Preparation, Characterization, and Scale-up of Ketoconazole with Enhanced Dissolution and Bioavailability

Autor: James E. Hitt, Shakil A. Saghir, Brian D. Scherzer, Dan A. Markham, Gary B. Kupperblatt, Jonathan C. Evans, Edmund J. Elder
Rok vydání: 2007
Předmět:
Zdroj: Drug Development and Industrial Pharmacy. 33:755-765
ISSN: 1520-5762
0363-9045
DOI: 10.1080/03639040601031882
Popis: Many new molecular entities targeted for pharmaceutical applications face serious development challenges because of poor water solubility. Although particle engineering technologies such as controlled precipitation have been shown to enhance aqueous dissolution and bioavailability of poorly water soluble active pharmaceutical ingredients, the data available are the results of laboratory-scale experiments. These technologies must be evaluated at larger scale to ensure that the property enhancement is scalable and that the modified drugs can be processed on conventional equipment. In experiments using ketoconazole as the model drug, the controlled precipitation process was shown to produce kg-scale modified drug powder with enhanced dissolution comparable to that of lab-scale powder. Ketoconazole was demonstrated to be stable throughout the controlled precipitation process, with a residual methanol level below the ICH limit. The modified crystalline powder can be formulated, and then compressed using conventional high-speed tableting equipment, and the resulting tablets showed bioavailability more than double that of commercial tablets. When appropriately protected from moisture, both the modified powder and tablets prepared from the modified powder showed no change in dissolution performance for at least 6 months following storage at accelerated conditions and for at least 18 months following storage at room temperature.
Databáze: OpenAIRE
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