Effect of Solvent on Crystal Habit and Dissolution Behavior of Tolbutamide by Initial Solvent Screening

By an initial solvent screening of 18 solvents, 14 pure good solvents were selected for the crystallization of tolbutamide. Solid generation by the solvent-change method was carried out using the pure good solvents. Crystals were generated in only 10 of the 14 solvents. Different crystal forms of tolbutamide were obtained. Crystals were subjected to evaluation tests such as differential scanning calorimetry, optical microscopy, and in vitro dissolution. All crystals were determined as isomorphic by differential scanning calorimetry. Dissolution rate was influenced by crystal form. Thus, the choice of suitable crystal habit and proper selection of solvent is important in manufacturing the drug tolbutamide. INTRODUCTION Solubility, crystallinity, and the crystal properties of an active pharmaceutical ingredient (API) play a critical role in the value chain of pharmaceutical development, manufacturing, and formulation. Because these properties are all solvent dependent, solvent screening is of fundamental and foremost importance to the pharmaceutical industry (1). The solubility of an API in solvents and solvent mixtures has a considerable influence on the choice of solvents and the course of operation in solvent-based processes such as chemical reactions, extraction, crystallization, filter-cake washing, and wet granulation (2). Most pharmaceutical manufacturing processes include a series of crystallization processes to achieve high purity and to produce the desired final crystal form. Use of different solvents and processing conditions during crystallization may alter the crystal habit of the purified drug, leading to variation in raw material characteristics such as melting point, solubility, true density, dissolution profile, flowability, compressibility, and tabletability (3–9). The amount of drug dissolved with time depends on the size and number of crystal faces exposed to the dissolution medium. Therefore, habit modification seems to provide an alternative means of modifying the dissolution behavior of drugs (8, 10, 11). Use of different solvents alters crystal habit, which may alter dissolution rate. Selection of a proper solvent for crystallization may give optimized crystal properties. Consequently, initial solvent screening is important in choosing a proper solvent for crystallization. This article promotes a solvent-screening strategy that is tailor-made for the processes of drug development and design of API solids. Tolbutamide (1-butyl-3-(p-tolysulfonyl) urea) (TBM), shown in Figure 1, was selected for our solvent-screening strategies because of the lack of extensive solvent studies on its solubility, crystallinity, and crystal habit. Tolbutamide is used as an oral hypoglycemic agent. The drug is practically insoluble in water, and its dissolution is supposed to be the rate-limiting step for its absorption from the gastrointestinal tract (12). Several studies on commercial brands of tolbutamide dosage forms have shown marked variations in dissolution rate and bioavailability (13–15). Reported methods for the enhancement of the dissolution rate of TBM include crystallization of tolbutamide from acetonitrile by a temperature-cooling method (16), spherical agglomerates prepared by spray-drying an ethanol solution of TBM with colloidal silica (17), complex formation with β–cyclodextrin (18), and tolbutamide-urea and tolbutamide-mannitol systems (19). The aim of this initial solvent-screening study was to produce different crystal forms of TBM by crystallizing it from different solvents and study the dissolution behavior of its different crystal forms. MATERIALS AND METHODS Solvents Table 1 lists the solvents used in the study and their properties. All solvents were purchased from s.d. fine-chem Ltd., except for ethanol (95.2% v/v), which was purchased from Baroda Chemical Industuries Ltd. Double-distilled water was used throughout the study. Active Pharmaceutical Ingredient Tolbutamide (C12H18N2O3S, mp = 126–130 °C, MW = 270.349) was supplied as a gift sample by Sanofi Aventis Pharma Limited at Ankleshwar. Solubility Studies Approximately 10 mg of the API was weighed in a 5-mL ria vial. Drops of solvent were titrated carefully with a *Corresponding author. diss-17-01-04.indd 16 2010-2-22 15:00:50 dx.doi.org/10.14227/DT170110P16