Category: Formulation and Quality
Purpose: Amorphous Solid Dispersion (ASD) represents one of the major enabling techniques to enhance the bioavailability of poorly water-soluble drugs. However, the potential excipient induced solid phase transformations in the ASD based formulation is not usually comprehensively evaluated during the product design and development. Magnesium Stearate (MgSt), a commonly used lubricant for solid oral dosage form, was found to induce accelerated drug recrystallization from an ASD containing compound A and HPMCAS under stressed conditions. The aim of this study is to investigate the influence of different types of lubricants and MgSt with different attributes on the physical stability of the ASD and to investigate the mechanisms of the lubricants-induced ASD recrystallization.
Methods: Most of the commercial MgSts are mixtures with magnesium stearate and magnesium palmitate as the main components. To eliminate the impact of the impurity in commercial lubricants, pure magnesium stearate and magnesium palmitate were synthesized by the solvent method. The particle size distribution of all samples were measured with laser light diffraction methods. ASD consisting of 20% compound A and 80% HPMCAS was prepared by spray drying. Binary physical mixtures of ASD with different commercial batches of MgSt and other type of lubricants were prepared at 9:1 weight ratio. The mixtures were mixed with an acoustic mixer before compressing into discs with a tablet compressor under the pressure of 200 MPa. The samples were stored at open dish 40 °C/80% RH condition. An X-Ray Powder Diffraction (XRPD) method was developed for semi-quantitative analysis of the recrystallization rate. FTIR was used to study the interaction between lubricants and ASD.
Results: The ASD showed no recrystallize following one month storage at 40 °C/80% RH, while all binary mixtures showed different extent of recrystallization (Figure 1A). The particle size and chemical composition of MgSt play a key role in the recrystallization kinetic of compound A. Specifically, the smaller the particle size, the faster the drug recrystallization rate. This can be attributed to the larger contact surface areas and thereby the more interfacial interactions between MgSt and the ASD. When the MgSt particle sizes are similar, MgSt with higher percentage of magnesium palmitate leads to faster drug recrystallization. For binary mixtures of ASD with different types of lubricants, stearic acid sample showed the highest recrystallization rate and sodium stearyl fumarate the lowest (Figure 1B). The XRPD and FTIR data suggested the interaction between magnesium stearate and polymeric carrier HPMCAS, but not between the free fatty acid and HPMCAS. The recrystallization kinetic of binary mixtures with different fatty acid and its corresponding magnesium salt was remarkably different indicating different recrystallization mechanisms at play.
Conclusion: Different ASD-lubricants binary mixtures showed remarkably different recrystallization rates, which could be attributed to different chemical composition and particle size of the lubricants. Magnesium palmitate is more potent than magnesium stearate in inducing the recrystallization of compound A. Free fatty acid and its magnesium salt form likely triggered the drug recrystallization through different mechanisms and the compatibility of lubricants with ASD should be thoroughly evaluated.
Hanmi Xi– West Point, Pennsylvania
Majid Mahjour– West Point, Pennsylvania
Yongchao Su– Principal Scientist, Merck & Co., Inc., West Point, Pennsylvania
Michael McNevin– West Point, Pennsylvania
Wei Xu– Director of Preformulation, Merck & Co., Inc., West Point, Pennsylvania