(208b) The Effect of Process and Design Parameters on Granule Content Uniformity in High Shear Granulation

In pharmaceutical products, uniform content of the active pharmaceutical ingredient (API) in the finished dosage form is a critical quality attribute (CQA). For high potent and low dosage drugs, the non-uniform distribution of API in the finished product can be extremely dangerous to the patient [1]. Regulatory agencies around the world including the food and drug administration of United States require the content uniformity test to performed as one of the measures to ensure quality of the final product [2]. For solid oral dosage forms such as tablets and capsules, the uniform distribution of API in the final product can be impacted by multiple unit operation such as mixing, granulation, blending, storage and tableting or capsule filling to name a few. Non uniform distribution of the API across the granule size during granulation process increases the chances of non-uniform final product due to size segregation which can occur while feeding the granules into tablet press or capsule filling machine [1]. High shear wet granulation process is often employed in pharmaceutical industry to convert the powder mix into larger granules to improve the flow property, bulk density, and to improve the homogeneity of the formulation ingredient [3,4]. Granulation also impacts the microstructure of the granules like porosity, and composition of granules across different size class which in turn affect the dissolution characteristics of the final product [4].

High shear wet granulation process steps includes a) addition and dry mixing of the raw materials using impeller in a granulation bowl b) addition of a liquid binder (binder solution or solvent) c) wet massing at higher impeller and chopper speed based on the product [5, 6]. Research studies show that the non-uniform distribution of API in granules can arise from any of these steps and can be affected by the process, formulation and design parameters of granulation [1, 3]. Particle size, material density, and the mixing conditions such as impeller speed and mixing time can contribute towards non uniform distribution of the material particles in dry mixing stage. Difference in the surface wettability of formulation component can also lead to non-uniform distribution of API by favoring or suppressing the interaction of particles with the binder droplet during the binder addition phase[1]. Coalescence, breakage, and consolidation during wet massing phase influence the re-distribution of individual components across the granule size classes [1]. The study performed to understand the origin of non-uniform distribution of material during wet granulation process by S. Oka. et al[1] shows that a sub-potent top layer at the end of dry mixing stage, during the wet granulation of a bi-component formulation, is one reason. The study also concluded that API concentration and wet massing time had the most significant impact on the uniform distribution of API in the granules.[1].

To design robust manufacturing process and minimize the potential for content non-uniformity in the granules used for producing tablets or capsules, it is important to understand the physics behind the effect of operational parameters at each processing step of wet granulation. In order to gain such an understanding, it is important to alleviate the effect of material properties of the powder mix. In this study, the fundamental process parameters of high shear wet granulation process affecting the content non uniformity of the output granules are being assessed. These parameters include loading pattern of dry powder mix, dry mixing time and impeller speed. The powder mix being used in this study represents the low dosage product. Alleviation of the impact of material property was achieved by using colored and non-colored MCC as a binary powder mix. One part of this binary powder system is colored using aqueous dye (Nigrosin), while the other part is used in its original form (white color). Such a binary powder mix eliminates the impact of primary powder particle size, shape, and wettability difference. The study focuses on assessing the impact of different loading patterns of powder such as top-bottom and side-by-side loading of formulation components in the granulator bowl, dry mixing time and impeller speed on the distribution of two components in the output granules which in turn affect the content uniformity of the granules. The homogeneity of the powder blend before the liquid addition phase is important to get the uniform output granules. The mixing studies shows that the mixing efficiency in the axial direction (top to bottom) is much smaller than the mixing in radial direction (Side to side) [7]. Thus, the loading pattern of side by side should exhibit more homogenous bed and granules with more uniform content than top bottom loading along with the change in dry mixing time and impeller speed.

Ref:

1. Oka, S., et al., Analysis of the origins of content non-uniformity in high shear wet granulation. International Journal of Pharmaceutics, 2017. 528: p. 578-585.
2. Pawar, P., et al., A “Large-N” Content Uniformity Process Analytical Technology (PAT) Method for Phenytoin Sodium Tablets. Journal of Pharmaceutical Sciences, 2019. 108:p. 494 -505.
3. Koide, T., et al., Detection of component segregation in granules manufactured by high shear granulation with over-granulation conditions using near-infrared chemical imaging. International Journal of Pharmaceutics, 2013. 441: 135–145.
4. Oka, S., et al., The effects of improper mixing and preferential wetting of active and excipient ingredients on content uniformity in high shear wet granulation. Powder Technology, 2015. 278: p. 266-277.
5. Belohlav, Z., et al., Effect of drug active substance particles on wet granulation process. Chemical Engineering Research and Design, 2007. Volume 85, Issue 7: p. 974-980.
6. Liu, B., et al., A review of high shear wet granulation for better process understanding, control and product development. Powder Technology, 2021. 381: 204-223.
7. Gao, W., et al., Discrete element analysis of the particle mixing performance in a ribbon mixer with a double U‑shaped vessel. Granular Matter, 2019. 21:12.