Polymorphism and melt crystallisation of racemic betaxolol, a β-adrenergic antagonist drug

• Published in: Journal of thermal analysis and calorimetry 2013-03, Vol.111 (3), p.2171-2178
• Main Authors: Maria, Teresa M. R., Castro, Ricardo A. E., Silva, M. Ramos, Ramos, M. Luísa, Justino, Licínia L. G., Burrows, Hugh D., Canotilho, João, Eusébio, M. Ermelinda S.
• Format: Article
• Language: English
• Subjects: Analytical Chemistry; Antihypertensive agents; Betaxolol; Biological and medical sciences; Calorimetry; Cardiovascular system; Chemistry; Chemistry and Materials Science; Diffraction; Eye; General pharmacology; Infrared spectroscopy; Inorganic Chemistry; Measurement Science and Instrumentation; Medical sciences; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Physical Chemistry; Polymer Sciences; Polymorphism (Crystallography); X-rays
• ISSN: 1388-6150; 1588-2926; 1572-8943
• DOI: 10.1007/s10973-012-2765-9

We report the polymorphic behaviour, in melt cooling experiments, of racemic betaxolol, a low aqueous solubility selective β 1 -adrenergic antagonist drug with a flexible molecular structure. A multidisciplinary approach is employed, using thermal analysis (differential scanning calorimetry, polarised light thermomicroscopy), spectroscopic methods (infrared spectroscopy, magic angle spinning 1 H NMR) and X-ray powder diffraction. A glass phase is obtained, T g  ~ −10 °C, on cooling the melt, unless the cooling rate is ≤0.5 °C min −1 , while a new metastable form, polymorph II, T fus  = 33 °C, is generated in subsequent heating runs in a two step process. Although either partial crystallisation from the melt in the first step or the formation of an intermediate, metastable, low ordered phase may explain these observations, our results favour the second hypothesis. The stable polymorph I, T fus  = 69 °C, which crystallizes on further heating after form II melting, has also been obtained either from polymorph II or from the molten phase, on standing at 25 °C. The racemic betaxolol crystalline phases are found to exhibit some degree of disorder.