Cocrystal solvates

Examples of other organic materials prepared by mechanochemical procedures, for which stmcture determination has been carried out directly from powder XRD data, include a hydrate cocrystal of 5-methyl-2-pyridone and trimesic acid, which was prepared by grinding a methanol solvate cocrystal of the same components... 

Aakeroy and coworkers used the seven new cocrystals of 1,4-diiodotetrafluorobenzene they discovered to critically discuss the progress made in the field, and to comment on challenges that remain unsolved [22]. The goal of the work was to match the desired supramo-lecular outcome with a strategy for synthesis of the intended system, and the investigators were able to obtain the anticipated intermolecular interactions in several cases. The crystallization of one intended system was complicated by the production of a solvated crystal form, and it was concluded that the serendipitous inclusion of solvent molecules in a crystal lattice was not always predictable, and the outcome not always favorable. 

Trimesic acid 5-Methyl-2-pyridone Structure of a new cocrystal product generated by solid-state grinding of the methanol solvate cocrystal [52]... 

A pharmaceutical cocrystal is composed of an API and complementary molecules including excipients (non-toxic ingredients) or other APIs. Cocrystals may include two or more different components and in most cases to date, two and three component systems are reported with the latter being mostly cocrystalline solvates, e.g., theophylline 5-fluorouracil hydrate. Table 1 presents some examples of pharmaceutical cocrystals and solvates. The term cocrystal generally refers to components that in their pure states are solids at room temperature. It is important to note that a... 

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. 

Fig. 6 Molecular interactions in carbamazepine cocrystals and solvates (A) dihydrate, (B) acetone solvate, (C) carbamazepine saccharin, (D) carbamazepine nicotinamide, (E) carbamazepine acetic acid, and (F) carbamazepine trimesic acid. (Reproduced from Ref...

Here, [A]t- = S and [B]j = 5 -f C as shown in Eq. (6), and the subscript T stands for total concentration in solution. This solubility behavior resembles that of the common ion effect in the case of sparingly soluble salts. But in contrast with the case of salts and that of solvates where analogous equilibria have been considered,cocrystals dissociate into primary components (at least two different molecules) that can crystallize as single component phases. 

This requirement may be deemed overly restrictive but it does offer an important distinction between solvates and cocrystals. However, in same cases, notably in the work by Boese and coworkers, it is clear that in their elegant work using low-temperature crystallizations they intentionally prepare co-crystals with a very clear and deliberate strategy (see e.g. M. T. Kirchner, R. Boese, A. Gehrke, D. Blaeser, CrystEngComm. 2004, 6, 360.)... 

AA -di(m-nitrophenyl)urea or DNPU (dinitrophenyl urea) exists in three concomitant polymorphic forms (a, and S) of different colours [25], It readily forms solvates and cocrystals with compounds having strong to moderate hydrogen bond acceptors [26], The characteristic urea network is absent except in the noncentrosymmetric /3-polymorph of DNPU whereas a and y polymorphs are sustained by N-H- -Onitro H bonds. We examined hydrogen bond competition in crystal structures of N-X-phenyl-A -p-nitrophenyl urea, abbreviated as PNPU-X [27] (Figure 5.15). A variety of X groups were considered. 

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. 

During drag development it is often desirable to identify solvents, which do not form solvates with a specific drag. Thermodynamically, solvate formation and cocrystal formation are strongly related and differ only by the fact that for solvates one of the reactants is liquid at the temperature of the experiment and thus having by definition a free energy of fusion AGg =0. Therefore, the just presented workflow for cocrystals can as well be applied to assess the potential or risk of solvents to form solvates. 

---