John W. Mauger

On the Analysis of Dissolution Data

AbstractDissolution profiles for solid dose forms represent several observations over time on an experimental unit such as a tablet or capsule. The pharmaceutical scientist is interested in a (statistical) comparison of these profiles under a variety of conditions relating to formulation characteristics, and lot-to-lot and brand-to-brand variation.This paper discusses the analysis of dissolution profiles using an analysis of variance approach. la particular, the profiles are tested for differences in level and shape. The latter characteristic is potentially important with respect to learning about differences in the dissolution mechanism.An approximate F test is discussed with the possibility of an arbitrary covariance matrix in mind, and alternative conservative analysis methods are presented.Results from the analysis of variance of typical dissolution data show several important features. First, the analysis does not rely on curve fitting procedures and the data are used in their native form or as a sim...

Dissolution rate studies from a stationary disk/rotating fluid system.

The dissolution rates for hydrocortisone alcohol and acetate were determined using a stationary disk/ rotating fluid system. The hydrocortisone was compressed in a tablet die, and the die placed in a vessel above a rotating magnetic bar. Dissolution rates were evaluated in aqueous media under conditions involving the following independent variables: solubility (Cs), diffusion coefficient (D), viscosity (v), rotational speed (ω), and tablet radius (r). A design equation which relates dissolution rate (R) to these variables was formulated for the system R α CsD2/3(v) −1/6(ω) 1/2( r)3/2 This design equation adequately represents the system, which is related to fluid mechanics and convective diffusion models. The fluid mechanics model assumes that the fluid ideally rotates as solid-body rotation and the momentum layer is initiated at the outside radius of the tablet die. The convective diffusion model is based on the formation of a diffusion layer at the outside radius of the dissolving surface and a predictable relationship between the momentum and the mass transport quantities of bulk viscosity and diffusion coefficient. This configuration, like the rotating disk in a stationary fluid, offers the attractive attribute of being useful to study drug release mechanisms for systems of pharmaceutical interest.

Tye Aqueous Solubility of Variously Substituted Barbituric Acids. I. Chemical Effects

AbstractThe aqueous solubility of fourteen variously substituted barbituric acid was determined at 25°C. There was an approximate relationship between aqueous solubility and the duration of activity. The magnitudes of solubility varied substantially for these compounds and these results are based upon the net chemical grouping effect from compound to compound. While several compounds possessed rather similar melting points, the solubilities also varied to a large extent. These results are discussed further in this communication.

Design and evaluation of a rotating filter-magnetic basket apparatus: tablet and basket position

Abstract The authors have designed a dissolution device which combines the properties of a rotating filter device developed by Shah and a magnetic basket designed by Shepard et al. The effects of stirring, tablet and basket placement were investigated. Visualization of flow and dissolution patterns was possible by testing non-disintegrating salicylic acid tablets containing 3% phenolphthalein in 0.1 N sodium hydroxide solution. Dissolution experiments were conducted on non-disintegrating salicylic acid in pH 7.4 U.S.P. phosphate buffer at 37°C. For the tablet placement experiments one tablet face and the tablet land was coated so that only a single tablet face was available for dissolution. The data for the same size tablets placed at the side of the bottom and at the center of the bottom of the dissolution fluid container indicated the importance of exact placement of a tablet in a dissolution fluid container. The differences in face position of the tablet either with or without a magnetic basket present indicates the importance of face position which must be accounted for especially in the testing of double-layer sustained release products. Through the dissolution data and the visualization studies the authors have characterized the hydrodynamics of this device.

Comment on the Importance of Data Transparency, Openness, and Reproducibility in Dissolution Science and Technology

A recent editorial published in Science by Jeremy Berg emphasizes that “ideas supported by welldefined and clearly described methods and evidence are one of the cornerstones of science” (1). The broad importance of this topic is reflected by a current project entitled Reproducibility and Replicability in Science undertaken by the National Academies of Science, Engineering, and Medicine to “assess research and data reproducibility and replicability issues, with a focus on topics that cross disciplines”(2).

Physicochemical Properties of Buffers Used in Simulated Biological Fluids with Potential Application for In Vitro Dissolution Testing: A Mini-review

This literature review focuses on the physicochemical properties of buffers used in biorelevant media for in vitro dissolution testing. Because biorelevant dissolution systems have been previously reviewed, this review is primarily related to the buffers used in biorelevant media and not the media, per se. It is based on a survey of the literature in areas including analytical chemistry; biochemistry; clinical, solution, and physical chemistry; dissolution science and technology; pharmaceutical sciences; simulated biological fluids; and buffer-related articles from the National Institute of Standards and Technology with the intent of identifying challenges in formulating buffered biorelevant dissolution media and also identifying general attributes that are useful in selecting a buffer for a particular dissolution application. Other topics include: (1) key physicochemical properties of buffers that affect experimental conditions and dissolution results; (2) buffer compatibility with a diverse array of ingredients found in biorelevant media; and (3) the potential to supplement the library of traditional buffers used for in vitro dissolution testing with zwitterionic buffers that were designed for biological application.

Formulating Buffered Dissolution Media for Sparingly Soluble Weak Acid and Weak Base Drug Compounds Based on Microenvironmental pH o Considerations

The theoretical framework for dissolution of weak acid and weak base drug compounds in buffered media is well established. Therefore, this article is intended to provide a review of this framework and apply it to formulate buffered dissolution media based on ionic equilibrium conditions within the diffusion layer at the solid–liquid interface. The pHo in the microenvironment is identified as a singularly important parameter that reflects ionic interactions between dissolving drug and buffer at the solid–liquid interface. This article is focused on (1) formulating buffered dissolution media based on ionic equilibrium conditions at the solid–liquid interface, (2) identifying key physicochemical parameters for both drug and buffer that are relevant to buffer formulation, and (3) providing experimental and calculation-based methods to estimate the pHo at the solid–liquid interface. A shift in emphasis from relying solely on bulk buffer pH properties forms a basis for formulating buffered dissolution media and also provides insight into the physicochemical factors that affect the dissolution rate of the drug compound.

Evaluation of a rotating filter apparatus: hydrodynamic characterization through modeling

Abstract In this study a rotating filter was evaluated using a two-dimensional convective diffusion model. Experimental model testing involved analysis of dissolution rates from non-disintegrating salicylic acid discs. For each dissolution run the disc was positioned at the bottom of the dissolution container. The tablets were coated so only a single salicyclic acid face on the side facing the stirrer was exposed for dissolution. Experimental variables included stirring speed, tablet radius and the distance of the tablet from the center of the container. From the data and visualization studies liquid flow inside the dissolution fluid container was described. The single-faced salicylic acid tablets proved to be an excellent system with which to test the convective diffusion model. The results seem to support the proposed convective diffusion theory which indicates the numerical exponents for stirring speed and tablet radius are 0.5 and 1.5, respectively.