Journal of Pharmacy Research Vol.5 Issue 8.August 2012 Gehan Balata et al. / Journal of Pharmacy Research 2012,5(8),4175-4181 4175-4181 Research Article ISSN: 0974-6943 Available online through www.jpronline.info * Corresponding author. Gehan Balata Department of Pharmaceutics, Faculty of Pharmacy, Zagazig University,Egypt Controlled Crystallization as a Tool to Enhance the Dissolution and Anti-Inflammatory Properties of Indomethacin Gehan Balata 1,3 * and Hanan Abd El Moneom 2,3 1 Department of pharmaceutics, Faculty of Pharmacy, Zagazig University, Egypt 2 Department of Pharmacology, Faculty of Medicine, El-Fayoum University, Egypt 3 Faculty of Pharmacy, Umm El Qura University, Makkah, Saudi Arabia Received on:10-04-2012; Revised on: 17-05-2012; Accepted on:25-06-2012 ABSTRACT Indomethacin (IND) is a water insoluble non-steroidal anti-inflammatory drug with analgesic and antipyretic effects. The aim of this study was to enhance the dissolution rate and anti-inflammatory effect of IND by controlled crystallization in different solutions (0.05, 0.1 and 0.2%) of protective colloids. The investigated polymers were hydroxypropyl methylcellulose, sodium alginate and polyvinyl alcohol. Physicochemical properties of the prepared crystals were characterized using differential scanning calorimetry and x-ray powder diffractometry. In addition, the dissolution rate was studied using USP-II apparatus (paddle method). Finally, the anti-inflammatory and analgesic effects of optimal indomethacin crystals (exhibited good dissolution results) versus raw IND were investigated. The differential scanning calorimetry and x-ray powder diffractometry results showed polymor- phism change from γ- to α- form of indomethacin with marked reduction in crystallinity in the processed crystals especially at 0.05% sodium alginate. IND crystals processed at 0.05% sodium alginate showed 5.6- and 1.5-folds increase in the dissolution percent after 10 min and the dissolution efficiency after 1 hour, respectively, when compared to the raw drug. These crystals when stored for one year at ambient conditions, exhibited transformation into γ- form but with marked reduction in crystallinity. Finally, IND crystals (processed in presence of 0.05% sodium alginate) showed rapid onset of anti- inflammatory effect when compared to the raw drug (significant reduction in paw edema after 30 min) with less gastric adverse effects. However, both the processed IND crystals and the raw drug had nearly similar analgesic effect. Key words: Controlled crystallization-indomethacin- polymorphism- sodium alginate- anti-inflammatory. I NTRODUCTI ON Indomethacin is a non-steroidal anti-inflammatory drug commonly used to reduce fever, pain, stiffness, and swelling [1]. It is practically insoluble in water and highly permeable (Class II) [2]. It was reported that indomethacin exhibits polymorphism and as a consequence the various forms (I, γ and II, α) have different solubilities and different bioavailabilities [3]. Alsaidan et al., reported that indomethacin may show low and erratic oral bioavailability and may increase the incidence of irritating side effects on the gastrointestinal tract because of a prolonged contact time with the mucosa [4]. So, enhancing the dissolution rate of poorly water-soluble drugs in order to increase the rate and extent of drug absorption is essential for optimizing the bioavailability [5]. Various methods are commonly used to improve the dissolution rate of poorly water-soluble drugs including size reduction [6], formation of solid dispersions [7], complex formation with cyclodextrins [8] , liquisolid compacts [9] , interactive mixtures [10], polymorphic transition [11 ], etc. Polymorphism is a critical issue in pharmaceutical development, since physical and chemical properties are known to vary with crystalline forms. Polymorphs are defined as thermodynamically different phases, which differ in solubility, melting point, stability, density, crystal shape and bioavailability [12]. Haleblian and Macrone, explained the applications of polymorphism in different pharmaceutical dosage forms (suspensions, creams, solutions and suppositories) and mentioned the thermodynamic activity, solubility and therapeutic blood levels of different polymorphs [13]. So, the aim of this study was to investigate the effect of different protective colloids on the controlled crystallization of indomethacin and consequently on its dissolution, anti-inflammatory and analgesic properties. Moreover, the histopathological effects of both therapeutic and toxic doses of selected IND crystals compared with raw drug on gastric tissues were studied. MATERIALS AND METHODS: Materials Indomethacin (IND) was obtained as a gift sample from Memphis Co. (Cairo, Egypt). Hydroxypropyl methylcellulose 4000 (HPMC 4000) was purchased from Sigma-Aldrich (St Louis, MO, USA). Polyvinyl alcohol (PVA), sodium alginate, di-sodium hydrogen phosphate and potassium di- hydrogen phosphate were purchased from Himedia Laboratories Pvt.Ltd. Mumbai, India. Acetone, acetic acid and formaldehyde were purchased from BDH chemicals Ltd Poole, England. Hard gelatin capsules (size 0) were purchased from EMBO Caps®, Suheung, Vietnam. Methods Preparation of IND crystals IND was dissolved in acetone (5% w/v, 20 ml) and mixed rapidly under stirring (Mechanical stirrer, Paul Marienfeld Gmbh & Co. kG, Germany) conditions at 1500 rpm with an aqueous solution containing an excipient (HPMC4000, sod-alginate and PVA at 0.05, 0.1, 0.2 % w/v, 80 ml). Experiments were carried out at room temperature. Precipitation of drug particles occurred immediately upon mixing and formed a suspension with a milky appearance. The precipitated crystals were immediately collected by filtration and washed twice with 10 ml dist. water. The obtained particles were oven-dried at 50 °C overnight [14].