The aim of the current study was to screen theophylline (125 mg) tablets manufactured via twin screw granulation in order to improve process understanding and knowledge of process variables which determine granule and tablet quality. A premix of theophylline anhydrate, α-lactose monohydrate and PVP (ratio: 30/67.5/2.5, w/w) was granulated with demineralized water. Experiments were done using the high shear wet granulation module (based on twin screw granulation) of the ConsiGma TM -25 unit (a continuous tablet manufacturing system) for particle size enlargement. After drying, granules were compressed using a MODUL TM P tablet press (compression force: 10 kN, tablet diameter: 12 mm). Using a D-optimal experimental design, the effect of several process variables (throughput (10 -25 kg/h), screw speed (600 -950 rpm), screw configuration (number (2, 4, 6 and 12) and angle (30, 60 and 90 degrees) of kneading elements), barrel temperature (25 -40°C) and method of binder addition (dry vs wet)) on the granulation process (torque and temperature increase of barrel wall), granule (particle size distribution, friability and flowability) and tablet (tensile strength, porosity, friability, disintegration time and dissolution) quality was evaluated. The results showed that the quality of granules and tablets can be optimized by adjusting specific process variables (number of kneading elements, barrel temperature and binder addition method) during a granulation process using a continuous twin screw granulator.

Context: Tableting is a complex process due to the large number of process parameters that can be varied. Knowledge and understanding of the influence of these parameters on the final product quality is of great importance for the industry, allowing economic efficiency and parametric release.Objective: The aim of this study was to investigate the influence of paddle speeds and fill depth at different tableting speeds on the weight and weight variability of tablets. Materials and methods:Two excipients possessing different flow behavior, microcrystalline cellulose (MCC) and dibasic calcium phosphate dihydrate (DCP), were selected as model powders. Tablets were manufactured via a high speed rotary tablet press using design of experiments (DoE). During each experiment also the volume of powder in the forced feeder was measured.Results and discussion: Analysis of the DoE revealed that paddle speeds are of minor importance for tablet weight but significantly affect volume of powder inside the feeder in case of powders with excellent flowability (DCP). The opposite effect of paddle speed was observed for fairly flowing powders (MCC). Tableting speed played a role in weight and weight variability, whereas changing fill depth exclusively influenced tablet weight. Conclusion:The DoE approach allowed predicting the optimum combination of process parameters leading to minimum tablet weight variability. Monte Carlo simulations allowed assessing the probability to exceed the acceptable response limits if factor settings were varied around their optimum. This multi-dimensional combination and interaction of input variables leading to response criteria with acceptable probability reflected the design space.

To refer to or to cite this work, please use the citation to the published version:Vanhoorne V., Bekaert B., Peeters E., De Beer T., Remon J.P., Vervaet C. (2016) Improved tabletability after a polymorphic transition of delta-mannitol during twin screw granulation. International Journal of Pharmaceutics 506 13-24 DOI: 10.1016/j.ijpharm.2016.04.025 AbstractIn most formulations processed via continuous twin screw granulation microcrystalline cellulose (MCC) and/or lactose are used as excipients, but mannitol is also a preferred excipient for wet granulation and tableting due to its non-hygroscopicity and inertness.Therefore, the aim of the current study was to investigate the influence of process parameters on critical quality attributes of granules (moisture content, solid state, morphology, size distribution, specific surface area, friability, flowability and hygroscopicity) and tablets (tensile strength and friability) after twin screw granulation of δ-mannitol. The δ-polymorph was selected since a moisture-induced transformation to β-mannitol was observed during batch wet granulation, which exhibited a unique morphology with a large surface area and improved tabletability. A full factorial experimental design was performed, varying screw speed (400 -900 rpm), granulation temperature (25 -40 °C), number of kneading elements (6 or 12) and liquid-to-solid (L/S) ratio, on the granulation unit of a ConsiGma TM -25 line (a continuous powder-to-tablet manufacturing system). After tray drying the granules were milled and tableted. The results showed that the polymorphic transition from δ-to β-mannitol also occurred during twin screw granulation, although the residence time and L/S ratios were much lower in continuous twin screw granulation compared to batch processing. However, the polymorphic transition was not complete in all experiments and depended on the L/S ratio, screw speed and number of kneading elements. Nevertheless all granules exhibited the unique morphology linked to the polymorphic transition and had a superior tabletability compared to granules produced with β-mannitol as starting material. This was attributed to enhanced plastic deformation of the granules manufactured using δ-mannitol as starting material. In addition, it was concluded that mannitol was granulated via a different mechanism than other, lesssoluble, excipients (e.g. lactose, microcrystalline cellulose) due to its high solubility and dissolution rate as the influence of process parameters on the mannitol granule characteristics was different.

No 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.

Since small scale is key for successful introduction of continuous techniques in the pharmaceutical industry to allow its use during formulation development and process optimization, it is essential to determine whether the product quality is similar when small quantities of materials are processed compared to the continuous processing of larger quantities. Therefore, the aim of this study was to investigate whether material processed in a single cell of the six-segmented fluid bed dryer of the ConsiGma™-25 system (a continuous twin screw granulation and drying system introduced by GEA Pharma Systems, Collette™, Wommelgem, Belgium) is predictive of granule and tablet quality during full-scale manufacturing when all drying cells are filled. Furthermore, the performance of the ConsiGma™-1 system (a mobile laboratory unit) was evaluated and compared to the ConsiGma™-25 system. A premix of two active ingredients, powdered cellulose, maize starch, pregelatinized starch and sodium starch glycolate was granulated with distilled water. After drying and milling (1000 μm, 800 rpm), granules were blended with magnesium stearate and compressed using a Modul™ P tablet press (tablet weight: 430 mg, main compression force: 12 kN). Single cell experiments using the ConsiGma™-25 system and ConsiGma™-1 system were performed in triplicate. Additionally, a 1h continuous run using the ConsiGma™-25 system was executed. Process outcomes (torque, barrel wall temperature, product temperature during drying) and granule (residual moisture content, particle size distribution, bulk and tapped density, hausner ratio, friability) as well as tablet (hardness, friability, disintegration time and dissolution) quality attributes were evaluated. By performing a 1h continuous run, it was detected that a stabilization period was needed for torque and barrel wall temperature due to initial layering of the screws and the screw chamber walls with material. Consequently, slightly deviating granule and tablet quality attributes were obtained during the start-up phase of the 1h run. For the single cell runs, granule and tablet properties were comparable with results obtained during the second part of the 1h run (after start-up). Although deviating granule quality (particle size distribution and Hausner ratio) was observed due to the divergent design of the ConsiGma™-1 unit and the ConsiGma™-25 system (horizontal set-up) used in this study, tablet quality produced from granules processed with the ConsiGma™-1 system was predictive for tablet quality obtained during continuous production using the ConsiGma™-25 system.

DankwoordMet deze doctoraatsthesis wil ik van de gelegenheid gebruik maken om eventjes terug te blikken op de voorbije jaren en de personen te bedanken die mede ervoor gezorgd hebben dat deze periode in mijn leven een unieke ervaring is geworden.Dit eindresultaat is mede tot stand gekomen dankzij de hulp, ervaring en wijze raad van vele boeiende mensen die ik heb mogen leren kennen tijdens afgelopen jaren. Elk op hun eigen wijze hebben ze hun steentje bijgedragen tot deze doctoraatsthesis. Een woord van dank is hier dan ook op zijn plaats.Vooreerst gaat mijn oprechte dank uit naar mijn promotoren Prof. Dr. J.P. Remon en Prof. Dr.C. Vervaet voor de kans die zij mij geboden hebben. Hun enthousiaste begeleiding en liefde voor wetenschap en onderzoek werkten aanstekelijk en hebben in belangrijke mate bijgedragen tot deze doctoraatsthesis.Prof. Remon en Chris, een welgemeende dank voor jullie onuitputtelijke wetenschappelijke raad, analytische geest en gedetailleerde correcties van manuscripten en abstracts. Mijn schoonouders en Kirsten, bedankt om lief en leed met mij te delen. Ik ben blij dat ik steeds mijn verhaal kwijt kon, ook wanneer ik van pure wetenschappelijke extase maar bleef doorrammen over 'droogsproeien'.En tenslotte, mijn allerdierbaarste: liefste Katrien, jij bent het mooiste dat mij ooit is overkomen. OBJECTIVESTablets are still the most commonly used dosage form because of the ease of manufacturing, convenience in administration, accurate dosing and excellent stability. Direct compression is the preferred method for the preparation of tablets. However, it has been estimated that less than 20 percent of the active pharmaceutical ingredients (API) can be processed into tablets via direct compression since the majority of API lack the flow, cohesion or lubricating properties required for direct compression. Therefore, the formulator has to resort to (wet) granulation techniques to obtain API/excipient agglomerates with suitable properties for compression. This involves several processing steps (dry mixing, granulation, drying), different equipment, numerous written procedures to be followed and extensive downstream testing for powder homogeneity/segregation. In addition, wet granulation is a batch process and scaling-up of this technique is a labour-intensive and time-consuming process.In this study an alternative method to improve the compactability of API will be developed through coprocessing of API and excipients via spray drying in order to obtain a fully continuous manufacturing process without granulation, milling and/or blending steps in between spray drying and compaction. This technique has already been used to develop excipient mixtures having superior properties (flowability, hygroscopicity and compactability) compared to the individual excipients or their physical mixtures. However, this concept has not been extended to the coprocessing of drug and excipient(s) to alter the physical properties of the drug. Co-spray drying is applied to generate a unique particle size, particle shape and ...

The UGent Institutional Repository is the electronic archiving and dissemination platform for all UGent research publications. Ghent University has implemented a mandate stipulating that all academic publications of UGent researchers should be deposited and archived in this repository. Except for items where current copyright restrictions apply, these papers are available in Open Access. This item is the archived peer-reviewed author-version of: Development and validation of an in-line NIR spectroscopic method for continuous blend potency determination in the feed frame of a tablet press