Dissertation
Material Properties and Drug Release from Polyethylene Oxide Based Abuse-Deterrent Tablets
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2021
DOI: 10.17077/etd.005765
Abstract
Abuse and misuse of prescription medicine is a major public health concern resulting in an increasing number of deaths every year. Abuse-deterrent formulations (ADFs) have been introduced to deter the abuse of prescription opioids by making the extraction and recovery of the active pharmaceutical ingredient difficult. Among various formulation approaches used to develop ADFs, sintered polyethylene oxide (PEO) matrices are widely used due to their simplicity in manufacturing. Although sintered polyethylene oxide is commonly used, the understanding of the impact of sintering on the formulation components and the dosage forms abuse-deterrent properties and performance is limited. Various active pharmaceutical ingredients were evaluated for their suitability in sintered PEO matrices; tablets prepared using dextromethorphan HBr monohydrate and ketoprofen led to changes in tablet dimensions and tablet microstructure following sintering at temperatures above the melting point of polyethylene oxide (80 °C). In contrast, the inclusion of promethazine HCl or theophylline did not impact tablet properties. Thermal characterization showed that dextromethorphan HBr monohydrate and ketoprofen were solubilized in the polyethylene oxide matrix, leading to tablet expansion and the creation of a more porous matrix after cooling. Additionally, sintering above PEO’s melting point led to decreased PEO crystallinity. These changes resulted in changes to the tablet’s dimensions, microstructure, and PEO crystallinity which contributed to the matrix's erosion, leading to faster API release from the dosage form. The results indicate that care must be taken while incorporating APIs able to dissolve in PEO to mitigate performance alterations.
The impact of various PEO grades and the sintering process on the ADFs' abuse-deterrent properties were studied. A sintering temperature above the melting point (80 °C) of PEO was necessary to impart adequate tablet hardness to resist manipulation. Lower molecular weight PEO resulted in less viscous gels able to be drawn into and pushed out of syringes with less effort. Sintering at 80 °C for longer durations (≥ 2 h) led to polymer degradation impacting the resistance to intravenous abuse (syringability and injectability). In addition to sintering duration and temperature, the weight fraction of PEO affected the abuse-deterrent properties of the dosage forms with tablets containing lower fractions (≤ 25% w/w) of PEO, resulting in a greater fraction of smaller granules (≤ 500 µm) which have increased potential for abuse.Finally, in-vitro release testing studies were conducted to evaluate the retention of the manipulated ADF's abuse-deterrent properties. Non-homogenous drug distribution among the granule fractions obtained from crushed matrices manufactured using direct compression were observed with higher amounts of the drug in the smaller size granules compared with the larger granules. Release testing performed on various granule fractions using USP type I (basket), type II (paddle), and type IV (flow-through) apparatus indicated high variability in release results using the USP type I and type II apparatus; sticking of the hydrated granules to the baskets and paddles; and ongoing PEO hydration with subsequent gel formation further altered particle sizes and impacted the rate of drug release. The use of a flow-through apparatus (USP type IV) resulted in improved discrimination of drug release from different size granules with less variability due to better dispersion of granules. Drug release profiles from the USP type IV apparatus showed that the larger size granules (> 500 μm) offered continued resistance to drug release following tablet manipulation, but the smaller size granules (< 500 μm) provided rapid drug release that was un-hindered by the hydrated granule matrix. Since < 500-μm size particles are preferred for nasal abuse, direct-compression ADF formulations should minimize and be carefully evaluated for the formation of these smaller-sized particles following tampering to maintain the product’s abuse-deterrent features.
Details
- Title: Subtitle
- Material Properties and Drug Release from Polyethylene Oxide Based Abuse-Deterrent Tablets
- Creators
- Saikishore Meruva
- Contributors
- Maureen Donovan (Advisor)Dale E Wurster (Committee Member)Ramprakash Govidanrajan (Committee Member)Lewis L Stevens (Committee Member)M L (Suresh) Raghavan (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Pharmacy
- Date degree season
- Spring 2021
- DOI
- 10.17077/etd.005765
- Publisher
- University of Iowa
- Number of pages
- xxiv, 174 pages
- Copyright
- Copyright 2021 Saikishore Meruva
- Language
- English
- Description illustrations
- color illustrations
- Public Abstract (ETD)
Abuse of prescription opioids is a global epidemic resulting in an increasing number of deaths. Abuse-deterrent formulations (ADFs) provide a potential solution by making the extraction and recovery of the drug more difficult. Sintering polyethylene oxide (PEO) is commonly used to impart abuse-deterrent features to extended-release tablets. This work is focused on studying the impact of formulation and process variables, along with material interactions, for the development of improved, PEO-based, abuse-deterrent tablets. The results show that drugs able to dissolve in molten PEO will alter the final tablet properties leading to faster drug release rates. Additionally, the concentration of PEO and sintering temperature and duration impacted the tablet’s abuse-deterrent features. Tablets containing low concentrations of PEO (≤ 25% w/w) did not provide sufficient resistance to mechanical manipulation, and a sintering temperature above the melting point (80 °C) of PEO was necessary to impart crush-resistant features. Sintering at 80 °C for long durations (≥ 2 h) led to polymer degradation negatively impacting the continued resistance of the tablet residue to intravenous abuse. Direct compression manufacturing methods were also associated with variations in the drug content of granules formed following grinding in attempts to defeat the abuse-deterrent features of the tablets.
- Academic Unit
- Pharmacy
- Record Identifier
- 9984097365102771
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