Physicochemical Characterization of Tamoxifen Citrate Pseudopolymorphs, Methanolate and Ethanolate

Abstract

During the development process of solid drugs, the most desirable crystal form should be appropriately selected based on the information of physicochemical properties including polymorphism, their salt 1,2) and co-crystal formation 3) of drug candidates, because physicochemical properties can affect efficacy, safety, 4-6) stability, 7,8) manufacturing process 9,10) and quality control. 11) Recently, understanding the polymorphism has been positioned as an important research, since polymorphs and pseudopolymorphs show different physicochemical properties 7,8,[12][13][14][15][16][17][18] including solubility. 6) Generally, a stable polymorph shows low solubility and high stability, and metastable polymorphs exhibit higher solubility and lower stability. From the viewpoint of the manufacturing process, information about organic solvates is also valuable for the selection of a crystallization solvent. Appropriate selection of the crystalline form from polymorphs and pseudopolymorphs should be conducted in order to achieve the purposes of development; this contributes to the improvement of stability, bioavailability and manufacturability.Tamoxifen, (Z )-2-[4-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethylethylamine, is one of the selective estrogen receptor modulators and tamoxifen citrate is widely used as a drug for the treatment of breast cancer. Tamoxifen has also been used as a model pharmaceutical compound for preformulation studies and several researches have been conducted.2,19-23) As for tamoxifen citrate (Fig. 1), two polymorphs, forms A and B, were identified. 24) Previously, we have investigated the photostability of forms A and B, and discussed the difference in photostability from the viewpoint of solid-state UV/Vis absorption spectroscopy.25) Even though tamoxifen citrate is widely used throughout the world, detailed characterization of its polymorphs and pseudopolymorphs has not been reported to the best of our knowledge.In this study, we prepared two novel pseudopolymorphs, methanolate and ethanolate, in addition to forms A and B reported previously. Their crystal forms were identified and characterized by powder and single crystal X-ray diffractometry, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), hot-stage microscopy, scanning electron microscopy (SEM) and diffuse reflectance infrared Fourier-transform spectroscopy (DRIFTS), and their physicochemical stability was also evaluated. ExperimentalPreparation of Modifications Tamoxifen citrate was obtained from EGIS Pharmaceuticals (Budapest, Hungary). All solvents were purchased from Wako Pure Chemical Industries (Osaka, Japan). Form A was bulk powder purchased from EGIS Pharmaceuticals. A small amount of form A for SEM observation was obtained by recrystallizing from saturated acetonitrile solution of the drug by seeding a small amount of bulk powder. Form B was obtained by recrystallizing from saturated isopropyl alcoholic solution of the drug with stirring overnight at room temperature. Form B was then filtrated and dried i...

Polymorphism and Solvatomorphism 2007

“…The crystal structure for the antimigraine agent zolmitripan has been reported,143 as have the structures of its solvates with chloroform144 and with its benzene solvate and phenol co‐crystal 145. The methanol and ethanol solvatomorphs of tamoxifen citrate have been obtained, and their properties and their tendency toward phase transformation of the known nonsolvated crystal forms studied 146…”

The co-crystal of two GRAS substances: (citric acid)·(nicotinamide). Formation of four hydrogen bonding heterosynthons in one co-crystal

“…in the formulation of taxomycin. 14 Other pharmaceutical co-crystals that have been prepared are with caffeine and theophylline. 15 On the other hand, co-crystals of nicotinamide have been prepared with a number of APIs, such as carbamazepine, 16 ethyl-paraben, 17 theophylline 18 and celoxib.…”