AAPS PharmSciTech

, Volume 18, Issue 4, pp 1270–1276 | Cite as

Morphological and Crystalline Transitions in Monohydrous and Anhydrous Aripiprazole for a Long-Acting Injectable Suspension

  • Xinyi Tan
  • Yue Zhong
  • Luying He
  • Yuanyuan Zhang
  • Guanghui Jing
  • Song Li
  • Jing Wang
  • Haibing He
  • Xing TangEmail author
Research Article


Many formulation and manufacturing processes can lead to morphological and crystalline transitions in many polycrystalline drugs, changing the properties of active pharmaceutical ingredients (APIs) such as solubility and physical stability which influence their therapeutic effects and safety and so limit their usefulness. Here, we report significant changes in crystal forms and morphology, including the shape and size of particles during the manufacture of off-white aripiprazole (APZ) dry powders used for long-acting and injectable suspensions. With the optimal top-down approach, powders were prepared by recrystallizing uniform monohydrous APZ (MA) and polycrystalline anhydrous APZ (AA) form III, characterized by thermal analysis, PXRD, and FT-IR. However, powders involving MA (MAP) with a lower mean size (2.126 μm), narrower distribution (span = 1.90), and higher stability compared with AA dry powders (AAP) were found to exhibit dehydration behavior and morphological changes after completion of the preparation processes based on the results of thermal analysis. In the case of APZ powders, we wished to obtain more information to guide in the industrial production and experimental design of suspensions in the future.


crystal growth dehydration behavior depot lyophilized suspensions polymorphism  



This research was supported by a grant from the National Science Foundation for Fostering Talents in Basic Research of China (Grant No. J1103606).


  1. 1.
    Potkin SG, Preda A. Aripiprazole once-monthly long-acting injectable for the treatment of schizophrenia. Expert Opin Pharmacother. 2016;17(3):395–407.CrossRefPubMedGoogle Scholar
  2. 2.
    Chue P, Chue J. A review of aripiprazole long-acting injection. Current medical research and opinion. 2015;1–12.Google Scholar
  3. 3.
    Zhu Z. Flash nanoprecipitation: prediction and enhancement of particle stability via drug structure. Mol Pharm. 2014;11(3):776–86.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Cresswell P, Paquette SM, Hickey M, Perkin K, Smith G, Liversidge E, et al. ARIPIPRAZOLE PRODRUG COMPOSITIONS. US Patent. 2016; 20,160,045,495.Google Scholar
  5. 5.
    Citrome L. Aripiprazole long-acting injectable formulations for schizophrenia: aripiprazole monohydrate and aripiprazole lauroxil. Expert review of clinical pharmacology. 2015;1–18.Google Scholar
  6. 6.
    Kostanski JW, Matsuda T, Nerurkar M, Naringrekar VH. Controlled release sterile injectable aripiprazole formulation and method. Google Patents. 2015.Google Scholar
  7. 7.
    Banfield JF, Welch SA, Zhang H, Ebert TT, Penn RL. Aggregation-based crystal growth and microstructure development in natural iron oxyhydroxide biomineralization products. Science. 2000;289(5480):751–4.CrossRefPubMedGoogle Scholar
  8. 8.
    Łaszcz M, Witkowska A. Studies of phase transitions in the aripiprazole solid dosage form. J Pharm Biomed Anal. 2016;117:298–303.CrossRefPubMedGoogle Scholar
  9. 9.
    Delaney SP, Pan D, Yin SX, Smith TM, Korter TM. Evaluating the roles of conformational strain and cohesive binding in crystalline polymorphs of aripiprazole. Cryst Growth Des. 2013;13(7):2943–52.CrossRefGoogle Scholar
  10. 10.
    Braun DE, Gelbrich T, Kahlenberg V, Tessadri R, Wieser J, Griesser UJ. Stability of solvates and packing systematics of nine crystal forms of the antipsychotic drug aripiprazole. Cryst Growth Des. 2008;9(2):1054–65.CrossRefGoogle Scholar
  11. 11.
    Kesisoglou F, Panmai S, Wu Y. Nanosizing—oral formulation development and biopharmaceutical evaluation. Adv Drug Deliv Rev. 2007;59(7):631–44.CrossRefPubMedGoogle Scholar
  12. 12.
    Chaubal MV, Popescu C. Conversion of nanosuspensions into dry powders by spray drying: a case study. Pharm Res. 2008;25(10):2302–8.CrossRefPubMedGoogle Scholar
  13. 13.
    Hartman P. Crystal growth: an introduction: North Holland. 1973.Google Scholar
  14. 14.
    Zhan H, Yang X, Wang C, Chen J, Wen Y, Liang C, et al. Multiple nucleation and crystal growth of barium titanate. Cryst Growth Des. 2012;12(3):1247–53.CrossRefGoogle Scholar
  15. 15.
    Griesser U, Hilfiker R. Polymorphism in the Pharmaceutical Industry. ed Rolf Hilfiker, Wiley-VCH Verlag GmbH & Co. 2006; 211–33.Google Scholar
  16. 16.
    Avdeef A, Tsinman O. Miniaturized rotating disk intrinsic dissolution rate measurement: effects of buffer capacity in comparisons to traditional Wood’s apparatus. Pharm Res. 2008;25(11):2613–27.CrossRefPubMedGoogle Scholar
  17. 17.
    Florey K. Profiles of drug substances, excipients and related methodology. New York: Academic; 1983.Google Scholar
  18. 18.
    Brittain HG. Aripiprazole: polymorphs and solvatomorphs. Prof Drug Subs Ex Relat Method. 2012;37:1–29.CrossRefGoogle Scholar
  19. 19.
    Kimura T, Koga N. Thermal dehydration of monohydrocalcite: overall kinetics and physico-geometrical mechanisms. J Phys Chem A. 2011;115(38):10491–501.CrossRefPubMedGoogle Scholar
  20. 20.
    Liu R, Liu F, Zhao S, Su Y, Wang D, Shen Q. Crystallization and oriented attachment of monohydrocalcite and its crystalline phase transformation. Cryst Eng Comm. 2013;15(3):509–15.CrossRefGoogle Scholar
  21. 21.
    Liu T, Ran Y, Wang B, Dong W, Wu S, Gong J. The dehydration behavior and non-isothermal dehydration kinetics of donepezil hydrochloride monohydrate (form I). Front Chem Sci Eng. 2014;8(1):55–63.CrossRefGoogle Scholar
  22. 22.
    Zhou W. Reversed crystal growth: implications for crystal engineering. Adv Mater. 2010;22(28):3086–92.CrossRefPubMedGoogle Scholar
  23. 23.
    Xu Y, Liu X, Lian R, Zheng S, Yin Z, Lu Y, et al. Enhanced dissolution and oral bioavailability of aripiprazole nanosuspensions prepared by nanoprecipitation/homogenization based on acid–base neutralization. Int J Pharm. 2012;438(1):287–95.CrossRefPubMedGoogle Scholar
  24. 24.
    Sander JR, Bučar D-K, Baltrusaitis J, MacGillivray LR. Organic nanocrystals of the resorcinarene hexamer via sonochemistry: evidence of reversed crystal growth involving hollow morphologies. J Am Chem Soc. 2012;134(16):6900–3.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2016

Authors and Affiliations

  • Xinyi Tan
    • 1
  • Yue Zhong
    • 1
  • Luying He
    • 1
  • Yuanyuan Zhang
    • 1
  • Guanghui Jing
    • 1
  • Song Li
    • 1
  • Jing Wang
    • 1
  • Haibing He
    • 1
  • Xing Tang
    • 1
    Email author
  1. 1.Department of PharmaceuticsShenyang Pharmaceutical UniversityShenyangChina

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