Novel solid forms of insomnia drug suvorexant with improved solubility and dissolution: accessing salts from a salt solvate route

Abstract

Suvorexant (SRX) is a dual orexin receptor antagonist used for the treatment of insomnia. It belongs to the Biopharmaceutics Classification System (BCS) class-II with high permeability and poor solubility in...

Applications of Isosteres of Piperazine in the Design of Biologically Active Compounds: Part 1

“…23,25−27 However, these compounds need to be used with caution since ingestion of 9 has been associated with seizure while 10 is hepatotoxic in vitro. The phenylpiperazines 13−15 are serotonergic agents related to quipazine (16), and combinations of 9 and 13 mimic the effects of 3,4-methylenedioxymethamphetamine (MDMA, 11), a drug of abuse known colloquially as ecstasy, that enhances the release of both serotonin and dopamine at neuronal synapses.…”

“…A broad-based and unbiased survey of potential homopiperazine bioisosteres was conducted in the context of the orexin antagonist 1 in an effort to identify compounds that would project the two pharmacophoric elements, the benzoxazole heterocycle and the amide moiety, in a topographical presentation that would preserve the dual-receptor antagonistic pharmacology of the prototype (Figure ). The homopiperazine ring of 1 , which originated with a screening lead, allows it to sample multiple conformations in solution and in the solid state, with a detailed analysis indicating that a twist boat topography of the core heterocycle is the low-energy form that presents the two pharmacophoric elements in a U-shaped arrangement, stabilized by intramolecular π-stacking interactions. ,, In the solid state, extended conformations of 1 are typically observed, while the quinazoline analogue 32 , a potent dual-receptor antagonist, crystallized in the low-energy U-shaped conformation, as depicted in Figure A. , This was proposed to be the bound conformation, a hypothesis that was confirmed with the evaluation of the constrained analogue 33 (Figure B), which fully retained the potency of 32 , and subsequent cocrystal structures of analogous ligands with the OX 1 and OX 2 receptors. − …”

“…The single-crystal X-ray structure of homopiperazine was solved in 2021 and revealed that, in the form isolated, the molecule adopts a pseudochair conformation with an N–N distance of 2.97 Å (Figure C) . However, the extra CH 2 in homopiperazine confers flexibility to the heterocyclic ring that allows it to explore a range of conformations in which the N–N distance varies from ∼2.75 Å in a U-shaped analogue of 1 to 3.05 in 1 itself and 3.20–3.28 Å in other examples where there are crystal structure data available. , As will be discussed, this conformational plasticity can be beneficial in the design of biologically active molecules. For the purpose of comparison, the N–N distance in 2,5-diazabicyclo[2.2.1]­heptane is similar to piperazine, but this is extended to 4.28 Å in 4-aminopiperidine and 2,4,5,6-tetrahydropyrrolo­[3,4- c ]­pyrazole (Figure ), all of which have been explored as potential bioisosteres of piperazine. , …”

“…14 However, the extra CH 2 in homopiperazine confers flexibility to the heterocyclic ring that allows it to explore a range of conformations in which the N−N distance varies from ∼2.75 Å in a U-shaped analogue of 1 to 3.05 in 1 itself and 3.20−3.28 Å in other examples where there are crystal structure data available. 15,16 As will be discussed, this conformational plasticity can be beneficial in the design of biologically active molecules.…”

Understanding the thermal stability of apalutamide crystalline solvates through crystal structure analyses and computational studies

“…8,13 It is well known that desolvation of different solvates can be used as a potential route for the preparation of specific or unknown polymorphic forms of single-and multicomponent crystals, which are difficult to attain by conventional crystallization techniques. [14][15][16][17] Desolvation has also been proved as an effective method for the purification of drug compounds (e.g. enzalutamide).…”