Surface Tension and Self-association Properties of Aqueous Polysorbate 20 HP and 80 HP Solutions: Insights into Protein Stabilisation Mechanisms

Garidel, Patrick; Blech, Michaela; Buske, Julia; Blume, Alfred

doi:10.1007/s12247-020-09488-4

Cited by 41 publications

(32 citation statements)

References 59 publications

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“…According to literature and industry experiences, PS concentrations were never present below their respective critical micelle concentrations (CMC range at 25 °C: 0.0018-0.009% (w/v) for PS20; 0.0009-0.002% (w/v) for PS80). 6 The PS levels may be higher for other medicinal products like vaccines (e.g., 0.225% PS80 for Fluad Tetra -Influenza 7 ), traditional Chinese medicine injections (e.g., up to 2% PS80 8 ), or when used as solubilizer in small molecules preparations for micellar injections (e.g., Taxotere, 540 mg/mL (54%) PS80 docetaxel for injection. 9 In recent years, there have been reports on PS-related stability issues related to the use of polysorbates in biopharmaceutical products, mainly due to PS degradation induced particle formation by free fatty acids (FFA).…”

Section: Introductionmentioning

confidence: 99%

“…Although there are multiple recent reviews on different aspects of PS such as their use in commercialized biopharmaceutical products, 2 safety aspects, [18][19][20][21][22][23] stabilizing properties for proteins 6,[24][25][26] and their analysis, 27 only a few papers reflect industry-wide positions and understanding on their role as protein interfacial stabilizer, 14 and summarize suggestions towards appropriate control strategies and lessons learned. 10,28 In this survey report we strive to provide an up-to-date, end-to-end view of the 16 participating biotechnology companies on the use and characterization of PS for biopharmaceutical products.…”

Section: Introductionmentioning

confidence: 99%

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Industry Perspective on the use and Characterization of Polysorbates for Biopharmaceutical Products Part 1: Survey Report on Current State and Common Practices for Handling and Control of Polysorbates

Wuchner

Chéry

et al. 2022

Journal of Pharmaceutical Sciences

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Industry Perspective on the use and Characterization of Polysorbates for Biopharmaceutical Products Part 1: Survey Report on Current State and Common Practices for Handling and Control of Polysorbates

Wuchner

Chéry

et al. 2022

Journal of Pharmaceutical Sciences

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“…4−6 PS20 is specified with an average EO number of 20 and with lauryl chains predominantly, and PS80 contains primarily oleyl chains. 7 The critical micelle concentration (cmc) or cmc transition ranges of PS80 in water were derived from surface tension measurements as 7−16, 8 11, 9 10−19, 10 and 18 μM, 11 using fluorescent probes as 15, 12 66, 13 and 25−107 μM, 13 and from absorption measurements as 19 μM. 14 The cmc of PS20 was obtained from surface tension measurements as 11, 11 48, 9 59, 15 and 80 μM 16 and from fluorescent probes as 50, 12 40−129, 13 and 152 μM.…”

Section: ■ Introductionmentioning

confidence: 99%

“…The critical micelle concentration (cmc) or cmc transition ranges of PS80 in water were derived from surface tension measurements as 7–16, 11, 10–19, and 18 μM, using fluorescent probes as 15, 66, and 25–107 μM, and from absorption measurements as 19 μM . The cmc of PS20 was obtained from surface tension measurements as 11, 15–75, 48, 59, and 80 μM and from fluorescent probes as 50, 40–129, and 152 μM . These values are often interpreted assuming that “below the cmc, there are insufficient surfactant molecules in the solutions to form micelles” .…”

Section: Introductionmentioning

confidence: 99%

Complex Micellization Behavior of the Polysorbates Tween 20 and Tween 80

et al. 2021

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Polysorbates (PSs, Tweens) are widely used surfactant products consisting of a sorbitan ring connecting up to four ethylene oxide (EO) chains of variable lengths, one or more of which are esterified with fatty acids of variable lengths and saturation degrees. Pharmaceutical applications include the stabilization of biologicals in solutions and the solubilization of poorly water soluble, active ingredients. This study characterizes the complex association behavior of compendial PSs PS20 and PS80, which is fundamentally different from that of single-component surfactants. To this end, a series of demicellization experiments of isothermal titration calorimetry with different PS concentrations are evaluated. Their experiment-dependent heats of titration are converted into a common function of the state of a sample, the micellar enthalpy Q m(c). These functions demonstrate that initial micelles are already present at the lowest concentrations investigated, 2 μM for PS20 and 10 μM for PS80. Initial micelles consist primarily of the surfactant species with the lowest individual critical micelle concentration (cmc). With increasing concentration, the other PS species gradually enter these micelles in the sequence of increasing individual cmc’s and hydrophilic–lipophilic balance. Concentration ranges with pronounced slopes of Q m(c) can be tentatively assigned to the uptake of the major components of the PS products. Micellization and the variation of the micelle properties progress up to at least 10 mM PS. That means the published cmc values or ranges of PS20 and PS80 may be related to certain, major components being incorporated into and forming specific micelles but must not be interpreted in terms of an absence of micelles below and constant properties, e.g., the surface activity, of the micelles above these ranges. The micellization enthalpy curves differ quite substantially between PS20 and PS80 and, in a subtler fashion, between individual quality grades such as high purity, pure lauric acid/pure oleic acid, super-refined, and China grade.

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“…Above its critical micelle concentration (CMC) or CMC range (CMR), , PS80 in aqueous solution is known to self-assemble into ellipsoidal core–shell micelles (see Figure 1 of refs and 1). Micelles formed by either all-oleate PS80 or commercial grade PS80 are suitably described by core–shell ellipsoid models. , A small-angle neutron scattering (SANS) study found that core–shell ellipsoid modeling was also suitable for another polysorbate surfactant, PS20, even when it was mixed with an anionic surfactant .…”

Section: Introductionmentioning

confidence: 99%

Aggregation Kinetics of Polysorbate 80/m-Cresol Solutions: A Small-Angle Neutron Scattering Study

et al. 2022

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Polysorbate 80 (PS80), a nonionic surfactant used in pharmaceutical formulation, is known to be incompatible with m-cresol, an antimicrobial agent for multidose injectable formulations. This incompatibility results in increased turbidity caused by micelle aggregation progressing over weeks or longer, where storage temperature, ionic strength, and component concentration influence the aggregation kinetics. Small-angle neutron scattering (SANS) analysis of PS80/m-cresol solutions over a pharmaceutically relevant concentration range of each component reveals the cause of aggregation, the coalescence mechanism, and aggregate structure. PS80 solutions containing m-cresol concentrations below ≈2.0 mg/mL and above ≈4.5 mg/mL are kinetically stable and do not aggregate over a 50 h period. At 5 mg/mL of m-cresol, the mixture forms a kinetically stable microemulsion phase, despite being well below the aqueous solubility limit of m-cresol. Solutions containing intermediate m-cresol concentrations (2.0−4.5 mg/mL) are unstable, resulting in aggregation, coalescence, and eventual phase separation. In unstable solutions, two stages of aggregate growth (nucleation and power-law growth) are observed at m-cresol concentrations at or below ≈3.6 mg/mL. At higher m-cresol concentrations, aggregates experience a third stage of exponential growth. A single kinetic model is developed to explain the stages of aggregate growth observed in both kinetic mechanisms. This work establishes the phase diagram of PS80/m-cresol solution stability and identifies component concentrations necessary for producing stable formulations.

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Surface Tension and Self-association Properties of Aqueous Polysorbate 20 HP and 80 HP Solutions: Insights into Protein Stabilisation Mechanisms

Cited by 41 publications

References 59 publications

Industry Perspective on the use and Characterization of Polysorbates for Biopharmaceutical Products Part 1: Survey Report on Current State and Common Practices for Handling and Control of Polysorbates

Industry Perspective on the use and Characterization of Polysorbates for Biopharmaceutical Products Part 1: Survey Report on Current State and Common Practices for Handling and Control of Polysorbates

Complex Micellization Behavior of the Polysorbates Tween 20 and Tween 80

Aggregation Kinetics of Polysorbate 80/m-Cresol Solutions: A Small-Angle Neutron Scattering Study

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