Cocrystal principles

The carbamazepine-nicotinamide cocrystal system has been used to illustrate a mechanism for the formation of cocrystals, for which nucle-ation and growth of solid products are determined by the combination of the reactant components to reduce the solubility of the intermolecular complex that eventually becomes crystallized [42], The principles were studied through the use of in situ monitoring of the cocrystallization process in solutions, suspensions, slurries, and wet solid phases of the... 

These principles of cocrystal formation were applied to the design of cocrystals of carbamazepine, an API that has the reliable carboxamide synthon (Fig. 4). Carbamazepine (CBZ) is also of interest because of its low water solubility and its well-known four polymorphs and solvates (water and acetone solvates). -" " The crystal packing of CBZ in... 

Studies with other cocrystalline systems are underway, in an effort to confirm the general applicability of these principles, mechanisms, and cocrystallization methods presented here. Transformation to cocrystal from single-component solid reactants has also been observed for sulfadimidine anthranilic acid and sulfadimidine salicylic acid from acetonitrile, ethanol, and water and carbamazepine saccharin from water and O.IN HCl. 

According to Kitaigorodskii s close-packing principle, molecules will pack in a manner that minimizes void space or, in other words, in a way to maximize van der Waals interactions [20]. Hence, effects of both molecular shape and size are important in crystal engineering. For example, since racemic crystals tend to pack into centrosymmetric space groups, this statistical preference was utilized to prepare cocrystal g in Appendix 2, which is a rare molecular compound called a quasiracemate. The formation of cocrystal g was made possible due to the isosteric nature of the isoptopenyl and dimethylamino substituents, indicating that shapes rather than dipoles can be in fact the dominant factor (cf. Ref. 31). 

Considering those attempts, a favorable cocrystal screening approach should satisfy several important aspects it should be comparatively fast to be able to scan molecular libraries in a decent amount of time, accurate, broadly applicable, and ideally based on sound physicochemical principles. 

We will discuss the SSNMR most common experiments used to investigate pharmaceutical compounds, including one- and two-dimensional experiments and relaxation time measurements. Additionally, we will mention some aspects of first principle calculation. Also we highlight the importance of NMR as a multinuclear technique. We will focus on SSNMR applied for charaaerization of new developed active pharmaceutical compounds and formulated drugs. We will pay attention to some particular topics as polymorphism, complexes with cyclodextrin and an emerging issue in pharmaceutical industry as it is the development of cocrystals. NMR crystallography is also discussed. 

Many binary cocrystals based on principles of molecular recognition have, however, been reported, e.g., (a) S. Shan, E. Batchelor, and W. Jones, Tetrahedron Lett.,... 

However, grinding in the presence of a small amount of a liquid phase (liquid-assisted grinding or LAG) was found to be highly efficient for the synthesis of co-crystals, resulting in rapid and quantitative formation of cocrystals, typically within 20 minutes. A suitable illustration of the greater efficiency of LAG for co-crystal screening is the proof-of-principle study of the... 

The most extensive studies of solid-state proton transfer have been undertaken on two types of systems - complexes (salts and cocrystals) of carboxylic acid with nitrogen bases, and carboxylic acid dimers. In the first case, the proton transfer occurs along the unsymmetrical H N, and in the other along a (usually) symmetrical O- -H- -O bond. As both these types of proton transfer can (in principle) also lead to tautomerization, we shall briefly expound the main finds of these studies. 

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