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Dissolution Challenges Associated with the Surface pH of Drug Particles: Integration into Mechanistic Oral Absorption Modeling

  • Research Article
  • Theme: Integrating In Vitro Systems and Physiologically-Based Pharmacokinetics Modeling to Optimize Drug Product Development
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Abstract

The present work aimed to differentiate between in vitro dissolution profiles of ibuprofen as input for GastroPlus™ and to see the impact on systemic exposure. In vitro dissolution profiles of ibuprofen obtained under low- and high-buffered dissolution media were used as input using the z-factor approach. In a second step, a customized surface pH calculator was applied to predict the surface pH of ibuprofen under these low- and high-buffered dissolution conditions. These surface pH values were adopted in GastroPlus™ and simulations were performed to predict the systemic outcome. Simulated data were compared with systemic data of ibuprofen obtained under fasted state conditions in healthy subjects. The slower dissolution rate observed when working under low-buffered conditions nicely matched with the slower dissolution rate as observed during the clinical aspiration study and was in line with the systemic exposure of the drug. Finally, a population simulation was performed to explore the impact of z-factor towards bioequivalence (BE) criteria (so-called safe space). Concerning future perspectives, the customized calculator should be developed in such a way to make it possible to predict the dissolution rate (being informed by the particle size distribution) which, in its turn, can be used as a surrogate to predict the USP2 dissolution curve. Subsequently, validation can be done by using this profile as input for PBPK platforms.

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Abbreviations

API:

Active pharmaceutical ingredient

BE:

Bioequivalence

CI:

Confidence interval

CV:

Coefficient of variation

FDA:

Food and Drug Administration

GI:

Gastrointestinal

IR:

Immediate-release

PBPK:

Physiologically based pharmacokinetic modeling

PSA:

Parameter sensitivity analysis

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Acknowledgements

The authors would like to thank the EPSRC for provision of a studentship on the Centre for Doctoral Training in Transformative Pharmaceutical Technologies (EP/S023054/1) to Nidhi Seegobin.

Funding

Data obtained from the ibuprofen clinical aspiration study were funded by the grant #HHSF223201510157C and #HHSF223201310144C by the US Food and Drug Administration (FDA).

Author information

Authors and Affiliations

  1. Drug Product Design, Pfizer, Discovery Park, Ramsgate Road, Sandwich, CT13 9ND, UK

    Bart Hens, Nidhi Seegobin, Nicola Clear & Mark McAllister

  2. UCL School of Pharmacy, 29-39 Brunswick Square, Bloomsbury, London, WC1N 1AX, UK

    Nidhi Seegobin

  3. Department of Engineering, Pharmacy Section, Miguel Hernandez University, 03550, San Juan de Alicante, Alicante, Spain

    Marival Bermejo

  4. Merck & Co., Inc, 126 E Lincoln Ave, Rahway, New Jersey, 07065, USA

    Yasuhiro Tsume

  5. Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, Michigan, 48109-1065, USA

    Gregory E. Amidon & Gordon L. Amidon

Authors
  1. Bart Hens
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  2. Nidhi Seegobin
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  3. Marival Bermejo
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  7. Gregory E. Amidon
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  8. Gordon L. Amidon
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Contributions

All authors were involved in the development of the manuscript, interpretation of data, and have read and approved the final version, and have met the criteria for authorship as established by the ICMJE.

Corresponding authors

Correspondence to Bart Hens or Gordon L. Amidon.

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Conflict of Interest

Bart Hens, Nicola Clear, and Mark McAllister are full-time employees of Pfizer UK. Yasuhiro Tsume is a full-time employee of Merck and Co., USA.

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Guest Editors: Rodrigo Cristofoletti and Lawrence Yu

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Hens, B., Seegobin, N., Bermejo, M. et al. Dissolution Challenges Associated with the Surface pH of Drug Particles: Integration into Mechanistic Oral Absorption Modeling. AAPS J 24, 17 (2022). https://doi.org/10.1208/s12248-021-00663-0

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  • DOI: https://doi.org/10.1208/s12248-021-00663-0

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