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Study of Top-down and Bottom-up Approaches by Using Design of Experiment (DoE) to Produce Meloxicam Nanocrystal Capsules

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Abstract

In order to investigate the correlation among energy input–related, drug-related, and stabilizer-related aspects for both top-down and bottom-up nanocrystal production, meloxicam nanosuspensions (NS) were produced by using three different methods (low-energy wet milling, high-pressure homogenization, and precipitation) and each method was optimized by using design of experiment (DoE). Box-Behnken design of 3 factors and 3 levels was applied for the optimization of each method. All the three models were found to be significant and the optimized process parameters were used for production of NS, respectively. Interestingly, by comparison of the top-down and bottom-up approaches, the influence of energy input (homogenization pressure or milling speed) from the instruments seemed not significant for top-down compared with bottom-up for this drug. Different mechanisms of homogenization (relatively high energy zone) and milling (relatively low energy zone) led to obtained various significant correlations for each method. Capsules containing nanocrystals were successfully produced by using a novel method applying NS (after wet bead milling and homogenization processes) as wetting agent for direct capsuling and showed superiority regarding as dissolution rate compared with the traditional two-step method (freeze-dried powder used for capsuling as the first step). Different NS preparation methodologies proved to have a direct influence on the following capsuling process and consequently, in the dissolution rate. This study also proved that residual DMSO in nanosuspension after precipitation process could affect the freeze-drying process, which might further alter the redispersion and influence the downstream processes.

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Funding

Tao Liu received financial support from A Project of Shandong Province Higher Educational Science and Technology Program (project no. J18KA269), Shandong Provincial Key R&D Program (project no. 2019GSF107006), and Qingdao Source Innovation Program (project no. 19-6-2-38-cg).

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Authors and Affiliations

  1. Department of Pharmaceutical Engineering, College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, China

    Tao Liu & Xinxin Yu

  2. Department of Internal Medicine, Qingdao orthopaedic Hospital, Qingdao, China

    Haipeng Yin

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  2. Xinxin Yu
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Correspondence to Tao Liu.

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Liu, T., Yu, X. & Yin, H. Study of Top-down and Bottom-up Approaches by Using Design of Experiment (DoE) to Produce Meloxicam Nanocrystal Capsules. AAPS PharmSciTech 21, 79 (2020). https://doi.org/10.1208/s12249-020-1621-7

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