Cocrystal formation

Keywords Solid-state grinding Cocrystal formation Crystal engineering Pharmaceutical materials Polymorphism... 

As mentioned above, Caira et al. implicated the stability of an ingoing cocrystallisation component as a factor in the preferential formation of a sulfadimidine cocrystal [36]. A year later,in a detailed structural analysis of three anthracene 16 cocrystals, Pedireddi et al. concluded that the ability of potential constituents to satisfy a network of hydrogen bonds dictated solid-state cocrystal formation [43]. Cocrystallisations of anthracene 16 with 4-chloro-3,5-dini-trobenzoic acid 17,3,5-dinitro-4-methylbenzoic acid 18 and 3,5-dinitrobenzoic... 

Lacking a meta constituent, it is clear that 19 alone cannot satisfy an analogous ring of continuous intermolecular interactions aroimd anthracene. Hence, no cocrystalhsation occurred by sohd-state grinding, and the incorporation of a benzene solvent molecule upon solution evaporation was necessary to permit cocrystalhsation (Fig. 4c). The authors thus attributed the lack of cocrystal formation by solid-state grinding to an inabihty of reactants to satisfy the desired intermolecular interactions, rather than the relative stabihty of reactants. 

Without stepping into any nomenclature controversies, for the purposes of this review, cocrystal systems will be regarded as those mixed crystal systems where the individual components exist as solids under ambient conditions [11]. Aakeroy has summarized guidelines for cocrystal formation from supramolecular synthons as being constructed from discrete neutral molecular species that are solids at ambient temperatures, and where the cocrystal is a structurally homogeneous crystalline material that contains the building blocks in definite stoichiometric amounts [12],... 

Of course, not all methods of cocrystal production require the use of auxiliary solvents. Thermal microscopy was used to determine if a particular carboxylic acid could cocrystallize with 2-[4-(4-chloro-2-fluorophe-noxy)phenyl]pyrimidine-4-carboxamide, with positive interactions being detected as crystalline material being produced at the binary interface [35]. Once identified, authentic cocrystal systems were prepared on a larger scale using solution-phase methods. In a similar study, hot-state microscopy was used to screen the possible interactions of nicotinamide with seven compounds of pharmaceutical interest that contained carboxylic acid groups [36]. A screening method for cocrystal formation based on differential scanning calorimetry has also been described, and used to demonstrate cocrystal formation in 16 out of 20 tested binary systems [37],... 

V.R. Pedireddi, W. Jones, A.P. Chorlton, R. Docherty, Creation of crystalline supramolecular arrays a comparison of cocrystal formation from solution and by solid-state grinding, Chem. Commun. (1996) 987-988. 

A. Jayasankar, A. Somwangthanaroj, Z.J. Shao, N. Rodriguez-Hornedo, Cocrystal formation during cogrinding and storage is mediated by amorphous phase, Pharm. Res. 23 (2006) 2381-2392. 

A.V. Trask, J. van de Streek, W.D.S. Motherwell, W. Jones, Achieving polymorphic and stoichiometric diversity in cocrystal formation importance of solid-state grinding, powder X-ray structure determination, and seeding, Cryst. Growth Des. 5 (2005) 2233-2241. 

An a priori prediction for cocrystal formation has been reported that is based on intermolecular pair interactions that have been characterized using pulsed gradient spin-echo nuclear magnetic resonance, and tested against the conventional ionization constant guideline for 25 molecular pairs [17]. This approach was shown to work well even in different... 

If is well known fhat this amide-containing compound forms cocrystal products with a variety of compounds, and fhe continued study within this system is being used to develop greater degrees of understanding about cocrystal formation. 

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. 

The observation that molecules which crystallize with more than one molecule in the crystallographic asymmetric unit exhibit a greater tendency toward cocrystal formation relative to compounds that crystallize in the pure form with one molecule in the imit has been investigated by categorizing such instances as contained in the Cambridge Structural Database [46]. The results of this analysis were experimentally demonstrated by isolation of the 1 1 cocrystal product formed by omidazole... 

T. Friscic, W. Jones, Recent advances in understanding the mechanism of cocrystal formation via grinding, Cryst. Growth Des. 9 (2009) 1621-1637. 

T. Friscic, S.L. Childs, S.A.A. Rizvi, W. Jones, The role of solvent in mechanochemical and sonochemical cocrystal formation a solubility-based approach for predicting cocrystallization outcome, CrystEngComm 11 (2009) 418M26. 

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. 

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... 

Examination of the crystal structures of solvates reveals hydrogen-bonding arrangements that can be applied to cocrystal formation. In many solvates, the solvent molecule is hydrogen-bonded to the API molecule, as shown for water or acetone in the CBZ structures in Figs. 6A and B. The solvent molecule is held by the exterior N-H... O hydrogen bond and occupies the space between two pairs of CBZ carboxamide homodimers. These solvates of CBZ confirm that the propensity of an API molecule to form solvates is related to molecular structures, hydrogen bond patterns. 

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. 

Fig. 15 compares the experimental and predicted cocrystal solubilities had solution complexation been neglected, according to Eq. (25). This analysis shows that 1 1 solution complexation of cocrystal components increases the solubility of a 1 1 cocrystal by a constant, which is the product of K p and ATn. Thus, when the solubility of cocrystal is known only in pure solvent, the K p estimate is useful in assessing the dependence of cocrystal solubility on ligand concentrations. This is valuable in identifying the ligand concentrations in pharmaceutical processes and formulations where cocrystal formation can occur. 

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