Two types of solvates for the antiangiogenesis drug apatinib mesylate were obtained, and their crystal structures were determined by single-crystal X-ray diffraction. The properties of these solvates were fully characterized by powder X-ray diffraction, dynamic vapor sorption, differential scanning calorimetry, and thermogravimetric analysis. Experimental and theoretical studies were performed on the solvates to understand the phase transitions induced by heat and humidity. An irreversible humidity-induced single-crystal-to-single-crystal transformation from ethanol solvate (type II) to monohydrate (type I) was elucidated. The stability of these solvates, including moisture-dependent and thermal stability, was studied. The comprehensive investigation of the solvates and hydrate provided essential knowledge about quality control of this important drug.

•New 2,3-difluorophenyl-linker compound derived from olaparib with good anti-tumor activities in both BRCA1 and BRCA2-mutated xenograft model was discovered.•The difluorobenzylphthalazinone fragment was the main metabolic site and aromatic hydroxylation was a major metabolic pathway.Poly (ADP-ribose) polymerase 1 (PARP1) is overexpressed in a variety of cancers, especially breast and ovarian cancers, and tumor cell lines deficient in breast cancer gene 1/2 (BRCA1/2) are highly sensitive to PARP1 inhibition. In this study, with the help of molecular docking, we identified a novel series of 2,3-difluorophenyl-linker analogues (15–54) derived from olaparib (1) as PARP1 inhibitors. Lead optimization led to the identification of 47, which showed high selectivity and high potency against PARP1 enzyme (IC50 = 1.3 nM), V-C8 cells (IC50 = 0.003 nM), Capan-1 cells (IC50 = 7.1 nM) and MDA-MB-436 cells (IC50 = 0.2 nM). Compound 47 had more potent PARP1-DNA trapping and double-strand breaks (DSBs)-induction activities than 1 and induced G2/M arrest and caspase-dependent apoptosis. Compound 47 (50 mg/kg, 94.2%) had a more beneficial effect on tumor growth inhibition than 1 (100 mg/kg, 65.0%) in a BRCA1-mutated xenograft model and significantly inhibited tumor growth (40 mg/kg, 48.1%) in a BRCA2-mutated xenograft model, with no negative influence on the body weight of the mice. Collectively, these data demonstrated that 47 might be an excellent drug candidate for the treatment of cancer, especially for BRCA-deficient tumors.Download high-res image (212KB)Download full-size image

Apatinib mesylate (ATM) is an orally administrated anticancer agent for the treatment of advanced gastric cancer. Single-crystal structures of four ATM solid forms, including two anhydrous polymorphs (I and II) and hydrates (HA and HB), were elucidated by single-crystal X-ray diffraction. The properties of these various forms were fully characterized by powder X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, Fourier transform-infrared spectroscopy, and Raman spectroscopy. The discrepant molecule conformations, H-bonding interactions, and packing arrangements in the crystal structures were analyzed associated with the hygroscopicity of forms I and II. Various form transformations induced by either moisture or solution conditions were examined, and the relative stability was established. The results revealed that HA is the most thermodynamically stable form and is superior to the currently marketed form.

Agomelatine is a new and novel non-SSRI potential treatment option for major depressive disorders, discovered and developed by Servier Laboratories with first marketing approval in 2009. In this work, the solution-mediated crystal form I to II transformation process was studied. The influence factors, such as system temperature, crystallization solvents, and some pharmaceutical excipients, were investigated. DSC, XRPD, SEM, react IR, and in situ FBRM were used to monitor the transformation process. Compared with crystal form I of agomelatine, form II was the thermodynamic stable one, therefore, the transformation was a spontaneous process. By increasing the system temperature and/or the volume ratio of IPA in the solvent mixture, the transformation process would be accelerated. Lactose hydrate and HPMC would slightly inhibit the transformation, while PVP K30 would accelerate transformation process by increasing the solubility.

The solubility data of two forms of MTX in ethanol, isopropanol, ethyl acetate and toluene was measured over the temperature range from 283.15 K to 323.15 K using shake flask method under atmospheric pressure. The experimental results indicated that the solubility of both forms of MTX increased as the temperature increased. And it was clear that the solubility of form B was lower than the solubility of form A at the same state. The experimental data was correlated by the modified Apelblat equation, the polynomial equation and the Buchowski–Ksiazczak λh equation. All these thermodynamic models gave satisfactory correlation results, with the polynomial equation showing better fitting degree than the other two equations. The results of thermodynamic parameters (△Hd > 0, △Sd > 0, △Gd > 0) indicated an endothermic, entropy driven and nonspontaneous dissolution process of MTX in selected pure solvents.

The polymorphism of sofosbuvir has been investigated. Three polymorphs have been identified and characterized by X-ray powder diffraction (XRPD) and thermal analysis. Form A and Form B were determined as enantiotropic systems according to the Heat of Fusion Rule. The melting data and isobaric heat capacities of both polymorph have been determined calorimetrically, and the solubility data of each polymorph in water at different temperatures have been determined. With these data, the transition temperature (Ttr) was then estimated using solubility extrapolation method, heat of transition (ΔHtr) method, melting data method, and configurational free energy (Gc) phase diagram method. The values of Ttr were found to be 93.29, 90.59, and 108.37 °C for the first three methods, respectively. In the Gc phase diagram method case, Ttr was found to be 109.25 °C when eq 19 was used compared to 109.28 °C when eq 20 was used.

Solubility of agomelatine crystal form II in five pure solvents and (isopropanol + water) binary mixtures was measured from 273.15 K to 313.15 K. The temperature and molar fraction of isopropanol were kept lower range to ensure that no polymorphic transformation would be observed during measuring solubility of form I, which would be determined by XRPD. Thus, solubility of form I was determined under temperature range (from 273.15 K to 293.15 K) in the same binary mixtures with lower molar fraction of isopropanol. All of experimental solubility were correlated by modified Apelblat equation. In addition, the change of molar enthalpy of agomelatine during dissolution was calculated by the empirical parameters of modified Apelblat equation. Furthermore, compared with solubility of form II in the same solvent system, solubility of form I is approximately twice higher than solubility of form II in isopropanol (xB = 0.0494 and 0.0642) + water binary mixtures under the temperature range (from 273.15 K to 293.15 K).

At the temperature range (273.15 to 308.15) K, the solubility of amorphous clopidogrel hydrogen sulfate (CHS) in pure 1-butanol, 2-butanol, 2-propanol, methyl acetate, ethyl acetate, acetone, and methyl tert-butyl ether (MTBE) were experimentally measured. The order of solubility of amorphous CHS is 1-butanol > acetone > 2-propanol > 2-butanol > methyl acetate > ethyl acetate > MTBE, which is in good agreement with the orders of CHS crystalline forms in the literature. However, the solubility of the amorphous ones is dozens of times higher than that of crystals, respectively. In addition, the modified Apelblat equation was used to correlate the temperature with the mole fraction solubility. Finally, the thermodynamic parameters were calculated by the fitting parameters of the modified Van’t Hoff equation.