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 Clonazepam 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 benzodiazepine 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 methanol 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 nitrogen. 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)