Article pubs.acs.org/OPRD
Correlation of Drug Substance Particle Size Distribution with Other Bulk Properties to Predict Critical Quality Attributes Henry G. Morrison,* Wenle Tao, William Trieu, Shawn D. Walker, Sheng Cui, Seth Huggins, and Karthik Nagapudi Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States S Supporting Information *
ABSTRACT: The purpose of this study was to correlate the particle size distribution (PSD) of a development molecule (1) with other bulk properties such as surface area and powder flow, to enable prediction of critical quality attributes (CQA) of the drug substance to support a roller compaction formulation process. Dry dispersion laser diffraction, wet dispersion laser diffraction, and wet dispersion image analysis PSD methods were developed for 1. Twenty eight (28) process batches were characterized by all three methods, and the resulting data were correlated to other bulk properties to determine if these correlations could be used to predict CQA values for future process batches. PSD metrics measured with wet dispersion laser diffraction and wet dispersion image analysis methods were found to have significantly better correlation to other bulk properties when compared to the metrics measured using the dry dispersion laser diffraction method. The correlations generated were found to be useful to predict resulting surface area and flow function values during process development. On the basis of these correlations, a target PSD range was identified for 1 that could support the roller compaction process. In order to further validate this methodology, various grades of lactose monohydrate were then used as a second model system to test correlation between PSD and other bulk properties.
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INTRODUCTION 1 is a development compound with two basic pKa values of 8.07 and 1.73. It was isolated as a crystalline dimethanesulfonate salt for phase Ib and phase II clinical trials. This salt was chosen to mitigate oxidative degradation seen in the free base; however, it was found to disproportionate in the drug product (DP) as has been previously documented for weak bases in the solid state.1 Due to the high water solubility of 1 (>25 mg/mL), it was found that the active pharmaceutical ingredient (API) could undergo microenvironmental dissolution in the DP matrix, thereby causing the crystalline dimethanesulfonate salt to convert to an amorphous phase of the drug substance (DS). This amorphous state would subsequently undergo reaction with the basic excipients in the DP causing disproportionation and ultimately chemical instability. From the DP standpoint, a multitiered approach was used to prevent amorphous formation including using lower moisture/ less hygroscopic excipients, manufacturing in low relative humidity-controlled rooms, storage of intermediate products (e.g., preblends, final blend, bulk tablets) under dry conditions, and decreasing environmental moisture availability through packaging. From the DS standpoint, it was determined that a target surface area of
