Elucidation of the powder flow pattern in a twin-screw LIW-feeder for various refill regimes.

The importance of residence time distribution modeling is acknowledged as a tool for enabling material tracking and control within a continuous manufacturing line in order to safeguard both product quality and production efficiency. One of the first unit-operations into a continuous direct compression line (i.e. CDC-line) worthwhile doing extensive RTD-analysis upon are the LIW-feeders since they dose the ingredients in a controlled way following the label claim and hence can directly influence critical quality attributes like content uniformity. An NIR measurement method was developed determining the RTD of selected powders at specific feeder settings. Step-change experiments using sodium saccharin as a tracer were conducted. In order to gain and in depth understanding of the material flow, spatial samples throughout the hopper were taken at predefined timepoints during the step change experiments. This revealed the presence of a bypass trajectory along the edges of the agitator, while in the center of the agitator an inner mixing volume in which the tracer concentration lags behind seemed to be present. Finally, a model based on a plug flow and continuous stirred tank reactor was evaluated. The fitted model was not able to capture this complex flow behavior and shows the need for an extended compartmental model distinguishing between a bypass trajectory formed by the agitator and an inner mixing volume.

Impact of blend properties and process variables on the blending performance.

In this study, quantitative relationships were established between blend properties, process settings and blending responses via multivariate data-analysis. Four divergent binary blends were composed in three different ratios and processed at various throughputs and impeller speeds. Additionally, different impeller configurations were tested to see their impact on the overall blending performance. During each run, feeder mass flows were compared with the API concentration (BU) in order to investigate the dampening potential of the blender. The blender hold-up mass (HM), mean residence time (MRT), strain on the powder (#BP) and BU variability (RSDBU) were determined as blending descriptors and analyzed via PLS-regression. This elucidated the correlation between process settings (i.e. throughput and impeller speed) and blending responses, as well as the impact of blend properties on MRT and RSDBU. Furthermore, the study revealed that HM does not need to be in steady state conditions to assure a stable BU, while it became clear that long/large feeder deviations can only be dampened by the blender when using dedicated impeller configurations. Overall, this study demonstrated the generic application of the blender, while the developed PLS models could be used to predict the blender performance based on the blend properties.

Determination of a quantitative relationship between material properties, process settings and screw feeding behavior via multivariate data-analysis.

In this study, a quantitative relationship between material properties, process settings and screw feeding responses of a high-throughput feeder was established via multivariate models (PLS). Thirteen divergent powders were selected and characterized for 44 material property descriptors. During volumetric feeder trials, the maximum feed capacity (FCCmax), the relative standard deviation on the maximum feed capacity (RSDFCmax), the short term variability (STRSD) and feed capacity decay (FCdecay) were determined. The gravimetric feeder trials generated values for the mass flow rate variability (RSDLC), short term variability (STRSD) and refill responses (Vrefill and RSDrefill). The developed PLS models elucidated that the material properties and process settings were clearly correlated to the feeding behavior. The extended volumetric feeder trials pointed out that there was a significant influence of the chosen screw type and screw speed on the feeding process. Furthermore, the process could be optimized by reducing the feeding variability through the application of optimized mass flow filters, high frequency vibrations, independent agitator control and optimized top-up systems. Overall, the models could allow the prediction of the feeding performance for a wide range of materials based on the characterization of a subset of material properties greatly reducing the number of required feeding experiments.

Downscaling of the tableting process: Feasibility of miniaturized forced feeders on a high-speed rotary tablet press.

With the current transformation of the pharmaceutical industry towards continuous manufacturing, there is an inherent need to embrace this concept already during the early stages of drug formulation. Therefore, this research paper investigated the feasibility of using miniaturized forced feeders on a high-speed rotary tablet press with the intention of downscaling the tableting process. Forced feeders with a reduced volume (up to 46% compared to the conventional two-compartment forced feeder) were designed by either sealing one compartment (i.e. R&D1) or lowering of the compartment height (i.e. R&D2). These feed frame designs were thoroughly analysed in combination with two paddle types over a wide range of process-settings (i.e. tableting speed, paddle speed, direction of paddle rotation, overfill-level). A poorly flowing model powder (i.e. MCC 101) was deliberately selected as challenging formulation. Empirical modelling of feed frame R&D1 revealed a positive impact on the die-filling variability when the radial curved cuboid paddles rotated in counterclockwise direction at high paddle speed. Moreover, a strong resemblance between the R&D2 feed frame and the conventional forced feeder was observed during multivariate data analysis, indicating that this miniaturized type could be used during downscaling studies of the conventional tableting process. The potential of this forced feeder was acknowledged by the similar trends in die-filling variability with respect to varying process settings, when a design-of-experiments (DOE) was performing including feed frame type as a qualitative factor. Overall, it was concluded that both types of miniaturized forced feeders can be used on a high-speed rotary tablet press when lower material consumption rates are desired while the R&D2 feed frame bears the highest predictability regarding the die-filling uniformity in the conventional larger two-compartment forced feeder.

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.

Optimizing feed frame design and tableting process parameters to increase die-filling uniformity on a high-speed rotary tablet press.

Despite the high quantities of tablets produced daily, many tableting processes are still operated at sub-optimal settings and hence lack the necessary flexibility to mitigate for possible process deviations. However, to ensure this flexibility on tableting throughput it is important to select the most robust feed frame design and settings regarding die-filling. In this research study, four paddle designs for a two-compartment forced feeder (equipped with a metering and a feeding paddle wheel) were evaluated at a wide range of process-settings (i.e. tableting speed, paddle speed, overfill level) and feed frame features (i.e. deaeration) for their impact on the die-filling step of a poorly flowing model formulation (i.e. MCC 101) using a quality-by-design approach. No benefit on die-filling was observed when using higher speeds of the metering paddle wheel compared to the feeding paddle wheel, and no convincing arguments were obtained to use the feed frame deaeration opening. Some combinations of paddle design and process-settings significantly increased the risk for inconsistent die-filling (i.e. high tablet weight variability) which can therefore limit the efficiency of the tableting process. The approach used in this study enabled to compare the paddle designs for their die-filling performance in function of varying tableting speeds, eventually resulting in the selection of a feed frame design that is most robust and therefore will provide a uniform die-filling over a wide range of throughputs. Selection of the most robust parameters is an important prerequisite for the ability of using the rotary tablet press as an agile unit-operation.

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.

Downstream processing from melt granulation towards tablets: In-depth analysis of a continuous twin-screw melt granulation process using polymeric binders.

The concept of twin-screw melt granulation (TSMG) has steadily (re)-gained interest in pharmaceutical formulation development as an intermediate step during tablet manufacturing. However, to be considered as a viable processing option for solid oral dosage forms there is a need to understand all critical sources of variability which could affect this granulation technique. The purpose of this study was to provide an in-depth analysis of the continuous TSMG process in order to expose the critical process parameters (CPP) and elucidate the impact of process and formulation parameters on the critical quality attributes (CQA) of granules and tablets during continuous TSMG. A first part of the study dealt with the screening of various amorphous polymers as binder for producing high-dosed melt granules of two model drug (i.e. acetaminophen and hydrochlorothiazide). The second part of this study described a quality-by-design (QbD) approach for melt granulation of hydrochlorothiazide in order to thoroughly evaluate TSMG, milling and tableting stage of the continuous TSMG line. Using amorphous polymeric binders resulted in melt granules with high milling efficiency due to their brittle behaviour without producing excessive amounts of fines, providing high granule yields with low friability. Therefore, it makes them extremely suitable for further downstream processing. One of the most important CPP during TSMG with polymeric binders was the granulation-torque, which - in case of polymers with high Tg - increased during longer granulation runs to critical levels endangering the continuous process flow. However, by optimizing both screw speed and throughput or changing to polymeric binders with lower Tg it was possible to significantly reduce this risk. This research paper highlighted that TSMG must be considered as a viable option during formulation development of solid oral dosage forms based on the robustness of the CQA of both melt granules and tablets.

Downstream processing from hot-melt extrusion towards tablets: A quality by design approach.

Since the concept of continuous processing is gaining momentum in pharmaceutical manufacturing, a thorough understanding on how process and formulation parameters can impact the critical quality attributes (CQA) of the end product is more than ever required. This study was designed to screen the influence of process parameters and drug load during HME on both extrudate properties and tableting behaviour of an amorphous solid dispersion formulation using a quality-by-design (QbD) approach. A full factorial experimental design with 19 experiments was used to evaluate the effect of several process variables (barrel temperature: 160-200°C, screw speed: 50-200rpm, throughput: 0.2-0.5kg/h) and drug load (0-20%) as formulation parameter on the hot-melt extrusion (HME) process, extrudate and tablet quality of Soluplus®-Celecoxib amorphous solid dispersions. A prominent impact of the formulation parameter on the CQA of the extrudates (i.e. solid state properties, moisture content, particle size distribution) and tablets (i.e. tabletability, compactibility, fragmentary behaviour, elastic recovery) was discovered. The resistance of the polymer matrix to thermo-mechanical stress during HME was confirmed throughout the experimental design space. In addition, the suitability of Raman spectroscopy as verification method for the active pharmaceutical ingredient (API) concentration in solid dispersions was evaluated. Incorporation of the Raman spectroscopy data in a PLS model enabled API quantification in the extrudate powders with none of the DOE-experiments resulting in extrudates with a CEL content deviating>3% of the label claim. This research paper emphasized that HME is a robust process throughout the experimental design space for obtaining amorphous glassy solutions and for tabletting of such formulations since only minimal impact of the process parameters was detected on the extrudate and tablet properties. However, the quality of extrudates and tablets can be optimized by adjusting specific formulations parameters (e.g. drug load).

Thermoplastic polyurethane-based intravaginal rings for prophylaxis and treatment of (recurrent) bacterial vaginosis.

The aim of the present study was to develop thermoplastic polyurethane (TPU)-based intravaginal rings (IVRs) for prophylaxis and treatment of bacterial vaginosis via hot melt extrusion/injection molding. Therefore, different TPU grades were processed in combination with lactic acid or metronidazole, targeting a sustained lactic acid release over a 28day-period and sustained metronidazole release over 4-7days. Hot melt extrusion of lactic acid/TPU combinations required a lower extrusion temperature due to the plasticizing properties of lactic acid, evidenced by the lower glass transition temperature (Tg) and cross-over point (Ttanδ=1) values. NIR-chemical imaging data showed a homogenous distribution of lactic acid in TPU matrices at drug loads up to 30% (w/w). The addition of metronidazole did not lower processing temperatures, as the active pharmaceutical ingredient remained crystalline in the TPU matrix. Hydrophobic TPUs with a low ratio between the soft and hard segments (SS/HS ratio) in the polymer structure were suitable carriers for the lactic acid-eluting device over a 28-day period, while hydrophilic TPUs were needed to achieve the required release rate of metronidazole-eluting IVRs. IVRs manufactured with a TPU grade having a higher SS/HS ratio and lactic acid/TPU ratio exhibited a more elastic behavior. The addition of 25% (w/w) metronidazole did not affect the mechanical properties of the IVRs. Hydrophilic TPUs were most prone to biofilm formation by Candida albicans and Staphylococcus aureus, but the incorporation of metronidazole in the device prevented biofilm formation. Based on the drug eluting performance and mechanical tests, a mixture of lactic acid and Tecoflex™ EG-93A (20/80, w/w) and a combination of metronidazole and Tecophilic™ SP-93A-100 (25/75, w/w) were selected to design IVRs for the prophylaxis and treatment of bacterial vaginosis, respectively. Slug mucosal irritation tests predicted low irritation potency for both devices.

In-line monitoring of compaction properties on a rotary tablet press during tablet manufacturing of hot-melt extruded amorphous solid dispersions.

As the number of applications for polymers in pharmaceutical development is increasing, there is need for fundamental understanding on how such compounds behave during tableting. This research is focussed on the tableting behaviour of amorphous polymers, their solid dispersions and the impact of hot-melt extrusion on the compaction properties of these materials. Soluplus, Kollidon VA 64 and Eudragit EPO were selected as amorphous polymers since these are widely studied carriers for solid dispersions, while Celecoxib was chosen as BCS class II model drug. Neat polymers and physical mixtures (up to 35% drug load) were processed by hot-melt extrusion (HME), milled and sieved to obtain powders with comparable particle sizes as the neat polymer. A novel approach was used for in-line analysis of the compaction properties on a rotary tablet press (Modul P, GEA) using complementary sensors and software (CDAAS, GEA). By combining 'in-die' and 'out-of-die' techniques, it was possible to investigate in a comprehensive way the impact of HME on the tableting behaviour of amorphous polymers and their formulations. The formation of stable glassy solutions altered the formulations towards more fragmentary behaviour under compression which was beneficial for the tabletability. Principal component analysis (PCA) was applied to summarize the behaviour during compaction of the formulations, enabling the selection of Soluplus and Kollidon VA 64 as the most favourable polymers for compaction of glassy solutions.

The use of partially hydrolysed polyvinyl alcohol for the production of high drug-loaded sustained release pellets via extrusion-spheronisation and coating: In vitro and in vivo evaluation.

Partially hydrolysed polyvinyl alcohol (PVA) was evaluated as a pelletisation aid for the production of pellets with a high acetaminophen and metformin hydrochloride concentration (>70%, w/w). Mixtures with varying drug concentration and PVA/microcrystalline cellulose (MCC) ratios were processed via extrusion-spheronisation, either after addition of PVA as a dry powder or as an aqueous solution. Finally, high drug- loaded metformin pellets were coated with a methacrylic acid copolymer (Eudragit™ NM 30D) and evaluated for their sustained release potency in vitro and in vivo. The plasticity index of the wet mass increased by the addition of PVA to the formulation, which resulted in enhanced extrusion-spheronisation properties, even at a high drug load. Although the MCC concentration was successfully lowered by adding PVA, the inclusion of MCC in the formulation was essential to overcome problems related to the tackiness effect of PVA during extrusion. Overall, wet addition of PVA was superior to dry addition, as pellets with a higher mechanical strength and narrower particle size distribution were obtained. Pellets containing 87% (w/w) metformin hydrochloride were successfully layered with 20% (w/w) coating material, yielding sustained release pellets with a final drug load of 70% (w/w). In addition, the sustained release characteristics of the PVA-based pellets with a high drug content were confirmed in vivo as no difference with the Glucophage™ SR reference formulation was observed.

A comparative study between melt granulation/compression and hot melt extrusion/injection molding for the manufacturing of oral sustained release thermoplastic polyurethane matrices.

During this project 3 techniques (twin screw melt granulation/compression (TSMG), hot melt extrusion (HME) and injection molding (IM)) were evaluated for the manufacturing of thermoplastic polyurethane (TPU)-based oral sustained release matrices, containing a high dose of the highly soluble metformin hydrochloride. Whereas formulations with a drug load between 0 and 70% (w/w) could be processed via HME/(IM), the drug content of granules prepared via melt granulation could only be varied between 85 and 90% (w/w) as these formulations contained the proper concentration of binder (i.e. TPU) to obtain a good size distribution of the granules. While release from HME matrices and IM tablets could be sustained over 24h, release from the TPU-based TSMG tablets was too fast (complete release within about 6h) linked to their higher drug load and porosity. By mixing hydrophilic and hydrophobic TPUs the in vitro release kinetics of both formulations could be adjusted: a higher content of hydrophobic TPU was correlated with a slower release rate. Although mini-matrices showed faster release kinetics than IM tablets, this observation was successfully countered by changing the hydrophobic/hydrophilic TPU ratio. In vivo experiments via oral administration to dogs confirmed the versatile potential of the TPU platform as intermediate-strong and low-intermediate sustained characteristics were obtained for the IM tablets and HME mini-matrices, respectively.

The impact of hot-melt extrusion on the tableting behaviour of polyvinyl alcohol.

There is evidence that processing techniques like hot-melt extrusion (HME) could alter the mechanical properties of pharmaceuticals, which may impede further processability (e.g. tableting). The purpose of this study was to evaluate if HME has an impact on the tableting behaviour of polyvinyl alcohol (PVA)-formulations. Mixtures of partially hydrolysed PVA grades (with a hydroxylation degree of 75 and 88%) and sorbitol (0, 10 and 40%) were extruded, (cryo-) milled and compressed into compacts of 350 ± 10 mg. Before compression all intermediate products were characterized for their solid-state (Tg, Tm, crystallinity) and material properties (particle size, moisture content, moisture sorption). Because both PVA-grades required higher extrusion temperatures (i.e. 180 °C), sorbitol was added to PVA as plasticizing agent to allow extrusion at 140 °C. Compaction experiments were performed on both physical mixtures and cryo-milled extrudates of PVA-sorbitol. By measuring tablet tensile strength and porosity in function of compaction pressure, tableting behaviour was compared before and after HME by means of the CTC-profiles (compressibility, tabletability, compactibility). A higher amorphous content in the formulation (as a result of HME) negatively influenced the tableting behaviour (i.e. lower tablet tensile strength). HME altered the mechanical properties towards more elastically deforming materials, thereby increasing tablet elastic recovery during decompression. The lower tensile strengths resulted from a combined effect of less interparticulate bonding areas (because of higher elastic recovery) and weaker bonding strengths per unit bonding area (between glassy particles).