Luc Quere

Pharmaceutical salts and co-crystals

Fundamental Aspects on Salts and Co-crystals Preparative Methods for Co-crystals Characterization of Co-crystals and Salts Applications of Co-crystals and Salts in Pharmaceutical Solid State Property Management

First dual NK1 antagonists–serotonin reuptake inhibitors: synthesis and SAR of a new class of potential antidepressants

Compounds combining NK(1) antagonism and serotonin reuptake inhibition are described, and potentially represent a new generation of antidepressants. Compound 24 displays good affinities for both the NK(1) receptor and the serotonin reuptake site (32 and 25 nM, respectively).

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).

Discovery of a new class of non-imidazole oxazoline-based histamine H(3) receptor (H(3)R) inverse agonists

H3R inverse agonists based on an aminopropoxy‐phenyloxazoline framework constitute highly valuable druglike lead compounds that display efficacy in a mouse model of recognition memory.

Alkyne–quinuclidine derivatives as potent and selective muscarinic antagonists for the treatment of COPD

SAR around alkyne-quinuclidine derivatives allowed the discovery of highly potent muscarinic antagonists displaying interesting preferential slow off-rates from the M3 receptor.

Discovery of orally bioavailable NK1 receptor antagonists

Benzyloxyphenethylpiperazines are a new class of high affinity NK1 receptor antagonists. Oral bioavailability and selectivity can be fine tuned by the nature of the substituents on the basic nitrogen atom. Addition of substituents with a carboxylic acid group led to very selective and orally active NK1 antagonists free of interaction with L-type calcium channels.

X-ray structural characterization of SR 142948, a novel potent synthetic neurotensin receptor antagonist

SR 142948 is an original and extremely potent neurotensin receptor antagonist developed in a promising approach to novel antipsychotic drugs. The X-ray structure was elucidated and compared to SR 48692 and levocabastine, providing new informations about the possible recognition process of NT receptor subtypes.

Chapter 16:Monographs of most Frequent Co-Crystal Formers

In terms of preparation of co-crystals, both the screening and the supramolecular synthon-based retrosynthetical approaches benefit from better knowledge of the physicochemical properties of co-crystal formers. This chapter aims to provide a listing of frequently encountered candidates. Besides more classical properties (pKa, melting point, solubility), powder X-ray diffractograms have been simulated in the most representative and informative cases. These characteristics should be affected upon formation of co-crystals and are thus a guide to the further identification of original formulations. The potential polymorphism of the co-crystal former is also flagged and selected examples of co-crystals are provided.

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.