| Co-Investigator(Kenkyū-buntansha) |
MATSUOKA Masakuni Tokyo University of Agriculture and Technology, Institute of Symbiotic Science and Technology, Professor, 大学院共生科学技術研究院, 教授 (40016671)
HADA Maiko Tokyo University of Agriculture and Technology, Institute of Symbiotic Science and Technology, Assistant Professor, 大学院共生科学技術研究院, 助手 (90365883)
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| Budget Amount *help |
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2006: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2005: ¥2,400,000 (Direct Cost: ¥2,400,000)
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| Research Abstract |
Polymorphism means that a compound has two or more crystal structures. Difference in crystal structures causes changes in crystalline and physicochemical properties. In the pharmaceutical industry, it is necessary to control polymorphs because of their differences in bioavailabilities. Anti-solvent crystallization is widely used in the pharmaceutical industry for high yield production. However, addition methods to control polymorphs in anti-solvent crystallization have not been discussed enough.
In this study, indomethacin, which has three polymorphs, was used. The purpose of this study is to establish a production method of the required polymorph in the anti-solvent crystallization.
Supersaturation was generated by adding anti-solvent. However, in order to obtain only stable form, solution compositions must not exceed the solubility of metastable form. A simulation was performed to determine the anti-solvent addition rate, which satisfied these solution conditions. The simulation was ba
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sed on the ternary phase diagram and the models that expressed the crystallization phenomena from a viewpoint of transport phenomena and mass balances. Experiments were carried out using four different kinds of addition methods. Method A adapted continuous addition at constant rates from the beginning to the end. In the case of Method B, addition rates were changed stepwise. Method C indicates intermittent addition. These three methods were operated at constant temperature.
While the constant temperature methods, stable form crystals were selectively obtained under the conditions determined by the simulations. In Method A and Method B, anti-solvent addition rate could not be high at early stages of experiments. Consequently, at early stages of experiments, anti-solvent addition rate was increased, and stable form was selectively obtained. By using a 3-dimensional (temperature, IMC concentration, and anti-solvent concentration) solubility diagram and the simulation, the required polymorph was successfully obtained in the anti-solvent crystallization. Less
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