The effect of particle size on the sublimation behavior of butylhydroxytoluene as antioxidant in tablets during storage and coating.

The effect of particle size on the sublimation behavior of butylhydroxytoluene (BHT) was investigated when BHT was included as antioxidant in tablets. Sublimation of pure BHT was found to be independent of its particle size, with pore formation on the surface of all tablets after storage at room temperature and above. Moreover, a higher residual BHT content after storage was detected in tablets containing a larger size fraction. X-ray µCT scans revealed the formation of peripherally larger pores at higher BHT particle sizes, implying a slower sublimation rate in the tablet core. A stability study indicated an increase in the extent of BHT sublimation at higher temperature and longer exposure time for all size fractions. The influence of BHT particle size was more pronounced when the tablets were stored at higher temperature, but the effect receded with longer exposure time. Similar trends were seen in film-coated tablets. Due to the short exposure time to elevated temperatures, a gradient in pore size was also observed at smaller particle sizes, with peripheral pores being larger in uncoated tablets. Superficial pores disappeared when a film coating was deposited onto the tablets. After storage of the film-coated tablets, less BHT had sublimated compared to the uncoated tablet. The coating layer did not prevent sublimation, but the process was slowed down.

Development of a 3D-Printed Dosing Platform to Aid in Zolpidem Withdrawal Therapy.

The long-term use of benzodiazepine receptor agonists (BZRAs) is associated with multiple side effects, such as increased sedation, hangover or an elevated risk of dependency and abuse. Unfortunately, the long-term use of BZRAs is reaching worrying intake rates, and therefore, the need for action is high. It was demonstrated already that the overall willingness of patients for deprescription increased when a slow dose reduction scheme with the possibility for dose increase, if needed, is employed. The current study aims to develop a flexible dosing platform of zolpidem hemitartrate (ZHT) to facilitate such withdrawal therapy. As this is the first report on the extrusion and 3D printing of ZHT, its thermal behaviour and sensitivity towards photolytic degradation was characterised. It was shown that ZHT possesses multiple polymorphs and was especially prone to oxidative photolysis. Next, a variety of immediate release polymers (Eudragit EPO, Kollidon VA64, Kollidon 12PF and Soluplus) were blended and extruded with Polyox WSR N10 to investigate their feedability and printability by mechanical and rheological analysis. The addition of PEO was shown to enable printing of these brittle pharmaceutical polymers, although the processing temperature was deemed critical to avoid surface defects on the resulting filaments. An EPO(70)PEO(30) system was selected based on its suitable mechanical properties and low hygroscopicity favoring ZHT stability. The matrix was blended with 1% or 10% API. The effect of certain printing parameters (caplet size, nozzle diameter, % overlap) on dissolution behaviour and caplet weight/dimensions/quality was assessed. A flexible dosing platform capable of delivering <1 mg and up to 10 mg of ZHT was created. Either caplet modification (incorporation of channels) or disintegrant addition (Primojel, Explotab, Ac-Di-Sol, Primellose and Polyplasdone-XL) failed to achieve an immediate release profile. This study provides the first report of a 3D-printed flexible dosing platform containing ZHT to aid in withdrawal therapy.