(M1030-09-61) Characterization of Stress Induced Amorphous Phase Formation during Tableting Detected by Solid-State NMR – Implications on Stability and Formulation Selection

Purpose: The study aims to identify the source of chiral impurity growth in tablet drug product by utilizing ¹⁹F solid-state Nuclear Magnetic Resonance (SSNMR) spectroscopy to characterize low levels of amorphous content. The study also aims to build a correlation between the amorphous content and drug product stability, understand factors influencing the growth of the impurity and ultimately identify the appropriate technology, formulation and processing parameters to minimize the growth of the chiral impurity in the drug product.

Methods: A validated High-Performance Liquid Chromatography (HPLC) method was utilized to evaluate the growth of the chiral impurity in tablet and drug-in-capsule samples during the stability study. To determine whether the growth of the impurity was caused by stress-induced amorphization, the crystalline API was compressed at different compaction forces using a Styl’One^TM Compaction simulator (Korsch America) and the samples were evaluated for Amorphous content. The crystalline API was also co-compressed with different fillers to understand the impact of filler and drug loading. The samples were also stored at 55 ^oC for 2 weeks to correlate the amorphous content with chiral growth. 100% amorphous samples were generated by spray drying and characterized to ensure lack of crystallinity using XRPD and SSNMR. Due to the lower amounts of amorphous content in the tablet drug product, quantification of % crystallinity was deemed not possible using convention XRPD techniques and ¹⁹F SSNMR was used instead. ¹⁹F Solid-state NMR experiments were acquired using a 400 MHz Bruker Avance NEO spectrometer, equipped with a a Revolution NMR HF probe and 4mm magic angle spinning (MAS) module. ¹⁹F spectra were acquired using Cross Polarization (CP) experiment and was able to distinguish the sharp resonance (-117 to -118 ppm) of crystalline material from the broad resonance (-122 ppm) of amorphous material. Amorphous content determination utilized a spectral subtraction technique to determine % amorphous content present in the samples. Different common blends were manufactured using dry granulation, high shear wet granulation and fluid bed granulation with similar formulation compositions to evaluate the impact of processing conditions on amorphization and subsequent chiral growth. Furthermore, common blends were converted into both capsules and tablets to differentiate the effects from encapsulation and tableting unit operations. The samples were also stored at 55 ^oC for 2 weeks and 40 ^oC/75%RH for 3 months to establish correlation between amorphous content and chiral growth.

Results: No significant growth was observed in the chiral impurity during stability for the DIC and 100% crystalline API samples, whereas growth in the chiral impurity was observed for tablets and 100% amorphous API samples at 25°C/60%RH and 40°C/75%RH conditions. This suggests that amorphous API is more prone to chiral conversion than crystalline API especially at higher temperatures and that amorphization is a possible cause for chiral impurity growth upon stability. ¹⁹F SSNMR data suggested an increase in amorphous content and subsequent chiral growth with increasing force for API samples. The presence of MCC increased the extent of amorphization and subsequent chiral growth. ¹⁹F SSNMR data also showed no differences in the spectra between the pre-blend and uncompressed API samples suggesting no amorphous conversion during blending. However, an increase in the amorphous content was observed with subsequent roller compacted final blend and the final core and coated tablets had even higher amorphous content than the final blend. Granules from other granulation technologies such as high shear wet granulation and fluid bed granulation were also prepared and compared with the roller compacted granules. Fluid bed granulation generated the lowest amount of amorphous content and a similar trend was observed with respect to the chiral impurity. No significant differences were observed between the granule and capsule samples and tableting increased the extent of amorphization. ¹⁹F SSNMR results were in good agreement with these results.

Conclusion: Stress-induced amorphization during processing was confirmed as the source for the impurity growth in the tablet drug product.¹⁹F SSNMR proved to be the best technique to quantify low levels of amorphous content ( < 5%) in the tablet drug product. Good correlations were observed between the amorphous level quantified using ¹⁹F SSNMR and the chiral growth observed at 55 ^oC for 2 weeks and 40 ^oC/75%RH for 3 months. Alternative granulation technologies such as fluid bed, high shear granulations were evaluated along with the optimization of fillers for dry granulation. Fluid bed granulation followed by encapsulation was found to be the best alternative to lower amorphization and better stability.

References: Huang C, Klinzing G, Procopio A, Yang F, Ren J, Burlage R, Zhu L, Su Y. Understanding Compression-Induced Amorphization of Crystalline Posaconazole. Mol Pharm. 2019 Feb 4;16(2):825-833. doi: 10.1021/acs.molpharmaceut.8b01122.
Quantitative phase analysis of amorphous components in mixtures by using the direct-derivation method”, J. Appl. Cryst. (2019). 52, 13-22

Acknowledgements: All authors contributed equally to the study. The authors would like to acknowledge Eric Munson, Michal Achmatowicz, Ron Chen, Aastha Chadda and Mehrdad Kheiripour for their valuable input.

a. Comparison of Chiral Growth for Crystalline and Amorphous API after storage at 55 degC for 2 weeks
b. Chiral Impurity Results for Crystalline API, DIC and tablet samples during Stability

19F SSNMR Results
A. Overlay of blend, granules and core tablet
B. Overlay of Crystalline and Amorphous peak locations in 100% Crystalline, 100% Amorphous and a physical 50:50 mixture of 100% Crystalline and 100% Amorphous samples

A. Impact of compression force on amorphous content
B. Impact of compression force and drug loading on chiral growth
C. Impact of granulation process and tableting on Chiral Growth
D. Impact of granulation process and tableting on amorphous content