Novel stirring method for small-scale dissolution test: Rotating vessel method: Original scientific article

Shiori Ishida; Samuel Lee; Balint Sinko; Karl Box; Kiyohiko Sugano

doi:10.5599/admet.3136

Authors

Shiori Ishida Molecular Pharmaceutics Lab., College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1, Noji-higashi, Kusatsu, Shiga 525-8577, Japan https://orcid.org/0009-0007-4760-5006
Samuel Lee Pion Inc. (UK) Ltd. Forest Row Business Park, Station Road, East Sussex, RH18 5DW, United Kingdom https://orcid.org/0009-0005-4379-2807
Balint Sinko Pion Inc. (UK) Ltd. Forest Row Business Park, Station Road, East Sussex, RH18 5DW, United Kingdom https://orcid.org/0009-0005-8256-4348
Karl Box Pion Inc. (UK) Ltd. Forest Row Business Park, Station Road, East Sussex, RH18 5DW, United Kingdom
Kiyohiko Sugano Molecular Pharmaceutics Lab., College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1, Noji-higashi, Kusatsu, Shiga 525-8577, Japan https://orcid.org/0000-0001-5652-1786

DOI:

https://doi.org/10.5599/admet.3136

Keywords:

Hydrodynamics, precipitation, magnetic stirrer, ibuprofen, carbamazepine

Abstract

Background and purpose: In the compendial dissolution test, the overhead rotating paddle method (ORP) has been used for stirring, whereas the magnetic stirring bar method (MSB) has been employed for small-scale dissolution tests, such as the μDISS Profiler^TM (μDISS). Previous reports have indicated that differences exist in the precipitation profiles of a drug between ORP and MSB, because the latter causes contact-induced nucleation. However, it has been difficult to use an ORP and an in situ UV probe simultaneously in μDISS. In this study, a novel stirring method, the rotating vessel method (RV), was developed for μDISS. The dissolution and precipitation profiles of model drugs in RV-μDISS were then compared with those in MSB-μDISS, as well as with the results of conventional dissolution tests using an ORP. Experimental approach: In RV-μDISS, a small paddle (approximately 1/4 of the conventional paddle) was fixed to the UV probe, and the glass vessel was rotated to produce a flow pattern similar to that of ORP. The dissolution and bulk-phase precipitation tests were performed for ibuprofen sodium (IBU Na) and carbamazepine (CBZ), respectively, using RV-μDISS and MSB-μDISS, as well as ORP with the conventional vessel (500 mL, for IBU Na) (CV) or the mini-vessel (50 mL, for CBZ) (MV). Key results: The dissolution rate of IBU Na was similar in all methods. Rapid precipitation of crystalline IBU free acid was observed in the MSB-μDISS method. In contrast, no crystalline precipitation was observed in RV-μDISS and ORP-CV, and the drug phase-separated as a liquid (oil) phase (liquid-liquid phase separation). The precipitation rate of CBZ in RV-μDISS was similar to that in ORP-MV, but slower than that in MSB-μDISS. Conclusion: The precipitation profile in RV-μDISS was close to those in ORP-CV and ORP-MV. RV-μDISS would be a useful tool for the assessment of the precipitation profiles of drugs.

Downloads

Download data is not yet available.

References

[1] G.M. Keserü, G.M. Makara. The influence of lead discovery strategies on the properties of drug candidates. Nature Reviews Drug Discovery 8 (2009) 203-212. https://doi.org/10.1038/nrd2796 DOI: https://doi.org/10.1038/nrd2796

[2] A.M. Thayer, C. Houston. Finding solutions. Custom manufacturers take on drug solubility issues to help pharmaceutical firms move products through development. Chem. Eng. News 88 (2010) 13-18. https://doi.org/10.1016/j.jenvp.2009.05.001 DOI: https://doi.org/10.1021/cen-v088n022.p013

[3] A.T.M. Serajuddin. Salt formation to improve drug solubility. Advanced Drug Delivery Reviews 59 (2007) 603-616. https://doi.org/10.1016/j.addr.2007.05.010 DOI: https://doi.org/10.1016/j.addr.2007.05.010

[4] N. Blagden, M. de Matas, P.T. Gavan, P. York. Crystal engineering of active pharmaceutical ingredients to improve solubility and dissolution rates. Advanced Drug Delivery Reviews 59 (2007) 617-630. https://doi.org/10.1016/j.addr.2007.05.011 DOI: https://doi.org/10.1016/j.addr.2007.05.011

[5] Marcus E. Brewster Patrick Augustijns. Brouwers Joachim. Supersaturating Drug Delivery Systems: The Answer to Solubility-Limited Oral Bioavailability? Journal of Pharmaceutical Sciences 98 (2009) 2549-2572. https://doi.org/10.1002/jps.21650 DOI: https://doi.org/10.1002/jps.21650

[6] S. Carlert, A. Pålsson, G. Hanisch, C.V. Corswant, C. Nilsson, L. Lindfors, H. Lennernäs, B. Abrahamsson. Predicting intestinal precipitation-A case example for a basic BCS class II drug. Pharmaceutical Research 27 (2010) 2119-2130. https://doi.org/10.1007/s11095-010-0213-8 DOI: https://doi.org/10.1007/s11095-010-0213-8

[7] R.R.E. Steendam, L. Keshavarz, M.A.R. Blijlevens, B. De Souza, D.M. Croker, P.J. Frawley. Effects of Scale-Up on the Mechanism and Kinetics of Crystal Nucleation. Crystal Growth & Design 18 (2018) 5547-5555. https://doi.org/10.1021/acs.cgd.8b00857 DOI: https://doi.org/10.1021/acs.cgd.8b00857

[8] K.E. Johansson, J. Plum, M. Mosleh, C.M. Madsen, T. Rades, A. Müllertz. Characterization of the hydrodynamics in a miniaturized dissolution apparatus. Journal of Pharmaceutical Sciences 107 (2018) 1095-1103. https://doi.org/10.1016/j.xphs.2017.11.022 DOI: https://doi.org/10.1016/j.xphs.2017.11.022

[9] L. Zöller, A. Avdeef, E. Karlsson, A. Borde, S. Carlert, C. Saal, J. Dressman. A comparison of USP 2 and μDISS ProfilerTM apparatus for studying dissolution phenomena of ibuprofen and its salts. European Journal of Pharmaceutical Sciences 193 (2024) 106684. https://doi.org/10.1016/j.ejps.2023.106684 DOI: https://doi.org/10.1016/j.ejps.2023.106684

[10] T. Uekusa, T. Watanabe, D. Watanabe, K. Sugano. Thermodynamic Correlation between Liquid-Liquid Phase Separation and Crystalline Solubility of Drug-Like Molecules. Pharmaceutics 14 (2022) 2560. https://doi.org/10.3390/pharmaceutics14122560 DOI: https://doi.org/10.3390/pharmaceutics14122560

[11] J. Oki, D. Watanabe, T. Uekusa, K. Sugano. Mechanism of Supersaturation Suppression in Dissolution Process of Acidic Drug Salt. Molecular Pharmaceutics 16 (2019) 1669-1677. https://doi.org/10.1021/acs.molpharmaceut.9b00006 DOI: https://doi.org/10.1021/acs.molpharmaceut.9b00006

[12] T. Uekusa, K. Sugano. Prediction of Liquid-Liquid Phase Separation at the Dissolving Drug Salt Particle Surface. Molecular Pharmaceutics 20 (2023) 3140-3149. https://doi.org/10.1021/acs.molpharmaceut.3c00157 DOI: https://doi.org/10.1021/acs.molpharmaceut.3c00157

[13] M. Omori, T. Uekusa, J. Oki, D. Inoue, K. Sugano. Solution-mediated phase transformation at particle surface during cocrystal dissolution. Journal of Drug Delivery Science and Technology 56 (2020) 101566. https://doi.org/10.1016/j.jddst.2020.101566 DOI: https://doi.org/10.1016/j.jddst.2020.101566

[14] H. Yamamoto, K. Sugano. Drug Crystal Precipitation in Biorelevant Bicarbonate Buffer: A Well-Controlled Comparative Study with Phosphate Buffer. Molecular Pharmaceutics 21 (2024) 2854-2864. https://doi.org/10.1021/acs.molpharmaceut.4c00028 DOI: https://doi.org/10.1021/acs.molpharmaceut.4c00028