Preferential Oxycodone Loss of Physically Manipulated Abuse Deterrent Oxycodone HCl Extended Release Tablets Prepared for Nasal Insufflation Studies.

A method to reproducibly mill abuse deterrent oxycodone hydrochloride (HCl) extended release (ER) tablets was developed for a nasal insufflation pharmacokinetic (PK) study. Several comminution methods were explored before determining that a conical mill resulted in controlled milling of tablets to a size range equal to or below 1000 µm. However, milling resulted in significant loss of oxycodone from abuse deterrent oxycodone HCl ER tablets compared to minimal oxycodone loss from oxycodone HCl immediate release (IR) tablets. Characterization of milled tablet powder showed that loss of oxycodone was not attributed to analytical procedures or oxycodone phase change during high intensity milling processes. The content uniformity of oxycodone in the milled tablet powder varied when ER and IR tablets were milled to a particle size distribution equal to or below 500 µm but did not vary when particles were sized above 500 µm to equal to or below 1000 µm. In addition, the initial excipient weight to drug substance weight ratio impacted the amount of oxycodone lost from the respective formulation. However, dissolution demonstrated that when oxycodone HCl ER tablets are milled, differences in excipient weight to drug substance weight ratio and particle size distribution of milled tablets did not result in significantly different release of oxycodone.

Physical Barrier Type Abuse-Deterrent Formulations: Mechanistic Understanding of Sintering-Induced Microstructural Changes in Polyethylene Oxide Placebo Tablets.

The main goal of the presented work was to understand changes in the microstructure of tablets, as well as the properties of its main component viz. polyethylene oxide (PEO) as a function of sintering. Key polymer variables and sintering conditions were investigated, and sintering-induced increase in tablet tensile strength was evaluated. For the current study, binary-component placebo tablets comprised of varying ratios of PEO and anhydrous dibasic calcium phosphate (DCP) were prepared at two levels of tablet solid fraction. The prepared tablets were sintered in an oven at 80°C at different time points ranging from 10 to 900 min and were evaluated for pore size, tablet expansion (%), and PEO crystallinity. The results showed that for efficient sintering and a significant increase in the tablet tensile strength, a minimum of 50% w/w PEO was required. Moreover, all microstructural changes in tablets were found to occur within 60 min of sintering, with no significant changes occurring thereafter. Sintering also resulted in a decrease in PEO crystallinity, causing changes in polymer ductility. These changes in PEO ductility resulted in tablets with higher tensile strength. Formulation variables such as PEO level and PEO particle size distribution were found to be important influencers of the sintering process. Additionally, tablets with high initial solid fraction and sintering duration of 60 min were found to be optimal conditions for efficient sintering of PEO-based compacts. Finally, prolonged sintering times were not found to provide any additional benefits in terms of abuse-deterrent properties.

Physical barrier type abuse-deterrent formulations: monitoring sintering-induced microstructural changes in polyethylene oxide placebo tablets by near infrared spectroscopy (NIRS).

OBJECTIVE: The monitoring and evaluation of sintering-induced tablet strength of a polyethylene oxide (PEO) based placebo tables was accomplished using infrared spectroscopy (NIRS). SIGNIFICANCE: Evaluation of high molecular weight PEO-based tablet matrices for abuse deterrent formulation applications is an analytical challenge. NIRS is one tool that can provide physical and chemical evaluation of this polymer and tablet system. In addition, the use of NIRS as a process analytical tool (PAT) to monitor oven sintering of pharmaceutical tablets has not been recorded in the literature. The multiplicative scattering correction (MSC) algorithm was also successfully applied as a new and fast way to calculate NIRS spectral slopes and intercepts to build models against tablet tensile strength with respect to sinter time. METHODS: Both spectral slope regression (SSR) and spectral intercept regression (SIR) models were compared to commonly used partial least squares analysis (PLS) to evaluate placebo PEO based pharmaceutical tablets comprised of PEO at 70, 50, 30% w/w that were compressed at two solid fraction (SF) levels. RESULTS: All three regression techniques, PLS, SSR, SIR, were evaluated for robustness and reliability and physical relevancy to the system studied. The methods were ranked in utility with SSR being the best method followed by SIR then PLS. CONCLUSIONS: The MSC algorithm was presented to quickly calculate spectral slopes and intercepts for use in SSR and SIR analysis. SSR models were successfully applied and assessed as the optimal modeling technique to monitor sintering of PEO-based matrix tablets.