Itraconazole Form III Crystallization for Stability
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Solution Overview
Problem
Poorly water-soluble drugs face challenges in oral bioavailability due to limited solubility and stability issues in their amorphous solid dispersion forms, which tend to recrystallize into less stable polymorphs, reducing their effectiveness.
Innovation Solution
A new crystalline form of itraconazole (Form III) is characterized by specific X-ray powder diffraction patterns and prepared through controlled heating of amorphous itraconazole, offering enhanced stability and solubility by inhibiting the formation of less stable polymorphs.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If amorphous solid dispersion is used to increase solubility and dissolution rate, then aqueous solubility and dissolution rate are improved, but physical stability deteriorates due to recrystallization into less stable polymorphs
Solution Approach 1:
The patent applies preliminary action by pre-heating amorphous itraconazole to a controlled temperature (30-100°C) before storage, which induces crystallization into the thermodynamically stable Form III polymorph. This preliminary crystallization prevents subsequent unwanted recrystallization into metastable polymorphs during storage, thereby maintaining physical stability and composition integrity throughout the product shelf life.
2Reliability
If amorphous solid dispersion is used to enhance solubility, then oral bioavailability is improved, but manufacturing precision deteriorates due to difficulty in controlling polymorph formation
Solution Approach 1:
The patent applies parameter changes by precisely controlling the heating temperature parameter (30-100°C) during the crystallization process. This specific temperature range enables selective formation of the desired Form III polymorph with high consistency, achieving manufacturing precision in polymorph control while maintaining the solubility advantages of the amorphous-to-crystalline transition for improved oral bioavailability.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The crystalline Form III of itraconazole exhibits improved physical stability and solubility, potentially increasing oral bioavailability and extending the shelf life of amorphous drug products.
Implementation Method 1
amorphous solids tend to revert back to their low-energy crystalline counterparts during storage, processing and/or dissolution
Implementation Method 2
Upon recrystallization from the amorphous state, the relatively unstable polymorph will form first
Implementation Method 3
characterized by an X-ray powder diffraction (XRPD) pattern comprising three or more peaks at 11.9, 16.7, 17.4, 18.7, 19.1, 20.0 and 21.1 degrees 2θ
Implementation Method 4
X-ray powder diffraction (XRPD) pattern
Implementation Method 5
heating solid amorphous itraconazole at a temperature of from about 30° C. to about 100° C., thereby preparing crystalline Form III
Data Source
AI summary
The present invention provides a new crystalline form of itraconazole as well as the method of making same.