Stability of Two Antifungal Agents, Fluconazole and Miconazole, Compounded in HUMCO RECURA Topical Cream to Determine Beyond-Use Date.

A novel compounding vehicle (RECURA) has previously been proven to penetrate the nail bed when compounded with the antifungal agent miconazole or fluconazole, providing for an effective treatment for onychomycosis. In this study, miconazole and fluconazole were compounded separately in RECURA compounding cream, and they were tested at different time points (0, 7, 14, 28, 45, 60, 90, and 180 days) to determine the beyond-use date of those formulations. The beyond-use date testing of both formulations (10% miconazole in RECURA and 10% fluconazole in RECURA) proved them to be physically, chemically, and microbiologically stable under International Conference of Harmonisation controlled room temperature (25°C ± 2°C/60% RH ±5%) for at least 180 days from the date of compounding. Stability-indicating analytical method validation was completed for the simultaneous determination of miconazole and fluconazole in RECURA base using high-performance liquid chromatography coupled with photodiode array detector prior to the study.

Rapidly dissolving repaglinide powders produced by the ultra-rapid freezing process.

The objective of the study was to produce rapidly dissolving formulations of the poorly water-soluble drug repaglinide using an innovative new technology, ultra-rapid freezing (URF), and to investigate the influence of excipient type on repaglinide stability. Repaglinide compositions containing different types and levels of excipients and different drug potencies (50%-86%) were produced by the URF technology. Repaglinide/excipient solutions were frozen on a cryogenic substrate, collected, and lyophilized to form a dry powder. Surfactants, including sodium dodecyl sulfate, and alkalizing agents such as diethanolamine (DEA) and tromethamine (TRIS) were incorporated into the compositions. Forced degradation of repaglinide was conducted under stressed conditions (eg, elevated temperature, exposure to peroxide) to determine the stability of the drug in such environments. The solubility of repaglinide increased as a function of increasing pH; therefore, incorporation of an alkalizing agent into the URF formulations increased the drug's solubility. Drug instability resulted when the drug was exposed to pH values above 9.0. URF formulations containing alkalizing agents showed no degradation or spontaneous recrystallization in the formulation, indicating that increased stability was afforded by processing. URF processing created nanostructured drug/excipient particles with higher dissolution rates than were achieved for unprocessed drug. Alkalizing agents such as TRIS and DEA, present at levels of 25% to 33% wt/wt in the formulations, did not cause degradation of the drug when processed using URF. URF processing, therefore, yielded fast-dissolving formulations that were physically and chemically stable, resistant to alkali degradation or spontaneous recrystallization in the formulation.

Evaluation of the USP dissolution test method A for enteric-coated articles by planar laser-induced fluorescence.

The USP drug release standard for delayed-release articles method A was evaluated using planar laser-induced fluorescence (PLIF). Prior authors have suggested that high pH "hot spots" could develop during the buffer medium addition of the method A enteric test. Additionally, previous studies have shown heterogeneous flow patterns and low-shear regions in the USP Apparatus II dissolution vessel, which may result in poor mixing of the buffer and acid media during the pH neutralization step of the method A enteric test. In this study, PLIF was used to evaluate the mixing patterns and evolution of pH neutralization during the buffer medium addition with rhodamine-B dye and the pH-sensitive dye fluorescein, respectively. Additionally, a comparison of the methods A and B enteric tests was performed with enteric-coated tablets containing rhodamine-B in the film so as to image the dissolution rate of the coating polymer with PLIF in order to determine if rapid buffer addition for the method A procedure accelerates the rate of film coat dissolution. Rapid addition of the 250 mL of buffer medium over 5 s to the 750 mL of acidic medium shows efficient mixing and pH neutralization due to the generation of large-scale stirring and enhanced turbulence resulting from the descending buffer medium. Slow addition near the paddle shaft over 5 min showed segregation in the recirculating region around the paddle shaft. In contrast, slow addition near the vessel wall introduces the medium into fluid outside of the recirculation region and enables transport over the entire vessel. Enteric-coated tablets tested according to method A with rapid medium addition and method B enteric tests performed identically, indicating no difference in polymer dissolution rate between the two tests. From the results of the PLIF imaging studies with rhodamine-B, fluorescein, and enteric-coated tablets, it was seen that "hot spots" affecting the dissolution performance of enteric dosage forms are not generated during the neutralization step of the method A enteric test namely when the media is added rapidly or outside of the recirculating region that surrounds the paddle shaft.

Cryogenic liquids, nanoparticles, and microencapsulation.

The biopharmaceutical classification system (BCS) is used to group pharmaceutical actives depending upon the solubility and permeability characteristics of the drug. BCS class II compounds are poorly soluble but highly permeable, exhibiting bioavailability that is limited by dissolution. The dissolution rate of BCS class II drug substances may be accelerated by enhancing the wetting of the bulk powder and by reducing the primary particle size of the drug to increase the surface area. These goals may be achieved by nucleating drug particles from solution in the presence of stabilizing excipients. In the spray freezing into liquid (SFL) process, a drug containing solution is atomized and frozen rapidly to engineer porous amorphous drug/excipient particles with high surface areas and dissolution rates. Aqueous suspensions of nanostructured particles may be produced from organic solutions by evaporative precipitation into aqueous solution (EPAS). The suspensions may be dried by lyophilization. The particle size and morphology may be controlled by the type and level of stabilizers. In vivo studies have shown increased bioavailability of a wide variety of drugs particles formed by SFL or EPAS. For both processes, increased serum levels of danazol (DAN) were observed in mice relative to bulk DAN and the commercial product, Danocrine. Orally dosed itraconazole (ITZ) compositions, formed by SFL, produce higher serum levels of the drug compared to the commercial product, Sporanox oral solution. Additionally, nebulized SFL processed ITZ particles suspended in normal saline have been dosed via the pulmonary route and led to extended survival times for mice inoculated with Aspergillis flavus. SFL and EPAS processes produce amorphous drug particles with increased wetting and dissolution rates, which will subsequently supersaturate biological fluids in vivo, resulting in increased drug bioavailability and efficacy.