Browsing by Subject "Drugs--Solubility"

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Enhancing the delivery of poorly water soluble drugs using particle engineering technologies
(2006-12) Sinswat, Prapasri, 1972-; Williams, Robert O., 1956-; Johnston, Keith P., 1955-
Improved oral bioavailability of poorly water soluble drugs using rapid freezing processes
(2006-12) Overhoff, Kirk Alan; Williams, Robert O., 1956-
A growing number of therapeutic compounds currently being developed by pharmaceutical companies are poorly water soluble leading to limited and/or erratic bioavailability. The rate limiting step for absorption of these compounds is dependent on the dissolution and apparent solubility. Nanoparticle formation has been exploited as a method to improve the bioavailability of these poorly water soluble active pharmaceutical ingredients (API) by increasing the dissolution rates and apparent solubilities. The influence of hydrophilic stabilizers in powder compositions prepared by the spray freezing into liquid (SFL) process using either an emulsion feed dispersion or organic co-solvent feed solutions on enhancing the wetting and dissolution properties of nanostructured aggregates containing itraconazole (ITZ). Subsequently, an in vivo pharmacokinetic study was conducted comparing the SFL processed powder to commercial Sporanox®. An ultra-rapid freezing (URF) technology has been developed to produce high surface area powders composed of solid solutions of an active pharmaceutical ingredient (API) and a polymer stabilizer. Rapid freezing technologies are known to enhance the physico-chemical properties of APIs and thus increase bioavailability. However, the effect of the different freezing geometries and rates in the URF process are unknown. Therefore, this study investigated how solvent properties and thin film geometry of the droplet affect the freezing rate and thus the physico-chemical properties of micronized danazol powders. Amorphous nanoparticles containing tacrolimus (TAC) in a solid dispersion were prepared using the Ultra-rapid Freezing (URF) process. The objective of this study was to assess the effects of combinations of polymeric stabilizers on the maximum degree and extent of supersaturation of TAC. An attempt to establish if an in vitro-in vivo correlation exists between supersaturation and improved pharmacokinetic parameters for orally dosed TAC was performed. Enteric solid dispersions could overcome limitations of premature precipitation of supersaturated solutions by 1.) delaying dissolution until the compound enters the intestines where absorption is favored and 2.) increasing the apparent solubility at higher pH to increase the driving force for absorption. The objective of the study is to investigate the influence of composition parameters including drug:polymer ratio and polymer type, and particle structure of enteric solid dispersions on the release of ITZ.
A nanoparticle engineering process: spray-freezing into liquid to enhance the dissolution of poorly water soluble drugs
(2003) Hu, Jiahui; Williams, Robert O.; Johnston, Keith P., 1955-
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. 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 (TB gB) on the stability of amorphous SFL danazol powders was determined. The influence of moisture content, danazol potency, and excipient type on TB gB 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.
Nanoparticle engineering processes: evaporative precipitation into aqueous solution (EPAS) and antisolvent precipitation to enhance the dissolution rates of poorly water soluble drugs
(2004) Chen, Xiaoxia; Johnston, Keith P., 1955-; Williams, Robert O., 1956-
It is estimated that more than 1/3 of the compounds being developed by the pharmaceutical industry are poorly water soluble. The bioavailability of these drugs is limited by their low dissolution rates. Two nanoparticle engineering processes, evaporative precipitation into aqueous solution (EPAS) and antisolvent precipitation were developed to enhance the dissolution rate of poorly water soluble drugs. EPAS is a process by which a drug solution in a water immiscible organic solvent is sprayed through an atomizer into an aqueous solution containing hydrophilic stabilizer (s) at high temperature. The rapid evaporation of the small organic droplets results in fast nucleation leading to submicron to micron particles suspensions. The adsorption of water soluble stabilizers on the drug particle surfaces facilitates the dissolution rates of the final powder after drying. The suspensions may be used in parenteral formulations to enhance bioavailability or may be dried to produce oral dosage forms with high dissolution rates due to small particle size and hydrophilic stabilizer that enhances wetting. The influence of EPAS process parameters on the physicochemical properties of poorly water soluble drugs was determined. The influence of the dissociation of drug molecules on the stability of nanosuspensions at high suspension concentration, as high as 30 mg/ml with a drug-to-surfactant ratio of 3:1, was investigated. High-potency (≥ 90%) drug particles with high dissolution rates were produced by removing the non-adsorbed surfactant. Antisolvent precipitation is a technique where a drug solution in a water miscible organic solvent is mixed with an aqueous solution containing a surfactant(s). Upon mixing, the supersaturated solution leads to nucleation and growth of drug particles, which may be stabilized by surfactants. Temperature was shown to have a large effect on the particle size distribution in the suspension. Crystalline drug particles with particle size of 300 nm were successfully recovered from the nanosuspensions by salt flocculation followed by filtration and vacuum drying with a drug yield higher than 92%. Upon redispersion, the average particle size was comparable to the value in the original aqueous suspension. The dissolution rate was correlated with the particle size after redispersion.