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Spherical Agglomerates of Lactose Reduce Segregation in Powder Blends and Improve Uniformity of Tablet Content at High Drug Loads


We report here on improved uniformity of blends of micronised active pharmaceutical ingredients (APIs) using addition of spherical agglomerates of lactose and enhanced blend flow to improve tablet content uniformity with higher API loads. Micromeritic properties and intra-particle porosity (using nano-computed X-ray tomography) of recently introduced spherical agglomerates of lactose and two standard lactose grades for the direct compression processes were compared. Powder blends of the individual lactose types and different micronised API drug loads were prepared and subjected to specific conditions that can induce API segregation. Tablet content uniformity during direct compression was related to the lactose material attributes. The distinctive micromeritic properties of the lactose types showed that spherical agglomerates of lactose had high intra-particle porosity and increased specific surface area. The stability of binary blends after intense sieving was governed by the intra-particle porosity and surface roughness of the lactose particles, which determined the retention of the model substance. Greater intra-particle porosity, powder specific surface area, and particle size of the spherical agglomerates provided greater adhesion of micronised particles, compared to granulated and spray-dried lactose. Thus the spherical agglomerates provided enhanced final blend flow and uniformity of tablet content at higher drug loads.

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  1. Reprinted from International Journal of Pharmaceutics, 516/1–2, Dejan Lamešić, Odon Planinšek, Zoran Lavrič, Ilija Ilić, Spherical agglomerates of lactose with enhanced mechanical properties, 247–257, 2017, with permission from Elsevier.


  1. Bi M, Sun CC, Alvarez F, Alvarez-Nunez F. The manufacture of low-dose oral solid dosage form to support early clinical studies using an automated micro-filing system. AAPS PharmSciTech. 2011;12(1):88–95.

    CAS  Article  PubMed  Google Scholar 

  2. Chen L, He Z, Kunnath KT, Fan S, Wei Y, Ding X, et al. Surface engineered excipients: III. Facilitating direct compaction tableting of binary blends containing fine cohesive poorly-compactable APIs. Int J Pharm. 2019;557:354–65.

    CAS  Article  PubMed  Google Scholar 

  3. Leane M, Pitt K, Reynolds G, Anwar J, Charlton S, Crean A, et al. A proposal for a drug product manufacturing classification system (MCS) for oral solid dosage forms. Pharm Dev Technol. 2015;20(1):12–21.

    CAS  Article  PubMed  Google Scholar 

  4. Ely DR, Carvajal MT. Determination of the scale of segregation of low dose tablets using hyperspectral imaging. Int J Pharm. 2011;414(1–2):157–60.

    CAS  Article  PubMed  Google Scholar 

  5. Gentzler M, Michaels JN, Tardos GI. Quantification of segregation potential for polydisperse, cohesive, multi-component powders and prediction of tablet die-filling performance - a methodology for practical testing, re-formulation and process design. Powder Technol. 2015;285:96–102.

    CAS  Article  Google Scholar 

  6. He X, Han X, Ladyzhynsky N, Deanne R. Assessing powder segregation potential by near infrared (NIR) spectroscopy and correlating segregation tendency to tabletting performance. Powder Technol. 2013;236:85–99.

    CAS  Article  Google Scholar 

  7. Jaklič M, Kočevar K, Srčič S, Dreu R. Particle size-based segregation of pharmaceutical powders in a vertical chute with a closed bottom: an experimental evaluation. Powder Technol. 2015;278:171–80.

    CAS  Article  Google Scholar 

  8. Liu R, Yin X, Li H, Shao Q, York P, He Y, et al. Visualization and quantitative profiling of mixing and segregation of granules using synchrotron radiation X-ray microtomography and three dimensional reconstruction. Int J Pharm. 2013;445(1–2):125–33.

    CAS  Article  PubMed  Google Scholar 

  9. Asachi M, Hassanpour A, Ghadiri M, Bayly A. Experimental evaluation of the effect of particle properties on the segregation of ternary powder mixtures. Powder Technol. 2018;336:240–54.

    CAS  Article  Google Scholar 

  10. Roskilly SJ, Colbourn EA, Alli O, Williams D, Paul KA, Welfare EH, et al. Investigating the effect of shape on particle segregation using a Monte Carlo simulation. Powder Technol. 2010;203(2):211–22.

    CAS  Article  Google Scholar 

  11. Alizadeh M, Hassanpour A, Pasha M, Ghadiri M, Bayly A. The effect of particle shape on predicted segregation in binary powder mixtures. Powder Technol. 2017;319:313–22.

    CAS  Article  Google Scholar 

  12. Tang P, Puri VM. Methods for minimizing segregation: a review. Part Sci Technol. 2004;22(4):321–37.

    CAS  Article  Google Scholar 

  13. Xie L, Wu H, Shen M, Augsburger LL, Lyon RC, Khan MA, et al. Quality-by-design (QbD): effects of testing parameters and formulation variables on the segregation tendency of pharmaceutical powder measured by the ASTM D 6940–04 segregation tester. J Pharm Sci. 2008;97(10):4485–97.

    CAS  Article  PubMed  Google Scholar 

  14. Scheibelhofer O, Balak N, Wahl PR, Koller DM, Glasser BJ, Khinast JG. Monitoring blending of pharmaceutical powders with multipoint NIR spectroscopy. AAPS PharmSciTech. 2013;14(1):234–44.

    CAS  Article  PubMed  Google Scholar 

  15. Harnby N. An engineering view of pharmaceutical powder mixing. Pharm Sci Technol Today. 2000;3(9):303–9.

    CAS  Article  PubMed  Google Scholar 

  16. Sommier N, Porion P, Evesque P, Leclerc B, Tchoreloff P, Couarraze G. Magnetic resonance imaging investigation of the mixing-segregation process in a pharmaceutical blender. Int J Pharm. 2001;222(2):243–58.

    CAS  Article  PubMed  Google Scholar 

  17. Xiao H, Fan Y, Jacob KV, Umbanhowar PB, Kodam M, Koch JF, et al. Continuum modeling of granular segregation during hopper discharge. Chem Eng Sci. 2019;193:188–204.

    CAS  Article  Google Scholar 

  18. Teżyk M, Jakubowska E, Milczewska K, Milanowski B, Voelkel A, Lulek J. The influence of direct compression powder blend transfer method from the container to the tablet press on product critical quality attributes: a case study. Drug Dev Ind Pharm. 2017;43(6):911–6.

    CAS  Article  PubMed  Google Scholar 

  19. Lakio S, Siiriä S, Räikkönen H, Airaksinen S, Närvänen T, Antikainen O, et al. New insights into segregation during tabletting. Int J Pharm. 2010;397(1–2):19–26.

    CAS  Article  PubMed  Google Scholar 

  20. Mateo-Ortiz D, Muzzio FJ, Méndez R. Particle size segregation promoted by powder flow in confined space: the die filling process case. Powder Technol. 2014;262:215–22.

    CAS  Article  Google Scholar 

  21. Williams JC. The segregation of particulate materials. A review Powder Technol. 1976;15(2):245–51.

    Article  Google Scholar 

  22. McCarthy JJ. Turning the corner in segregation. Powder Technol. 2009;192(2):137–42.

    CAS  Article  Google Scholar 

  23. Li H, McCarthy JJ. Cohesive particle mixing and segregation under shear. Powder Technol. 2006;164(1):58–64.

    CAS  Article  Google Scholar 

  24. Li H, McCarthy JJ. Controlling cohesive particle mixing and segregation. Phys Rev Lett. 2003;90(18):4.

    CAS  Article  Google Scholar 

  25. Yip CW, Hersey JA. Ordered powder mixing. Nature. 1976 Jul 1;262(5565):202–3.

    CAS  Article  Google Scholar 

  26. Hersey JA. Ordered mixing: a new concept in powder mixing practice. Powder Technol. 1975;11(1):41–4.

    Article  Google Scholar 

  27. 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.

    CAS  Article  Google Scholar 

  28. Johnson MCR. Powder mixing in direct compression formulation by ordered and random processes. J Pharm Pharmacol. 1979;31(1):273–6.

    CAS  Article  PubMed  Google Scholar 

  29. Mao C, Thalladi VR, Kim DK, Ma SH, Edgren D, Karaborni S. Harnessing ordered mixing to enable direct-compression process for low-dose tablet manufacturing at production scale. Powder Technol. 2013;239:290–9.

    CAS  Article  Google Scholar 

  30. Swaminathan V, Kildsig DO. The effect of particle morphology on the physical stability of pharmaceutical powder mixtures: the effect of surface roughness of the carrier on the stability of ordered mixtures. Drug Dev Ind Pharm. 2000;26(4):365–73.

    CAS  Article  PubMed  Google Scholar 

  31. Gohel MC, Jogani PD. A review of co-processed directly compressible excipients. J Pharm Pharm Sci. 2005;8(1):76–93.

    CAS  PubMed  Google Scholar 

  32. Lamešić D, Planinšek O, Lavrič Z, Ilić I. Spherical agglomerates of lactose with enhanced mechanical properties. Int J Pharm. 2017 Jan 10;516(1–2):247–57.

    CAS  Article  PubMed  Google Scholar 

  33. Lamešić D, Planinšek O, German II. Modified equation for particle bonding area and strength with inclusion of powder fragmentation propensity. Eur J Pharm Sci. 2018 May;121:218–27.

    CAS  Article  PubMed  Google Scholar 

  34. Sundell-bredenberg S, Nystrom C. The possibility of achieving an interactive mixture with high dose homogeneity containing an extremely low proportion of a micronised drug. 2001;12:285–95.

    CAS  Article  Google Scholar 

  35. Brunauer S, Emmett PH, Teller E. Adsorption of gases in multimolecular layers. J Am Chem Soc. 1938;60(2):309–19.

    CAS  Article  Google Scholar 

  36. Hausner HH. Friction conditions in a mass of metal powder. Int J Powder Met. 1967;3(4):7–13.

    Google Scholar 

  37. Shah UV, Karde V, Ghoroi C, Heng JYY. Influence of particle properties on powder bulk behaviour and processability. Int J Pharm. 2017;518(1–2):138–54.

    CAS  Article  PubMed  Google Scholar 

  38. Farber L, Tardos G, Michaels JN. Use of X-ray tomography to study the porosity and morphology of granules. 2003;132:57–63.

    CAS  Article  Google Scholar 

  39. Zeitler JA, Gladden LF. In-vitro tomography and non-destructive imaging at depth of pharmaceutical solid dosage forms. Eur J Pharm Biopharm. 2008;71(1):2–22.

    CAS  Article  PubMed  Google Scholar 

  40. Alexander B, Roddy M, Brone D, et al. A method to quantitatively describe powder segregation during discharge from a vessel. Pharm. Tech. 2000 Yearbook. 6–21.

  41. Marucci M, Al-Saaigh B, Boissier C, Wahlgren M, Wikström H. Sifting segregation of ideal blends in a two-hopper tester: segregation profiles and segregation magnitudes. Powder Technol. 2018;331:60–7.

    CAS  Article  Google Scholar 

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The authors would like to thank dr. Ilija German Ilić from the Faculty of Pharmacy, University of Ljubljana, for support for the direct compression experiments.


The authors acknowledge financial support from the Slovenian Research Agency (research core funding, No. P1-0189).

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Authors and Affiliations



Dejan Lamešić: concept, design of the work, acquisition, analysis and interpretation of the data, drafting the manuscript.

Blaž Grilc: design of the work, acquisition, analysis and interpretation of the data, revising the work

Robert Roškar: acquisition, analysis and interpretation of the data, revising the work

Selina Kolokytha: acquisition, analysis and interpretation of the data, revising the work

Jürgen Hofmann: design of the work, acquisition, analysis and interpretation of the data, revising the work

Andreas Malekos: acquisition, analysis and interpretation of the data, revising the work

Rolf Kaufmann: design of the work, revising the work

Odon Planinšek: design of the work, revising the work, final approval for published work

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Correspondence to Dejan Lamešić.

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The authors declare the granted patent for spherical agglomerates of lactose (US 10,568,837 B2).

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Lamešić, D., Grilc, B., Roškar, R. et al. Spherical Agglomerates of Lactose Reduce Segregation in Powder Blends and Improve Uniformity of Tablet Content at High Drug Loads. AAPS PharmSciTech 23, 17 (2022).

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  • lactose
  • segregation
  • spherical agglomerates
  • direct compression
  • nano-computed x-ray tomography