Improving the Solubility of Aripiprazole by Multicomponent Crystallization

Aripiprazole (ARI) is a third-generation antipsychotic with few side effects but a poor solubility. Salt formation, as one common form of multicomponent crystals, is an effective strategy to improve pharmacokinetic profiles. In this work, a new ARI salt with adipic acid (ADI) and its acetone hemisolvate were obtained successfully, along with a known ARI salt with salicylic acid (SAL). Their comprehensive characterizations were conducted using X-ray diffraction and differential scanning calorimetry. The crystal structures of the ARI-ADI salt acetone hemisolvate and ARI-SAL salt were elucidated by single-crystal X-ray diffraction for the first time, demonstrating the proton transfer from a carboxyl group of acid to ARI piperazine. Theoretical calculations were also performed on weak interactions. Moreover, comparative studies on pharmaceutical properties, including powder hygroscopicity, stability, solubility, and the intrinsic dissolution rate, were carried out. The results indicated that the solubility and intrinsic dissolution rate of the ARI-ADI salt and its acetone hemisolvate significantly improved, clearly outperforming that of the ARI-SAL salt and the untreated ARI. The study presented one potential alternative salt of aripiprazole and provided a potential strategy to increase the solubility of poorly water-soluble drugs.

Discovery, Characterization, and Pharmaceutical Applications of Two Loratadine–Oxalic Acid Cocrystals

Loratadine (Lor) is an antihistamine drug commonly used to relieve the symptoms of allergy. It has high permeability but low solubility under physiological conditions. To overcome the problem of low solubility, we synthesized and characterized two Loratadine multi-component crystalline phases with oxalic acid (Oxa), i.e., a 1:1 Lor-Oxa conjugate acid-base (CAB) cocrystal (Lor-Oxa CAB) and a 2:1 Lor-Oxa cocrystal monohydrate (Lor-Oxa hydrate). Both cocrystals exhibited an enhanced solubility and intrinsic dissolution rate (IDR) compared to Lor and adequate physical stability. The intrinsic dissolution rate of Lor-Oxa CAB is 95 times that of Lor, which makes it a promising candidate for tablet formulation development.

Intrinsic Dissolution Rate Profiling of Poorly Water-Soluble Compounds in Biorelevant Dissolution Media

The intrinsic dissolution rate (IDR) of active pharmaceutical ingredients (API) is a key property that aids in early drug development, especially selecting formulation strategies to improve dissolution and thereby drug absorption in the intestine. Here, we developed a robust method for rapid, medium throughput screening of IDR and established the largest IDR dataset in open literature to date that can be used for pharmaceutical computational modeling. Eighteen compounds with diverse physicochemical properties were studied in both fasted and fed state simulated intestinal fluids. Dissolution profiles were measured in small-scale experimental assays using compound suspensions or discs. IDR measurements were not solely linked to API solubility in either dissolution media. Multivariate data analysis revealed that IDR strongly depends on compound partitioning into bile salt and phospholipid micelles in the simulated intestinal fluids, a process that in turn is governed by API lipophilicity, hydrophobicity, and ionization.

Mechanochemical Formation of Racemic Praziquantel Hemihydrate with Improved Biopharmaceutical Properties

Praziquantel (PZQ) is the first-line drug used against schistosomiasis, one of the most common parasitic diseases in the world. A series of crystalline structures including two new polymorphs of the pure drug and a series of cocrystals of PZQ have been discovered and deposited in the Cambridge Structural Database (CSD). This work adds to the list of multicomponent forms of PZQ a relevant example of a racemic hemihydrate (PZQ-HH), obtainable from commercial PZQ (polymorphic Form A) through mechanochemistry. Noteworthy, the formation of the new hemihydrate strongly depends on the initial polymorphic form of PZQ and on the experimental conditions used. The new PZQ-HH has been fully characterized by means of HPLC, Differential Scanning Calorimetry (DSC), Thermogravimetric Analysis (TGA), Hot-Stage Microscopy (SEM), Powder X-Ray Diffraction (PXRD), Scanning Electron Microscopy (SEM), FT-IR, polarimetry, solid-state NMR (SS-NMR), solubility and intrinsic dissolution rate (IDR), and in vitro tests on Schistosoma mansoni adults. The crystal structure was solved from the powder X-ray diffraction pattern and validated by periodic-DFT calculations. The new bioactive hemihydrate was physically stable for three months and showed peculiar biopharmaceutical features including enhanced solubility and a double intrinsic dissolution rate in water in comparison to the commercially available PZQ Form A.