The influence of amorphous amounts in active pharmaceutical ingredients on the aerodynamic particle size distribution and on storage stability

T. Müller, R. Krehl, J. Schiewe, C. Weiler, H. Steckel

Background: There are changes of the carrier and active pharmaceutical ingredients (APIs) during the production of dry powder inhalers (DPIs). Standard pharmaceutical operations, like milling and blending, change specific particle characteristics which have a huge effect on drug delivery and product stability. Especially amorphous parts absorb water, re-crystallize and may lead to particle growth.

Methods: In this study a hydrophilic and a hydrophobic model API were micronized to introduce different amorphous parts to the particle surface which were partially re-crystallized. After blending the mixtures were stored at 45%RH in a desiccator and the aerodynamic particle size distributions (APSD) were determined. The study target was to find out differences between the contrasting APIs, to evaluate the influence of amorphous parts and the storage stability over a six-month period.

Results: Conditioning of the micronized APIs resulted in different amorphous amounts and similar particle sizes were received. The APSD showed contrasting results for both APIs. Very high fine particle fractions (FPFs) for the hydrophilic sample were determined at the beginning, which decreased over time. For the hydrophobic API the FPFs were very low and increased over time. The amorphous amounts showed a huge effect on dispersion behaviour and both mixtures showed differences in storage stability.

Conclusions: This investigation showed that the control of amorphous content is of extreme importance because it influences the behaviour and the performance of DPIs. The storage stability showed especially for the hydrophobic CS blends an incalculable behaviour. The hydrophilic SBS led to constant FPFs after re-crystallisation. Therefore it is necessary that amorphous parts are determined and re-crystallised under controlled conditions.

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