John L. Lach

Use of Adsorbents in Enhancement of Drug Dissolution I

A new approach is described for increasing the dissolution rates of relatively insoluble powders. It is based on the concept of increasing the surface available for contact with dissolution media. This is accomplished by equilibration of the drug in an organic solvent (e.g., acetone) on an insoluble excipient with an extensive surface (e.g., fumed silicon dioxide). The drugs studied included indomethacin, aspirin, sulfaethidole, griseofulvin, reserpine, chloramphenicol, oxolinic acid, probucol, and hydrochlorothiazide. The effects of pH, wetting agents, and agitation intensity were investigated in some systems. An increased rate of release from the minuscular drug delivery system was observed in all instances.

Structural Effects on the Binding of Amine Drugs with the Diphenylmethyl Functionality to Cyclodextrins. I. A Microcalorimetric Study

Solution calorimetry has been employed to evaluate the stability constants and enthalpy changes associated with complex formation between α-, β, or -γ-cyclodextrin (CD) and a group of amine compounds having the diphenylmethyl functionality. Data from thermal titrations of the compounds were analyzed using nonlinear least squares. The standard free energy decrease accompanying the formation of inclusion complexes is generally due to a negative standard enthalpy change (ΔH°). The standard entropy change (ΔS°) was negative, except in the case of complexes formed with γ-CD. Of the 13 compounds studied, only 2 formed complexes with 1:2 (compound: (β-CD) stoichiometry, terfenadine · HC1 and cinnarizine · 2HC1. All the others formed 1:1 complexes. The structural effect on the stability constants, thermodynamics, and inclusion geometry was explored by relating the calorimetric results to the chemical structures of the guest molecules and the cavity sizes of the CD molecules. The results suggest that one of the phenyl groups of the diphenylmethyl functionality resides in the CD cavity and is in van der Waals contact with the inside wall of the CD cavity. In the case of α- and β-CDs, van der Waals interaction dominates in the stabilization. On the other hand, the interaction between these compounds and γ-CD is largely entropically driven. Adiphenine · HC1 forms a more stable complex with β-CD than proadifen · HC1, suggesting that hydrogen bonding to the carbonyl oxygen by the hydroxyl group on the rim of the CD ring can influence the strength of the binding interaction.

Microcalorimetric investigation of the complexation between 2-hydroxypropyl-β-cyclodextrin and amine drugs with the diphenylmethyl functionality

Solution calorimetry has been employed to evaluate the stability constants and standard-enthalpy changes (delta H degrees) associated with complex formation between 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and a group of amine compounds having the diphenylmethyl functionality in aqueous solution at 298.15 K. Data from microcalorimetric titrations of the compounds were analysed using a nonlinear least-squares method. Of the 12 compounds studied, only terfenadine.HCl formed a 1:2 (compound:HP-beta-CD) complex. All the others formed 1:1 complexes. The standard free energy decrease accompanying the formation of inclusion complexes is generally due to a negative delta H degrees. This exothermic delta H degrees can be interpreted as indicating that the binding forces for complexation include both the hydrophobic effect and strong van der Waals interactions. When a halogen substituent is in the aromatic ring, stability constants are higher and standard-entropy changes (delta S degrees) become positive, suggesting greater hydrophobic interaction. Both adiphenine.HCl and proadifen.HCl form more stable complexes, suggesting that hydrogen bonding to the carbonyl oxygen by the hydroxyl-group on the rim of the CD ring could be an important contributor to the complexation. Substitution on the aliphatic carbon of the diphenylmethyl group was also found to be important in determining the ability of compounds to bind with HP-beta-CD. The independence of the thermodynamic constants on the degree of protonation in the case of bifunctional amines indicates that the amine functional groups do not penetrate into the HP-beta-CD cavity.

Structural Effects on the Binding of Amine Drugs with the Diphenylmethyl Functionality to Cyclodextrins. II. A Molecular Modeling Study

Molecular modeling has been used to study the complexation between α, β, or γ-cyclodextrin (CD) and a group of amine compounds having the diphenylmethyl functionality. The computer program SYBYL 5.3 and the Tripos force field (version 5.2) were used for all the calculations. Three-dimensional structures of 13 amine compounds were built individually from their atoms, and CDs were built based on the X-ray crystallographic coordinates. The diphenylmethyl derivative-CD complexes were constructed and optimized. Based on the calculated binding energies accompanying the inclusion process, the preferred method of approach of the compounds to the cavities of the CD molecules, and the structural effects on the binding between amine compounds and three CDs were explored. The calculated binding energies exhibited a good correlation with the stability constants obtained from solution calorimetric titrations. The present study shows that for similar ligand molecules, the molecular modeling technique should enable us to visualize the structure of the inclusion complexes and will also assist us in determining the ability of a potential drug molecule to form a stable complex with CDs.

Comparative Bioavailability of Papaverine Hydrochloride, Papaverine Hexametaphosphate and Papaverine Polymetaphosphate

AbstractPapaverine hexametaphosphate and papaverine polymetaphosphate salts were Prepared and isolated. Experiments were conducted in mongrel dogs to compare the bioavailability of papaverine hydro-chloride, papaverine hexametaphosphate and papaverine polymeta-phosphate. The metaphosphates resulted in greater area under the curve compared to the hydrochloride salt, however, there was no difference observed in the lag time, apparent absorption rate constant, time of peak or maximum plasma concentrations obtained by any of the three salts. Intravenous doses of papaverine hydrochloride were given to all dogs to determine the absolute bioavailability. The pharmacokinetic parameters and first order transfer constants for drug disposition were calculated from the intravenous data; whereas, the apparent absorption rate constant was estimated from percent unabsorbed versus time plots. The pharmacokinetic analysis confirm a three compartment model for the drug in the mongrel dog.

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...

High Performance Liquid Chromatographic Assay for Papaverine in Plasma

AbstractA simple and sensitive assay for papaverine in plasma was developed. Plasma was extracted into n-heptane and back extracted into 0.1 N HCl. An aliquot of 0.1 N HC1 was injected onto a reversed-phase column. The mobile phase consisted of 33% acetonitrile in 0.05 M phosphate buffer, pH 3.0, at a flow rate of 1.6 ml/min. The retention times of papaverine and the internal standard (diphenylhy-dramine hydrochloride) were 4.0 and 7.0 minutes respectively. The coefficient of variation over 2-50 nanogram/ml range for spiked samples (n = 6) was 9.9% suitability of this method for plasma sample analysis from a bioavailability study was demonstrated.