Date of Award


Degree Type


Degree Name

Doctor of Philosophy in Pharmaceutical Sciences


Interdepartmental Program

First Advisor

Hossein Zia


Majority of the drug substances are administered to patients in the form of oral solid dosage forms. The drug substance is mixed with excipients and the resulting powder blend is compressed into tablets. For a pharmaceutical powder to be compressed into uniform solid dosage forms, it is essential that the powder blend has good flow and compaction properties. The flow and compression properties of a pharmaceutical blend depend on the physicochemical properties of the individual components and their relative proportions in the mixture. Poor compressibility along with the poor flowable nature of most of the pharmaceutical mixtures poses tremendous challenges during the scale up and production stages. Vast majority of the tableting research was performed using single components though a typical tablet is a multi-component system. In this investigation, an attempt was made to study the flow and compression behaviors of multi-component mixtures containing several of the most commonly used pharmaceutical excipients. The effect of triboelectric charging during powder processing was also evaluated. The objectives of this study include: i) to investigate the relationship between the individual components and their mixed systems; ii) to analyze and predict the flow behavior of a mixed system from individual components using an experimental design; iii) to determine the optimum conditions for a mixture to exhibit better flow behavior; iv) to investigate the compression behavior of statistically designed multi-component mixtures using an instrumented tablet press; v) to determine the effect of mixing time, mixer type and batch size on triboelectrification of powders in a high shear mixer; and vi) to compare the antistatic effect of different lubricants/glidants on electronegative and electropositive materials. ( Lactose Anhydrous (97%w/w) blends were prepared with 3%w/w lubricant/glidant(s) in a planetary mixer as per simplex experimental design. The lubricants evaluated were: magnesium stearate, NF, stearic acid and colloidal silicon dioxide, NF (Cab-0-Sil M5). The relative amounts of lubricants/glidants were varied from 0 to 3% as per simplex design. One set of powder blends were prepared with a constant mix time of 3 minutes. Another set of powder blends were prepared with varying mix time until a relatively constant value for bulk density was achieved for specific blend. A total of ten powder blends of 500 grams each were prepared for each experiment. Response surface methodology was used to correlate the variation in lubricant/glidant(s) with the flow behavior. The powder blends and individual components were evaluated for bulk density, tapped density, aerated bulk density, packed bulk density, compressibility index, angle of repose, angle of spatula, angle of fall, angle of difference, cohesiveness, dispersibility, moisture content and particle size distribution. The data was analyzed using StatGraphics software and the special cubic model was fitted to generate mathematical equations. Contour plots were obtained to interpret the flow behavior of powder blends as a function of mixture composition. The compression behavior of experimentally designed multi-component mixtures using an instrumented tablet press was studied. The mixtures comprised of anhydrous lactose, NF, microcrystalline cellulose, NF (Avicel® PH101) and pregelatinized starch, NF (Starch 1500) with individual quantities varying from 0 to 99% w/w based on a simplex design. Magnesium stearate, NF was added as lubricant at 1 % w/w level. The batch size was 900 grams (equivalent to 3000 tablets). Ten experimental mixtures were prepared in a Collette Gral 10 High Shear Mixer with 3 minutes of pre-blending and 1 minute of lubricant mixing. The powder mixtures were ( evaluated for bulk and tapped densities, particle size distribution and moisture content. The powder blends were compressed using a 10-station instrumented Piccola rotary tablet press (Model: 026 BIO) equipped with a compression research system (PC-30, SMI Inc.). Tablets were prepared with 12/32" standard concave tooling with compressjon forces of 1000 lbs, 2000 lbs, 3000 lbs, 4000 lbs, 5000 lbs, 6000 lbs and maximum achievable force. The compression force-time profiles were recorded to measure the compression force and ejection force for each compression cycle. The tablets were evaluated for hardness, weight, thickness, friability and disintegration time. The true densities of tablets and powder blends were measured using a helium pycnometer (Ultrapycnometer 1000). The compression force-time pulses for all the mixtures at each compression force were compared to investigate the effect of mixture composition on the compression behavior of powder blends. Events such as rise time, fall time, dwell time, contact time, areas and pulse widths that characterize the nature of each compression pulse were evaluated using a response surface method (StatgraphicsP/us). Tablet surface area and volume was calculated using Natoli computer program. Contour plots were generated to study the effect of formulation composition on bulk density, tablet hardness, dwell time, total area of compression force-time curve, ejection force, tablet surface area, and porosity. Heckel relationships were plotted using the compressibility model. The effect of high shear mixing on electrical properties of pharmaceutical materials such as pregelatinized starch (Starch 1500), microcrystalline cellulose (Avicel® PHIOI) and cimetidine formulation (cimetidine:lactose anhydrous:Avicel® PHIOI:Starch 1500: lubricant = 69:10:10:10:1) was determined as a function of mixing time. Different lubricants/ glidants such as magnesium stearate, stearic acid, ( colloidal silicon dioxide (Cab-0-Sil MS) and sodium stearyl fumarate (Pruv®) were evaluated for their antistatic effect. The selected material(s) were screened through a 30-mesh hand screen and were mixed in a Collette Gral 10 high shear mixer for 10 minutes at a mixer arm speed of 660 rpm and a chopper speed of 3000 rpm. Lubricant/glidant at 1 % w/w level was added to the pre-blend and the mixing was continued for an additional 3 minutes. The electrostatic charges on powder blends were measured using the Faraday Cup connected to NanoCoulomb Electrometer after 0, S, 10, 11, 12 and 13 minutes of mixing. Mixer type effect was evaluated by mixing powders in Collette Gral 10 high shear mixer and Kitchen Aid Planetary Mixer and determining the electrostatic measurements. Batch sizes of O.S kg and 2.S kg were evaluated to determine the batch size effect on triboelectrification during high shear mixing. The last contact surface for all electrostatic measurements was kept constant with teflon coated stainless steel surface. From different flow parameters evaluated for lactose anhydrous blends, it can be summarized that the relationship for powder properties between the mixture and its components is non-linear. Significant differences were observed in the flow behavior of powder blends obtained with constant mixing time and those obtained with variable mixing times. Among the three variable components as per the simplex design, Cab- 0-Sil MS had a significant effect on the time required to achieve the constant bulk density for a specific powder blend. It was demonstrated that using the special cubic simplex design, the flow behavior of lactose blend can be optimized. For constant mix time study, the model predicted that Lactose Anhydrous would show optimum flow behavior with formulation composition of 0.2S%w/w Magnesium Stearate, 1.48%w/w Stearic Acid and l .27%w/w Cab-0-Sil MS. Thus from the response surface contour ( plots and the mathematical model equations, one can determine the composition of the flow enhancers required, mix time to achieve constant bulk density so that the final blend will display optimum flow behavior. The statistically designed powder blends comprising Lactose Anhydrous, Avicel® PHlOl, Starch 1500 and Magnesium Stearate were compressed using an instrumented tablet press. The compression force-time curves and ejection force-time curves were evaluated and critical compression parameters such as ejection force, dwell time, tablet surface area, porosity and Heckel plots were determined. The compression parameters generated in this study, provide valuable insights into how multi-component mixtures behave under pressure. The key findings can be summarized as follows: The weight variation, tablet thickness, tablet surface area and volume of tablets increased with an increase in the concentration of Starch 1500 in the mixture. As the level of A vice!® PH 101 in the blend increases, so does the hardness profile for tablets. Maximum disintegration times were observed for tablets prepared from blend containing Avicel® PH101 and Lactose Anhydrous at 49.5% level. Maximum dwell time of 107 msec was observed for 99% Lactose Anhydrous at maximum achievable force (~8500 lbs) and a minimum dwell time of 51 msec was observed for the same blend at 1000 lbs of applied force. The compressibility of blends increased with an increase in the amount of Avicel® PHlOl in mixture. The amount of ejection force required for tablets increased with an increase in the concentration of Anhydrous Lactose in the blend. Tablets prepared from the blend containing 49.5% Anhydrous Lactose and 49.5% Starch 1500 displayed maximum amount of porosity. The presence of Starch 1500 has a significant effect on tablets with high porosity values. Heckel plots were generated to elucidate the densification and deformation mechanism of various mixtures. Based on the shapes of the curves, the dominant component of the mixture seems to dictate the deformation mechanism. In mixtures containing the components in equal amounts, the deformation mechanism seems to be complex. The results provide critical information on compression behavior of multi-component mixtures for comparative purposes as there are hardly any published reports in this area. When evaluated individually, cimetidine displayed electropositive charge whereas all other excipients displayed electronegative charges. Cab-0-Sil M5 was found to be the most electronegative whereas stearic acid was found to be the least electronegative among the excipients examined. Based on the results obtained in this study, when Starch 1500 was blended with 1 % lubricant/glidant in a Collette Oral 10 High Shear Mixer, the lubricants/glidants can be arranged as follows in the decreasing order of their ability to reduce the static charges produced during the blending process: magnesium stearate > Pruv® > stearic acid > Cab-0-Sil M5. For Avicel® PHlOl blends, the antistatic effect of the same agents can be arranged in the decreasing order as: magnesium stearate > stearic acid> Pruv® > Cab-0-Sil M5. As the mixing time with lubricants/glidants increased from 1 minute to 3 minutes, the antistatic effect seems to reduce. The antistatic effect of lubricants/glidants was dependent on the electrical charge behavior of the materials studied. The mixer design and type played an important role in determining the electrostatic charges of powder blends in pharmaceutical processing. Powders blended in Collette Oral 10 High Shear Mixer produced more electrostatic charges as compared to those blended in Kitchen Aid Planetary Mixer. The mixer loading also played an important role in determining the electrostatic charges of powder blends in powder processing. The triboelectrification ( of the blend in a high shear mixer decreased with an increase in the batch size from 0.5 kg to 2.5 kg. Thus by measuring static charges present on drugs/excipients during developmental stage, formulation scientist can utilize triboelectrification process to obtain powder blends that have low segregation problems. In summary, the results indicated that by varying the m1xmg time and/or relative proportion and type of lubricants/flow enhancers, it is possible to achieve powder blends with markedly improved flow properties. The current findings on compression behavior of multi-component mixtures will help formulation scientists to design and develop a robust tablet dosage form that meets the desired quality attributes and is free of processing problems during scale up and production. Selection of formulation components based on their electrical behavior will enhance the development of dosage forms that have good flow and compression behavior. With the advent of so many new polymeric materials, further studies will definitely shed more light on the complex process of compaction, since there are only a few published reports concerning multi-component mixtures are available so far.



To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.