Conformational Color Polymorphism and Control of Crystallization of 5‐Methyl‐2‐[(4‐methyl‐2‐nitrophenyl)amino]‐3‐thiophenecarbonitrile

• Published in: Journal of pharmaceutical sciences Vol. 90; no. 3; pp. 371 - 388
• Main Authors: He, Xiaorong, Griesser, Ulrich J., Stowell, Joseph G., Borchardt, Thomas B., Byrn, Stephen R.
• Format: Journal Article
• Language: English
• Published: New York Elsevier Inc 01.03.2001; John Wiley & Sons, Inc; Wiley; American Pharmaceutical Association
• Subjects: Biological and medical sciences; Calorimetry, Differential Scanning; color polymorphism; conformational polymorphism; crystal forms; Crystallization; Crystallography, X-Ray; energy-temperature diagram; General pharmacology; Hydrogen-Ion Concentration; Medical sciences; Molecular Conformation; Pharmacology. Drug treatments; phase transition; Physicochemical properties. Structure-activity relationships; solid state; solubility; Spectrum Analysis; Thermodynamics; Thiophenes - chemistry; energy–temperature diagram; color polymorphism; crystallization; thermodynamics; solubility; conformational polymorphism; crystal forms; phase transition; solid state; Differential scanning calorimetry; Fourier transformation; Crystallization; Solubility; X ray diffraction; Phase transitions; Infrared spectrometry; Solid state; Thermodynamics; Thiophene derivatives; Raman spectrometry; Thermal analysis; Physicochemical properties; Quantitative analysis; Polymorphism
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/1520-6017(200103)90:3<371::AID-JPS12>3.0.CO;2-N

5‐Methyl‐2‐[(4‐methyl‐2‐nitrophenyl)amino]‐3‐thiophenecarbonitrile is an example of conformational and color polymorphism. The compound crystallizes in red (R), dark red (DR), light red (LR), and orange (O) modifications. There are two specific goals for this study. One is to characterize the complex thermodynamic relationship among these four known forms, and the other is to use the knowledge of the thermodynamic relationship to control the crystallization of these forms. The different forms were characterized by X‐ray powder diffractometry as well as Fourier‐transform infrared (FT‐IR) and Raman spectroscopy; their complex thermodynamic relationships were determined by thermal analysis, solubility measurements, and slurry conversion studies. According to the solubility results, all forms are enantiotropically related: R is the thermodynamically most stable form above 60°C, O is the most stable form between room temperature and 60°C, LR is the most stable form below −15°C, and DR is metas‐table throughout the entire temperature range. DR, LR, and O have very similar free energy at ambient temperature, which is the reason for the complex transition behavior. Finally, a schematic energy–temperature diagram was constructed that combines all experimental data in a comprehensive thermodynamic picture and provides insights into how to control the crystallization of the individual forms. © 2001 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:371–388, 2001