Investigation of continuous manufacturing technologies suitable for production of acetaminophen tablets

Abstract

The desirable properties of granules and tablets can be achieved by choosing proper manufacturing technique and formulation composition. Currently, Continuous Manufacturing (CM) finds wider application in pharmaceutical field as a new approach, alternative to batch methods. CM has a great potential to overcome the classical problems such as scale-up related, lack of or insufficient real time quality control, and long manufacturing cycles. Moreover, CM methods are promising to overcome the poor physico-mechanical properties of drugs. In addition, these can provide desirable drug release with improving solubility of the drugs.

In this thesis, acetaminophen was explored as a model drug that exhibits poor technological properties. The principal concept was to develop novel robust tablets, with desired release profile, manufactured from granules produced via hot melt continuous techniques such as hot melt extrusion (HME), twin screw melt granulation (TSMG) and injection moulding (IM). The granules and tablets were subjected to evaluation according to the common compendial tests.

Materials were firstly analysed for their thermal stability and crystallinity using TGA, DSC and PXRD, respectively. A preliminary assessment of the solid state of drug/polymer matrix and performed physical stability helped in the attempt to gain better understanding of this solid form. It was shown that hot melt techniques impacted properties of granules and related tablets. It was found that milled extrudates prepared via HME when compared to the granules produced via conventional methods often exhibited better particle size distribution and flow properties. Satisfactory results were also obtained for granules achieved via TSMG. This melt granulation was highly effective in improving acetaminophen tabletability.

Overall, tablets manufactured from extruded blend met immediate release requirement, however, there was significant difference in the dissolution performance between conventional and extruded formulations. This was principally due to high density of the extruded matrix. Therefore, tablets produced via IM method did not meet immediate release requirements even though the extrudates utilised for producing these tablets met this test. In case of tablets made from granules produced via TSMG, the drug extended release profile was not achieved especially at the beginning of the dissolution process.

In summary, granules produced via HME and TSMG method resulted in decent blend characteristics, and the produced tablets had good mechanical strength. These techniques have shown the potential for their application as the manufacturing methods suitable to overcome poor physico-mechanical properties of acetaminophen, and can be an alternative method of manufacturing acetaminophen tablet, with the potential for practical and wider application in pharmaceutical industry.

Date of Award	Dec 2023
Original language	English
Awarding Institution	Queen's University Belfast
Supervisor	Gavin Andrews (Supervisor), David Jones (Supervisor) & Colin McCoy (Supervisor)