Engineering and manufacturing of pharmaceutical co-crystals: a review of solvent-free manufacturing technologies

Abstract

Design and synthesis of pharmaceutical cocrystals have received great interest in recent years. Cocrystallization of drug substances offers a tremendous opportunity for the development of new drug products with superior physical and pharmacological properties such as solubility, stability, hydroscopicity, dissolution rates and bioavailability. It is now possible to engineer and develop cocrystals via 'green chemistry' and environmentally friendly approaches such as solid-state synthesis in the absence of organic solvents. In addition, significant efforts have been directed towards computational screening, cocrystal manufacturing in a continuous manner and real-time monitoring for quality purposes by using various analytical tools. Pharmaceutical cocrystals are not fully exploited yet and there is a lot of ground to cover before they can be successfully utilized as medical products.

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] .…”

“…Stability of solvates will be different from unsolvated forms because of presence of solvent in crystal lattice. Solvates/hydrates are quite unstable, because they lose solvent/water at high temperature and low humidity during storage and the physiochemical properties will be different for hydrated/dehydrated forms [22][23][24] . Dissolution rate of the drug was enhanced by the solvated forms of spironolactone [25] .…”

“…Supramolecular synthon approaches are of two types: supramolecular homosynthons and supramolecular heterosynthons. Supramolecular homosynthons are composed by same functional groups present in API and coformer such as the amide-amide homosynthons, carboxylic acid-acid homosynthons whereas supramolecular heterosynthons are formed by different functional groups such as the carboxylic acid-amide heterosynthons, the acid-pyridine heterosynthons [24] . Supramolecular heterosynthons are generally more favoured than homosynthons, e.g., the acid-amide and the acid-pyridine heterosynthons are commonly used as compared to carboxylic acid and amide homodimers [22] .…”

“…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.…”

“…The most commonly used techniques for determination of melting point and thermal analysis are differential scanning calorimetry (DSC) and thermal gravimetric analysis (TGA). Melting point of pharmaceutical cocrystals can be tailored by judicious selection of the coformers [24,30] . Melting point of about 50 cocrystals was analysed and the results showed that 51% cocrystals showed melting points between API and coformers, while 39% cocrystals have melting point lower than either API or coformer, 6% have high melting point than both API and coformer, and 4% had same about API or coformer [16] .…”