Skip to main content
SpringerLink
Log in

Determining the Impact of Roller Compaction Processing Conditions on Granulate and API Properties: Impact of Formulation API Load

  • Research Article
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

Previous work demonstrated that roller compaction of a 40%w/w theophylline–loaded formulation resulted in granulate consisting of un-compacted fractions which were shown to constitute between 34 and 48%v/v of the granulate dependent on processing conditions. The active pharmaceutical ingredient (API) primary particle size within the un-compacted fraction was also shown to have undergone notable size reduction. The aim of the current work was to test the hypothesis that the observations may be more indicative of the relative compactability of the API due to the formulation being above the percolation threshold. This was done by assessing the impact of varied API loads in the formulation on the non-granulated fraction of the final granulate and the extent of attrition of API particles within the non-granulated fraction. The influence of processing conditions for all formulations was also investigated. The results verify that the observations, both of this study and the previous work, are not a consequence of exceeding the percolation threshold. The volume of un-compacted material within the granulate samples was observed to range between 34.7 and 65.5% depending on the API load and roll pressure, whilst the API attrition was equivalent across all conditions.

Graphical Abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Nesarikar VV, Patel C, Early W, Vatsaraj N, Sprockel O, Jerzweski R. Roller compaction process development and scale up using Johanson model calibrated with instrumented roll data. Int J Pharm. 2012;436(1–2):486–507.

    Article  CAS  PubMed  Google Scholar 

  2. Leane M, Pitt K, Reynolds G, Group MCSW. A proposal for a drug product Manufacturing Classification System (MCS) for oral solid dosage forms. Pharm Dev Technol. 2015;20(1):12–21.

    Article  Google Scholar 

  3. Kleinebudde P. Roll compaction/dry granulation: pharmaceutical applications. Eur J Pharm Biopharm. 2004;58(2):317–26.

    Article  CAS  PubMed  Google Scholar 

  4. Gamble JF, Tobyn M, Dennis AB, Shah T. Roller compaction: application of an in-gap ribbon porosity calculation for the optimization of downstream granule flow and compactability characteristics. Pharm Dev Technol. 2010;15(3):223–9.

    Article  CAS  PubMed  Google Scholar 

  5. Wiedey R, Šibanc R, Wilms A, Kleinebudde P. How relevant is ribbon homogeneity in roll compaction/dry granulation and can it be influenced? Eur J Pharm Biopharm. 2018;133:232–9.

    Article  CAS  PubMed  Google Scholar 

  6. Sun CC, Kleinebudde P. Mini review: mechanisms to the loss of tabletability by dry granulation. Eur J Pharm Biopharm. 2016;106:9–14.

    Article  CAS  PubMed  Google Scholar 

  7. Perez-Gandarillas L, Perez-Gago A, Mazor A, Kleinebudde P, Lecoq O, Michrafy A. Effect of roll-compaction and milling conditions on granules and tablet properties. Eur J Pharm Biopharm. 2016;106:38–49.

    Article  CAS  PubMed  Google Scholar 

  8. Souihi N, Reynolds G, Tajarobi P, Wikström H, Haeffler G, Josefson M, et al. Roll compaction process modeling: transfer between equipment and impact of process parameters. Int J Pharm. 2015;484(1–2):192–206.

    Article  CAS  PubMed  Google Scholar 

  9. Herting MG, Kleinebudde P. Roll compaction/dry granulation: effect of raw material particle size on granule and tablet properties. Int J Pharm. 2007;338(1–2):110–8.

    Article  CAS  PubMed  Google Scholar 

  10. Inghelbrecht S, Remon JP. Reducing dust and improving granule and tablet quality in the roller compaction process. Int J Pharm. 1998;171(2):195–206.

    Article  CAS  Google Scholar 

  11. Hwang K-M, Kim S-Y, Nguyen T-T, Cho C-H, Park E-S. Use of roller compaction and fines recycling process in the preparation of erlotinib hydrochloride tablets. Eur J Pharm Sci. 2019;131:99–110.

    Article  CAS  PubMed  Google Scholar 

  12. Chattoraj S, Daugherity P, McDermott T, Olsofsky A, Roth WJ, Tobyn M. Sticking and picking in pharmaceutical tablet compression: an IQ Consortium review. J Pharm Sci. 2018;107(9):2267–82.

    Article  CAS  PubMed  Google Scholar 

  13. Gamble JF, Akseli I, Ferreira AP, Leane M, Thomas S, Tobyn M, et al. Morphological distribution mapping: utilisation of modelling to integrate particle size and shape distributions. Int J Pharm. 2023;635: 122743.

    Article  CAS  PubMed  Google Scholar 

  14. 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.

    Article  CAS  PubMed  Google Scholar 

  15. Scherließ R, Bock S, Bungert N, Neustock A, Valentin L. Particle engineering in dry powders for inhalation. Eur J Pharm Sci. 2022;172: 106158.

    Article  PubMed  Google Scholar 

  16. Chattoraj S, Sun CC. Crystal and particle engineering strategies for improving powder compression and flow properties to enable continuous tablet manufacturing by direct compression. J Pharm Sci. 2018;107(4):968–74.

    Article  CAS  PubMed  Google Scholar 

  17. Gamble J, Jones J, Tobyn M. Understanding the effect of API changes in pharmaceutical processing. Eur Pharm Rev. 2017;22(1):20–2.

    Google Scholar 

  18. MacLeod CS, Muller FL. On the fracture of pharmaceutical needle-shaped crystals during pressure filtration: case studies and mechanistic understanding. Org Process Res Dev. 2012;16(3):425–34.

    Article  CAS  Google Scholar 

  19. Lekhal A, Girard K, Brown M, Kiang S, Khinast J, Glasser B. The effect of agitated drying on the morphology of l-threonine (needle-like) crystals. Int J Pharm. 2004;270(1–2):263–77.

    Article  CAS  PubMed  Google Scholar 

  20. Taylor L, Papadopoulos D, Dunn P, Bentham A, Dawson N, Mitchell J, et al. Predictive milling of pharmaceutical materials using nanoindentation of single crystals. Org Process Res Dev. 2004;8(4):674–9.

    Article  CAS  Google Scholar 

  21. Hamilton P, Littlejohn D, Nordon A, Sefcik J, Slavin P, Andrews J, et al. Investigation of factors affecting isolation of needle-shaped particles in a vacuum-agitated filter drier through non-invasive measurements by Raman spectrometry. Chem Eng Sci. 2013;101:878–85.

    Article  CAS  Google Scholar 

  22. Fukunaka T, Golman B, Shinohara K. Batch grinding kinetics of ethenzamide particles by fluidized-bed jet-milling. Int J Pharm. 2006;311(1):89–96.

    Article  CAS  PubMed  Google Scholar 

  23. Kulkarni SS, Janssen PHM, Dickhoff BHJ. The impact of material chemistry and morphology on attrition behavior of excipients during high shear blending. Powder Technol. 2023;427: 118694.

    Article  CAS  Google Scholar 

  24. Mendez R, Velazquez C, Muzzio FJ. Effect of feed frame design and operating parameters on powder attrition, particle breakage, and powder properties. Powder Technol. 2012;229:253–60.

    Article  CAS  Google Scholar 

  25. Paul S, Taylor LJ, Murphy B, Krzyzaniak JF, Dawson N, Mullarney MP, et al. Powder properties and compaction parameters that influence punch sticking propensity of pharmaceuticals. Int J Pharm. 2017;521(1–2):374–83.

    Article  CAS  PubMed  Google Scholar 

  26. Dembélé M, Hudon S, Simard J-S, Abatzoglou N, Gosselin R. A multivariate data analysis approach to tablet sticking on an industrial scale: a qualitative case study of an ibuprofen-based formulation. Pharm Dev Technol. 2022;27(10):1093–109.

    Article  PubMed  Google Scholar 

  27. Paul S, Taylor LJ, Murphy B, Krzyzaniak JF, Dawson N, Mullarney MP, et al. Toward a molecular understanding of the impact of crystal size and shape on punch sticking. Mol Pharm. 2020;17(4):1148–58.

    Article  CAS  PubMed  Google Scholar 

  28. Pishnamazi M, Casilagan S, Clancy C, Shirazian S, Iqbal J, Egan D, et al. Microcrystalline cellulose, lactose and lignin blends: process mapping of dry granulation via roll compaction. Powder Technol. 2019;341:38–50.

    Article  CAS  Google Scholar 

  29. Sajjia M, Shirazian S, Egan D, Iqbal J, Albadarin AB, Southern M, et al. Mechanistic modelling of industrial-scale roller compactor ‘Freund TF-MINI model.’ Comput Chem Eng. 2017;104:141–50.

    Article  CAS  Google Scholar 

  30. Reynolds G, Ingale R, Roberts R, Kothari S, Gururajan B. Practical application of roller compaction process modeling. Comput Chem Eng. 2010;34(7):1049–57.

    Article  CAS  Google Scholar 

  31. Dec RT, Zavaliangos A, Cunningham JC. Comparison of various modeling methods for analysis of powder compaction in roller press. Powder Technol. 2003;130(1–3):265–71.

    Article  CAS  Google Scholar 

  32. Hassan L, Jensen R, Megarry A, Blaabjerg LI. Simulation of roller compaction by combination of a compaction simulator and oscillating mill – a material sparing approach. Int J Pharm. 2023;644: 123281.

    Article  CAS  PubMed  Google Scholar 

  33. Kammrath BW, Koutrakos A, Castillo J, Langley C, Huck-Jones D. Morphologically-directed Raman spectroscopy for forensic soil analysis. Forensic Sci Int. 2018;285:e25–33.

    Article  CAS  PubMed  Google Scholar 

  34. Thomas BJ, Absar M, Delvadia R, Conti DS, Witzmann K, Guo C. Analytical method development for characterizing ingredient-specific particle size distributions of nasal spray suspension products. J Pharm Sci. 2021;110(7):2778–88.

    Article  CAS  PubMed  Google Scholar 

  35. Liu Q, Absar M, Saluja B, Guo C, Chowdhury B, Lionberger R, et al. Scientific considerations for the review and approval of first generic mometasone furoate nasal suspension spray in the United States from the bioequivalence perspective. AAPS J. 2019;21:1–6.

    Article  Google Scholar 

  36. Gamble JF, Hoffmann M, Hughes H, Hutchins P, Tobyn M. Monitoring process induced attrition of drug substance particles within formulated blends. Int J Pharm. 2014;470(1–2):77–87.

    Article  CAS  PubMed  Google Scholar 

  37. Gamble JF, Dennis AB, Hutchins P, Jones JW, Musembi P, Tobyn M. Determination of process variables affecting drug particle attrition within multi-component blends during powder feed transmission. Pharm Dev Technol. 2017;22(7):904–9.

    Article  CAS  PubMed  Google Scholar 

  38. Clarke J, Gamble JF, Jones JW, Tobyn M, Dawson N, Davies C, et al. Determining the impact of roller compaction processing conditions on granule and API properties. AAPS PharmSciTech. 2020;21(6):218.

    Article  CAS  PubMed  Google Scholar 

  39. Leuenberger H. The application of percolation theory in powder technology. Adv Powder Technol. 1999;10(4):323–52.

    Article  Google Scholar 

  40. Queiroz ALP, Faisal W, Devine K, Garvie-Cook H, Vucen S, Crean AM. The application of percolation threshold theory to predict compaction behaviour of pharmaceutical powder blends. Powder Technol. 2019;354:188–98.

    Article  CAS  Google Scholar 

  41. Fuertes I, Miranda A, Millán M, Caraballo I. Estimation of the percolation thresholds in acyclovir hydrophilic matrix tablets. Eur J Pharm Biopharm. 2006;64(3):336–42.

    Article  CAS  PubMed  Google Scholar 

  42. Leuenberger H, Rohera B, Haas C. Percolation theory—a novel approach to solid dosage form design. Int J Pharm. 1987;38(1–3):109–15.

    Article  CAS  Google Scholar 

  43. Leane M, Pitt K, Reynolds GK, Dawson N, Ziegler I, Szepes A, et al. Manufacturing Classification System in the real world: factors influencing manufacturing process choices for filed commercial oral solid dosage formulations, case studies from industry and considerations for continuous processing. Pharm Dev Technol. 2018;23(10):964–77.

    Article  CAS  PubMed  Google Scholar 

  44. Leuenberger H, Rohera BD, Haas C. Percolation theory — a novel approach to solid dosage form design. Int J Pharm. 1987;38(1):109–15.

    Article  CAS  Google Scholar 

  45. Millán M, Caraballo I, Rabasco AM. The role of the drug/excipient particle size ratio in the percolation model for tablets. Pharm Res. 1998;15(2):216–20.

    Article  PubMed  Google Scholar 

  46. Allen T. Sampling of powders. In: Allen T, editor. Particle size measurement. Dordrecht: Springer, Netherlands; 1990. p. 1–40.

    Chapter  Google Scholar 

  47. Gamble JF, Tobyn M, Hamey R. Application of image-based particle size and shape characterization systems in the development of small molecule pharmaceuticals. J Pharm Sci. 2015;104(5):1563–4.

  48. Gamble JF, Chiu WS, Tobyn M. Investigation into the impact of sub-populations of agglomerates on the particle size distribution and flow properties of conventional microcrystalline cellulose grades. Pharm Dev Technol. 2011;16(5):542–8.

    Article  CAS  PubMed  Google Scholar 

  49. Kendall K. The impossibility of comminuting small particles by compression. Nature. 1978;272(5655):710–1.

    Article  CAS  Google Scholar 

  50. Hoffmann M, Wray PS, Gamble JF, Tobyn M. Investigation into process-induced de-aggregation of cohesive micronised API particles. Int J Pharm. 2015;493(1–2):341–6.

    Article  CAS  PubMed  Google Scholar 

  51. Clarke J, Gamble JF, Jones JW, Tobyn M, Greenwood R, Ingram A. Alternative approach for defining the particle population requirements for static image analysis based particle characterization methods. Adv Powder Technol. 2019;30(5):920–9.

    Article  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Tracy Gaebele, Srini Sridharan and Andrew Dennis (Bristol Myers Squibb).

Funding

The authors would like to acknowledge the EPSRC for funding.

Author information

Authors and Affiliations

  1. School of Chemical Engineering, University of Birmingham, Birmingham, B15 2TT, UK

    James Clarke, Andrew Ingram & Richard Greenwood

  2. Bristol Myers Squibb, Reeds Lane, Moreton, Wirral, CH46 1QW, UK

    John F. Gamble, John W. Jones & Mike Tobyn

Authors
  1. James Clarke
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John F. Gamble
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. John W. Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mike Tobyn
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Andrew Ingram
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Richard Greenwood
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

JC: conceptualization, analysis, interpretation, writing – review and editing. JFG: conceptualization, interpretation, supervision, writing – drafting, review and editing, final approval. JWJ: writing – review and editing. MT: conceptualization, writing – review and editing, final approval. AI: supervision, writing – drafting, review and editing, final approval. RG: supervision, writing – drafting, review and editing, final approval.

Corresponding author

Correspondence to John F. Gamble.

Ethics declarations

Competing Interest

The authors declare no competing interests. The authors alone are responsible for the content and writing of this paper.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Clarke, J., Gamble, J.F., Jones, J.W. et al. Determining the Impact of Roller Compaction Processing Conditions on Granulate and API Properties: Impact of Formulation API Load. AAPS PharmSciTech 25, 24 (2024). https://doi.org/10.1208/s12249-024-02744-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1208/s12249-024-02744-7

Keywords

Search

Navigation