Formulation and Evaluation of Gliclazide Tablets Containing PVP-K30 and Hydroxypropyl-β-cyclodextrin Solid Dispersion

Transcription

1 176 International Int J Pharm Journal Sci of Nanotech Pharmaceutical Vol 5; Sciences Issue 2 July September and Nanotechnology 12 Research Paper Volume 5 Issue 2 July September 12 MS ID: IJPSN VARMA Formulation and Evaluation of Gliclazide Tablets Containing PVP-K3 and Hydroxypropyl-β-cyclodextrin Solid Dispersion M. Mohan Varma* and P. Satish Kumar Shri Vishnu College of Pharmacy, Vishnupur, Bhimavaram-5342, Andhra Pradesh, India. Received April 6, 12; accepted April 3, 12 ABSTRACT Gliclazide is an anti-diabetic drug. It is a BCS class-ii (poorly water soluble) drug and its bioavailability is dissolution rate limited. The dissolution rate of the drug was enhanced by using the solid dispersion technique. Solid dispersions were prepared using PVP-K3 (polyvinylpyrrolidone) and hydroxypropyl-β-cyclodextrin (HP BCD) as the hydrophilic carriers. The solid dispersions were characterized by using DSC (Differential scanning calorimetry), XRD (X-ray diffractometry) and FTIR (Fourier transform infrared spectroscopy). Solid dispersions were formulated into tablets. The formulated tablets were evaluated for the quality control parameters and dissolution rates. The solid-dispersion tablets enhanced the dissolution rate of the poorly soluble drug. The optimized formulation showed a 3 fold faster drug release compared to the branded tablet. The XRD studies demonstrated the remarkable reduction in the crystallinity of the drug in the solid dispersion. The faster dissolution rate of the drug from the solid dispersion is attributed to the marked reduction in the crystallinity of the drug. The DSC and FTIR studies demonstrated the absence of the drug-polymer interaction. KEYWORDS: Gliclazide; solid dispersions; PVP-K3; hydroxypropyl-β-cyclodextrin Introduction One of the areas of current interest in pharmaceutical technology that has had significant impact on clinical therapy is the enhancement of dissolution rate and bioavailability of insoluble and poorly water soluble drugs (Konno et al., 8; Urbanetz and Lippold, 5). The poor aqueous solubility and wettability of these drugs gave rise to difficulty in the design of pharmaceutical formulation and leads to variable oral bioavailability (Choiu and Riegelman, 1971). The enhancement of oral bioavailability of poorly soluble drugs remains one of the most challenging aspects of drug development (Batra et al., 8; Christian and Dressman, ). Salt formation, solubilization and size reduction have commonly been used to increase the dissolution rate and, thereby, the oral absorption and bioavailability of such drugs. There are some practical limitations of these techniques. Solid dispersion technology is the science of dispersing one or more active ingredients in an inert matrix in the solid state in order to achieve an increased dissolution rate, sustained release of drugs, altered solid state properties and enhanced bioavailability (Leuner and Dressman, ; Sheu et al., 1994). The solid dispersion approach has been widely and successfully applied to improve the solubility, dissolution rate and consequently the bioavailability of poorly soluble drugs (Babu et al., 2; Craig, 2; Sudha et al., 2; Varma and Pandit, 5). Many hydrophilic excipients like PVP, cyclodextrins, PEG 4, PEG 6, mannitol, and poloxamers can be used to enhance the dissolution of poorly soluble drugs (Dahlberga et al., 1; Weuts et al., 5). Gliclazide is a second-generation hypoglycemic sulfonylurea used in the treatment of type 2 diabetes mellitus (Betageri and Makarla, 1995; Zkan et al., ). It stimulates beta cells of the Islet of Langerhans in the pancreas to release insulin. It also enhances peripheral insulin sensitivity. Overall, it potentiates insulin release and improves insulin dynamics. One of the major problems of gliclazide is its poor aqueous solubility and hence low dissolution rate in water, which results in poor bioavailability after oral administration. Solid dispersions of gliclazide in PEG 6 have been developed to increase the dissolution rate (Biswal et al., 8). In the present study, an attempt was made to improve the dissolution rate of the poorly water soluble drug gliclazide by solid dispersion technique using PVP- K3 and hydroxypropyl-β-cyclodextrin (HP-BCD) as the hydrophilic carriers. The solid dispersions were characterized by FTIR, DSC and XRD. The solid dispersions were compressed into fast dissolving tablets and were evaluated for the quality control parameters and the dissolution rate. 176

2 Varma and Kumar: Formulation and Evaluation of Gliclazide Tablets Containing PVP-K3 and Cyclodextrin Solid Dispersion 177 Drugs and Chemicals Materials and Methods Gliclazide was obtained as a gift sample from Indi Pharma Pvt. Ltd., Mumbai. PVP K3, hydroxypropyl-βcyclodextrin,lactose, sodium starch glycolate (SSG) and croscarmellose sodium (Ac-Di-Sol) were procured from S.D. Fine Chem. Ltd., Mumbai. The marketed tablets BR1, BR2, BR3 manufactured by different industries were purchased from the local pharmacy store. All other chemicals used were of analytical grade. Formulation and Evaluation Methodology Estimation of Gliclazide A spectrophotometric method based on the absorbance of UV rays at λmax of 226 nm was developed in the present study for the estimation of the amount of gliclazide present in the solid dispersions and in the tablets. The 1 mg of gliclazide was accurately weighed, dissolved in 3. ml of.1 N NaOH solution and the volume was adjusted up to 1. ml with ph 7.4 phosphate buffer in a volumetric flask to get 1 µg/ml solution (stock I). The 1. ml solution from the stock I was accurately measured and diluted to 1. ml with ph 7.4 phosphate buffer in a volumetric flask to get 1. µg/ml solution (stock-ii). Subsequent dilutions were made to get the series of dilutions 2., 4., 8., 1., 12., 16.,. and 25. µg/ml solutions. The absorbance values of above solutions were measured at 226. nm (λmax of gliclazide) on a UV-Visible Spectrophotometer (Lab India). The graph was plotted by taking concentrations (µg/ml) on x-axis and absorbance values on y-axis. Preparation of Solid Dispersions of Gliclazide with PVP K3/ HP BCD Solid dispersions of gliclazide and PVP K3 or HP BCD were prepared using the kneading technique. The drug-pvp solid dispersions in 1:1 (DP1), 1:2 (DP2), 1:5 (DP5) weight ratios and the drug-hp BCD solid dispersions in 1:1 (DH1), 1:2 (DH2), 1:5 (DH5) weight ratios respectively were prepared by the following stepwise method: the drug and excipient in a definite ratio was taken in a dry mortar and mixed for 1 minutes with the pestle to form the physical mixture of drug and the excipient; a homogenous solution of water and acetone (1:1 volume ratio) was added drop wise to the above with constant mixing of the contents with a pestle to form a smooth paste; the trituration was continued for 1 hour, with addition of small volumes of water and acetone mixture to prevent drying of the mass and to disperse the drug substance in the polymer matrix; after 1 hour, the dried mass was scrapped from the mortar and it was kept in the desiccator for 24 hours to remove the traces of solvent present in the formed dispersion. Preparation of Physical mixtures of Gliclazide with PVP K3/ HP BCD Physical mixtures of drug and the PVP (1:1,PP)/HP BCD(1:1,PH) were prepared by adding them in a 1:1 ratio (drug and excipient in weight, respectively) into a dry mortar and mixed by triturating with a pestle for 1 minutes. The mixture formed was then passed through #6 sieve (ASTM) and stored in the air tight containers until their further use. Formulation of Tablets with Gliclazide Solid dispersions The tablets were prepared by direct compression. Solid dispersion and the excipients required for tablet compression are passed through # 6 sieve (ASTM). Quantities of the drug substance and the excipients are weighed accurately as mentioned in Table 1a and 1b. The solid dispersion was mixed with the excipients by geometric dilution technique and then it was blended for 1 minutes to get the blend uniformity. From the above blend, a definite quantity which was equivalent to 4 mg of drug substance was weighed and compressed in to a tablet by using the single punch tablet compression machine (Cadmach). TABLE 1(a) Composition of tablets containing drug-pvp solid dispersions. FORMULATION COMPOSITION P1 P2 P3 P4 P5 P6 P7 P8 Gliclazide & PVP K3 solid dispersion (mg) Lactose (mg) SSG (mg) Ac Di Sol (mg) Talc (mg) Magnesium Stearate (mg) Total weight (mg)

3 178 Int J Pharm Sci Nanotech Vol 5; Issue 2 July September 12 TABLE 1(b) Composition of tablets containing drug-hp BCD solid dispersions. FORMULATION COMPOSITION H1 H2 H3 H4 H5 H6 H7 H8 DC Gliclazide & HPBCD solid _ dispersion (mg) Gliclazide pure drug (mg) Lactose (mg) SSG (mg) Ac Di Sol (mg) Talc (mg) Magnesium Stearate (mg) Total weight (mg) Solid state characterization of Drug, Physical mixtures and Solid dispersions Solid state characterization of drug, physical mixtures and solid dispersions was performed with the help of FTIR, DSC and XRD techniques. Fourier-Transform Infrared spectroscopy The FTIR study was undertaken to assess the drugpolymer interaction. FTIR spectra of pure drug, physical mixtures and solid dispersions were recorded on a Bruker FTIR spectrophotometer. The potassium bromide pellet method was employed. Each spectrum was recorded in the region 4-4 cm -1 at spectral resolution of 2 cm -1. Differential Scanning Calorimetry (DSC) The DSC measurements were carried out on a Mettler Toledo DSC-822e model. The accurately weighed sample was placed in an aluminum pan. An empty aluminum pan was used as the reference. The experiment was carried out in a nitrogen atmosphere at a scanning rate of 1 C/min in the range of 3 C 2 C. X-Ray diffractometry (XRD) The XRD patterns of all the samples were recorded using Bruker X-Ray diffractometer with the tube anode Cu over the interval, 5-5 /2θ. The generator tension (voltage) and the generator current were kept at 4 kv and 3 ma respectively with scanning speed of 2 /minute. Evaluation of Tablets The formulated tablets were evaluated for the following physicochemical characteristics. Hardness test Hardness of the tablets was determined by using the Monsanto hardness tester. The lower plunger was placed in contact with the tablet and a zero reading was taken. The plunger was then forced against a spring by turning a threaded bolt until the tablet fractured. As the spring was compressed a pointer rides along a gauge in the barrel to indicate the force required to break the tablet. The average hardness of 5 tablets was recorded. Friability test The 1 previously weighed tablets were placed in the Friability apparatus (Electrolab) and rotated at 25 rpm for 4 minutes to give the result of 1 revolutions and the tablets were dedusted and weighed after the completion of the test. The percentage friability was calculated by using the following formula, Percent friability = (initial weight final weight) / initial weight 1. Weight Variation The tablets were selected and weighed collectively and individually. From the collective weight, the average weight was calculated. Each tablet weight was then compared with the average weight to ascertain the weight of the tablets within the permissible limits. Not more than two of the individual weights deviated from the average weight by more than 7.5% for >3 mg tablets and none by more than double that percentage. Disintegration time Disintegration tests were performed with the tablet formulations to measure the disintegration time of the tablets. Every time, a single tablet was placed in each tube, totally in 6 tubes and the holder was placed in a beaker with water at 37 o C ±.2 o C and operated until no palpable mass was observed on the surface of the mesh placed in bottom of the each tube in the Disintegration testing apparatus (Electrolab) and the average values of 6 tablets were recorded. Drug content The 1 tablets of each formulation were weighed and powdered. The quantity of powder equivalent to 4 mg of gliclazide was transferred to a 1 ml volumetric flask, dissolved in a small volume of.1 N NaOH solution and

4 Varma and Kumar: Formulation and Evaluation of Gliclazide Tablets Containing PVP-K3 and Cyclodextrin Solid Dispersion 179 the final volume was adjusted with ph 7.4 phosphate buffer. Further dilutions were made from the above solution and the solutions were analyzed at 226 nm employing the UV-Visible spectrophotometer. The average values of 3 trials were recorded. In vitro dissolution studies In vitro dissolution studies of the drug substance, physical mixtures, solid dispersions, fabricated formulations and the marketed formulations were carried out to estimate the cumulative% drug release with respect to time. The 9 ml of ph 7.2 phosphate buffer was placed in each vessel and the dissolution apparatus (USP paddle method) was assembled. The medium was allowed to equilibrate to a temperature of 37 o C ±.5 o C. One tablet (equivalent to 4 mg of drug) was placed in each vessel and the dissolution study was carried out for 1 hour. At definite time intervals (, 5, 1,, 3, 45, and 6 minutes), 1 ml of the sample was withdrawn, filtered prior to analysis. The 1 ml of fresh dissolution media was replaced after each sample withdrawal to maintain the sink condition in the vessel. The samples analyzed spectrophotometrically at 226 nm on a UV-Visible spectrophotometer. An average of three trials was recoded. The values of dissolution efficiency were calculated as reported by Khan and Rhodes, Results and Discussion Preparation of solid dispersions The solid dispersions of gliclazide were prepared using PVP-K3 and HP BCD, the hydrophilic carriers by the kneading method. All prepared batches of solid dispersions were found to be non-hygroscopic and free flowing powders. All prepared solid dispersions exhibited uniformity of drug content. The drug content of the solid dispersions was found in the range of 96% to 14%. The solid dispersions showed a remarkable increase in dissolution rate compared to the pure drug in ph 7.4 phosphate buffer (Figure 1-3). Mean Cumulative % DR DP1 DP2 DP5 PD Fig. 1. Dissolution profiles of pure drug (PD) and drug-pvp (1:1, DP1; 1:2, DP2; 1:5, DP5) solid dispersions Time (in min) Fig. 2. Dissolution profiles of drug-hpbcd (1:1, DH1; 1:2, DH2; 1:5, DH5) solid dispersions.

5 171 Int J Pharm Sci Nanotech Vol 5; Issue 2 July September Mean Cum % DR PD PP PH DP1 DH1 Fig. 3. Dissolution profiles of physical mixtures (drug-pvp, 1:1, PP; drug-hp BCD, 1:1, PH) and solid dispersions (DP1, DH1) Time(in min) Evaluation of Tablets The fast release solid dispersions were formulated into fast dissolving tablets by the direct compression method. The tablet formulations exhibited uniform drug content. The quality control parameters of all the tablet formulations are represented in Table 2. The drug content of all the tablet formulations was found in the range: 96.74% to 99.24%. The drug content of the marketed tablets (BR1, BR2, BR3) ranged from 95.23% to 97.42%. All the formulated tablets fulfilled the compendia limits of weight variation, hardness, friability and the disintegration time (Table 2). The friability values of the formulated tablets ranged from.212% to.765%. The friability values of the braded tablets ranged from.371 to.984%. The hardness of the formulated tablets ranged from 3.64 to 4.31 Kg/cm 2, where as the hardness of the marketed tablets ranged from 2.33 to 3.66 Kg/cm 2. The disintegration time (DT) of the fabricated tablets ranged from seconds, the values of DT of the branded tablets varied from seconds. Dissolution Studies In the present research work, the kneading technique was employed to prepare the solid dispersions and water: on acetone blend in a 1:1 volume ratio was used as a solvent since the drug dissolves in acetone and the polymer in water. During the preparation, the volatile solvent evaporates and forms a semi solid mass at the end by dispersing the fine drug particles in the hydrophilic polymer matrix, thereby increasing the dissolution rate. The time taken for 5% drug to be dissolved, for the pure drug (in ph7.4 phosphate buffer) was more than 45 minutes, whereas it was less than 1 minutes for both PVP and HP BCD solid dispersions, less than minutes for PVP physical mixture and less than 3 minutes for HP BCD physical mixture (Figure 1-3). The pure drug exhibited a very poor dissolution rate due to its hydrophobic nature and poor wettability. The hydrophobic drug crystals of the pure drug floated above the dissolution medium because of its poor wettability. The pure drug showed 3.11% drug release in 3 minutes and only 52.66% drug release in 6 minutes. The drug- PVP (1:1) solid dispersion exhibited 1% drug release in 5 minutes. The drug-hp BCD (1:1) solid dispersion showed 91% drug release in 1 minutes. Based on the time taken for 5% drug release, the drug-pvp (1:1) solid dispersion demonstrated more than a 1 fold increase in the dissolution rate compared to the pure drug. The physical mixtures showed better drug release than the pure drug, this is because of the hydrophilic carriers PVP and HP BCD can improve the wettability of the drug and decrease the aggregation of the hydrophobic drug particles. The dissolution profiles of the different tablet formulations are depicted in Figure 4-1. The tablet formulation prepared with pure drug (DC) exhibited very poor dissolution rate due to the hydrophobic and the crystalline nature of gliclazide. The formulation DC showed 46% drug release in 3 minutes and 46.4% release in 6 min, respectively. The formulation did not achieve 5% drug release even after 1 hr of the dissolution study. An increase in the dissolution rate in the first 1 minutes for the H1 formulation than the H5 formulation was observed in which both formulations were prepared with a 4% concentration of SSG. This may be due to the presence of a high concentration of the polymer which restricts the diffusion of drug from the hydrophilic polymer in the H5 formulation. Similarly, more than 85% of drug was released for the P1 formulation in less than 45 min., whereas for P5, it took more than 45 minutes in which both the batches are prepared with 4% SSG. An increase in the dissolution rate was observed with 1:1 solid-dispersion containing tablets than the tablets prepared with 1:5 solid dispersion (independent of the disintegrant and its concentration was observed). An increase in the disintegrant concentration from 4% to 8% increased the drug release in the first 1 minutes. Among all the formulations, H2 had shown the highest drug release in the first 1min. Tablets prepared with HP BCD solid dispersion showed higher drug release than tablets

6 Varma and Kumar: Formulation and Evaluation of Gliclazide Tablets Containing PVP-K3 and Cyclodextrin Solid Dispersion 1711 prepared with PVP solid dispersion with both disintegrants, SSG and Ac-Di-Sol. This might be due to the more hydrophilic nature of HP BCD than the PVP. When the optimized formulations H2 and P2 were compared with the marketed brands, more than 85% drug release was obtained in less than minutes, for both the formulations, whereas for the brands it was found that 85% drug was released in more than 3 minutes (Figure 1). Among the brands studied the brand BR1 showed the best dissolution rate. However, the optimized formulation H2 exhibited better dissolution rate than brand BR1. Based on the time taken for 9% drug release, the optimized formulation H2 achieved a more than 3 fold increase in the dissolution rate compared to brand BR1.The different brands (BR1, BR2, BR3) exhibited variation in the dissolution profiles and also showed variation in the dissolution parameters. This is because different manufactures may use different excipients (hydrophilic or hydrophobic), which can influence the drug release of the hydrophobic gliclazide. The brand BR3 demonstrated poor drug release. It did not achieve 9% drug release even at the end of 1 hour of the dissolution study. The dissolution parameters of the different formulations are indicated in Table 3. The values of dissolution efficiency in 3 minutes (DE3) and in 6 minutes (DE6), respectively, for the optimized formulations were found to be higher than the other fabricated formulations and the marketed brands. The times for 5% drug release (T5) and 9% drug release (T9) were also found to be less for the optimized formulations than the other fabricated formulations. The marketed brands and the results are summarized in Table 3. TABLE 2 Physical parameters of the tablets. Formulations Weight variation (%) Friability (%) Hardness (Kg/cm 2 ) Disintegration Time (seconds) Drug content (%) DC ± P ± ± P ± ± P ± ± P ±.34 16± P ± ± P ±. 392± P ± ± P ±.3 384± H ± ± H ± ± H ± ± H ±.43 84± H ±.28 12± H ± ± H ± ± H ±.31 16± BR ± ± BR ±.3 182± BR ± ± TABLE 3 Dissolution parameters of tablets. Formulations DE 3 (percentage) DE 6 (percentage) T 5 (minutes) T 9 (minutes) DC >6 >6 P P P P P >6 P P P H <5 13 H <5 8 H <5 18 H <5 17 Table 3 Contd

7 1712 Int J Pharm Sci Nanotech Vol 5; Issue 2 July September 12 Formulations DE 3 (percentage) DE 6 (percentage) T 5 (minutes) T 9 (minutes) H H H H BR BR BR >6 1 Mean Cumulative % DR DC P5 P6 P7 P8 Fig. 4. Dissolution profiles of tablets containing drug: PVP (1:5) solid dispersion Time(in min) 1 Mean Cumulative % DR DC H5 H6 H7 H8 Fig 5. Dissolution profiles of tablets containing drug: HP BCD(1:5) solid dispersion Time(in min) 1 Mean Cumulative % DR DC P1 P2 P3 P4 Fig. 6. Dissolution profiles of tablets containing drug: PVP (1:1) solid dispersion Time(in min)

8 Varma and Kumar: Formulation and Evaluation of Gliclazide Tablets Containing PVP-K3 and Cyclodextrin Solid Dispersion Mean Cumulative % DR DC H1 H2 H3 H4 Fig. 7. Dissolution profiles of tablets containing drug: HP BCD (1:1) solid dispersion Time(in min) Fig. 8. Dissolution profiles of tablets (to study the effect of disintegrant and its concentration-ssg). Mean Cumulative % DR DC P3 P4 H3 H4 Fig. 9. Dissolution profiles of tablets (to study the effect of disintegrant and its concentration- Ac-Di-Sol) Time(in min) Mean Cumulative % DR P2 H2 BR1 BR2 BR3 Fig. 1. Dissolution profiles of optimized formulations and marketed brands Time(in min)

9 1714 Int J Pharm Sci Nanotech Vol 5; Issue 2 July September 12 The results of the dissolution study indicate an improvement of the dissolution rate of gliclazide in the solid dispersion tablets. The improvement in the dissolution rate is achieved due to several factors such as: the strong hydrophilic property of the polymeric carriers, which improves the water penetration and the wettability of the hydrophobic drug; the optimal dispersion of the drug in the hydrophilic polymeric carrier; the absence of crystals (amorphous dispersions) corresponds to lower energy required for dissolution; the molecular dispersion of drug on the polymeric carrier improves the hydrophilic characteristics of the hydrophobic drug (Karavas et al., 3). Also, the decrease in the particle size, decrease in the aggregation and the agglomeration of the hydrophobic drug particles and the improvement in the dispersibility of the hydrophobic drug particles can improve the dissolution rate of the drug (Ford, 1986; Varma and Pandit, 5). FTIR studies The Figure 11a-11e displays the FTIR spectra of gliclazide, physical mixtures and the solid dispersions. The FTIR spectrum of pure gliclazide demonstrated the FTIR peaks at cm -1 (carbonyl sulfonyl urea group), cm -1 (-NH group), 1349 and 1162 cm -1 (sulfonyl group bands). The same peaks were observed in the drug substance, physical mixtures and solid dispersions. The absence of any new peaks in the solid dispersions indicates that there are no polymorphic changes in the drug substance during the preparation of solid dispersions with PVP K3/ HP BCD. Furthermore, the absence of shifts in the wave numbers of the FTIR peaks of the solid dispersions compared to the physical mixtures indicates the lack of significant interaction between the drug and the polymer components in the solid dispersion at the molecular level. Fig. 11a. FTIR spectrum of pure drug. Fig. 11b. FTIR spectrum of drug-hp BCD (1:1) solid dispersion.

10 Varma and Kumar: Formulation and Evaluation of Gliclazide Tablets Containing PVP-K3 and Cyclodextrin Solid Dispersion 1715 Fig. 11c. FTIR spectrum of drug-hp BCD (1:1) physical mixture. Fig. 11d. FTIR spectrum of drug-pvp (1:1) solid dispersion. Fig. 11e. FTIR spectrum of drug-pvp (1:1) physical mixture.

11 1716 Int J Pharm Sci Nanotech Vol 5; Issue 2 July September 12 DSC studies DSC thermograms of pure drug, physical mixtures and the solid dispersions are shown in Figures 12a-12e. A sharp endothermic peak at o C was observed indicating the melting point of the crystalline drug, gliclazide. The melting point was observed at o C in the drug-hp BCD (1:1 weight ratio) solid dispersion and the melting point of the drug-hp BCD (1:1 weight ratio) physical mixture was observed at o C. The presence of the sharp endotherm clearly indicates the absence of the drug-polymer interaction in the drug-hp BCD solid dispersion and also in the drug-hp BCD physical mixture. Two broad endothermic peaks were observed at o C (attributed to the evaporation of absorbed water) and o C (lower melting point is ascribed to the melting point depression) in the drug-pvp K3 (1:1 weight ratio) solid dispersion. The existence of a broad endothermic peak clearly indicates the marked reduction in the crystallinity of the drug in the PVP solid dispersion. Also, two endothermic peaks were observed at o C (due to evaporation of absorbed water) and o C (melting point of drug) in the drug- PVP K3 (1:1 weight ratio) physical mixture. The appearance of the sharp endothermic peak at o C in the drug-pvp K3 physical mixture demonstrated the absence of the drug-polymer interaction. In the drug-pvp solid dispersion system, the endotherm of the drug was shifted towards lower temperature ºC and the peak was gradually reduced in area. The lower melting point (temperature) of the drug in the PVP solid dispersion was because of the melting point depression. As the intensity of the endotherm was markedly decreased in the drug-pvp solid dispersion, the faster dissolution rate of the drug from the solid dispersion is attributed to the reduction in the crystallinity of the drug. Crystallization inhibition is attributed to the entrapment of drug molecules in the polymer matrix during the solvent evaporation (Bettinetti et al., 1991). Numerous studies have shown that polymers like HPMC, PVP used in the solid dispersions can inhibit the crystallization of drugs resulting in an amorphous form of the drug in the solid dispersions (Yamashita et al., 3; Tantishaiyakul et al., 1999). Fig. 12a. DSC thermogram of pure drug. Fig. 12b. DSC thermogram of drug-hp BCD (1:1) solid dispersion.

12 Varma and Kumar: Formulation and Evaluation of Gliclazide Tablets Containing PVP-K3 and Cyclodextrin Solid Dispersion 1717 Fig. 12c. DSC thermogram of drug-hp BCD (1:1) physical mixture. Fig. 12d. DSC thermogram of drug-pvp (1:1) solid dispersion. Fig. 12e. DSC thermogram of drug-pvp(1:1) physical mixture.

13 1718 Int J Pharm Sci Nanotech Vol 5; Issue 2 July September 12 XRD studies The XRD patterns of PD, DH, DP, PH and PP are shown in Figure 13. The intensity of the XRD peaks of the drug, physical mixtures and the solid dispersions are recorded in the Table 4. This study reveals the decrease in the crystallinity of the drug in the solid dispersions. The crystallinity was decreased to a higher extent in the drug-pvp solid dispersion than in the drug-hp BCD solid dispersion. The X-ray diffraction pattern of gliclazide exhibited sharp, highly intense and less diffused peaks indicating the crystalline nature of the drug. The drug-hp BCD (1:1) solid dispersion displayed less intense and highly diffused peaks as compared to the gliclazide and the corresponding physical mixture. The XRD studies revealed the reduction in the crystalline nature of the drug in the drug-pvp (1:1) physical mixture, as the sharp, high-intensity peaks of the drug were absent, the peaks were diffuse and of very low intensity. The crystalline peaks of the drug were completely absent in the drug-pvp (1:1) solid dispersion, and the drug was present in the amorphous form in the PVP solid dispersion. The enhancement in the dissolution rate of the drug from the drug-pvp solid dispersion and the drug-hp BCD is ascribed to the marked reduction in the crystallinity of the drug. The microcrystals are formed as a consequence of evaporation of solvent during the preparation of solid dispersions by the solvent evaporation technique. Evaporation of the solvent increases the viscosity very rapidly leading to a decrease in drug mobility preventing re-crystallization. When the solvent is evaporated completely, drug molecules are frozen in the polymer. A crystal lattice is not formed, but the drug molecules are of randomly dispersed order (Van den Mooter et al., 1998) over only a few molecular dimensions. TABLE 4 Data of XRD studies. Angle (degrees 2θ) Drug substance 2 θ values DH DP PH PP Fig. 13. XRD of PD(pure drug), DH (drug-hp BCD,1:1 solid dispersion), PH (drug-hp BCD, 1:1 physical mixture), DP (drug- PVP, 1:1 solid dispersion) and PP (drug-pvp,1:1 physical mixture).

14 Varma and Kumar: Formulation and Evaluation of Gliclazide Tablets Containing PVP-K3 and Cyclodextrin Solid Dispersion 1719 Conclusion A robust tablet formulation with higher in vitro drug release can be developed by preparing solid dispersions of gliclazide with PVP K3/ HP BCD. Super disintegrants like sodium starch glycolate or croscarmellose sodium can be used in the tablet formulations to disintegrate the tablets and to get the higher drug release in less than 15 minutes. The tablets prepared by direct compression technique containing, drug-hp BCD /PVP K3 solid dispersions (prepared by kneading technique) with 8% sodium starch glycolate showed higher dissolution rates over marketed products. The drug dissolution rate was highest at the drug-to-polymer composition of 1:1(w/w). Based on the time taken for 9% drug release, the optimized formulation, H2, achieved a 3 fold faster dissolution rate than the marketed brand BR1. The XRD and DSC indicated the reduction in the crytallinity of the drug in the solid dispersions. The FTIR and DSC revealed the absence of the drug-polymer interaction in the solid dispersions. The remarkable increase in the dissolution rate of the drug from the solid dispersions is attributed to a marked reduction in the crystallinity of the drug. Acknowledgements The authors are thankful to the Director, Principal and the Management of the Shri Vishnu College of Pharmacy for encouraging this research work. References Babu GVMM, Prasad CDS and Murthy KVR (2). Evaluation of modified gum karaya as carrier for the dissolution enhancement of poorly water soluble drug nimodipine. Int. J Pharm. 234: Batra V, Shirolkar VS and Deshpande AD(8). Solubility and Dissolution Enhancement of Glipizide by Solid Dispersion Technique. Ind J Pharm. Edu Res. 42 : Betageri GV and Makarla KR(1995). Enhancement of dissolution of glyburide by solid dispersion and lyophilization techniques. 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Improvement of water solubility and in vitro dissolution rate of gliclazide by complexation with β-cyclodextrin. Pharm.Acta Helv. 4: Address correspondence to: M. Mohan Varma, Shri Vishnu College of Pharmacy Vishnupur, Bhimavaram-5342, Andhra Pradesh, India. mohan_pharm@rediffmail.com