Lloyd E. Matheson

Prediction of adsorption from multicomponent solutions by activated carbon using single-solute parameters

The adsorption of 3 barbiturates—phenobarbital, mephobarbital, and primidone—from simulated intestinal fluid (SIF), without pancreatin, by activated carbon was studied using the rotating bottle method. The concentrations of each drug remaining in solution at equilibrium were determined with the aid of a high-performance liquid chromatography (HPLC) system employing a reversed-phase column. The competitive Langmuir-like model, the modified competitive Langmuir-like model, and the LeVan-Vermeulen model were each fit to the data. Excellent agreement was obtained between the experimental and predicted data using the modified competitive Langmuir-like model and the LeVan-Vermeulen model. The agreement obtained from the original competitive Langmuir-like model was less satisfactory. These observations are not surprising because the competitive Langmuir-like model assumes that the capacities of the adsorbates are equal, while the other 2 models take into account the differences in the capacities of the components.The results of these studies indicate that the adsorbates employed are competing for the same binding sites on the activated carbon surface. The results also demonstrate that it is possible to accurately predict multicomponent adsorption isotherms using only single-solute isotherm parameters. Such prediction is likely to be useful for improving in vivo/in vitro correlations.

Prediction of flux through polydimethylsiloxane membranes using atomic charge calculations: Application to an extended data set

Abstract The maximum steady state flux of 171 compounds through PDMS membranes was predicted using a refinement of a previously developed empirical quantitative structure-transportability relationship (QSTR) produced using the reported flux data for 103 compounds. The model utilized partial atomic charge, solubility, and molecular weight as predictors. The predicted data set includes a variety of substituted benzenes, naphthalenes, thiophenes, benzimidazoles, pyridines, quinolines, isoquinolines, pyrimidines, triazoles and lesser numbers of other heterocyclic classes of compounds over a wide range of polarity. Maximum steady state flux was measured using isopropyl alcohol as solvent. Molecular models of all the compounds were simulated using SYBYL 6.0 molecular modeling software. The atomic charge of each individual compound was computed with the Gast-Huck method using the same software. Results show that the simple QSTR equation is capable of accurately predicting the steady state flux of a variety of compounds. Contribution of atomic charge to mass transport phenomena was further verified by the prediction of the apparent permeability calculated from the steady state flux data. Permeability decreases significantly as the atomic charge of diffusant is increased. Predicted results show that atomic charges can be used to represent the polarity and be correlated to the polarity-related properties of an electrically neutral compound.

Prediction of flux through polydimethylsiloxane membranes using atomic charge calculations

Abstract A quantitative structure-transportability relationship (QSTR) for the prediction of flux of aromatic compounds through a polydimethylsiloxane (PDMS) membrane was developed using molecular modeling, A total of 103 compounds in 15 ring classes, including benzene, quinoline, naphthalene, pyridine, naphthyridine, furan, benzofuran, imidazole, benzimidazole, indole, thiophene, pyrrole, pyrazole, pyridazine and pyrazine, was studied. Maximum steady state flux was measured using isopropyl alcohol as solvent. Atomic charges in each molecule were computed using the Huckel-Gasteiger method. Flux was found to be significantly affected by atomic charge. Partial charge calculations combined with solubility and molecular weight provided a universal QSTR model for the estimation of flux for all 15 classes of compounds. The flux of the imidazoles was found to be systematically slower than expected while that of aliphatic amines was faster. An indicator variable for each of these two types of compounds was included in order to achieve the best predictive model. Crossvalidation, in which half of the data set is predicted by the other half, demonstrates that the model is robust and highly applicable.

Comparative Molecular Field Analysis Combined with Physicochemical Parameters for Prediction of Polydimethylsiloxane Membrane Flux in Isopropanol

Comparative molecular field analysis (CoMFA) combined with various physicochemical parameters were used to develop three-dimensional quantitative structure–transportability relationships (3-D QSTR) to predict membrane flux for 108 aromatic and heteroaromatic compounds through polydimethylsiloxane (PDMS) membranes in isopropyl alcohol (IPA). Sybyl, a comprehensive computational molecular modeling package, was used to analyze the data. Optimized molecular models were selected using molecular modeling techniques. Partial least-squares (PLS) regression combined with crossvalidation or bootstrapping was used as the statistical method to establish the predictive models. Prediction was good for the steady-state flux using both steric and electrostatic field descriptors combined with a functional group classification technique. Predictive ability was substantially increased in a model using CoMFA descriptors along with log mole fraction solubility for the penetrants in isopropanol, a hydrophobic term, fchex, which is used to estimate the partition coefficient between cyclohexane and water, and the addition of an intramolecular hydrogen bonding (IHB) term. The crossvalidated r2 and the conventional r2 for this model were 0.951 and 0.973, respectively. Excellent predictions are demonstrated for the membrane flux of the compounds both inside and outside the data domain.

The development of a predictive method for the estimation of flux through polydimethylsiloxane membranes. I : Identification of critical variables for a series of substituted benzenes

Abstract The steady-state flux of 31 monosubstituted benzene derivatives was determined through polydimethylsiloxane membranes using isopropyl alcohol as the solvent. These diffusants constituted a diverse group of compounds possessing a wide range of hydrophobic, steric and electronic characteristics. Various parameters representing these physico-chemical properties were employed to develop an empirical model capable of relating the flux to these characteristics of the substituent on the benzene ring. Molecular volume and hydrophobicity greatly influenced the flux, while electronic properties of the substituent had a relatively small, but significant, effect on the flux. Higher diffusion rates were observed for compounds possessing lipophilic, exiguous, electron-donating substituents. Molar refractivity was the best descriptor of molecular volume while cyclohexane-water fragmental constants were better predictors of hydrophobicity.

The development of a predictive method for the estimation of flux through polydimethylsiloxane membranes. II. Derivation of a diffusion parameter and its application to multisubstituted benzenes

Abstract A substituent diffusion parameter, Y , was obtained from experimental diffusion data of a series of monosubstituted benzenes. This additive, constitutive parameter was correlated with the flux of 24 multisubstituted benzene derivatives consisting of ortho , meta and para disubstituted and several trisubstituted compounds. The correlation was significantly improved by the use of an indicator variable signifying the presence of intramolecular hydrogen bonding in some of the ortho compounds. The ability of the two models to predict flux was tested by application to a series of 20 benzene derivatives which were not part of the model data set.

Quantitative structure-transportability relationship for the release of a series of substituted pyridines from a planar polydimethylsiloxane matrix

Abstract The release of 52 compounds into water, loaded at their solubility limits in a filler-supported polydimethylsiloxane matrix, was studied using a quantitative structure-activity relationship (QSAR) approach. Half of the compounds studied were benzene derivatives and half were pyridine derivatives. Solubility of all the solid compounds in the matrix was related to the melting point, molecular weight, partial atomic charge of the solutes and an indicator variable for the pyridine class. Release of the compounds from the matrix into water was matrix controlled with the initial release following the square root of time relationship. The slope of the linear portion of the Q vs √t plot was defined as the release coefficient. It was found that the release coefficient could be predicted by a QSAR model using melting point, hydrogen bonding energy group contribution, partial atomic charge and an indicator variable as predictors. Applicability of the model was examined by cross-validation. On the average, predicted results were accurate to within a factor of two for release coefficients over a 20000-fold range.

The development of a predictive method for the estimation of flux through polydimethylsiloxane membranes. III. Application to a series of substituted pyridines.

The steady-state flux of 35 substituted pyridine derivatives was determined in polydimethylsiloxane membranes using isopropyl alcohol as the receiver solvent. These diffusants constituted a diverse group of compounds possessing a wide range of hydrophobic, steric, and electronic characteristics. Various parameters representing these physicochemical properties such as cyclohexane–water fragmental constants, molar refractivity, Hammetts σ constants, melting point, and mole fraction solubility were employed to develop empirical models capable of relating the flux to these characteristics of either the substituent on the pyridine ring or the compound itself.

Evaluation of Cefmetazole Rectal Suppository Formulation(s)

AbstractThe objective of this study was to determine formulation parameters necessary to develop a cefmetazole suppository. Three 1 gram cefmetazole rectal suppository formulations were compared using in-vitro testing of melting behavior, dissolution times and fracture weight; and in-vivo dog studies of the three suppository formulations compared to IM single dose. The in-vivo study compared the dosage forms in four dogs by a cross-over design. The formulation containing one gram of sodium 5-methoxysalicylate as adjuvant gave a relative bioavailability of 29.4%, while the suppository containing sodium salicylate as adjuvant gave 17.5% relative bioavailability. The formulation which did not contain adjuvant neither dissolved properly in-vitro nor produced observable plasma levels during the in-vivo dog study. Despite the relatively large size (4.9 grams), the suppositories were easily inserted and no leakage occurred from medium-sized dogs. Proctoscopic examinations were performed following blood collectio...

Comparison of In VitroRelease Rates of Multisource Sustained-Release Papaverine Hydrochloride Products

AbstractThe extent of differences in the In vitro release rate among 24 lots of 150 mg sustained-release papaverine hydrochloride products from six manufacturers was investigated.The rotating bottle method for timed-release capsules, official in N.F. XIV, was used. Quantitation of papaverine hydrochloride in solution was done using ultra-violet spectrophotometry at two wavelengths to assure that there was no interference from other components of the formulation.While in vitro dissolution data by itself cannot predict in vivo performance, variations from one manufacturer to another and also for the same manufacturer were observed. These included variations in the amount released both in the first hour and also in the total amount released.Of the six products tested, Pavabid and Cerespan demonstrated the most consistent release patterns with slightly better consistency observed for the former. Observed differences may or may not be of clinical significance.