(M1530-06-32) How the Physical Form of Mannitol Affects Tablet Ejection Force

Purpose: Ejection Force (EF) experienced during tablet compression is the combined result of the Active Pharmaceutical Ingredient (API) physical properties, excipient selection, and compression parameters. High EFs can negatively impact the manufacturing process to a level where industrial manufacturing may not be economically viable anymore. EFs may increase through a detrimental combination of API and excipients. API properties, type of filler, lubricant level, and speed of manufacturing all impact EF to some extent. Mannitol naturally occurs as a crystalline solid exhibiting poor flow properties, limiting its use as a pharmaceutical excipient to wet granulation applications. Advances in manufacturing technologies have yielded free-flowing spherical mannitol particles via spray drying, enabling its use in direct compression (DC) tablet manufacturing. The density of mannitol powder directly impacts tablet characteristics such as hardness and strength. This study focuses on the impact of mannitol as a filler on EFs during DC tablet manufacturing. The study also investigates the impact of a model drug (ibuprofen) on the EF observed during compression.

Methods: The desired amounts of mannitol, ibuprofen, and magnesium stearate were weighed out with respect to their percent make-up in final blend. The mannitol and ibuprofen were mixed using a Turbula T2F mixer for 5 minutes at 49 rpm. Magnesium stearate was then added to the blend and mixed for 2 minutes at 49 rpm. Tablet compression was done on the STYL’One Evolution Compaction Simulator using Euro B 10mm standard convex tooling and Euro B Elizabeth D10R10 die while simulating the Korsch XL 400 Euro B tableting machine. Compression was performed at five compression forces of 5, 10, 15, 20, and 25 kN and up to four speeds including 10 rpm, 25 rpm, 50 rpm, and 100 rpm.

Results: Particle deformation can inherently be either plastic, elastic, or brittle. Brittle materials are known to produce high EF due to the generation of new, unlubricated surfaces during compression. For mannitol powders, an increase in the compression force does not always result in a harder tablet. Impact of mannitol density: As a tablet is compressed, air is forced out of the powder, drastically increasing the contact surface area of the individual particles. In certain situations, if the air is removed too quickly, a fault line may be developed which may cause the tablet to split in half (capping). When starting with a higher density mannitol, the amount of air that needs to be removed is reduced, thereby also reducing the capping tendency for a tablet. Figure 1a compares two mannitol grades P 200 SD and P 200 GT with a density of 0.48 g/cm3 and 0.63 g/cm3 respectively. Lubrication level: Lubricants decrease tablet ejection forces by reducing friction between the die wall and tablet. Figure 1b demonstrates the effect of the level of magnesium stearate on the tablet ejection force. At low lubrication level of 0.5%, tablet manufacturing process experiences high ejection forces of 800 N at low manufacturing speed (10 rpm). Increasing the lubrication level to 1% decreased the ejection force to 400 N. Further increase in lubricant levels did not significantly decrease the ejection forces. Speed of manufacturing: Turret speed controls the dwell time in which the air is pushed out of the tablet during compression. At higher manufacturing speeds, the time for pushing air out of the tablet is greatly reduced. Ejection forces can drastically increase at higher manufacturing speeds (Figure 2) due to the reduced dwell time. Impact of the API: Certain APIs have a tendency to increase ejection forces during tablet manufacturing due to inherent properties such as brittle fracture and adhesive forces. In these situations, it is critical to select a tablet filler that complements this effect. Figure 3 shows high EF generated with low-density mannitol and corresponding EF lowering by substitution with a high-density mannitol. The EF lowering is a combined result of less air in the blend as well as lower level of fines. The data shown contains 10% ibuprofen.

Conclusion: Factors impacting the ejection force on tablet compression were evaluated while using mannitol as a filler. Impact of mannitol grade, amount of lubricant, and speed of manufacturing on ejection forces experienced during tablet manufacturing were demonstrated. Formulations consisting of a crystalline active-ibuprofen demonstrate ejection force lowering ability of higher density mannitol (P 200 GT). These are important considerations for early-stage formulation development with a potential to positively impact commercial scale manufacturing. Selecting the right mannitol type, optimizing lubricant levels, and optimizing process parameters is crucial for a successful product.

Figure 1: (a) Impact of mannitol density on tablet capping (b) Impact of magnesium stearate level on placebo mannitol tablet compression.

Figure 2: Ejection force increases at higher tablet compression speed.

Figure 3: Impact of API: Ejection force lowering effect of P200GT (high density) in comparison with P200SD (low density) mannitol powders.