Arthur H. Goldberg

Viscoelastic Properties of Polyacrylic Acid Gels in Mixed Solvents

The objective of this study is to investigate the viscoelastic properties of Carbopol 934P polymeric systems in a variety of mixtures of pharmaceutical solvents. Carbopol 934P neutralized with a 1:1 equivalent ratio of triethanolamine was dissolved in various binary or ternary solvent mixtures consisting of propylene glycol, glycerol formal, and water. Dynamic moduli G′ and G″, complex viscosities, η′ and η″, and loss tangent, tanδ, were examined over a frequency range of 10-3 to 10 Hz using an oscillatory viscoelastic rheometer at 30°C. The results indicated that for 0.5-1.5 wt% neutralized Carbopol in ternary mixtures, G′ and G″ increased by 3-4 orders of magnitude and the phase angle decreased from 80 to 25° when the water content in the solvent mixture increased from 10 to 80 wt%. These studies also indicated that the addition of water to nonaqueous Carbopol 934P polymer systems transforms them from low-viscosity solutions to gels with significant elastic behavior involving physical interaction and entanglement of polymer segments with solvents.

Mixture Experimental Design in the Development of a Mucoadhesive Gel Formulation

The objective of the present study is to apply response surface methodology to the design and analysis of composite experiments containing independent covariate(s). The approach is illustrated here by the study of viscosity characteristics of a polymeric mucoadhesive formulation in multicomponent solvent vehicles. The nonaqueous formulation will produce a gel network with significant rheological change when in contact with body fluids. The process of water inclusion will induce not only solvent compositional change of the mixture but also concomitant dilution of the polymer concentration. To study the viscosity change over the solvent compositions and polymeric concentrations of interest, an experimental design is utilized consisting of a 10-point simplex-centroid lattice augmented with three interior points at each polymeric concentration. The contour patterns are compared with the experimental, data using the variance and lack of fit, starting with the Scheffe linear model and building up to the full cubic model including the covariate terms. The fitted model provides information needed to predict optimum formulations, i.e., initial viscosity of less than 100 cP, but yielding rheological profiles commensurate with high degrees of substantivity when diluted with water. For illustrative purposes, the Carbopol resins neutralized with a 1:1 molar equivalent ratio of triethanolamine in three primary solvents, propylene glycol, glycerol formal, and water, were chosen for this study.

Viscometric study of polyacrylic acid systems as mucoadhesive sustained-release gels.

This report describes a novel nonaqueous polymeric formulation that exhibits low-viscosity fluid behavior for ease of spraying with conventional nebulizer, which when sprayed into the nasal cavity, transforms to a high-viscosity gel for efficient retention and drug absorption. The transformation occurs because of the rheological changes induced by a change in the solvent composition of the polymeric formulation in the moist nasal cavity. Such a rheological change would then facilitate enhanced residence time of the drug at the site of administration in order to avoid drainage losses. This study reports the results of the effects of a variety of factors such as solvent composition and polymer concentration on the rheological properties of a polyacrylic acid polymer. An attempt to correlate viscosity enhancement effects with enhanced and sustained-release behavior of propranolol, a drug that undergoes extensive first-pass effects, from such formulations via nasal administration in beagle dogs is also described.

Viscoelasticity of cellulose polymers and mucociliary transport on frog palates

Summary The viscoelastic properties of model polymer, hydroxypropylmethylcellulose (HPMC), in ternary solvent mixtures and the variation of viscoelastic properties under dilution with water were investigated. HPMC was dispersed in mixtures of glycerol formal (GF) or ethyl alcohol, propylene glycol (PG), and water. Each polymeric sample was oscillated at different frequencies with fixed stress amplitude and the changes in elastic modulus, viscous modulus, and apparent viscosity were measured at 30°C. The moisture absorption rate of HPMC in PG:GF solvent mixtures in a 94% relative humidified environment was also studied. A linear relationship between the elastic modulus or viscous modulus and polymer concentration was observed for the HPMC samples. The relative mucociliary transport rate tested on the non-depleted frog palate model revealed a curvilinear correlation with the loss tangent (a ratio of the viscous modulus to the elastic modulus) of the polymeric solution. Using GF as a solvent for HPMC resulted in a formation of a rigid gel with the highest elastic modulus and viscous modulus among solvents selected. A higher affinity for water was found for HPMC in the PG : GF 90 : 10 mixture compared with HPMC in the PG : GF 70 : 30 mixture. However, the elastic modulus and viscous modulus were much higher for HPMC in the PG : GF 70 : 30 mixture.

The role of rheological properties in mucociliary transport by frog palate ciliated model

The effect of viscoelastic properties on mucociliary transport rate was investigated using the frog palate ciliated model. Mucociliary transportability of several hydrophilic polymeric gels with widely different viscoelastic characteristics were tested on the frog palate mucociliary model. An apparent negative relationship is observed between the relative transport rate (TR) and storage (G1) or loss (G2) modulus. However, a minimum in relative transport rate is observed at an apparent loss tangent (tan δ) value of between 0.7 and 0.9. A theoretical model for mucociliary transport is presented. The model predicted a minimum in transport rate at tan δ equal to 1.74 after adjustment for primary variation due to storage modulus (G1) which is in agreement with the observed frog palate transport rate. The model isolates the loss tangent (tan δ) and the magnitude of the complex modulus (|G*|) as the important viscoelastic parameters for mucociliary transport. Optimum rheological characteristics with respect to slow transport rate can be achieved by using hydrophilic polymer gels with a large complex modulus and simultaneously with a loss tangent equal to 1.74.

Report of the Workshop on Controlled Release Dosage Forms: Issues and Controversies: Academy of Pharmaceutical Sciences American Society for Clinical Pharmacology 3 Therapeutics Drug Information Association and Food and Drug Administration

AbstractControlled release pharmaceutical dosage forms may offer one or several advantages over conventional dosage forms of the same drug, including reduced dosing frequency, decreased incidence and/or intensity of adverse effects, greater selectivity of pharmacologic activity and a more constant therapeutic effect. In other instances, controlled release products may have no significant advantages or they may actually be less effective and/or more hazardous than conventional dosage forms of the same drug. In some cases, controlled release products may be therapeutically advantageous primarily for certain subpopulations of patients.