Examination of metformin hydrochloride in a continuous dissolution/HDM system.

A continuous dissolution/absorption system using a hexadecane membrane (HDM) as the permeation measurement has been examined for three distinct formulations of metformin hydrochloride. This system was used to correlate the absorption rate of metformin through the membrane after release from the dosage form to rate of appearance of metformin in the plasma from the same formulations. These correlations were then used to make predictions of the in vivo plasma profile for each formulation. Successful predictions of AUC were accomplished for both immediate release and extended release formulations of metformin hydrochloride.

Predicting human drug pharmacokinetics from in vitro permeability using an absorption-disposition model.

The purpose of this research is to simulate the in vivo performance of drugs with a wide range of solubility and permeability characteristics formulated as oral dosage forms. The absorption-disposition model was developed using a number of physiological parameters as well as in vitro permeability data generated with Caco-2 cells, 2/4/A1 cells, and hexadecane membranes. A total of 13 drugs with varying solubility and permeability properties were examined using the absorption-disposition model to predict their pharmacokinetic profile. The correlation of predicted and experimentally determined AUC and Cmax, as measures of the pharmacokinetic profile, were >0.96 for all permeation techniques examined. The predictive ability of the model is influenced by the type of permeation method employed; 2/4/A1 cell data yielded the highest degree of accuracy in predicting Cmax and AUC values. The absorption-disposition model developed in this work accurately predicts the in vivo performance of a wide range of orally administered drugs with 8 of 9 drugs examined falling within 80-125% of the experimental value of AUC when using 2/4/A1 cells.

Profiling of medium chain glycerides used in pharmaceutical formulation development by reversed-phase HPLC.

Medium chain length (C8, C10) mono-, di- and triacylglycerols (MCGs) are used in pharmaceutical formulation development of poorly soluble compounds, as a means to increase their oral bioavailability. The ratios of C8 and C10 fatty acid components along with the ratio of monoglycerides, diglycerides and triglycerides can significantly impact overall solubilizing characteristics both in vitro and in vivo. Existing literature methods either do not have the desired selectivity or simplicity to adequately characterize these MCGs. A reversed-phase HPLC method has been developed utilizing a Waters Symmetry C18 (150 mm x 4.6 mm, 3.5 microm particle size) column with a gradient of acetonitrile and water. The effluent was monitored using a UV detector at 220 nm and relative response factors were determined for all components with available standards to allow for accurate quantitation. The RP-HPLC method was optimized for selectivity, sensitivity and efficiency and was successfully applied to the characterization of commercial samples yielding superior sensitivity and ease of preparation compared to existing compendial methods.

Profiling of metal ions leached from pharmaceutical packaging materials.

Metal leachables from packaging components can affect the safety and efficacy of a pharmaceutical formulation. As liquid formulations continue to contain surfactants, salts, and chelating agents coupled with lower drug levels, the interaction between the formulation and the packaging material becomes more important. This study examines the interaction of commonly used packaging materials with extraction solvents representative of liquid formulations found in the pharmaceutical industry stressed under conditions encountered during accelerated stability studies.