Category: Formulation and Quality
Purpose: Abuse deterrent formulations (ADFs) have the potential to decrease opioid abuse by preventing physical (e.g., crushing, chewing) and chemical (e.g., drug extraction) tampering. There are currently several commercial ADF formulations with abuse deterrent labelling and features that utilize high molecular weight PEO (HMW PEO)1. In almost all these products, the PEO offers crush resistance and extraction resistance properties that is further improved when the products containing PEO are thermally processed, such as in hot melt extrusion, injection molding, heated compression, etc. Although the thermally processed compositions containing PEO generally contain antioxidants to protect the PEO from any potential thermal oxidation, such compositions can be exposed to very unsafe and risky temperature regimens if thermally manipulated by abusers. In this study, we aimed to manipulate the pure HMW PEO and the tablets containing HMW PEO to evaluate the structural and functional properties of the PEO and the PEO tablets under abuse conditions.
Methods: HMW PEO powder (Sentry™ Polyox™ WSR-301, Mw 4,000,000 Da) was spread over a glass plate, and heated in an air-circulated oven at 180oC for 1 hr. A single station compression press tableting machine was also used to prepare PEO tablets (200 mg) using a direct compression method (2000 lb compression force, ½ inch diameter die). The tablets were also heated in an air-circulated oven at 80oC and 180oC for 1 hr. Followed by cooling to room temperature, the control and heat-treated tablets were dissolved in an appropriate amount of water to obtain a 2% w/v solutions. A cone & plate rheometer (Brookfield DV-III Ultra) was used to evaluate the rheological properties of the prepared solutions. The viscosity values were used as an indicator of abuse deterrence via extraction for subsequent injection.
Results: The FTIR spectra (Figure 1) of the HMW PEO powder treated at 180oC indicated an oxidative degradation at 1720 CM -1. No degradation peak was observed for the control PEO and the PEO heated at lower temperature of 80oC.
Figure 1. FTIR spectra of PEO at room temperature, 80oC and 180oC (left), picture of the control and treated samples (right).
The rheological behavior including viscosity and yield stress of the PEO solutions are shown in Figure 2. The control solution displayed a pseudoplastic flow behavior, whereas the heat-treated sample showed almost no viscosity when manipulated at 180oC. For instance, at the shear rate of 600 sec-1, the shear stress was approximately 10 N.mm-2 for the heat-treated PEO, whereas it was around 650 N.mm-2 for the control one. This dramatic change in flow behavior can be explained by the thermal oxidation of the PEO at the temperature of 180oC. Resistance to initial flow or the stress required to move the fluid is determined by the yield point or yield stress. For the 2% solutions of the control and the heat-treated PEOs, the yield stresses were found around 350 N.mm-2 and 5 N.mm-2, respectively. Once again, the dramatic 70-fold decrease in yield stress can be explained by the thermal oxidation of the PEO at 180oC.
Figure 2. Rheological behavior of the control and heat-treated HMW PEO powders at 2% solution concentration.
Figure 3 shows the rheological behavior of the 2% solutions of the control PEO tablet as well as the heat-treated PEO tablets (manipulated at 80 and 180oC). While the aqueous solutions of the control tablet and the treated tablet at 80oC show a pseudoplastic behavior, the aqueous solution of the manipulated tablet at 180oC showed almost no viscosity over a wide range of shear rates studied. Moreover, the flow behavior of the tablet manipulated at lower temperature of 80oC was much closer to the control tablet than the tablet manipulated at the temperature of 180oC. Alternatively, the control and thermally manipulated samples of PEO solutions display the yield stresses of 400 (control), 320 (manipulated at 80oC), and 12 (manipulated at 180oC) N.mm-2. These data suggest that PEO can still undergo some thermal oxidation at lower temperatures, although the thermal oxidation process becomes dramatically faster and more effective as temperature rises to close and above the degradation point of the PEO. Such thermal manipulation can reduce the 2% PEO solution viscosity down to almost 2% as suggested by the rheological data obtained in this study.
Figure 3. Rheological behavior of the control and heat-treated HMW PEO tablets at 2wt% solution concentration.
Conclusion: HMW PEO is extremely sensitive to thermal manipulations. If the dosage forms containing this polymer are thermally manipulated at temperatures as high as its degradation temperature, almost all deterrent features of this polymer will be lost as evidenced by dramatic changes in its structure and flow behavior.
Hossein Omidian– Fort Lauderdale, Florida