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Improving solubility with promiscuous multi-component drug crystals

22 October 2015  •  Author(s): Masataka Ito, Kiyohiko Sugano and Katsuhide Terada Faculty of Pharmaceutical Sciences, Toho University

The physicochemical properties of active pharmaceutical ingredients (APIs) are critical to the success of drug development. Most of the APIs in oral solid dosage forms are contained as drug crystals.

Improving solubility with promiscuous multi-component drug crystals

Drug crystals can be categorised as single and multiple component systems, the latter of which include salts, co-crystals and solvates. When the solvent is water, the drug solvate is referred to as a hydrate. Salts formation is defined as proton transfer from a drug molecule to a guest molecule and the guest molecule (i.e., a counter-ion) is bonded to the drug molecule (i.e., a drug) by one or several ionic bonds. In a co-crystal and a solvate, a guest molecule (a co-crystal co-former or a solvent) is bonded to the drug via inter-molecular interactions other than the ionic bond, such as with hydrogen bonds. Co-crystal co-formers are non-volatile molecules at ambient conditions. In most cases, the drug solvates of APIs are hydrates; however, they can be organic solvents.

Multi-component crystals are widely used to improve the physico-chemical properties of APIs, such as solubility, stability, powder compaction and bioavailability. When the drug possesses a dissociable group, salt formation is usually utilised. Recently, co-crystals have been intensively investigated for their ability to improve the solubility of undissociable drugs. Although organic solvates have received less attention compared with co-crystals, some have also been utilised as APIs, including indinavir sulphate ethanolate, efonidipine hydrochloride ethanolate, metildigoxin acetonate, ledipasvir acetonate, and dapagliflozin propylene glycolate hydrate. Moreover, some drugs tend to form several organic solvates, which are collectively referred to as ‘promiscuous solvate formers’. These promiscuous solvate formers offer new opportunities to improve the solubility of a drug; however, they could also be problematic from the viewpoint of manufacturability. In this review, several examples of promiscuous solvate formers are discussed…

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