DISSOLUTION RATE ENHANCEMENT OF PIOGLITAZONE BY SOLID DISPERSION TECHNIQUE

Transcription

1 Page2664 Indo American Journal of Pharmaceutical Research, 2015 ISSN NO: DISSOLUTION RATE ENHANCEMENT OF PIOGLITAZONE BY SOLID DISPERSION TECHNIQUE Prabhjot Kour 1, Mahesh Kumar Kataria 2, Ajay Bilandi 3 1 Student, M. Pharmacy 4 th Semester (Pharmaceutics), Seth G.L. Bihani S.D. College of Technical Education, Sri Ganganagar. 2 Professor and Head of Department (Pharmaceutics), Seth G.L. Bihani S.D. College of Technical Education, Sri Ganganagar. 3 Assistant Professor, Seth G.L. Bihani S.D. College of Technical education, Sri Ganganagar. ARTICLE INFO Article history Received 29/07/2015 Available online 31/07/2015 Keywords Solid Dispersion, Dissolution Enhancement, Poorly-Soluble Drugs, Solvent Evaporation Method, Croscarmellose Sodium, Sodium Starch Glycolate. ABSTRACT Pioglitazone an oral hypoglycaemic second generation agent is characterized by low solubility in gastric fluid, low dissolution rate and inter-individual variability in bioavaibility. The objective of study was therefore to design optimized solid dispersion of Pioglitazone with polymer like Croscarmellose sodium and sodium starch glycolate. The binary systems i.e. both physical mixtures as well as solid dispersions were prepared with drug and polymers. The solid dispersions were prepared by solvent evaporation method. Infrared spectroscopy was performed to identify any physicochemical interaction between the drug and the carrier. Tablets containing best solid dispersion formulation, optimized, having Croscarmellose sodium (1:5 ratio of Pioglitazone & Croscarmellose sodium) were formulated and compared with the commercial conventional release product. The tablets formulation under investigation was then characterized for their various physicochemical properties such as weight variation, percentage friability, disintegration and in vitro dissolution profiles. A significant improvement in the dissolution of Pioglitazone in solid dispersion products has been observed (>91% within 60 minutes). Tablets containing solid dispersion exhibited better dissolution profile than commercial tablets with same release kinetics i.e. higuchi model. Thus, it may be concluded that solid dispersion technique can be successfully used for the improvement of dissolution of Pioglitazone. Corresponding author Prabhjot kour Student, M. Pharmacy 4 th semester (Pharmaceutics), Seth G.L. Bihani S.D. College of Technical education, Sri Ganganagar. Please cite this article in press as Prabhjot kour et al. Dissolution Rate Enhancement of Pioglitazone By Solid Dispersion Technique. Indo American Journal of Pharm Research.2015:5(07). Copy right 2015 This is an Open Access article distributed under the terms of the Indo American journal of Pharmaceutical Research, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

2 Page2665 INTRODUCTION More than 40% NCEs (new chemical entities) developed in pharmaceutical industry are practically insoluble in water, The solubility and dissolution properties of drugs play an important role in the process of formulation development hence solubility is a major challenge for formulation[1]. The important aspect which may greatly affect the performance of the drug is solubility for the proper absorption of drug in body. This is an important physicochemical property of drug, especially aqueous solubility. To exert better therapeutic efficacy or better bio-availability, the drug must be in solution state and to have drug in the solution state, it must have high dissolution rate and high solubility. Thus the bio-availability of poorly water soluble drug is often limited to its dissolution rate. A drug with poor aqueous solubility typically exhibit dissolution rate limited absorption. Several methods have been introduced to overcome this problem [2,3,4]. Pioglitazone, a widely prescribed oral antidiabetic drug belongs to class II under BCS and exhibit low and variable oral bioavailability due to its poor aqueous solubility. As such the oral absorption of Pioglitazone is dissolution rate limited and it requires enhancement in the solubility and dissolution rate for increasing its oral bioavailability. Several techniques such as Micronization, Cyclodextrin Complexation, use of surfactants and Solubilizers, solid dispersion in water soluble and dispersible carriers, use of salts, pro drugs and polymorphs which exhibit high solubility, micro emulsions and self emulsifying micro and nano disperse systems have been used to enhance the solubility, dissolution rate and bioavailability of poorly soluble drugs. Among the various techniques solid dispersion in water soluble and insoluble excipients is a simple and industrially useful technique for enhancing the dissolution rate of poorly soluble drugs [4, 5]. Pioglitazone is, (RS)-5-(4-[2-(5-ethylpyridine-2-yl) ethoxy] benzyl thiazolidine-2,4 dione has molecular weight and chemical formula is C 19 H 2 ON 2 O 3 S.HCl, as shown in figure 1. Figure-1-Structure of Pioglitazone. Pioglitazone contains not less than 90.0 per cent and not more than per cent of C 19 H 2 ON 2 O 3 S.HCl, calculated on anhydrous basis. It is a Thiazolidinedione antidiabetic agent that depends on the presence of insulin for its mechanism of action1, 2. PG is a potent and highly selective agonist for peroxisome proliferators-activated receptor-gamma (PPARg). The drug decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output [6,7]. Thus the solid dispersion of Pioglitazone may be prepared with Croscarmellose and sodium starch glycolate, the well proven and acceptable polymers having least limitations. MATERIALS Pioglitazone was kindly provided by Ananta Medicare Ltd, Sri-Ganganagar, Croscarmellose sodium (CCS) and Sodium Starch Glycolate (SSG) from Maple Biotech Pvt Ltd, Bhosari. All other chemicals and reagents used were laboratory reagent grade. METHODS PREFORMULATION STUDIES Preformulation studies focus on those physiochemical properties of the drug that could affect performance and development of an efficacious dosage form. It is necessary to determine purity of active pharmaceutical ingredient (API) before formulation of any dosage form. Preformulation studies are useful in determining the formulation components and physiochemical properties of new drug substance. Description of drug The sample of drug was observed for colour, state and solubility. Drug Identification By absorption spectrum method Accurately weighed 15 mg of Pioglitazone and dissolved in sufficient volume of methanol and 100ml 0f 0.1N HCl buffer at ph 1.2 then scan was obtained on UV-VIS spectrophotometer. The wavelength at which maximum absorbance obtained was considered as maximum wavelength (λ max ). The test spectrum was confirmed with reference spectra. i.e nm for the pure drug[8].

3 Page2666 By infra-red spectrum method Accurately weighed 15mg of Pioglitazone was mixed with KBr to prepare pallet and IRt spectrum was taken between 400nm to 4000nm and confirmed with reference spectrum [9, 10]. Drug Excipients Compatibility Study Before formulating a dosage form it is very necessary to confirm that drug is not interacting with the polymer under certain experimental conditions. Interaction among drug and polymer may affect the efficacy of final dosage form. Drug and excipients were accurately weighed and mixed and the resulting mixtures were scaled in screw glass vials and kept at a 50 C for 15 days [11]. Table 1: Quantity used for Drug Polymer Identification. No. of Vials S. No. API and Excipient Quantity per vial (mg) After 15 Days Initial 50 0 C 1. Pioglitazone Croscarmellose Sodium Sodium Starch Glycollate Development of standard calibration curve Accurately weighed 15 mg of drug, dissolved in sufficient volume of methanol and then made up volume up to 100 ml with 0.1 N HCl, phosphate buffer ph 1.2or 3 and then working solutions of different concentrations (2, 4, 6, 8, 10 and 12 μg/ml) were prepared. The absorbance was obtained at λ max 269.4nm and calibration curve was plotted between concentration and absorbance. All spectral absorbance measurements were made on Shimadzu-1700 UV-visible spectrophotometer [11]. Formulation and evaluation of physical mixture and solid dispersion Formulation Eight different formulation batches of binary systems of Pioglitazone i.e. both physical mixture and solid dispersion were prepared with two different polymers Croscarmellose sodium, sodium starch glycolate in four different ratio (1:1, 1:3, 1:5 and 1:7) as shown in Table 2 respectively [11]. Table 2 : Formulation batches with formulation code. S.NO. METHOD RATIO FORMULATION CODE Drug: Polymer CCS SSG 1 1:1 SD 1 SD5 2 Solid 1:3 SD 2 SD6 3 Dispersion 1:5 SD3 SD7 4 1:7 SD4 SD8 5 1:1 PM1 PM 5 6 Physical Mixture 1:3 PM2 PM 6 7 1:5 PM3 PM 7 8 1:7 PM4 PM8 CCS: Croscarmellose sodium, SSG: Sodium starch glycolate Formulation of physical mixture Physical mixtures of Pioglitazone were prepared by mixing Pioglitazone with the hydrophilic carriers for 5min in a mortar until a homogenous mixture was obtained. The resulting mixture was then sieved. The powders were stored in screw cap bottles in desiccators for further analysis [11]. Formulation of solid dispersion Solvent Evaporation method: Drug and polymer were taken in different ratio (1:1, 1:3, 1:5 and 1:7) to form solid dispersions by solvent evaporation method using methanol as solvent. The required amount of Pioglitazone was dissolved in sufficient volume of methanol. After that the required amount of carrier/polymer was dispersed properly. This mixture was then placed on hot plate at 45 o C with continuous stirring until no trace amount of solvent was remaining. The dried mass was scraped out with spatula, pulverized and passed through 44 mesh sieve, packed and stored in screw-cap bottles in desiccators for further analysis [14].

4 Page2667 Table3: Formulation batches of solid dispersion of Pioglitazone. Ingredients SD 1 SD 2 SD 3 SD 4 SD 5 SD 6 SD 7 SD 8 1:1 1:3 1:5 1:7 1:1 1:3 1:5 1:7 Pioglitazone CCS SSG Evaluation of Solid Dispersion The formulations of solid dispersion were evaluated by the following parameters: Percentage Practical Yield The percentage practical yield of physical mixture and solid dispersion was then calculated by using the following formula and results are shown respectively [10], Percentage Yield = 100 Dissolution study of Solid dispersion Accurately weighed preparations equivalent to 20 mg of Pioglitazone was filled into a capsule (size 0) and placed in the basket (Dissolution apparatus I) in vessel containing 500 ml of dissolution media (1.2pH HCL buffer) maintained at 37 ± 0.5 C at 100 rpm. Prefect sink conditions maintained during the drug release studies. Five milliliter aliquots were withdrawn through a 5µm membrane filter at the interval of 5, 10, 15 30, 35 and 60 min and replaced with fresh buffer dissolution media. The collected samples were analyzed spectrophotometically at λ max nm using double beam UV-visible spectrophotometer against the blank. Drug release studies were carried out in triplicate. The dissolution of pure Pioglitazone and commercial product were performed similarly and compared with solid dispersion. The release profile data were analyzed for cumulative percent dissolved at different time intervals [15]. OPTIMIZATION OF THE FORMULATION ANOVA: ANOVA was applied to determine significant difference between the formulations. The p values (table 16) showed that there was a significant difference between formulations of the drug with different polymers. The solid dispersion of Pioglitazone with Croscarmellose sodium (1:5) showed highest dug release i.e %. This optimized formulation was used for the preparation of the tablet [15]. Differential scanning calorimetry (DSC) of the optimized solid dispersion DSC studies of drug-polymer mixture and solid dispersions were performed to access what changes had actually occurred when SD were prepared. Analysis of samples was carried out on Differential Scanning Calorimeters (DSC 200F3 Maia, NETZSCH) instruments having an aluminum pan at a rate of 31 o C /10 (K/min). The measurements were performed at a heating range of 31 o C to 400 o C. Formulation and Evaluation of Tablet of Optimized Solid Dispersion Formulation Formulation of Powder blend The powder blend of optimized solid dispersion were prepared with lactose 20% as diluents, talc 1.5% as Glidant and magnesium stearate 1.5% as lubricant and mixed them properly. The quantities of all the ingredients are shown in the table 4. Table-4 : Composition of optimized solid dispersion tablet (150 mg) containing 20 mg drug. S. No. Ingredients Role Quantity per 1 tablet (mg) 1. Pioglitazone: CCS Solid dispersion 20: Lactose Diluent Talc Glidant Magnesium stearate Lubricant 1.5

5 Page2668 Evaluation of powder blend The evaluation of the powder blend was done by following parameters: Bulk density The bulk density of the formulated granules was evaluated using a bulk density apparatus. It is expressed in gm/ml and is calculated by formula, Bulk Density (ρ b ) = Tapped density The tapped volume was measured by tapping the powder to constant volume on tap density apparatus. It is expressed in gm/ml and is calculated by formula, Tapped Density (ρ t ) = = Compressibility Index and Hausner Ratio The Compressibility index (I) and Hausner s ratio (HR) measure of the property of a powder to be compressed and the flow ability of granule. Carr s index and Hausner s ratio were calculated using following formula and is given in table 15. Carr s Index (I) = 100 Hausner s ratio (HR) = Where, ρ t Tapped density of the powder, ρ b Bulk density of the powder Table 5: Carr's index & Hausner ratio of powder blend. Compressibility index (%) Flow Property Hausner ratio 5-15 Excellent Good Fair to Passable Poor Very poor >40 Extremely poor >1.60 Angle of repose Angle of repose was determined by Neumann s method and calculated by using the formula for unlubricated as well as lubricated granules. It is calculated by formula given below and shown in table 15. tanθ = Where, h = height of pile, r = radius of the pile base. θ = tan -1 Table 6: Angle of repose as an indication of powder flow properties. Flow Property Angle of Repose (Degrees) Excellent <25 Good Passable-may hang up Very poor >40 Compression of Powder Blend into Tablet Based on the dissolution profile, powder blend containing solid dispersion of Pioglitazone with cross Croscarmellose sodium (1:5) was selected as optimized formulation for the preparation of tablets. Tablets were formulated by wet granulation method using motorized single punch tablet compression machine [15].

6 Page2669 TABLET EVALUATION The following evaluation parameters were used to evaluate the tablets: Shape of Tablets Compressed tablets were examined under the magnifying lens for the shape of the tablets. Tablet thickness Thickness of tablets was measured using Vernier Calipers. It was determined by checking ten tablets from final formulation (table 16). It is expressed in mm. Hardness Hardness indicates the ability of a tablet to withstand mechanical shocks while handling. The hardness of the tablets was determined using Pfizer hardness tester (table 16). It should not be more than 5 kg/cm 2. Friability It is performed as per IP specification and shown in table 16. Maximum loss of weight (from a single test or from the mean of the three tests) not more than 1.0 per cent is acceptable for the tablets. Uniformity of Weight Weigh individually 20 units selected at random or, for single dose preparations in individual containers, the contents of 20 units, and calculate the average weight. Not more than two of the individual weights deviate from the average weight by more than the percentage shown in the table and none deviates by more than twice that percentage as shown in table 16. Disintegration test The in vitro disintegration time was determined using Disintegration Test Apparatus. To test for disintegration, one tablet was placed in each of the six tubes of apparatus and one disc was added to each tube. The basket rack assembly was positioned in ph N HCL buffer at 37±0.2 o C. The time taken for complete disintegration of the tablet with no palpable mass remaining in the apparatus was measured in minutes and is shown in table 16. In-vitro dissolution test In vitro dissolution studies for all the fabricated tablets were carried out using USP apparatus II (paddle method) in 500 ml of 0.1N HCl buffer (ph 1.2) as dissolution media, maintained at 37±0.5 o C at 50 rpm. Five milliliter aliquots were withdrawn at 5, 10, 15, 30, 45, 60 min and replaced by 5 ml of fresh dissolution media (37 o ±0.5 o C). The collected samples were analyzed after suitable dilution (if required) at λ max 269.2nm using UV-VIS spectrophotometer against HCL buffer (ph 1.2) as the blank. The release profile data were analyzed for cumulative percent dissolved at different time intervals as shown in table 12. Determination of Drug Content Solid dispersions of Pioglitazone were placed in 25 ml volumetric flask. Methanol (10 ml) was added, mixed thoroughly using a rotating shaker for 1hour. The volume was made up to the mark with methanol. The solution was suitably diluted with methanol and spectrophotometically assayed for drug content at λ max 269.4nm [18]. DRUG RELEASE KINETICS Model Independent Parameters Dissolution efficiency The dissolution efficiency (DE) of a pharmaceutical different dosage form is defined as the area under the dissolution curve up to a certain time, t, expressed as a percentage of the area of the rectangle described by 100% dissolution in the same time. It is calculated by following equation: DE= Where SA is shaded area and R is rectangle area (y 100 ) y is the drug percent dissolved at time t.

7 Page2670 DISSOLUTION PROFILE COMPARISON Determination of Similar Factor (f2) and difference factor (f1) A model independent approach estimate the dissimilarity factor (f1) and similarity factor (f2) to compare the dissolution profile of optimized formulation (SD3) with commercial product. The dissolution study of optimized Pioglitazone solid dispersion tablet was performed and compared with commercial conventional release tablet by calculating the similarity factor and difference factor. The following equations were used for calculating f1 and f 2 : f1 = f2 = 50 log {[1+ 2 ] -0.5 x100} Where n = no of time points, R t = dissolution value of the reference batch at time t, T t = dissolution value of the test batch at same time point. Number of time points, n = 6 where both products 85%. Number of points in R t and T t must be the same and must be the similar to n. The standard values of similarity factor and dissimilarity factor are 50 and 15 respectively. Model Dependent Kinetics Data obtained from in vitro release studies was fitted to various kinetics equations to find out the mechanism of release of drug from the formulation compared to the commercial preparation. The kinetics models used were Zero order, First order, Hixoncrowell model, Weibull model, Higuchi and Korsmeyer Peppas model. In order to obtained meaningful information for release models, the drug release profiles were fitted to various kinetic models. Table 20 summarized the correlation coefficient for different release kinetic models of optimized formulation and Commercial product. Models with higher correlation coefficient were judged to be more appropriate model for dissolution data. The in vitro release data obtained from Formulation SD3was fitted to kinetic models shown in Table 21. In case of zero order the graph was plotted in cumulative percent of drug released versus time and in first order release kinetics (Log C= log C 0 - Kt/2.303) the graph was plotted in log cumulative percent of drug remaining versus time. For Higuchi model kinetics (Q= K H t 1/2 ) the graph was plotted in cumulative percent of drug released versus square root of time, and for higuchi model [m= 1- exp ( ] the graph was plotted in log cumulative percent of drug released versus log time (Figure 13-14). The release of formulation SD3 was indicated by highest r 2 values in higuchi model and equivalent to that of Commercial product which also showed highest value of r 2 in higuchi model. RESULTS AND DISCUSSION Description of drug: Table-7 Description of Pioglitazone. S. No. Properties Inference 1. Colour White Colour 2. Odour Odourless 3. Shape Spherical Drug Identification (λ max ) By absorption spectrum method: The wavelength at which maximum absorbance obtained was considered as maximum wavelength (λ max ) i.e nm for the drug. Infra-red spectrum method: Drug and polymers identified by infra-red spectrum which are compared with its standard IR. The IR spectrum given below shown that the peaks obtained in the test spectrum is similar to that given in standard.

8 Page Transmittance [%] Transmittance [%] Figure-2: Reference FTIR spectrum of Pioglitazone. The IR spectrum of Pioglitazone revealed the presence of peak at cm 1 due to N-H stretching while peaks at and cm 1 is due to aliphatic C-H stretching. Strong absorption peaks observed at and cm 1 were assigned to drug carbonyl stretching vibration (C=O). A peak at 1612 cm 1 indicates the aromatic ring and a peak at 1238 cm 1 is due to C-O Ar group. Peaks obtained in spectrum of pure drug (immediate & after 15 days) were similar to that given in standard Wavenumber cm-1 D:\backup\BRUKER\ \ OR61 Instrument type and / or accessory 16/02/2015 Page 1/1 Figure -3: FT IR spectrum of Pioglitazone (Fresh sample) Wavenumber cm-1 D:\backup\BRUKER\ \ Instrument type and / or accessory 16/02/2015 Page 1/1 Figure-4 : FT IR spectrum of Pioglitazone (After 15 days).

9 Page Transmittance [%] Transmittance [%] Transmittance [%] Wavenumber cm-1 D:\backup\BRUKER\ \ Instrument type and / or accessory 18/02/2015 Page 1/1 Figure-5: FT IR spectrum of Pioglitazone+ sodium starch glycolate (Fresh sample) Wavenumber cm-1 D:\backup\BRUKER\ \ Instrument type and / or accessory 18/02/2015 Page 1/1 Figure - 6: FT IR spectrum of pioglitazone + sodium starch glycolate(after 15 days) Wavenumber cm-1 D:\backup\BRUKER\ \ Instrument type and / or accessory 18/02/2015 Page 1/1 Figure-7 : FT IR spectrum of pioglitazone+ crosscarmilose sodium (Fresh sample).

10 Page Transmittance [%] Wavenumber cm-1 D:\backup\BRUKER\ \ Instrument type and / or accessory 18/02/2015 Page 1/1 Figure -8: FT IR spectrum of Pioglitazone+ Croscarmellose sodium (After 15 days). Development of Calibration Curve The calibration curve for Pioglitazone was prepared in 0.1N HCl and ph 3 buffer. Table 8: Standard calibration curve in 0.1N HCl (ph 1.2) at λ max nm. Concentration(μg/ml) Absorbance Figure -9: Standard calibration curve in 0.1N HCl (ph 1.2) at λ max nm. Table 9: Pioglitazone standard calibration curve in 0.1N HCL (ph 3) at λ max 269.4nm. Concentration(μg/ml) Absorbance

11 Page2674 Figure 10: Standard calibration curve in 0.1N HCL ph 3 at λ max 269.4nm. FORMULATION AND EVALUATION OF SOLID DISPERSION Formulation Eight different formulation batches of binary systems of Pioglitazone i.e. both physical mixture and solid dispersion were prepared with 2 different polymers Croscarmellose sodium, sodium starch glycolate in 4 different ratio (1:1, 1:3, 1:5 and 1:7) as shown in Table10 and 11. Percentage Practical Yield Percentage yield of different formulation was determined by weighing the solid dispersion after drying. The percentage yield of different formulation was in range of % as shown in Table 10,11. Table10-Percentage practical yield of physical mixture. S. No Formulation % Practical Yield 1. PM PM PM PM PM PM PM PM Table 11: Percentage practical yield of the prepared solid dispersion. S. No. FORMULATION % Practical yield 1. SD SD SD SD SD SD SD SD Drug release/in vitro release studies of the formulations: Dissolution Studies of Solid Dispersion Formulations Pioglitazone solid dispersions showed a dissolution pattern better than the pure Pioglitazone. Pioglitazone solid dispersion with Croscarmellose sodium showed a marked increase in the cumulative % drug release up to 91.08%. Similarly solid dispersion of Pioglitazone with sodium starch glycolate was up to % as shown in table 12.Thus on the basic of above observation SD3 formulation was selected for the final formulation for tablet formation.

12 Page2675 Table -12 Dissolution Studies of tablet of Optimized solid dispersion Formulation, Pure Drug and Commercial Conventional Release Tablet. S. Cumulative % Release at Different Time Intervals (min) Batch No Pure drug Commercial conventional tablet SD SD SD SD SD SD SD SD Figure-11: In-vitro drug release of solid dispersion of Pioglitazone with different polymers. Pioglitazone solid dispersions presented better dissolution performance over corresponding pure drug. Solid dispersion of Pioglitazone with Croscarmellose sodium showed a marked increase in the cumulative % drug release up to 91.08%. Similarly solid dispersion of Pioglitazone with sodium starch glycolate showed release up to 70.26%. The enhanced dissolution was observed in case of solid dispersion of Pioglitazone: Croscarmellose sodium in 1:5 ratios. DRUG CONTENT STUDY The drug content of the formulations were determined and reported in table 13. Table 13: Drug content: S. No Formulation Drug content (%) 1. PM PM PM PM PM PM PM PM SD SD SD SD SD SD SD SD

13 Page2676 OPTIMIZATION OF THE FORMULATION ANOVA: The solid dispersion of Pioglitazone with Croscarmellose sodium (1:5) showed highest dug release i.e %. This optimized formulation was used for the preparation of the tablet. ANOVA showed significant difference between the formulations. The p values showed that there was a significant difference between formulations of the drug with different polymers. The p vales and F values are given in the Table 14 as follows: Table 14: p and F values of solid dispersion and mixture. The ANOVA justify that there is significant difference between different formulations and the design of the formulation thus is acceptable. The overall conclusion thus can be drawn that the SD3 reveals best results viz. dissolution, percentage practical yield & drug content among all formulations and can be carry forward for formulation of tablet. Formulation and Evaluation of Tablet of Optimized Solid Dispersion Formulation Formulation of Powder blend The powder blend was prepared by using solid dispersion, lactose 86% as diluents, talcs 2.5% as Glidant and magnesium stearate 1.25% as lubricant and mixed them properly. Evaluation of Tablets Pre-compression parameters S. No. Formulation p value F value Degree of freedom Sum of square 1. CCS CCS (SD+PM) SSG SSG (SD+PM) Table 15: Physical parameters of powder blend evaluation. S. No. Parameters Results 1. Bulk density 0.7 gm/ml 2. Tapped density 0.770gm/ml 3. Carr s index % 4. Hausner ratio Angle of repose 14 o.66 Post-compression parameters Evaluation of the tablets prepared from optimized solid dispersion showed that all the parameters were within limits and are shown in table 16. Table 16: Evaluation of prepared tablet. S. No. Parameter Result 1. Thickness 3.1 mm 2. Hardness 4.16 kg/cm 2 3. Friability 0.95 % 4. Weight variation mg 5. Disintegration time 30.5 sec Table 17: Dissolution profiles of pure drug, optimized formulation of solid dispersion and commercial conventional release tablet. S. Cumulative % Release at Different Time Intervals in min Batches No Pioglitazone(API) Commercial conventional tablet Pioglitazone 3. solid dispersion tablet with CCS(1:5)

14 Page2677 Figure -12: Cumulative % release of drug from pure drug, commercial Conventional drug with Croscarmellose sodium. release tablet and solid dispersion of DRUG RELEASE KINETICS Model Independent Parameters Dissolution efficiency Tablet prepared by solid dispersion of drug with Croscarmellose sodium (optimized formulation, SD3) showed greater percentage dissolution efficiency {%DE} from conventional commercial tablet within 60 min as shown in table 18. Table 18: Dissolution efficiency of optimized solid dispersion tablet and conventional commercial tablet. S. No. Formulation % DE 1. Optimized solid dispersion tablet Conventional commercial tablet 75.6 Dissolution profile comparison Determination of Similar Factor (f 2 ) and Difference factor (f 1 ) The similarity factor and difference factor obtained for Pioglitazone was found to be within the standards i.e. 52 and respectively as shown in Table 19. There was no significant variation in the in vitro drug release profile of commercial product and optimized solid dispersion tablet. The calculated similarity factor (f2 value) was 52. It was more than standard value indicating similarity between both the dissolution profiles. Calculation of difference factor (f 1 ) and similarity factor (f 2 ) for optimized formulation and commercial conventional release tablet is given below in table19. Table 19: Calculation of Difference factor (f 1 ) and Similarity factor (f 2 ). Time R t T t {R t - T t } (R t - T t ) 2 Similarity factor (f 2 ) Difference factor (f 1 ) Sum R t = Cumulative percentage dissolved of reference product (commercial) at time t T t = Cumulative percentage dissolved of test product (Solid dispersion) at time t The similarity factor is above 50 and difference factor is below 15, shows that the formulation prepared do not vary with the conventional marketed tablet. Model Dependent Kinetics Data obtained from dissolution studies was fitted to various kinetics equations to find out the mechanism of release of drug from the formulation compared to the commercial preparation. The kinetics models used were Zero order, First order, Hixon Croswell model, Higuchi model and Korsmeyer Peppas model. The following table 20 shows release kinetics of optimized formulation solid dispersion tablet & Commercial conventional release tablet:

15 Page2678 Table 20: Release kinetics of optimized formulation solid dispersion tablet & Commercial conventional release tablet. Square Root of log time %CDR log % CDR log % CDR remaining Time Time (min) Tablet Tablet Tablet Tablet Marketed Marketed Markete Marketed Formula Formulat Formulat Formulate Tablet Tablet d Tablet Tablet ted ed ed d Table 20 summarized the correlation coefficients for different release kinetic models of Pioglitazone optimized tablet and commercial conventional release tablet. The release of formulation SD3 was indicated by highest r 2 values in highchi model, and equivalent to that of commercial product which also showed highest value of r in higuchi model. This model was judged to be more appropriate model for dissolution data. Table 21: Model dependent parameters of tablet of optimized formulation and commercial conventional release tablet. S. No. Formulations Evaluation parameter Zero order First order higuchi model Peppas model 1. Tablet of optimized formulation Value of r Commercial formulation Value of r Release kinetics of SD3 Release kinetics of commercial conventional release tablet Figure-13: Comparison with Zero order release kinetics of Solid dispersion of Croscarmellose sodium and conventional release tablet.

16 Page2679 Release kinetics of SD3 Release kinetics of commercial conventional release tablet Figure-14: Comparison with First order release kinetics of Solid dispersion of Croscarmellose sodium and conventional release tablet. Release kinetics of SD3 Release kinetics of commercial conventional release tablet Figure-15: Comparison with Higuchi model kinetics of Solid dispersion of Croscarmellose sodium and conventional release tablet. Release kinetics of SD3 Release kinetics of commercial conventional release tablet Figure-16: Comparison with Korsmeyer Peppas model of Solid dispersion of Croscarmellose sodium and conventional release tablet.

17 Page2680 The conventional marketed tablet and the formulated tablet follows higuchi model of kinetics, thus the formulated tablet dosage form meets with the marketed tablet. CONCLUSION This research showed that when Pioglitazone dispersed in suitable water-soluble carriers such as sodium starch glycolate, Croscarmellose sodium; its dissolution was enhanced compared with pure drugs. The FTIR spectroscopic studies showed the absence of any specific chemical interaction between Pioglitazone and Croscarmellose sodium in solid state. In comparison to sodium starch glycolate, Croscarmellose sodium show best result from both the physical mixture and solid dispersion in 1:5(drug: polymer) ratio. By in-vitro study, it is clearly proved that preparation of solid dispersion of Pioglitazone with Croscarmellose sodium show 20% improved dissolution rate of drug from marketed conventional release tablet and two times greater than pure drug. Finally, it can be concluded that Pioglitazone solid dispersions with Croscarmellose sodium provides a promising way to enhance solubility and dissolution rate of Pioglitazone. Further the stability studies, Differential Thermal Scanning (DSC), XRD etc. different studies may be conducted for establishment of the formulation. ACKNOWLEDGMENT The author is thankful to the Management, Director, Academic Director, Joint Director and Director/Principal, Seth G. L. Bihani S. D. College of Technical Education, Sri Ganganagar (Raj.) for their favourable gesture and support during entire work and stay in the institute. Conflict of Interest: There is no conflict of interest. REFERENCES 1. Chowdary KPR, Chandra D. Udaya, N. Mahesh. Enhancement of Dissolution Rate and Formulation Development of Pioglitazone: A BCS Class II Drug, Journal of Pharmacy Research 2011; 4(11): Chowdary KPR, K. Surya Prakasa Rao. Formulation Development of Pioglitazone Tablets Employing β Cyclodextrin-Poloxamer 407- PVP K30: A Factorial Study, Scholars Research Library 2011; 3 (6): Chowdary KPR, A. Kumar Pawn. Recent Research On Formulation Development of BCS Class II Drugs, International Research Journal of Pharmaceutical and Applied, Sciences (2013) 3(1): Singh C, Kumar P. Solvent Evaporation Method for Amorphous Solid Dispersions: Predictive Tools for Improve the Dissolution Rate of Pioglitazone hydrochloride, International Journal of Pharmaceutical, Chemical and Biological Science 2013; 3(2): Mishra SR. Solid Dispersion Technique for Enhancement for Dissolution Rate of Pioglitazone International Research Journal of Pharmacy 2011; 8(2): Darna B, Posala M., Kumar D. Formulation and Characterization of Pioglitazone HCl Self Emulsifying Drug Delivery system, Scholars Research Library 2013; 5 (2): Hirasawa N, Ishise S, Miyata H, Danio K. Stabilize Nilvadipine Solid Dispersion by the Use of Ternary Systems. Drug Development and Industrial Pharmacy 2009; 29(9): Shingne NS, Nagpure SV, Deshmane SV, Biyani KR. Modified Hupu Gum: A Novel Application in Solid Dispersion Containing Pioglitazone HCl, American Journal of Pharmtech Research 2013;3(4), Faisal KS, Giri A, Hassan R, Azam KR, Rahman M, Harun AR. Solid dispersion formulations of Pioglitazone HCl using Five Different Polymers for Enhancing Dissolution Profile, International Journal of Pharmacy and Life Science 2013;4(1), Kiran T, Shastri N, Ramakrishna S, Sadanandam M. Surface Solid Dispersion of Glimepiride for Enhancement of Dissolution Rate. International Journal of Pharmaceutical Research and Technology 2009; 1(3): Rao BR, Chandrasekhar B. Preparation and Characterization of Pioglitazone HCL Solid Inclusion Complex an Solubility Enhancement Technique, International Journal of Bio pharmaceutics 2014; 5(3): Hyma P, Ravikanth, Reddy P. Improvement of Solubility and Dissolution Rate of Pioglitazone by Solid Dispersions Technique, An International Journal of Advances In Pharmaceutical Sciences 2012; 6 (3) : Kumar KK, Reddy MN. Formulation and Evaluation of Bilayermatrix Tablet of Pioglitazone HCL Metformin HCL, Asian Journal Pharm Clinres 2013; 6(3), Darwish MK, Foad MM. Enhancement of the Dissolution Profile of Tenoxicam by a Solid Dispersion Technique and Its Analytical Evaluation using HPLC. Drug Discoveries & Therapeutics 2009; 3(1): Gupta A, Kataria MK, Bilandi A. Formulation and Evaluation of Solid Dispersion of Glipizide for Solubility and Dissolution Rate Enhancement. International Journal of Pharmaceutics and Drug Analysis 2014; 2(2): Jagtap VK,Vidyasagar G, Dwivedi SC. Kneaded Pioglitazone Poloxamer Solid Dispersions for Enhancement of In Vitro Dissolution and In Vivo Bioavailability, International Journal of Pharm. & Life Science 2012; 3(7): Singh J, Walia M, Kumar H. Solublity Enhancement by Dissolution Method A Review, Journal of Drug Delivery and Therapeutics 2013; 3(5): Singh V, Kataria MK, Bilandi A. Formulation and evaluation of Solid dispersion of Aceclofenac for Solubility and Dissolution Rate Enhancement. International journal of pharmaceutical sciences letters 2014; 4(3):

18 Page Brahmanker DM, Jaiswal BSl, Biopharmaceutics and Pharmacokinetics A Treatise, Second edition, Vallabh Prakhashan Delhi Sharma HL, Sharma KK, Principles of Pharmacology.2007.First Edition, Paras Medical Publisher, Hydrabad ; Indian Pharmacopoeia Volume III Government of India. Ministry of health & family welfare. The Indian pharmacopoeia commission, Ghaziabad Croscarmellose Sodium. (N.D.) Available from [Accessed 09th September 2013] 23. Croscarmellose- Compound Summary. (N.D.) Pubchem Compound. [Online] AvailableForm: #itabs-2d [Accessed 06 th September 2013]