INTERPHEX USA 80-1 ROUTINE EVALUATION OF FILM COATING PROCESSES. M. Talei, Pharm.D., Ph.D. ALZA Corporation Palo Alto, CA INTRODUCTION

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1 80-1 INTERPHEX USA ROUTINE EVALUATION OF FILM COATING PROCESSES M. Talei, Pharm.D., Ph.D. ALZA Corporation Palo Alto, CA INTRODUCTION Film coating of solid dosage forms has been carried out in the pharmaceutical industry for its esthetic as well as protective values, such as controlling the dissolution behavior of the product. Evaluation of independent formulation and process factors that may affect the quality and functionality of the membrane has become of prime concern. Formulation factors, such as the tablet core, polymer, and additives, may influence membrane characteristics. Process variables, such as the solvent concentration, flow rate, and the temperature at which the coating solution is applied onto the tablet substrate, also may affect membrane characteristics, as well as the process efficiency. Efficiency of the operation depends, to a large extent, on the type of equipment and the mode of application used in the film formation. All these factors show the need for a simple technique for routine evaluation of film coating processes with the ultimate goal of its optimal standardization. Optimization may be achieved if accurate measurements from reliable dependent variables e.g., membrane weight and thickness were made throughout the operation. Time analyses of variations among samples will indicate the extent of process dependability. The optimization criterion is used to investigate all factors that affect the membrane deposition pattern and the process variation in an attempt to reduce the variation to an ideal minimal level. Studies such as the one reported here could be potentially useful in evaluating aqueous-based film coating systems, which have been the recent trend in the pharmaceutical industry. 2 THEORETICAL CONSIDERATIONS In a tablet bed, the time courses of the membrane weight (Wt) and thickness (Ht) may be expressed by: Wt = c f n t (1) and Ht = c f t n p s (2) 1

2 Where c is the percent solids (w/v) of the coating formulation; f, the solution flow rate (cm³/min); n, the number of tablets; s, the surface area of the tablet (cm²); and p, the density of the deposited membrane (g/cm³). Dividing equation (2) by equation (1) yields: Ht = 1 Wt p s (3) which defines the relationship between membrane weight and membrane thickness. With the surface area of the tablet known, linear regression analysis of the data collected on membrane weight and thickness at intervals throughout the coating operation will yield the density of the membrane in its applied form, as determined by the slope of the line according to equation (3). For the dynamic time-analysis, process efficiency may be defined as the ratio of experimentally obtained W t over the expected W t, as calculated from equation (1) with known parameters. An alternative to that is a single-value efficiency ratio. Equations (1) and (2) may be rewritten as: Wt = αt, where α = c f n (4) Ht = βt, where β = c f n p s (5) With known values for c, f, n, s, and p, the ideal slopes, α, and β, can be calculated from equations (4) and (5). Actual values for these slopes may be determined from collected experimental data. If the actual slopes are denoted by a and b, the efficiency ratios (i.e., actual slopes to the ideal slopes), a/α and b/β, can be calculated. As these ratios approach 1.0, the process becomes more predictable, and also more efficient. 3 EXPERIMENTAL The primary parameters involved in these calculations were concentration and flow rate of the coating solution, and the number of tablets in the tablet bed. It thus seemed appropriate to investigate the effect of these parameters on the process efficiency. Temperature was also examined throughout this study. The experimental conditions for the cases investigated are listed in Table I. Potassium chloride tablets with 1.11 cm diameter, surface area of 3/14 cm², average weight of g (99.5% active), and density of 1.85 g/cm³ were used in the coating operations. The coating solution was prepared by dissolving cellulosic polymers in a 20:80 (w/w) methanol: methylene dichloride (ACS) solvent system. INTERPHEX USA 2

3 Fluidized bed equipment 1 with an air-spray system was used for coating trials. The glass-coating chamber had a diameter of cm and a length of cm. An adjustable partition column of 7.62 cm diameter and cm length was placed within the coating chamber. The chamber was equipped with a sampler. The clearance between the perforation plate and the partition column, and the air flow rate (2-3 m 3 /min) were adjusted so as to obtain a smooth laminar tablet flow throughout the 1-2 hour coating trials. Samples of ten tablets were removed every 10 minutes throughout each coating trial and dried overnight in a 50 C oven. The dried tablets were then marked and individually weighed. The membrane weight was calculated by subtracting the tablet core weight from the coated system weight: Wt = Coated tablet wt. Uncoated tablet wt. (6) Three coated tablets from each sample were randomly selected. These tablets were then sliced through the center using a sharp razor blade and exposed to heated iodine vapor to enhance the visibility of the membrane. Microscopic 2 measurements of membrane thickness were taken, eight at the center of each tablet and four from each side. 4 RESULTS AND DISCUSSION The effects of coating solution concentration on membrane deposition pattern, process efficiency, and density of the formed membrane will be discussed in detail in order to exemplify the utility of this approach. a. Coating Solution Concentration The four solution concentrations employed in this study were 1.9, 3.8, 5.7, and 7.6% (w/v). Figures lald show the average membrane thickness vs. average weight values of data obtained during coating trials with these solution concentrations. The lowest concentration (i.e., 1.9%) exhibited poor correlation between membrane thickness and weight values; in contrast, higher concentrations significantly improved the membrane deposition pattern, thereby indicating a more predictable and efficient process. The dynamic efficiency profiles for the coating trials with various solution concentrations are shown in Figure 2. Initially, efficiency values were substantially higher than the ideal 100% level possibly because of solvent sorption by the tablet and also random errors involved in weight measurements, which would have been reflected on the membrane weight, as shown by equation (6). Equilibrium, however, was observed after 20 minutes in most cases. A plot of the average process efficiency after this period against the solution concentration (Figure 3) demonstrated that the process efficiency was only 50% at a 1.9% coating solution concentration but approached 100% at higher concentrations. The wasted material had gone through the exhaust system since no dried films were found in the coating chamber. INTERPHEX USA 1 Wurster Unit, Dairy Equipment Co., Madison, WI 2 Mitutoyo Toolmakers Microscope, MTI Corp., Los Angeles, CA 3

4 The average membrane thickness and weight data were subjected to linear regression analyses. Table II summarizes the relationships between various variables and also contains the ideal slopes, calculated from equations (4) and (5). Figures 4 and 5 show the trends in membrane weight and membrane thickness with time during the coating trials. These figures further collaborate the findings of better, more predictable deposition patterns, as well as greater process efficiencies at higher concentrations. Figure 6 shows the average efficiency ratios (from Table II), as defined by a/α and b/β, plotted against the solution concentration. This figure indicates that efficiency was significantly affected by the solution concentrations employed in these coating trial. Regression analyses of thickness vs. weight values (Figure 1) yielded the membrane density in applied form. Data collected during the coating trial with 1.9% solution (Figures 1, 4, and 5) were so scattered as to make an estimate of membrane density unreliable from the slope of the membrane thickness vs. weight plot. For the other solution concentrations, however, satisfactory deposition patterns yielded reliable membrane density values (Table II). Figure 7 demonstrates that solution concentration significantly affected the density of the membrane. The density of a melt-pressed film was determined to be 1.33 g/cm 3. Spray coating of the film, as expected, reduced membrane density. Increasing the concentration of the coating solution caused a further decrease in the membrane density, possibly a result of a change in the solvent evaporation rate and/or polymer compaction. With increasing concentrations of polymer in the coating solution, solvent concentration decreased, resulting in a smaller volume of solvent being evaporated per unit time. With higher solution concentrations, the relatively small volume of solvent readily evaporated, resulting in a frozen polymeric structure, which had a large number of pores. The porous nature of the polymeric structure thus yielded a membrane of relatively lower density. At low concentration, the solvent was in such an excess volume that evaporation took a relatively long time. Throughout this drying period, high solvent concentrations in the deposited membrane allowed for closer packing of the polymer and hence, denser films. Based on this hypothesis, denser films might be expected at higher coating solution flow rates and also at lower coating temperatures. Both of these process variables should increase the drying time and allow for a higher degree of polymer compaction. b. Coating Solution Flow Rate Table III summarizes the data from the coating trials conducted with flow rates of 30, 50, 75, and 100 cm 3 /min. The coating operation performed with a 30 cm 3 /min flow rate gave a tremendous scattering among the data points, as reflected by the R 2 values of the best fits (Table III). Further increases in flow rate significantly improved the membrane deposition pattern, yielding process efficiencies close to 100%. Flow rate did no affect membrane density (Table III); the average density was 1.15 g/cm 3, which was substantially lower than the 1.33 g/cm 3 density of the melt-pressed film. These results thus indicated that, at all flow rates, drying was sufficiently rapid during one cycle time, which was the time needed for a tablet to move around the partition column once. INTERPHEX USA c. Tablet Bed Load 4

5 Table IV summarizes the data from coating trials with various tablet bed loads. Tablet bed load did not appreciably affect process efficiency; the average efficiency ratio was 85%. No trend could be established between load and membrane density. The tow extreme loads, however, seemed to have resulted in membranes with a slightly higher density than the middle-range loads. d. Coating Temperature Coating temperature had significant effects on process efficiency and membrane density (Table V). The process efficiency was close to 100% for coating temperatures between C. Because of excess heat at 65 C, premature drying of the membranes occurred, resulting in segments of dried film in the coating chamber; as a consequence, process efficiency dropped to 86%. An increase in the coating temperature augmented the rate of solvent evaporation, thereby producing a relatively more porous membrane of lower density. 5 CONCLUSIONS The simple technique of collecting and analyzing membrane thickness and weight data throughout film coating operations was shown to be of some utility. Most operational parameters have impact on the pattern of membrane deposition, process efficiency, and membrane morphology. For coating trials with solution concentrations below 3.8% (w/v), flow rates less than 50 cm 3 /min, and temperatures above 55 C, the patterns of membrane deposition were unsatisfactory and process efficiencies were very low for the cases studied. Tablet load did not have any appreciable effect on these variables. The influence of some process parameters on characteristics of the formed membrane was quite significant. Higher coating solution concentrations or coating temperatures produced membranes that were more porous and that consequently had lower densities. 6 ACKNOWLEDGMENT The author wishes to express his gratitude for the invaluable technical support of Mr. D. Bates in conducting the experiments and Ms. S. Parkinson for performing the microscopic measurements. The author thanks Dr. F. Theeuwes and Mr. J. Yuen for reviewing this manuscript and Dr. S.K. Chandrasekaran for his support and comments. INTERPHEX USA 5

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Real-Time Prediction of Polymer-Coated Multiparticulate Dissolution using Process Analytical Technology Authors: Piyush Patel A, Edward Godek B, Chris O Callaghan C, Dr. Ian Jones D A Colorcon, PA, USA