Impact of Silicone Oil on Free Fatty Acid Particle Formation due to Polysorbate 20 Degradation

Abstract

Purpose

Polysorbate 20 (PS20), a commonly used surfactant in biopharmaceutical formulations, can undergo hydrolytic degradation resulting in free fatty acids (FFAs) that precipitate to form particles. This work investigates the ability for silicone oil (si-oil) coated on the interior walls of prefilled syringes (PFSs) to act as a sink for FFAs and potentially delay FFA particle formation.

Methods

Myristic acid distribution coefficient was measured in a two-phase system containing si-oil and formulation buffer at a range of aqueous conditions. An empirical model was built from these data to predict distribution coefficient based on aqueous conditions. To verify the model, PS20 was degraded using model lipases side-by-side in glass vials and PFSs while monitoring sub-visible particles.

Results

The empirical model demonstrates that the partitioning of myristic acid into si-oil is maximized at low pH and low PS20 concentration. The model predicts that the presence of si-oil at levels typical in PFSs provides at most an 8.5% increase in the total carrying capacity for myristic acid compared to a non-coated glass vial. The time to onset of FFA particles was equivalent between degradations performed in two PFS models coated with differing levels of silicone oil and in non-coated glass vials.

Conclusion

Herein, we demonstrate that FFAs partition from aqueous solution into si-oil. However, the extent of the partitioning effect is not large enough to delay PS20-related FFA particle formation at typical formulation conditions (pH 5.0–7.5, 0.01% - 0.1% w/v PS20) filled in typical PFSs (<1.0 mg si-oil/mL aqueous fill).

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Abbreviations

FFA:

Free fatty acid

PFS:

Pre-filled syringe

PS20:

Polysorbate-20

SI-OIL:

Silicone oil

FB:

Formulation buffer

D:

Distribution coefficient

P:

Partition coefficient

PCL:

Pseudomonas cepacea lipase

CALB:

Candida antarctica lipase B

RP-UHPLC:

Reverse-phase ultra-high performance liquid chromatography

MM-HPLC:

Mixed-mode high performance liquid chromatography

ELSD:

Evaporative light scattering detection

RP-HPLC:

Reverse-phase high performance liquid chromatography

HA:

Protonated (non-ionized) fatty acid

A :

Deprotonated (ionized) fatty acid

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Correspondence to Nidhi Doshi.

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Fish, R., Lin, J. & Doshi, N. Impact of Silicone Oil on Free Fatty Acid Particle Formation due to Polysorbate 20 Degradation. Pharm Res 37, 216 (2020). https://doi.org/10.1007/s11095-020-02936-3

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Key Words

  • formulation
  • free fatty acid
  • particles
  • polysorbate degradation
  • silicone oil