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

Latest Issue
PharmTech

Latest Issue
PharmTech Europe

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.


Pharmaceutical Technology
Volume 33, Issue 5, pp. 62-72


(NICHOLAS RIGG/GETTY IMAGES)
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).


ADVERTISEMENT

blog comments powered by Disqus
LCGC E-mail Newsletters

Subscribe: Click to learn more about the newsletter
| Weekly
| Monthly
|Monthly
| Weekly

Survey
FDASIA was signed into law two years ago. Where has the most progress been made in implementation?
Reducing drug shortages
Breakthrough designations
Protecting the supply chain
Expedited reviews of drug submissions
More stakeholder involvement
Reducing drug shortages
32%
Breakthrough designations
8%
Protecting the supply chain
40%
Expedited reviews of drug submissions
8%
More stakeholder involvement
12%
View Results
Jim Miller Outsourcing Outlook Jim Miller Health Systems Raise the Bar on Reimbursing New Drugs
Cynthia Challener, PhD Ingredients Insider Cynthia ChallenerThe Mainstreaming of Continuous Flow API Synthesis
Jill Wechsler Regulatory Watch Jill Wechsler Industry Seeks Clearer Standards for Track and Trace
Siegfried Schmitt Ask the Expert Siegfried SchmittData Integrity
Sandoz Wins Biosimilar Filing Race
NIH Translational Research Partnership Yields Promising Therapy
Clusters set to benefit from improved funding climate but IP rights are even more critical
Supplier Audit Program Marks Progress
FDA, Drug Companies Struggle with Compassionate Use Requests
Source: Pharmaceutical Technology,
Click here