Dissolution properties, solid-state transformation and polymorphic crystallization: progesterone case study

• Published in: Pharmaceutical development and technology Vol. 19; no. 7; pp. 779 - 788
• Main Authors: Araya-Sibaja, Andrea Mariela, Paulino, Amarilis Scremin, Rauber, Gabriela Schneider, Campos, Carlos Eduardo Maduro, Cardoso, Simone Gonçalves, Monti, Gustavo Alberto, Heredia, Valeria, Bianco, Ismael, Beltrano, Dante, Cuffini, Silvia Lucia
• Format: Journal Article
• Language: English
• Published: England Informa Healthcare USA, Inc 01-11-2014; Taylor & Francis
• Subjects: Crystallization; Intrinsic dissolution rate; Magnetic Resonance Spectroscopy; phase transformation; polymorphism; Powder Diffraction; progesterone; Progesterone - chemistry; Progestins - chemistry; solid-state characterization; Solubility; Spectroscopy, Fourier Transform Infrared; Spectrum Analysis, Raman; X-Ray Diffraction
• ISSN: 1083-7450; 1097-9867
• DOI: 10.3109/10837450.2013.829096

Abstract
Progesterone is a natural steroid hormone and a poor soluble drug which presents two polymorphs (forms 1 and 2). Different methods to obtain form 2 were tested and a complete solid-state characterization of both polymorphs (forms 1 and 2) was conducted. X-ray powder diffraction, hot stage microscopy, Fourier transform infrared, dispersive Raman, 13C solid-state nuclear magnetic resonance spectroscopy, thermal analysis, scanning electron microscopy techniques and intrinsic dissolution rates (IDR) were applied to investigate physical-chemical and dissolution properties of these two polymorphs. Form 2 was obtained from diluted solutions and from melting after cooling at room temperature. Form 1 was obtained from concentrated solutions and, a mixture of both polymorphs was crystallized from intermediate solutions. The crystal habit was not a distinctive characteristic of each polymorph. The effect of mechanical stress was evaluated in the metastable polymorph (form 2). We observed that grinding form 2 produced seeds of form 1 that induced the transformation of form 2 into form 1 at high temperature. The polymorphic quantification from XRD patterns of ground samples were carried out by the Rietveld method. After grinding and at room temperature conditions (∼25 °C), it was observed the transformation of 17% of form 2 into form 1 in 10 days.