigate the possibility of improving the solubility and dissolution rate of FBz by (a) solid dispersion with PVP K25, Urea and (b) complexation with B-cyclodextrin. In order to characterize the prepared dispersions and inclusion complexes, analyses using FTIR as well as dissolution and solubility studies etc. were carried out. MATERIAL AND METHODS FBz was obtained from Karnataka antibiotics pharmaceutical limited, Bangalore (India) as a gift sample. Polyvinylpyrrolidone K-25 (PVP K25), beta-cyclodextrin, methanol etc were purchased from S.D Fine chemical limited, Mumbai (India). All other chemicals and reagents used in this study were of analytical grade. Method of preparations Solid dispersions

Solid dispersions of FBz in PVP K25 and Urea containing three different ratios (1:2, 1:4, and 1:6 w/w) were prepared by the solvent evaporation method. Accurately weighed amount of FBz and the polymers were dissolved in a minimum amount of methanol. The solvent was then removed by evaporation under reduced

pressure at 40o C. The resulting residue was dried and stored overnight in desiccators. After drying the residue as ground in a mortar, and then passed through a 60 no sieve. The resultant formulations were stored in desiccators until further investigation14-17. Inclusion complexes Kneading method was used for the preparation of inclusion complexes. Here beta cyclodextrin and pure drug was taken in mortar and little amount of water was added and mixed to obtained a homogeneous paste. Slowly, slurry was kneaded for 45 mins and then dried at 450C. The dried mass was pulverized and sieved through mesh no 60. The resultant formulations were stored in desiccators until further investigation shown in table 1. Evaluation of prepared solid dispersions and inclusion complexes Drug content

Preparation equivalent to 50 mg was weighed accurately and dissolved in small volume of methanol and after suitable dilution with 0.1N Hcl the absorbance was measured at 293nm using UV spectrophotometer (Shimadzu 1700) 18. Percentage yield Percentage practical yield were calculated to know about percent yield or efficiency of any method, thus it helps in selection of appropriate method of production. Solid dispersions were collected and weighed to determine practical yield (PY) from the following equation:

Practical weight of Solid dispersion Percentage yield = x 100 …………… (1) Theoretical weight of Solid dispersion In vitro drug release studies The dissolution studies of FBz and different drug – polymer concentration were performed in water at 370c. Sample equivalent to 50mg and FBz 50mg were added to 900ml of distilled water, which was stirred with a rotating basket at 50 rpm. The sample (5ml) withdrawn at different time intervals was filtered through whatmann filter paper. And analyzed spectrophotometrically at 293nm19. Determination of solubility Phase solubility studies carried out according to Higuchi and Connors method. Excess amounts of FBz added to water at room temperature. The suspensions formed were equilibrated under continuous agitation for 3days and then filtered through a 0.45 µm membrane filter to obtain a clear solution. Similarly excess amount of FBz was added to aqueous solutions containing various concentrations of PVP K25, Urea, Beta-cyclodextrin (5, 10, 15 and 20% w/v, respectively). The suspensions were

shaken at 37±0.5 ◦C for 3 days, and then the samples were filtered through a 0.45 µm membrane filter. The FBz concentrations were determined using the spectrophotometric method20. Release kinetic To study the release kinetics, the data obtained from in vitro drug release studies were plotted in Various kinetic models. Zero order, as cumulative amount of drug released vs. time, describes concentration Independent drug release rate from the formulation (Equation 2)

C = kot (1) ……… (2) Where ko is the zero-order rate constant expressed in units of concentration/time and t is the time in hours. First order, as log cumulative percent drug remaining vs. time, describes concentration dependent drug release from the system. (Equation 3)

Nagesh C et al. IRJP 2 (8) 2011 100-104

IRJP 2 (8) August 2011 Page 100-104

LogC= LogC0- kt/ 2.303 ……….. (3) Where C0 is the initial concentration of drug and k is the first order constant Higuchi’s model [10], as cumulative percentage of drug released vs. square root of time, described the release of drug based on Fickian diffusion as a square root of time dependent process from swell able insoluble matrix. (Equation 4)

Q = kt1/ 2 …………… (4) Where k is the constant reflecting the design variables of the system Infrared spectroscopy The Infrared spectra (IR) of FBz and some selected preparations were obtained using FTIR (Perkin Elmer 1600 Series). The IR spectroscopy was carried out by KBR pellet method. Stability studies Stability studies on all solid dispersions were performed by storing at different temperatures (15, 32, 40 and 50 ◦C) for 30 days. The sample was analyzed for drugs content and dissolution profile. RESULTS AND DISSCUSSION Drug content analysis The content of FBz in each preparation was assayed by UV spectroscopy. All the formulation has shown better drug content. It indicates that the drug was uniformly dispersed in all formulation. Therefore, the method used in this study appears to be reproducible for the preparation of solid dispersions and complexes shown in table:2. Percentage yield Percentage practical yield were calculated for all the formation and show good percentage yield Kneading method give good percentage yield when compare to solvent evaporation method shown in figure:1 In vitro drug release The in vitro drug release characteristics of different types of preparations were compared with the pure drug. The solid dispersions and complexations of FBz with PVPK25, urea, and beta-cyclodextrin have shown improved dissolution when compared with pure drug. Dissolution of FBz increased with increase in proportion in all the polymers. Dissolution of the drug more with beta cyclodextrin complexes than other formulations. Among all the formulations, VA3 drug-betacyclodextrin ratio was found to be better with respect to dissolution shown in figure:2, Release kinetics Drug release data was analyzed according to zero order, first order, Higuchi square root, (table 3).The regression coefficients obtained for zero order kinetics (R2= 0.965 to 0.996), for first order kinetics (R2= 0.720 to 0.999),

and for Higuchi model (R2= 0.959 to .0987) The correlation coefficient (r) values of the first order release model are found to be slightly higher when compared to the zero order kinetics and Higuchi model. Hence the release of drug from the preparations followed predominantly first order kinetics. First order kinetics show good linearity indicating that drug release dependent upon concentration from all formulation shown in table:3 and figure :3, 4.

Zero order < first order > Higuchi Solubility studies The solubility of FBz in water at 37 ◦C was found to be 1.1µg/ml. In the phase-solubility diagrams (Fig. 5), the results that the concentration of FBz in water increased as a function of PVP K25, Urea and beta-cyclodextrin concentration were observed at room temperature. The improvement of the solubility due to presence of hydrophilic excipients might be attributed to the improved wetting properties of FBz shown in figure:5. Stability studies The samples stored at different ambient temperatures did not show significant changes in the drugs content & dissolution profiles of FBz. Infrared spectroscopy FTIR of pure FBz showed sharp characteristic peaks and all above characteristic peaks appear in the spectra of all formulation at the same wave number. We found that from the FTIR spectra of pure drug and all formulation there is no interaction between pure drug and hydrophilic polymers. CONCLUSION The solid dispersion and inclusion complexes of FBz were prepared and elevated. It was confirmed from our study that the increased solubility and dissolution rate of FBz has been achieved by both solid dispersion with PVPK25, Urea and by inclusion complexes with Beta-cyclodextrin. Based on the results, the result confirmed that beta-cyclodextrin (BCD) has shown better solubility and dissolution characteristics when compared to polyvinylpyrrolidone K-25 (PVP K25) and Urea. Solid dispersion and inclusion complexes based solid dosage forms could be formulated for better dissolution and bioavailability. ACKNOWLEDGEMENT Author’s are thankful to T.M.A.E’.s SOCIETY and Principal of S.C.S. College of Pharmacy, Harapanahalli (India) for providing research laboratory to carry out this project work and also extend thanks to Karnataka Antibiotics Pvt. Ltd., Bangalore for providing gift sample of FBz.

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IRJP 2 (8) August 2011 Page 100-104

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Table: 1Detail of formulation

Formulation code

Polymer Drug:polymer ratio

Method used

V1 PVPK25 1:2 Solvent evaporation

method V2 PVPK25 1:4 ,,

V3 PVPK25 1:6 ,,

VL1 Urea 1:2 Kneading method

VL2 Urea 1:4 ,,

VL3 Urea 1:6 ,,

VA1 Beta-cyclodextrin

1:2 Kneading method

VA2 Beta-cyclodextrin

1:4 ,,

VA3 Beta-cyclodextrin

1:6 ,,

Table: 2 Drug content

S. no Formulation code Amount of drug % drug content

1 VI 45.76 91.12

2 V2 47.95 95.23

3 V3 46.85 92.28

4 VA1 46.87 93.70

5 VA2 48.12 96.24

6 VA3 46.14 92.28

7 VL1 42.27 84.54

8 VL2 44.54 89.08

9 VL3 45.10 90.20

Table: 3 Release kinetic

Formulation code Zero order (r2)

First order (r2) Higuchi (r2)

V1 0.976 0.840 0.984

V2 0.986 0.932 0.977

V3 0.993 0.999 0.987

VA1 0.976 0.720 0.966

VA2 0.981 0.903 0.97

VA3 0.971 0.991 0.986

VL1 0.965 0.720 0.979

VL2 0.981 0.840 0.959

VL3 0.996 0.976 0.967

Nagesh C et al. IRJP 2 (8) 2011 100-104

IRJP 2 (8) August 2011 Page 100-104

Fig: 1 Percentage yield of all formulation

Fig.2 Dissolution of FBz from all solid dispersions and inclusion complexes

Fig: 4 Higuchi release model of FBz from solid dispersions and Complexation

Fig.5 Phase solubility diagram for FBz in the presence of PVP, BCD, and Urea in water at room temperature

Fig: 3 first order release of FBz from solid dispersions and Complexation

Source of support: Nil, Conflict of interest: None Declared