Anhydrates and hemihydrate of tasimelteon: Synthesis, structure, and pharmacokinetic study

Kaihang Liu; Xinbo Zhou; Zhejing Xu; Hongzhen Bai; Jianrong Zhu; Jianming Gu; Guping Tang; Xingang Liu; Xiurong Hu

doi:10.1016/j.jpba.2017.12.035

Anhydrates and hemihydrate of tasimelteon: Synthesis, structure, and pharmacokinetic study

J Pharm Biomed Anal. 2018 Mar 20:151:235-243. doi: 10.1016/j.jpba.2017.12.035.

Authors

Kaihang Liu¹, Xinbo Zhou², Zhejing Xu³, Hongzhen Bai¹, Jianrong Zhu², Jianming Gu¹, Guping Tang¹, Xingang Liu⁴, Xiurong Hu⁵

Affiliations

¹ Department of Chemistry, Zhejiang University, Hangzhou, PR China.
² Zhejiang Jingxin Pharmaceutical Co., Ltd., Xinchang, Zhejiang, PR China.
³ College of Agriculture and Biotechnology, Zhejiang University, Hangzhou, PR China.
⁴ Department of Chemistry, Zhejiang University, Hangzhou, PR China. Electronic address: liuxg@zju.edu.cn.
⁵ Department of Chemistry, Zhejiang University, Hangzhou, PR China. Electronic address: huxiurong@zju.edu.cn.

PMID: 29413972
DOI: 10.1016/j.jpba.2017.12.035

Abstract

Two new crystal forms of tasimelteon TSM-I and TSM-II were reported here. Crystallization of crude in methanol or mixture solvent results in anhydrate crystal form (TSM-I) and hemihydrate crystal form (TSM-II) respectively. To the best of our knowledge, it is the first report about crystalline form of tasimelteon. The two crystal forms were exhaustively characterized by Scanning Electron Microscopy, Fourier Transform Infrared Spectroscopy, Raman Spectra, Differential Scanning Calorimetry, Thermogravimetric Analysis, Solid State NMR Spectroscopy and Powder X-ray diffraction and Single Crystal X-ray Diffraction. Furthermore, the pharmacokinetic behavior of TSM-I and TSM-II in rats were measured. We found that though TSM-II is considerably more soluble than TSM-I under water (pH = 7.0) and pH 1.2 buffer conditions, the bioavailability of TSM-Ivia oral administration was better compared to that of TSM-II.

Keywords: Anhydrates; Hemihydrate; Pharmacokinetic study; Tasimelteon.

MeSH terms

Administration, Oral
Animals
Benzofurans / chemistry*
Benzofurans / pharmacokinetics*
Biological Availability
Calorimetry, Differential Scanning / instrumentation
Calorimetry, Differential Scanning / methods
Chemistry, Pharmaceutical / instrumentation
Chemistry, Pharmaceutical / methods
Crystallization
Crystallography, X-Ray / instrumentation
Crystallography, X-Ray / methods
Cyclopropanes / chemistry*
Cyclopropanes / pharmacokinetics*
Drug Liberation*
Hydrogen-Ion Concentration
Male
Mice
Mice, Inbred BALB C
Microscopy, Electron, Scanning
Receptors, Melatonin / agonists*
Solubility
Spectrophotometry / instrumentation
Spectrophotometry / methods
Water / chemistry

Substances

Benzofurans
Cyclopropanes
Receptors, Melatonin
Water
tasimelteon