Research Article Swati C. Jagdale et al. / Journal of Pharmacy Research 2011,4(2),480-487 ISSN: 0974-6943 Available online through http://jprsolutions.info Solid State Characterization of in Solid Dispersion and Formulation of Fast Dissolving Tablet Swati C. Jagdale*, Ajay S. Bhadoriya, Bhanudas S. Kuchekar, Aniruddha R. Chabukswar Department of Pharmaceutics, MAEER’s Maharashtra Institute of Pharmacy, MIT Campus, S.No124, Kothrud, Pune- 411 038, Maharashtra, India. Received on: 15-09-2010; Revised on: 18-10-2010; Accepted on:09-01-2011

ABSTRACT Solid dispersions of Clonazepam in polyethylene glycol 4000 and 6000 were prepared by employing various techniques in the ratio of 1:1, 1:0.5 and 1:0.25 with the aim to increase its aqueous solubility. Drug polymer interactions were investigated using Fourier transform infrared spectroscopy and UV spectroscopy. By these determinations no drug-polymer interactions were evidenced. Solubility and dissolution study were performed and both solubility and dissolution rate of the drug in these formulations were increased. Finally, tablets were produced by direct compression and dissolution tests were realized in order to evaluate the dissolution profiles. The results show that the tablets can be classified as immediate release dosage forms due to clonazepam fast release, and such release was dependent on the amount of superdisintigrant (cross-povidone and doshion P544) in the formulation.

Key words: Clonazepam, Solid dispersions, PEG 4000, doshion, tablets, stability constant INTRODUCTION According to Biopharmaceutics Classification System (BCS) for solubility, many MATERIALS AND METHODS new drugs can be categorized as Class II or IV. Class II drugs are poorly water Materials soluble but once dissolved, they rapidly pass biological membranes like the Clonazepam (CLZ) was kindly supplied by Piramal Health Care, (Baddi, India), gastro- intestinal wall. As a consequence, Class II drugs slowly dissolve in the polyethylene glycol 4000 and polyethylene glycol 6000 (PEG 4000 & PEG aqueous environment of the gastro-intestinal tract after oral administration and 6000) was obtained from Analab Fine Chemicals, Mumbai. result in a poor bioavailability, while increasing the dissolution rate will also improve bioavailability[1-4]. Preparation of solid dispersions Solid dispersions were prepared by various methods using Physical mixtures Various techniques have been used to improve the solubility/dissolution rate of (PM) [10],Co-Grinding Method (COG) [11, 12],Solvent Evaporation Method poorly water soluble drugs. Among them, the solid dispersion technique [5] and (SE) [13,124],Closed Melting Method (CM)[15],Co-Precipitation Method the complexation with cyclodextrin [6] are most frequently used. In solid disper- (COP)[16],Kneading Method (KN) [17].Drug : carrier ratio in the range of 1:0.25, sion, hydrophilic polymers have been commonly used as carriers[7]. 1:0.5 and 1:1. Preparation methods were same for PEG 4000 and 6000.

Solid dispersion (SD) is defined as the dispersion of one or more active ingredi- Characterization of Solid Dispersion of Clonazepam ents in inert carriers at solid state prepared by fusion, solvent, or solvent-fusion methods. The physical state of the drug in solid dispersions is often transformed Phase solubility studies from crystalline to amorphous and the dissolution surface increases because of An excess amount of CLZ was added to the aqueous solutions of each carrier particle size reduction.Due to impaired swallowing ability, many elderly patients containing increasing concentrations of the individual carrier (i.e., 0.1%, 0.2%, find it difficult to take some conventional dosage forms such as tablets, capsules, 0.3%, 0.4% and 0.5% w/v). The flasks were sealed and shaken at 37 0C for 48 hr. and powders. In order to solve this problem, the fast dissolving tablet was in a thermostatically controlled water bath and the samples were filtered through developed that disintegrate rapidly or dissolve even when taken orally without a 0.45 µm membrane filter. The filtrate was suitably diluted and analyzed spec- water is being undertaken[8]. trophotometrically (Varian carry 100, UV–Vis Spectrophotometer, Australia) at ? max 245 nm [18]. Fast dissolving tablets (FDTs) are solid single-unit dosage forms that are placed in the mouth, allowed to disperse/dissolve in the saliva and then swallowed Saturation solubility studies without the need for water. Pure Clonazepam, physical mixtures and solid dispersions with carrier (excess quantity of all) were placed separately in glass stoppered flasks containing 10 ml Clonazepam (CLZ) belongs to a class of anticonvulsants that enhances gamma- distilled water. Then the flasks were maintained at 25°C for 48 hr. The saturated aminobutyric acid (GABA) receptor responses. CLZ exerts its action by binding solution was sonicated for 20 min. and then centrifuged; the supernatant were to the site of the GABA receptors, which causes an enhance- filtered using Whatman filter paper no. 41. The filtered samples were diluted ment of the electric effect of GABA binding on neurons [16]. It is a light yellow suitably in distilled water and assayed spectrophotometrically at 245 nm [19]. crystalline powder freely very soluble in and practically insoluble in water (at 25°C<0.1 mg/ml) [9]. The aim of the present study was to prepare and Percentage drug content study evaluate the physicochemical properties of solid dispersions of CLZ in polyeth- Accurately weighed SDs, equivalent to 2 mg of drug, dissolved in methanol and ylene glycol 4000 & polyethylene glycol 6000 (PEG 4000 & PEG 6000) and to solution kept in ultrasonicator for 10 min. After that volume was adjusted to formulate the fast dissolving tablet. 100 ml with methanol. Then solution was filtered through Whatman filter paper and suitably diluted. The absorbance was measured at 245 nm using double *Corresponding author. beam UV spectrophotometer. The clonazepam content was calculated using the Dr. Swati C. Jagdale, calibration curve [20]. The prepared solid dispersions were weighed and the yield Professor and Head, was calculated for each preparation using following formula: Department of Pharmaceutics, % Yield = (a/b) × 100 ………… (1) MAEER’s Maharashtra Institute of Pharmacy, Where, ‘a’ is the practical weight of solid dispersion obtained and ‘b’ is the MIT Campus, S.No124, Kothrud, theoretical Weight of solid dispersion preparation. Pune- 411 038, Maharashtra, India.

Journal of Pharmacy Research Vol.4.Issue 2. February 2011 480-487 Swati C. Jagdale et al. / Journal of Pharmacy Research 2011,4(2),480-487 Drug: Carrier Interaction Study: Evaluation of the Prepared Tablets All prepared solid dispersions were subjected to Infrared spectroscopic, UV- spectroscopic studies to determine drug carrier interaction. Evaluation of powder blend Fourier transform infrared spectroscopy (FTIR) The powder blends were subjected for loose bulk density, tapped density, compressibility [26] FTIR spectra of pure drugs and polymers, and of solid dispersions and physical index, and Hausner ratio and result calculated using formulae given below . mixtures, were recorded in scanning range of 4000 to 400 cm-1 with FTIR [21] Evaluation of Tablets spectrophotometer (640 IR, Varian, Australia), using KBr disk . Tablets were subjected to various tests like hardness (Monsanto tablet hardness tester), Stability of drug in solution friability (Roche” friabilator), uniformity of drug content, and weight variation as per US Stability of drug in solution was performed by uv-visible spectroscopy at 245 nm Pharmacopeia [27] (USP). [22]. Physical Characterization In vitro disintegration, wetting time and water absorption ratio studies Physical characterization was performed by recording differential scanning calo- For determination of in vitro disintegration time, one tablet placed in beaker containing 0 rimetry (DSC) and powder X-ray diffractometry (PXRD) on selected method of 10ml of pH 6.8 phosphate buffer at 37 + 0.5 C and the time required for complete dispersion (with mild shaking ) was measured [28].On the other hand, the wetting time was SDs based on saturation solubility and dissolution study. measured by keeping a sample tablet in Petri dish (10 mm in diameter) containing 10 ml water at room temperature [29]. The wetted tablet was then weighed. Water absorption Differential scanning calorimetry ratio, R, was determined according to the following equation: [30]. DSC curves representing the rates of heat uptake from sample [23]. About 2-10mg W - W of sample was weighed in a standard open aluminum pans of differential scan- R = a b ´ 100 …………(2) ning calorimeter (DSC 823e, Mettler Toledo, Switzerland) were scanned from W a 20-450°C, at a heating rate of 10°C/min while being purged with dry . where W a and W b are the weight before and after water absorption, respectively. These test carried out in triplicate and results are shown in Table 6 for the different Powder X-ray diffractometry samples. Powder X-ray diffraction (PXRD) patterns were traced employing X-ray diffractometer (Philips PW 1729 Netherlands.) for the all samples, using Ni In vitro dissolution filter, CuK (a) radiation, a voltage of kV, a current of 20 mA and receiving slit In vitro dissolution studies of FDTs (tablets containing solid dispersion SD) and com- of 0.2 in. The samples were analyzed over 2? range of 5° to 60°, with scan step mercial tablets LONAZEP (containing 2 mg) of CLZ from (SUN Pharmaceutical ind. ltd., Silvassa, India) and were carried using 900-ml pH 6.8 phosphate buffer using the basket size of 0.020° (2?) and scan step time of 1 second [24]. method at 75 rpm.

In vitro Dissolution Studies Short-term Stability studies Dissolution studies were carried out using the basket method (USP apparatus I) The FDTs were packed in Alu – Alu pouches and stored under the following conditions at 75 rpm. for a period as prescribed by ICH guidelines for accelerated studies at 30 + 2 o C and RH 65 % + 5% and 40 + 2 o C and RH 75 % + 5%The tablets were withdrawn after a period Preparation of Clonazepam Tablet of 7, 14 days, 1, 2 and 3 month and analyzed for physical characterization (Visual defects, The (FDTs) was prepared by direct compression method form optimized batches Hardness, Disintegration, and percentage assay etc.) (P40-COP1 & P60-COP1 based upon dissolution and saturation solubility of Data analysis SDs) of SDs using two different super disintegrants. The control (which contain Phase-solubility studies no superdisintegrant) and formulation batches were prepared according to the The values of apparent stability constant, Ks, between each drug–carrier combination formula[25]. given in Table 1 and Table 2. using 8-station Rotary Tablet Machine were computed from the phase-solubility profiles, as described below: Minipress-II (Rimek Ltd.) equipped with flat-faced 8-mm punches, separately Slope Ks = …..………(3) Table 1. Tablet Formula for P40-COP1 Intercept (1 - Slope ) Sr. Ingredient Formulation code* The values of Gibbs free energy of transfer, ?Go , of CLZ from aqueous solution No A A A A A tr Cont. CP8 CP12 DO8 DO12 of the carriers were calculated according to the following relationship: 1 Cross-povidone (CP) (%) - 20.8 (8%) 31.2(12%) - - 2 Doshion(DO) (%) - - - 20.8 (8%) 31.2 (12%) S o …..……… (4) 3 P40-COP1** 4 4 4 4 4 DGo tr = -2.303RT .log 4 Mannitol 142 125.2 114.8 125.2 114.8 S 5 MCC 100 100 100 100 100 s 6 Talc 5 5 5 5 5 Where, S and S are the molar solubility of CLZ in 1% w/v aqueous solution of 7 Aspartame 5 5 5 5 5 o s 8 Magnesium Stearate 2 2 2 2 2 the carrier, respectively. 9 Flavor (orange) 2 2 2 2 2 Dissolution kinetic modeling All weight was in mg, *A is P40-COP1, CP is cross-Povidone, Do is doshio The in vitro drug release data was fitted into Zero order, First order, Higuchi’s model, Hixson-Crowell , Korsmeyer and Peppas model and of data treatment P544 and 8 & 12 is % conc. ** P40-COP1 4mg, equivalent to 2mg of CLZ. for the solid dispersion [22].

Table 2. Tablet Formula for P60-COP1 Dissolution efficiency (DE) studies The drug release profiles was characterize by calculating the DE which is defined Sr Ingredient Formulation code* as the area under the dissolution curve up to a certain time t, expressed as a No. B Cont. BCP8 BCP12 B DO8 B DO12 percentage of the area of the rectangle arising from 100% dissolution in the 1 Cross-povidone (CP)(%) - 20.8 (8%) 31.2 (12%) - - same time. DE can be calculated by the following equation: 2 Doshion P544 (DO)(%) - - - 20.8 (8%) 31.2 (12%) 3 P60-COP1** 4 4 4 4 4 æ dt ö 4 Mannitol 142 125.2 114.8 125.2 114.8 DE = y ç ÷ ....……..(5) 5 MCC 100 100 100 100 100 è 100 t ø 6 Talc 5 5 5 5 5 7 Aspartame 5 5 5 5 5 Where y is the drug percent dissolved at time t [31]. 8 Magnesium Stearate 2 2 2 2 2 9 Flavor (orange) 2 2 2 2 2 Similarity factor (f2) The similarity factor between the two formulations (LNZ and test) was deter- All weight was in mg ,*B is P60-COP1, CP is cross-povidone, Do is doshio mined using the data obtained from the drug release studies. The data were P544 and 8 & 12 is % conc. ** P60-COP1 4mg, equivalent to 2mg of CLZ. analyzed by the following formula. n 2 - 0.5 ....……..(6) f 2 = 50 log{[ 1 + (1 / n )å w t ( R t - T t ) ] }100 t =1 Journal of Pharmacy Research Vol.4.Issue 2. February 2011 480-487 Swati C. Jagdale et al. / Journal of Pharmacy Research 2011,4(2),480-487 where, n is the number of withdrawal points, R is the percentage dissolved of reference at the t Characterization of Solid Dispersion time point t, and T t is the percentage dissolved of test at the time point t. A value of 100% for the f 2 suggests that the test and reference profiles are identical. Values between 50 and 100 indicate that the dissolution profiles are similar whilst smaller values imply an increase in Stability of Drug in Solution dissimilarity between release profiles [32]. In UV-visible spectrophotometric the position of ? max was not change for all the SDs, which indicates there is no interaction between this binary system RESULTS AND DISCUSSION: (Figure 2 and 3).

Phase solubility studies From phase solubility graph of CLZ (Figure 1) it can be seen that the apparent solubility of CLZ increased with increasing carrier concentrations. The stability constant data obtained by phase solubility study was (Ks) 30.27, slope 0.8823 with R2 value 0.9906 for PEG 4000 and for PEG 6000 was Ks 53.10, slope 0.9400 with R2 value 0.9974. The negative nature of the Gibbs free energy changes (?Gotr) (– 11.63, -16.18, and -18.90 for PEG 4000 and for PEG 6000 ?Gotr was –15.42, – 18.30 and – 20.65 for carrier conc. 0.3 %, 0.4 % and 0.5 % w/v carrier conc. respectively) are indicative of the spontaneity of the process. The endother- mic heats of solution further explain the increase in solubility with temperature.

Figure 2. UV Spectra of clonazepam SD’s with PEG 4000.

P60= PEG 6000, P40= PEG 4000 Figure 1. Solubility of CLZ (g/100ml) in aqueous solutions of PEG 6000 and PEG 4000 in water at 25ºC. Saturation solubility studies: The saturation solubility of CLZ was 30.54 µg/ml at 25ºC. It was found that Figure 3. UV Spectra of Clonazepam SD’s with PEG 6000. solubility increased with the increase in carrier proportion in solid dispersions Fourier transform infrared spectroscopy prepared by all the five methods (Table 3), though solid dispersions prepared by The presence and absence of characteristic peaks associated with specific structural character- PEG 6000 showed comparatively less enhancement in solubility than those istics of the molecule (Figure 4 and 5).The characteristic shoulders of pure clonazepam prepared by PEG 4000. shows specific structural group at 3221 cm-1 (N-H stretching), 3,066 cm-1 (aromatic C-H stretching), 1,765 cm-1 (carbonyl stretching), 1,623, 1,582 cm-1 (aromatic ring), 1356 cm-1 -1 Content uniformity and percent practical yield (symmetric stretching NO2 stretching), 766 cm (four adjacent free Hs and aromatic C-H out The drug content of prepared solid dispersions of all formulations was found to of plane bending), and 850 cm-1 (two adjacent free Hs and aromatic C-H out of plane be in the range of 86.48 to 112.49 % w/w (Table 3). bending).Important vibrations detected in the spectrum of PEG 4000 was detected in the spectrum are at 3425 cm–1 for OH stretch, at 1109 cm–1 for C-O-C stretch and at 2889 cm– Table 3. Percent Drug Content, Percent yield of SDs of Clonazepam 1 for CH stretch. While vibration frequency for PEG 6000 are the C–H stretching at 2890 cm- and saturation solubility with PEG 4000 and PEG 6000. 1 and the C–O (ether) stretching at 1125 cm-1.

Preparation Abrav. PEG 4000 PEG 6000 P40-COP Methods % Drug Mean % Saturation % Drug Mean % Saturation 0.25 Content Yield solubility Content Yield solubility ±SD* ±SD* µg/ml ±SD* ±SD* µg/ml

Physical Mixture PM1 95.17±0.4 96.73±1.01 63.64 96.11±0.46 94.66±0.60 51.43 P40-KN 0.5 PM2 94.90±0.18 96.59±1.06 56.581 93.57±0.75 92.32±1.52 45.29 PM3 88.33±0.42 95.93±0.51 43.97 95.43±0.45 88.31±1 39.82

Kneading KN1 95.17±0.42 97.13±1.37 88.52 98.57±0.42 96.89±0.57 71.26 P40-COP Methods KN2 104.93±0.86 94.18±0.61 70.13 97.52±1.1 97.36±0.17 66.36 0.5 KN3 98.33±0.25 96.14±0.73 67.21 100.88±0.09 98.39±0.57 45.38 Closed Melting P40-KN 1 Methods CG1 95.50±1.11 87.31±0.55 48.61 91.45±0.088 88.8±0.46 43.27 CG2 109.08±1.11 89.57±0.64 36.12 95.30±0.16 84.25±1.13 49.49 CG3 105.60±0.56 92.46±1.55 40.96 89.90±0.12 86.17±0.77 38.40

Co-Grinding CG1 94.92±0.64 93.12±1.33 86.8 94.18±1.11 90.95±0.37 49.72 P40-COP 1 Methods CG2 91.09±0.14 90.42±1.77 75.11 87.55±0.54 92.64±0.30 43.39 CG3 86.74±0.02 94.26±3.8 47.20 92.16±0.44 85.82±0.32 42.21 Co-Precipitation Methods CP1 100.65±0.26 92.42±0.4 91.09 98.37±0.066 98.93±0.42 82.53 P40-PM 1 CP2 98.56±0.17 91.31±0.68 73.48 98.67±0.044 95.33±0.44 58.65 CP3 99.33±0.46 95.06±0.45 50.68 99.82±0.1 93.84±0.55 46.83 Solvent PEG-4000 Evaporation SE1 112.09±0.78 94.03±1.00 56.39 97.47±0.39 87.43±0.57 46.56 Methods SE2 90.43±0.44 84.68±2.06 52.62 91.1±0.42 90.12±0.85 38.43 SE3 99.60±0.69 82.71±1.00 42.25 99.47±0.14 89.03±0.28 39.78 CLZ * Average of three determinations. ±SD - Standard deviation. n = 3,1, 2, 3, - ratio 1:1, 1:0.5 and 1:0.25 ratio of drug: carriers. PM- Physical Mixture, KN- Kneading, CM- Closed Melting, CG- Co-grinding, CP- Co-precipitation, SE- Solvent Evaporation Figure 4. FTIR spectra of Clonazepam solid dispersions in PEG 4000.

Journal of Pharmacy Research Vol.4.Issue 2. February 2011 480-487 Swati C. Jagdale et al. / Journal of Pharmacy Research 2011,4(2),480-487 The shape of DSC curve of all the SDs characterized by the presence of sharp endothermic peak corresponding to PEG. The sharp endothermic peaks corresponding to melting of CLZ becomes dull and broad in DSC thermograms of SDs. It might be due to the P60-KN 0.25 amorphous form of CLZ in the solid dispersion or dissolution of crystalline CLZ into the molten carrier during the DSC scan. DSC of co-precipitation and kneading method showed a weak sharp exothermic peak was equivalent to the crystalline drug (CLZ) P60-COP 0.5 (Figure 6d to 6e and Figure 7c to 7d). The behavior of exothermic nature of peak around 250-275 0C was indicative of thermal degradation of CLZ. The DSC curve of P40-COP1 and P60-COP1 Figure 6c & 7f showed the disappearance of peak of CLZ. It indicates least P60-KN 0.5 crystalinity, more amorphousness.

P60-KN 1 Powder X-ray Diffraction Analysis Powder X-ray diffraction spectroscopy has been used to assess the degree of crystallinity P60-COP 1 of the given sample. CLZ shows major peak at 2? values for drugs (CLZ) are 11.84, 14.75, 14.98, 18.22, 18.50, 20.03, 20.45, 22.98, 23.91, 24.32, 26.07, 27.14, 27.38, 27.80, and 30.22. P60-PM 1

PEG-6000

CLZ

Figure 5. FTIR spectra of Clonazepam solid dispersions in PEG 6000. In the spectra of CLZ solid dispersions in PEGs, the characteristic peaks of PEG were present at almost the same positions, whereas peaks due to CLZ were also present but intensity of absorption reduced indicating trapping of CLZ inside the PEG matrix. All the spectra show no peaks other than those assigned to CLZ and PEGs which indicates the absence of any well-defined chemical interactions. Differential Scanning Calorimetry Analysis

DSC enables the quantitative detection of all processes in which energy is required or produced (i.e., endothermic or exothermic phase transformations). The thermogram of CLZ showed a single downward melting peak at 238.86°C. Analogously, The DSC curve of PEG 4000 shows endothermic peaks at 59.2 °C and PEG 6000 showed sharp endothermic peaks at 62.7 ºC due to fusion which was corresponding to its melting point. (Figure 6 and 7). Figure 8. PXRD of; a) PEG 4000, b) CLZ, c) P40-KN0.5, d) P40-KN1, e) P40-COP1, e) P40- COP0.5.

Figure 6. DSC Thermogram of; a) CLZ, b) PEG 4000, c) P40-COP1, d) P40-COP0.5, e) P40- KN1 f) P40-KN0.5.

Figure 9. PXRD of; a) PEG 6000, b) CLZ, a) P60-KN0.5, b) P60-KN1, c) P60-COP1, d) P60- COP0.5.

Pure PEG 4000 showed two peaks with highest intensity at 2? of 19.3 and 26.2. The PEG 6000 alone exhibited two high intensity peaks at 15.12; 19.20 and 23.508 (Figure 8 and 9). The lack of the numerous distinctive peaks of the drug in SDs demonstrated that a high concentration of the drug was dissolved in solid state carrier matrix in an amorphous state. Suggesting, the CLZ present in the solid dispersion would be mostly in amorphous state and only with few partially crystallized drug molecules.

Degree of crystallinity was decreased to maximum extent in case of P40-COP1 and P60- COP1 indicates samples amorphousness increases more than other samples. Figure 7. DSC Thermogram of; a) CLZ, b) PEG 6000, c) P60-COP0.5, d) P60-KN0.5, e) P60- COP1, e) P60-KN1. Journal of Pharmacy Research Vol.4.Issue 2. February 2011 480-487 Swati C. Jagdale et al. / Journal of Pharmacy Research 2011,4(2),480-487 Dissolution Studies of CLZ Solid Dispersion I. PEG 4000 SDs drug released results

Figure 10a. In vitro Dissolution profile of CLZ-PEG 4000 binary systems by 1:1 ratio. Figure 11b. In vitro Drug release profile of CLZ-PEG 6000 binary systems from ratio 1:0.5.

Figure 10b. In vitro Dissolution profile of CLZ-PEG 4000 binary systems by 1:05 ratio

Figure 11c. In vitro Drug release profile of CLZ-PEG 6000 binary sys- tems from ratio 1:0.25.

The cumulative % drug release was found in the range of 34.43 to 3 to 101.02 % w/v for CLZ -PEG 6000 solid dispersion batches (Table 5). In-vitro release studies revealed that there was a marked increase in dissolution rate of CLZ from all solid dispersions when compared to pure clonazepam itself except P60-PM1, P60-PM0.25, and P60-CM3 might be due to the improper distri- bution of drug in these formulations (Figure 11a, 11b and 11c).

Figure 10c. In vitro Dissolution profile of CLZ-PEG 4000 binary systems by 1:25 ratio. The polymer, PEG is crystalline and water soluble with two parallel helices in a unit cell. Significant amount of drug can be entrapped in the helical intersti- In-vitro release studies revealed that there was a marked increase in dissolution rate of CLZ tial space when PEG and drug are solidified. It thus acts to reduce the size of from all solid dispersions when compared to pure clonazepam itself (Figure 10a, 10b and the drug particle by decreasing their aggregation and, thereby enhancing the 10c). The cumulative % drug release was found in the range of 32.03 to 78.57 % w/v for CLZ dissolution of drug. Among the different ratios prepared, the enhancement of -PEG 4000 solid dispersion batches (Table 5). dissolution rate was found to be 1:1 >1:0.5>1:0.25.

From the release profile of ratio 1:1 and 1:0.5 ratios of KN and COP methods shows Data Analysis uniformity in the release pattern of drug after 120 minutes and the rate of drug release was Dissolution Kinetic Modeling almost same for these two method (Table 4). But in case of ratio 1:0.25, the uniformity in To interpret the release kinetics and mechanism of drug release from solid drug release was not found. This loss of uniformity was due to high loading of drug in PEG dispersions. The coefficient of determination was considered as main param- 4000 there on proper mixing of drug and carrier. eter for interpreting the results. The value of ‘n’ gives an indication of the II. PEG 6000 SDs drug released results release mechanism; when n = 1, the release rate is independent of time (zero- order) (case II transport), n = 0.5 for Fickian diffusion and when 0.5 < n <1.0, diffusion and non-Fickian transport are implicated. Lastly, when n > 1.0 super case II transport is apparent.

Kinetic treatment for PEG 4000 solid dispersions: Formulations P40-CM2, P40-CM3, P40-COG1, P40-COG3, P40- COP2, P40- COP3 and P40-SE2 follows zero order kinetics only one formulation i.e. P40- SE1 followed first order kinetics. All the remaining formulation showed Peppas kinetic of drug release (Table 4).

All formulations with n values ranged from 0.6098 to 0.9517 shows non- Fickian type of transport pattern as predominant mechanism of drug release. While n value of all the remaining formulation was in the range from 1.0870 to 1.2950 which is the indication of Super Case-II transport. Figure 11a. In vitro Drug release profile of CLZ-PEG 6000 binary systems from ratio 1:1. Journal of Pharmacy Research Vol.4.Issue 2. February 2011 480-487 Swati C. Jagdale et al. / Journal of Pharmacy Research 2011,4(2),480-487

Table 4. Dissolution Parameter of Solid Dispersion of PEG 4000 their f2 value is more than 50 (84.94, 70.57, 66.03 and 63.81, respectively) but other DP %DE method was dissimilar in release behavior of drug. Study of % drug release (DP) after 60

Solid Dispersion DP60 DP120 T50% DE60 DE120 Best Fit n= f 2 and 120 minute confirmed that the drug release form the dispersion was much better than Method & Modle pure CLZ (15.38 to 27.82, respectively) as compare to solid dispersions, and highest Ratio amount of drug release was found with method kneading and co-precipitation. CLZ 15.38±1.25 27.82± 0.37 215.67 6.41±0.41 15.47±0.37 Zero order 0.9758 - P40-KN1 48.39±0.26 78.57±0.82 76.36 15.37±0.72 19.77±0.43 Hix.Crow 1.2950 56.33 PEG 6000: P40-KN2 74.28±0.25 74.28±0.46 80.77 19.47±0.69 26.41±0.47 Hix.Crow 0.8799 47.61 P40-KN3 16.82±0.74 30.17±0.22 198.83 14.57±0.31 20.33±0.79 Peppas 0.9517 58.31 Similar result of data analysis for PEG 6000 and CLZ is shown in Table 5 study of P40-PM1 28.55±0.36 50.60±0.67 118.52 22.03±0.87 38.75± Peppas 1.1211 32.10 dissolution efficiency at 60 and 120 min. and time require to release 50% and 90% of drug P40-PM2 58.49±0.24 58.49±0.08 102.57 33.02±1.41 43.52±0.19 Peppas 0.9184 29.58 clearly indicate the superiority of dispersion technique over pure drug. Similarity factor P40-PM3 35.63±0.22 60.81±0.11 98.65 28.8±0.54 38.22±0.52 Hix.Crow 0.6337 32.78 P40-CM1 43.75±0.17 67.2±0.50 89.28 15.21±0.57 24.86±0.46 Peppas 0.9278 49.60 was indicate that the method P60-PM1, P60-PM3, P60-CM2, P60CM3 and P60-SE1 P40-CM2 64.87±0.34 64.87±0.29 92.47 13.30±0.68 20.35± Zero order 1.2501 58.87 follows similar pattern as that of CLZ as their f2 value is more than 50 (56.33, 58.31, 58. P40-CM3 9.98±0.39 32.03±0.34 187.30 15.36±0.93 20.64±.56 Zero order 0.6098 55.87 87, 55.87 and 55.03, respectively) but other method was dissimilar in release behavior of P40-COG1 13.92±0.27 37.95±0.92 158.09 26.33±0.720.4141.52±0.82 Zero order 0.9191 31.45 drug. Study of % drug release after 60 and 120 minute confirmed that the drug release form P40-COG2 25.18±0.52 53.50±0.46 112.13 22.05±0.82 22.05±0.76 Peppas 1.0327 43.24 P40-COG3 27.97±0.49 54.3±0.94 110.46 22.83±0.49 32.50±0.32 Zero order 0.8377 40.44 the dispersion was much better than pure CLZ (15.38 to 27.82, respectively) as compare P40- COP1 53.38±0.74 93.66±0.58 64.09 56.66±0.76 75.45±0.28 Peppas 1.2548 13.64 to solid dispersions, and highest amount of drug release was found with method kneading P40- COP2 33.65±1.25 75.90±0.67 79.04 20.29±0.940.70 33.92±0.46 Zero order 1.0870 38.02 and co-precipitation. P40- COP3 31.80±0.23 67.08±0.23 89.43 17.14±0.73 31.82±1.05 Zero order 1.0912 30.74 P40-SE1 20.42±0.42 34.23±0.64 175.24 15.89±0.22 21.88±0.47 First order 0.9897 55.03 Tablet Characterization & Dissolution P40-SE2 62.44±0.37 62.44±0.15 96.08 22.65±0.19 31.76±0.64 Zero order 1.1686 40.93 P40-SE3 44.45±0.57 69.98±0.28 85.73 26.19±0.06 30.57±0.75 Hix.Crow 0.9099 39.41 To prepare fast dissolving tablet, optimized batches of CLZ with PEG 4000 and PEG 6000 binary mixture were selected based on its saturation solubility and in-vitro dissolu- ±SD - Standard deviation. n = 3 tion performance. The batch selected was P40-COP1 and P60-COP1. Two different 1, 2, 3, - ratio 1:1, 1:0.5 and 1:0.25 ratio of drug: carriers. superdisintegrants, crosspovidone (CP) and doshion P544 (DO) were tried to achieve fast P40- PEG 4000. DP- % drug release, DE- dissolution efficiency, dispersion of tablets in different concentration and they were coded as A Cont., ACP8, A CP12, T50%- time require to release 50% drug. ADO8 and A DO12 for PEG 4000 and BCont. BCP8, BCP12, BDO8 and BDO12 PEG 6000.The Bulk PM- Physical Mixture, SE- Solvent Evaporation, KN- Kneading, Density (BD) and Tapped Density (TD) were found to be in range of 0.317 to 0.4333 gm/ CM- Closed Melting, CP- Co-precipitation, CG- Co-grinding. cm3 and 0.382 to 0.481 gm/cm3, respectively (Table 6). From density data, % compress- Kinetic treatment for PEG 6000 solid dispersions: Formulations, P60-KN1, P60-CM1, and P60- COP3 follows zero order kinetics while only one formulation P60-CM2 followed first order kinetics. Formulations P60-KN2,

P60-KN3, P60-PM3, P60-COG2, P60-COG3, P60-SE1, P60-SE2, and P60-SE3 fol- DO12% lows Higuchi kinetics. Formulation shown Korsemeyer Peppas was P60-PM1, P60- B 0.382 0.481 20.58 1.25 2.9±0.48 0.78 3.5±0.62 16.0±0.16 30.60±0.82 131.25±0.63 99.07±1.07 263.8±0.35 PM2, P60-CM3 and P60- COP2.

The n value for all the formulation was in the range of 0.2987 to 0.6385 indicating that DO8% the release mechanism from these systems was anomalous type (Non Fickian transport), B 0.393 0.464 15.15 1.17 3.0±0.12 0.80 3.1±0.18 17.0±0.57 25.0±1.01 144.18±0.77 98.50±0.95 261.6±0.62 which refers to a combination of both diffusion and erosion controlled-drug release (Table 5). CP12%

Table 5. Dissolution Parameter of Solid Dispersion of PEG 6000 B 0.382 0.481 17.64 1.21 3.3±0.68 0.67 3.3±0.29 15.0±.43 21.53±0.99 118.07±0.67 98.89±0.62 260.6±0.03

Solid Dispersion Method & DP %DE Best Fit n= f

2 CP8%

Ratio DP60 DP120 T50% DE60 DE120 Modle B 0.393 0.481 18.18 1.22 3.0±0.11 0.72 3.2±0.47 24.0±0.72 27.25±0.49 123.5±0.60 100.03±0.84 262±0.30 CLZ 15.38±1.25 27.82± 0.37 215.67 6.41±0.41 15.47±0.37 Zero order 0.9758 P60-KN1 25.90±0.78 73.8±0.41 81.28 15.37±0.77 29.63±0.46 Zero order 0.5410 43.94 P60-KN2 45.68±0.49 58.86±0.14 101.92 14.25±0.41 27.88±0.84 Higuchi square0.5502 44.24

P60-KN3 35.65±0.06 56.17±0.86 106.80 20.48±0.26 35.28±0.73 Higuchi square0.2987 37.08 Cont. P60-PM1 20.24±0.92 25.90±0.64 231.61 21.13±0.18 44.18±0.64 Peppas 0.3375 28.17 B 0.325 0.406 20.0 1.14 3.0±0.70 0.47 3.0±0.59 102.0±0.88 270±0.97 55.64±0.44 98.03±0.31 269±0.61 P60-PM2 26.27±0.60 35.93±0.40 166.97 25.10±0.25 41.53±0.52 Peppas 0.4208 30.74 P60-PM3 20.05±0.47 27.57±0.11 217.57 7.73±0.53 17.41±0.48 Higuchi square0.3813 84.79 P60-CM1 22.28±0.81 46.70±0.27 128.46 19.99±0.49 41.49±0.29 Zero order 0.4331 31.63 P60-CM2 16.62±0.43 35.46±0.39 169.16 16.73±0.76 37.39±0.32 First order 0.4033 34.37 DO12%

P60-CM3 21.26±0.63 25.53±0.46 234.98 8.03±0.47 14.24± Peppas 0.3197 70.57 A 0.406 0.464 20.0 1.14 3.1±0.48 0.68 3.2±0.46 25.0±0.82 46.15±0.42 154.82±0.32 99.56±0.17 262.8±0.45 P60-COG1 42.15±0.67 67.78±1.62 88.52 9.94±0.28 18.19±0.90 Hix.Crow. 0.6385 66.03 P60-COG2 29.71±0.15 39.27±0.47 152.76 11.94±0.09 24.94±0.73 Higuchi square0.5340 48.98 P60-COG3 35.28±0.21 45.21±0.97 132.68 17.52±0.44 28.14±0.67 Higuchi square0.5335 44.29 P60- COP1 79.29±0.58 101.20±0.25 59.28 24.20±0.75 50.93±0.42 Peppas 0.4738 23.58

P60- COP2 32.49±0.44 60.72±0.32 98.80 20.50±0.68 36.99±0.15 Hix.Crow. 0.6087 33.35 DO8% P60- COP3 34.44±0.39 57.84±0.69 103.72 16.79±0.40 34.42±0.76 Zero order 0.5871 36.75 A 0.433 0.448 17.14 1.20 3.3±0.12 0.88 3.1±0.53 32.0±1.01 33.13±0.11 126.23±0.94 101.28±0.45 261.6±0.12 P60-SE1 22.09±0.68 32.3±.034 185.68 11.63±0.71 20.07±0.46 Higuchi square0.4464 63.81 P60-SE2 34.16±047 45.21±0.45 132.68 17.11±0.27 31.23±0.22 Higuchi square0.5408 39.96 P60-SE3 30.82±0.25 39.74±0.48 150.98 23.98±0.47 41.51±0.51 Higuchi square0.4085 31.38 Table 6. Evaluation of Fast Dissolving T ablet

±SD - Standard deviation. n = 3 CP12% A 0.371 0.481 16.66 1.20 3.3±0.68 0.73 3.2±0.56 18.0±0.99 27.0±0.86 119.23±0.55 100.29±0.29 261.6±0.53 1, 2, 3, - ratio 1:1, 1:0.5 and 1:0.25 ratio of drug: carriers. P60-PEG 6000, DP- % drug release, DE- dissolution efficiency,

T50%- time require to release 50% drug.

PM- Physical Mixture, SE- Solvent Evaporation, KN- Kneading, CP8% CM- Closed Melting, CP- Co-precipitation, CG- Co-grinding. A 0.371 0.464 12.5 1.25 3.1±0.11 0.97 3.2±1.27 20.0±0.49 30.0±0.27 123.93±0.66 98.74±0.44 260.21±0.21

Dissolution Efficiency and Similarity Factor Percent dissolution efficiency (%DE) was computed at level of %DE at 60 min (%DE min)

60 Cont. and 120 min (%DE120min) for each preparation. Similarity factor was used to compare the Formulation code A 0.317 0.382 17.07 1.20 3.3±0.70 0.58 3.1±0.43 98.0±0.23 252.0±0.97 61.92±0.74 99.93±0.34 263±0.38 similarity in dissolution profile (or bioavailability) of pure drug and prepared solid dispersion. ) 2 PEG 4000:

From the study of dissolution efficiency at 60 and 120 min. and time require to release (Kg/cm 50% and 90% of drug indicate the superiority of dispersion technique over pure drug * (Table 4). Calculated result of similarity factor indicate that the method P40-KN3, P40- Average±SD n=6, A- is PEG 4000 and B- 6000

COG1, P40-COG2 and P40-SE1 follows similar dissolution pattern as that of CLZ as * T est parameter Bulk density T apped density Compressibility index Hausner ratio Hardness Friability (%) Thickness(mm) In-Vitro Disintegration time* (s) Wetting Time* (s) Water absorption Ratio*(%) Percent Drug Content* Average Weight (mg) *

Journal of Pharmacy Research Vol.4.Issue 2. February 2011 480-487 Swati C. Jagdale et al. / Journal of Pharmacy Research 2011,4(2),480-487 ibility and Hausner’s ratio was calculated and was found to be in between 20.50% - tested in formulations, so the optimized batches of both SDs and FD tablets are stable. 12.50% and 1.25 – 1.17, hence, it was concluded that the powder blend show good to fair to passable flow properties.All the formulations exhibited white color, odorless, flat CONCLUSION circular in shape with smooth surface. Hardness and friability of all formulations were SDs of CLZ prepared with PEG by the KN1, KN0.5, COP1 and COP.05 method resulted within acceptable limits. Hardness of tablets prepared by direct compression was in range 2 in greater increases in drug dissolution. As demonstrated by both X-ray diffraction and of 2.9 to 3.3 kg/cm . The friability of all formulations was found to be less than 1.0 %. DSC, a decreased crystallinity of CLZ and the surface morphology of the polymeric The average weight of the FDTs prepared by direct compression method was 260.21 to particles explained this improved dissolution rate. The prepared FDTs had drug dissolu- 263.08 mg. Weight variation of FDTs was within 0.03% – 0.51 % w/w. While, thickness tion profiles that were better than those of CTs. Moreover, flow properties of the tablet of tablet was found in range of 3.2 to 3.5 mm. The drug content of the prepared tablets was in the range of 98.50 to 101.28 mg per tablet (Table 6). powder as well as disintegration analysis and technological parameters of the tablets indicated that tablet powder blend of excipients is a suitable for the development of CLZ- Disintegration time is important for FDTs, according to EP disintegration time should be FD tablets. within 3 min. This rapid disintegration assists swallowing and also plays a role in drug absorption in buccal cavity, thus promoting bioavailability [33]. The control formulation, ACKNOWLEDGEMENTS which does not contain superdisintegrant, showed disintegration time 215 sec. and The authors are grateful to Maharashtra Institute of pharmacy, Pune for providing essential disintegration time of prepared FDTs was in the range of 16.0 to 32.0 sec. (Table 6). laboratory conditions for present research work. Also an author acknowledges to Depart- These superdisintegrants accelerate dispersion of tablets by virtue of their ability to absorb ment of Physics, University of Pune for allowing the X-ray Diffraction and Differential a large amount of water when exposed to an aqueous environment. The absorption of water Scanning Calorimetric studies. results in breaking of tablets and therefore faster dispersion. REFERENCE Wetting time is used as an indicator from the ease of the tablet disintegration in buccal 1. 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Source of support: Nil, Conflict of interest: None Declared

Journal of Pharmacy Research Vol.4.Issue 2. February 2011 480-487