Cocrystal melting point

Other hand, when an equimolar mixture of 2,5-DSP and l OEt is recrystallized from benzene, yellow crystals, comprising 2,5-DSP and l OEt in a molar ratio of 1 2, deposit. In the DSC curve of this crystal, a single endothermic peak is observed at 166°C, which is different from the melting point of either 2,5-DSP (223°C) or l OEt (156°C). Furthermore, the X-ray powder diffraction pattern of the crystal is quite different from those of the homocrystals 2,5-DSP and l OEt. Upon irradiation the cocrystal 2,5-DSP-l OEt affords a crystalline polymer (77i h = 1.0 dl g in trifluoroacetic acid). The nmr spectrum of the polymer coincides perfectly with that of a 1 2 mixture of poly-2,5-DSP and poly-1 OEt. In the dimer, only 2,5-DSP-dimer and l OEt-dimer are detected by hplc analysis, but the corresponding cross-dimer consisting of 2,5-DSP and l OEt is not detected at all (Hasegawa et al., 1993). These observations by nmr and hplc indicate that the photoproduct obtained from the cocrystal 2,5-DSP-l OEt is not a copolymer but a mixture of poly-2,5-DSP and poly-l OEt in the ratio 1 2. 

A. Lemmerer, N.B. Bathori, S.A. Bourne, Chiral carboxylic acids and their effects on melting-point behavior in cocrystals with isonicotinamide, Acta Cryst. B64 (2008) 780-790. 

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. 

The melting points of carbamazepine nicotinamide (CBZ NCT) and carbamazepine saccharin (CBZ SAC) cocrystals lie in between the melting points of the pure component phases. ° CBZ NCT melts at... 

Papageorgiou GZ, Achilias DS, Karayannidis GP. Melting point depression and cocrystal-lizafion behavior of poly(ethylene-co-butylene... 

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. 

Finally, in order to find a way of fine-tuning melting point and aqueous solubility of a representative. A, of a family of anticancer compounds, Aakeroy and coworkers reported the synthesis of five cocrystals with aliphatic, even-chained, dicarboxylic acids. The supramolecular synthesis was driven by the well-known COOH- py hydrogen-bond-based synthon, and in each reported case, infinite APT diacid- API- diacid chains were obtained, and these were subsequently arranged into 2D layers driven by API-based self-complementary amide- amide hydrogen bonds (Scheme 23). 

The structural consistency in the series of five cocrystals implies that differences in physical properties of the cocrystals may be, to a first approximation, directly related to difference in molecular properties of the cocrystallizing agent (the diacid). The subsequent study of thermal properties confirms this approach (Scheme 24) as the highest melting cocrystal contains the dicarboxylic add with the highest melting point. The relationship between molecular structure and the bulk property shows a strong positive correlation. 

Scheme 24 Melting points of five cocrystals A1-A5 as a function of melting point of the corresponding carboxylic acid (1 = succinic acid, 2 = adipic acid, 3 = sebacic acid, 4 = suberic acid, 5 = dodecanedioic acid).

Figure 16 Comparison between point alternation of dicar-boxylic acids (black triangle) and of the cocrystals (white triangle). The melting of [N(CH2CH2)3N]-H-[OOC(CH2)4COOH] corresponds to the melting point of an uncharacterized form, resulting from two subsequent and very close phase-transition processes. (Reproduced from Ref. 97. WUey-VCH, 2003.)...

The application of LAG to form co-crystals of low-solubility APIs was further demonstrated using the model compound theobromine (Figure 8.5(a)). Grinding theobromine with trifluoroacetic and malonic acid resulted in cocrystals, while none were obtained by crystallisation from solution. Additionally, because of the high melting point of theobromine (>400°Q the two co-crystals could not be obtained from the melt. The inability to obtain the two co-crystals from solution also prevented their structural characterisation through single crystal X-ray diffraction. 

Comparison of melting point data of the neutral organic acids and of the cocrystals and salts discussed herein yields another interesting observation. As shown in Fig. 17, the melting points of compounds 1C3-1C9 follow a trend very similar to that of the acids, i.e. they show an alternation of melting points as a function of the even-odd carbon chain length. 

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