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Anti-solvent crystallization is widely used in the pharmaceutical industry for high yield production. However, addition methods to control polymorph in anti-solvent crystallization have not been discussed enough. In this study, indomethacin (IMC), which has three polymorphs ( α -form, α ′-form and γ -form) was used. The purpose of this study is to establish a production method of the required polymorph ( γ -form). Acetone was used as the original solvent and heptane was used as the anti-solvent. In order to prevent the α - or α ′-form deposition, the solution compositions must not exceed the solubility of the α - or α ′-form, respectively. A simulation was performed to determine the anti-solvent addition rate, which satisfies these solution conditions based on the ternary phase diagram. Experiments were carried out using four different kinds of addition methods. Method A, B and C were performed under isothermal condition but they have different anti-solvent addition methods. Method D was continuous addition at the constant rate with a particular temperature profile. In order to determine both the anti-solvent addition rate and a temperature profile, the temperature dependent ternary phase diagram was determined. Using this phase diagram and the simulation, the required polymorph was successfully obtained in the anti-solvent crystallization with a certain level of yield. |
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