Exploratory data analysis of the dependencies between skin permeability, molecular weight and log P.

Molecular weight and log P remain the most frequently used physicochemical properties in models that predict skin permeability. However, several reports over the past two decades have suggested that predictions made by these models may not be sufficiently accurate. In this study, exploratory data analysis of the probabilistic dependencies between molecular weight, log P and log Kp was performed on a dataset constructed from the combination of several popular datasets. The results suggest that, in general, molecular weight and log P are poorly correlated to log Kp. However, after employing several exploratory data analysis techniques, regions within the dataset of statistically significant dependence were identified. As an example of the applicability of the information extracted from the exploratory data analyses, a multiple linear regression model was constructed, bounded by the ranges of dependence. This model gave reasonable approximations to log Kp values obtained from skin permeability studies of selected non-steroidal ant-inflammatory drugs (NSAIDs) administered from a buffer solution and a lipid-based drug delivery system. A method of testing whether a given drug falls within the regions of statistical dependence was also presented. Knowing the ranges within which molecular weight and log P are statistically related to log Kp can supplement existing methods of screening, risk analysis or early drug development decision making to add confidence to predictions made regarding skin permeability.

Preparation and evaluation of metastable solid-state forms of lopinavir.

In this work, we present the preparation and evaluation of previously unreported metastable forms of the antiretroviral drug, lopinavir. By maintaining the chemical structure, physicochemical properties like the glass transition temperature (T(g)), dissolution and solubility can be readily attributed to the stability of the system. Commercially-available lopinavir was used to prepare partially amorphous crystals, semicrystalline needles, resins and glasses. The physicochemical properties of each were investigated using differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR) and powder X-ray diffraction (PXRD). Each sample's thermal and spectroscopic analyses, as well as dissolution and solubility studies were performed one month after sample preparation, for better comparability. Glass transition temperature, activation energy for global molecular mobility (deltaE(Tg)), and activation energy for local molecular mobility (deltaE(beta)) were assessed as primary indicators for structural stability of the systems. Relating these properties to aqueous solubility revealed that each metastable form possessed its own unique equilibrium solubility. Cumulative dissolved fractions (alpha) were fitted against deceleratory kinetics models, and from the data hereby obtained the dissolution process was determined to followed first-order kinetics (R2 = 0.998). From the rate constants, the activation energy for dissolution (deltaE(Diss)) of each sample was calculated. The results suggest that multiple metastable solid-state forms of lopinavir can exist under similar conditions, depending on the preparation conditions.