The effect of hydroxypropyl methylcellulose (HPMC) and methylcellulose (Methocel ® 60 HG) on the dissolution behavior of two cocrystals derived from nitazoxanide (NTZ), viz., nitazoxanide-glutaric acid (NTZ-GLU, 1:1) and nitazoxanide-succinic acid (NTZ-SUC, 2:1), was explored. Powder dissolution experiments under non-sink conditions showed similar dissolution profiles for the cocrystals and pure NTZ. However, pre-dissolved cellulosic polymer in the phosphate dissolution medium (pH 7.5) modified the dissolution profile of NTZ when starting from the cocrystals, achieving transient drug supersaturation. Subsequent dissolution studies under sink conditions of polymer-based pharmaceutical powder formulations with NTZ-SUC cocrystals gave a significant improvement of the apparent solubility of NTZ when compared with analogous formulations of pure NTZ and the physical mixture of NTZ and SUC. Scanning electron microscopy and powder X-ray diffraction analysis of samples recovered after the powder dissolution studies showed that the cocrystals undergo fast dissolution, drug supersaturation and precipitation both in the absence and presence of polymer, suggesting that the solubilization enhancement is due to polymer-induced delay of nucleation and crystal growth of the less soluble NTZ form. The study demonstrates that the incorporation of an appropriate excipient in adequate concentration can be a key factor for inducing and maintaining the solubilization of poorly soluble drugs starting from co-crystallized solid forms. In such a way, cocrystals can be suitable for the development of solid dosage forms with improved bioavailability and efficacy in the treatment of important parasitic and viral diseases, among others.

Baclofen (BAC) is an important chiral active pharmaceutical ingredient for the treatment of specific neurological disorders that is commercially available only as RS-BAC (racemate). Using the liquid-assisted grinding technique, combination of RS-BAC with DL-MA in 1:1 stoichiometric ratio yielded a crystalline solid phase mixture of the enantiomeric salts R-BAC:L-MA and S-BAC:D-MA. Single-crystals suitable for SCXRD analysis of R-BAC:L-MA were obtained by fractional crystallization from a solution of RS-BAC and L-MA in a solvent mixture of ethyl acetate and water. Analysis of the supramolecular interaction patterns revealed that the crystal structure is stabilized by strong N+–H···–O, N+–H···O and O–H···–O hydrogen-bonding interactions. A comparative study with structurally related compounds enabled to identify common homo- and heterosynthons involving RNH3 +, OH, and COOH/COO– groups. The spectroscopic, structural and thermogravimetric studies of the enantiomeric solid phase mixture of R-BAC:L-MA and S-BAC:D-MA was accomplished by examination of some basic pharmaceutically relevant physicochemical properties. Phase stability studies in aqueous media simulating the gastrointestinal tract physiological conditions (pH 1.2 and 4.5) showed that R-BAC:L-MA/S-BAC:D-MA transforms into BAC within a few minutes. However, upon exposure to standard thermal/humidity stress conditions, the phases were stable. The decomposition changes the kinetics of the dissolution process under sink conditions, but the calculated intrinsic dissolution rates of RS-BAC and R-BAC:L-MA/S-BAC:L-MA resulted to be quite similar.

A cocrystal of the antihypertensive drug chlorthalidone (CTD) with caffeine (CAF) was obtained (CTD-CAF) by the slurry method, for which a 2:1 stoichiometric ratio was found by powder and single-crystal X-ray diffraction analysis. Cocrystal CTD-CAF showed a supramolecular organization in which CAF molecules are embedded in channels of a 3D network of CTD molecules. The advantage of the cocrystal in comparison to CTD is reflected in a threefold solubility increase and in the dose/solubility ratios, which diminished from near-unit values for D0D to 0.29 for D0CC. Furthermore, dissolution experiments under non-sink conditions showed improved performance of CTD-CAF compared with pure CTD. Subsequent studies showed that CTD-CAF cocrystals transform to CTD form I where CTD precipitation inhibition could be achieved in the presence of pre-dissolved polymer HPMC 80–120 cPs, maintaining supersaturation drug concentrations for at least 180 min. Finally, dissolution experiments under sink conditions unveiled that the CTD-CAF cocrystal induced, in pH-independent manner, faster and more complete CTD dissolution when compared to commercial tablets of CTD. Due to the stability and dissolution behavior of the novel CTD-CAF cocrystal, it could be used to develop solid dosage forms using a lower CTD dose to obtain the same therapeutic response and fewer adverse effects.

Two novel cocrystals of the pharmaceutically active enantiomer R-Praziquantel (R-PZQ) were formed with glutaric acid (R-PZQ/GA) and succinic acid (R-PZQ/SA) in a 1:1 stoichiometric ratio by liquid-assisted mechanical grinding. The characterization of the cocrystals by structural and physicochemical methods revealed properties distinct from the cocrystal analogues with racemic PZQ, i.e., RS-PZQ/GA and RS-PZQ/SA, reported previously in the literature. However, all four cocrystals exhibit improved intrinsic dissolution rates in a medium simulating the physiological conditions of the gastric fluid (pH 1.2) compared to the solid phases of the pristine drug (R-PZQ•0.5H 2 O and RS-PZQ). Nonsink powder dissolution tests showed that the cocrystals with R-and RS-PZQ can generate transient supersaturated solutions with solubility advantages of 1.3-to 2.2-fold compared to the pristine drugs. In the presence of predissolved hydrophobic polymers such as MC60HG and HPC 80,000, the supersaturation state is prolonged for 20−30 min providing solubility advantages of up to 2.7-fold and an even larger advantage compared to the pristine forms of Praziquantel.