Enhanced drug dissolution and bulk properties of solid dispersions granulated with a surface adsorbent.

A combination of solid dispersion and surface adsorption techniques was used to enhance the dissolution of a poorly water-soluble drug, BAY 12-9566. In addition to dissolution enhancement, this method allows compression of the granulated dispersion into tablets. Gelucire 50/13 (polyglycolized glycerides) was used as the solid dispersion carrier. Hot-melt granulation was performed to adsorb the melt of the drug and Gelucire 50/13 onto the surface of Neusilin US2 (magnesium alumino silicate), the surface adsorbent. Dispersion granules using various ratios of drug-Gelucire 50/13-Neusilin US2 were thus prepared. The dissolution profiles of BAY 12-9566 from the dispersion granules and corresponding physical mixtures were evaluated using USP Type II apparatus at 75 rpm. The dissolution medium consisted of 0.1 N hydrochloric acid (HCl) with 1% w/v sodium lauryl sulfate (SLS). Dissolution of BAY 12-9566 from the dispersion granules was enhanced compared to the physical mixture. The dissolution of BAY 12-9566 increased as a function of increased Gelucire 50/13 and Neusilin US2 loading and decreased with increased drug loading. In contrast to the usually observed decrease in dissolution on storage, an enhancement in dissolution was observed for the dispersion granules stored at 40 degrees C/75% relative humidity (RH) for 2 and 4 weeks. Additionally, the flow and compressibility properties of dispersion granules were improved significantly when compared to the drug alone or the corresponding physical mixture. The ternary dispersion granules were compressed easily into tablets with up to 30% w/w drug loading. The extent of dissolution of drug from these tablets was greater than that from the uncompressed dispersion granules.

Release of morphine sulfate from compounded slow-release capsules: the effect of formulation on release.

Morphine sulfate is often used to treat severe pain. Pharmacists have been requested to compound morphine sulfate sustained-release capsules in dosages that are not available commercially. However, there has been considerable controversy about the advisability of that practice. This study determined the release of six formulations of 300 mg morphine sulfate sustained-release capsules by means of a United States Pharmacopeia (USP) type III dissolution apparatus. The formulation suggested by a reputable compounding consulting company released almost half the morphine in the first hour of a time-release test and did not adequately sustain the release of the remainder. With increases in the level of hydroxypropyl methylcellulose (Methocel), the release was prolonged and the amount of drug released during the first hour was reduced. One formulation of encapsulated compressed pellets showed that the release could be sustained significantly beyond that of the original formulation. In addition, the increased agitation that occurs in the gastointestinal tract when the medication is taken after a meal reduced the period of sustained release and slightly increased the amount of morphine released during the first hour after administration. In conclusion, the original formula of morphine sulfate sustained-release capsules (Formula A) is probably not adequate for most applications. The formulations with a greater percentage of Methocel are preferred. In addition, the pelleted formulation was superior; however, it may not be feasible to use this labor-intensive approach to compound capsules.

The application of malononitriles as microviscosity probes in pharmaceutical systems.

Three molecules were investigated for their ability to distinguish variations in the microviscosity of the surrounding medium. Julolidinemalononitrile (JMN), p-(N-dimethylaminobenzylidene) malononitrile (BMN), and p-(N-dimethylaminocinnamylidene) malononitrile (CMN) were dissolved in media of various micro- and bulk viscosities. The fluorescence intensity of each dissolved probe and the bulk viscosity of each medium were measured. In solutions of low molecular weight substances, where the micro- and bulk viscosities are expected to correspond, the fluorescence behavior of each probe was a function of bulk viscosity and was independent of solution composition. In contrast, in aqueous solutions of methylcellulose, the fluorescence behavior of the probes corresponds to microviscosities significantly lower than the measured bulk viscosities. Thus, the probes are useful in resolving the microviscosity from bulk viscosity of neat liquid and solution systems. The sensitivity of the probes to viscosity is in the order JMN > BMN > CMN. Due to its limited water solubility, JMN is not particularly useful for pharmaceutical systems. CMN is the preferred probe for these applications due to its high fluorescence intensity over a large viscosity range.