Fred A. Rowley Solid Dosage Training
Pharmaceutical and nutraceutical production personnel often struggle to achieve the same tablet hardness as that achieved during R&D and sometimes fail to reach even the specified minimum hardness. While the tablets may be fine in all other aspects, such as weight, thickness, and disintegration time, they are softer than those produced during R&D. Insufficient tablet hardness can lead to defects such as lamination and erosion of some tablets during coating. Often, the problem is related to blending, and fixing the problem begins with a new understanding of the blending unit operation.
Total volume versus working volume
A blender’s total volume (or capacity) is the total amount of material the vessel can hold, typically expressed in liters. A blender’s working volume is the amount of material the vessel is capable of mixing at once, also typically expressed in liters and sometimes given as a narrow range.
When discussing working volume, it can be helpful to use the term “occupancy,” which more accurately describes what we are trying to achieve. Every blender class has a target fill level—an ideal occupancy level— regardless of the material’s weight and bulk density. For example, 5 kilograms of popcorn will occupy a different volume of space than 5 kilograms of wet sand in a blender, so the ideal occupancy level of popcorn for a given blender will have a different weight than the ideal occupancy level of wet sand for that same blender.
Successful scale-up depends in part on understanding this concept of occupancy. Blender classes such as twin shell, double cone, cube, and bin, each have different target fill levels. Even slight changes in a blender’s fill level or rotation rate during operation can induce changes in the material’s mixing pattern that may result in segregation. The further away the blender’s fill level is from the target, the more trouble you’re likely to have.
Regardless of a blender’s size, when particle velocities in specific regions of the vessel are below a critical value, one mixing pattern appears, and when the particle velocity increase above that value (through a change in the rotation rate or fill level, for example), a different mixing pattern emerges, which can result in a different blending outcome. This effect increases the further the fill level strays from the target unless you alter the corresponding blending and lubrication times.
Blending action
All tumble blenders (also called gravity blenders) operate primarily on the principles of diffusion blending (up and down, around and around) and axial blending (side to side). Under the FDA’s scale-up and post-approval changes (SUPAC) guidance1, eight subclasses of dry powder blenders are currently in use in pharmaceutical and nutraceutical manufacturing. The most common are listed in Table 1.
Notice that these subclasses use varying ratios of diffusion versus axial blending. In addition, for twin-shell and double-cone blenders, the ratio of diffusion versus axial blending varies between first- and second-generation models, as shown in Figure 1.
Some classes of blenders have less-than-optimal ratios between diffusion and axial blending and may not be capable of precisely blending cohesive or static-sensitive active ingredients. Examples are high-energy horizontal blenders, bin blenders, and cube blenders.
Component blending
Because each formulation contains different components and a unique ratio of particle sizes and shapes, some formulations will blend and lubricate much faster than others in the same blender. The unique end point of component blending is well defined in the FDA’s SUPAC IR2 and “Uniformity of Dosage Units”3 guidance documents. Blend studies determine the proper endpoint for content but offer no real help in determining when the lubricant is properly distributed.
Lubricant blending
Once you have documented what kind of mixing behavior you have, you can determine the optimal lubricant mixing time. There is no magic formula. Also, the idea that most or all of the particles in a blend must be coated with lubricant for successful tablet compression is a myth. This would insulate the particles and prevent them from bonding to each other during tablet compression, as shown in Figure 2. Die lubrication is accomplished by having lubricant particles in direct contact with or close to the die wall. These particles are smeared on the die-wall surface as the punch tip moves into the die bore, effectively forming a film of lubricant, which is not necessarily uniform or continuous. Some of the lubricant remains on the punch tips and in the die after tablet compression.
Thus, the nature of lubrication between the formulation and the die wall is mixed, where both adequate and inadequate contact between the unprotected metal surfaces of the punch and die results in smooth tablet ejection or partial adhesion/release and sometimes even partial seizure, which produces lamination at the bottom of the tablet. The pressure applied to the die during tableting is not uniform, which sometimes causes uneven and heterogeneous pressure on finished tablets. Over lubrication of particles insulates them and prevents the bonding required to form hard tablets. Following these principles, the proper ratio of diffusion and axial blending combined with the correct component blending time and blender speed, will produce a high degree of homogeneity in the blend.
Equipment supplier differences
In the past, twin-shell and double-cone blenders were under patent. With those patents expiring, any company can make a blender, and those blenders may be SUPAC equivalent yet produce very different results when using the same processing parameters.
This problem also occurs in bin, cube, and octagonal blenders, where the blender shapes differ greatly, yet the blenders are expected to produce equivalent lubrication. And the differences don’t stop at the vessel shape; there is also no universal approach to baffle configuration or placement, as shown by the examples in Figure 3.
Conclusion
If R&D was able to obtain both the target and maximum tablet hardness values and establish a specification but production cannot achieve those values, something has changed, and that change may have been to the blending process. Causes of soft tablets include using a different blender fill volume (occupancy), a key raw material with a different bulk density, a different blender type (though it may be SUPAC-equivalent), a different lubricant morphology, or all of the above (see Table 2). These blending-related process differences can have real impacts on tablet hardness and can be damaging to product quality if not addressed.
References
1. “SUPAC: Manufacturing Equipment Addendum Guidance for Industry.” December 2014. Available at: https://www.fda.gov/regulatory-information/searchfda- guidance-documents/supac-manufacturingequipment- addendum.
2. “SUPAC-IR: Immediate-Release Solid Oral Dosage Forms: Scale-Up and Post-Approval Changes: Chemistry, Manufacturing and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation.” November 1995. Available at: https://www.fda.gov/regulatory-inform ation/search-fda-guidance-documents/supac-ir-immediaterelease- solid-oral-dosage-forms-scale-and-post-approvalchanges- chemistry.
3. “Q4B Annex 6: Uniformity of Dosage Units General Chapter.” June 2014. Available at: https://www.fda.gov/ regulatory-information/search-fda-guidance-documents/ q4b-annex-6-uniformity-dosage-units-general-chapter.
Fred A. Rowley is president and chief guest lecturer at Solid Dosage Training (925 352 5724, bostonmarathonironman@ yahoo.com). Rowley is also a member of Tablets & Capsules’ editorial advisory board.