Solvates, Salts, and Cocrystals: A Proposal for a Feasible Classification System

Abstract

The design of pharmaceutical cocrystals has initiated widespread debate on the classification of cocrystals. Current attempts to classify multicomponent crystals suffer from ambiguity, which has led to inconsistent definitions for cocrystals and for multicomponent crystals in general. Inspired by the work of Aitipamula et al. (Cryst. Growth Des. 2012, 12, 2147–2152), we present a feasible classification system for all multicomponent crystals. The present classification enables us to analyze and classify multicomponent crystal structures present in the Cambridge Structural Database (CSD). This reveals that all seven classes proposed are relevant in terms of frequency of occurrence. Lists of CSD refcodes for all classes are provided. We identified over 5000 cocrystals in the CSD, as well as over 12 000 crystals with more than two components. This illustrates that the possibilities for alternative drug formulations can be increased significantly by considering more than two components in drug design.

Boric acid co-crystals in guar gelation

“…10 Co-crystallization is of increasing interest in the pharmaceutical industry as a formulation strategy in order to modify the solubility, bioavailability and processing characteristics of active pharmaceutical ingredients. [11][12][13][14][15][16][17][18][19][20] There are also emerging applications of co-crystals in agrochemicals. 21 As a method of modifying the solid state properties and dissolution characteristics of active ingredients, co-crystallisation (and the formation of co-amorphous phases 22,23 ) represents a general strategy and should also be applicable to other industry sectors.…”

Novel solid forms of lonidamine: crystal structures and physicochemical properties

“…5,6 Solvent and/or water molecules may be present as an additional molecule giving rise to co-crystal solvates and/or hydrates. Recently, de Gelder et al 7 proposed a classification system for all multicomponent crystal systems consisting of seven classes arising from three main groups. This allows pure co-crystals to be distinguished from salts, solvates, and hybrid structures (which bridge the, for example, cocrystal-salt boundary).…”

Pharmaceutical salts of the antidepressants Paroxetine and Fluoxetine, selective serotonin reuptake inhibitors: crystal engineering, solid-state characterization and thermodynamic aspects

“…72,79 On the other hand, the ionization of species as a result of the association in the solid results in the formation of salts. 72,88 As described by Grothe and co-authors 82 , the crystalline multicomponent forms can be classified into co-crystals, salts, solvates and sub-classes formed by their combinations (Figure 6b). As focus of this thesis, the following sections will depict in details the definition of polymorphs, pharmaceutical hydrates, and pharmaceutical salts.…”

“…7273,77,79-81 On the other hand, the classification and designation of these multicomponent solid forms is still being discussed. 67,79,82 Figure 6 it is assumed that the API contains one or more ionisable functional groups and it is implied that all of these forms can exhibit polymorphism. Hydrates and solvates, for example, are the most common form in crystallization screens 83 and it occurs when the solvent molecules from crystallization medium are included in the lattice.…”