Purpose: Wet high shear granulation is performed as a precursor to extrusion granulation and rotary granulation (spheronization) process in the manufacturing of multi-particulates. This study evaluates the effect of impeller speed, amount of binder solution, and mixing time during the wet granulation process on the yield (between 16/30 mesh) as well as dissolution profile of a multi-particulate product (encapsulated) containing Biopharmaceutical Classification System (BCS) class 2 compound (API).
Methods: Wet high shear granulation was performed using a Diosna P1/6 high shear granulator, extrusion granulation using a LCI MG-55 extruder, and rotary granulation using a LCI QJ-230T marumerizer. Drying was performed on a Mini-Glatt fluid bed dryer. The formulation consisted of 70 % API, 24 % fillers, 3 % binder, and 3 % disintegrant, with purified water used as the binder solution. A placket burmen design was generated with 3 factors evaluated at 3 levels, 12 runs, and 1 replicate for the design space analysis using the Minitab 17® software. The impeller speed, mixing time, and amount of binder solution used were identified as the process variables, whereas the % yield and % dissolution at 15 minutes were measured as response variables. The impeller speed was evaluated between 250 – 350 rpm, the mixing time was evaluated between 3 – 10 minutes, and the binder solution was evaluated in the range of 30 % - 45 % w/w. Contour plots were generated to understand the effect of the selected process variables on response variables.
Results: The amount of binder solution added to the formulation had a significant impact on the yield and dissolution profile of active pharmaceutical ingredient (API). The yield increased proportionally from 40 % with 30 % w/w binder solution and 3 minute mixing time to 72 % or higher with the addition of 45 % w/w binder solution and 10 minute mixing time. The increase in binder solution from 30 % to 45 % reduced the amount of drug released in the first 15 minutes of dissolution from 100 % to 60 %, unaffected by the mixing time. However, all formulations tested passed the acceptance criteria of 75 % (Q) in 30 minutes per the current USP monograph for the compound. The mixing time did not appear to impact the dissolution of API from the formulation when compared with the amount of binder solution added, but a mixing time of 8 minutes or higher favored a greater yield.
The impeller speed did not appear to have a significant impact on dissolution or yield when compared with the amount of water added to the granulation. However, the impeller speed did affect the dissolution and yield when compared with the mixing time. Optimum dissolution profile was obtained with a combination of low impeller speed of 250 – 300 rpm with a mixing time of 3 – 8 minutes, and impeller speed of 300 – 350 rpm with a mixing time of 7 – 10 minutes, both increasing proportionally in each case. The yield was maximum with an impeller speed of 250 – 300 rpm with mixing time of 8 – 10 minutes when both were increased proportionally. Thus the ideal range for maximum yield was identified within the 275 – 300 rpm range a mixing time of 8 – 10 minutes.
Conclusion: This study identified the amount of binder solution as the most critical parameter that affects the dissolution profile from the granulated multi-particulate formulation. The dissolution profile was also proportionally affected by the mixing time and impeller speed when evaluated at constant amount of binder solution added. The yield is significantly affected by a combination of all three variables. The current formulation presented differences in dissolution profiles with changes in the processing parameters, but passed the acceptance criteria of 75 % (Q) in 30 minutes, therefore the ideal set-up for maximum yield was identified in the range of 275 – 300 rpm impeller speed with 8 – 10 minutes of mixing time and 42 – 45 % w/w binder solution.
Karthikeyan Selvaraj– Lonza Inc.
Nithin Vidiyala– Lonza Inc.
Ryan Larmon– Lonza Inc.
Danica Cartwright– Lonza Inc.
Naveen Mangu– Lonza Inc.
Parag Ved– Team Leader - Formulation, Lonza Inc., Lutz, Florida
James Evans– Team Leader - Analytical, Lonza Inc.
Jeffrey Williamson– Director - Product Development, Lonza Inc.