Preparation of sterile long-acting injectable medroxyprogesterone acetate microcrystals based on anti-solvent precipitation and crystal habit control

ABSTRACT

Background: To overcome the rigorous aseptic process widely adopted by commercial long-acting injections, this work aimed to prepare a sterile MPA injection by manipulating the crystal habit through a bottom-up method.

Methods: The habit of the precipitated crystals was modified by changing the process conditions. Wherein, the cubic crystal (MPA-C) was obtained by mixing acetonitrile and water at a ratio of 1:4 (v/v) under an ultrasonic condition. Spherical crystal (MPA-S) was prepared with acetonitrile-water mixture (1:20, v/v). The addition of external additives could stop a certain crystal surface growth to obtain rod-like crystal (MPA-R) and branched crystal (MPA-B).

Results: All these crystals were proved to be of the same crystal form with different preferential growth orientation by PXRD, DSC, and SEM. The in vitro release of MPA-R microcrystal suspensions is faster than MPA-DP, while that of MPA-C is slightly slower. The relative bioavailability of MPA-C and MPA-R was 103.3% and 68.5%, respectively. The PK profile of MPA-C was most close to the commercial Depo-Provera® (MPA-DP) after intramuscular administration to male SD rats.

Conclusions: A cubic crystal of MPA was successfully prepared by anti-solvent precipitation method with the aid of sonication, providing an alternative strategy for the preparation of long-acting injections.

KEYWORDS:

• Medroxyprogesterone acetate
• crystal habit
• anti-solvent method
• formation mechanism

Author contributions

R Sun and Y Guo contributed to the conception and design of the experiments. N Yin, J Yin, and J Gou helped perform the experiments. T Yin and H He contributed to the analysis and interpretation of the data. R Sun, Y Guo, Y Zhang, X Tang contributed to the drafting of the paper or revising it critically for intellectual content. All authors approved the version to be published. All authors agree to be accountable for all aspects of the work.

Acknowledgments

The authors would like to thank Dr Amanda Pearce for their correction of this manuscript and Professor Ting Cai for their help in crystallography.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Supplementary material

The supplemental data for this article can be accessed here.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China No.81673378.