Prediction of aqueous solubility from SCRATCH.

This study proposes the SCRATCH model for the aqueous solubility estimation of a compound directly from its structure. The algorithm utilizes predicted melting points and predicted aqueous activity coefficients. It uses two additive, constitutive molecular descriptors (enthalpy of melting and aqueous activity coefficient) and two non-additive molecular descriptors (symmetry and flexibility). The latter are used to determine the entropy of melting. The melting point prediction is trained on over 2200 compounds whereas the aqueous activity coefficient is trained on about 1640 compounds, making the model very rigorous and robust. The model is validated using a 10-fold cross-validation on a dataset of 883 compounds for the aqueous solubility prediction. A comparison with the general solubility equation (GSE) suggests that the SCRATCH predicted aqueous solubilities have a slightly greater average absolute error. This could result from the fact that SCRATCH uses two predicted parameters whereas the GSE utilizes one measured property, the melting point. Although the GSE is simpler to use, the drawback of requiring an experimental melting point is overcome in SCRATCH which can predict the aqueous solubility of a compound based solely on its structure and no experimental values.

Preformulation and pharmacokinetic studies on antalarmin: a novel stress inhibitor.

The preformulation, solubilization and pharmacokinetic evaluation of antalarmin, a stress inhibitor, have been conducted. Antalarmin has a poor water solubility of less than 1 microg/mL and is weakly basic with an experimentally determined pK(a) of 5.0. Multiple solubilization approaches including pH-control either alone or in combination with cosolvents, surfactants and complexing agents have been investigated. The applicability of lipid-based systems has also been explored. Four formulations, each with a targeted drug loading capacity of 100 mg/mL, show potential for oral administration. Three of these formulations are aqueous solutions (10% ethanol + 40% propylene glycol; 20% cremophor EL; 20% sulfobutylether-beta-cyclodextrin) each buffered at pH 1. The fourth formulation is a lipid-based formulation comprising of 20% oleic acid, 40% cremophor EL and 40% Labrasol. No precipitation was observed following dilution of the four formulations with water and enzyme free simulated gastric fluid. However, only the lipid-based formulation successfully resisted drug precipitation following dilution with enzyme free simulated intestinal fluid. Pharmacokinetic analysis conducted in rats revealed that the 20% cremophor EL solution formulation has a fivefold higher oral bioavailability compared to a suspension formulation. The lipid-based formulation resulted in over 12-fold higher bioavailability as compared to the suspension formulation, the highest amongst the formulations examined.

Comparison of aqueous solubility estimation from AQUAFAC and the GSE.

The GSE (General Solubility Equation) and AQUAFAC (Aqueous Functional Group Activity Coefficients) are two empirical models for aqueous solubility prediction. This study compares the aqueous solubility estimation of a set of 1642 pharmaceutically and environmentally related compounds, using the two methods. The average absolute errors in the solubility prediction are 0.543 log units for AQUAFAC and 0.576 log units for the GSE. About 88.0% of the AQUAFAC solubilities and 83.0% of the GSE molar aqueous solubilities are predicted within one log unit of the observed values. The marginally greater accuracy of AQUAFAC is due to the fact that it utilizes fitted-parameters for many structural fragments and is based on experimental solubility data. The GSE on the other hand is a simpler, non-regression based equation which uses two parameters for solubility prediction.

Formulation and in vivo evaluation of chlorpropham (CIPC) oral formulations.

The objective of these studies was to examine the in vivo performance of oral formulations of chlorpropham (CIPC). In order to develop a new oral formulation several different solubilization techniques were evaluated, namely: cosolvents, surfactants, and complexing agents. The solubilization data indicated that a conventional solution formulation was not plausible. Two self-emulsifying drug delivery systems (SEDDS) were developed and evaluated for stability. Both SEDDS formulations were found to be chemically stable. In vivo analysis of a SEDDS formulation, a suspension formulation and an intravenous bolus dose was conducted in F344 rats. Pharmacokinetic analysis of the formulation data indicated that the SEDDS formulation provided only marginally better oral bioavailability compared to a suspension formulation. While SEDDS formulations often result in greater bioavailability this was not observed for CIPC. In vivo analysis indicate that CIPC results in a situation where the dissolution rate of CIPC from the suspension is not rate limiting, rather the absorption rate in the GI tract is rate-limiting. This paradigm is the result of CIPCs low melting point and the relatively small particle size of the suspension which facilitate the dissolution in the GI tract.

Solubilization of poorly soluble compounds using 2-pyrrolidone.

The solubilization of nine poorly soluble compounds in aqueous solution by 2-pyrrolidone has been studied. Solubility enhancement as high as 500-fold is achieved using 20% 2-pyrrolidone. A comparison shows that 2-pyrrolidone is a better solubilizer than glycerin, propylene glycol, polyethylene glycol 400 or ethanol. The observed solubilization curves are deconvoluted into components representing complexation and cosolvency. A clear linear relationship exists between the cosolvency solubilization power (sigma) of 2-pyrrolidone and the partition coefficient (log K(ow)) of the drug (R(2)=0.96) extending over three orders of magnitude. The stability constants for the formation of 1:1 complex (K(1:1)) involving 2-pyrrolidone and the drugs have been calculated. A weaker correlation (R(2)=0.74) is observed between the complexation constants and the partition coefficients of respective drugs. This study indicates that 2-pyrrolidone, like NMP, can act as a complexant at low concentrations and as a cosolvent at high concentrations and that both these properties are affected by the partition coefficient of the solute.

Transfersomes--a novel vesicular carrier for enhanced transdermal delivery: development, characterization, and performance evaluation.

This work describes the use of a novel vesicular drug carrier system called transfersomes, which is composed of phospholipid, surfactant, and water for enhanced transdermal delivery. The transfersomal system was much more efficient at delivering a low and high molecular weight drug to the skin in terms of quantity and depth. In the present study transfersomes and liposomes were prepared by using dexamethasone as a model drug. The system was evaluated in vitro for vesicle shape and size, entrapment efficiency, degree of deformability, number of vesicles per cubic mm, and drug diffusion across the artificial membrane and rat skin. The effects of surfactant type, composition, charge, and concentration of surfactant were studied. The in vivo performance of selected formulation was evaluated by using a carrageenan-induced rat paw edema model. Fluorescence microscopy by using rhodamine-123 and 6-carboxyfluorescein as fluorescence probe was performed. The stability study was performed at 4 degrees C and 37 degrees C. An in vitro drug release study has shown a nearly zero order release of drug and no lag phase. The absence of lag phase in comparison to liposomes and ointment is attributed to the greater deformability, which may account for better skin permeability of transfersomes. In vivo studies of transfersomes showed better antiedema activity in comparison to liposomes and ointment, indicating better permeation through the penetration barrier of the skin. This was further confirmed through a fluorescence microscopy study. Finally, it may be concluded from the study that complex lipid molecules, transfersomes, can increase the transdermal flux, prolong the release, and improve the site specificity of bioactive molecules.