Comprehensive determination of the solid state stability of bethanechol chloride active pharmaceutical ingredient using combined analytical tools

International audienceThe use of an integrative analytical approach allowed us to establish the intrinsic solid state stability of bethanechol chloride (BC), an active pharmaceutical ingredient used in the treatment of urinary retention. First, the crystal structure of the monoclinic form has been described using single crystal X-ray diffraction studies. Second, thermal analyses revealed that the compound degrades upon melting, with an apparent melting temperature estimated to be 231 °C. No transition from the monoclinic to the orthorhombic form has been observed, suggesting that the monoclinic form is the stable one. Third, the two-step melting–decomposition process has been elucidated by liquid chromatography and thermogravimetry coupled to mass spectrometry. The first step corresponds to the sample liquefaction, which consists of the gradual dissolution of bethanechol chloride in its liquid degradant, i.e. betamethylcholine chloride. This step is in agreement with Bawn kinetics and the activation energy of the reaction has been estimated at 35.5 kcal mol−1. The second step occurs with accelerated degradation in the melt. Elucidation of secondary decomposition pathways evidenced autocatalytic properties conferred by the formation of both isocyanic acid and methyl chloride. Finally, dynamic water vapor sorption analysis showed a substantial hygroscopicity of the drug substance. A deliquescent point has been determined at 56% relative humidity at 25 °C

Prenucleation self-assembly and chiral discrimination mechanisms during solution crystallisation of racemic diprophylline

The crystallisation behaviour of (RS)-diprophylline (DPL) in two different solvents is investigated to assess the incidence of solvated pre-associations on nucleation, crystal growth and chiral discrimination. In the solvated state, Raman spectroscopy shows that dimeric associations similar to those depicted in the crystalline solid solution (ssRII) predominate in isopropanol (IPA), which may account for the systematic spontaneous nucleation of this crystal form from this solvent. By contrast, spontaneous nucleation in DMF yields the stable racemic compound RI, consistently with the distinct features of the Raman spectrum collected in this solvent. A crystal growth study of ssRII in IPA reveals that the crystal habitus is impacted by the solution enantiomeric excess; this is explained by increased competition between homo- and heterochiral pre-associations. This is supported by a molecular modelling study on the enantiomeric selectivity of the DPL crystal lattices. The combination of assessment methods on solution chemistry, nucleation and chiral discrimination provides methodological tools from which the occurrence of solid solutions can be rationalised

Importance de l’étude expérimentale des équilibres solide-vapeur lors du développement d’un solide actif pharmaceutique (mais pas que….)

International audienc

Importance de l’étude des équilibres solide-vapeur lors du développement d’un solide actif pharmaceutique.

International audienc

Hydration of solids : studies on solid/vapor equilibria to develop new solid materials.

International audienc

Les alliages à base de plomb pour batteries acides : A) Etude thermodynamique des alliages PbCaSn ; B) Optimisation d'un nouveau procédé d'élaboration des grilles d'électrodes par métallurgie des poudres

Lead calcium tin alloys are extremely used as electrodes in acid batteries. They are structural hardening alloys, synthesized by casting/hardening and subject to microstructural evolution during use. The change from an "aged" metallurgic structure to an "over-aged" structure is associated, in particular, with a decrease of mechanical properties. The aged state can be stabilized with an optimization of the structural hardening process. The thermodynamic modeling of the PbCaSn system has been performed according to the CALPHAD approach in order to appreciate the oversaturation degree after casting and to optimize the necessary thermal treatment to obtain the stabilization of the aged state. A new elaboration process has been developed. It is based on Pb/TiO2 composite synthesis by hot compaction (sintering). Even if the electrochemical properties are not optimized, mechanical properties are improved in comparison with PbCaSn alloys synthesized by die casting and stabilized in aged state.Les alliages PbCaSn sont largement utilisés en tant qu'électrodes de batteries acides. Ce sont des alliages à durcissement structural, synthétisés par coulée/trempe qui sont sujets à des changements microstructuraux en cours de fonctionnement. Ainsi, le passage de la structure métallurgique " vieillie " à la structure " survieillie " s'accompagne en particulier d'une chute des propriétés mécaniques. La stabilisation temporelle de l'état " vieilli " peut passer par une optimisation de l'étape de durcissement structural. La modélisation thermodynamique par une approche CALPHAD du système PbCaSn permet d'apprécier le degré de sursaturation après trempe du calcium et de l'étain et d'optimiser le traitement thermique nécessaire à la stabilisation de l'état " vieilli ". Par ailleurs, un nouveau procédé de synthèse des électrodes a été développé. Celui-ci se base sur la synthèse de composites Pb/TiO2 par compaction à chaud (frittage). Même si les propriétés électrochimiques ne sont pas optimales, une amélioration très nette des propriétés mécaniques est constatée en comparaison aux alliages PbCaSn coulés et stabilisés en l'état " vieilli "

Diagrammes de phases appliqués à la Cristallisation

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Diagrammes de phases appliqués à la Cristallisation

National audienc

Master 2 « Cristallisation » à l’université de Rouen : de l’expertise en recherche à la formation initiale

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