Date of Award

1991

Degree Type

Dissertation

Degree Name

Doctor of Pharmacy (PharmD)

First Advisor

Christopher T. Rhodes

Abstract

In the pharmaceutical industry, the product and process development problems usually involve a number of independent variables and are normally characterized by multiple objectives. Computer optimization techniques consisting of statistically valid experimental design can be employed to provide an economical way to obtain efficiently these multiple response parameters.

Acetaminophen is a poorly compressible analgesic and very large tablet with high dose level resulting in a corresponding very large table and poor compactability, the amount of added compressible excipient required to produce acceptable compaction behavior therefore is increased. Also, most commercially available high does (500 mg) acetaminophen tablets are manufactured from slugging or a pateneted roller-compactor process. In this present study, the utility of 50 micron microcrystalline cellulose (Emcocel) as a wet granulation excipient in the high does acetaminophen tablet formulation was investifated. A four factor factorial, central, composity Box-Wilson experimental design was applied to optimize a tablet forumlation containing high dose (500 mg) acetaminophen (ACMPT), EmcocelTM, a 50 micron microcrystalline cellulose (MCC), and povidone. The percentage of EmcocelTM,, percentage of povidone amount of granulating water and wet granulation time were used as independent variables for optimizing some tablets response parameters. Response parameters for final ACMP tablets were percentage of ACMP dissolved at fifteen, minutes, disintegration time, required compression force was producing 8 Kg hardness tablets and friability. The data were analyzed by means of quadratic response surface models. Response surfaces were generated for tablet percentage of dissolution, disintegration time, required compression force and friability as a function of independent variables. The models were validated for accurate prediction of response characteristics and used to identify the optimum formation. The results suggest that an optimum 500 mgACMO tablets having a volume similar to commercial products made by precompacted ACMP can be produced by wet granulation process utilizing 50 micron EmcocelTM. The tablets made also showed acceptable dissolution behavior, hardness, disintegration time and low friability when compared to commercially available 500 mg ACMP tablets.

Additionally, a two factor factorial central, composite Box-Wilson experimental design was employed to develop and optimize a novel extended release floating and biodhesive tablet formulation containing 240 mg stalol hydrocholiride and polymeric components. The ration of sodium carboxymethycellulose (NaCMC) to hydroxypropylmethycellulose (HPMC) and the ratio of ethycellulose to crossprovidone were used as formulation variables for optimizing some tablets response parameters, such as biodahesive capability, dissolution characteristics, tablet density and required compression force by means of quadratic response surface model. Response surfaces were generated as a function of formulation variables. An optimum direct compression bioadhesive and floating tablet formulation of sotalol HCI tablet was achieved by considering dissolution release characteristic as primary objective and using required compression force, bioadhesive capability as constraints within the experimental region. The surface model was validated by preparing and evaluating the predicted optimum formulation.

To understand the release mechanism of drug from extended release polymeric matrix tablet, the swelling and dissolution behavior of different molecular weight PEO ) polyethylene oxide) polymers in distill water at 37 °C was investigated. Due to the swelling of PEO matrix discs, considerable volume expansion was observed. Molecular weight is an important determinant of PEO dissolution rate, which was inversely proportional to the molecular weight of PEO. The results supported the hypothesis that dissolution of high molecular weight of PEO is controlled by the inward diffusion of water and outward diffusion of polymer through the boundary layer. The influence of the molecular size and solubility of four tracer (phenylpropanolamine HCI, theophylline, sotalol HCI and bovine serum albumin) and the effect of the tracer/PEO ratio on the dissolution rate in SIF (simulated intestinal fluid) were determined.

In the process of bioadhesion assessment, as apparatus to be equipped with Instron tensile tester was developed to evaluatie quantitavely the bioadhesive properties of vaious bioadhesive tablets. The equipment was designed to measure the forces required to separate two parallel surfaces (tablet and membrane) in both horizontal and vertical planes. In this work, in addition to the detachment force and adhesion work, the shear force necessary for separating bioadhesive tablet and synthetic membrane or biological tissue (rabbit stomach mucosa) were also determined since the majority of gastrintestinal mocosasurface area possess some elements of tangential shear motion. The effects of different quantities and types of bioadhesive polymer on the tablet bioadhesive capability were also determined. The results showed good agreement with some previous findings that the relative adhesion of the tablet formulations was dependent on the bioadhesive polymer content. It was also found that tablet made with sodium carboxymethycellulose (NaCMC) possessed the best bioadhesive power when compared to tablets made with polycarbophil and carbopol 974P.

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