Skip to main content
SpringerLink
Log in

Effect of Manufacturing Conditions on Particle Characteristics in the Drug-Layering Process of a Novel Melt Granulation Technology, MALCORE®, Using a Design of Experiments

  • Original Article
  • Published:
Journal of Pharmaceutical Innovation Aims and scope Submit manuscript

Abstract

Purpose

MALCORE®, a manufacturing technology of drug-containing particles (DCPs) for coating, consists of a 2-step melt granulation process. The drug-layering process in the technology is important for determining the characteristics of the resulting DCPs. However, the effect of the manufacturing conditions of the drug-layering process on particle characteristics has not been clarified. The aim of this study was to investigate the effect of the manufacturing conditions for MALCORE® on particle characteristics using the design of experiments (DoE) method.

Method

A high-shear granulator was used in the drug-layering process, and the product temperature, melt granulation time, and blade rotation speed were selected as input factors for the DoE. The available yield, d10 and d50, flowability, particle strength, and drug dissolution of DCPs were evaluated, and the relationship between the manufacturing conditions and particle characteristics was clarified using statistical methods.

Results

The available yield and d50 were affected by all manufacturing conditions while the particle strength was affected only by the blade rotation speed. Drug dissolution was unaffected by the manufacturing conditions. The predicted and measured values in the design space of the manufacturing conditions constructed based on these results were almost identical, thereby indicating the validity of the DoE.

Conclusion

The results of this study revealed the effect of manufacturing conditions on particle characteristics for a unique manufacturing technology MALCORE®, in which the drug is layered on the core particles by melt granulation. The findings provide useful information for the implementation of MALCORE® in pharmaceutical formulation development.

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
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data Availability

The datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

References

  1. Yoshihara N, Kimata R, Terukina T, Kanazawa T, Kondo H. Novel preparation approach with a 2-step process for spherical particles with high drug loading and controlled size distribution using melt granulation: MALCORE®. Adv Powder Technol. 2022;33(2): 103409. https://doi.org/10.1016/j.apt.2021.103409.

    Article  CAS  Google Scholar 

  2. Kimata R, Yoshihara N, Terukina T, Kanazawa T, Kondo H. Impact of properties of hydrated silicon dioxide as core material on the characteristics of drug-containing particles prepared by the 2-step process melt granulation technology, MALCORE®. AAPS PhrarmSciTech. 2022;24:28. https://doi.org/10.1208/s12249-022-02492-6.

    Article  CAS  Google Scholar 

  3. Sekyi NKG, Kelly A, Rahmanian N. Comparative analysis of granule properties in continuous granulators. Powder Technol. 2023;425. https://doi.org/10.1016/j.powtec.2023.118557.

  4. Campisi B, Vojnovic D, Chicco D, Phan-Tan-Luu R. Melt granulation in a high shear mixer: optimization of mixture and process variables using a combined experimental design. Chemom Intell Lab Syst. 1999;48:59–70. https://doi.org/10.1016/S0169-7439(99)00008-8.

    Article  CAS  Google Scholar 

  5. Kittikunakorn N, Sun CC, Zhang F. Effect of screw profile and processing conditions on physical transformation and chemical degradation of gabapentin during twin-screw melt granulation. Eur J Pharm Sci. 2019;131:243–53. https://doi.org/10.1016/j.ejps.2019.02.024.

    Article  CAS  PubMed  Google Scholar 

  6. Sotthivirat S, Ren J, Wasylaschuk W, Afanador N, Rosenberg K, Taggart RV, et al. An integrated approach for high-shear wet granulation (HSWG) processing of TPGS-based formulations: demonstration of process robustness through experimental design conditions. J Pharm Sci. 2021;110:2934–45. https://doi.org/10.1016/j.xphs.2021.03.015.

    Article  CAS  PubMed  Google Scholar 

  7. Meng W, Dvořák J, Kumar R, Hofmeister R, Štěpánek F, Ramachandran R, et al. Continuous high-shear granulation: mechanistic understanding of the influence of process parameters on critical quality attributes via elucidating the internal physical and chemical microstructure. Adv Powder Technol. 2019;30:1765–81. https://doi.org/10.1016/j.apt.2019.04.028.

    Article  CAS  Google Scholar 

  8. Kimura S, Iwao Y, Ishida M, Uchimoto T, Miyagishima A, Sonobe T, et al. Optimal conditions to prepare fine globular granules with a multi-functional rotor processor. Int J Pharm. 2010;391:244–7. https://doi.org/10.1016/j.ijpharm.2010.03.005.

    Article  CAS  PubMed  Google Scholar 

  9. ICH. Q8 (R2) guideline (ICH, 2009). https://database.ich.org/sites/default/files/Q8_R2_Guideline.pdf. Accessed 21 Jul 2023. Pharm Dev Q8. International Conference on Harmonization; 2009. ICH harmonized tripartite guideline. (p. R2).

  10. Bukovec P, Krošelj V, Turk S, Vrečer F. Optimization of melt pelletization in a high shear mixer. Int J Pharm. 2009;381:192–8. https://doi.org/10.1016/j.ijpharm.2009.06.036.

    Article  CAS  PubMed  Google Scholar 

  11. Andrade TC, Martins RM, LA Freitas P. Granulation of indomethacin and a hydrophilic carrier by fluidized hot melt method: the drug solubility enhancement. Powder Technol. 2015;270:453–60. https://doi.org/10.1016/j.powtec.2014.07.030.

    Article  CAS  Google Scholar 

  12. Vieira MMS, Martins RM, Freitas LAP. Characteristics of piroxicam granules prepared by fluidized bed hot melt granulation. Adv Powder Technol. 2018;29:934–40. https://doi.org/10.1016/j.apt.2018.01.011.

    Article  CAS  Google Scholar 

  13. Mamidi HK, Palekar S, Nukala PK, Mishra SM, Patki M, Fu Yige, et al. Process optimization of twin-screw melt granulation of fenofibrate using design of experiment (DoE). Int J Pharm. 2021;593:120101. https://doi.org/10.1016/j.ijpharm.2020.120101.

  14. Van de Steene S, Van Renterghem J, Vanhoorne V, Vervaet C, Kumar A, De Beer T. Elucidation of granulation mechanisms along the length of the barrel in continuous twin-screw melt granulation. Int J Pharm. 2023;639:122986. https://doi.org/10.1016/j.ijpharm.2023.122986.

    Article  CAS  PubMed  Google Scholar 

  15. Box GEP, Behnken DW. Some new three level designs for the study of quantitative variables. Technometrics. 1960;2:455–75. https://doi.org/10.1080/00401706.1960.10489912.

    Article  Google Scholar 

  16. Liu Huolong, Wang K, Schlindwein W, Li M. Using the Box–Behnken experimental design to optimise operating parameters in pulsed spray fluidised bed granulation. Int J Pharm. 2013;448:329–38. https://doi.org/10.1016/j.ijpharm.2013.03.057.

  17. PubChem® of National Center for Biotechnology Information. Density of stearic acid compound summary, modified 2023. https://pubchem.ncbi.nlm.nih.gov/compound/Stearic-Acid#section=Solubility. Accessed 21 Jul 2023. p. 3.2.9.

  18. Powder flow of the United States of America Pharmacopeial Convention. The pharmacopeial discussion group (PDG) Sign-Off Cover Page. https://www.usp.org/sites/default/files/usp/document/harmonization/gen-chapter/g05_pf_30_6_2004.pdf. Accessed 21 Jul 2023; 2004.

  19. Shiino K, Fujinami Y, Kimura SI, Iwao Y, Noguchi S, Itai S. Melt adsorption as a manufacturing method for fine particles of wax matrices without any agglomerates. Chem Pharm Bull (Tokyo). 2017;65:726–31. https://doi.org/10.1248/cpb.c17-00108.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Dr. Shoji Yokota and Dr. Kenji Nozawa for providing the opportunity to prepare this paper.

Author information

Authors and Affiliations

  1. School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan

    Naoki Yoshihara, Ryota Kimata, Takayuki Terukina & Hiromu Kondo

  2. Pharmaceutical Development Department, Sawai Pharmaceutical Co., Ltd, 2-30, Miyahara 5-chome, Yodogawa-ku, Osaka 532-0003, Japan

    Naoki Yoshihara & Ryota Kimata

Authors
  1. Naoki Yoshihara
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ryota Kimata
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Takayuki Terukina
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hiromu Kondo
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization: Naoki Yoshihara, Ryota Kimata. Methodology: Naoki Yoshihara, Ryota Kimata. Formal analysis and investigation: Naoki Yoshihara, Ryota Kimata. Writing—original draft preparation: Naoki Yoshihara. Writing—review and editing: Takayuki Terukina, Hiromu Kondo. Supervision: Hiromu Kondo. All authors agreed to be accountable for all aspects of the work.

Corresponding author

Correspondence to Hiromu Kondo.

Ethics declarations

Ethics Approval

This research does not contain any studies with human or animal subjects performed by any of the authors.

Conflict of Interest

The authors declare no competing interests.

Additional information

Publisher's Note

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

Summary

MALCORE®, a manufacturing technology of drug-containing particles (DCPs) for coating, consists of a 2-step melt granulation process. The 2nd step of MALCORE® is drug-layering process, which is important for determining the characteristics of the resulting DCPs. In this study, the effect of the manufacturing conditions of the 2nd step on the particle characteristics was investigated using design of experiments (DoE). The DCPs were prepared at arbitrary points in the design space constructed using the predictive equations for each particle characteristic, and the validity of the DoE was shown by comparing the predicted and measured values.

Teaser

The effect of the manufacturing conditions for a novel melt granulation technology (MALCORE®) on particle characteristics was evaluated using the design of experiments method, which was validated from the results.

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

Yoshihara, N., Kimata, R., Terukina, T. et al. Effect of Manufacturing Conditions on Particle Characteristics in the Drug-Layering Process of a Novel Melt Granulation Technology, MALCORE®, Using a Design of Experiments. J Pharm Innov 18, 2158–2169 (2023). https://doi.org/10.1007/s12247-023-09781-y

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12247-023-09781-y

Keywords

Search

Navigation