Hydrochlorothiazide (HCT) is a diuretic and a BCS class IV drug with low solubility and low permeability, exhibiting poor oral absorption. The present study attempts to improve the physicochemical properties of the drug using a crystal engineering approach with cocrystals. Such multicomponent crystals of HCT with nicotinic acid (NIC), nicotinamide (NCT), 4-aminobenzoic acid (PABA), succinamide (SAM), and resorcinol (RES) were prepared using liquid-assisted grinding, and their solubilities in pH 7.4 buffer were evaluated. Diffusion and membrane permeability were studied using a Franz diffusion cell. Except for the SAM and NIC cocrystals, all other binary systems exhibited improved solubility. All of the cocrystals showed improved diffusion/membrane permeability compared to that of HCT with the exception of the SAM cocrystal. When the solubility was high, as in the case of PABA, NCT, and RES cocrystals, the flux/permeability dropped slightly. This is in agreement with the expected interplay between solubility and permeability. Improved solubility/permeability is attributed to new drug-coformer interactions. Cocrystals of SAM, however, showed poor solubility and flux. This cocrystal contains a primary sulfonamide dimer synthon similar to that of HCT polymorphs, which may be a reason for its unusual behavior. Hirshfeld surface analysis was carried out in all cases to determine whether a correlation exists between cocrystal permeability and drug-coformer interactions.

An elastic organic crystal, 2,6-dichlorobenzylidine-4-fluoro-3-nitroaniline (DFNA), which also shows thermosalient behavior, is studied. The presence of these two distinct properties in the same crystal is unusual and unprecedented because they follow respectively from isotropy and anisotropy in the crystal packing. Therefore, while both properties lead from the crystal structure, the mechanisms for bending and thermosalience are quite independent of one another. Crystals of the low-temperature (α) form of the title compound are bent easily without any signs of fracture with the application of deforming stress, and this bending is within the elastic limit. The crystal structure of the α-form was determined (P21/c, Z = 4, a = 3.927(7) Å, b = 21.98(4) Å, c = 15.32(3) Å). There is an irreversible phase transition at 138 °C of this form to the high-temperature β-form followed by melting at 140 °C. Variable-temperature X-ray powder diffraction was used to investigate the structural changes across the phase transition and, along with an FTIR study, establishes the structure of the β-form. A possible rationale for strain build-up is given. Thermosalient behavior arises from anisotropic changes in the three unit cell parameters across the phase transition, notably an increase in the b axis parameter from 21.98 to 22.30 Å. A rationale is provided for the existence of both elasticity and thermosalience in the same crystal. FTIR studies across the phase transition reveal important mechanistic insights: (i) increased π···π repulsions along [100] lead to expansion along the a axis; (ii) change in alignment of C-Cl and NO2 groups result from density changes; and (iii) competition between short-range repulsive (π···π) interactions and long-range attractive dipolar interactions (C-Cl and NO2) could lie at the origin of the existence of two distinctive properties.

Multicomponent solid forms of the BCS class IV drug furosemide (FSM) were obtained upon liquid assisted grinding with coformers anthranilamide (ANT), 4-toluamide (TOL), 2-picolinamide (PCM), piperazine (PPZ), 2,3,5,6-tetramethylpyrazine (TMPZ), pyrazine (PYZ), 2-picolinic acid (PIC), isoniazid (INZ), and theophylline (THP), and identified with powder X-ray diffraction. Solid forms FSM–TMPZ (2:1), FSM–ANT (1:1), FSM–PPZ (1:1), and FSM–TOL ethanol solvate (1:1:1) were further characterized with single crystal X-ray diffraction and differential scanning calorimetry; a sesquihydrate structure for FSM–PCM (1:1:1.5) was additionally confirmed with thermogravimetric analysis. The thermodynamically stable form I of FSM contains O–H···O acid···acid and N–H···O sulfonamide dimer synthons and chains. These synthons are modified in the cocrystals/salts sometimes leading to changes in physicochemical properties. The FSM–PPZ (1:1) salt converted to a thermodynamically more stable form FSM–PPZ (2:1) within 1 h. The apparent solubility of FSM–PPZ (1:1) salt is ∼3 times higher than the equilibrium solubility of the thermodynamically stable FSM–PPZ (2:1) salt. The solubilities of FSM–TMPZ and FSM–ANT are comparable to FSM, and this could be linked to coformer solubility. The metastable FSM–PCM sesquihydrate exhibited unusually high FSM concentration in solution as a function of time and as monitored in a slurry experiment. This prolonged presence of FSM in solution is rationalized by a synthon-extended-spring-and-parachute model. Our rationale starts with Nangia’s explanation of the apparently high solubility of pharmaceutical cocrystals based on the simple spring-and-parachute model of Guzman et al. and later detailed by Brouwers et al. We go on to suggest that certain heteromolecular aggregates might well persist in soluble amorphous forms leading to a higher persistence of the drug in solution. Cocrystals/salts with higher solubility show higher values of initial diffusion/flux. A few bases when used as coformers render stable salt/cocrystals that resulted in low solubility/diffusion. In the new solid forms of FSM studied here, solubility and flux are seen to go hand in handan observation of import in drug absorption.

Sildenafil is a drug used to treat erectile dysfunction and pulmonary arterial hypertension. Because of poor aqueous solubility of the drug, the citrate salt, with improved solubility and pharmacokinetics, has been marketed. However, the citrate salt requires an hour to reach its peak plasma concentration. Thus, to improve solubility and bioavailability characteristics, cocrystals and salts of the drug have been prepared by treating aliphatic dicarboxylic acids with sildenafil; the N-methylated piperazine of the drug molecule interacts with the carboxyl group of the acid to form a heterosynthon. Salts are formed with oxalic and fumaric acid; salt monoanions are formed with succinic and glutaric acid. Sildenafil forms cocrystals with longer chain dicarboxylic acids such as adipic, pimelic, suberic, and sebacic acids. Auxiliary stabilization via C-H···O interactions is also present in these cocrystals and salts. Solubility experiments of sildenafil cocrystal/salts were carried out in 0.1N HCl aqueous medium and compared with the solubility of the citrate salt. The glutarate salt and pimelic acid cocrystal dissolve faster than the citrate salt in a two hour dissolution experiment. The glutarate salt exhibits improved solubility (3.2-fold) compared to the citrate salt in water. Solubilities of the binary salts follow an inverse correlation with their melting points, while the solubilities of the cocrystals follow solubilities of the coformer. Pharmacokinetic studies on rats showed that the glutarate salt exhibits doubled plasma AUC values in a single dose within an hour compared to the citrate salt. The high solubility of glutaric acid, in part originating from the strained conformation of the molecule and its high permeability, may be the reason for higher plasma levels of the drug.

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A new multicomponent solid consisting of an antibacterial (norfloxacin) and an antimicrobial (sulfathiazole) was made and characterized with single crystal X-ray diffraction, PXRD, FTIR, and DSC. The title salt shows enhanced solubility in different pH buffers and improved diffusion as well as release and inhibition of bacterial and fungal species relative to the parent drugs. The enhanced in vitro biological properties of the drug-drug salt hydrate may be attributed to the higher extent of its supersaturation with respect to the individual components, which leads to higher diffusion rates.

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There is a need to understand how solvent structuring influences drug presentation in pharmaceutical preparations, and the aim of this study was to characterize the properties of propylene glycol (PG)/water supramolecular structures such that their functional consequences on drug delivery could be assessed. Shifts to higher wavenumbers in the C-H and C-O infrared stretching vibrations of PG (up to 8.6 and 11 cm(-1), respectively) implied that water supramolecular structures were being formed as a consequence of hydrophobic hydration. However, unlike analogous binary solvent systems, water structuring was not enhanced by the presence of the cosolvent. Two discrete populations of supramolecular structures were evident from the infrared spectroscopy: water-rich structures, predominant below a PG volume fraction (f(PG)) of 0.4 (unmoving water bending vibration at 1211 cm(-1)) and PG-rich structures, predominant above 0.4 f(PG) (both C-H and water peaks moved to lower wavenumbers). The un-ionized diclofenac log-linear solubility and transmembrane transport altered dramatically when f(PG) > 0.55 (a 10-fold increase in transport from 0.28 ± 0.06 μg·cm(-2)·h(-1) at 0.2 f(PG) to 2.81 ± 0.16 μg·cm(-2)·h(-1) at 0.9 f(PG)), and this demonstrated the ability of the PG rich supramolecular structures, formed in the PG/water solvent, to specifically modify the behavior of un-ionized diclofenac.