Category: Formulation and Quality
Purpose: Inclusion of polyethylene oxide (PEO) as a tablet matrix former followed by sintering is one of the most commonly used approaches employed to develop abuse-deterrent oral formulations (ADFs). However, little has been reported about the impact of process and formulation variables on the abuse-deterrent features of the resulting PEO-matrix tablets, especially regarding PEO molecular weight and duration of sintering.
Purpose: The objective of this study was to evaluate the impact of process and formulation variables on the crystallinity of PEO, crushing strength of tablets, particle sizes following grinding, and the rheological behavior, syringeability and injectability of hydrated PEO gels obtained from ADFs. The process variables evaluated include sintering temperature (50 °C and 80 °C) and sintering duration (30 min, 2h, 4h, and 6h); the formulation variables investigated included PEO molecular weight (100,000; 900,000; and 5,000,000) and PEO concentration in the tablet (10%, 25%, 50%, and 80% w/w).
Methods: Tablets (200±2 mg) were produced by direct compression using a single station Manesty F-3 tablet press equipped with 7.14 mm standard concave tooling. The compression force was adjusted for each blend to produce tablets of similar thickness (5±0.3 mm). Tablets were sintered at 50 °C or 80 °C using a hot air oven, and the thickness and the diameter of the tablets were measured before and after the thermal treatment. Tablet hardness was determined using a Universal Stress-Strain analyzer with a 500 N load cell. The load was applied with a crosshead speed of 0.05 mm/sec. Particle size analysis was performed on the granules obtained after mechanical manipulation of the tablets (untreated and sintered tablets) using a coffee grinder. Thermal characterization was performed on the untreated and sintered PEO’s using DSC at a heating rate of 10 °C/min. PEO gels (2% w/v) prepared from the various molecular weight PEO’s (untreated and sintered PEO powders) were used to study the rheological behavior of gels formed following hydration using a controlled stress rheometer. The injectability and syringeability of the prepared PEO gels were evaluated using a uniaxial extension tester equipped with a 50N load cell.
Results: Untreated tablets and tablets sintered at 50 °C underwent fracture upon the application of force with no impact of PEO molecular weight or concentration on tablet hardness. Tablets sintered at 80 °C, in comparison, showed an increase in tablet hardness that was dependent on PEO molecular weight and concentration. Sintered tablets (80 °C) containing 10% and 25% w/w PEO resulted in only a slight increase in tablet hardness compared to untreated tablets while the hardness of sintered tablets (80 °C) containing 50% and 80% w/w of higher molecular weight PEO (900,000 and 5,000,000) was beyond the testing range of the instrument (i.e. >500 N). The duration of sintering at both temperatures (50 °C and 80 °C) had no impact on the extent of the increase in tablet hardness. The particle size of the granules obtained after mechanical manipulation was dependent on both the sintering temperature and PEO concentration. Tablets containing higher fractions of PEO when sintered at 80 °C resulted in a decreased number of granules with particle sizes less than 500 microns. Flow curves from PEO gels containing higher molecular weight PEOs (900,000 and 5,000,000) showed a non-Newtonian behavior consistent with pseudo-plastic materials whereas PEO gels containing lower molecular weight PEO showed Newtonian behavior. Higher molecular weight PEOs offered significantly higher resistance to syringeability and injectability of the PEO gels. DSC showed a decrease in melting enthalpy value of PEOs when sintered at 80 °C indicating a decrease in PEO crystallinity. The reduction in melting enthalpy was dependent on PEO molecular weight and duration of sintering. The most significant reductions in melting enthalpies were observed for higher molecular weight PEOs (900,000 and 5,000,000) following longer sintering durations (2h, 4h, and 6h). Sintering at 80 °C for longer times (2h, 4h, and 6h) resulted in PEO gels with decreased viscosity compared to gels from untreated PEO suggesting the degradation of PEO to lower molecular weight fractions. Longer sintering times also affected the syringeability and injectability of the PEO gels resulting in gels that were easier to draw into and deliver from a syringe, likely due to reduced viscosities of the gels.
Conclusion: Sintering is an efficient manufacturing technique to impart abuse-deterrent features to PEO-based matrix tablets, but formulation variables including molecular weight of PEO and process variables including sintering temperature and duration impact both the abuse-deterrent features of the resulting tablets and the material properties of the components of the tablets. Long sintering times at temperatures above the melting point of the selected PEO result in reduced PEO crystallinity and increased PEO degradation impacting the syringeability and injectability of the PEO gels and reducing their abuse-deterrent properties.
Maureen Donovan– University of Iowa, Iowa City, Iowa