Crystal Engineering of Pharmaceutical Cocrystals in the Discovery and Development of Improved Drugs

Abstract

The subject of crystal engineering started in the 1970s with the study of topochemical reactions in the solid state. A broad chemical definition of crystal engineering was published in 1989, and the supramolecular synthon concept was proposed in 1995 followed by heterosynthons and their potential applications for the design of pharmaceutical cocrystals in 2004. This review traces the development of supramolecular synthons as robust and recurring hydrogen bond patterns for the design and construction of supramolecular architectures, notably, pharmaceutical cocrystals beginning in the early 2000s to the present time. The ability of a cocrystal between an active pharmaceutical ingredient (API) and a pharmaceutically acceptable coformer to systematically tune the physicochemical properties of a drug (i.e., solubility, permeability, hydration, color, compaction, tableting, bioavailability) without changing its molecular structure is the hallmark of the pharmaceutical cocrystals platform, as a bridge between drug discovery and pharmaceutical development. With the design of cocrystals via heterosynthons and prototype case studies to improve drug solubility in place (2000–2015), the period between 2015 to the present time has witnessed the launch of several salt–cocrystal drugs with improved efficacy and high bioavailability. This review on the design, synthesis, and applications of pharmaceutical cocrystals to afford improved drug products and drug substances will interest researchers in crystal engineering, supramolecular chemistry, medicinal chemistry, process development, and pharmaceutical and materials sciences. The scale-up of drug cocrystals and salts using continuous manufacturing technologies provides high-value pharmaceuticals with economic and environmental benefits.

Synthesis of Ternary Cocrystals, Salts, and Hydrates of Acefylline with Enhanced Dissolution and High Permeability

“…ACF can be categorized as a BCS class IV drug (Biopharmaceutics Classification System) owing to its low solubility and low permeability. , The permeability plots in Figure a,b show an increase in the flux of ACF for the binary and ternary systems. The diffusion behavior was studied using a Franz cell membrane in an aqueous buffer (pH 7.4) measured at hourly intervals over 8 h. A change in the pH of the receptor solution compartment was observed with the final pH being about 4 after the diffusion experiment of the cocrystals, which were stable in the permeability medium, namely, ACF-GA, ACF-INA, and ACF-INA-GA Form 1 salts–cocrystals.…”

“…Crystal engineering and heterosynthon-based strategies to improve solubility, 54−56 solubility and permeability, 57,58 and stability 59 in multicomponent cocrystals 60 continue to be reported for important API categories. 61 Acefylline (ACF) is one such API having poor aqueous solubility (1 mg/mL) and relatively low membrane permeability (log P −0.8 to −1.1) in the BCS class IV category, and its piperazine salt has a higher solubility of 14.7 mg/mL. 62 ACF consists of one hydrogen-bond-donating and (COOH) multiple hydrogen-bond-accepting sites (heteroaromatic Ns and C  Os), which can participate in hydrogen-bonding pairing with molecules such as aromatic carboxylic acids, amides, and piperazine with the expectation to form 1:1 binary cocrystals/salts (shown in Figure S1 for acefylline acid).…”

“…Perlovich built a database of cocrystals and the individual APIs and coformers based on their melting points and fusion enthalpy along with prediction of solubility based on the solubility of the individual components. Crystal engineering and heterosynthon-based strategies to improve solubility, − solubility and permeability, , and stability in multicomponent cocrystals continue to be reported for important API categories …”

The Relevance of Crystal Forms in the Pharmaceutical Field: Sword of Damocles or Innovation Tools?

“…The subject has been addressed in a number of books, publications, and reviews. Good entry points are the books cited above [ 6 , 7 ], while reviews on the subject matter, with a focus on pharmaceutical co-crystals, were written by Zaworotko et al in 2016 [ 74 ] and, very recently, by Nangia et al [ 75 ]. The occurrence of polymorphism in multicomponent systems, including co-crystals, has also been reviewed recently [ 76 ].…”

Polymorphs and isostructural cocrystals of dexamethasone: towards the improvement of aqueous solubility

“…Cocrystals are wellknown to modulate drug properties such as solubility/ dissolution rate by substituting the robust homosynthon between the drug molecules with the more preferable heterosynthon established between the drug and a biologically safe coformer. 3 Cocrystals with a similar molecular arrangement in the crystal lattices are defined as isostructural cocrystals. 4,5 The design of isostructural cocrystals involves either the incorporation of structural homologues or the exchange of atoms/functional groups with equivalent van der Waals radii/volume.…”