Assessing the Risk of Salt Disproportionation Using Crystal Structure and Surface Topography Analysis
| Autor: | Suman Luthra, Kapildev K. Arora, Sheri L. Shamblin, Joseph F. Krzyzaniak, Mitulkumar A. Patel, Lynne S. Taylor |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
chemistry.chemical_classification
Excipient Free base Salt (chemistry) Disproportionation 02 engineering and technology General Chemistry Crystal structure 021001 nanoscience & nanotechnology Condensed Matter Physics 030226 pharmacology & pharmacy 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine chemistry Computational chemistry medicine Drug product General Materials Science Magnesium stearate Solubility 0210 nano-technology medicine.drug |
| Zdroj: | Crystal Growth & Design. 18:7027-7040 |
| ISSN: | 1528-7505 1528-7483 |
| DOI: | 10.1021/acs.cgd.8b01188 |
| Popis: | Salt disproportionation is a major issue for pharmaceutical products containing a salt form of a weakly basic drug, because conversion to the free base during processing or storage in the presence of excipients may negatively impact stability and bioperformance of the drug product. Several factors influencing disproportionation tendency have been elucidated; however, a complete mechanistic understanding of this phenomenon is still lacking. Specifically, it is unclear if the crystal structure of the salt plays a role, beyond influencing the salt solubility. Herein, by utilizing model compounds with similar pKa and pHmax values, and hence similar thermodynamic driving forces for disproportionation, we demonstrate that salt crystal structure appears to play a major role in influencing disproportionation tendency. Some salts with low pHmax values were found to be resistant to disproportionation, while other systems transformed to the free base following contact with the basic excipient, magnesium stearate. Fo... |
| Databáze: | OpenAIRE |
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