Crystallization from solutions is not only an important step in the fabrication of various functional materials in biological systems, but also a key separation and purification process in the manufacture of many fine chemicals and specialty chemicals, especially pharmaceuticals (1, 2). Pharmaceutical crystallizations are often carried out in batches of organic solvents or mixtures of solvents through temperature cooling (3). Because of the excess properties (i.e., the difference between the real properties and the ideal properties) for a real solution, the solubility of an active pharmaceutical ingredient (API) in a solvent mixture is sometimes higher than its solubility in a single solvent as the activity coefficient decreases (4, 5). The solubility enhancement that the solvent mix offers can bring three main advantages to pharmaceutical batch crystallization:
Binary-solvent mixtures result when a second solvent (i.e., an antisolvent or cosolvent) is added to a subsaturated solution until the degree of supersaturation is high enough for crystallization to take place under isothermal conditions. Performing further crystallization in ternary solvent mixtures may be a new method of influencing the nucleation rate, the shape of the product crystals, the size distribution of the entire crystallized mass, aggregate and agglomeration properties, the purity of the crystals, and polymorphism (9–14).
Because solubility, crystal yield, and polymorphism are solvent dependent, solution recrystallization by solvent screening is of fundamental and of foremost importance to many chemical process industries. The process is especially important for manufacturing APIs (15–22). Pharmaceutical companies have a limited amount of time and materials to advance new chemical entities from candidacy to Phase I clinical trials (23).The aim of this article is to extend initial solvent screening for a single-solvent system to the cocktail solvent screening of binary and ternary solvent mixtures on a small scale through temperature cooling from 60 to 25 °C, which is often used in drug development and manufacturing (24).
Under the initial solvent-screening strategy of single solvent systems, 24 solvents, mostly useful for scale-up, were selected (25). If all 24 solvents had been taken into account, the possible combinations for binary and ternary solvent mixtures would have been 24! ÷ (22!2!) = 276 and 24! ÷ (21!3!) = 2024, respectively. However, for the purpose of showing the feasibility of cocktail-solvent screening, the authors limited the screening to three miscible green solvents (acetonitrile, n-propanol, and water) and their combinations. N-propanol and acetonitrile produce Form I and Form IV sulfathiazole crystals, respectively. Water is a common solvent in the manufacture of sulfathiazole (15, 26).