Initial Solvent Screening of Carbamazepine, Cimetidine, and Phenylbutazone: Part 1 of 2

The authors describe the importance of a rapid and an abbreviated screening strategy by initial solvent screening in 20-mL scintillation vials.
May 02, 2009
Volume 33, Issue 5

Many recent important solvent-based processes such as spherical crystallization, the spreading of cube-shaped particles, monodispersed double emulsions, microemulsions, and organic nanocrystal fabrication, involve combinations of two or three solvents (1–26). However, to the authors' knowledge, no literature has laid out a systematic way to identify the best solvent combinations, even though the composition ratio of the solution at the time of nucleation profoundly determines the solubility, polymorphism, and crystal habits of organic compounds functioning as in the case of the active pharmaceutical ingredients (APIs) (7, 8, 27).

Figure 1: Initial solvent screening in a 20-mL scintillation vial provides engineering information about (counterclockwise from top) solubility curves, polymorphism, solubility spheres, crystal habits, and form space for solvent-based processes. (ALL FIGURES ARE COURTESY OF THE AUTHORS)
This article will re-emphasize the importance of a rapid and abbreviated screening strategy by initial solvent screening in 20-mL scintillation vials. The screen provides engineering information in solubility curves, solubility spheres, polymorphs, crystallinity, form spaces (also known as solvent miscibility plots), and crystal habits of a given compound for solvent-based processes (see Figure 1) (28–31). The attractiveness of this strategy is its ability to be adopted or automated by common laboratories with only a small amount of chemical compounds. The probable solvent combinations of a good solvent, an antisolvent, and a bridging liquid for solvent-based processes are summarized systematically in the form space and can be graphically deduced.

Figure 2: Molecular structures of (a) carbamazepine (5H-dibenze[b,f]azepine-5-carboxamide), (b) cimetidine (N"-cyano-N-methyl-N'-[2-[[5-methyl-1H-imidazol-4-yl]methyl]thio]-ethyl]-guanidine), and (c) phenylbutazone (1,2-diphenyl-4-n-butyl-3,5-pyrazolidinedione).
Initial solvent screening was thoroughly tested using three model APIs: carbamazepine (5H-dibenze[b,f]azepine-5-carboxamide), an anticonvulsant used to treat epilepsy and trigeminal neuralgia (see Figure 2a); cimetidine (N"-cyano-N-methyl-N'-[2-[[5-methyl-1H-imidazol-4-yl]methyl]thio]-ethyl]-guanidine), a specific competitive histamine H2-receptor antagonist used in the treatment of human peptic ulcers (see Figure 2b); and phenylbutazone (1,2-diphenyl-4-n-butyl-3,5-pyrazolidinedione), a nonsteroidal anti-inflammatory drug with antipyretic and analgesic activity (see Figure 2c). These compounds were studied because of their commercial value; their abundant characterization information in the literature (see Table Ia–c); the lack of extensive solvent studies on their solubility, polymorphism, crystallinity, and crystal habits; and the variety of their naturally occurring polymorphs, hydrates, and solvates (see Figure 3) (32–69).