Category: Formulation and Quality
Purpose: Amorphous solid dispersion (ASD) has become one of the most commonly used enabling formulation technologies to improve the oral bioavailability of poorly water-soluble drugs. The mechanistic impact of excipients on the physical stability of ASD is critical for the design and development of ASD formulations. Magnesium stearate (MgSt), a commonly used lubricant for solid oral dosage form, was found to trigger a faster recrystallization of compound A in spray dried ASD containing HPMCAS under stressed conditions. The goal of this study is to investigate the mechanisms of MgSt-facilitated recrystallization of compound A. Our hypothesis is that MgSt interacts with the acidic impurity of HPMCAS, and the fatty acids formed in situ as the result of this interaction accelerates the recrystallization.
Methods: The binary mixtures of HPMCAS-MgSt and HPMC-MgSt were prepared at 9:1 weight ratio. The physical mixtures were produced using an acoustic mixer before being compressing into discs with a tablet compressor under the pressure of 200 MPa. The samples were stored in open dish at 40 °C/80% RH condition. X-ray powder diffraction (XRPD) and Fourier Transform Infrared Spectroscopy (FTIR) were used to compare the interactions in HPMCAS-MgSt and HPMC-MgSt mixtures. 10% of succinic acid was introduced to the binary mixture of HPMC-MgSt and the interactions between MgSt and succinic acid were investigated with XRPD and FTIR. The ASD was prepared by spray drying at 20% drug loading with HPMCAS LF as the polymeric carrier. Different binary physical mixtures of ASD with different fatty acids (myristic acid, palmitic acid, stearic acid and arachidic acid) were prepared at 9:1 weight ratio. Re-spray dried compound A ASDs with 1% succinic acid, stearic acid, palmitic acid and control samples were prepared under the same condition. Modulated differential scanning calorimetry (mDSC) was used to measure the glass transition temperature of the re-spray dried ASD samples. XRPD was utilized for qualitative and quantitative analysis of the recrystallization of re-spray dried ASDs and different binary physical mixtures of ASDs containing different fatty acids.
Results: A fast generation of MgSt trihydrate in the HPMCAS-MgSt mixture was observed by XRPD, but not in the HPMC-MgSt mixture despite the fact that HPMC is more hygroscopic than HPMCAS. FTIR spectra of HPMCAS-MgSt showed several new peaks that could be attributed to MgSt disproportionation, indicating potential interactions between MgSt and HPMCAS leading to the formation of new salt and free fatty acid. The introduction of succinic acid in the HPMC-MgSt binary mixture produced similar XRPD and FTIR results. In the binary with 10% magnesium palmitate, the re-spray dried compound A ASDs with 1% succinic acid showed 4 times faster drug recrystallization than the control sample in the first week (Figure 1A). In addition, binary mixtures of ASD with different fatty acids showed the following order of recrystallization rate: myristic acid > palmitic acid > stearic acid ≈ arachidic acid (Figure 1B). Furthermore, re-spray dried ASDs with 1% stearic acid or palmitic acid showed a much faster recrystallization rate comparing with the binary mixtures. Both samples have similar glass transition temperatures though the palmitic acid is more effective than stearic acid in inducing drug recrystallization.
Conclusion: The drug recrystallization rate of binary physical mixture of ASD with different fatty acids shows an inverse correlation with the length of the fatty acid chain. The FTIR and XRPD results suggest that the interaction between MgSt and HPMCAS can presumably induce MgSt disproportionation and the generation of free fatty acid, which accelerates the drug recrystallization. Our study has probed the mechanism of MgSt led accelerated drug recrystallization in HPMCAS based ASD, and demonstrates the importance of a deep understanding of the excipient compatibility during product development.
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