Cocrystal properties

Relatively high molecular weight is a feature of the chemotype exemplified by 4-11 and this can require creative formulation techniques. Pharmacokinetic properties of a lead candidate (structure unknown) from the same series that provided 10 were inadequate to provide sufficient exposures at high doses to support preclinical safety studies. However, cocrystal formulations with saccharin or gentisic acid improved water solubility by 50-fold and increased oral exposures up to 10-fold relative to traditional formulations at 20mg/kg [64]. 

In an extraordinarily comprehensive review of polymorph screening procedures, it has been reported that during the conduct of 245 polymorph screens, about 90% of the systems studied exhibited multiple crystalline and noncrystalline forms, and about 50% exhibited polymorphism [38]. As to cocrystal screening, it was concluded that it is most efficient to use a combination of structural and physical property evaluation methods in conjunction with screening protocols similar to those used to detect new polymorphic forms. Data from 64 cocrystal screening studies were considered, and it was shown that cocrystals were found in 61% of the studied systems. 

In one study, a solvent evaporation method was used to produce cocrystals of nicotinamide with ibuprofen (2-(4-isobutylphenyl)propanoic acid) [53]. The properties of the cocrystal could be studied in the solid state, but the synthon proved to be too weak to survive in fluid solutions. Nevertheless, the solubility of ibuprofen was enhanced by 62 times when the nicotinamide concentration was 13.3 mg/ml, suggesting that the... 

As part of a more extensive study of cocrystals formed by isonicotinamide with carboxylic acids, 1 1 products containing the dicarboxylic fumaric or succinic acids [59]. In the structures of these particular cocrystals, the typical discrete dimeric synthon was not observed, but instead effectively infinite assemblies of one-dimensional chains were found instead. In a subsequent work, cocrystals of isonicotinamide containing mixed fumaric/succinic acids were prepared using both solid-state grinding and solution crystallization [60]. A full physical characterization of the products demonstrated that the products consisted of a single cocrystal phase, and were not simple physical mixtures of two cocrystal components. Such solid solutions were proposed as yet another method whereby one might obtain even finer control over the physical properties of cocrystal systems proposed as drug substances. 

In a demonstration of the pharmaceutical advantage that can be realized through the use of a cocrystal form of a substance, it was shown that the 1 1 cocrystal of caffeine and methyl gallate exhibited significantly improved powder compaction properties [64], The compression characteristics of the cocrystal were reported to be excellent over the entire pressure range studied, with the tablet tensile strength of the cocrystal being twice that of caffeine at pressures less than 200 MPa. The superior compaction properties of the cocrystal product were attributed to the presence of slip planes in crystal structure. 

Given the insolubility of indomethacin, a number of formulation approaches have been taken to improve the physical properties of this nonsteroidal anti-inflammatory drug substance. A 1 1 cocrystal was successfully prepared with saccharin using both solid-state dry grinding and... 

Itraconazole (Sporanox, 13.11) is an approved antifungal (Figure 13.5). The drug has a log P value of 6.5, so its very low aqueous solubility is no surprise. Early efforts to improve the properties of itraconazole focused on making an acid salt. Because of the very weak basicity of all the nitrogens in itraconazole, the idea of an acid salt was soon abandoned. Cocrystals were then explored. A library of amides and acids were... 

As scientists become more aware of a substantial expansion in the scope of solid-state structural variations that can be obtained through the cocrystallization of several molecules in a single lattice structure, studies of the mixed molecular crystal systems known as cocrystals have mushroomed [1-3]. Along these lines, workers have researched the assembly of supramolecular symthons and crystal engineering in ever-increasing efforts to produce materials having new and useful properties [4],... 

The mixed-crystal system formed by indomethacin and saccharin (l,2-benzisothiazol-3(2H)-one-l,1-dioxide) has been used to evaluate the feasibility of using supercritical fluids as media for the design and preparation of new cocrystals [44]. In this work, the relative merits of supercritical fluid processes (i.e., cocrystallization with a supercritical solvent, supercritical fluid as anti-solvent, and the atomization and anti-solvent technique) were evaluated, as well as the influence of processing parameters on product formation and particle properties of the yields. It was reported that while the anti-solvent and atomization procedures yielded pure cocrystal products, only partial to no cocrystal formation took place when using the crystallization process. 

N. Schultheiss, A. Newman, Pharmaceutical cocrystals and their physicochemical properties, Cryst. Growth Des. 9 (2009) 2950-2967. 

We will first describe some of the theoretical aspects for cocrystal design, followed by a summary of the pharmaceutical properties of cocrystals, including their solubility dependence on cocrystal component concentration and in some cases on solution pH. Processes for cocrystal formation will be presented by considering the factors that control cocrystallization kinetics and mechanisms in solution and in solid-state mediated processes. This article will be useful to the reader who wishes to anticipate cocrystal formation during pharmaceutical processes and storage and to those who wish to proactively discover new phases. 

While establishing molecular networks for cocrystal design and determining crystal structures is very important, the value of cocrystals of pharmaceutical components lies in the ability to tailor the functionality of materials. In contrast to polymorphs that have the same chemical composition, cocrystals do not. As such, one would expect that with cocrystals one could introduce greater changes in material properties than with polymorphs. Properties that relate to pharmaceutical performance and that can be controlled by cocrystal formation include melting point, solubility, dissolution, chemical stability, hygroscopicity, mechanical properties, and bioavailability. The cocrystals for which pharmaceutical properties have been studied are few and some of these are presented below. Clearly further research in this area is needed. 

Cocrystals Design, Properties and Formation Mechanisms Carbamazepine... 

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