Skip to main content

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


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.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8


  1. Potkin SG, Preda A. Aripiprazole once-monthly long-acting injectable for the treatment of schizophrenia. Expert Opin Pharmacother. 2016;17(3):395–407.

    CAS  Article  PubMed  Google Scholar 

  2. Chue P, Chue J. A review of aripiprazole long-acting injection. Current medical research and opinion. 2015;1–12.

  3. Zhu Z. Flash nanoprecipitation: prediction and enhancement of particle stability via drug structure. Mol Pharm. 2014;11(3):776–86.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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.

  5. Citrome L. Aripiprazole long-acting injectable formulations for schizophrenia: aripiprazole monohydrate and aripiprazole lauroxil. Expert review of clinical pharmacology. 2015;1–18.

  6. Kostanski JW, Matsuda T, Nerurkar M, Naringrekar VH. Controlled release sterile injectable aripiprazole formulation and method. Google Patents. 2015.

  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.

    CAS  Article  PubMed  Google Scholar 

  8. Łaszcz M, Witkowska A. Studies of phase transitions in the aripiprazole solid dosage form. J Pharm Biomed Anal. 2016;117:298–303.

    Article  PubMed  Google Scholar 

  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.

    CAS  Article  Google Scholar 

  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.

    Article  Google Scholar 

  11. Kesisoglou F, Panmai S, Wu Y. Nanosizing—oral formulation development and biopharmaceutical evaluation. Adv Drug Deliv Rev. 2007;59(7):631–44.

    CAS  Article  PubMed  Google Scholar 

  12. Chaubal MV, Popescu C. Conversion of nanosuspensions into dry powders by spray drying: a case study. Pharm Res. 2008;25(10):2302–8.

    CAS  Article  PubMed  Google Scholar 

  13. Hartman P. Crystal growth: an introduction: North Holland. 1973.

  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.

    CAS  Article  Google Scholar 

  15. Griesser U, Hilfiker R. Polymorphism in the Pharmaceutical Industry. ed Rolf Hilfiker, Wiley-VCH Verlag GmbH & Co. 2006; 211–33.

  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.

    CAS  Article  PubMed  Google Scholar 

  17. Florey K. Profiles of drug substances, excipients and related methodology. New York: Academic; 1983.

  18. Brittain HG. Aripiprazole: polymorphs and solvatomorphs. Prof Drug Subs Ex Relat Method. 2012;37:1–29.

    CAS  Article  Google Scholar 

  19. Kimura T, Koga N. Thermal dehydration of monohydrocalcite: overall kinetics and physico-geometrical mechanisms. J Phys Chem A. 2011;115(38):10491–501.

    CAS  Article  PubMed  Google Scholar 

  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.

    CAS  Article  Google Scholar 

  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.

    CAS  Article  Google Scholar 

  22. Zhou W. Reversed crystal growth: implications for crystal engineering. Adv Mater. 2010;22(28):3086–92.

    CAS  Article  PubMed  Google Scholar 

  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.

    CAS  Article  PubMed  Google Scholar 

  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.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references


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

Author information

Authors and Affiliations


Corresponding author

Correspondence to Xing Tang.

Additional information

Xinyi Tan and Yue Zhong contributed equally to this work.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Tan, X., Zhong, Y., He, L. et al. Morphological and Crystalline Transitions in Monohydrous and Anhydrous Aripiprazole for a Long-Acting Injectable Suspension. AAPS PharmSciTech 18, 1270–1276 (2017).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


  • crystal growth
  • dehydration behavior
  • depot
  • lyophilized suspensions
  • polymorphism