design of experiments for tablet compression

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A Design of Experiments for Tablet Compression

The author prepared and analyzed a detailed design of experiments for the manufacture of a simple tablet formulation. The aim was to test whether tablet hardness and weight could be controlled during the compression process by adjusting certain machine parameters.

The tablet is perhaps the most common pharmaceutical dosage form, and the one with which patients are most familiar. Tablets have been a preferred dosage form for many decades, yet it is still challenging for formulation scientists to develop a robust tablet while minimizing the amount of waste created during the development process.

The current study was intended to determine whether tablet hardness and weight could be controlled during the compression process with proper adjustment to certain machine parameters. In this study, a Pharmatech MB015 intermediate bulk container (IBC) blender was used to prepare a blend consisting of microcrystalline cellulose (MCC, Avicel PH102, FMC BioPolymer) as the bulk ingredient and magnesium stearate (Ligamed) as a lubricant to improve flow behavior. The blend ratio of 98% MCC to 2% magnesium stearate was rotated in the asymmetrical IBC bin for 10 min at a speed of 20 rpm.

Following the blending process, the powder mixture was dispensed into a hopper above a Fette (Rockaway, NJ) 102i tablet press. The 102i is a 24-station research-scale rotary tablet press capable of producing 172,800 tablets/h at its maximum rotational speed. For this set of experiments, 12 of the tablet press's stations were set up, and the selected tablet tooling produced a standard convex round tablet with a 7.5-mm diameter and a cup depth of 0.79 mm. Pretrial testing was performed to establish upper and lower limits for the variables that were determined crucial to producing a robust tablet. All testing was performed during the course of three days in a controlled environment of 70 °F and 45% relative humidity.

Five parameters were selected as main variables for the tableting process. The first was turret speed, for which a limit of 20,000–70,000 tablets/h was set. The turret speed, normally converted from tablets/h to rpm, is simply the rotational speed of the circular table in which the tablet die sits. Increases in speed increase the production rate.

The second variable was feed-frame paddle speed, for which limits of 10–70 rpm were set. Tablet presses use either a gravity-fed feeder or a paddle feeder. The press used in this study incorporated a paddle feeder, which rotates several paddle wheels inside a housing where the powder blend is dispensed. The paddles sweep over the tablet dies and fill them as the paddles rotate. High speeds typically push more powder into the die cavity than low speeds do.

The third variable was tablet-cylinder height during precompression, for which limits of 2–4 mm were set. This variable represents how low the compression roller is set to force the tablet punches through the precompression zone to tamp down the powder and compact the blend slightly before main compression occurs. Large numbers indicate that less force is applied to the powder. Tablet-cylinder height is often converted into a force measured in kilonewtons. Small values typically result in hard, thin tablets, assuming that the amount of powder fill is constant. The purpose of precompression is to remove entrapped air from the filled tablet-die cavity. This task aids the main compression step in producing a robust tablet.

The fourth variable was tablet-cylinder height during main compression, for which limits of 2–3 mm were set. Like the precompression cylinder height, the main compression height is also set at a distance that directly affects the main compression force applied to form the tablet. Large numbers result in soft tablets. Small values typically result in hard, thin tablets, assuming that the amount of powder fill is constant.

The final variable was fill-cam height. A fixed fill cam of 12 mm was chosen for this study. The weight-adjustment ramp determines how low the lower tablet punch sits inside the die at the moment that the feed frame scrapes away the last of the excess material so that the material in the die cavity is level with the die table. This setting affects how much the final tablet will weigh. Large numbers result in heavy tablets. A large fill cam–weight adjustment height means that more powder will be inserted into the die, which typically results in a heavy tablet. The term "fill-cam height" is useful for the purposes of this study simply because it is a shorter description of the weight-adjustment process step.

A tablet is expected to conform to numerous requirements, such as dissolution rate, content uniformity, friability, and thickness. Only the following two responses were selected for the current experiments:

• Tablet hardness (kP): For this study, a Dr. Schleuniger (Manchester, NH) model 8M hardness tester was selected. The tablet is set into the test zone on its flat surface while an actuated arm squeezes the tablet until it fractures. The amount of kilogram-force needed to fracture the tablet is measured and recorded. Four tablets were tested from each experiment, and the average value was recorded.
• Tablet weight (g): During each experiment, 10 tablets were weighed on a Mettler Toledo XS603-S laboratory balance, and the average value was recorded.

Because each factor listed above had a wide range, the pretrial testing focused on producing a tablet with a testable hardness value. The lower limit for the selected Dr. Schleuniger model 8M is 0.8 kp. A tablet hardness of less than 0.8 kP is too soft to hold its shape and falls apart with gentle handling. The upper limit for tablet hardness was chosen based on the maximum allowable compression force of the selected 7.5-mm round tablet tooling. Once the Fette tablet press achieved the maximum allowable force, the upper precompression and main compression limits were selected at a value just below that of the maximum force.

Assuming excellent powder-blend flow properties, tablet weight is primarily a function of the fill-cam size and weight-adjustment ramp setting. Fill cams are produced by the tablet press manufacturer and come in a range of sizes. The cam size is selected according to the desired tablet thickness or weight range. Fill-cam selection also can depend on the shape and size of the tablet being produced. For the 7.5-mm round tablet used in this study, a fixed 12-mm fill cam was selected. This selection permitted the experiments to test the upper and lower limits of the cam size required to produce a tablet that held its shape when handled. It was determined that the weight adjustment ramp should be set to lower and upper limits of 8 and 10 mm, respectively.

Experimental process and screening-study results

Once pretrial experiments were completed, a broad design envelope was established using the five factors previously defined. A screening study was designed using a 2 5–1 -level fractional factorial approach, which produced 16 experiments, as opposed to a full factorial experimental design, which would require 32 experiments. Although only 16 experiments were performed in the screening study, the fractional factorial design produces the same resolution as the full factorial design. In addition to reducing time and material, this 2 5–1 fractional factorial design tests for interactions between each of the five factors. For the screening study, three centerpoint experiments were added to the design to test for nonlinearity (i.e., curvature in the data) and to help determine whether there was a significant lack of fit to the resulting model equation. Centerpoint experiments set all five factors to their midpoint between the low and high limits.

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Critical Tools in Tableting Research: Using Compaction Simulator and Quality by Design (QbD) to Evaluate Lubricants’ Effect in Direct Compressible Formulation

• Research Article
• Published: 11 May 2021
• Volume 22 , article number  151 , ( 2021 )

Cite this article

• Nailla Jiwa 1 ,
• Yildiz Ozalp 1 ,
• Gizem Yegen 2 &
• Buket Aksu 2  

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As commonly known, the product development stage is quite complex, requires intensive knowledge, and is time-consuming. The selection of the excipients with the proper functionality and their corresponding levels is critical to drug product performance. The objective of this study was to apply quality by design (QbD) principles for formulation development and to define the desired product quality profile (QTPP) and critical quality attributes (CQA) of a product. QbD is a risk- and science-based holistic approach for upgraded pharmaceutical development. In this study, Ibuprofen DC 85W was used as a model drug, Cellactose® 80 along with MicroceLac® 100 as a filler, and magnesium stearate, stearic acid, and sodium stearyl fumarate as lubricants. By applying different formulation parameters to the filler and lubricants, the QbD approach furthers the understanding of the effect of critical formulation and process parameters on CQAs and the contribution to the overall quality of the drug product. An experimental design study was conducted to determine the changes of the obtained outputs of the formulations, which were evaluated using the Modde Pro 12.1 statistical computer program that enables optimization by modeling complex relationships. The results of the optimum formulation revealed that MicroceLac® 100 was the superior filler, while magnesium stearate at 1% was the optimum lubricant. A design space that indicates the safety operation limits for the process and formulation variables was also created. This study enriches the understanding of the effect of excipients in formulation and assists in enhancing formulation design using experimental design and mathematical modeling methods in the frame of the QbD approach.

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Acknowledgements

The authors would like to thank BASF (Ludwigshafen, Germany) for generously donating Ibuprofen DC 85 W and Meggle (Wasserburg, Germany) for Cellactose® 80 and MicroceLac® 100 for our Ph.D. thesis study.

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Department of Pharmaceutical Technology, Faculty of Pharmacy, Near East University, Nicosia, Turkish Republic of Northern Cyprus

Nailla Jiwa & Yildiz Ozalp

Department of Pharmaceutical Technology, Faculty of Pharmacy, Altinbas University, Istanbul, Turkey

Gizem Yegen & Buket Aksu

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Jiwa, N., Ozalp, Y., Yegen, G. et al. Critical Tools in Tableting Research: Using Compaction Simulator and Quality by Design (QbD) to Evaluate Lubricants’ Effect in Direct Compressible Formulation. AAPS PharmSciTech 22 , 151 (2021). https://doi.org/10.1208/s12249-021-02004-y

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Received : 16 December 2020

Accepted : 27 March 2021

Published : 11 May 2021

DOI : https://doi.org/10.1208/s12249-021-02004-y

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