Prediction of quality attributes of continuously produced granules using complementary pat tools

Abstract

Manufacturers of pharmaceutical solid dosage forms aim for a reduced production time and a shorter 'time-to-market'. Therefore continuous manufacturing gains increasing interest in the pharmaceutical industry. For continuous manufacturing, the quality of produced pharmaceuticals should be assessed in real-time (in-line, on-line and at-line) and not via the traditional off-line, often destructive and time-consuming analysis methods which supply the desired information only hours after sampling. This research paper evaluates three Process Analytical Technology (PAT) tools for the real-time at-line analysis of granules, which were produced using a continuous wet twin-screw granulator being part of a from powder-to-tablet production line (ConsiGma™-25). A Raman and NIR spectrometer were used together with a photometric imaging technique in order to acquire solid state information and granule size data. These multivariate data were then used to predict the granules' moisture content, tapped and bulk density and flowability. The three PAT tools provided complementary information for predicting these quality attributes of the continuously produced granules. The residual moisture content was mostly correlated with the spectroscopic data, whereas the imaging-data had the highest predictive capability for the flowability of the granules.

Real‐Time Monitoring of Changes of Adsorbed and Crystalline Water Contents in Tablet Formulation Powder Containing Theophylline Anhydrate at Various Temperatures During Agitated Granulation by Near‐Infrared Spectroscopy

“…Otsuka et al reported that various polymorphic forms of carbamazepine transformed into the dihydrate form during wet granulation and their dissolution of tablets obtained from their dried granules was delayed depending on the amount of hydrate during granulation. All of the previous studies reported that polymorphic transformation during granulation significantly affected the pharmaceutical properties of final tablet preparations, and induced variability of the products . Debnath and Suryanarayanan reported that THA transformed into THM during wet granulation and their THA tablets obtained from their dried granules were tested for their pharmaceutical properties.…”

“…THA bulk powder in the pharmaceuticals was transformed into THM during storage and the wet granulation process, and the phase transformation of THA during processing affected the bioavailability of the products through their dissolution behaviors . To obtain high‐quality products, hydrate formation of THA during wet granulation with agitating and fluid bed granulators was studied quantitatively by in‐line NIR and Raman methods and multivariate analysis as real‐time analysis . Wikström et al reported in‐line monitoring of THA hydrate formation during high shear wet granulation using Raman spectroscopy.…”

Raman spectroscopy as a process analytical technology for pharmaceutical manufacturing and bioprocessing

“…These examples demonstrate that Raman is an important on-line PAT in continuous synthesis. In secondary manufacturing, Fonteyne et al reported successful prediction of residual moisture content using on-line Raman and near-infrared and prediction of granule flowability using photometric imaging during a continuous granulation production [64]. …”

Comparison of a continuous ring layer wet granulation process with batch high shear and fluidized bed granulation processes

“…Single screw and twin-screw extruders for pharmaceutical granulation were introduced in the late 1980s and have been developed subsequently in recent years [16][17][18][19][20]. In one study, the semi-continuous extrusion wet granulation was compared with the high shear granulation using formulations containing varying lactose grades and an active pharmaceutical ingredient (paracetamol and cimetidine).…”