Robert A. Nash

Iontophoretic transport of a homologous series of ionized and nonionized model compounds: influence of hydrophobicity and mechanistic interpretation.

An in vitro study was carried out to elucidate the mechanisms controlling iontophoretic transport. The investigation focused on three areas, including the nature of the permeant (state of ionization and hydrophobicity), skin structures (hair follicle distribution and stratum corneum), and various parameters influencing iontophoresis (current, permeant concentration, and competitive ion effects). The data indicate that iontophoretic-facilitated transport is essentially pore mediated and that the transport of ionized and nonionized molecules may be enhanced through the pore-type pathway. The data presented show that iontophoresis has a detrimental effect on the lipoidal transport pathway and that the transport of more hydrophobic nonionized molecules is decreased compared with passive diffusion. The iontophoretic enhancement values decreased linearly with increasing alkyl chain length of n-alkanols. The iontophoretic permeability coefficients of ionized n-alkanoic acids was shown to decrease with increasing permeant hydrophobicity.

The Possibility of Lidocaine Ion Pair Absorption Through Excised Hairless Mouse Skin

The purpose of the present research was to test the ion pair absorption hypothesis with respect to the topical route of drug delivery. The experiment consisted of preparing various lidocaine-n-alkanoate ion pairs, then characterizing them by proton magnetic resonance spectroscopy, elemental analysis and conductivity. Percutaneous absorption studies through excised hairless mouse skin were carried out using ethanolic solution of radiolabeled 14C-lidocaine-octanoate, 14C-lidocaine-decanoate and 14C-lidocaine-dodecanoate. Studies were conducted under steady-state conditions using Bronaughs flow-through apparatus and normal saline as the receptor fluid. Ethanolic solution of a lidocaine base served as a control. The apparent differences in flux between lidocaine and the various ion pairs were statistically significant (p less than 0.05). The differences among the fluxes of the various ion pairs were not statistically significant (p greater than 0.05), nor were the differences in lag times (p greater than 0.05). The difference between the flux values of lidocaine-1-14C-dodecanoate and 14C-lidocaine-dodecanoate infers that lidocaine-dodecanoate did not cross the excised, full-thickness, hairless mouse skin as an intact 1:1 ion pair. The formation of weakly associated ion pairs was suggested by the apparent low-association constants (Ka = 15-17 liters/mol) obtained at 25 degrees C in methanol by conductometric analysis.

Solubility enhancement of nucleosides and structurally related compounds by complex formation

Water-soluble vitamins, amino acids, and nontoxic pharmaceutical excipients were studied as solubilizing agents for poorly water-soluble adenine (nucleic acid base), guanosine (nucleoside), and structurally related drugs (acyclovir and triamterene). The apparent solubility of the substrates (adenine, guanosine, acyclovir, or triamterene) was appreciably increased by forming complexes with the ligands (vitamins, amino acids, or other ligand). Apparent association constants (Ka ) values were measured at 25°C in pH 7 phosphate buffer using phase solubility analysis. The effect of combination ligands on substrate solubility was also studied. Additive solubility enhancement was obtained for several ligand pairs.

The development of a microwave fluid-bed processor. II: Drying performance and physical characteristics of typical pharmaceutical granulations

Four typical pharmaceutical granulations were used to measure the enhanced drying performance of a laboratory-sized microwave fluid-bed processor, the design and construction of which were presented in Part I of this work (preceding paper). Results demonstrate improvements in observed drying rates by as much as sixfold depending upon the granulation type and drying conditions. At a low inlet temperature (30°C), drying was achieved with microwave power inputs of 100–125 W/liter of working capacity, whereas similar targeted moisture levels were unattainable using conventional fluid-bed drying. Microwave energy available for heating and drying was 68 to 86% of the total microwave energy inputted.

The development of a microwave fluid-bed processor. I. Construction and qualification of a prototype laboratory unit.

The static bed- and planetary-type microwave dryers currently available to process pharmaceutical materials are not designed to use hot-air fluidization for the purpose of maximizing microwave energy inputs and particle drying. To take advantage of the benefits offered by fluidization, a 1-kg Uni-Gatt laboratory fluid bed processor was modified to support microwave-assisted fluid bed drying of several representative pharmaceutical granulations. The construction, design features, and validation of this new microwave fluid bed processor are presented.

Process Validation: A 17-Year Retrospective of Solid-Dosage Forms

The author takes the reader through the various stages, phases, and steps in the product and process development sequence of solid-dosage form design (tablet and capsule) using process validation principles and practices as a guide. The challenge for the pharmaceutical industry as it approaches the next millennium is to streamline and/or simplify validation requirements without sacrificing product quality and process flexibility. Cost-containment pressures in the future will necessitate the use of more process automation and innovative ways of manufacturing products. In the final analysis, these objectives can best be accomplished with the cooperation of a worldwide regulatory commitment to achieving harmonization goals for both good manufacturing practices and process validation.

Studies on the efficacy of methyl esters of n-alkyl fatty acids as penetration enhancers

The efficacy of the methyl esters of medium chain n-alkyl fatty acids as penetration enhancers was evaluated in vitro using various animal and human skins with minoxidil as the test drug. Both methyl nonanoate and methyl caprate at a 10% concentration were found to be effective penetration enhancers for a 2% solution of minoxidil in alcohol USP. The percent of the applied radioactive dose of minoxidil penetrated after 17 h was 5-8 times greater for methyl non-anoate and methyl caprate enhanced solutions than for a 2% solution of minoxidil in alcohol USP alone or with the addition of 10% Azone, dimethylsulfoxide (DMSO) or N,N-diethyl-m-toluamide (DEET). The penetration enhancing activity of methyl caprate was effective for human, mouse, and hamster skins. Methyl caprate also enhanced the penetration of vitamin D3, erythromycin, triamcinolone acetonide, testosterone, and hydrocortisone.

A New Linear Model for Stability Prediction

AbstractBased upon Okusas observation (Chem. Pharm. Bull. 1975) that the slopes of a linear plot of logo log fraction of active substance degraded vs log time for first order decay kinetics and a linear plot of log of drug remaining vs log time for a zero order decay kinetics are both unity, an algorithm has been developed to resolve both the energy of activation (E) and the rate constant (Ko or Lo) at the desired shelf-life temperature (To) by analysis of the y-intercepts of parallel slopes at more than one elevated temperature (T).Preliminary estimates of both E and either Ko or Lo are then substituted into a series of mathematical expressions based upon well known Arrhenius relationship:k = A ·exp -E/1.987) (1/T-l/To) where A = Ko or LoUsing converging and interative techniques to treat elevated temperature data, the resulting mean loss rate (eithri Ko or Lo at the designated shelf-life temperature plus a residual error term thus obtained, is used to distinguish statistically between zero and first or...

Size-exclusion chromatographic behavior of bovine serum albumin in uni-uni valent ions solutions

SummaryMolecular interaction between uni-uni valent ions and bovine serum albumin was investigated by size-exclusion chromatography. Elution profiles are first presented for salt and protein solutions as samples with water as the mobile phase; then for water and protein as samples with salt solutions as the mobile phase. The results suggest the existence of a dynamic equilibrium between the salt ions and the protein ions as reactants and the ion-pair (salt-protein) complex as a product.

The Behavior of Copper (II) Chelates of Aliphatic Aminocarboxylic Acids in Aqueous Solutions

AbstractThe effective overall stability constants (log Ke values) and molar combining ratios for nine aliphatic aminocarboxylic acids (C2 to c6) with copper (II) ion were calculated from spectrophotometric and potentiometric data at pH 3.0, 4.0 and 5.0 and 25°C. In addition, calculated overall stability constants (log Kn values), using Bjerrums method of analyzing potentiometric data, showed that chelates of alpha- and beta-aminocarboxylic acids with copper (II) were more stable than those of gamma-and epsilon-aminocarboxylic acids. Using Jobs method of continuous variations for analyzing absorbance data, it was observed that while the alpha- and beta-aminocarboxylic acids formed both bicoordinated (1:1) and tetracoordinated (2:1) chelates with copper (II) ion at pH 4:O and 5:O and the alpha-aminocarboxylic acids formed only a (1:1) chelate at pH 3.0, the gamma and epsilon-aminocarboxylic acids showed only bicoordinated (1:1) chelate formation at pH 5.0.The complexation of epsilon-aminocarboxylic acid l...