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Formulation and Delivery - Biomolecular

(M1030-05-25) Impact of Using 2-Hydroxypropyl-b-cyclodextrin (HPbCD) as an Excipient in Biologic Formulations on Solution Properties and Compatibility

Monday, October 21, 2024
10:30 AM – 11:30 AM MT

    Presenting Author(s)

  • RD

    Rakesh Dachineni, Ph.D.

    Scientist
    Teva Branded Pharmaceutical Products R&D, Inc.
    Downingtown, Pennsylvania, United States

    • Main Author(s)

  • RD

    Rakesh Dachineni, Ph.D.

    Scientist
    Teva Branded Pharmaceutical Products R&D, Inc.
    Downingtown, Pennsylvania, United States

    • Co-Author(s)

  • Haichen Nie, Ph.D. (he/him/his)

    Associate Director
    Teva Branded Pharmaceutical Products R&D, Inc.
    West Chester, Pennsylvania, United States

Purpose: In the past 2 decades, several research scientists have explored the use of 2-Hydroxypropyl-b-cyclodextrin (HPbCD), in biological formulations as a stabilizer in both liquid and freeze-dried formulations [1], and as a replacement for polysorbates [2]. We screened multiple commercially available HPbCDs with different degrees of substitution for their solution properties and their interaction with sucrose and non-ionic surfactants.

Methods: Viscosity profiles for HPbCDs were generated using a v-ROC Initium RheoSense viscometer (RheoSense, San Ramon, CA, USA). For osmolality profiles, 2 types of osmometers were used: OsmoPRO® Multi-Sample Micro-Osmometer (Advanced instruments, MA, USA) with freeze-point depression as operating principle and VAPRO® Model 5600 Osmometer (Wescro Inc, UT, USA) with vapor-pressure depression as operating principle. Glass transition temperatures (Tg’) of HPbCD and sucrose blends were measured using Discovery DSC (TA instruments, DE, USA) with nitrogen purge. Dynamic surface tension (DST) profiles of HPbCD/Polysorbate 80 (PS80) samples were measured using BP100 Bubble Pressure Dynamic Surface Tensiometer (Kruss Company, Germany).

Results: We used HPbCDs with different degrees of hydroxy propyl substitution (DS) on bCD [3]. HPbCD molecules screened in this study had similar viscosity profiles up to 250 mM. At 300 mM, HPbCD with higher DS had a higher viscosity (~10 cps) than the one with lower DS (~ 8 cps), whereas at 500 mM HPbCD with lower DS has double the viscosity (~ 400 cps) of HPbCD with high DS (~ 200 cps). This difference at 500 mM might be due to the slight differences in solubility with varied DS.  At concentrations ≤100 mM, no difference in osmolality was observed between calculated to measured, and also between the osmometers, but osmolality of the HPbCD solutions deviated from calculated values when their concentrations were >100 mM. Measured Tg’ for HPbCD with higher DS (-13.7°C) and HPbCD with lower DS (-10.7°C), and both aligned well with the predicted Tg’ using the FOX equation in Kleptose/sucrose blends indicating compatible, miscible, and uniform blends [4]. Both PS80 and HPbCD are surface-active molecules, but a smaller amount of PS80 is required compared to HPbCD [5]. Dynamic surface tension (DST) profiles showed that HPbCD with PS80 have an additive effect on the surface tension and showed a lower DST compared to HPbCD or PS80 alone.

Conclusion: This study has provided insights into the solution properties of HPbCD with various degrees of substitution. The difference in viscosity and osmolality properties, based on DS, started to appear at 250 mM and at 150 mM concentrations of HPbCD respectively. Based on the viscosity profiles, 250 - 300 mM HPbCD seems to be suitable for an initial stock solution to avoid process-related issues due to high viscosity. Osmolality is a critical quality attribute in injectable formulations and method development, on sample alteration or choice of osmometers, must be done when a concentration of HPbCD >100 mM is used in the final formulations. The use of HPbCD increases the Tg’ of the solutions containing sucrose, which helps in developing a lyophilization process that can operate at higher temperatures and faster primary drying cycles, and also helps in storing the frozen drug substance at higher temperatures. The combination of HPbCD with PS80 gave lower DST than HPbCD and PS80 individually, indicating the synergy of applying HPbCD/PS80 together in biologic formulations to reduce the interfacial tension.

References: 1. Serno, T., Carpenter, J. F., Randolph, T. W., & Winter, G. (2010). Inhibition of agitation‐induced aggregation of an IgG‐antibody by hydroxypropyl‐β‐cyclodextrin. Journal of pharmaceutical sciences, 99(3), 1193-1206.
2. Zhang, H., Hong, S., Tan, S. S. K., Peng, T., Goh, L. Y. H., Lam, K. H., ... & Gokhale, R. (2022). Polysorbates versus Hydroxypropyl Beta-Cyclodextrin (HPβCD): Comparative Study on Excipient Stability and Stabilization Benefits on Monoclonal Antibodies. Molecules, 27(19), 6497.
3. Loftsson T. and Brewster M.E. (2010). Pharmaceutical applications of cyclodextrins: basic science and product development. J Pharm Pharmacol. 62(11):1607-21.
4. Brostow, W., Chiu, R., Kalogeras, I. M., & Vassilikou-Dova, A. (2008). Prediction of glass transition temperatures: Binary blends and copolymers. Materials Letters, 62(17-18), 3152-3155.
5. Serno, T., Härtl, E., Besheer, A., Miller, R., & Winter, G. (2013). The role of polysorbate 80 and HPβCD at the air-water interface of IgG solutions. Pharmaceutical research, 30, 117-130.