Skip to main content
SpringerLink
Log in

A Kinetic Study of the Polymorphic Transformation of Nimodipine and Indomethacin during High Shear Granulation

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

Abstract

The objective of the present study was to investigate the mechanism, kinetics, and factors affecting the polymorphic transformation of nimodipine (NMD) and indomethacin (IMC) during high shear granulation. Granules containing active pharmaceutical ingredient, microcrystalline cellulose, and low-substituted hydroxypropylcellulose were prepared with ethanolic hydroxypropylcellulose solution, and the effects of independent process variables including impeller speed and granulating temperature were taken into consideration. Two polymorphs of the model drugs and granules were characterized by X-ray powder diffraction analysis and quantitatively determined by differential scanning calorimetry. A theoretical kinetic method of ten kinetic models was applied to analyze the polymorphic transformation of model drugs. The results obtained revealed that both the transformation of modification I to modification II of NMD and the transformation of the α form to the γ form of IMC followed a two-dimensional nuclei growth mechanism. The activation energy of transformation was calculated to be 7.933 and 56.09 kJ·mol−1 from Arrhenius plot, respectively. Both the granulating temperature and the impeller speed affected the transformation rate of the drugs and, in particular, the high shear stress significantly accelerated the transformation process. By analyzing the growth mechanisms of granules in high-shear mixer, it was concluded that the polymorphic transformation of NMD and IMC took place in accordance with granule growth in a high-shear mixer.

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
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11

Similar content being viewed by others

References

  1. Haleblian J, McCrone W. Pharmaceutical applications of polymorphism. J Pharm Sci. 1969;58:911–29.

    Article  PubMed  CAS  Google Scholar 

  2. Grunenberg A, Keil B, Henck JO. Polymorphism in binary mixture, as exemplified by nimodipine. Int J Pharm. 1995;118:11–21.

    Article  CAS  Google Scholar 

  3. Yamamoto H. 1-Acyl-indoles. II. A new syntheses of 1-(p-chlorobenzoyl)-5-methoxy-3-indolylacetic acid and its polymorphism. Chem Pharm Bull. 1968;16:17–9.

    PubMed  CAS  Google Scholar 

  4. Joshi V. Physical transformations in solvated pharmaceuticals. Ph.D. Dissertation, Purdue University, West Lafayette, IN; 1998.

  5. Wu T, Yu L. Origin of enhanced crystal growth kinetics near T g probed with indomethacin polymorphs. J Phys Chem B. 2006;110:15694–9.

    Article  PubMed  CAS  Google Scholar 

  6. Kaneniwa N, Otsuka M, Hayashi T. Physicochemical characterization of indomethacin polymorphs and the transformation kinetics in ethanol. Chem Pharm Bull. 1985;33:3447–55.

    PubMed  CAS  Google Scholar 

  7. Morris KR, Griesser UJ, Eckhardt CJ, Stowell JG. Theoretical approaches to physical transformations of active pharmaceutical ingredients during manufacturing processes. Adv Drug Deliv Rev. 2001;48:91–114.

    Article  PubMed  CAS  Google Scholar 

  8. Zhang GG, Law D, Schmitt EA, Qiu YH. Phase transformation considerations during process development and manufacture of solid oral dosage forms. Adv Drug Deliv Rev. 2004;56:371–90.

    Article  PubMed  CAS  Google Scholar 

  9. Schæfer T, Holm P, Kristensen G. Melt pelletization in a high shear mixer. I. Effects of process variables and binder. Acta Pharm Nord. 1992;4:133–40.

    Google Scholar 

  10. Wang S, Ye G, Heng PWS, Ma M. Investigation of high shear wet granulation processes using different parameters and formulation. Chem Pharm Bull. 2008;56:22–7.

    Article  PubMed  CAS  Google Scholar 

  11. Schæfer T, Mathiesen C. Melt pelletization in a high shear mixer. VII. Effects of product temperature. Int J Pharm. 1996;134:105–17.

    Article  Google Scholar 

  12. Voinovich D, Campsi B, Moneghini M, Vincenzi C, Phan-Tan-Luu R. Screening of high shear mixer melt granulation process variables using an asymmetrical factorial design. Int J Pharm. 1999;190:73–81.

    Article  PubMed  CAS  Google Scholar 

  13. Keningley ST, Knight PC, Marson AD. An investigation into the effects of binder viscosity on agglomeration behaviour. Powder Technol. 1997;91:95–103.

    Article  CAS  Google Scholar 

  14. Schaefer T, Holm P, Kristensen G. Melt pelletization in a high shear mixer. III. Effects of lactose quality. Acta Pharm Nord. 1992;4:245–52.

    CAS  Google Scholar 

  15. Pan X, Julian T, Augsburger L. Increasing the dissolution rate of a low-solubility drug through a crystalline-amorphous transition: a case study with indomethacin. Drug Dev Ind Pharm. 2008;34:221–31.

    Article  PubMed  CAS  Google Scholar 

  16. Pan X, Julian T, Augsburger L. Quantitative measurement of indomethacin crystallinity in indomethacin-silica gel binary system using differential scanning calorimetry and X-ray powder diffractometry. AAPS Pharm Sci Tech. 2006;7:E72–8.

    Article  Google Scholar 

  17. He Z, Zhong D, Chen X, Liu X, Tang X, Zhao L. Development of a dissolution medium for nimodipine tablets based on bioavailability evaluation. Eur J Pharm Sci. 2004;21:487–91.

    Article  PubMed  CAS  Google Scholar 

  18. Barmpalexis P, Kachrimanis K, Georgarakis E. Solid dispersions in the development of a nimodipine floating tablet formulation and optimization by artificial neural networks and genetic programming. Eur J Pharm Biopharm. 2011;77:122–31.

    Article  PubMed  CAS  Google Scholar 

  19. Murali Mohan Babu GV, Prasad CHDS, Ramana Murthy KV. Evaluation of modified gum karaya as carrier for the dissolution enhancement of poorly water-soluble drug nimodipine. Int J Pharm. 2002;234:1–17.

    Article  PubMed  CAS  Google Scholar 

  20. Otsuka M, Kato F, Matsuda Y, Ozaki Y. Comparative determination of polymorphs of indomethacin in powders and tablets by chemometrical near-infrared spectroscopy and X-ray powder diffractometry. AAPS Pharm Sci Tech. 2003;4:1–12.

    Google Scholar 

  21. Aceves-Hernadez JM, Nicolás-Vázquez I, Aceves FJ, Hinojosa-Torres J, Paz M, Castaño VM. Indomethacin polymorphs: experimental and conformational analysis. J Pharm Sci. 2009;98:2448–63.

    Article  Google Scholar 

  22. Hancock JD, Sharp JH. Method of comparing solid-state kinetic data and its application to the decomposition of kaolinite, brucite, and BaCO3. J Am Ceram Soc. 1972;55:74–7.

    Article  CAS  Google Scholar 

  23. Criado JM, Morales J, Rives V. Computer kinetic analysis of simultaneously obtained TG and DTG curves. J Thermal Anal. 1978;14:221–8.

    Article  CAS  Google Scholar 

  24. Hirayama F, Wang Z, Uekama K. Effect of 2-hydroxypropyl-β-cyclodextrin on crystallization and polymorphic transition of nifedipine in solid state. Pharm Res. 1994;11:1766–70.

    Article  PubMed  CAS  Google Scholar 

  25. Grunenberg A, Henck JO, Siesler HW. Theoretical derivation and practical application of energy/temperature diagrams as an instrument in preformulation studies of polymorphic drug substances. Int J Pharm. 1996;129:147–58.

    Article  CAS  Google Scholar 

  26. Bauer-Brandl A. Polymorphic transitions of cimetidine during manufacture of solid dosage forms. Int J Pharm. 1996;140:195–206.

    Article  CAS  Google Scholar 

  27. Iveson SM, Litster JD. Growth regime map for liquid-bounded granules. AICHE J. 1998;44:1510–8.

    Article  CAS  Google Scholar 

  28. Tu W, Ingram A, Seville J, Hsiau S. Exploring the regime map for high-shear mixer granulation. Chem Eng J. 2009;145:505–13.

    Article  CAS  Google Scholar 

  29. Vonk P, Guillaume CPF, Ramaker JS, Vromans H, Kossen NWF. Growth mechanisms of high-shear pelletization. Int J Pharm. 1997;157:93–102.

    Article  CAS  Google Scholar 

Download references

ACKNOWLEDGMENT

The authors would like to thank Collette N.V, Belgium, for supplying the MicroGral® high-shear mixers and for their logistic and technical support. This work was supported by the National Basic Research Program of China (973 Program; No.2009CB930300) and Major National Platform for Innovative Pharmaceuticals (No. 2009ZX09301-012).

Author information

Authors and Affiliations

  1. School of Pharmacy, Shenyang Pharmaceutical University, No.103 Wenhua Road, No. 32 P.O. Box, Shenyang, 110016, People’s Republic of China

    Zhen Guo, Tianyi Wang, Di Chang, Tongying Jiang & Siling Wang

  2. Shenyang Xingqi Pharmaceutical Co. Ltd., Shenyang, 110024, People’s Republic of China

    Mingxin Ma

Authors
  1. Zhen Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mingxin Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tianyi Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Di Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tongying Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Siling Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Siling Wang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Guo, Z., Ma, M., Wang, T. et al. A Kinetic Study of the Polymorphic Transformation of Nimodipine and Indomethacin during High Shear Granulation. AAPS PharmSciTech 12, 610–619 (2011). https://doi.org/10.1208/s12249-011-9628-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12249-011-9628-8

KEY WORDS

Search

Navigation