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

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.

• Intrinsic dissolution rate
• phase transformation
• polymorphism
• progesterone
• solid-state characterization

Acknowledgements

The authors thank Laboratório de Difração de Raio-X (LDRX), Laboratório de Síntese de Cristais Líquidos e Materiais Moleculares Funcionais at UFSC for XRPD and MHS analysis, respectively, LCME-UFSC for technical support during electron microscopy work. CNPq, CAPES, FAPESC, CLAF, Fundación Sauberan and CONICET for student fellowships and financial support. Silvia L. Cuffini thanks CAPES for Visited Professor fellowship. Silvia L. Cuffini, Ismael Bianco, Dante Beltramo and Gustavo A. Monti are fellows of CONICET, Argentina. Thanks are given also to the Consejo Superior de Investigaciones Científicas (CSIC) of Spain for the award of a license for the use of the CSD.