Solution Stability of Pharmaceutical Cocrystals

Abstract

In recent years, pharmaceutical cocrystals as a new solid form have received considerable attention among the applied novel methods for modifying drug substance characteristics. Crystal engineering offers an excellent opportunity to improve physicochemical and pharmacokinetic properties such as solubility, dissolution rate, permeability, bioavailability, biochemical/physical stability, etc. Application of the cocrystal form in the pharmaceutical industry and in academia is becoming a popular method to overcome solubility disadvantages of the active pharmaceutical ingredient (API). Due to manipulation of the API crystalline structure by cocrystal formation, solubility is not the only affected property; some other properties of the newly produced solid form must be considered to fulfill the desired therapeutic efficacy. The stability of the cocrystal in solution is one of these influential features. Regarding the aqueous nature of the gastrointestinal tract, unwanted solution-mediated phase transformation of a cocrystal to a more stable form causes inefficient drug delivery. It may potentially reduce the drug concentration in the circulation. Cocrystal transformation products could be a different polymorph, hydrated form, or mixture of the API and coformer. This review focuses on the solution stability of cocrystals and the effects of various factors such as polymers, surfactants, biorelevant media, organic solvents, and pH.

Virtual Screening, Structural Analysis, and Formation Thermodynamics of Carbamazepine Cocrystals

“…The stability of a cocrystal in aqueous solution under stoichiometric conditions is an important characteristic that may have a profound effect on the supersaturated dissolution profile of an API and in vivo performance [ 98 , 99 , 100 ]. It is widely accepted that the solution stability and the intrinsic solubility of a cocrystal depend on several parameters, including the strength of intermolecular interactions in the cocrystal (lattice energy), the API-to-coformer solubility ratio, and the cocrystal stoichiometry [ 101 ].…”

Anomalous Properties of Cyclodextrins and Their Complexes in Aqueous Solutions

“…A supersaturated drug solution is unstable and can result in rapid drug precipitation. Pharmaceutical excipients that inhibit nucleation and crystal growth are referred to as drug precipitation inhibitors and include numerous polymers, such as hydroxypropyl methylcellulose and polyvinylpyrrolidone, cocrystals, and surfactants, as well as CDs [ 98 , 99 , 100 ]. The mechanism of inhabitation may include changes in surface tension, an increase in viscosity, and adsorption to the crystal layer, thereby blocking crystal growth.…”

Polymorphs, cocrystal and hydrate of nilutamide

“…70–74 Thus, only a short-term transient supersaturation of a drug during cocrystal dissolution can be detected unless additional formulation techniques are implemented. 70,75–77…”

“…[70][71][72][73][74] Thus, only a short-term transient supersaturation of a drug during cocrystal dissolution can be detected unless additional formulation techniques are implemented. 70,[75][76][77] In our previous work, we determined the solubility of neat forms I and II of Nil at pH 6.8 and 37 °C. 24 In this study, the same experimental conditions were applied to assess the aqueous thermodynamic solubility of the [Nil + Adn] (1 : 1) cocrystal by measuring component concentrations at the eutectic point, where the cocrystal and drug solid phases are in equilibrium with solution.…”

“…It has been extensively reported that utilization of various pharmaceutically acceptable polymers (e.g., HPMC, PVP, and PEG) can effectively delay or suppress nucleation of drug compounds from supersaturated aqueous solutions and, therefore, inhibit precipitation of a poorly soluble component, improving the solution stability of a cocrystal. [70][71][72][73][80][81][82][83][84][85][86] In this study, we employed HPMC, a biocompatible polymer commonly used in the development of cocrystal formulations, 77 as a Nil precipitation inhibitor. Preliminary solubility studies have shown that HPMC at 0.1% concentration had virtually no effect on the thermodynamic solubility of Nil form I.…”