Continuous direct compression as manufacturing platform for sustained release tablets

This study presents a framework for process and product development on a continuous direct compression manufacturing platform. A challenging sustained release formulation with high content of a poorly flowing low density drug was selected. Two HPMC grades were evaluated as matrix former: standard Methocel CR and directly compressible Methocel DC2. The feeding behavior of each formulation component was investigated by deriving feed factor profiles. The maximum feed factor was used to estimate the drive command and depended strongly upon the density of the material. Furthermore, the shape of the feed factor profile allowed definition of a customized refill regime for each material. Inline NIRs was used to estimate the residence time distribution (RTD) in the mixer and monitor blend uniformity. Tablet content and weight variability were determined as additional measures of mixing performance. For Methocel CR, the best axial mixing (i.e. feeder fluctuation dampening) was achieved when an impeller with high number of radial mixing blades operated at low speed. However, the variability in tablet weight and content uniformity deteriorated under this condition. One can therefore conclude that balancing axial mixing with tablet quality is critical for Methocel CR. However, reformulating with the direct compressible Methocel DC2 as matrix former improved tablet quality vastly. Furthermore, both process and product were significantly more robust to changes in process and design variables. This observation underpins the importance of flowability during continuous blending and die-filling. At the compaction stage, blends with Methocel CR showed better tabletability driven by a higher compressibility as the smaller CR particles have a higher bonding area. However, tablets of similar strength were achieved using Methocel DC2 by targeting equal porosity. Compaction pressure impacted tablet properties and dissolution. Hence controlling thickness during continuous manufacturing of sustained release tablets was crucial to ensure reproducible dissolution. (C) 2017 Elsevier B.V. All rights reserved

A multivariate approach to predict the volumetric and gravimetric feeding behavior of a low feed rate feeder based on raw material properties

In this study, the volumetric and gravimetric feeding behavior of 15 pharmaceutical powders on a low feed rate feeder was correlated with their material properties through a multivariate approach. The powders under investigation differ substantially in terms of material properties, making the selected powders representative for powders typically used in pharmaceutical manufacturing. The material properties were described by 25 material property descriptors, obtained from a rational selection of critical characterization techniques that provided maximal information with minimal characterization effort. From volumetric feeding experiments (i.e., powder feed rate not controlled), the maximum feeding capacity (maximum feed factor (FFmax)) and optimal hopper fill level at which the feeder should be refilled during gravimetric feeding (feed factor decay (FFdecay)) were obtained. During gravimetric feeding experiments (i.e., powder feed rate controlled), the variability on the feed rate (relative standard deviation (RSD)) and the difference between the setpoint and mean feed rate (relative error (RE)) were determined. Partial least squares (PLS) regression was applied to correlate the volumetric and gravimetric feeding responses (Y) with the material property descriptors (X). The predictive ability of the developed PLS models was assessed by predicting the feeding responses of two new powders (i.e., validation set). Overall, the volumetric feeding responses (FFmax, and FFdecay) were predicted better than the gravimetric feeding responses (RSD and RE), since in gravimetric mode the impact of material properties on the feeding behavior is reduced due to the control system of the feeder. Especially RE was weakly correlated with material properties as RE of most powders varied around zero with only a small numerical variation. Interestingly, this confirms that the control system is working properly and that the feeder is capable of feeding different powders accurately at low feed rates. The developed models allowed to predict the feeding behavior of new powders based on their material properties. Consequently the number of feeding experiments during process development can be greatly reduced, thereby leading to a more efficient and faster development of new drug products

Impact of blend properties on die filling during tableting

Based on characterization of a wide range of fillers and APIs, thirty divergent blends were composed and subsequently compressed on a rotary tablet press, varying paddle speed and turret speed. The tablet weight variability was determined of 20 grab samples consisting of each 20 tablets. Additionally, the bulk residence time, ejection force, pre-compression displacement, main compression force, die fill fraction and feed frame fill fraction were determined during each run. Multivariate data analysis was applied to investigate the relation between the process parameters, blend characteristics, product and process responses. Blends with metoprolol tartrate as API showed high ejection forces. This behavior could be linked to the high wall friction value of metoprolol tartrate. The main responses related to the die filling could be predicted via a PLS model based on blend characteristics. Tablet weight variability was highly correlated with the variability on pre-compression displacement and main compression force. A good predictive model for tablet weight variability was obtained taking the porosity, wall friction angle, flowability, density, compressibility and permeability into account. Additionally, turret speed and paddle speed were included in the calibration of the model. The applied approach can save resources (material, time) during early drug product development

3D printing of high drug loaded dosage forms using thermoplastic polyurethanes

It was the aim of this study to develop high drug loaded (> 30%, w/w), thermoplastic polyurethane (TPU)-based dosage forms via fused deposition modelling (FDM). Model drugs with different particle size and aqueous solubility were pre-processed in combination with diverse TPU grades via hot melt extrusion (HME) into filaments with a diameter of 1.75 +/- 0.05 mm. Subsequently, TPU-based filaments which featured acceptable quality attributes (i.e. consistent filament diameter, smooth surface morphology and good mechanical properties) were printed into tablets. The sustained release potential of the 3D printed dosage forms was tested in vitro. Moreover, the impact of printing parameters on the in vitro drug release was investigated. TPU-based filaments could be loaded with 60% (w/w) fine drug powder without observing severe shark skinning or inconsistent filament diameter. During 3D printing experiments, HME filaments based on hard TPU grades were successfully converted into personalized dosage forms containing a high concentration of crystalline drug (up to 60%, w/w). In vitro release kinetics were mainly affected by the matrix composition and tablet infill degree. Therefore, this study clearly demonstrated that TPU-based FDM feedstock material offers a lot of formulation freedom for the development of personalized dosage forms