Drop-on-Demand System for Manufacturing of Melt-based Solid Oral Dosage: Effect of Critical Process Parameters on Product Quality

Abstract

The features of a drop-on-demand-based system developed for the manufacture of melt-based pharmaceuticals have been previously reported. In this paper, a supervisory control system, which is designed to ensure reproducible production of high quality of melt-based solid oral dosages, is presented. This control system enables the production of individual dosage forms with the desired critical quality attributes: amount of active ingredient and drug morphology by monitoring and controlling critical process parameters, such as drop size and product and process temperatures. The effects of these process parameters on the final product quality are investigated, and the properties of the produced dosage forms characterized using various techniques, such as Raman spectroscopy, optical microscopy, and dissolution testing. A crystallization temperature control strategy, including controlled temperature cycles, is presented to tailor the crystallization behavior of drug deposits and to achieve consistent drug morphology. This control strategy can be used to achieve the desired bioavailability of the drug by mitigating variations in the dissolution profiles. The supervisor control strategy enables the application of the drop-on-demand system to the production of individualized dosage required for personalized drug regimens.

Keywords: critical process parameters; critical quality attributes; drop-on-demand; drug printing; supervisory control.

Fig. 1

Dropwise additive manufacturing system (1 material reservoir, 2 precision P/D pump, 3 nozzle, 4 camera, 5 substrate, 6 xy-stage, dotted box online imaging system)

Fig. 2

Melt-based drops (NAP-PEG 3350) deposited on the polymeric film substrate

Fig. 3

Supervisory control framework for the dropwise additive manufacturing process

Fig. 4

Raman spectra of a pure NAP, b pure PEG 3350, c co-melt of NAP-PEG 3350 (15:85). Characteristic peaks at 760 and 1280 cm-1 are shown with red and blue arrows, respectively

Fig. 5

Raman map of melt-based deposits of NAP-PEG 3350 (15:85). Map area 660 μm × 1000 μm

Fig. 6

Temperature profiles applied on the substrate

Fig. 7

Optical microscopy images of melt-based deposits (NAP-PEG 3350) after a fast cooling b slow cooling c cycling

Fig. 8

Dissolution profiles of the dosage forms solidified with different cooling rates. a Dosage forms containing small drops. b Dosage forms containing large drops

Fig. 9

Dissolution profiles of the dosage forms created with two different drop sizes and solidified at different temperature profiles a constant temperature, b fast cooling, c slow cooling, d cycling

Fig. 10

Infrared camera image of melt-based deposits solidifying at room temperature