Preparation and Characterization of Two Crystalline Forms of 4-Amino-5-chloro-2-methoxy-N-[(2S, 4S)-1-ethyl-2-hydroxymethyl-4-pyrrolidinyl]benzamide (TKS159)

Toshiharu YANAGI; Jun-ichi MIZOGUCHI; Tsutomu ADACHI; Seiji SATO; Kazuya KODAMA; Kinsei ANZAI; Yasushi TAKAGISHI; Chiaki KAMEI; Manabu FUJIWARA; Takayuki MATSUSHITA; Yuko YAMASHOJI; Yoshihisa INOUE

doi:10.1248/cpb.48.366

Toshiharu YANAGI, Jun-ichi MIZOGUCHI, Tsutomu ADACHI, Seiji SATO, Kazuya KODAMA, Kinsei ANZAI, Yasushi TAKAGISHI, Chiaki KAMEI, Manabu FUJIWARA, Takayuki MATSUSHITA, Yuko YAMASHOJI, Yoshihisa INOUE

Author information

Toshiharu YANAGI
Jun-ichi MIZOGUCHI
Tsutomu ADACHI
Seiji SATO
Kazuya KODAMA
Kinsei ANZAI
Yasushi TAKAGISHI
Chiaki KAMEI
Manabu FUJIWARA
Takayuki MATSUSHITA
Yuko YAMASHOJI
Yoshihisa INOUE
Author's Organization：
Research and Development Department, Teikoku Chemical Industries Co., Ltd., :Department of Pharmacology, Faculty of Pharmaceutical Sciences, Okayama University
Research and Development Department, Teikoku Chemical Industries Co., Ltd.,
Research and Development Department, Teikoku Chemical Industries Co., Ltd.,
Research and Development Department, Teikoku Chemical Industries Co., Ltd.,
Research and Development Department, Teikoku Chemical Industries Co., Ltd.,
Research and Development Department, Teikoku Chemical Industries Co., Ltd.,
Research and Development Department, Teikoku Chemical Industries Co., Ltd.,
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Okayama University
Department of Materials Chemistry, Faculty of Science and Technology, Ryukoku University
Department of Materials Chemistry, Faculty of Science and Technology, Ryukoku University
Department of Molecular Chemistry, Faculty of Engineering, Osaka University
Department of Molecular Chemistry, Faculty of Engineering, Osaka University

Keywords: TKS159, polymorph, X-ray powder diffractometry, thermal analysis, ^<13>C-NMR spectroscopy, 4-amino-5-chloro-2-methoxy-N-[(2S, 4S)-1-ethyl-2-hydroxymethyl-4-pyrrolidinyl]benzamide

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2000 Volume 48 Issue 3 Pages 366-369

DOI https://doi.org/10.1248/cpb.48.366

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Abstract

For 4-amino-5-chloro-2-methoxy-N-[(2S, 4S)-1-ethyl-2-hydroxymethyl-4-pyrrolidinyl]benzamide (TKS159), two polymorphs, forms α and β, were prepared and characterized by means of X-ray powder diffractometry, thermal analysis, infrared spectroscopy and ¹³C-NMR spectroscoy, both in the solution and solid phases. The X-ray powder diffraction analysis gave different patterns for forms α and β. In the thermogravimetry and differential thermal analysis profiles, form β exhibited characteristic endo- and exothermic peaks at 112.7°C and 116.2°C, respectively, due to the partial melting-induced phase transition to form α without accompanying weight loss, and these were followed by an additional endothermic peak at 138.2°C due to fusion. For form α, only an endothermic peak at 137.8°C due to fusion was observed. The IR spectroscopic analyses of forms α and β gave different absorption bands assigned to N-H and O-H stretching, N-H bending, and C=O stretching vibrations. From the data obtained by thermal analysis, form α was shown to be thermodynamically more stable than form β.

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