When speaking of multicomponent solid forms of organic molecules, terms such as solvates, hydrates, salts and cocrystals are often used. From these forms, the cocrystals have recently gained much attention. By the term cocrystal, a stoichiometric multicomponent solid with host and guest molecules arranged in a common crystal lattice, is meant. In the case of pharmaceutical cocrystal, one of the components is an active pharmaceutical ingredient (API); the other is a pharmaceutically acceptable coformer. In the generic pharmaceutical industry, cocrystals are used to widen the portfolio of solid forms of APIs, from which the form with the optimal physico-chemical properties is formulated into the drug product.
To obtain as many solid forms of API as possible, a systematic screening is undertaken during the early development stages of the compound. Thus, polymorphs and solvates are obtained from various solvent-based techniques. When combining API to counterions or coformers (in many cases the counterions and coformers are the same compounds), a salt or a cocrystal can be prepared. Such forms can be further screened for polymorphs and solvates/hydrates.
The uniqueness of the novel crystalline form is usually determined by X-ray crystallography. In the past, the powder X-ray diffraction patterns were used to differentiate between the forms of pharmaceutical substances (especially in patent literature); more recently, the structure determination from single crystal X-ray diffraction is the most common technique to describe the novel form.
When deciding between a cocrystal and a salt, the difference often lies merely in the position of a proton between its donor and acceptor. To determine the position of a proton and, thus, decide whether the new form is a cocrystal or a salt, can be achieved via various analytical techniques; solid state NMR, infrared and Raman spectroscopy being useful tools as well as neutron diffraction. The decision is crucial for registration. While the pharmaceutical salts of API are not considered equivalent with API, the cocrystals of API are considered as its intermediates, thus permitting easier acceptance by authorities. As such, they can compete with polymorphs and hydrates of API.
In the presented case studies, two cocrystals of pharmaceutical substances are described.
Cocrystal with fumaric acid (2:1) is a stable form of a prodrug. However, in the marketed drug product, a mixture of salt fumarate (1:1) and the cocrystal was identified, as both forms are related and convert from one to another. The challenge of stabilizing the salt, thus avoiding the conversion into the cocrystal, has been faced. The excipients and wet granulation contribute to the conversion to the cocrystal, causing physical impurities in the bulk. The pH measurements of excipients mixtures have shown that increased pH accelerates the conversion. The addition of citric acid to adjust pH has proven successful in stabilizing the desired form during the formulation.
In the other case, a pharmaceutical salt used for the treatment of angina pectoris was screened for cocrystals, and a hit with (S)-mandelic acid was identified. Upon structure determination and characterization by solid state analytical techniques, the formation of cocrystal was confirmed. Its physico-chemical properties were compared with other solid forms of the API by stress studies. Both physical and chemical stability was satisfying, selecting the cocrystal as a drug form comparable with the form used in the original drug product.
While the cocrystal with fumaric acid was an undesired phase in the developed drug product, the cocrystal with (S)-mandelic acid was chosen as the form with optimal properties for formulation. The drug products formulated within cocrystals of APIs are officially not yet marketed (apart from pharmaceutical salts being in their nature rather cocrystalline), but pharmaceutical industry has already adapted to large scale cocrystal production and formulation.