Pharmaceutical Tablet Manufacturing Research Articles

Accelerating pharmaceutical tablet development by transfer of powder compaction equipment across types and scales

Roller compaction is a key unit operation in a dry granulation line for pharmaceutical tablet manufacturing. During product development, one would like to find the roller compactor (RC) settings that are required to achieve a desired ribbon solid fraction. These settings can be determined from the compression profile of the powder mixture being compacted and a mathematical model that interprets it. However, establishing compression profiles in an RC requires relatively large amounts of powder, which are expensive and may not be available during drug development. As a cost-effective alternative to an RC, a compactor simulator (CS) can be used, which is a small-scale equipment that uses minimal amounts of powder to build the compression profile. However, since the working principles of a CS and an RC are different, the compression profiles obtained from the two devices for a given powder are also different. In this study, we propose a transfer learning approach that allows the RC compression profile of a given powder to be easily predicted from the compression profile obtained in a CS for the same powder. Based on the well-known Johanson model and on the mass correction factor theory, we examine the compaction behavior of six formulations, two of which including active ingredients, and we find that the mass correction factor does not depend significantly on the powder being compacted. We develop a simple, generalized correlation (transfer model) that allows the mass correction factor to be predicted solely as a function of the pressure at which the compaction is carried out. By using the proposed transfer model, the prediction of the RC compression profiles for the validation powders is significantly improved over the case where a constant value of the mass correction factor is used.

An experimental study on flow behaviour of pharmaceutical powders during suction filling

Die filling is a crucial step in the pharmaceutical tablet manufacturing process. For industrial-scale production using rotary presses, suction filling is typically employed due to its significant efficiency advantages over gravity filling. Despite its widespread use, our understanding of the suction filling process remains limited. Specifically, there is insufficient comprehension of how filling performance is influenced by factors such as suction velocity, filling velocity, and the properties of the powder materials. Building on our previous research, this study aims to further investigate the effects of powder properties and process parameters (e.g., filling velocity, suction velocity, fill depth) on suction filling behaviour. A systematic experimental investigation was conducted using a model suction filling system, considering both cohesive and free-flowing pharmaceutical powders. The effect of fill depth on suction filling of these powders was examined at different filling and suction velocities. The results demonstrate that two distinctive flow regimes for suction filling can be identified: slow filling and fast filling. These regimes are delineated by a critical filling-to-suction velocity ratio. In the slow filling regime, the filling-to-suction velocity ratio is lower than the critical ratio, meaning that the filling phase is slower than the suction phase. Conversely, the fast filling regime occurs when the filling-to-suction velocity ratio exceeds the critical ratio, implying that the filling phase is faster than the suction phase. This study reveals, for the first time, that when the powder flow pattern during suction filling is dominated by plug flow, full die fill (i.e., the fill ratio equals unity) is achieved in the slow filling regime. However, in the fast filling regime, incomplete die fill is obtained. It is also found that when plug flow prevails during fast filling, the fill ratio has an inverse correlation with the filling-to-suction velocity ratio. This study further reveals that when the plug flow assumption is valid, the filling ratio at various fill-to-suction velocity ratios can be well predicted mathematically. Furthermore, it is also found that once the powder flow pattern differs from the ideal plug flow, which could be induced by the filling conditions and powder cohesion, the fill ratio can be overpredicted.

Effect of geometrical features on the capping behavior of biconvex tablets

Capping is a common industrial issue during the manufacturing of pharmaceutical tablets. It is influenced by both process and formulation parameters. In this work, a systematic study of the influence of the geometrical features of biconvex tablets on capping occurrence was performed on a model formulation, using a design of experiment. Capping was characterized by the pressure at which half of the produced tablets were capped. The influence of the tablet geometry was assessed by varying three parameters: the diameter (D), the band thickness (W) and the ratio between the radius of curvature (R) and the diameter, i.e. R/D. Results showed that having a large diameter, a low band thickness and a high curvature (i.e. a low R/D) favored capping occurrence. Moreover, the effects are not independent as cross-effect were detected. Finally, even for homothetic tablets (i.e. same R/D and W/D) it is shown that a large diameter increases capping occurrence. These results could be used in the future as a guideline for punch selection during tablet development.

Data-Knowledge-Driven Modeling and Operational Adjustment for the Pharmaceutical Tablet Manufacturing Process via Wet Granulation.

In the context of Pharma 4.0, pharmaceutical quality control (PQC) is beset by issues such as uncertainties from ever-changing critical material attributes and strong coupling between variables in the multi-unit pharmaceutical tablet manufacturing process (PTMP), and how to timely adjust the operational variables to deal with such challenges has become a key problem in PQC. In this study, we propose a novel data-knowledge-driven modeling and operational adjustment framework for PTMP by integrating Bayesian network (BN) and case-based reasoning (CBR). At the modeling level, first, a distributed concept is introduced, i.e., the BN model for each subunit of PTMP is established in accordance with the operation process sequence, and the transition variables are given by the BN model established first and retrieved as the new query for the next unit. Once the BN models of all subunits are built, they are integrated into a global BN model. At the operational adjustment level, by taking the expected critical quality attributes (CQAs) and related prior information as evidence, the operational adjustment is achieved through global BN reasoning. Finally, the case study in a sprayed fluidized-bed granulation-based PTMP demonstrates the feasibility and effectiveness in improving the terminal CQAs of the proposed method, which is also compared with other methods to showcase its efficacy and merits.

Interpretable artificial neural networks for retrospective QbD of pharmaceutical tablet manufacturing based on a pilot-scale developmental dataset

As the pharmaceutical industry increasingly adopts the Pharma 4.0. concept, there is a growing need to effectively predict the product quality based on manufacturing or in-process data. Although artificial neural networks (ANNs) have emerged as powerful tools in data-rich environments, their implementation in pharmaceutical manufacturing is hindered by their black-box nature. In this work, ANNs were developed and interpreted to demonstrate their applicability to increase process understanding by retrospective analysis of developmental or manufacturing data. The in vitro dissolution and hardness of extended-release, directly compressed tablets were predicted from manufacturing and spectroscopic data of pilot-scale development. The ANNs using material attributes and operational parameters provided better results than using NIR or Raman spectra as predictors. ANNs were interpreted by sensitivity analysis, helping to identify the root cause of the batch-to-batch variability, e.g., the variability in particle size, grade, or substitution of the hydroxypropyl methylcellulose excipient. An ANN-based control strategy was also successfully utilized to mitigate the batch-to-batch variability by flexibly operating the tableting process. The presented methodology can be adapted to arbitrary data-rich manufacturing steps from active substance synthesis to formulation to predict the quality from manufacturing or development data and gain process understanding and consistent product quality.

Application of Twin-Screw Melt Granulation to Overcome the Poor Tabletability of a High Dose Drug.

Pharmaceutical tablet manufacturing has seen a paradigm shift toward continuous manufacturing and twin-screw granulation-based technologies have catalyzed this shift. Twin-screw granulator can simultaneously perform unit operations like mixing, granulation, and drying of the granules. The present study investigates the impact of polymer concentration and processing parameters of twin-screw melt granulation, on flow properties and compaction characteristics of a model drug having high dose and poor tabletability. Acetaminophen (AAP) and polyvinylpyrrolidone vinyl acetate (PVPVA) were used as a model drug (90-95% w/w) and polymeric binder (5-10%w/w), respectively, for the current study. Feed rate (~650-1150g/h), extruder screw speed (150-300rpm), and temperature (60-150°C) were used as processing variables. Results showed the reduction in particle size of drug in the extrudates (D90 of 15-25μm from ~80μm), irrespective of processing condition, while flow properties were a function of polymer concentration. Overall, good flowability of the products and their tablets with optimum tensile strength can be obtained through using high polymer concentration (i.e., 10% w/w), lower feed rate (~650g/h), lower extruder screw speed (150rpm), and higher processing temperatures (up to 120°C). The findings from the current study can be useful for continuous manufacturing of tablets of high dose drugs with minimal excipient loading in the final dosage form.

Impact of unloading kinematics on the occurrence of capping during the production of pharmaceutical tablets

Capping is a common defect that can occur during the manufacturing of pharmaceutical tablets. Several studies showed that decreasing the unloading speed of the manufacturing cycle plays a role in the occurrence of such defects. Following this idea, we study in this work the influence of the unloading step on capping using a compaction simulator.Measuring the die wall pressure made it possible to detect precisely that tablets capped just after the unloading (some milliseconds only). To evaluate the impact of the unloading speed on capping, we developed a two-step unloading phase controlled by three manufacturing parameters. It was possible to mitigate capping by decreasing the speed at which the contact between the punches and the tablet was lost. Capping seemed due to dynamical effects related to the release of the axial pressure. The modification of the unloading step to mitigate capping led to significant changes in tablet density but no clear trends were found for the residual die-wall pressure and tablet strength.This work made it possible to improve the understanding of capping. Moreover, the two-step unloading cycle gave a new idea for possible modifications that could be done on rotary presses in order to mitigate capping.

Investigating the Trade-Off between Design and Operational Flexibility in Continuous Manufacturing of Pharmaceutical Tablets: A Case Study of the Fluid Bed Dryer

Market globalisation, shortened patent lifetimes and the ongoing shift towards personalised medicines exert unprecedented pressure on the pharmaceutical industry. In the push for continuous pharmaceutical manufacturing, processes need to be shown to be agile and robust enough to handle variations with respect to product demands and operating conditions. In this paper we examine the use of operational envelopes to study the trade-off between the design and operational flexibility of the fluid bed dryer at the heart of a tablet manufacturing process. The operating flexibility of this unit is key to the flexibility of the full process and its supply chain. The methodology shows that for the fluid bed dryer case study there is significant effect on flexibility of the process at different drying times with the optimal obtained at 700 s. The flexibility is not affected by the change in volumetric flowrate, but only by the change in temperature. Here the method used a black box model to show how it could be done without access to the full model equation set, as this often needs to be the case in commercial settings.

System model driven selection of robust tablet manufacturing processes based on drug loading and formulation physical attributes

Mechanistic process modeling presents an opportunity to reduce experimental burden, enabling relationships between process parameters and product attributes to be mapped out using in-silico experiments. A system model of a pharmaceutical tablet manufacturing process comparing dry granulation with direct compression is developed to answer key material and process design questions. The system model links API physical properties and formulation to process parameters to map out the robust operating space. To demonstrate the application of the model, several drug product formulation design questions were considered:•Which processing route is the most robust given the API material properties and dosage requirements?•How does drug loading and tablet size impact the robustness of the manufacturing process?•What process settings are required for a robust manufacturing route for the API material properties and drug loading requirements?A computational framework was developed using the system models to generate process classification and design space maps to aid robust pharmaceutical formulation and process decision making. Process classification maps were produced to assess the feasibility of roller compaction and direct compression for different material properties and formulations. Constraints on the critical quality attributes of the intermediate and final products were defined using the Manufacturing Classification System. Design space maps presented here demonstrate how system models can be used to support formulation and process design. The design space maps illustrate how the process operating space can be increased or decreased as the API mass fraction is varied.The process design and selection system model demonstrate how an understanding of the API physical properties can be used to model the impact of formulation and process design. Furthermore, these models can be instrumental in the dialogue with colleagues developing the API in order to set the requirements of the API physical properties to ensure successful and robust formulation and process designs.

Computational Modeling of Drying of Pharmaceutical Wet Granules in a Fluidized Bed Dryer Using Coupled CFD-DEM Approach.

Drying of wet granules in a fluidized bed dryer is an important part of the pharmaceutical tablet manufacturing process. Complicated gas-solid flow patterns appear in the fluidized bed dryer, and interphase momentum, heat, and mass transfer happen during the drying process. A coupled computational fluid dynamics (CFD)-discrete element method (DEM)-based approach was used to model the drying process of pharmaceutical wet granules in a fluidized bed dryer. The evaporation of water from the surfaces of the particles and the cohesion force between the particles due to the formation of liquid bridges between the particles were also considered in this model. The model was validated by comparing the model predictions with the experimental data available from the literatures. The validated model was used to investigate the drying kinetics of the wet granules in the fluidized bed dryer. The results from numerical simulations showed that the dynamics and rate of increase of temperature of wet particles were considerably different from those of dry particles. Finally, the model was used to investigate the effects of inlet air velocity and inlet air temperature on the drying process. The model predicted increase in drying rate with the increase of inlet air velocity and inlet air temperature. This model can help not only to understand the multiphase multicomponent flow in fluidized bed dryer but also to optimize the drying process in the fluidized bed dryer.

Real-Time Monitoring of Powder Mass Flowrates for Plant-Wide Control of a Continuous Direct Compaction Tablet Manufacturing Process

While measurement and monitoring of powder/particulate mass flow rate are not essential to the execution of traditional batch pharmaceutical tablet manufacturing, in continuous operation, it is an important additional critical process parameter. It has a key role both in establishing that the process is in a state of control, and as a controlled variable in process control system design. In current continuous tableting line operations, the pharmaceutical community relies on loss-in-weight feeders to monitor and understand upstream powder flow dynamics. However, due to the absence of established sensing technologies for measuring particulate flow rates, the downstream flow of the feeders is monitored and controlled using various indirect strategies. For example, the hopper level of the tablet press is maintained as a controlled process output by adjusting the turret speed of the tablet press, which indirectly controlling the flow rate. This gap in monitoring and control of the critical process flow motivates our investigation of a novel PAT tool, a capacitance-based sensor (ECVT), and its effective integration into the plant-wide control of a direct compaction process. First, the results of stand-alone experimental studies are reported, which confirm that the ECVT sensor can provide real-time measurements of mass flow rate with measurement error within -1.8 ~ 3.3% and with RMSE of 0.1 kg/h over the range of flow rates from 2 to 10 kg/h. The key caveat is that the powder flowability has to be good enough to avoid powder fouling on the transfer line walls. Next, simulation case studies are carried out using a dynamic flowsheet model of a continuous direct compression line implemented in Matlab/Simulink to demonstrate the potential structural and performance advantages in plant-wide process control enabled by mass flow sensing. Finally, experimental studies are performed on a direct compaction pilot plant in which the ECVT sensor is located at the exit of the blender, to confirm that the powder flow can be monitored instantaneously and controlled effectively at the specified setpoint within a plant-wide feedback controller system.

Use of impulse excitation technique for the characterization of the elastic anisotropy of pharmaceutical tablets

Capping and lamination are common defects occurring during the manufacturing of pharmaceutical tablets. Several studies showed that tablet anisotropy can play a role in the occurrence of such defects. In this work, we propose a new and easy methodology to characterize the anisotropy of flat-faced cylindrical tablets, which are considered as transversally isotropic due to the process, through the study of their elastic properties using impulse excitation technique and finite-element method (FEM) simulations. The study was performed for tablets with a thickness-to-diameter-ratio between 0.160 and 0.222. FEM simulations showed that it was possible to determine three out of the five elastic constants of the tablet using the first three natural vibration modes. An anisotropic index was then built as the ratio of the two apparent shear moduli. Moreover, in order to simplify the estimation of tablet anisotropy and to avoid the systematic use of FEM simulations, an analytical model was also developed. It only requires the measurement of the tablet dimensions and of the first three natural frequencies. Using this technique, experimental measurements on tablets made of classical pharmaceutical excipients were done and found coherent with the existing literature. This indicates thus that this methodology is a quick, easy and reliable characterization method in order to access tablet anisotropy.

Development of a pilot-scale HuskyJet binder jet 3D printer for additive manufacturing of pharmaceutical tablets

This paper reports a custom-built binder jet 3D printer for pilot-scale manufacturing of pharmaceutical tablets. The printer is equipped with high-throughput piezoelectric inkjet print heads and allows direct control of several key process parameters, including the build layer thickness, amount of jetted liquid binder, and powder spreading rate. The effects of these parameters on the properties of the as-printed tablets were studied using a powder mixture of lactose monohydrate and Kollidon® VA64 (KL) and an aqueous binder containing 5% of KL. The appropriate processing windows for two different powder spreading rates were identified, and the final properties of the printed samples were explained using a dimensionless “degree of overlap” parameter which is defined as the ratio between the penetrating depth of the binder into the powder and the build layer thickness. Lastly, 10% of indomethacin was added to the powder feedstock as a model drug. Drug-loaded tablets were produced at a rate of 32 tablets/min, having an average breaking force of 9.4 kgf, a friability of 2.5%, and an average disintegration time of 8 s. These properties are comparable to commercially available tablets and represent one of the best values reported in the literature of 3D printed tablets thus far.

Evaluation of the drying methods influences on the flowability of multi-components formulation

Powder flowability is an important aspect to have effectual and productive manufacturing of pharmaceutical tablets. Therefore, this study compared the flowability behaviour in terms of Carr index (C I ) and Hausner ratio (Hr) of multi-components formulation of naproxen sodium which dried using different drying techniques. A wet formulation of naproxen sodium, microcrystalline cellulose, and polyvinylpyrrolidone was prepared and subjected to microwave drying and three conventional drying techniques - freeze drying, convective drying and vacuum drying. This study revealed that microwave and freeze drying granules were of the highest C I and Hr with possible flowability, while a vacuum and convective drying had the lower C I and Hr with fair flowability. Modelling the correlation between flowability factors and dried samples were presented. The variability in the particle size and the specific surface area of the dried granules showed significant effects on C I and Hr thereby powder flowability. Although the influences of the drying process on the drug powder flowability were indirect, drying method can improve or degrade the textural properties of resultant dried granules such as particle size, specific surface area, moisture content, friability and degree of amorphous/crystallinity and consequently change their flowability.

Effect of material properties on the residence time distribution (RTD) of a tablet press feed frame.

In continuous manufacturing (CM) of pharmaceutical tablets, the residence time distribution (RTD) of the tablet press feed frame plays an important role in ensuring the critical quality attributes (CQAs) of the final product. Knowledge of factors affecting the RTD of the feed frame is necessary for sufficient RTD model development. The aim of this work is to investigate the effect of material properties on the mean residence time (MRT) and the lag time. Seven materials with different powder properties were used and the tracer concentration as a function of time were obtained. The RTD model obtained by tracer experiments is approximated using a plug flow reactor (PFR) and a continuous stirred tank reactor (CSTR). The loading plots of principle component analysis (PCA) indicated that the powder bulk density is correlated with the RTD model parameters. Therefore, we focus on establishing the relationship between the bulk density and the MRT. As a result, a linear correlation is obtained to describe the relation between the MRT and the powder bulk density. The simulated results show that the material with lower bulk density had higher risk of producing out-of-specification (OOS) products in comparison to higher bulk density powders.

Role of Precompression in the Mitigation of Capping: A Case Study

Capping is an important industrial problem that can arise during the manufacturing of pharmaceutical tablets. It corresponds, for biconvex tablets, to the detachment of one of the cups of the tablet during the ejection from the press or after relaxation. Solutions to this problem remain mainly empirical. Among them, precompression is widely used.One of the most popular explanation of the role of precompression in the mitigation of capping is that it increases the total time under compression. Following this interpretation, press manufacturers developped devices or machines that make it possible to maintain the pressure between precompression and main compression.In this note, we present a case study of capping. For the formulation proposed, a precompression that was maintained until the compression gave similar results as no precompression at all, i.e. capping of all the tablets. On the contrary, if the precompression was released before compression, capping stops completely. In this case, the effect of precompression is thus due to the separation of two compression events. Moreover, results prove that this separation must last long enough for the precompression to be efficient. This example shows that effect of precompression is more complex than often described in the literature.

Characterization and modeling of the viscoelasticity of pharmaceutical tablets.

Evolution of the compaction properties of powders with the compaction speed (strain rate sensitivity, SRS) is a common phenomenon during the manufacturing of pharmaceutical tablets. Nevertheless, several different phenomena can be responsible of the SRS like friction, viscoelasticity, viscoplasticity or air entrapment. In this work, an original experimental methodology was developed to characterize specifically the viscoelasticity of tablets using a compaction simulator. After various compressions, tablets were finally loaded elastically at different constant strain rates. This methodology made it possible to measure the apparent bulk and shear moduli as a function of the strain rate. The methodology was successfully applied to microcrystalline cellulose (MCC), Starch, Lactose monohydrate (GLac) and Anhydrous Calcium Phosphate (ACP). No significant evolution of the moduli was found for Lac and ACP as expected. On the contrary, for MCC and Starch, both shear and bulk moduli were found to increase along with the strain rate. The viscoelastic behavior was then successfully modeled using prony series. Assessment of the model parameters was achieved by inverse identification using an analytical model and a finite element analysis.

Review of real-time release testing of pharmaceutical tablets: State-of-the art, challenges and future perspective.

In the last decade significant advances have been made in process analytical technologies and digital manufacturing of pharmaceutical oral solid dosage forms leading to enhanced product knowledge and process understanding. These developments provide an excellent platform for realising real-time release testing (RTRT) to eliminate all, or certain, off-line end product tests assuring that the drug product is of intended quality. This review article presents the state of the art, an RTRT development workflow as well as challenges and opportunities of RTRT in batch and continuous manufacturing of pharmaceutical tablets. Critical quality attributes, regulatory aspects and the scientific basis of enabling technologies and models for RTRT are discussed and a systematic development workflow for the robust design of an RTRT environment is presented. This includes the discussion of key considerations for the identification of the critical quality attributes and points of testing as well as the development of the sampling strategy, a hard and/or soft sensor approach and operational procedures. The final sections present two RTRT use cases in an industrial setting as well as critically discuss challenges and provide a future perspective of RTRT.

Characterization of Near-Infrared and Raman Spectroscopy for In-Line Monitoring of a Low-Drug Load Formulation in a Continuous Manufacturing Process.

Reflectance spectroscopy is an excellent candidate for process analytical technology (PAT) applications in continuous manufacturing of pharmaceutical tablets. Spectroscopic methods provide a real-time, nondestructive measurement of the active pharmaceutical ingredient (API) concentration in order to ensure product quality and uniformity. Of particular challenge is the powder blends with low drug loads (<5% w/w) where the measurement of the signal-to-noise and, in turn, precision limit the ability of the method. We evaluate both near-infrared (NIR) and Raman spectroscopy for use in PAT applications by measuring pharmaceutical blends of varying active ingredient concentrations. Both spectrometers are equipped with a fiber-optically coupled probe head for noncontact measurement of powder blends. A mockup of the interface between the spectrometer and powders within the feed frame of a rotary tablet press is used to simulate the movement of powder blends from the mixer to the press. A port on the feed frame allows measurement by NIR or Raman spectroscopy of the blends just before tablet compression. For our model compound, Raman spectroscopy is shown to have a lower limit-of-detection and less day-to-day variability than NIR spectroscopy. Raman spectroscopy was chosen as the PAT platform to support process development, and working distance and spot size were both optimized for use in the feed-frame of a tablet press. Sufficient limit-of-detection was achieved for monitoring active pharmaceutical ingredient concentrations (API) down to 1% w/w during a semicontinuous manufacturing of tablets. An innovative optimization-based model (EIOT) was used to trend API concentration and demonstrated that the process could be capable of detecting out-of-trend material.

Dynamic Flowsheet Model Development and Sensitivity Analysis of a Continuous Pharmaceutical Tablet Manufacturing Process Using the Wet Granulation Route

In view of growing interest and investment in continuous manufacturing, the development and utilization of mathematical model(s) of the manufacturing line is of prime importance. These models are essential for understanding the complex interplay between process-wide critical process parameters (CPPs) and critical quality attributes (CQAs) beyond the individual process operations. In this work, a flowsheet model that is an approximate representation of the ConsiGma TM -25 line for continuous tablet manufacturing, including wet granulation, is developed. The manufacturing line involves various unit operations, i.e., feeders, blenders, a twin-screw wet granulator, a fluidized bed dryer, a mill, and a tablet press. The unit operations are simulated using various modeling approaches such as data-driven models, semi-empirical models, population balance models, and mechanistic models. Intermediate feeders, blenders, and transfer lines between the units are also simulated. The continuous process is simulated using the flowsheet model thus developed and case studies are provided to demonstrate its application for dynamic simulation. Finally, the flowsheet model is used to systematically identify critical process parameters (CPPs) that affect process responses of interest using global sensitivity analysis methods. Liquid feed rate to the granulator, and air temperature and drying time in the dryer are identified as CPPs affecting the tablet properties.