Luc Aerts

Combining piracetam and lithium salts: ionic co-crystals and co-drugs?

Mechanochemical reaction of solid piracetam with the inorganic salts LiCl and LiBr yields ionic co-crystals which are also co-drugs, characterized by markedly different thermal properties with respect to pure components, also depending on the method for preparation and/or conditions of measurements; single crystal and powder X-ray diffraction at variable temperatures, DSC, TGA, hot stage microscopy (HSM) and intrinsic dissolution rate have been used to fully characterize the solid products.

Ionic co-crystals of racetams: solid-state properties enhancement of neutral active pharmaceutical ingredients via addition of Mg2+ and Ca2+ chlorides

Mechanochemical and solution based reactions of solid brivaracetam (BRV) and seletracetam (SEL), antiepileptic drugs from UCBs pipeline, with the inorganic salts MgCl2 and CaCl2, yield ionic co-crystals with changed or improved physico-chemical properties with respect to pure drugs (melting point, hygroscopicity, crystal morphology). All co-crystals are characterized via a combination of solid-state techniques, i.e. single crystal and powder X-ray diffraction, variable temperature X-ray diffraction, DSC, TGA and hot-stage microscopy (HSM).

Solid-liquid phase diagrams for the determination of the solid state nature of both polymorphs of (RS)-2-(2-oxo-pyrrolidin-1-yl)-butyramide.

This work focuses on the determination of the solid state nature of (RS)-2-(2-oxo-pyrrolidin-1-yl)-butyramide (Etiracetam), the racemic intermediate of (S)-2-(2-oxo-pyrrolidin-1-yl)-butyramide, an Active Pharmaceutical Ingredient, marketed under the name Levetiracetam(®). It is show how this information can easily be extracted from solid-liquid phase diagrams of the racemic system. As two polymorphs of Etiracetam are known (Forms I and II), the analyses have been performed considering both polymorphs. The solid-liquid phase diagrams are determined experimentally, using Differential Scanning Calorimetry, and theoretically, using the Prigogine-Defay and Schroeder-Van Laar equations. Only the phase diagram involving the polymorph stable at higher temperatures (Form II) can be constructed experimentally. The theoretical phase diagram involving this polymorph compares well with the experimental one, thus allowing the use of theoretical equations for the prediction of the solid-liquid phase diagram involving Form I, which is meta-stable above 30.5 °C. Our findings confirm that both polymorphs are racemic compounds, which is also confirmed by XRPD analysis.

Investigation of the Crystallization Kinetics of Dextrose Monohydrate Using In Situ Particle Size and Supersaturation Monitoring

In this work, a seeded batch cooling crystallizer was used to study dextrose monohydrate crystallization using in situ techniques. Experiments were conducted to investigate the influence of cooling profile (natural, linear, and controlled cooling) and seed mass on dextrose monohydrate crystallization. Two in situ techniques, Lasentec focused beam reflectance measurement (FBRM) and an in-line process refractometer for monitoring aqueous crystallization of dextrose monohydrate, were used. The seed mass and cooling profile were focused on, in particular, determining the effect of secondary nucleation and crystal growth rate on the final crystal size distribution, the evolution of supersaturation, and yield of dextrose monohydrate. Experimental results were analyzed to evaluate the kinetic constants from growth and nucleation power law functions with supersaturation. The results showed that increasing the seed mass decreased the level and the peak of supersaturation and increased the crystal growth rate. The experiment performed with natural cooling and with high seed mass resulted in the highest yield. Furthermore, the results showed a significant increase in the final crystal size with decreasing seed mass.

Impact of sodium chloride on the expansion of a liquid-liquid miscibility gap in an API/water system. Case study of Brivaracetam

Brivaracetam, or (2S)-2-[(4R)-2-oxo-4-propyl-pyrrolidin-1-yl] butanamide, is an active pharmaceutical ingredient designed for the treatment of epilepsy. During the development of the IV administration mode, a liquid-liquid miscibility gap has been observed with pure water, isotonic and hypertonic solutions (vehicle at 0.9% w/w and 5%w/w NaCl respectively). The study reveals that the NaCl concentration has a direct impact on the extent of the demixing domain; from a sub-micronic demixing in pure water towards a macroscopic miscibility gap in hypertonic aqueous solutions. The thorough exploration of these heterogeneous equilibria led to define experimental parameters for safe IV injections without risk of liquid - liquid miscibility gap at 37°C.

CCDC 988342: Experimental Crystal Structure Determination

Related Article: Fabrizia Grepioni, Johan Wouters, Dario Braga, Saverio Nanna, Baptiste Fours, Gerard Coquerel, Geraldine Longfils, Sandrine Rome, Luc Aerts, Luc Quere|2014|CrystEngComm|16|5887|doi:10.1039/C4CE00409D