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:
- It replaces excellent but environmentally harmful solvents such as tetrahydrofuran (THF), N, N-dimethylformamide (DMF), and N, N-dimethylacetamide (DMA) with greener solvents such as alcohols, acetonitrile, and water
- It gives a higher crystal yield
- It increases the degree of supersaturation, thus allowing nucleation to be controlled by the lowest nucleation barrier so
that the metastable, instead of the thermodynamically stable crystalline phase, is induced (6–8).
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).
Sulfathiazole, a valuable antimicrobical sulfa drug used in veterinary medicine (see Figure 1), was chosen for this study
mainly because of its commercial value and its five polymorphs, which are well-characterized by Fourier-transform infrared
spectroscopy (FTIR), powder X-ray diffraction (PXRD), and differential scanning calorimetry (DSC) (10, 15, 17).
Figure 1 (IMAGES AND FIGURES ARE COURTESY OF THE AUTHORS)
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).