Transferability of cocrystallization propensities between aromatic and heteroaromatic amides

Structural Chemistry, Apr 2016

New virtual cocrystal screening was proposed taking advantage of the similarities between cocrystallization landscapes of different compounds. Assuming that cocrystallization propensities can be modeled by miscibility affinities of liquid components under supercooled conditions, the quantitative rules of likeness were formulated and validated for 45 aromatic and heteroaromatic amides interacting with a variety of coformers. The most important finding comes from the observed linear trends between the values of mixing enthalpies of amides with respect to a reference molecule. Particularly isonicotinamide was found as a very convenient comparative system since it constitutes 97 binary cocrystals. Many experimentally observed cocrystals were used for supporting the analogy hypothesis, which states that a properly selected reference molecule, for which cocrystals were experimentally documented, can provide practical information about cocrystallization propensities of another compound provided that two criterions are met, namely sufficiently high similarities and high enough affinities. Hence, it is not necessary to perform experimental cocrystallization of every pair of coformers since miscibility in the solid state of one compound can be transferred to another one at least in the case of aromatic or hetero-aromatic amides.

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Transferability of cocrystallization propensities between aromatic and heteroaromatic amides

Struct Chem Transferability of cocrystallization propensities between aromatic and heteroaromatic amides Piotr Cysewski 0 1 0 Chair and Department of Physical Chemistry, Pharmacy Faculty, Collegium Medicum of Bydgoszcz, Nicolaus Copernicus University in Torun ́ , Kurpin ́skiego 5, 85-950 Bydgoszcz , Poland 1 & Piotr Cysewski New virtual cocrystal screening was proposed taking advantage of the similarities between cocrystallization landscapes of different compounds. Assuming that cocrystallization propensities can be modeled by miscibility affinities of liquid components under supercooled conditions, the quantitative rules of likeness were formulated and validated for 45 aromatic and heteroaromatic amides interacting with a variety of coformers. The most important finding comes from the observed linear trends between the values of mixing enthalpies of amides with respect to a reference molecule. Particularly isonicotinamide was found as a very convenient comparative system since it constitutes 97 binary cocrystals. Many experimentally observed cocrystals were used for supporting the analogy hypothesis, which states that a properly selected reference molecule, for which cocrystals were experimentally documented, can provide practical information about cocrystallization propensities of another compound provided that two criterions are met, namely sufficiently high similarities and high enough affinities. Hence, it is not necessary to perform experimental cocrystallization of every pair of coformers since miscibility in the solid state of one compound can be transferred Cocrystal screening; Mixing enthalpy; COSMO-RS; Active pharmaceutical ingredients; Amides; Solubility - to another one at least in the case of aromatic or heteroaromatic amides. Introduction Cocrystals are important products of materials science, and many branches of industry take advantage [ 1 ] of the possibility of tuning properties of solids [ 2 ]. This covers, among other domains, the pharmaceutical [ 3, 4 ], agrochemical [ 5, 6 ] or high-energy industries [ 6–8 ]. Not all multicomponent solids are classified as cocrystals [ 9 ] since at least two criterions must be met [ 9–13 ]. First of all, after cocrystallization, the molded homogeneous phase should comprise stoichiometric proportions of the components. Besides, all coformers should be solids under ambient conditions. The possibility of alteration of the physicochemical properties after successful cocrystallization is especially welcomed in the case of active pharmaceutical ingredients (API). There are many examples of significant improvements of API behaviors both in vivo and in vitro [ 14, 15 ] due to enhancement of pharmacokinetic properties as solubility [ 4, 16, 17 ] and bioavailability [ 18–20 ]. Also many other physicochemical properties can be modulated by cocrystallization including stability [ 21–24 ], hygroscopicity [ 25 ] and prolonged shelf life [ 26 ]. Among many drugs, aromatic amides acting either as APIs or as excipients attract nowadays substantial attention [ 27–35 ]. These compounds are known for their important roles in medical applications. For example, vitamin B3 or PP are synonyms for nicotinamide, which is an important compound functioning as a component of the coenzyme NAD [ 36 ]. Pyrazinamide with its bacteriostatic and bacteriocidal activities, acting as an efficient antitubercular agent [ 37 ], was also recognized as an important medication. Also salicylamide and ethenzamide are known as analgesic and antipyretic drugs [ 38 ]. They are used as non-prescription painkillers belonging to nonsteroidal anti-inflammatory agents with medicinal uses similar to those of aspirin. Temozolomide, known under different brand names as Temodar, Temodal or Temcad, is an orally administered alkylating agent used in chemotherapy for treatment of some types of brain cancer and a first-line treatment for glioblastoma multiforme [ 39, 40 ]. Majority of aromatic or heteroaromatic amides are poorly soluble in water, and cocrystallization with more soluble formers might be one of the remedies for this limitation [ 4 ]. Although many pharmaceutical cocrystals containing amides have been studied [ 27–35 ], the data deposited in the Cambridge Structural Database (CSD) [ 41 ] are rather variable in the sense that many coformers were used for synthesis of diverse cocrystals. For example cocrystals of fumaric acid with benzamide, isonicotinamide or nicotinamide are known under refcodes YOPBUB, LUNNOX and EDAPOQ, respectively, but there is no information about solids of these coformers with temozolomide. There are information about 4-hydroxybenzoic acid and 4-nitrobenzoic acid cocrystallization with isonicotinamide, but cocrystal of nicotinamide is known only with the former compound. There are many such ‘‘gaps,’’ which can be highlighted by retrieving of corresponding data from the latest edition of the CSD. Of course, lack of the structu (...truncated)


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Piotr Cysewski. Transferability of cocrystallization propensities between aromatic and heteroaromatic amides, Structural Chemistry, 2016, pp. 1403-1412, Volume 27, Issue 5, DOI: 10.1007/s11224-016-0760-7