TABLETING FORMULATIONS AND PROCESSES: EXAMINATION OF THE ADSORPTIVE PROPERTIES OF MICROCRYSTALLINE CELLULOSE AND THE DEVELOPMENT OF A COMPARATIVE COST MODEL AND SIMULATION FOR PHARMACEUTICAL TABLETING PROCESSES

ROBERT MICHAEL FRANZ, Purdue University

Abstract

The drugs fluphenazine dihydrochloride and promethazine hydrochloride have been shown to adsorb to various pharmaceutical excipients. Microcrystalline cellulose is a common tablet excipient frequently used in both direct compression and wet granulation tablet formulations. In the first section of this study, experiments were conducted to determine if the above phenothiazine derivatives adsorbed to the tableting excipient microcrystalline cellulose in vitro. It was necessary to undertake studies to determine how this adsorption phenomenon was affected by the type of phenothiazine derivative, the type of microcrystalline cellulose (Avicel 101 or Avicel 105), the effect of ionic strength adjustment, the electrolyte used to adjust the ionic strength, and the pH. A standard ultraviolet spectrophotometric technique was used to determine the amount of phenothiazine derivative remaining in the aqueous supernatant of a drug-cellulose suspension after equilibrium adsorption was attained. It was found that these drugs are significantly adsorbed to microcrystalline cellulose. Fluphenazine dihydrochloride was adsorbed to a greater extent and appeared to have a stronger interaction with the microcrystalline cellulose surface than did promethazine hydrochloride. The smaller the particle size of the microcrystalline cellulose, the more drug was adsorbed. The adjusted ionic strength, the pH, and the valency of the cation used to change the ionic strength all had a major effect on the extent of adsorption. The adsorption process was rapidly and completely reversed in vitro at gastric pH values and ionic strengths. The hypothesis was made that the adsorption phenomenon could possibly affect the content uniformity of fluphenazine dihydrochloride and promethazine hydrochloride tablets by decreasing drug migration during the drying operation of a wet granulation tablet manufacturing procedure. In the second part of this research, a simulation model and a subsequent computer program were developed as experimentation methods for evaluating tableting processes with respect to cost. These methods also allow estimation of the various times involved in a tableting operation (i.e., the processing time). The model was programmed in FORTRAN using the GASP IV simulation language. After verification and validation of the program, two separate studies were conducted using the simulation model. The first study evaluated the costs and processing times involved in the preparation of a tablet product by the direct compression or wet granulation procedure at two different batch sizes. The second study compared different levels of specific input variables to determine which variables had an effect on the cost-time relationships of a particular tablet processing method. Among the possible input variables chosen for evaluation were the drying method, the type of tableting machine, the batch size, the labor rate, and the utilization of the equipment in the process. An analysis of variance was performed, and from regression analysis of the data three regression equations were developed that described the relationship between the input variables and the dependent variables of processing cost and time. Graphs were developed from the regression equations by manipulating them through a series of different independent variables. These graphs then were used in determining minimum costs and times, breakeven points, and rates of change, as well as in evaluating processes through graphic representation. By using the simulation program to run experiments and then by analyzing them, results may be obtained that can be an aid in decision making about the cost-time relationships of a particular tableting procedure before it is implemented.

Degree

Ph.D.

Subject Area

Pharmaceuticals

COinS