Solubility Enhancement of Anticancer Drug Belinostat via the Co-crystallization Strategy: Synthesis, Characterization, and Antitumor Activity In Vitro Evaluation

Abstract

Belinostat (PXD101), a biopharmaceutical classification system II (BCSII) drug approved for treating refractory T-cell lymphoma, is currently administered by intravenous injection. To improve patient compliance, the development of oral formulations of PXD101 has attracted attention. Because the solubility and dissolution rate of active pharmaceutical ingredients can affect the therapeutic effect of the oral formulations, this work explores solid-state form modification of PXD101 by co-crystallization with four coformers, namely, theophylline, isonicotinamide (INA), isoniazid (INH), and l-proline (l-Pro) to solve the problem of poor water solubility. The four cocrystals were obtained on the basis of N–H···O, O–H···O, and O–H···N synthons. All the four obtained multicomponent crystals were characterized by powder X-ray diffraction (PXRD) and thermal analysis, meanwhile, crystal structure determination was performed by single-crystal XRD. The results of CrystalCMP show the similar packing patterns of PXD101-INA and PXD101-INH cocrystals. The data analysis from powder dissolution experiments suggested that the apparent solubility of the obtained multicomponent crystals is 1.14–2.22 times more than that of PXD101, and PXD101-l-Pro shows a completely different dissolution behavior from that of the other three cocrystals. Finally, 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay experiments demonstrated that the PXD101-INA cocrystal can significantly inhibit the proliferation of Michigan Cancer Foundation-7 (MCF-7) cells even at a low concentration (0.01 μM). Such results shed light on the potential value of multicomponent crystals in the further development of pharmaceutical products.

Exploring New Solid Forms of Antirheumatic Drug Hydroxychloroquine: Novel Salts with Sustained‐Release Performance

“…The analysis of the PXRD data was done using Jade 6.0 software. [34] Synthesis of HCQ Salts-Thermal Analysis: DSC analyses were performed on the TA (Q2000) instrument. [35] 1-3 mg samples were sealed and heated in an aluminum pan at a constant rate of 10 °C min −1 (under nitrogen flow of 50 mL min −1 ).…”

Salt Cocrystal and Salt of Marbofloxacin with Butenedioic Acid: Impact of cis–trans Isomerism of Coformer on the Conformation and Properties of Marbofloxacin

“…Differences in the effects of different coformers on the physicochemical properties of pharmaceutical cocrystals make it possible to modulate the physicochemical behavior of active pharmaceutical ingredients (APIs) at the molecular scale. − The importance of discovering the rule of different coformers affecting the physicochemical properties of APIs provides an impetus to move forward in the study of pharmaceutical cocrystals/salts. Pharmaceutical cocrystallization technology has the advantage of being faster, more cost-effective, and efficient as a means of improving the physicochemical properties of APIs without chemical modification. , In fact, the physicochemical properties of the crystal form of APIs are essentially dependent on the conformation of the molecules, packing arrangements, and the strength of the intermolecular interactions, , which implies that through the effective control of the crystal arrangement by suitable coformers, multiple and comprehensive tuning of the properties can be achieved. However, the regulation of API physical and chemical properties by pharmaceutical cocrystals/salts is not always better, and there are some cocrystals for which the solubility, dissolution, or permeability is reduced or remains unchanged. − The same is true for salt cocrystals, a pharmaceutical cocrystalline form that differs from pharmaceutical cocrystals (nonionic supramolecules) and salts (anion and cation) by having a salt structure with a neutral molecule. − As often happens, it is hard to predict the changes in the arrangement and physicochemical properties of pharmaceutical molecules in cocrystals/salt produced by coformers.…”

“…Pharmaceutical cocrystallization technology has the advantage of being faster, more cost-effective, and efficient as a means of improving the physicochemical properties of APIs without chemical modification. 4,5 In fact, the physicochemical properties of the crystal form of APIs are essentially dependent on the conformation of the molecules, packing arrangements, and the strength of the intermolecular interactions, 6,7 which implies that through the effective control of the crystal arrangement by suitable coformers, multiple and comprehensive tuning of the properties can be achieved. However, the regulation of API physical and chemical properties by pharmaceutical cocrystals/salts is not always better, and there are some cocrystals for which the solubility, dissolution, or permeability is reduced or remains unchanged.…”