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Impact of Surfactants on the Performance of Clopidogrel-Copovidone Amorphous Solid Dispersions: Increased Drug Loading and Stabilization of Nanodroplets

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Abstract

Purpose

Surfactants are increasingly being added to amorphous solid dispersion (ASDs) formulations to enhance processability and release performance. The goal of the current work was to investigate the impact of cationic, anionic and non-ionic surfactants on the rate and extent of clopidogrel (CPD) release from copovidone-based ASDs.

Methods

CPD release was evaluated for ASDs with different drug loadings using a surface normalized intrinsic dissolution apparatus. Studies were also carried out using dynamic light scattering, zeta potential measurements, and nuclear magnetic resonance spectroscopy to probe the impact of surfactants on drug-rich nanodroplet physical stability and clopidogrel-surfactant interactions.

Results

CPD ASDs showed good release for drug loadings as high as 40%, before the release fell off a cliff at higher drug loadings. Only sodium dodecyl sulfate, added at a 5% level, was able to improve the release at 50% drug loading, with other surfactants proving to be ineffective. However, some of the surfactants evaluated did show some benefits in improving nanodroplet stability against size enlargement. Ionic and non-ionic surfactants were observed to interact differently with CPD-rich nanodroplets, and variations in the kinetics and morphology of water-induced phase separation were noted in the presence and absence of surfactants in ASD films.

Conclusions

In summary, addition of surfactants to ASD formulations may lead to some improvements in formulation performance, but predictive capabilities and mechanisms of surfactant effect still require further studies.

Graphical abstract

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Abbreviations

API:

Active pharmaceutical ingredient

ASD:

Amorphous solid dispersion

AUC:

Area under the curve

CMC:

Critical micelle concentration

CPD:

Clopidogrel

CTAB:

Cetrimonium bromide

DLS:

Dynamic light scattering

GLPS:

Glass liquid phase separation

HLB:

Hydrophilic lipophilic balance

HPLC:

High performance liquid chromatography

LLPS:

Liquid liquid phase separation

LoC:

Limit of Congruency

NMR:

Nuclear magnetic resonance

NTA:

Nanoparticle tracking analysis

PVPVA:

Copovidone

SDS:

Sodium dodecyl sulfate

T g :

Glass transition temperature

TPGS:

D-α-tocopherol polyethylene glycol 1000 succinate

TWN:

Tween 80

UV:

Ultraviolet

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Authors and Affiliations

  1. Department of Industrial and Physical Pharmacy College of Pharmacy, Purdue University, Indiana, 47907, West Lafayette, USA

    Clara E. Correa Soto & Lynne S. Taylor

  2. Science and Technology, Operations, AbbVie Inc., North Chicago, Illinois, 60064, USA

    Yi Gao

  3. Drug Product Development, Research and Development, AbbVie Inc., North Chicago, Illinois, 60064, USA

    Anura S. Indulkar & Geoff G. Z. Zhang

  4. Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8675, Japan

    Keisuke Ueda

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  1. Clara E. Correa Soto
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Liquid-liquid phase separation in the presence of surfactants, nanodroplet size stabilization by surfactants, 1H solution NMR spectra and analysis, ASD surface normalized dissolution. (DOCX 1683 kb)

ACKNOWLEDGMENTS AND DISCLOSURES

The authors would like to thank Abbvie Inc., for the financial support. The authors declare the following competing financial interest(s): Purdue University and AbbVie jointly participated in study design, research, data collection, analysis and interpretation of data, writing, reviewing, and approving the publication. C.C.S. is a graduate students; L.S.T. is a professor; all are at Purdue University. K.U. was a visiting scholar at Purdue University at the time of the study; They all have no additional conflicts of interest to report. A.S.I., Y.G., and G.G.Z.Z. are employees of AbbVie and may own AbbVie stock.

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Correa Soto, C.E., Gao, Y., Indulkar, A.S. et al. Impact of Surfactants on the Performance of Clopidogrel-Copovidone Amorphous Solid Dispersions: Increased Drug Loading and Stabilization of Nanodroplets. Pharm Res 39, 167–188 (2022). https://doi.org/10.1007/s11095-021-03159-w

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