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.

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.

Tuberculosis (TB) is one of the major causes of mortality in developing countries. Its high incidence and prevalence turns TB a global health problem. The TB treatment is based on the use of drugs as a fixed-dose combination (FDC) tablet which can simplify the TB treatment. However, one of the main concerns about the use of anti-TB drugs lies in the high hygroscopicity of Ethambutol (ETB) and limited solubility of Ethionamide (ETH). The development of multicomponent crystal forms, e.g. salts and cocrystals, represents an important branch of pharmaceutical sciences as alternative route to improve drug's physicochemical properties (aqueous solubility, hygroscopicity and thermal stability). Salt or cocrystal formation is a process strictly governed by the acidity/basicity of the ionizable groups in the drug and in the salt coformers. In general, pharmaceutical acceptable strong acids are used to protonate a basic drug, such as ETB and ETH and thereby convert it into salts. For ionizable drugs, salt formation is still the most effective low-cost method and consequently the preferential one to increase the low solubility and bioavailability of the parent drug. Based on the crystal engineering approach, we developed novel pharmaceutical salts of Isoniazid (INH), ETH and ETB anti-TB drugs. These salts were crystal engineered and supramolecular synthesized using a series of inorganic and carboxylic acids formers (maleic, nitric, sulfuric and oxalic) in order to overcome the undesirable effects of these drugs. The new salts obtained were study by single crystal X-ray diffraction as well as thermal and spectroscopy analysis. These studies showed that the assembly of ETH maleate salt is dominated by a cyclic tetramer arrangement where two ETH+ cations are alternately linked to two counterions. ETH nitrate crystallized with four independent ionic pairs in the asymmetric unit being the first ETH structure with Z'>1 reported. Each ionic pair is stabilized by a strong pyridinium…NO3-H-bond. Solubility studies show that ETH nitrate salt is about 240-fold more soluble than ETH commercial API. In the INH sulfate salt, the INH+ cations form a rather unexpected R(_2^2)(10) homodimers. The sulfate anions, in turn, bridge these homodimers into a 1-D chain via a R(_2^2)(10) motif formed by pyridinium…SO4-H-bonds. Due to the presence of a much stronger anion-INH+ H-bonds, this salt presents a high melting point (204 oC) when compared than INH parent form (m.p 170 oC). Analysis of the crystal structure and packing of ETB oxalate salt revealed that min this case the ion-pairs (ETB+/OXA-) are stabilized by the expected NH+… COO-synthons. Hygroscopicity tests of the ETB oxalate salt showed that this salt is non-hygroscopic making a suitable candidate for the anti-TB multiple-drug therapy formulation.