Category: Formulation and Quality
Purpose: Magnesium Stearate (MgSt) is the most commonly used excipient in tablet formulations. MgSt consists of multiple fatty acid salts, primarily stearate and palmitate, and has at least five crystal forms, including several hydrates. It is typically used as a tablet lubricant in the range of 0.5% to 2% of a formulation by weight. Too low a concentration of MgSt can cause manufacturing issues, while too high a concentration can slow the dissolution rate. It is generally accepted that blending time and particle size impact MgSt dissolution, with an increase in blending time or decrease in particle size of MgSt in a formulation causing a slower dissolution profile. In this study, the effect of blending time and particle size fractions on the dissolution of indomethacin tablets is explored for monohydrate and dihydrate forms of MgSt.
Methods: In order to control form, MgSt was synthesized using a bath and a melt method. After synthesis, MgSt was sieved into particle size fractions greater than 250 µm, 125 to 250 µm, 75 to 125 µm, 45 to 75 µm, and less than 45 µm. In all studies, MgSt was formulated at 2% by weight with indomethacin (16.7%), Avicel PH-102 (34%), and α-Lactose monohydrate (47.3%). Each particle size fraction was blended into the formulation for 60 minutes in a Turbula mixer. Tablets were compressed at 50 to 200 bar into 150 mg tablets using a single tablet press. The effects of blending time were studied by varying the mixing time from 2 minutes to 4 hours in the Turbula mixer for each hydrate. Dissolution was performed on indomethacin tablets using a USP2 dissolution setup using Pion μDiss fiber optic probes.
Results: The melt synthesis method yielded the monohydrate form and the bath method produced the dihydrate form. Variations in particle size did not show an effect on the dissolution of the dihydrate formulation which all had 15-minute dissolutions around 80%, but the monohydrate formulation did show slower dissolution with decreasing particle size. The formulations with monohydrate sieve fractions 125 to 250 μm and 75 to 125 μm had 15-minute dissolutions of approximately 81%, 45 to 75 μm had 76%, and less than 45 μm had 66%. Increasing the formulation blending time showed slower dissolution for both hydrates, but the monohydrate formulation had a relatively slower dissolution. Dihydrate formulations dissolutions at 15 minutes were: mixed for 2 minutes had 88% dissolution, mixed for 30 minutes had 84% dissolution, mixed for 60 minutes had 77% dissolution and mixed for 4 hours had 71%. Monohydrate formulations dissolution at 15 minutes were: mixed for 2 minutes had 86% dissolution, mixed for 30 minutes had 85% dissolution, mixed for 60 minutes had 71% dissolution and mixed for 4 hours had 61% dissolution. Altering the compaction pressure of smaller particle size MgSt in a formulation had a greater effect on monohydrate than dihydrate, although the impact was small. Dihydrate formulations from the sieve fraction less than 45 μm had 15-minute dissolutions near 76% for 100 bar and 200 bar. Monohydrate formulations from the same size fraction had 15-minute dissolutions of 76% at 100 bar and 73% at 200 bar.
Conclusion: The different hydrate forms of MgSt impacted dissolution in different ways, when the properties of the MgSt impact were studied by sieving, mixing, and tablet compression. These variations can be attributed to the differences between the monohydrate and dihydrate forms.