Abstract:
:Process-induced phase transformations (PIPTs) of active pharmaceutical ingredients (APIs) can alter APIs' physicochemical properties and impact performance of pharmaceutical drug products. In this study, we investigated compression-induced amorphization of crystalline posaconazole (POSA), where the impact of mechanical stresses and excipients on amorphization were explored. 19F solid-state NMR (ssNMR) was utilized to detect and quantify amorphous content in the compressed tablets, and finite element analysis (FEA) was conducted to understand stress distributions in the compression process. Both applied macroscopic axial stress and shear stress were found to be important to amorphization of crystalline POSA. Punch velocity, an important compression process parameter, had negligible effect on amorphization up to 100 mm/s. Two diluents, microcrystalline cellulose (MCC) and dibasic calcium phosphate anhydrous (DCPA), and one lubricant, magnesium stearate (MgSt), were evaluated for their impact on amorphization in this study. It was found that both MCC and DCPA significantly enhanced amorphization of POSA at a low drug loading (5% w/w). The 1% (w/w) blended lubricant effectively reduced the amorphous content in MCC-POSA tablets; however, it had minimal effect on either neat POSA or DCPA-POSA tablets. Drug loading, or excipient concentration, was demonstrated to have a significant impact on the extent of amorphization. These observed excipient effects support the important role of interparticulate stresses in amorphization of crystalline POSA.
journal_name
Mol Pharmjournal_title
Molecular pharmaceuticsauthors
Huang C,Klinzing G,Procopio A,Yang F,Ren J,Burlage R,Zhu L,Su Ydoi
10.1021/acs.molpharmaceut.8b01122subject
Has Abstractpub_date
2019-02-04 00:00:00pages
825-833issue
2eissn
1543-8384issn
1543-8392journal_volume
16pub_type
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