3 research outputs found
Ălaboration de cocristaux pharmaceutiques par procĂ©dĂ©s assistĂ©s au CO2
For the pharmaceutical industry, cocrystal design allows tuning physicochemical propertiesof an active compound without altering its therapeutic activity. These monophasic solidscontain two or more different species interacting by weak and neutral bonds. Whereas themajority of cocrystallization studies pertain to generation and characterization of newcocrystalline phases, this work was aiming at exploring a new way of cocrystal fabrication,using supercritical CO2-assisted processes. The possibility of interaction formation betweendifferent types of compounds when these are precipitated by antisolvent CO2 has beenstudied by the batch GAS (Gaseous Anti-Solvent) and the semi-continuous SAS(Supercritical Anti-Solvent) versions of the antisolvent method on two different molecularsystems: naproxen-nicotinamide and acetazolamide-theophylline. Naproxen being a chiralcompound, its cocrystallization with nicotinamide from a racemic mixture has also beenaddressed. A known naproxen-based cocrystal and a new racemic cocrystalline phase havebeen obtained thanks to the antisolvent precipitation. A new acetazolamide-theophyllinecocrystal has also been produced for the first time with the GAS process. The influence ofGAS and SAS operational parameters such as CO2 feed rate, species molar ratio andconcentrations in the initial solution, has been investigated to allow a better understanding ofthe mechanisms involved in supercritical CO2-induced cocrystallization. Results have shownthat purity in cocrystal of the produced powders is influenced by the CO2 composition of thesolution/antisolvent mixture and by the ratio and concentrations of the solutes(thermodynamic equilibria), but also by the homogeneity of the mixture in the precipitationchamber of the process.Pour lâindustrie pharmaceutique, la conception de cocristaux permet de moduler les propriĂ©tĂ©s physico-chimiques de composĂ©s dâintĂ©rĂȘt sans en altĂ©rer lâactivitĂ© thĂ©rapeutique.Ces solides monophasĂ©s sont dĂ©finis comme Ă©tant des structures comportant plusieurs espĂšces reliĂ©es entre elles par des liaisons faibles et neutres. Alors que la majoritĂ© des Ă©tudes de cocristallisation sont centrĂ©es sur la gĂ©nĂ©ration et la caractĂ©risation de nouvelles phases, ce travail a eu pour objectif dâexplorer une nouvelle mĂ©thode de fabrication de cocristaux, en utilisant des procĂ©dĂ©s assistĂ©s au CO2 supercritique. La possibilitĂ© de formerdes interactions entre composĂ©s de diffĂ©rentes natures par recristallisation au CO2antisolvant a Ă©tĂ© Ă©tudiĂ©e avec les versions discontinue GAS (Gaseous Anti-Solvent) et semicontinue SAS (Supercritical Anti-Solvent) sur deux systĂšmes: naproxĂšne-nicotinamide et acĂ©tazolamide-thĂ©ophylline. Le naproxĂšne Ă©tant chiral, la cocristallisation Ă partir du mĂ©lange naproxĂšne racĂ©mique-nicotinamide a Ă©galement Ă©tĂ© abordĂ©e. Un cocristal connu etdeux phases cocristallines jamais observĂ©es, dont une racĂ©mique, ont pu ĂȘtre synthĂ©tisĂ©s.LâĂ©tude de lâinfluence de divers paramĂštres opĂ©ratoires des procĂ©dĂ©s GAS et SAS, tels que la concentration de la solution initiale, le ratio des espĂšces ou le dĂ©bit dâajout de lâantisolvant,a permis une meilleure comprĂ©hension de la cocristallisation induite par CO2 supercritique.Les rĂ©sultats ont montrĂ© que la puretĂ© en cocristaux des poudres obtenues Ă©tait influencĂ©e Ă la fois par la proportion de CO2 dans le mĂ©lange solution/CO2 et les concentrations des espĂšces en solution (contribution des Ă©quilibres thermodynamiques) mais Ă©galement par lâhomogĂ©nĂ©itĂ© du rĂ©acteur de prĂ©cipitation
Elaboration of pharmaceutical cocrystals by CO2-assisted processes
Pour lâindustrie pharmaceutique, la conception de cocristaux permet de moduler les propriĂ©tĂ©s physico-chimiques de composĂ©s dâintĂ©rĂȘt sans en altĂ©rer lâactivitĂ© thĂ©rapeutique.Ces solides monophasĂ©s sont dĂ©finis comme Ă©tant des structures comportant plusieurs espĂšces reliĂ©es entre elles par des liaisons faibles et neutres. Alors que la majoritĂ© des Ă©tudes de cocristallisation sont centrĂ©es sur la gĂ©nĂ©ration et la caractĂ©risation de nouvelles phases, ce travail a eu pour objectif dâexplorer une nouvelle mĂ©thode de fabrication de cocristaux, en utilisant des procĂ©dĂ©s assistĂ©s au CO2 supercritique. La possibilitĂ© de formerdes interactions entre composĂ©s de diffĂ©rentes natures par recristallisation au CO2antisolvant a Ă©tĂ© Ă©tudiĂ©e avec les versions discontinue GAS (Gaseous Anti-Solvent) et semicontinue SAS (Supercritical Anti-Solvent) sur deux systĂšmes: naproxĂšne-nicotinamide et acĂ©tazolamide-thĂ©ophylline. Le naproxĂšne Ă©tant chiral, la cocristallisation Ă partir du mĂ©lange naproxĂšne racĂ©mique-nicotinamide a Ă©galement Ă©tĂ© abordĂ©e. Un cocristal connu etdeux phases cocristallines jamais observĂ©es, dont une racĂ©mique, ont pu ĂȘtre synthĂ©tisĂ©s.LâĂ©tude de lâinfluence de divers paramĂštres opĂ©ratoires des procĂ©dĂ©s GAS et SAS, tels que la concentration de la solution initiale, le ratio des espĂšces ou le dĂ©bit dâajout de lâantisolvant,a permis une meilleure comprĂ©hension de la cocristallisation induite par CO2 supercritique.Les rĂ©sultats ont montrĂ© que la puretĂ© en cocristaux des poudres obtenues Ă©tait influencĂ©e Ă la fois par la proportion de CO2 dans le mĂ©lange solution/CO2 et les concentrations des espĂšces en solution (contribution des Ă©quilibres thermodynamiques) mais Ă©galement par lâhomogĂ©nĂ©itĂ© du rĂ©acteur de prĂ©cipitation.For the pharmaceutical industry, cocrystal design allows tuning physicochemical propertiesof an active compound without altering its therapeutic activity. These monophasic solidscontain two or more different species interacting by weak and neutral bonds. Whereas themajority of cocrystallization studies pertain to generation and characterization of newcocrystalline phases, this work was aiming at exploring a new way of cocrystal fabrication,using supercritical CO2-assisted processes. The possibility of interaction formation betweendifferent types of compounds when these are precipitated by antisolvent CO2 has beenstudied by the batch GAS (Gaseous Anti-Solvent) and the semi-continuous SAS(Supercritical Anti-Solvent) versions of the antisolvent method on two different molecularsystems: naproxen-nicotinamide and acetazolamide-theophylline. Naproxen being a chiralcompound, its cocrystallization with nicotinamide from a racemic mixture has also beenaddressed. A known naproxen-based cocrystal and a new racemic cocrystalline phase havebeen obtained thanks to the antisolvent precipitation. A new acetazolamide-theophyllinecocrystal has also been produced for the first time with the GAS process. The influence ofGAS and SAS operational parameters such as CO2 feed rate, species molar ratio andconcentrations in the initial solution, has been investigated to allow a better understanding ofthe mechanisms involved in supercritical CO2-induced cocrystallization. Results have shownthat purity in cocrystal of the produced powders is influenced by the CO2 composition of thesolution/antisolvent mixture and by the ratio and concentrations of the solutes(thermodynamic equilibria), but also by the homogeneity of the mixture in the precipitationchamber of the process
NaproxenâNicotinamide Cocrystals: Racemic and Conglomerate Structures Generated by CO<sub>2</sub> Antisolvent Crystallization
Cocrystallization of naproxen racemic
mixture and nicotinamide
was investigated in this work, using compressed CO<sub>2</sub> as
antisolvent. A novel racemic cocrystal structure containing both enantiomers
of naproxen linked to nicotinamide has been produced thanks to the
CO<sub>2</sub> antisolvent batch crystallization process. The structure
of the molecular complex and its intermolecular interactions were
investigated by single-crystal X-ray diffraction and attenuated total
reflectance Fourier transform infrared spectroscopy. The antisolvent
feed rate was found to have a direct influence on the cocrystallization
outcome. The racemic cocrystal was obtained at slow and moderate CO<sub>2</sub> feed rate, while very fast introduction of CO<sub>2</sub> resulted in the formation of a mixture of chiral cocrystals (conglomerate).
Cross-seedings, thermal analysis, and temperature-resolved X-ray powder
diffraction were used to probe the relationship between the different
phases. In addition, all powders produced with CO<sub>2</sub> technology
were obtained as cocrystal-pure, without significant excess of naproxen
or nicotinamide homocrystals