A nanoparticle engineering process: Spray-freezing into liquid to enhance the dissolution of poorly water soluble drugs.

摘要

It is estimated that about 40% of compounds being developed by the pharmaceutical industry are poorly water soluble. A limiting factor in the oral bioavailability of poorly water soluble compounds is their inadequate dissolution rates. Increasing the dissolution rate of poorly water soluble active pharmaceutical ingredients (APIs) has become a major challenge in pharmaceutical formulation development. The spray freezing into liquid (SFL) particle engineering process was developed to enhance the wetting and dissolution properties of poorly water soluble APIs.; The SFL process was developed and optimized in order to achieve broad applications in drug delivery systems. Firstly the use of the SFL process to enhance the dissolution of poorly water soluble APIs was investigated and the influence of the SFL process on the physicochemical properties of poorly water soluble API was determined and compared to the current particle formation techniques including milling, co-grinding, and freeze-drying.; The SFL process was further enhanced for preparation of nanoparticles of poorly water soluble APIs, using organic solvents like acetonitrile, as the solution source solvent. Using acetonitrile as the solution source solvent increased drug loading in the feed solution and reduced the drying time in the SFL process. In addition, the influence of the solution type (organic vs aqueous/organic) on physicochemical properties of SFL micronized powders was determined.; The SFL process was then extended to produce rapidly dissolving high potency powders with high surface areas and dissolution rates. The potencies ranged from 50% to 90%, in contrast with typical values of only 33% in previous studies.{09}In order to achieve these high potencies, high concentrations of APIs were dissolved in pure or mixed organic solvents to prepare the feed solutions. This study tested the hypothesis that only small amounts of surfactant or polymer were sufficient to form SFL nanostructured aggregates with amorphous API, high surface areas, and enhanced wettability, properties which enhance dissolution.; Furthermore, the ability of stabilization of amorphous SFL micronized powders was investigated. The influence of excipient type and glass transition temperature (Tg) on the stability of amorphous SFL danazol powders was determined. The influence of moisture content, danazol potency, and excipient type on Tg of SFL micronized powders was determined.; Lastly, the incorporation of SFL micronized powder into rapid release tablet formulations by direct compression was studied. The hypothesis of this study was that the high dissolution properties of SFL micronized powder would be maintained during the blending and direct compression processes by optimizing the SFL powder composition and tablet excipient type. Influence of SFL powder composition and tabletting excipient composition on the rapid release of poorly water soluble API from tablets was determined.; The results of this research demonstrated that the SFL process offers a highly effective approach to produce nanoparticles of poorly water soluble drug contained in larger structured aggregates with high potency, high surface area, amorphous API, enhanced wettability, and rapid dissolution rates. Therefore, the SFL process is an effective particle engineering process for pharmaceutical development and manufacturing to improve dissolution rates of poorly water soluble APIs.