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Physical Barrier Type Abuse-Deterrent Formulations: Mechanistic Understanding of Sintering-Induced Microstructural Changes in Polyethylene Oxide Placebo Tablets

Abstract

The main goal of the presented work was to understand changes in the microstructure of tablets, as well as the properties of its main component viz. polyethylene oxide (PEO) as a function of sintering. Key polymer variables and sintering conditions were investigated, and sintering-induced increase in tablet tensile strength was evaluated. For the current study, binary-component placebo tablets comprised of varying ratios of PEO and anhydrous dibasic calcium phosphate (DCP) were prepared at two levels of tablet solid fraction. The prepared tablets were sintered in an oven at 80°C at different time points ranging from 10 to 900 min and were evaluated for pore size, tablet expansion (%), and PEO crystallinity. The results showed that for efficient sintering and a significant increase in the tablet tensile strength, a minimum of 50% w/w PEO was required. Moreover, all microstructural changes in tablets were found to occur within 60 min of sintering, with no significant changes occurring thereafter. Sintering also resulted in a decrease in PEO crystallinity, causing changes in polymer ductility. These changes in PEO ductility resulted in tablets with higher tensile strength. Formulation variables such as PEO level and PEO particle size distribution were found to be important influencers of the sintering process. Additionally, tablets with high initial solid fraction and sintering duration of 60 min were found to be optimal conditions for efficient sintering of PEO-based compacts. Finally, prolonged sintering times were not found to provide any additional benefits in terms of abuse-deterrent properties.

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Acknowledgments

We would like to thank Mark Mabry and Matthew Bloomfield of Cobalt Light Systems for their technical support of the TRS100 and Cobalt Light Systems for allowing us to conduct studies using the TRS100. We also would like to acknowledge Micromeritics Instrument Company for the generous donation of analytical services to conduct the mercury porosimetry and surface area measurements. We would also like to acknowledge DOW Chemical for the generous donation of POLYOX material and Elizabeth Tocce of Dow for her insightful knowledge on PEO. We would like to recognize Wen Qu of the Office of Pharmaceutical Quality, U.S. Food and Drug Administration and Bhawana Saluja from the Office of Clinical Pharmacology, U.S. Food and Drug Administration for their guidance and support on this project. This paper was written in partial fulfillment of a Ph.D. thesis.

Funding

The authors would like to acknowledge the National Institute for Pharmaceutical Technology and Education (NIPTE) and the U.S. Food and Drug Administration (FDA) for providing funds for this research. This study was funded by the FDA contract to NIPTE # HHSF223201301189P.

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Correspondence to Stephen W. Hoag.

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Guest Editors: Heather Boyce, Steve R. Byrn, and Stephen W. Hoag

Electronic Supplementary Material

Figure S1
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Representative DSC profile for 70% w/w PEO content tablets at low porosity sintered at 0.167, 0.5, 1, 3, 9, 15 h and tablet with no heat treatment (NHT). (PNG 909 kb)

Figure S2
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Principal component analysis of entire data set including porosity level, PEO composition (30, 50, 70% w/w) and sinter time. (PNG 2094 kb)

Figure S3
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A force diagram for a 100% PEO tablet compacted at 4 KN is shown in to demonstrate the ductile behavior of PEO under compressive strain. (PNG 280 kb)

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High Resolution Image (TIF 380 kb)

High Resolution Image (TIF 64 kb)

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Boyce, H.J., Dave, V.S., Scoggins, M. et al. Physical Barrier Type Abuse-Deterrent Formulations: Mechanistic Understanding of Sintering-Induced Microstructural Changes in Polyethylene Oxide Placebo Tablets. AAPS PharmSciTech 21, 86 (2020). https://doi.org/10.1208/s12249-019-1594-6

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Keywords

  • abuse-deterrent formulations (ADF)
  • polyethylene oxide (PEO)
  • sintering
  • tensile strength