Effects of Impurities on Crystal Polymorphism of an Imidazopyridine Derivative Developed as a Drug Substance for Osteoporosis
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- Machiya Koji
- Department of Applied Chemistry and Bioengineering, Graduate School of Engineering, Osaka City University Process Chemistry Laboratories, Astellas Pharma Inc.
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- Ieda Shigeru
- Process Chemistry Laboratories, Astellas Pharma Inc.
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- Hirano Masaru
- Department of Applied Chemistry and Bioengineering, Graduate School of Engineering, Osaka City University
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- Ooshima Hiroshi
- Department of Applied Chemistry and Bioengineering, Graduate School of Engineering, Osaka City University
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Abstract
A drug substance, (8-(2,6-dichlorobenzoyl-amino)-3-hydroxymethyl-2-trifluoromethylimidazo [1,2-a] pyridine (named BPPI)), developed for osteoporosis treatment, has two crystal polymorphs: an unstable B01-form and a stable B02-form. In the early stage of development, only the B01-form was always obtained from an ethanol/water solution. However, after improvements in purity of BPPI, only the B02-form was obtained. Four major impurities incorporated in the B01-form are identified and 4 analogues of BPPI are separately synthesized. The inhibitory effects on the solvent-mediated transformation of the B01-form to the B02-form are examined to explain the disappearance of the B01-form and the new appearance of the B02-form. As a result, it is found that the dimer of BPPI, which was a by-product of the last reaction of BPPI synthesis, had inhibited nucleation of the B02-form crystals. 0.107 mg/mL of dimer completely inhibited the transformation of the B01-form. The inhibitory effect of the dimer on the nucleation of the B02-form is discussed by focusing on the failure of two intermolecular hydrogen bondings that should be formed in the B02-form crystal.
Journal
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- JOURNAL OF CHEMICAL ENGINEERING OF JAPAN
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JOURNAL OF CHEMICAL ENGINEERING OF JAPAN 42 (3), 147-152, 2009
The Society of Chemical Engineers, Japan
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Keywords
Details 詳細情報について
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- CRID
- 1390282679546668160
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- NII Article ID
- 10025305749
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- NII Book ID
- AA00709658
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- ISSN
- 18811299
- 00219592
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- NDL BIB ID
- 10191434
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- Text Lang
- en
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- Data Source
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- JaLC
- NDL
- Crossref
- CiNii Articles
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- Abstract License Flag
- Disallowed