Pharmaceutical cocrystals: along the path to improved medicines

Abstract

Cocrystals, a long known but understudied class of crystalline solids, have attracted interest from crystal engineers and pharmaceutical scientists in the past decade and are now an integral part of the preformulation stage of drug development. This is largely because cocrystals that contain a drug molecule, pharmaceutical cocrystals, can modify physicochemical properties without the need for covalent modification of the drug molecule. This review presents a brief history of cocrystals before addressing recent advances in design, discovery and development of pharmaceutical cocrystals that have occurred since an earlier review published in 2004. We address four aspects of cocrystals: nomenclature; design using hydrogen-bonded supramolecular synthons; methods of discovery and synthesis; development of pharmaceutical cocrystals as drug products. Cocrystals can be classified into molecular cocrystals (MCCs) that contain only neutral components (coformers) and ionic cocrystals (ICCs), which are comprised of at least one ionic coformer that is a salt. That cocrystals, especially ICCs, offer much greater diversity in terms of composition and properties than single component crystal forms and are amenable to design makes them of continuing interest. Seven recent case studies that illustrate how pharmaceutical cocrystals can improve physicochemical properties and clinical performance of drug substances, including a recently approved drug product based upon an ICC, are presented.

Insight into Flufenamic Acid Cocrystal Dissolution in the Presence of a Polymer in Solution: from Single Crystal to Powder Dissolution

“…The resolution of a measurement was 512×512 points with equal steps along the x and y directions. Three scans on the same area were conducted at 80x80 µm 2 …”

“…[1][2][3] A highly supersaturated solution concentration, which is significantly greater than the equilibrium saturation concentration of the parent drug, can be generated due to rapid dissolution of cocrystals, which is a key requirement for improved drug oral absorption. 4 However, maintaining such a supersaturated state is challenging because of the tendency for rapid precipitation of a more stable form of the parent drug during dissolution.…”

Pharmaceutical Cocrystals: An Overview

“…Thus, although the regulatory perspectives of US-FDA and EMA are different, it does demonstrate the growing interest in the use of pharmaceutical cocrystals as potential marketable drugs. Development, screening and evaluation of new cocrystals of drugs require a lot of time and energy; however, various researchers have used some knowledge based approaches for selection of coformers, designing and screening of cocrystals, as highlighted in earlier sections [10,24,116] . Research into cocrystals continues to grow and as more drug products that are based on cocrystals research hit the market, it can only be expected for pharmaceutical cocrystals to gain a stronger grip in drug development.…”

“…This technique is expensive and time consuming. For selection of suitable coformers and screening of cocrystals, researchers have used some different knowledge based approaches which include the followings: hydrogen-bonding propensity, synthonic engineering, supramolecular compatibility by Cambridge Structure Database (CSD), pKa based models, Fabian's method, Lattice energy calculation, the conductor-like screening model for real solvents (COSMO-RS), Hansen solubility parameter, virtual cocrystal screening (based upon molecular electrostatic potential surfaces-MEPS), thermal analysis, measuring saturation temperature, Kofler contact method and matching [10,62] .…”

“…In 2004, pharmaceutical cocrystals were described as a distinct class of novel, crystalline materials which could alter the physicochemical properties of APIs and this was the beginning of the new era in crystal engineering and cocrystal formation [9] . Duggirala and coworkers classified the cocrystals into molecular and ionic depending on the type of coformers [10] . In molecular cocrystals, neutral or non-ionized coformers are present in a stoichiometric ratio and mostly reported cocrystals come in this category.…”