Cocrystal Screening

Crystal structure prediction can give insights into molecular packing and the relevant solid-state interactions of cocrystals [46,47] but is yet too time consuming to be of practical use for flexible, multicomponent systems, or even for the screening over several coformers. 

Fabian analyzed cocrystal structures stored within the Cambridge Structural Database, statistically establishing a QSPR-like approach [48], which was reported to yield likely cofoimers in the case of artemisinin [49]. 

Musumeci and coworkers used the molecular electrostatic potential (MEP) of drug and coformer derived from a DFT calculation to identify potential cocrystals by a hierarchical mapping of complementary donor and acceptor sites [50]. 

A study by Seaton relates cocrystal formation with Hanunett constants, which is limited to compounds where such constants are available or measurable [51]. 

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. 

---

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. 

E. Lu, N. Rodriguez-Hornedo, R. Suryanarayanan, A rapid thermal method for cocrystal screening, CrystEngComm 10 (2008) 665-668. 

This article will address key questions concerning pharmaceutical cocrystals (i) Do cocrystals offer any advantages over other solid-state forms (ii) What are the criteria for cocrystal former selection (iii) Can cocrystal screening and crystallization methods be theoretically based and (iv) Can cocrystals form as a result of stresses encountered during pharmaceutical processes and storage ... 

Research on cocrystal formation by cogrinding crystalline components has focused on cocrystal screening and structure determination, and the methods used for cocrystal formation are mostly based on trial and error. Key questions regarding the factors that determine cocrystallization by mechanochemical processes remain to be addressed. 

The CSD-related scientific and software tools developed for polymorph risk mitigation, and cocrystal design, are the central focus of this chapter. We begin with a brief summary of the CSDS, and then discuss (i) the development and application of H-bond propensity analysis, (ii) the study of H-bond landscapes and (iii) informatics-based cocrystal screening. In each case we provide case studies to exemplify the methodology. Ongoing development areas and new opportunities are noted in the section Conclusions and Outlook . 

In both steps of the cocrystal screening method described earlier, coformers are treated individually allowing the effects of differences in, for example, substitution patterns to be considered in the analysis. 

In the following paragraphs, some application examples will be presented, starting with a short introduction to COSMO-RS (Section 9.2), followed by solubility predictions in pure and mixed solvents (Section 9.3). A modification using several reference solubilities is shown in Section 9.4 whereas Section 9.5 is about quantitative structure-property relationship (QSPR) models of the melting point and the enthalpy of fusion. The final Sections 9.6 and 9.7 deal with COSMO-RS-based coformer selection for cocrystal screening and the related issue of solvent selection to avoid solvate formation. 

Those criteria are met by a cocrystal screening based on COSMO-RS theory, using the mixing enthalpy (or equivalently the excess enthalpy of a supercooled cocrystal mixture [18]. The main reason for the predictive capability of this theory concerning cocrystal formation is its accurate description of intermolecular interactions. The idea behind a COSMO-RS-based screening can be best understood by having a look at the thermodynamic cycle shown in Scheme 9.1. 

TABLE 9.6 Results of COSMO-RS-Based Virtual Cocrystal Screenings... 

Computed AUC scores as obtained by comparison with different experimental cocrystal screening sets as taken from the literature, number of coformers in the set (fi, the number of observed cocrystals and references to the experiments are presented. In the last row, the averaged AUC score and the standard deviation are given. Coformers were ranked according to their mixing enthalpy (AUC, and... 

Table 6 Confusion matrix showing the paformance of descriptor-based filtering in cocrystal screening experiments.

The above database results can be translated into simple qualitative rules for selecting co-crystal formers. Choosing co-formers with similar shapes, similar fractional polarities and similar dipole moments to the API should increase the chances of successful co-crystal formation. Because of the relative weakness of the underlying trends, a large number of experiments is required to demonstrate convincingly that consideration of these factors improves the success rate of cocrystal screening experiments. 

Co-crystals represent a novel class of crystalline solids which possess scientific and regulatory advantages along with enormous intellectual property potential. In the earlier stages of pharmaceutical process development, an efficient cocrystal screening is essential in order to determine the different possible stoichiometries and the different polymorphic forms for each stoichiometry. When all the different phases are identified, the relative stability of the solid phases in solution has to be determined. This step requires the construction of the... 

---