Pharmaceutical cocrystals: walking the talk

Abstract

Pharmaceutical cocrystals belong to a sub-class of cocrystals wherein one of the components is a drug molecule (or an active pharmaceutical ingredient, API) and the second is a benign food or drug grade additive (generally regarded as safe, GRAS). The two components are hydrogen-bonded in a fixed stoichiometric ratio in the crystal lattice. In the past decade, pharmaceutical cocrystals have demonstrated significant promise in their ability to modify the physicochemical and pharmacokinetic properties of drug substances, such as the solubility and dissolution rate, bioavailability, particle morphology and size, tableting and compaction, melting point, physical form, biochemical and hydration stability, and permeability. In this feature review, we highlight some prominent examples of drug cocrystals which exhibit variable hardness/softness and elasticity/plasticity depending on coformer selection, improvement of solubility and permeability in the same cocrystal, increase of the melting point for solid formulation, enhanced color performance, photostability and hydration stability, and a longer half-life. Cocrystals of flavanoids and polyphenols can make improved pharmaceuticals and also extend to the larger class of nutraceuticals. The application of crystal engineering to assemble ternary cocrystals expands this field to drug-drug cocrystals which may be useful in multi-drug resistance, mitigating side effects of drugs, or attenuating/enhancing drug action synergistically by rational selection. The advent of new techniques for structural characterization beyond the standard X-ray diffraction will provide a better understanding of drug phases which are at the borderline of crystalline-amorphous nature and even newer opportunities in the future.

Pharmaceutical Cocrystals: An Overview

“…The key advantage of formulating the cocrystals is that without altering the pharmacological properties, the APIs will benefit of their physicochemical properties enhancements because of the presence of coformer in crystal structure which is a property modifying component. The effect on the physicochemical properties of the API is dependent on the available coformer [16,24,27,28] . Another unique advantage of cocrystals over the more common salts is that cocrystals can be made for non-ionisable APIs as well as for those complex drugs which have sensitive functional groups that may not survive the harsh reaction conditions of strong acids or bases [12,28] .…”

“…The effect on the physicochemical properties of the API is dependent on the available coformer [16,24,27,28] . Another unique advantage of cocrystals over the more common salts is that cocrystals can be made for non-ionisable APIs as well as for those complex drugs which have sensitive functional groups that may not survive the harsh reaction conditions of strong acids or bases [12,28] . There are several other main advantages behind the formulating the cocrystals.…”

“…Pharmaceutical cocrystals are structurally different to their bulk forms; it is possible to patent cocrystals of existing APIs as a new crystal form. Different formulations of pharmaceutical cocrystals are available in the market such as Viagra (Pfizer) to treat erectile dysfunction and pulmonary arterial hypertension, Entresto (Novartis) for treatment of chronic heart failure and some others under clinical developments [12,14,16,24,28] . Pharmaceutical cocrystals can enhance the physicochemical properties of drugs such as melting point, tabletability, solubility, stability, bioavailability, permeability and these properties are highlighted here with suitable examples.…”

“…Permeability of drugs mainly depends upon the n-octanol/water partition coefficient by using log P and (C log P) for unchanged form of drug [28] . Permeability of a BCS class-III drug, 5-fluorouracil, was enhanced by cocrystallization with different coformers such as 3-hyroxybenzoic acid, 4-aminobenzoic acid and cinnamic acid [57] .…”

13. Crystal chemistry of the isomeric N,N'-bis(pyridin-n-ylmethyl)-ethanediamides, n = 2, 3 or 4

“…An overview of the co-crystals formed by 2 LH2 will then be presented, then of any salts, followed by complexation patterns to metals in neutral form and then ionic forms. The subsequent sections will cover the structural chemistry of the higher homologues, 3 LH2 and 4 LH2. Data, in the form of CIF's, were extracted from the Cambridge Crystallographic Database [4] and interrogated using PLATON [5]; diagrams were drawn with DIAMOND [6].…”