Trimorphism of Betamethasone Valerate: Preparation, Crystal Structures, and Thermodynamic Relations

Abstract

The glucocorticoide bethamethasone valerate was investigated for polymorphism. The commercially available modification (Form I) and one methanol solvate were characterized by single crystal structure analysis. DTA-TG and DSC investigations reveal that on solvent removal the methanol solvate decomposes into a new polymorphic modification (Form III), which, upon further heating, transforms into another modification (Form II) via melting and recrystallization. The crystal structures of forms II and III were determined by a combination of 13 C NMR spectroscopy and X-ray powder diffraction. In all modifications as well as in the methanol solvate differences in the conformation and the packing of the molecules are observed. Solvent mediated conversion experiments reveal that form I represents the thermodynamically stable form at room temperature. Thermomicroscopic, XRPD, and heating rate dependent DSC measurements on forms I−III do not show any interconversion of these forms via the solid. Further DSC measurements indicate both a higher melting point and heat of fusion for form I compared to form II and form III. Therefore, form I should also be the thermodynamically stable form over the whole temperature range and all forms seems to be monotropically related.

Solvent-Mediated Polymorphic Transformation of Famoxadone from Form II to Form I in Several Mixed Solvent Systems

“…According to the heat of fusion rule [27], it was demonstrated that Form I is the most thermodynamically-stable polymorph. Based on the relevant thermodynamic data and phenomenon, Form I and Form II are in monotropic system [28]; thus, the transformation from Form II to Form I should proceed spontaneously. The stability experiments of the six famoxadone polymorphs are shown in Figures S2-S4.…”

“…phenomenon, Form I and Form II are in monotropic system [28]; thus, the transformation from Form II to Form I should proceed spontaneously. The stability experiments of the six famoxadone polymorphs are shown in Figures S2-S4.…”

Solvates and polymorphs of rebamipide: preparation, characterization, and physicochemical analysis

“…8 Thus, investigating the polymorphism of APIs is crucial and has practical utility in pharmaceutical research and development. 9,10 Solvates, the crystal forms of a compound that differ in the species or stoichiometry of the included solvent molecules, are widely applied in the pharmaceutical industry. 10 Accidental solvate formation is undesirable during drug processing because of potentially uncontrollable changes in the physicochemical properties of the drug product.…”

“…9,10 Solvates, the crystal forms of a compound that differ in the species or stoichiometry of the included solvent molecules, are widely applied in the pharmaceutical industry. 10 Accidental solvate formation is undesirable during drug processing because of potentially uncontrollable changes in the physicochemical properties of the drug product. 11 Conversely, solvates with pharmaceutically relevant solvents may improve the physicochemical properties of drugs.…”

Dimorphism of 1,4-dibromo-2,5-bis(bromomethyl)benzene: crystallographic and physico-chemical investigations

“…[8][9][10][11][12] In some cases these may be difficult tasks, and much effort, involving a variety of physico-chemical investigations, may be needed to establish all the thermodynamic relationships and to construct the energy-temperature diagram. [13][14][15][16] The energy difference between polymorphic modifications is usually small, but may be large enough to allow for different conformations and/or to redistribute weak intermolecular interactions, thus generating a different packing. 1,4 This might well be the case for solid state structures of polybrominated aromatic systems, in which we are interested particularly with respect to their intermolecular bromine-bromine interactions.…”