Development and in vitro Characterization of Meclizine Hydrochloride Solid Dispersions

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The present research was aimed to develop the meclizine hydrochloride-polyethylene glycol 20000 solid dispersions to enhance the solubility and dissolution rate. They were prepared using solvent evaporation method and evaluated for solubility
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   American Journal of Advanced Drug Delivery  www.ajadd.co.uk   American Journal of Advanced Drug Delivery  www.ajadd.co.uk     Original Article Development and in vitro   Characterization of Meclizine Hydrochloride Solid Dispersions Bhaskar Daravath 1,2  and Rama Rao Tadikonda* 3 1 Department of Pharmaceutics, Sri Shivani College of Pharmacy, Mulugu Road, Warangal, Andhara Pradesh, India-506007 2 Acharya Nagarjuna University, Nagarjuna Nagar, Guntur, Andhra Pradesh, India-522510 3 Department of Pharmaceutics, Avanthi institute of Pharmaceutical sciences, Hayath Nagar, Ranga Reddy (D), Hyderabad, Andhra Pradesh, India-500090 ABSTRACT   The present research was aimed to develop the meclizine hydrochloride-polyethylene glycol 20000 solid dispersions to enhance the solubility and dissolution rate. They were prepared using solvent evaporation method and evaluated for solubility studies, drug-carrier compatibility studies and in vitro  dissolution studies. From the solubility studies, formulation F4 was selected to prepare the fast dissolving tablets and compared with control tablets (conventional tablets using pure drug). From the results of in vitro  dissolution study, tablets containing polyethylene glycol 20000 showed almost complete drug release within the 15 min. The percent drug release in 15 min (Q 15 ) and initial dissolution rate for formulation F4 was 98.46±1.24%, 6.56%/min. These were very much higher compared to control tablets (32.49±1.29 %, 2.17%/min). The relative dissolution rate was found to be 3.03 and dissolution efficiency was found to be 54.44 and it is increased by 3.4 fold with F4 formulation compared to control tablets (16.55). Thus the formulation of polyethylene glycol 20000 solid dispersions is a suitable method to enhance the solubility and dissolution rate of meclizine hydrochloride. Keywords : Dissolution efficiency, Initial dissolution rate, Relative dissolution rate, Solvent evaporation method, Solubility studies. INTRODUCTION  From the last few decades, the  pharmaceutical formulation scientists are widely focusing on the development of oral dosage forms of poor aqueous solubility drugs by enhancing the solubility using Date of Receipt- 13/02/2014 Date of Revision- 20/02/2014 Date of Acceptance- 10/04/2014 Address for Correspondence Department of Pharmaceutics, Avanthi institute of Pharmaceutical sciences, Hayath Nagar, Ranga Reddy (D), Hyderabad, Andhra Pradesh, India-500090. E-mail: tadikondarao @yahoomail.com     Tadikonda  et al_________________________________________________    ISSN 2321-547X    AJADD[2][2][2014]238-247  different approaches 1 . In these, solid dispersions is one of the widely used approaches to of improve the solubility and dissolution rate of poorly water-soluble drugs and in turn their oral bioavailability 2 . Solid dispersions are molecular dispersions of drugs in a polymer in solid form and these can be prepared by various methods. Solvent evaporation method and fusion method are widely used to fabricate the solid dispersions 3 . The present study is aimed to formulate and develop Meclizine hydrochloride (MCZ) fast dissolving tablets of using solid dispersion method to improve the solubility and dissolution rate. MCZ is a first-generation antihistamine of the  piperazine class drug, used in the treatment of motion sickness. It is acting as H 1  receptor antagonist and practically insoluble in water  4 . Some of the recent research examples on MCZ are Meclizine hydro chloride mouth dissolving tablets 5 , Cyclodextrin-meclizine HCl inclusion complexes 6 , Metabolism and pharmaco-kinetics of meclizine suspension 7 , Meclizine HCl orally disintegrating tablets 8 , Meclazine - maltodextrin oro-dissolving tablets 9 . In the  present study an attempt was made to  prepare a solid dispersion of MCZ using PEG 20000 by solvent evaporation method. PEG act as continuous phase in the solid dispersion in which MCZ is dispersed as internal phase. Some of the reported drugs as PEGs solid dispersions are nisoldipine 10 , simmvastatin 11 , diclofenac sodium 12 , clopidrogel 13 , gliclazide 14 . From the support of above literature, it was planned to prepare the MCZ-PEG 20000 solid dispersions to enhance the dissolution rate. MATERIALS AND METHODS Materials Meclizine hydrochloride was gift sample from FDC Limited, Mumbai, India. PEG 20000 was obtained from CDH, Delhi, India and all other reagents used were of analytical grade and obtained from S.D. Fine Chemicals, Mumbai, India. Preparation of solid dispersions by solvent evaporation method    MCZ-PEG 20000 solid dispersions were prepared by the solvent evaporation method (Table 1). Accurately weighed amount of drug and carriers in various ratios dissolved in ethanol in a round bottom flask and the solvent was evaporated at 45°C temperature. Solid dispersions were subsequently stored in a vacuum oven at room temperature for 48 h to remove the residual solvent. The dried solid dispersions were grinded in a mortar and pestle and  passed through sieve # 60 and were stored in desiccators until use. Solubility studies   The prepared solid dispersions were subjected to solubility studies in 0.1 N HCl, distilled water and 7.4 pH phosphate buffers. An excess amount of MCZ solid dispersion was weighed and transferred into conical flasks which contain 10 ml of media. The content in conical flask were sonicated for 2 h at room temperature, there after the samples were placed on a shaker, agitated at room temperature for 48 h. Subsequently, the suspensions were filtered through a Whatman filter paper. The filtrate was suitably diluted and analyzed spectrophotometrically at a wavelength of 232 nm using a double beam UV-Visible spectrophotometer. Drug-carrier compatibility studies   The thermograms were recorded for drug, carrier, and physical mixture using differential scanning calorimeter (Shimadzu, Japan). About 2-4 mg sample in an open aluminium standard pan was heated at a scanning rate of 5 0 C/min from a   Tadikonda  et al_________________________________________________    ISSN 2321-547X    AJADD[2][2][2014]238-247  temperature 0 to 450 0 C under a nitrogen gas flow. Micromeritic properties of blend    The flow properties were studied through measuring the angle of repose, Carr’s index. Powder mixtures of different formulations were evaluated for angle of repose, bulk density, tapped density and compressibility index. The fixed funnel method was employed to measure the angle of repose (θ) and it was calculated using the following formula: Tan θ = h/r   ……………….… [1] In which, θ is the angle of repose, h is the height of the cone and r is radius of the cone base. To measure the angle of repose, a funnel was fixed to a stand so that the lower tip of funnel was 2.5 cm above the surface. A graph paper was placed on a flat surface. The powder blend was allowed to fall freely on the graph paper through the funnel (6.8 cm diameter), till the tip (8 mm diameter) of heap formed just touches the funnel. The radius of heap was noted and from this angle of repose was determined. The bulk density ( ρb) of a powder is determined by measuring the volume of a known mass of powder sample that may have been passed through a screen, into a 50 ml graduated cylinder. Tapped density (ρtap) of powder samples were determined  by a tap density apparatus. The apparatus was set for 500 tapings for 5 min at stroke height 20 mm at the rate of 100 strokes/min15. The Carr’s Index is a measure of the propensity of a powder to be compressed and it is calculated using the following formula: Carr’s Index = [(ρ tap -  ρ b  ) / ρ tap ] / ×100 … [2]   Preparation of fast dissolving tablets   From the results of dissolution and solubility studies, the fast dissolving tablets (FDTs) were prepared for selected solid dispersion preparations (Table 4). The FDTs were prepared by direct compression method. The solid dispersion powder equivalent to 25 mg of MCZ, Crospovidone and other tabletting excipients were passed through a mesh no 60. The powdered solid dispersion was mixed with proper portion of Crospovidone. Then excipients other than glidant and lubricant were added and mixed in a poly bag for 5-10 min. The obtained  blend was lubricated with talc and magnesium stearate for another 5 min and the resultant mixture was directly compressed into tablets using rotary tabletting machine. Evaluation of physical parameters   The designed formulations were studied for their physical properties like weight variation, hardness and friability. For estimating weight variation, 20 tablets of each formulation were weighed using an electronic weighing balance (AW 120, Shimadzu Corporation, Japan). The hardness of six tablets was measured using Monsanto tablet hardness tester. Friability was determined on ten tablets in a Roche friabilator (Electrolab, Mumbai, India). For estimation of drug content, ten tablets were crushed, and 100 mg of the powder was accurately weighed and transferred to a 100 ml volumetric flask. Initially about 50 ml of 7.4 pH phosphate  buffer was added to the volumetric flask and allowed to stand for 6-8 h with intermittent shaking to ensure complete solubility of the drug. Then the volume was made up to 100 ml with buffer, filtered and analyzed for MCZ content at 232 nm.  In vitro  disintegration time    In vitro  disintegration time of FDT’s was determined by following the procedure described by Gohel et al . Briefly, 10 ml of water at room temperature was taken in a  petridish of 10 cm in diameter. The tablet was then carefully placed in the centre of petridish and the time required for the tablet to completely disintegrate into fine particles was   Tadikonda  et al_________________________________________________    ISSN 2321-547X    AJADD[2][2][2014]238-247  noted. Measurements were carried out in triplicates 16 .  In vitro  Dissolution Study   The release of MCZ from FDTs was carried out using USP XXIV Type II dissolution apparatus (Electro lab, TDT-08L) at a rotation speed of 50 rpm, and a temperature of 37±0.5 °C. The drug release studies were carried out in 7.4 pH phosphate  buffer. An aliquot of 5 ml was collected at  predetermined time intervals and replaced with fresh dissolution medium. The samples were filtered, by passing through 0.45 µm membrane filters (Millipore, USA) and analyzed spectrophotometrically at 232 nm. Then a graph was plotted using cumulative  percent drug release as a function of time and  percent drug release in 15 min (Q15) was calculated. Initial dissolution rate (IDR) was calculated as percentage dissolved of drug over the first 15 min per min. Dissolution efficiency (DE) was calculated from the area under the dissolution curve at time t (measured using the trapezoidal rule) and expressed as a percentage of the area of the rectangle described by 100% dissolution in the same time. Relative dissolution rate (RDR) is the ratio between amount of drug dissolved from optimized formulation and that dissolved from the control formulation at 15 min. Stability studies   The stability studies of prepared tablets were planned on the best formulation according to ICH guidelines. The packed samples (n=3) were stored in the stability chamber maintained at 40±2 0 C and 75±5% RH for six months. After six months of storage, the samples were collected and analyzed for assay and in vitro  dissolution rate. Then the data was analyzed using paired t-test to test the significant variation at 0.05 level of significance (LS). Then the similarity index (F2) was calculated between dissolution rates of tablets before and after storage to  prove the stability of tablets 17,18 . RESULTS AND DISCUSSION Solubility studies of MCZ solid dispersions   The solubility studies were conducted in different media for all the prepared solid dispersions and compared with pure drug. The aqueous solubility of the solid dispersion formulations of different carriers was determined in different media i.e., 0.1 N HCl, distilled water and phosphate buffer pH 7.4. From the solubility studies, it was found that as the increase in pH of the media increased the solubility i.e. MCZ showed greater solubility in 7.4 pH phosphate buffer when compared others. The solubility data of different formulations using different carriers showed in Table 2. From the results given in above tables, solid dispersions with PEG 20000 showed significant improvement in solubility with increasing PEG ratio up to 1:4 ratios, but after no significant improvement in solubility by increasing the ratio of carrier. From all the solid dispersions, formulation F4 showed highest solubility in 7.4 pH phosphate  buffer. Similar type of results observed in Patel et al  study i.e., the solubility of flurbiprofen was measured in four different media and the results showed that the solubility of the flurbiprofen was highest at  pH 7.2, and decreased as the pH decreases 19 . Drug-carrier compatibility studies   The thermograms of the MCZ, PEG 20000, of MCZ with PEG 20000 were shown in Figure 1. The DSC thermograms of MCZ exhibited physical mixture a sharp endothermal peak around 206.66 0 C corresponding to melting point. The DSC thermogram of PEG 20000 exhibited a broad endothermal peak around 69.8 o C corresponding to its melting point. The thermogram of physical mixture with PEG 20000 showed a short endothermal peak of   Tadikonda  et al_________________________________________________    ISSN 2321-547X    AJADD[2][2][2014]238-247  drug at 206 0 C indicating that there were no interactions between drug and carrier. Micromeritic properties of blend    The powder mixture for tablets were characterized with respect to angle of repose,  bulk density, tapped density and Carr’s index, (Table 3). Angle of repose was less than 35° and Carr’s index values were less than 21 for the powder mixture of all the batches indicating good to fair flowability 20 . Evaluation of Fast Dissolving Tablets   Based on the solubility studies, the  better solid dispersions were converted into tablets. Table 5 showed all the physical  parameters determined for MCZ tablets. In weight variation test, the pharmacopoeial limits for the tablets of not more than 5% of the average weight. The tablet hardness and friability were found to be around 3.0 kg/cm 2  and 0.38%, demonstrating the integrity and strength of tablets. The tablets assay was found to contain 99.14±1.32%. From the disintegration test, the prepared tablets were disintegrated rapidly and it was found to be around 120 sec. Dissolution Studies of Fast Dissolving Tablets   From the in vitro  dissolution studies, tablets made from 1:4 ratio solid dispersion (F4) showed fast dissolution (98.46±1.24% in 15 min) than other formulations and improved significantly when compared to control tablet (32.49±1.29 in 15 min). Figure 2 demonstrated the MCZ release patterns by above formulations. From the in vitro  dissolution studies, MCZ in the form of solid dispersion (F4 formulation i.e., 1:4 ratio) showed significant increase in dissolution rate when compared to tablets with pure MCZ. In the following reported study by Singh et al ., similar type of solubility enhancement was observed with PEG 6000 solid dispersions 13 . The probable reasons and mechanisms of increased dissolution rates of solid dispersions have been proposed by Ford. It includes a decrease in crystallite size, solubilization effect of the carrier, absence of aggregation of drug crystallites, enhanced wettability and dispersibility of the drug from the dispersion, dissolution of the drug in the hydrophilic carrier, drug conversion to amorphous state and finally, a combination of the mentioned mechanisms 2 . The percent drug release in 15 min (Q 15 ) and initial dissolution rate for formulation F4 was 98.46±1.24%, 6.56%/min. These were very much higher compared to control tablets (32.49±1.29 %, 2.17%/min). The relative dissolution rate was found to be 3.03 and dissolution efficiency was found to be 54.44 and it is increased by 3.4 fold with F4 formulation compared to control tablets (16.55). Overall increase in the dissolution performance of the optimized formulation was described in terms of dissolution parameters (IDR, DE, RDR) and when compared with pure drug, all the above  parameters were increased in case of F4 formulation (Table 6). Similar type of improvement in IDR, DE, RDR was reported in the study of Vemula et al 21 . Stability studies   After storage of six months, the formulation F4 was subjected to a drug assay and in vitro  dissolution studies (Table 7) and from the statistical analysis there was no significant difference between before and after storage ( P <0.05). The similarity index value between dissolution profiles of optimized formulation before and after storage was found to be 85.11, which is more than 50 indicates similarity between the dissolution profile before and after storage 17,18 .
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