Universitas Indonesia Conferences, Asian Federation for Pharmaceutical Sciences (AFPS) 2019

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Elucidation of destabilization mechanism of amorphous cyclosporin A nanosuspension prepared by wet bead milling with poloxamer 407
Ziqiao Chen, Keisuke Ueda, Kenjirou Higashi, Kunikazu Moribe

Last modified: 2019-06-16


Background: The poor solubility of drug with mid-molecular weight derived from its structural complexity results in poor bioavailability after oral administration. Amorphous drug nanosuspension is one of the effective strategies to improve drug dissolution performance, owing to the synergetic effect of drug amorphization and nanosizing. However, the development of formulations based on amorphous drug nanosuspension still involves much trial and error as drug crystallization and particle size increase can occur on storage. Objective: The present study aims to clarify the destabilization mechanism of amorphous drug nanosuspension by molecular-level characterization. Materials and Methods: Cyclosporin A (CyA) was used as a model of poorly water-soluble drugs with mid-molecular weight. Poloxamer 407 (P407) was used as the suspension stabilizer. Wet bead milling was exploited to prepare the amorphous CyA nanosuspension. The molecular state of the prepared amorphous CyA nanosuspension was investigated by suspended-state NMR measurement. The freeze-dried CyA nanosuspension was characterized by differential scanning calorimetry (DSC) and solid-state NMR measurements. Results and Discussion: A CyA nanosuspension with the size of ca. 370 nm was successfully prepared by wet bead milling with P407. The suspended-state NMR measurement of the fleshly prepared CyA nanosuspension showed that CyA in the nanoparticles existed in the amorphous state. DSC and solid-state NMR measurements of the freeze-dried amorphous CyA nanosuspension revealed that a portion of P407 was embedded into the amorphous CyA nanoparticles just after milling. The particles size was nano-order after the storage at 25ºC for 1 day. In-situ suspended-state NMR measurement showed gradual CyA crystallization on storage. Solid state NMR measurement indicated that P407 was excluded from the CyA nanoparticles with CyA crystallization. This study provides important insights into the destabilization mechanism of amorphous nanosuspension of drugs with mid-molecular weight.