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Amorphization of Atorvastatin Calcium by Mechanical Process: Characterization and Stabilization Within Polymeric Matrix

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Abstract

The structural changes of crystalline atorvastatin upon high-energy ball milling at room temperature have been studied. The study investigates the effect of polyvinylpyrrolidone (PVP) and hydroxypropylmethyl cellulose (HPMC) polymeric matrix on stabilizing amorphous atorvastatin before and after storage under ambient and elevated humidity conditions. The materials were characterized by X-ray diffraction (XRD), Fourier transform infrared spectrophotometry (FTIR), differential scanning calorimetry (DSC), scanning electron microscopy (SEM), 19F MAS NMR spectroscopy, and dissolution testing. The results indicate that this drug has undergone a direct crystal-to-glass transformation upon milling. Stable amorphous form of atorvastatin calcium has been obtained with PVP and HPMC (in 1:1 ratios).

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References

  1. Brittain HG. Polymorphism in pharmaceutical solids. New York: Informa Healthcare; 2009.

    Google Scholar 

  2. David PE, James EP, René H. The solid-state continuum: a perspective on the interrelationships between different solid-state forms in drug substance and drug product. J Pharm Pharmacol. 2014;67(6):757–72.

    Google Scholar 

  3. Yu L. Amorphous pharmaceutical solids: preparation, characterization and stabilization. Adv Drug Deliv Rev. 2001;48:27–42.

    Article  CAS  PubMed  Google Scholar 

  4. Rodriguez-Spong B, Price CP, Jayasankar A, Matzger AJ, Rodriguez-Hornedo N. General principles of pharmaceutical solid polymorphism: a supramolecular perspective. Adv Drug Deliv Rev. 2004;56:241–74.

    Article  CAS  PubMed  Google Scholar 

  5. Norman Chieng, Thomas Rades, Jaakko Aaltonen. An overview of recent studies on the analysis of pharmaceutical polymorphs. J Pharm Biomed Anal. 2010;55:618–644.

  6. Hirofumi T, Shinsuke N, Hiromitsu Y, Yoshiaki K. Solid dispersion particles of tolbutamide prepared with fine silica particles by the spray-drying method. Powder Technol. 2004;141:187–95.

    Article  Google Scholar 

  7. Craig DQ, Royall PG, Kett VL, Hopton ML. The relevance of the amorphous state to pharmaceutical dosage forms: glassy drugs and freeze dried systems. Int J Pharm. 1999;179:179–207.

    Article  CAS  PubMed  Google Scholar 

  8. Liu R. Water-insoluble drug formulation. Taylor and Francis, London 2008; pp 88–455.

  9. Zhao H, Wang JX, Wang QA, Chen JF, Yun J. Ind Eng Chem Res. 2007;46:8229–35.

    Article  CAS  Google Scholar 

  10. PAUL RO, NCHI QL, LYNN ER. Physics of crystal-to-glass transformations. Solid State Phys. 1999;52:1–135.

    Article  Google Scholar 

  11. Fecht H. Defect-induced melting and solid-state amorphization. Nature. 1992;356:133–5.

    Article  CAS  Google Scholar 

  12. Vincent C, Yun H, Lidia T, Andrea E, Owen IC, Patrick M, Anne MH. Amorphous solid dispersions of sulfonamide/soluplus and sulfonamide/PVP prepared by ball milling. AAPS PharmSciTech. 2013;14:464–74.

  13. Deepak B, Robin HB. Amorphization of indomethacin by co-grinding with Neusilin US2: amorphization kinetics, physical stability and mechanism. Pharm Res. 2006;23(10):2317–25.

  14. Lefort R, Gusseme AD, Willart JF, Danède F, Descamps M. Solid state NMR and DSC methods for quantifying the amorphous content in solid dosage forms: an application to ball milling of trehalose. Int J Pharm. 2004;280:209–19.

    Article  CAS  PubMed  Google Scholar 

  15. Lepek P, Sawicki W, Wlodarski K, Wojnarowska Z, Paluch M, Guzik L. Effect of amorphization method on telmisartan solubility and the tableting process. Eur J Pharm Biopharm. 2013;83:114–21.

    Article  CAS  PubMed  Google Scholar 

  16. Yun H, PoL M, Vincent C, Lidia T, Anne Marie H, Andrea E, Patrick M. Formation, physical stability, and quantification of process-induced disorder in cryomilled samples of a model polymorphic drug. J Pharm Sci. 2013;102:93–103.

  17. Bahl D, Hudak J, Bogner RH. Comparison of the ability of various pharmaceutical silicates to amorphize and enhance dissolution of indomethacin upon co grinding. Pharm Dev Technol. 2008;13:255–69.

    Article  CAS  PubMed  Google Scholar 

  18. Colombo I, Grassi G, Grassi M. Drug mechanochemical activation. J Pharm Sci. 2009;98:3961–86.

    Article  CAS  PubMed  Google Scholar 

  19. Lennernas H. Clinical pharmacokinetics of atorvastatin. Clin Pharmacokinet. 2003;42:1141–60.

    Article  PubMed  Google Scholar 

  20. Jeong-Soo K, Min-Soo K, Hee Jun P, Shun-Ji J, Sibeum L, Sung-Joo H. Physicochemical properties and oral bioavailability of amorphous atorvastatin hemi-calcium using spray-drying and SAS process. Int J Pharm. 2008;359:211–9.

    Article  Google Scholar 

  21. Min-Soo K, Shun-Ji J, Jeong-Soo K, Hee Jun P, Ha-Seung S, Reinhard HN, Sung-Joo H. Preparation, characterization and in vivo evaluation of amorphous atorvastatin calcium nanoparticles using supercritical antisolvent (SAS) process. Eur J Pharm Biopharm. 2008;69:454–65.

    Article  Google Scholar 

  22. Taksande JB, Lade SN, Trivedi RV, Mahore JG, Umekar MJ. Effect of hydrophilic polymer on solubility and dissolution of atorvastatin inclusion complex. International journal of pharmaceutical and chemical sciences. 2012;1:374–85.

    Google Scholar 

  23. Bobe KR, Subrahmanya CR, Sarasija S, Gaikwad DT, Patil MD, Khade TS, Gavitre BB, Kulkarni VS, Gaikwad UT. Formulation and evaluation of solid dispersion of atorvastatin with various carriers. Pharmacie Globale: International Journal of Comprehensive Pharmacy. 2011;2(1):1-6.

  24. Briggs CA, Wade JR, Harasawa K, Ichikawa S, Minohara K, Nakagawa S. Inventors, crystalline [R- (R*, R*)]-2-(4-difluoro-phenyl)3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid hemi calcium salt (atorvastatin). 1999; US Patent 5969156.

  25. Ganesh S, Vibha P, Lokesh K, Arvind KB. Solid state characterization of commercial crystalline and amorphous atorvastatin calcium samples. AAPS PharmSciTech. AAPS Pharm Sci Tech. 2010;11:598-609.

  26. Willart JF, Caron V, Lefort R, Danéde F, Prévost D, Descamps M. A thermal character of the solid state amorphization of lactose induced by ball milling. Solid State Commun. 2004;132:693–6.

    Article  CAS  Google Scholar 

  27. Descamps M, Willart JF, Dudognon E, Caron V. Transformation of pharmaceutical compounds upon milling and comilling: the role of Tg. J Pharm Sci. 2007;96:1398–407.

    Article  CAS  PubMed  Google Scholar 

  28. Willart J, Descamps N, Caron V, Capet F, Danède F, Descamps M. Formation of lactose-mannitol molecular alloys by solid state vitrification. Solid State Commun. 2006;138:194–9.

    Article  CAS  Google Scholar 

  29. ANN N, GEORGE Z. Critical considerations for the qualitative and quantitative determination of process-induced disorder in crystalline solids. J Pharm Sci. 2014;103:2595–604.

    Article  Google Scholar 

  30. Wang WD, Gao X, Strohmeier M, Wang W, Bai S, Dybowski C. Solid-state NMR studies of form I of atorvastatin calcium. J Phys Chem. 2012;116:3641–9.

    Article  CAS  Google Scholar 

  31. Suryanarayan R. X-ray powder diffractometry. In: Brittain HG, editor. Physical characterization of pharmaceutical solids. New York: Marcel Dekker, Inc.; 1995. p. 187–221.

    Chapter  Google Scholar 

  32. Jojart-Larczkovich O, Szabo-Revesz P. Amorphization of a crystalline active pharmaceutical ingredient and thermoanalytical measurements on this glassy form. J Therm Calorim. 2010;102:243–7.

    Article  Google Scholar 

  33. Kerc J, Srcic S. Thermal analysis of glassy pharmaceuticals. Thermochim Acta. 1995;248:81–95.

    Article  CAS  Google Scholar 

  34. Urbanova M, Brus J, Sedenkova I, Policianova O, Kobera L. Characterization of polymer dispersion of active pharmaceutical ingredients by 19 F MAS NMR and factor analysis. Spectrochim Acta. 2013;100:59–66.

    Article  CAS  Google Scholar 

  35. Brus J, Urbanova M, Sedenkova I, Brusova H. New perspectives of 19F MAS NMR in the characterization of amorphous forms of atorvastatin in dosage formulations. Int J Pharm. 2011;409:62–74.

    Article  CAS  PubMed  Google Scholar 

  36. Marsac PJ, Li T, Taylor LS. Estimation of drug–polymer miscibility and solubility in amorphous solid dispersions using experimentally determined interaction parameters. Pharm Res. 2009;26:139–51.

    Article  CAS  PubMed  Google Scholar 

  37. Qian F, Huang J, Hussain MA. Drug–polymer solubility and miscibility: stability consideration and practical challenges in amorphous solid dispersion development. J Pharm Sci. 2010;99:2941–7.

    Article  CAS  PubMed  Google Scholar 

  38. Renu C, Kapoor VK, Kumar A. Analytic techniques used to characterize drug-polyvinylpyrrolidone systems in solid and liquid states—an overview. J Sci Ind Res. 2006;65:459–69.

    Google Scholar 

  39. Molyneux P. Water soluble synthetic polymers: properties and behavior. Boca Raton: CRC Press; 1983.

    Google Scholar 

  40. Subhashree S, Chandra KC, Pradipta KB. Spectroscopic investigations of a ciprofloxacin/hpmc mucoadhesive suspension. Int J App Pharm. 2012;4:1–8.

    Google Scholar 

  41. Angus F, John H, Thomas R. Characterization of glass solutions of poorly water soluble drugs produced by melt extrusion with hydrophilic amorphous polymers. JPP. 2001;53:303–15.

    Article  Google Scholar 

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Authors and Affiliations

  1. Laboratoire Matériaux, Traitement et Analyse, INRAP, BiotechPole Sidi Thabet, 2020, Ariana, Tunisia

    Malek Lemsi, Haykel Galai & Rafik Kalfat

  2. Faculté des sciences de Tunis, Université de Tunis El Manar, 2092, Tunis, Tunisia

    Malek Lemsi

  3. Laboratoire National de contrôle de Médicaments, 1006, Tunis, Tunisia

    Mohamed Radhouan Louhaichi

  4. Laboratoire d’Automatique et de Génie des Procédés, UMR CNRS 5007, UCB Lyon 1, ESCPE-Lyon, 43 Bd du 11 Novembre 1918, 69 622, Villeurbanne Cedex, France

    Hatem Fessi

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  1. Malek Lemsi
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  2. Haykel Galai
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  4. Hatem Fessi
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Correspondence to Malek Lemsi.

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Lemsi, M., Galai, H., Louhaichi, M.R. et al. Amorphization of Atorvastatin Calcium by Mechanical Process: Characterization and Stabilization Within Polymeric Matrix. J Pharm Innov 12, 216–225 (2017). https://doi.org/10.1007/s12247-017-9282-0

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