Arch Pharm Res Vol 35, No 7, 1223-1230, 2012 DOI 10.1007/s12272-012-0713-7 1223 Effects of Solvents and Crystallization Conditions on the Polymorphic Behaviors and Dissolution Rates of Valsartan Thao Truong-Dinh Tran 1,2 , Phuong Ha-Lien Tran 1,2 , Jun-Bom Park 2 , and Beom-Jin Lee 2,3 1 Biomedical Engineering Department, International University-Vietnam National Universities, Ho Chi Minh City, Vietnam, 2 Bioavailability Control Laboratory, College of Pharmacy, Kangwon National University, Chuncheon 200-701, Korea, and 3 College of Pharmacy, Ajou University, Suwon 443-749, Korea (Received January 3, 2012/Revised April 1, 2012/Accepted April 4, 2012) For the quality evaluation of raw materials, the influence of various types of solvents on the polymorphic crystallization behaviors and dissolution rates of two sources of valsartan (VAL) from China and India was investigated. Samples were prepared by recrystallization from water or organic solvents, such as acetonitrile, acetone and ethanol, using methods with and without heating. Recrystallization behaviors were characterized by differential scanning calo- rimetry (DSC) and powder X-ray diffraction (PXRD). Scanning electron microscopy (SEM) was also used to observe the morphology of samples. The dissolution rate of recrystallized samples in water was evaluated and compared to the original VAL sample. There were significant dif- ferences in morphology, crystal structure and dissolution rate among the samples recrystal- lized using organic solvents. VAL was transformed into another polymorphic form by the solvents and recrystallization conditions. These physical properties of VAL also differed between the two sources of VAL. Thus, the physicochemical differences of raw materials should be carefully considered in early dosage formulation approaches. Key words: Valsartan, Crystallization condition, Structural behavior, Solvent type, Polymor- phism, Dissolution rate INTRODUCTION It is known that pharmaceutical compounds can exist in more than one crystalline form, each of which can have different physicochemical properties. This phenomenon is called polymorphism (Näther et al., 2002; Suitchmezian et al., 2006; Barone et al., 2011; Remko et al., 2011; Mandal et al., 2012). These changeable behaviors can impact the solubility, dissolution, bioavailability and manufacturability of the drug product (Singhal and Curatolo, 2004; Pilcer et al., 2012). Thus, the physico- chemical quality of various raw materials should be fully evaluated. Factors commonly cited that affect the crystal forma- tion of pharmaceutical compounds include supersatur- ation, agitation rate, cooling rate, solvent composition, temperature, seed crystals, additives and impurities (Kitamura and Ishizu, 1998; Li et al., 1999; Shekunov and York, 2000; Shan et al., 2002). Among these factors, the solvent is considered to have a strong influence on the crystalline structure (Femi-Oyewo and Spring, 1994; Horst et al., 2001). Hence, solvent screening is of foremost importance for the pharmaceutical industry to avoid the unexpected appearance of a polymorphic form of a drug, which may lead to serious pharmaceuti- cal consequences resulting in delay of drug production. Solid polymorphism of drug substances, therefore, has received much scrutiny in the development of dosage forms of pharmaceutical products. Valsartan (VAL) (Fig. 1), N-(1-oxopentyl)-N-[[2'-(1H- tetrazol-5-yl) [1,1'-bi-phenyl]-4-yl]methyl]-L-valine, is a selective angiotensin II type 1 receptor blocker indi- cated for the treatment of hypertension (Krishnaiah et al., 2010). The absolute bioavailability of oral VAL has been reported to be low because VAL belongs to the class II category according to the Biopharmaceutics Classification System (i.e., water-insoluble and highly Correspondence to: Beom-Jin Lee, College of Pharmacy, Ajou University, Suwon 443-749, Korea Tel: 82-31-219-3442, Fax: 82-31-212-3653 E-mail: beomjinlee@gmail.com