Investigation of an Amide-Pseudo Amide Hydrogen Bonding Motif within a Series of Theophylline:Amide Cocrystals

Abstract

The pharmaceutically active compound theophylline (T) was cocrystallized with the amides formamide (1), acetamide (2), N-methylformamide (3), N,N-dimethylformamide (4), benzamide (5), and pyrazinamide (6), with systems T:1, T:5, and T:6 displaying polymorphic behavior. The cocrystals with formamide (T:1), acetamide (T:2), and benzamide (T:5), and one polymorph of the cocrystal with pyrazinamide (T:6-I), contain an R 2 2 (9) hydrogen bonding motif between the amide cocrystal formers and the HN−C−CO moiety of the theophylline molecule (an amide-pseudo amide synthon). This motif was, however, absent from the other polymorph of the pyrazinamide cocrystal (T:6-II) and also from the N-methylformamide cocrystal (T:3) (and is not possible in the N,N-dimethylformamide cocrystal (T:4)). These observations are rationalized using hydrogen bond propensity calculations, although limitations of using such calculations for predicting cocrystallization are noted. The amide-pseudo amide synthon is favored when theophylline cocrystallizes with both primary amides and with secondary amides which are locked in a cis configuration. On heating, all cocrystals were found to dissociate before melting due to loss of the amide, making stability to dissociation a more meaningful measure of cocrystal stability than melting point for these systems. On dissociation of the cocrystals, theophylline typically crystallizes as the commonly observed polymorph Form II. In the case of the acetamide cocrystal (T:2), however, the rarely observed metastable polymorph, Form V, crystallizes concomitantly with Form II suggesting that cocrystal dissociation on heating could be a strategy for identifying novel polymorphic forms of compounds.

Novel Polymorph of Favipiravir—An Antiviral Medication

“…The tool is based on occurrences of various H-bonded synthons in the Cambridge Structural Database containing more than 1,000,000 crystal structures of small organic and organometallic compounds [ 30 ]. The tool was previously applied for analysis of H-bonding systems in some drug molecules [ 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ]. The results of ranking synthons by propensity for the favipiravir molecule are listed in Table 2 .…”

The phase relationship between the pyrazinamide polymorphs α and γ

“…Cocrystals containing pyrazinamide with carboxylic acids (Abourahma et al, 2015;Adalder et al, 2012;Kulla et al, 2016;Luo and Sun, 2013), with haloperfluorinated compounds (Choquesillo-Lazarte et al, 2017), with hydrochlorothiazide (Wang et al, 2014), with pyrogallol (Thakuria et al, 2012) and with diflunisal (Évora et al, 2011) have been described. Several polymorphs of cocrystals of PZA with succinic acid (Cherukuvada and Nangia, 2012;Luo and Sun, 2013), malonic acid (Kulla et al, 2017) and theophylline (Eddleston et al, 2015) have been found and investigated. Different binary mixtures leading to either cocrystals or eutectic systems have been described by Rajbongshi et al (Rajbongshi et al, 2018).…”

First-line antituberculosis drug, pyrazinamide, its pharmaceutically relevant cocrystals and a salt

“…S1-S5 of the supporting information. 2013; Lou et al, 2015;Wang et al, 2014Wang et al, , 2015Abourahma et al, 2011;Luo & Sun, 2013;Eddleston et al, 2016;Aree & Chaichit, 2009;Adalder et al, 2012;Aakerö y et al, 2004;Grobelny et al, 2011;Thakuria et al, 2012;Abourahma et al, 2015;McMahon et al, 2005;Thorat et al, 2015). From the structural analysis of the reported cocrystals it was observed that acid-pyridine (synthon I), acid-acid, amideamide and acid-amide dimers (synthon II, III and IV, respectively) are more common for cocrystals of Pyz containing coformers with acid functionality.…”