Crystalline Multicomponent Solids: An Alternative for Addressing the Hygroscopicity Issue in Pharmaceutical Materials

Abstract

The ambient humidity varies with seasons and geographical altitude across the regions. A change in relative humidity during processing, storage, and transportation can cause instability to the active pharmaceutical ingredient (API) solid form, which may sometimes lead to the formation of hydrates, decomposition, and dissociation (or disproportionation) of the drug product. A thorough understanding of the interaction of crystalline solid with atmospheric water is necessary to understand this phenomenon and to develop a potential solution to this problem. In this review, we discuss various aspects of this phenomenon along with some examples from the literature wherein the physical stability enhancement of an API is addressed through the multicomponent solid form (salts, cocrystals, and eutectics) development. The review also presents an overview of computational approaches employed to predict the hydration behavior of an API, their susceptibility to form hydrates, and studies on the crystal structure prediction of hydrates. Additionally, a few representative studies highlighting the moisture-induced phase transformations to polymorphs, hydrates, and cocrystal formation and their dissociation are discussed.

Enhancing the stability of active pharmaceutical ingredients by the cocrystal strategy

“…And the hygroscopic behavior of the API solid form would lead to the transformation of polymorphs, amorphous phases, hydrates, and new multicomponent phases. 23 Approximately one-third of all compounds used in the manufacture of medicines are able to hydrate, 24 and the potential dehydration and subsequent form change would occur at an elevated temperature, or in a variable humidity. 25,26 Such a phase transformation is not desired in the pharmaceutical industry as it might lower the dissolution rate and diminish oral bioavailability.…”

Ciprofloxacin salt and salt co-crystal with dihydroxybenzoic acids

“…The formation of multi-component crystals, i.e. salts and co-crystals through a crystal-engineering approach has been continuously demonstrated as a versatile tool to improve the physicochemical properties of APIs (Kavanagh et al, 2019;Putra & Uekusa, 2020;Thakur & Thakuria, 2020). Recently, the co-crystallization of salt APIs or salt co-crystal formation has been increasingly studied.…”

Multicomponent Crystal of Trimethoprim and Citric Acid: Solid State Characterization and Dissolution Rate Studies

“…One of the recent strategies applied to enhance physicochemical properties of active pharmaceutical compounds is by forming a multi-component crystal phase with an inert and safe coformer. This approach has shown successful improvement in solubility, dissolution rate, physical and chemical stability, and compressibility [6], [7], [8], [9], [10]. Multicomponent crystal phase between active pharmaceutical compounds and coformers could be formed due to non-covalent intermolecular interactions such as van der Waals bonds and hydrogen bonds [11].…”