Exploring Solid Form Landscape of Anticancer Drug Dimethylaminomicheliolide Fumarate: Crystal Structures Analysis, Phase Transformation Behavior, and Physicochemical Properties Characterization

Abstract

Brain tumors are still the deadliest among all types of cancer even after decades of extensive research. Glioblastoma is the most common and aggressive form of primary malignant brain tumors. As an efficient NF-κB inhibitor, dimethylaminomicheliolide fumarate has shown excellent therapeutic effect for glioblastoma in clinical trials. To date, no reports about the solid forms of dimethylaminomicheliolide fumarate have been disclosed. Dimethylaminomicheliolide fumarate was thus an interesting subject for polymorphism exploration. In this work, four solid forms (Forms B, C, D, and E) were successfully obtained. The crystal structures exhibit similarity in molecular conformation and packing arrangements between Form C and Form E. The PXRD patterns and phase transition behavior suggest that Form B and Form D are likely to have similarities. Hirshfeld surfaces were generated for a better understanding of the relationships of different crystal forms. They were also characterized and evaluated by thermal analysis, polarizing microscope, and dynamic vapor sorption as well as powder properties tests. The comprehensive exploration of the solid form landscape provided essential knowledge for product development and quality control of this potential drug.

Two anhydrous forms and one monohydrate of a cocrystal of axitinib and glutaric acid: characterization, property evaluation and phase transition study

“…Hirshfeld surface analysis is a useful tool to understand the intermolecular contacts in a quantified visible manner. 39–41 Hirshfeld surface analysis based on the single crystal structures of AXI-GA·H 2 O and AXI-GA I was carried out. The 2D fingerprint plots are graphed in Fig.…”

Structural Insights into the Highly Solvating System of Axitinib via Binary and Ternary Solvates

“…Although many solvates cannot be used directly due to the toxicity, it is still an important part to develop the polymorph landscape of API, and some are the precursors to form specific polymorphs. 7 In particular, determination of the relative stability of polymorphs is sufficient to prevent unexpected solid forms after the approval of a drug. 8,9 Furthermore, formation of solvate can develop the morphology and particle size of the crystals, leading to crystal products with a narrow and homogeneous particle size distribution.…”

“…Finding as many solid forms as possible is an essential step in the active pharmaceutical ingredient (API) development, as different polymorphs, hydrates, and solvates show different properties, such as densities, hygroscopicity, stability, mechanical properties, solubility, and bioavailability. − In addition, solvates may inevitably be formed during the solution crystallization process, causing considerable interest to study. Although many solvates cannot be used directly due to the toxicity, it is still an important part to develop the polymorph landscape of API, and some are the precursors to form specific polymorphs . In particular, determination of the relative stability of polymorphs is sufficient to prevent unexpected solid forms after the approval of a drug. , Furthermore, formation of solvate can develop the morphology and particle size of the crystals, leading to crystal products with a narrow and homogeneous particle size distribution .…”

Highly Efficient Production of Desired Solid Forms of Drugs with Improved Mechanical Properties via an Organic Solvent-Free Sublimation Process

“…The calibration of the instrument using indium and zinc was performed to check the measurement accuracy of temperature and enthalpy prior to measurement. The 1 H and 13 C nuclear magnetic resonance (NMR) spectra were recorded in dimethyl sulfoxide-d 6 using a Bruker AVANCE III (400 MHz) spectrometer. The crystal morphologies of PZA polymorphs (α, δ, γ) were simulated from their crystal structures (CSD codes PYRZIN, 53 PYRZIN02 54 and PYRZIN17, 51 respectively) using the Bravais− Friedel−Donnay−Harker (BFDH) model.…”

“…The bioavailability, processability, and shelf life of active pharmaceutical ingredients (APIs) depend upon the use of crystalline form. It is thereby essential to conduct thorough and reliable solid-state form screening at an early preformulation stage of new drug development, identifying the most suitable crystalline form for further development. − In addition, new drug candidates can be scarce and invaluable at this stage in which the minimized use of drug candidate is often required. Therefore, it is particularly crucial to develop highly efficient screening and production methods for solid-state forms of drugs with the least possible amount of sample.…”