Abstract
In direct compression of tablets, it is crucial to maintain content uniformity within acceptable margins, especially in formulations with low drug loading. To assure it, complex and multistep mixing processes are utilized in the industry. In this study, we suggest the use of a simple segregation test to evaluate mixing process performance and mixture segregation to produce tablets having satisfying content uniformity while keeping the process as simple and low cost as possible. Eventually, the formulation propensity to segregation can be evaluated using process analytical technology (PAT) to adjust the mixing process parameters to changing source drug properties. In this study, that approach was examined on a model drug with a broad batch-to-batch variability in particle size and shape. Excipients were chosen so that the resulting blend composition mimicked some marketed formulations. For each drug batch, two formulation blends were prepared through different preparation processes (one simple and one complex) and subsequently subjected to segregation tests. From those, segregation coefficients were obtained to compare segregation tendencies and homogeneity robustness between the drug batches and the blend preparation methods. The inter-particulate interactions were substantially influenced by the drug particle morphology and size and resulted in different segregation behavior. Based on these findings, a simple segregation test proved to be a useful tool for determining the suitability of different batches of the model drug to be used in a certain formulation. Moreover, for a particular batch A, the test revealed a potential for mixing process simplification and therefore process intensification and cost reduction.
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Acknowledgements
The authors would like to thank Adam Vít and David Novák at the University of Chemistry and Technology Prague for their assistance with some of the experiments.
Funding
This work was supported by the grant of specific university research (MSMT No 21-SVV/2021)—grant No. A2_FCHT_2021_043. Technical and scientific support was also provided from The Parc.
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All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Simona Römerová, under the supervision of Petr Zámostný. The first draft of the manuscript was written by Simona Römerová. Petr Zámostný and Ondřej Dammer reviewed, edited, and commented on previous versions of the manuscript. All authors read and approved the final manuscript.
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Supplementary Information
Supplementary Fig. 1
Main used excipients SEM images. Microcrystalline cellulose, upper left; pregelatinized corn starch, upper right; crospovidone, bottom. 200x mag (PNG 30419 kb)
Supplementary Fig. 2
Model mixtures SEM images. Batch A, upper left; batch B, upper right; batch C, bottom left; batch D, bottom right (drug particles are darker gray needles or columns). 300x mag (PNG 52921 kb)
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Römerová, S., Dammer, O. & Zámostný, P. Streamlining of the Powder Mixing Process based on a Segregation Test. AAPS PharmSciTech 22, 190 (2021). https://doi.org/10.1208/s12249-021-02073-z
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DOI: https://doi.org/10.1208/s12249-021-02073-z