A Cambridge Structural Database (CSD) analysis was conducted in order to evaluate the hierarchy of supramolecular heterosynthons that involve two of the most relevant functional groups in the context of active pharmaceutical ingredients, carboxylic acids and alcohols, in competitive environments. The study revealed that 34% of the 5690 molecular carboxylic acid entries and 26% of the 25 035 molecular alcohol entries form supramolecular homosynthons, whereas the remaining entries form supramolecular heterosynthons with other functional groups, in particular Narom, CONH2, C−O−C, CO, and chloride anions. Further refinement of this raw data revealed the following: 98% occurrence of the COOH···Narom supramolecular heterosynthon in the 126 crystal structures that contain acid and pyridine moieties in the absence of other hydrogen bond donors or acceptors; and 78% occurrence of the OH···Narom supramolecular heterosynthon in 228 crystal structures that contain hydroxyl and pyridine moieties (excluding intramolecular hydrogen bonding). Such high frequencies indicate that these supramolecular heterosynthons are strongly favored over their respective COOH···COOH and OH···OH supramolecular homosynthons. However, the CSD does not contain enough information to evaluate the predictability of even common supramolecular heterosynthons in the presence of competing hydrogen bonding moieties; for example, there are only 15 entries when -COOH, -OH, and Narom moieties are present exclusively (no other hydrogen bond donors and acceptors groups) in a molecule. We have addressed the competition between the COOH···Narom and the OH···Narom supramolecular heterosynthons by analyzing these 15 entries in CSD and characterizing 15 new compounds (cocrystals 1−13; salts 14 and 15) that are composed of cocrystal formers which contain a permutation of -COOH, -OH and Narom functional groups. Analysis of this group of compounds reveals that supramolecular heterosynthons are favored over the respective supramolecular homosynthons. We also address the methodologies that can be used to prepare 1−15 in the context of solvent evaporation, solvent-drop grinding, and slurrying.

This contribution addresses the role of water molecules in crystal engineering by studying the crystal structures and thermal stabilities of 11 new cocrystal hydrates, all of which were characterized by single crystal X-ray crystallography, powder X-ray diffraction (PXRD), infrared spectroscopy (IR), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC). The cocrystal hydrates can be grouped into four categories based upon thermal stability: (1) water is lost at <100 °C; (2) water is lost between 100 and 120 °C; (3) water is lost at >120 °C; (4) dehydration occurs concurrently with the melt of the cocrystal. In order to address if there is any correlation between structure and stability, the following factors were considered: type of hydrate (tunnel hydrate or isolated hydrate); number of hydrogen bond donors and acceptors; hydrogen bond distances; packing efficiency. Category 1 hydrates exhibit water molecules in tunnels. However, no structure/stability correlations exist in any of the other categories of hydrate. To complement the cocrystal hydrates reported herein, a Cambridge Structural Database (CSD) analysis was conducted in order to address the supramolecular heterosynthons that water molecules exhibit with two of the most relevant functional groups in the context of active pharmaceutical ingredients, carboxylic acids, and alcohols. The CSD analysis suggests that, unlike cocrystals, there is great diversity in the supramolecular heterosynthons exhibited by water molecules when they form hydrogen bonds with carboxylic acids or alcohols. It can therefore be concluded that the promiscuity of water molecules in terms of their supramolecular synthons and their unpredictable thermal stability makes them a special challenge in the context of crystal engineering.

Whereas carboxylic acids are well explored in the context of cocrystals, the same cannot be said about carboxylate moieties. This Cambridge Structural Database (CSD) and experimental study demonstrates that carboxylate moieties persistently form charge-assisted H-bonds with weakly acidic hydroxyl moieties such as phenols. CSD statistics reveal that 58 of 103 relevant structures exhibit carboxylate-hydroxyl (phenolic) supramolecular heterosynthons even in the presence of competing functional groups. The following neutral cocrystal formers sustain 15 new cocrystals of zwitterions and their crystal structures reveal that all exhibit carboxylate-hydroxyl supramolecular heterosynthons: citric acid (CIT), L-ascorbic acid (ASC), hesperetin (HES), quercetin (QUE), resveratrol (RES), catechol (CAT), protocatechuic acid (PCA), ferulic acid (FER), ellagic acid (ELA), and gallic acid (GAL). Zwitterions used were betaine (BTN), sarcosine (SAR), dimethyl glycine (DMG), baclofen (BAC), nicotinic acid (NAC), and isonicotinic acid (INA). Carboxylate-hydroxyl supramolecular heterosynthons were observed as follows: 2-point carboxylate-vicinal diol R 2 2 (9) in ASCSAR, ASCNAC, and BTNASC; R 4 4 (18) between two carboxylate and two catechol moieties in BTNGAL, ELASAR, and ELADMG; CITINA 3 2H 2 O, GALINA 3 H 2 O, and HESNAC (þ and ( forms) exhibit 1-point H-bonds.

The goal was to investigate the correlation between molecular mobility and physical stability in amorphous itraconazole and identify the specific mobility mode responsible for its instability. The molecular mobility of amorphous itraconazole, in the glassy as well as the supercooled liquid state, was comprehensively characterized using dynamic dielectric spectroscopy. Isothermal frequency sweeps in the 5-40 °C temperature range revealed a β-relaxation which exhibited Arrhenius temperature dependence. As the temperature approached T(g), β-relaxation became progressively less resolved due to interference from the high frequency tail of the α-relaxation and then transformed into an excess wing. Above T(g), nonlinear temperature dependence of the α-relaxation was described by the Vogel-Tammann-Fulcher (VTF) model. Itraconazole was found to be a fragile glass former with a VTF strength parameter of ∼4. Isothermal crystallization kinetics, at several temperatures over the range of 75 to 95 °C, was best described by the 3-dimensional nucleation and growth model. Primary relaxation appeared to be the mobility responsible for the observed physical instability at temperatures above T(g) as indicated by the linear correlation of α-relaxation with both crystallization onset and kinetics (represented by the inverse of the crystallization rate constant). A strong coupling between global mobility and crystallization onset was evident. However, for growth kinetics, the coupling was less pronounced, indicating the involvement of factors other than global mobility.

Caffeine-oxalic acid cocrystal, widely reported to be stable under high humidity, dissociated in the presence of numerous pharmaceutical excipients. In cocrystal-excipient binary systems, the water mediated dissociation reaction occurred under pharmaceutically relevant storage conditions. Powder X-ray diffractometry was used to identify the dissociated products obtained as a consequence of coformer-excipient interaction. The proposed cocrystal dissociation mechanism involved water sorption, dissolution of cocrystal and excipient in the sorbed water, proton transfer from oxalic acid to the excipient, and formation of metal salts and caffeine hydrate. In compressed tablets with magnesium stearate, the cocrystal dissociation was readily discerned from the appearance of peaks attributable to caffeine hydrate and stearic acid. Neutral excipients provide an avenue to circumvent the risk of water mediated cocrystal dissociation.

The most abundant polyphenol in green tea, epigallocatechin-3-gallate (EGCg), has recently received considerable attention due to the discovery of numerous health-promoting bioactivities. Despite reports of its poor oral bioavailability, EGCg has been included in many dietary supplement formulations. Conventional preformulation methods have been employed to improve the bioavailability of EGCg. However, these methods have limitations that hinder the development of EGCg as an effective therapeutic agent. In this study, we have utilized the basic concepts of crystal engineering and several crystallization techniques to screen for various solid crystalline forms of EGCg and evaluated the efficacy of crystal engineering for modulating the pharmacokinetics of EGCg. We synthesized and characterized seven previously undescribed crystal forms of EGCg including the pure crystal structure of EGCg. The aqueous solubility profiles of four new EGCg cocrystals were determined. These cocrystals were subsequently dosed at 100 mg EGCg per kg body weight in rats, and the plasma levels were monitored over the course of eight hours following the single oral dose. Two of the EGCg cocrystals were found to exhibit modest improvements in relative bioavailability. Further, cocrystallization resulted in marked effects on pharmacokinetic parameters including Cmax, Tmax, area under curve, relative bioavailability, and apparent terminal half-life. Our findings suggest that modulation of the pharmacokinetic profile of EGCg is possible using cocrystallization and that it offers certain opportunities that could be useful during its development as a therapeutic agent.

Gallic acid monohydrate is the first tetramorphic hydrate for which fractional coordinates have been determined, and analysis of the hydrogen bonding patterns in these and other polymorphic hydrates suggests that waters of hydration are a nemesis to crystal engineers.

Supramolecular assemblies of 1,2,4,5-benzenetetracarboxylic acid, 1, with aza donor molecules such as 1,10-phenanthroline, 2, 1,7-phenanthroline, 3, phenazine, 4, 4-(N,N-dimethylamino)pyridine, 5, 1,2-bis(4-pyridyl)ethene, 6, and 1,2-bis(4-pyridyl)ethane, 7, have been synthesized and characterized by single-crystal X-ray diffraction methods. All the complexes crystallize in the triclinic, Ponemacr; space group. In the complexes of 2 and 4, water is also present in the resultant assembly, but the complexes of 5, 6, and 7 crystallize without any water molecules or solvent of crystallization. However, 3 forms two types of complexes, a hydrate and a nonhydrate complex, depending upon whether water is used as a solvent or not. These assemblies divide into two classes, host-guest systems (with aza molecules being in the channels created by the acid molecules) and assemblies with infinite molecular tapes. While the assemblies of the compounds 2, 4, and 5 belong to the former class, the assemblies of compounds 6 and 7 form molecular tapes, which are arranged in two dimensions to form sheet structures. The two structures of 3, in fact, bridge the two classes with each one falling into different categories.