Novel Pharmaceutical Cocrystal of Apalutamide, a Nonsteroidal Antiandrogen Drug: Synthesis, Crystal Structure, Dissolution, Stress, and Excipient Compatibility

Abstract

Apalutamide (APA), a second-generation nonsteroidal antiandrogen BCS Class II drug with poor solubility and high permeability. A novel 1:1 cocrystal of Apalutamide (APA) with methylparaben (MP) was identified by cooling crystallization during the cocrystal screening and characterized by various solid-state techniques, such as PXRD, DSC, TGA, FT-IR, and 13C solid-state CP-MAS NMR spectroscopy. The crystal structures of APA and its cocrystal (APA-MP) were determined by the SC-XRD technique. The crystal structure analysis of the APA-MP cocrystal revealed that the APA and MP molecules are connected through strong O–H···O hydrogen bonds. The novel cocrystal improves the solubility and dissolution rate in different physiological conditions compared to poorly soluble APA due to strong hydrogen bond between the drug and the coformer. The cocrystal is stable (physically and chemically) under stress conditions, such as exposure to the relative humidity, mechanical grinding, open exposure to atmosphere at cRT (critical room temperature) and compression pressure of 10 tons. In addition, the compatibility of the cocrystal with excipients used in the drug product of APA (ERLEADA) was also investigated, and no disproportionation of cocrystal was observed.

Understanding the thermal stability of apalutamide crystalline solvates through crystal structure analyses and computational studies

“…2a) and matched with the reported APA structure published recently. 37 The amide N-H⋯O, C-H⋯O, C-H⋯N and C-H⋯S interactions aggregate the apalutamide molecules into the two-dimensional hydrogen-bonded network (Fig. 2b).…”

“…[34][35][36] We have to note that in the course of drafting this manuscript, crystal structures of non-solvated APA (Form B; CSD Refcode: FAVYEK) and its cocrystal with methylparaben (CSD Ref code: FAVYAG) have been published, providing the first instance of crystallographic data in the academic literature as well as the CSD. 37 The lack of structural information on this drug prompted us to undertake a comprehensive screening for different polymorphic modifications and solvates of APA to extend currently known set of the drug's solid forms and to gain deeper knowledge of its structural chemistry. In this work, anhydrous form of apalutamide (APA) and nine solvates namely, apalutamide-dimethylformamide (APA-DMF 2 : 1 & 1 : 1), apalutamide-1,4-dioxane (APA-DOX), apalutamide-N,N-dimethylacetamide (APA-DMA), apalutamide-cyclohexanone (APA-CYH), apalutamideacetonitrile (APA-ACN), apalutamide-acetone (APA-ACE), apalutamide-2-butanol (APA-BUT) and apalutamide-ethanol (APA-EtOH) were obtained and characterized by single-crystal X-ray diffraction (SCXRD) and other analytical techniques, including hot-stage microscopy (HSM), differential scanning calorimetry (DSC) and thermogravimetric analysis (TG).…”

Two Cocrystals of Olaparib with Flavonoids toward Sustained Release: Structure, Dissolution Behavior, and Anticancer Activity Analysis

“…Pharmaceutical cocrystals are multicomponent crystalline substances formed by active pharmaceutical ingredients (APIs) and cocrystal formers (CCFs) in the same crystal lattice according to a fixed stoichiometric ratio. − Drug cocrystals can usually modify the physicochemical properties of APIs without changing the pharmacological properties and have received increased attention from academia and the pharmaceutical industry. , Cocrystallization of APIs with active CCFs, such as natural flavonoids, can achieve better biosafety profiles and improved therapeutic efficacy, demonstrating a promising approach to achieve superior therapeutic effects. , Currently, many researchers have focused on improving APIs’ solubility and dissolution, − and fewer studies have been conducted to reduce the release rate through drug cocrystals. , Compared with slow-release technologies such as film coating technology, osmotic pump technology, and nanotechnology, , cocrystallization technology has high flexibility and a simple production process, and can also reduce the use of excipients …”

Stable Fatty Acid Solvates of Dasatinib, a Tyrosine Kinase Inhibitor: Prediction, Process, and Physicochemical Properties

“…3,4 Pharmaceutical molecules belonging to BCS Classes I and III are ideal over those of classes II and IV in terms of their better biopharmaceutical properties. 5 Several methods such as molecular modification 6,7 (acceptable salts with ionizable molecules), change in solid-state forms 8 (crystalline to amorphous, metastable polymorphs), cocrystallization, 9 solvate formation with pharmaceutically acceptable solvents, 10 and solid dispersions 11−13 have been reported in the literature for improving apparent solubility and dissolution rate. Among the above approaches, solvate formation (pseudopolymorph) is one of the useful methods to improve physicochemical properties.…”

“…Several methods such as molecular modification , (acceptable salts with ionizable molecules), change in solid-state forms (crystalline to amorphous, metastable polymorphs), co-crystallization, solvate formation with pharmaceutically acceptable solvents, and solid dispersions − have been reported in the literature for improving apparent solubility and dissolution rate. Among the above approaches, solvate formation (pseudopolymorph) is one of the useful methods to improve physicochemical properties. − Solvate formation is achieved when drug substances are exposed to different solvents during the crystallization process. , The crystallization process includes fast solvent evaporation, slow solvent evaporation, recrystallization from the required solvent, vapor diffusion, solvent/antisolvent precipitation, cooling crystallization, and slurry-mediated solvate formation .…”