Purpose: Introduction: Abuse deterrent dosage forms (ADFs) have been developed to reduce the ready extraction of opioids and amphetamines to limit prescription drug abuse. The introduction of these dosage forms has altered preferences for specific products and has resulted in an increased demand for additional ADFs. Incorporation of polyethylene oxide (PEO) with subsequent thermal treatment to form a fused matrix is a widely used approach in the development of ADFs. However, little has been studied about the effects of thermal treatment on the properties of PEO and the effects of drug-PEO interactions on tablet properties. A better understanding of the material attributes and potential drug-excipient (PEO) interactions associated with the manufacturing process will improve the ability to quickly develop new ADF products for drugs associated with potential abuse.
Purpose: The objective of this study was to investigate the effects of drug-polymer interactions and thermal treatment on the physical properties and performance of PEO-based, directly-compressible, abuse-deterrent tablet formulations. The drugs investigated included dextromethorphan HBr monohydrate, ketoprofen, promethazine HCl, and anhydrous theophylline. The model drugs investigated possess a variety of physicochemical properties that allow for a broader understanding of drug-associated effects in the performance of abuse-deterrent dosage forms.
Methods: Tablet blends (59% PEO, 40% drug, and 1% magnesium stearate) were compressed into cylindrical compacts using a hydraulic Carver press at a compression pressure of 2300 lbs for 10 seconds. The compressed tablets were thermally-treated at 50 °C or 80 °C using a hot air oven, and the thickness and the diameter of the tablets were measured using a thickness gauge and Vernier callipers before and after the thermal treatment. The crushing strength of the tablets 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. Thermal characterization was performed on the APIs, excipients, and untreated and thermally-treated tablets using DSC at a heating rate of 10 °C/min and a 5 °C/min cooling rate. The crystallinity of the API before and after thermal treatment was measured by powder X-ray diffraction (PXRD). The diffraction patterns were obtained from untreated and thermally-treated tablets over a 2θ range of 5° to 40° with a step size of 0.02°. SEM photomicrographs were obtained to evaluate the surface and internal morphology of the tablets before and after thermal treatment. Drug release studies were performed on untreated and thermally-treated tablets using a USP Type II apparatus operated at 75 rpm with stationary quadrangular baskets using 600 mL phosphate buffer (pH 6.8) as the release media.
Results: The untreated and thermally-treated (50 °C) ADF prototype tablets underwent fracture upon application of force. The tablets thermally-treated at 80 °C showed an increase in crushing strength and the tablets were deformed but remained intact beyond the testing limit of the instrument (>500 N), indicating that the thermally-treated tablets (80 °C) were resistant to manipulation such as breaking and grinding. Thermal treatment also resulted in dimensional changes of the tablets and changes in the microstructure of the tablets when either dextromethorphan HBr monohydrate or ketoprofen were incorporated. However, these changes were not observed when promethazine HCl or anhydrous theophylline were incorporated. SEM images revealed an increase in the apparent porosity of the thermally-treated dextromethorphan and ketoprofen tablets while DSC revealed an interaction between dextromethorphan-PEO and ketoprofen-PEO which led to the solubilization of the APIs in the molten PEO during thermal treatment. PXRD analysis revealed that the PEO-solubilized drug re-crystallized upon room-temperature storage. DSC studies revealed that thermal treatment also led to decreased PEO crystallinity. Drug release studies showed a somewhat faster release from the thermally-treated tablets (80 °C) compared to untreated tablets for dextromethorphan, ketoprofen, or theophylline containing tablets. Visual differences in the hydration and dissolution properties of the PEO matrix were also observed, and these changes resulted in differences in erosion behavior among the tablets. The differences in PEO properties after thermal treatment, along with the measurable dimensional and microstructural changes resulted in changes in release behaviors from the ADFs, yet all of the thermally-treated ADFs were able to retain good extended-release properties.
Conclusion: Thermal treatment is an efficient manufacturing methodology to impart abuse-deterrent features to extended-release tablets based on PEO matrices, but drug-polymer interactions and changes in polymer crystallinity induced or enhanced by thermal treatment may have an impact on the properties and performance of the resulting ADF tablets. Drugs that are highly soluble in the molten PEO may significantly alter the final matrix structure and reduction in PEO crystallinity following thermal treatment may also result in changes to the hydration properties of the ADFs. These results demonstrate that preformulation characterization should be performed to identify drug-matrix interactions which may result in changes to tablet quality and performance characteristics.