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Assessment of Resonant Acoustic Mixing for Low-Dose Pharmaceutical Powder Blends

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Abstract

Obtaining a homogeneous low-dose pharmaceutical powder blend without multi-step processing remains a challenge. One promising technology to address this risk is resonant acoustic mixing (RAM). In this study, the performance of a laboratory resonant acoustic mixer (LabRAM) was studied at low active pharmaceutical ingredient (API) concentrations (0.1–0.5% w/w), using three commercial grades of a model API (Acetaminophen) and diluents with varying physical properties. The performance was assessed by evaluating blend uniformity (BU) and capsule content uniformity (CU) as a function of mixing time. Overall, the LabRAM achieved acceptable BU in a single step even at 0.1% w/w drug loading. A reduction in API primary particle size led to improved mixing efficiency and uniformity. Moreover, the presence of surface cavities in the diluents used appeared to have led to improved uniformity. The results demonstrated that RAM could achieve uniform powder blends without multi-step processing, for low-dose formulations.

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References

  1. Zheng J, editor. Formulation and analytical development for low-dose oral drug products. Wiley; 2009.

    Google Scholar 

  2. Deveswaran R, Bharath S, Basavaraj BV, Abraham S, Furtado S, Madhavan V. Concepts and techniques of pharmaceutical powder mixing process: a current update. Res J Pharm Technol. 2009;2(2):245–9.

    CAS  Google Scholar 

  3. Paul EL, Atiemo-Obeng VA, Kresta SM, editors. Handbook of industrial mixing: science and practice. Wiley; 2003.

    Google Scholar 

  4. Muzzio FJ, Alexander A, Goodridge C, Shen E, Shinbrot T, Manjunath K, Dhodapkar S, Jacob K. Solids mixing. Handbook of industrial mixing. 2004:887-985.

  5. Figueroa I, Li H, McCarthy J. Predicting the impact of adhesive forces on particle mixing and segregation. Powder Technol. 2009;195(3):203–12.

    Article  CAS  Google Scholar 

  6. Chaudhuri B, Mehrotra A, Muzzio FJ, Tomassone MS. Cohesive effects in powder mixing in a tumbling blender. Powder Technol. 2006;165(2):105–14.

    Article  CAS  Google Scholar 

  7. US Food and Drug Administration. CFR-code of federal regulations title 21.

  8. Massol-Chaudeur S, Berthiaux H, Dodds JA. Experimental study of the mixing kinetics of binary pharmaceutical powder mixtures in a laboratory hoop mixer. Chem Eng Sci. 2002;57(19):4053–65.

    Article  CAS  Google Scholar 

  9. Lemieux M, Bertrand F, Chaouki J, Gosselin P. Comparative study of the mixing of free-flowing particles in a V-blender and a bin-blender. Chem Eng Sci. 2007;62(6):1783–802.

    Article  CAS  Google Scholar 

  10. Perrault M, Bertrand F, Chaouki J. An investigation of magnesium stearate mixing in a V-blender through gamma-ray detection. Powder Technol. 2010;200(3):234–45.

    Article  CAS  Google Scholar 

  11. Alexander A, Muzzio FJ, Shinbrot T. Segregation patterns in V-blenders. Chem Eng Sci. 2003;58(2):487–96.

    Article  CAS  Google Scholar 

  12. Brone D, Wightman C, Connor K, Alexander A, Muzzioa FJ, Robinson P. Using flow perturbations to enhance mixing of dry powders in V-blenders. Powder Technol. 1997;91(3):165–72.

    Article  CAS  Google Scholar 

  13. Alexander A, Shinbrot T, Johnson B, Muzzio FJ. V-blender segregation patterns for free-flowing materials: effects of blender capacity and fill level. Int J Pharm. 2004;269(1):19–28.

    Article  CAS  Google Scholar 

  14. Mehrotra A, Muzzio FJ. Comparing mixing performance of uniaxial and biaxial bin blenders. Powder Technol. 2009;196(1):1–7.

    Article  CAS  Google Scholar 

  15. Sudah OS, Coffin-Beach D, Muzzio FJ. Quantitative characterization of mixing of free-flowing granular material in tote (bin)-blenders. Powder Technol. 2002;126(2):191–200.

    Article  CAS  Google Scholar 

  16. Arratia PE, Duong NH, Muzzio FJ, Godbole P, Lange A, Reynolds S. Characterizing mixing and lubrication in the Bohle Bin blender. Powder Technol. 2006;161(3):202–8.

    Article  CAS  Google Scholar 

  17. Kaye BH. Powder mixing, vol. 10. Springer Science & Business Media; 1997.

    Google Scholar 

  18. Mixing & Blending. Available from: https://www.powderbulksolids.com/mixers-blenders/mixing-blending-3. Accessed 05 Oct 2020.

  19. The science behind the mixing zone. Available from: https://www.powderbulksolids.com/mixers-blenders/science-behind-mixing-zone. Accessed 26 Jan 2021.

  20. Mahmoudi ZN, Do N, Farrell TP, Rajabi-siahboomi AR. Influence of filler type in the blend uniformity of micronized drugs. 2019;2019:19438.

  21. Starch 1500 ® Application data assessment of low dose content uniformity of indomethacin in excipient blends using FT-Raman map** spectroscopy.

  22. Ahmed H, Shah N. Formulation of low dose medicines - theory and practice. Am Pharm Rev. 2000;3(3):1–5.

    Google Scholar 

  23. Osorio JG, Muzzio FJ. Evaluation of resonant acoustic mixing performance. Powder Technol. 2015;278:46–56.

    Article  CAS  Google Scholar 

  24. Osorio JG, Hernández E, Romañach RJ, Muzzio FJ. Characterization of resonant acoustic mixing using near-infrared chemical imaging. Powder Technol. 2016 Sep;1(297):349–56.

    Article  Google Scholar 

  25. Resodyn Technical Library - Resodyn Acoustic Mixers. Available from: https://resodynmixers.com/technical-library/. Accessed 03 Oct 2020.

  26. Coguill S, Farrar L. Mixers RA. InInternational Pyrotechnics Seminar: Resonant acoustic mixing of PBX; 2014.

    Google Scholar 

  27. Tanaka R, Takahashi N, Nakamura Y, Hattori Y, Ashizawa K, Otsuka M. Verification of the mixing processes of the active pharmaceutical ingredient, excipient and lubricant in a pharmaceutical formulation using a resonant acoustic mixing technology. RSC Adv. 2016;6(90):87049–57.

    Article  CAS  Google Scholar 

  28. Applying Dry Powder Coatings | Pharmaceutical Technology. Available from: https://www.pharmtech.com/view/applying-dry-powder-coatings. Accessed 06 Oct 2020.

  29. Goldstein JI, Newbury DE, Michael JR, Ritchie NW, Scott JH, Joy DC. Scanning electron microscopy and X-ray microanalysis. Springer; 2017 Nov 17.

    Google Scholar 

  30. Hare C, Zafar U, Ghadiri M, Freeman T, Clayton J, Murtagh MJ. Analysis of the dynamics of the FT4 powder rheometer. Powder Technol. 2015 Nov;1(285):123–7.

    Article  Google Scholar 

  31. Jenike AW. Storage and flow of solids:(REV. 1980.). BULLETIN OF THE UTAH ENGINEERING EXPERIMENT. 1980(123).

  32. Schulze D. Powders and bulk solids. Behaviour, characterization, storage and flow. Springer. 2008;22.

  33. Wang Y, Osorio JG, Li T, Muzzio FJ. Controlled shear system and resonant acoustic mixing: effects on lubrication and flow properties of pharmaceutical blends. Powder Technol. 2017;322:332–9.

    Article  CAS  Google Scholar 

  34. Guidance for industry powder blends and finished dosage units-stratified in-process dosage unit sampling and assessment draft guidance. Available from: http://www.fda.gov/cder/guidance/index.htm. Accessed 04 Oct 2020.

  35. Domike RD, Cooney CL. Particles and blending. Pharm Blend Mixing. 2015;11:81.

    Google Scholar 

  36. Muzzio FJ, Shinbrot T, Glasser BJ. Powder technology in the pharmaceutical industry: the need to catch up fast. Powder Technol. 2002;124(1-2):1–7.

    Article  CAS  Google Scholar 

  37. Ottino JM, Khakhar DV. Mixing and segregation of granular materials. Annu Rev Fluid Mech. 2000 Jan;32(1):55–91.

    Article  Google Scholar 

  38. Llusa M, Sturm K, Sudah O, Stamato H, Goldfarb DJ, Ramachandruni H, Hammond S, Smith MR, Muzzio FJ. Effect of high shear blending protocols and blender parameters on the degree of API agglomeration in solid formulations. Ind Eng Chem Res. 2009;48(1):93–101.

    Article  CAS  Google Scholar 

  39. De Villiers MM. Description of the kinetics of the deagglomeration of drug particle agglomerates during powder mixing. Int J Pharm. 1997;151(1):1–6.

    Article  Google Scholar 

  40. Yalkowsky SH, Bolton S. Particle size and content uniformity. Pharm Res An Off J Am Assoc Pharm Sci. 1990;7(9):962–6.

    CAS  Google Scholar 

  41. Huang CY, Ku MS. Prediction of drug particle size and content uniformity in low-dose solid dosage forms. Int J Pharm. 2010;383(1-2):70–80.

    Article  CAS  Google Scholar 

  42. Alyami H, Dahmash E, Bowen J, Mohammed AR. An investigation into the effects of excipient particle size, blending techniques & processing parameters on the homogeneity & content uniformity of a blend containing low-dose model drug. PLoS One. 2017;12(6):1–19.

    Article  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Jason Sweeney, Daozhong Zou, Kalyan Vasudevan, Uday Jain, Yuchuan Gong, Anjali Agrawal, Ho-Wah Hui, Shyam Karki, and Bill Bowen from BMS, Drug Product Development for their valuable discussion and supporting this work as a part of Shashwat’s summer internship.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Author notes

  1. Juan G. Osorio

    Present address: On Demand Pharmaceuticals, Rockville, Maryland, 20850, USA

Authors and Affiliations

  1. Chemical and Biochemical Engineering, Rutgers University, 98 Brett Road, Piscataway, New Jersey, 08854, USA

    Shashwat Gupta

  2. Synthetic Molecule Design and Development, Eli Lilly and Company, Indianapolis, Indiana, 46225, USA

    Shashwat Gupta

  3. Drug Product Development, Bristol Myers Squibb, 556 Morris Avenue, Summit, New Jersey, 07901, USA

    Yu Elaine Pu, Minglu Li, Zhengmao Li & Juan G. Osorio

Authors
  1. Shashwat Gupta
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  2. Yu Elaine Pu
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  3. Minglu Li
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  4. Zhengmao Li
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  5. Juan G. Osorio
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Contributions

Shashwat Gupta: investigation, methodology, data curation, formal analysis, visualization, writing — original draft. Yu (Elaine) Pu: methodology, visualization, resources, writing — review and editing. Minglu Li: investigation; methodology. Zhengmao Li: methodology; Juan G. Osorio: conceptualization; funding acquisition; project administration; resources; formal analysis; supervision; writing — review and editing.

Corresponding author

Correspondence to Juan G. Osorio.

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Gupta, S., Pu, Y., Li, M. et al. Assessment of Resonant Acoustic Mixing for Low-Dose Pharmaceutical Powder Blends. AAPS PharmSciTech 23, 126 (2022). https://doi.org/10.1208/s12249-022-02262-4

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