Skip to main content
SpringerLink
Log in

Pre-clinical Formulation Development of an in situ Meglumine Salt of AZD5991: A Novel Macrocyclic Mcl-1 Inhibitor

  • Original Research Article
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose

AZD5991 is a potent and selective macrocyclic inhibitor of Mcl-1 in clinical development. Developing an intravenous solution formulation for AZD5991 proved to be challenging primarily due to the poor intrinsic solubility of AZD5991. In this article are described studies performed to select a suitable crystalline form and to assess physicochemical properties of AZD5991 to aid in the design of a solution formulation for preclinical studies.

Methods

It is preferable that the preclinical formulation has a line of sight for clinical formulation. For AZD5991, a concentration of at least 20 mg/ml was required for toxicology studies. Toward this goal, extensive pre-formulation characterization of AZD5991 including solid form analysis, pH-solubility profiling and solubility determination in cosolvents and other solubilizing media were carried out.

Results & discussion

Crystalline Form A, which is more stable in aqueous solution and possesses acceptable thermal stability, was selected for preclinical and clinical development of AZD5991.

Extensive solubility evaluation revealed an interesting pH-solubility profile that significantly enhances solubilization at pH > 8.5 to allow solution concentrations of at least 30 mg/ml by in situ meglumine salt formation.

Conclusion

Developing pre-clinical formulations to support in vivo studies requires a good understanding of the physicochemical properties of the drug candidates. Candidates with challenging pharmaceutic properties like the novel macrocycle molecule AZD5991, demand extensive characterization in its polymorph landscape, solubility profile and suitability evaluation of the excipients. Meglumine, a pH-adjusting and solubilizing agent, was found to be the best choice for formulating AZD5991 into an intravenous product to support preclinical studies.

Graphical Abstract

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
Fig. 12

Similar content being viewed by others

Data Availability

The crystallographic data for AZD5991-Form A and AZD5991-Form F are available from The Cambridge Crystallographic Data Centre (www.ccdc.cam.ac.ukldata_request/cif ) with CCDC numbers of 2252069 and 2252070 respectively.

References

  1. Beroukhim R, Mermel CH, Porter D, Wei G, Raychaudhuri S, Donovan J, et al. The landscape of somatic copy-number alteration across human cancers. Nature. 2010;463(7283):899–905.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Stewart ML, Fire E, Keating AE, Walensky LD. The MCL-1 BH3 helix is an exclusive MCL-1 inhibitor and apoptosis sensitizer. Nat Chem Biol. 2010;6(8):595–601.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Alexander Hird MAB, Wenzhan Yang, John Paul Secrist, Daniel William Robbins, Steven Lee Kazmirski, Dedong Wu, Bo Peng, Jeffrey Johannes, Michelle Laurae Lamb, Qing Ye, Xiaolan Zheng., InventorMacrocyclic mcl1 inhibitors for treating cancer. 2016 USA patent US11472816B2

  4. Tron AE, Belmonte MA, Adam A, Aquila BM, Boise LH, Chiarparin E, et al. Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia. Nat Commun. 2018;9(1):5341.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Smith MC, Gestwicki JE. Features of protein-protein interactions that translate into potent inhibitors: topology, surface area and affinity. Expert Rev Mol Med. 2012;14: e16.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Study of AZD5991 alone or in combination with venetoclax in relapsed or refractory haematologic malignancies (NCT03218683). ClinicalTrials.gov database. NIH National Lib Med. Bethesda, 2022.  https://clinicaltrials.gov/ct2/show/NCT03218683?term=NCT03218683&draw=2&rank=1. Accessed 1 Sept 2022.

  7. Barrett JA, Yang W, Skolnik SM, Belliveau LM, Patros KM. Discovery solubility measurement and assessment of small molecules with drug development in mind. Drug Discov Today. 2022;27(5):1315–25.

    Article  CAS  PubMed  Google Scholar 

  8. Lee EH. A practical guide to pharmaceutical polymorph screening & selection. Asian J Pharm Sci. 2014;9(4):163–75.

    Article  Google Scholar 

  9. Lindfors L, Skantze P, Skantze U, Rasmusson M, Zackrisson A, Olsson U. Amorphous drug nanosuspensions. 1. Inhibition of Ostwald ripening. Langmuir : ACS J Surf Colloids. 2006;22(3):906–10.

    Article  CAS  Google Scholar 

  10. Raijada D, Bond AD, Larsen FH, Cornett C, Qu H, Rantanen J. Exploring the solid-form landscape of pharmaceutical hydrates: transformation pathways of the sodium naproxen anhydrate-hydrate system. Pharm Res. 2013;30(1):280–9.

    Article  CAS  PubMed  Google Scholar 

  11. Brittain HG. Polymorphism and solvatomorphism 2010. J Pharm Sci. 2012;101(2):464–84.

    Article  CAS  PubMed  Google Scholar 

  12. Avdeef A. Solubility of sparingly-soluble ionizable drugs. Adv Drug Deliv Rev. 2007;59(7):568–90.

    Article  CAS  PubMed  Google Scholar 

  13. Roseman TJ, Yalkowsky SH. Physicochemical properties of prostaglandin F2 alpha (tromethamine salt): solubility behavior, surface properties, and ionization constants. J Pharm Sci. 1973;62(10):1680–5.

    Article  CAS  PubMed  Google Scholar 

  14. Serajuddin AT, Rosoff M. pH-Solubility profile of papaverine hydrochloride and its relationship to the dissolution rate of sustained-release pellets. J Pharm Sci. 1984;73(9):1203–8.

    Article  CAS  PubMed  Google Scholar 

  15. Ledwidge MT, Corrigan OI. Effects of surface active characteristics and solid state forms on the pH solubility profiles of drug–salt systems. Int J Pharm. 1998;174(1):187–200.

    Article  CAS  Google Scholar 

  16. Fuguet E, Subirats X, Ràfols C, Bosch E, Avdeef A. Ionizable Drug Self-Associations and the Solubility Dependence on pH: Detection of Aggregates in Saturated Solutions Using Mass Spectrometry (ESI-Q-TOF-MS/MS). Mol Pharm. 2021;18(6):2311–21.

    Article  CAS  PubMed  Google Scholar 

  17. Mantik P, Xie M, Wong H, La H, Steigerwalt RW, Devanaboyina U, et al. Cyclodextrin Reduces Intravenous Toxicity of a Model Compound. J Pharm Sci. 2019;108(6):1934–43.

    Article  CAS  PubMed  Google Scholar 

  18. Barrett JA, Yang W, Skolnik SM, Belliveau LM, Patros KM. Discovery solubility measurement and assessment of small molecules with drug development in mind. Drug Discovery Today. 2022;27(5):1315–25.

    Article  CAS  PubMed  Google Scholar 

  19. Tong WQ, Whitesell G. In situ salt screening–a useful technique for discovery support and preformulation studies. Pharm Dev Technol. 1998;3(2):215–23.

    Article  CAS  PubMed  Google Scholar 

  20. Shah SM, Jain AS, Kaushik R, Nagarsenker MS, Nerurkar MJ. Preclinical formulations: insight, strategies, and practical considerations. AAPS PharmSciTech. 2014;15(5):1307–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Bhattachar SN, Bender DM, Sweetana SA, Wesley JA. Discovery formulations: approaches and practices in early preclinical development. In: Templeton AC, Byrn SR, Haskell RJ, Prisinzano TE, editors. Discovering and developing molecules with optimal drug-like properties. New York: Springer New York; 2015. p. 49–94.

    Chapter  Google Scholar 

  22. Yang W. Meglumine monograph. In: Rowe RC, Sheskey PJ, Cook WG, Fenton ME, editors. Handbook of pharmaceutical excipients. London; Philadelphia: Washington, DC: Pharmaceutical Press; American Pharmacists Association; 2012. p. 489–90.

    Google Scholar 

  23. Cystogragin (diatrizoate meglumine) injection solution. DailyMed database. NIH National Lib Med. Bethesda, 2002. https://www.dailymed.nlm.nih.gov/dailymed/search.cfm?labeltype=all&query=CYSTOGRAFIN. Accessed 1 Sept 2022

Download references

Acknowledgements

The authors would like to thank Weijia Zheng, Stacey Marden, Jianyan Wang, Robert Casella, Clive Washington, Iain Grant, and Hyungchul Kim at AstraZeneca for helpful suggestions, comments and discussions pertaining to the work reported in this manuscript.

Author information

Authors and Affiliations

  1. Advanced Drug Delivery, Pharmaceutical Sciences, R&D, AstraZeneca, Boston, USA

    Wenzhan Yang, Steve Cook & Dedong Wu

Authors
  1. Wenzhan Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Steve Cook
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dedong Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wenzhan Yang.

Ethics declarations

Conflict of Interest

There are no conflicts of interest to disclose.

Additional information

Publisher's Note

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

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

Yang, W., Cook, S. & Wu, D. Pre-clinical Formulation Development of an in situ Meglumine Salt of AZD5991: A Novel Macrocyclic Mcl-1 Inhibitor. Pharm Res 40, 977–988 (2023). https://doi.org/10.1007/s11095-023-03503-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-023-03503-2

Keywords

Search

Navigation