NIR Evaluation of Sintered Polyethylene Oxide Placebo Tablets for Abuse Deterrent Formulation Applications in Pharmaceutics

Abuse deterrent formulations (ADF) deter misuse and abuse of prescription narcotics. One ADF mechanism is to increase the tablet strength, which increases resistance of tablet grinding, cutting, and breaking. Increasing the tablet strength could be accomplished by several approaches including, but not limited to, incorporation of polyethylene oxide (PEO) in the formulation and sintering the tablet. PEO also forms a gel when exposed to moisture (i.e. attempted extraction) and will retard the release of the drug. The sintering process involves heating the tablet at 80°C allowing the polymer particles to fuse together creating shifts in tablet porosity and structure. Near Infrared Spectroscopy (NIR) is a technique that captures chemical and physical information about the sample. The goal of this study was to capture the physical changes that occur in the tablet during sintering to understand the sintering mechanism and how it relates to increased tablet strength.
A fractional factorial design was used with three placebo formulations and five sintering times: 0, 1, 3, 9 and 15 hr at 80°C. The formulations were prepared with PEO (30, 50 and 70 wt% PEO) mixed with anhydrous dibasic calcium phosphate. Magnesium stearate 1.0 wt% was added to each blend. A Metrohm-Foss XDS diffuse reflectance NIR spectrometer was used. Fifteen tablets for each point in the design were scanned for a total of 225 spectra. The tablets were crushed using Key® tablet hardness tester. Five of the 15 spectra for each point were used for the validation set.
The baseline of the spectra increased with sintering times indicating a structural change with time. It is believed this occurs because the PEO fuses during heating altering the pore structure and tablet density.
The tablet tensile strength increased with increased sintering times for the 70 wt% PEO tablets. The tensile strength of the 50 wt% PEO tablets also increased but the changes were not as pronounced in this set. The tensile strength for the 30 wt% PEO tablets remained constant for all sintering times. NIR was able to capture this trend. Several pre-processing methods were evaluated to specifically model the physical information of the spectra. It was decided to use only mean centering. Partial least squares (PLS) regression was used to correlate tensile strength and NIR spectra. For the 70 wt% PEO tablets with respect to sintering time a good correlation was observed (R2=0.85, RMSEC = 2.84, RMSECV=2.97). For the 50 wt% PEO tablets similar degree of correlation with tensile strength and NIR spectra was observed (R2=0.75, RMSEC = 2.32, RMSECV=2.54). The tensile strength of the 30 wt% PEO tablets did not correlate well to the NIR spectra with respect to sintering time (R2=0.12, RMSEC = 0.005, RMSECV=0.006). Partial least square regression of all 225 tablets correlates well with the NIR spectra with respect to sintering time (R2=0.81, RMSEC = 2.57, RMSECV=2.59).
The NIR spectra analysis shows that to achieve an increase in tablet tensile strength, specific conditions must be met regarding the sintering time and PEO concentration in the formulation.