Cocrystallizations Cocrystals

Diphenylurea Crystallization. 1,3-hfsphenylurea (13) is the parent compound of a large family of derivatives, most of which do not cocrystallize with guest molecules (Etter et al. 1990). Even when put into solution with strong hydrogen bond acceptors, e.g., dimethyl sulfoxide (DMSO), triphenylphosphineoxide (TPPO) and tetrahydrofuran (THF), most diphenyl ureas crystallize with other molecules of the same kind in a connectivity pattern viewed as is shown below (14), instead of forming cocrystals (e.g., 15). 

With the recognition that many substances may cocrystallize in a single continuous lattice structure, scientists have more recently initiated intense studies of the mixed molecular crystal systems that have become known as cocrystals [10]. This particular area of solid-state research has led pharmaceutical scientists into the areas of crystal engineering and assembly of appropriate supramolecular synthons, with particular emphasis on understanding the origins of the molecular self-assembly that takes place in the formation of cocrystal systems. 

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],... 

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... 

When two different achiral molecules form a chiral cocrystal by spontaneous chiral cocrystallization, the occurrence of absolute asymmetric intermolecular photoreaction can be expected. In fact, we have achieved enantio- and diastereo-selective photodecarboxylative condensation, as well as absolute asymmetric pho-todecarboxylative condensation. The development of intermolecular photoreao tions leads to an extension of the scope of solid-state chiral photochemistry. Reactivity in a cocrystal is controlled by the crystal packing arrangement, so the key point is the preparation of photoreactive cocrystals. 

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. 

Characterization of the cocrystals obtained using [58] solution crystallization, high-throughput cocrystallization, dry grinding, and solvent-drop grinding... 

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. 

Childs et al. formulated crystalline complexes with a salt form of an API with carboxylic acids. The antidepressant, fluoxetine hydrochloride, was cocrystallized with benzoic acid, succinic acid, and fumaric acid where the chloride ion acts as a hydrogen bond acceptor for the carboxylic acid groups of the three ligands. Intrinsic dissolution studies were carried out at 10°C because at 25°C, the rates were so rapid that the dissolution rates of the cocrystals could not be distinguished from one another. The fumaric acid 2 1 complex had a similar dissolution rate to that of the crystalline fluoxetine hydrochloride, but the dissolution rate for the benzoic acid 1 1 complex was half that of fluoxetine hydrochloride. Fluoxetine hydrochloride succinic acid 2 1 complex had approximately three times higher dissolution rate, but the dissolution was so fast that an accurate value was difficult to measure. ... 

Cocrystallization by mixing solutions of reactants in non-stoichiometric conditions has been shown for CBZ NCT cocrystals from various solvents. Cocrystallization by dissolution of a solid reactant in a solution of the second reactant is shown in Fig. 19 for the cocrystallization of CBZ NCT by dissolving anhydrous CBZ(III) in solutions of nicotinamide at two different supersaturation levels. The higher concentration of NCT in the dissolution/cocrystallization... 

A priori knowledge of the solubility of cocrystal in pure solvent is useful to predict the ligand transition concentration and to determine conditions under which cocrystals dissolve or cocrystallize. Fig. 20 shows... 

Cocrystals can also be prepared in situ in covered depression slides on the polarized optical light microscope or Raman microscope by adding a small drop of solvent to the solid reactants. This has been shown for cocrystals of CBZ NCT with ethanol, ethyl acetate or 2-propanol. Photographs obtained through the polarized light microscope are shown in Fig. 22. These images show cocrystal formation in less than three minutes after solvent addition. In this case, the cocrystallization reaction proceeds by a similar pathway to those of macro-phase suspensions described above. In micro-phases the solvent added must allow for dissolution of both reactants so that concentrations 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. 

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. 

Amorphous phases are attractive to study mechanisms of cocrystal formation because they require very small samples (3-5 mg) and can be prepared and studied in situ (by melt-quenching) in a calorimeter or on a microscope stage. Cocrystallization pathways can then be identified and kinetics measured from the analysis of thermal events, photomicrographs and spectroscopic analysis in real time. An example of the cocrystallization of CBZ NCT from an amorphous film of equimolar composition of reactants is shown in Fig. 24. 

Fig. 27 Cocrystallization of CBZ SAC during storage. Cocrystal formation increases with RH. (Reproduced from Jayasankar, A. Somwangthanaroj, A. Shao, Z.J. Rodriguez-Hornedo, N. Cocrystal formation during cogrinding and storage is mediated by amorphous phase. Pharm. Res. 2006. The original publication is available at www.springerlink.com.)...

Cocrystals are becoming increasingly important as a means of controlling the properties of pharmaceutical solids by designing multiple component molecular networks that introduce the desired functionality. Because cocrystal design is based on supramolecular synthesis, it provides a powerful approach for the proactive discovery of novel pharmaceutical solid phases. Application of the fundamental concepts presented here on cocrystallization processes is essential for the pharmaceutical scientist to anticipate the formation of cocrystals during pharmaceutical processes and storage, as well as to develop reliable methods for cocrystal discovery and production. 

Acridine and phenothiazine cocrystallized to give two kinds of hydrogen-bonded CT crystals. Both crystals showed some photoreactivity and appear to have given many photoproducts (Scheme 18) [44]. Although this crystalline complex is complicated in terms of stoichiometry, crystal structure, and photoreaction, a transient study by femtosecond diffuse reflectance spectroscopy was carried out, as had been done for durene-pyromellitic dianhydride cocrystal [45]. For the yellow cocrystal, a transient absorption spectrum with maxima around 600 and 520 nm was obtained, which decayed biexponentially with lifetimes of 2 and 50 ps. The two absorption maxima were ascribed to the acridine anion radical and the phenothiazine cation radical, respectively. 

Another approach is cocrystallization of a substituted urea (host) and a diacetylene (guest) [48]. Substituted ureas are used to prepare layered diacetylene crystals. Two examples are shown in Scheme 21. Such a host-guest/cocrystal approach to supramolecular synthesis should be general. In this strategy, the host is used to control the structure and the guest provides the function (optical, electrical, chemical, or physical). 

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