(T1330-02-08) Super-Fast Fabrication of Drug Nanocrystals Using Dual Asymmetric Centrifugation: An Efficient Approach for High-Throughput Formulation Screening

Purpose: The advancement of drug delivery systems has significantly impacted pharmaceutical research, particularly for poorly water-soluble drugs, which often present challenges related to low bioavailability. Nanocrystals (NCs) have emerged as a promising approach to address these issues, as reducing particle size (PS) increases the surface area which improves drug absorption and bioavailability. However, conventional methods for producing NCs, such as wet media milling (WMM), tend to be time-consuming and resource-intensive, requiring hours to days to produce suitable formulations. This limitation hampers the efficiency of formulation development and high-throughput screening processes. This study aims to evaluate dual asymmetric centrifugation (DAC) as a rapid, efficient, and reproducible method to produce drug NCs within just 1-minute of processing, offering a significant reduction in production time compared to conventional techniques and enabling high-throughput formulation screening for drugs NC formulations.

Methods: DAC was used to reproduce ten NC formulations described in the literature by other authors in a single 1-minute milling cycle, employing zirconia beads as the milling media. Particle size (PS) and polydispersity index (PDI) were measured and used as parameters to assess the capability and reproducibility of the method. Three model drugs—albendazole (CAS RN 54965-21-8), metronidazole (CAS RN 443-48-1), and curcumin (CAS RN 458-37-7)—were selected for further study to evaluate the effects of formulation parameters (drug/stabiliser ratio, bead size, bead volume) and process variables (velocity, number of cycles, duration of cycles, container size, etc.) on NC characteristics. Physicochemical properties, morphology, and contamination levels were characterised using differential scanning calorimetry (DSC), transmission electron microscopy (TEM), optical microscopy, and nanoparticle tracking analysis (NTA). Curcumin was further selected for a Plackett–Burman design of experiments (DoE), which identified key factors influencing process optimisation. Additionally, a microhydrodynamic model was employed to quantify milling conditions and compare DAC efficiency with conventional wet media milling.

Results: To assess the method’s versatility and robustness, ten poorly water-soluble drugs from different chemical classes were initially screened. In this sense, the DAC method enabled the super-fast production of NCs in just 1 minute for 9 out of 10 drugs, achieving particle sizes between 174 and 563 nm with low variability between replicates (17–79 nm), demonstrating good reproducibility and highlighting its broad applicability (Table 1). From the screening of ABZ, MTZ, and CUR, it was observed that repeated 1-minute milling cycles further reduced particle size (PS) and polydispersity index (PDI). Formulation parameters significantly impacted the outcome: higher stabiliser concentrations consistently led to smaller NCs, while elevated drug concentrations tended to increase PS. Milling was further enhanced by using smaller beads and higher bead volumes (Fig. 1A I-V). Characterisation confirmed the preservation of crystallinity and revealed nearly spherical NCs coated with stabilising agents (Fig. 1B). Contamination during the process remained below 1%. A multiple-response optimisation study, employing Plackett–Burman DoE, identified the most influential process variables (Figure 1C) and established a quantitative relationship between these variables and PS, allowing prediction of PS and PDI with a prediction error below 15% (Table 2). Additionally, a microhydrodynamic analysis showed that DAC generated significantly higher granular temperatures than conventional wet media milling (p < 0.05), which may contribute to its enhanced performance. Overall, the findings demonstrate that DAC significantly outperforms conventional laboratory-scale WMM in terms of milling efficiency.

Conclusion: DAC proved to be a reproducible and efficient method, delivering NCs in just 1 minute, representing up to a 1440-fold reduction in processing time compared to conventional techniques, emerging as a game-changing tool for high-throughput formulation screening of drug NCs.

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Acknowledgements: This work was partially supported by a Springboard Award from the Academy of Medical Sciences (grant SBF009\1019).

Table 1. Comparison between literature-reported PS and PDI values and those obtained after a 1-minute milling cycle (triplicates).

Figure 1. A) Effect of individual formulation and process parameters on CUR NCs particle size and PDI. B) TEM image. C) Response surface plots showing the impact of: (I) bead diameter and container size; (II) stabilizer volume and weight; (III) stabilizer and drug weight; (IV) drug weight and centrifugation speed on particle size.

Table 2. Predicted and obtained values using Plackett–Burman DoE.