Design and characterization of a surfactant-enriched tablet formulation for oral delivery of a poorly water-soluble immunosuppressive agent.

The feasibility of incorporating significant quantities of the anionic surfactant, sodium lauryl sulfate (SDS), into an immediate release tablet formulation of a poorly water-soluble immunosuppressive agent was investigated. Despite the extremely poor compressibility of SDS and poor chemical stability of the drug, a commercializable, direct-compression tablet formulation with satisfactory mechanical properties and acceptable chemical stability was achieved. Optimal in vitro release of the drug from the tablet formulation was achieved by establishing the minimum molar uptake ratio necessary to achieve complete micellar solubilization of the drug, after which formulation studies were conducted to determine the influence of formulation and process variables on the rate and extent of drug release. A model-independent analysis of dissolution results in a reduced volume (250 ml) of modified simulated gastric fluid demonstrated that the rate and extent of drug release was highly dependent on the mean particle size of the bulk drug, but independent of compression force above that required to achieve a compact of acceptable mechanical strength. Employing the Korsmeyer-Peppas model of Fickian and non-Fickian drug release, it was further shown that release of the drug from the dosage form was governed largely by surface erosion of the surfactant-enriched tablet matrix.

Quantitative determination of the extent of neutralization of carboxylic acid functionality in carbopol 974P NF by diffuse reflectance fourier transform infrared spectrometry using Kubelka-Munk function.

PURPOSE: The purpose of this study was to develop an analytical method for the quantitative determination of the extent of neutralization of the carboxylic acid function in Carbopol 974P NF using Diffuse Reflectance Fourier Transform Infrared Spectroscopy (DRIFT) with Kubelka-Munk function analysis. METHODS: Carbopol 974P NF is a high molecular weight, chemically crosslinked polymer of acrylic acid, that has the C=O stretching band of the unionized carboxylic acid function at 1695 cm(-1). The quantitative determination of the extent of neutralization of the carboxylic acid function in Carbopol 974P NF is based upon the asymmetrical C=O stretching of the carboxylate anion at 1570 cm(-1) measured by DRIFT spectroscopy. RESULTS: To overcome spectral differences arising from sample preparation (powders, granules and tablets) and in an effort to increase the precision of the analytical method, the following approaches were used: (1) an internal standard, (2) first derivative of the spectrum to eliminate the effect of baseline drift and (3) the ratio of the first derivative of the C=O stretch of the carboxylate anion peak (1570 cm(-1)) in the neutralized Carbopol 974P NF to that of the peak of the internal standard (866 cm(-1)). The above data treatment techniques proved to be superior to the usual methods of peak height or peak area. The calibration curve of the ratio of the first derivative (1570 cm(-1)/866 cm(-1)) was a linear function of the mass of sodium carboxylate over the range from 0.0% to 100.0% neutralization of the carboxylic acid function in Carbopol 974P NF (Fig. 1a). No particle size or sample preparation effects were noted within the experimental error. CONCLUSIONS: DRIFT spectroscopy using the Kubelka-Munk function is a powerful tool for the routine determination of the extent of neutralization of the carboxylic acid function in Carbopol 974P NF in complex pharmaceutical formulations.

Improved oral absorption of L-365,260, a poorly soluble drug.

L-365,260, a specific and potent nonpeptide antagonist of the CCKB receptor, is under investigation for its potential utility in the treatment of anxiety and panic disorders. This drug has a very low aqueous solubility (< 2 micrograms mL-1). When L-365,260 was given orally as a suspension in 0.5% methylcellulose (5 mg kg-1), the absorption was rapid but incomplete. The peak concentrations occurred in about 30-40 min, and the bioavailability was 8.6% for the dog and 13.6% for the rat. The poor bioavailability could be attributed to poor absorption or extensive first-pass metabolism. By comparing the drug concentrations in the systemic circulation during portal and femoral (or cephalic) vein infusion, the hepatic first-pass metabolism was estimated to be 0.30 for the rat and 0.14 for the dog, suggesting that first-pass metabolism is not the main reason for the low bioavailability of the drug in rats and dogs. The limited bioavailability is, therefore, more likely due to its poor absorption as a result of its poor aqueous solubility and slow dissolution rate. However, while the absorption was substantially improved when the drug was given orally as a solution in PEG 600 solution, the bioavailability increased threefold to fourfold in rats and sixfold to sevenfold in dogs. Although the underlying mechanism for the improved absorption is unknown, PEG 600 may have exerted a cosolubilizing effect which enhances the dissolution rate of L-365,260 in the GI tract, resulting in better absorption. Kinetic analysis by a deconvolution technique revealed that PEG 600 increased both the extent and rate of absorption. These results are consistent with the notion that absorption of L-365,260 is rate limited by its dissolution rate. The data from these animal studies provides valuable information in selecting the formulation for clinical trials.

Development of a flow microcalorimetry method for the assessment of surface properties of powders.

PURPOSE: This study describes the development of a microcalorimetric flow cell which allows powder surface energetics to be probed my means of measuring their interaction with water vapour. METHODS: A flow cell has been constructed and tested in an isothermal microcalorimeter to assess the interaction between water vapour and powder surfaces. The cell was constructed to mix two separate air streams (0% and 100% relative humidity respectively) to create any humidity at a standard flow rate. The powder sample was equilibrated in dry air and then exposed to sequential increments in humidity. RESULTS: Adsorption isotherms were constructed from the cumulative heat as a function of humidity. It was possible to differentiate between different samples of alpha-lactose monohydrate (which appeared identical by contact angle determination). It was also possible to measure adsorption to two different alkyl p-hydroxybenzoates which were hydrophobic and of low surface area. CONCLUSIONS: This technique offers a very sensitive and versatile method of obtaining a reliable indication of powder surface energetics and as such is a major advance in the field.

Enthalpies of solution of a series of m-alkoxy phenols in water, n-octanol and water-n-octanol mutually saturated: derivation of the thermodynamic parameters for solute transfer between these solvents.

Enthalpies of solution in both water and n-octanol have been determined for a series of phenols, in a microcalorimeter modified for titration. The thermodynamic data for solution in n-octanol and in water, as well as for transfer between the two, have been calculated from the free energies of transfer, based upon partition coefficients, and the free energies of solution, based upon solubility data. The results are discussed in terms of solute-solvent interactions in both phases and are used to assess, critically, the use of n-octanol as lipid-like solvent in QSAR studies.

The measurement of phenol coefficients by flow microcalorimetry.

Microcalorimetric bioassay procedures have been applied to the determination of phenol coefficients and dilution coefficients. The derived values are compared with those from a standard AOAC test procedure. This microcalorimetric results indicate close agreement with AOAC values, good reproducibility (+/- 2%), rapidity (30 min per test), potential for automation and the determination of in-use dilutions of disinfectants.

Quantitative structure-activity relationships: the Van't Hoff heats of transfer of resorcinol monoethers from water to n-octanol.

The partition coefficients of resorcinol and some resorcinol monoalkyl-ethers from water to n-octanol have been measured as a function of temperature. These data are used to evaluate delta G, delta H and delta S for the solute transfer process. The data suggest direct calorimetric measurement of these parameters should be performed. Correlation with calorimetrically determined 'biological response' will permit a more detailed and precise commentary upon the quantitative structure-activity relationships for these compounds.