ABSTRACT
Twin-screw wet granulation (TSG) is a continuous manufacturing technique either for granules as final dosage form or as an intermediate before tableting or capsule filling. A comprehensive process understanding is required to implement TSG, considering various parameters influencing granule and tablet quality. This study investigates the impact of screw configuration on granule properties followed by tableting, using a systematic approach for lactose-microcrystalline cellulose (lactose-MCC) and ibuprofen-mannitol (IBU) formulations. The most affecting factor, as observed by other researchers, was the L/S ratio impacting the granule size, strength and tabletability. Introducing tooth-mixing-elements at the end of the screw, as for the IBU formulation, resulted in a high proportion of oversized granules, with values between 36% and 78%. Increasing the thickness of kneading elements (KEs) produced denser, less friable granules with reduced tablet tensile strength. Granulation with more KEs, larger thickness or stagger angle increased torque values and residence time from 30 to 65 s. Generally, IBU granules exhibited high tabletability, requiring low compression pressure for sufficient tensile strength. At a compression pressure of 50 MPa, IBU tablets where at least one kneading zone was included resulted in approximately 2.5 MPa compared to lactose-MCC with 0.5 MPa. In conclusion, the TSG process demonstrated robustness by varying the screw design with minimal impact on subsequent tableting processes.
ABSTRACT
The barrel fill level is defined as the fraction of the free available volume for a given screw configuration that is occupied by the wet material and is an interplay of the material throughput, screw speed, screw setup, barrel length of the twin-screw granulator used and the properties of the starting material. The fill level has a major impact on mixing and densification of the wetted mass and thus on the granules produced. It influences the twin-screw granulation process accordingly. In the current study, a model has been developed which is predictive in terms of material hold-ups in the barrel at various process settings by considering the geometries of the different screw elements in a configuration and the conveying velocity of the wet mass through the barrel. The model was checked on two granulators of different dimensions with various screw configurations, different materials and at different process settings. The model represents a step forward in predicting the barrel fill level but further research with a broader spectrum of materials, screw configurations and process settings is still needed and additional twin-screw granulators of other dimensions must be investigated.
ABSTRACT
Real-time monitoring of critical quality attributes, such as residual water in granules after drying which can be determined through loss-on-drying (LOD), during wet granulation and drying is essential in continuous manufacturing. Near-infrared (NIR) spectroscopy has been widely used as process analytical technology (PAT) for in-line LOD monitoring. This study aims to develop and apply a model for predicting the LOD based on process parameters. Additionally, the efficacy of an orthogonal PAT approach using NIR and mass balance (MB) for a vibrating fluidized bed dryer (VFBD) is demonstrated. An in-house-built, cost-effective NIR sensor was utilized for measurements and exhibited good correlation compared to standard method via infrared drying. The combination of NIR and MB, as independent methods, has demonstrated their applicability. A good correlation, with a Pearson r above 0.99, was observed for LOD up to 16 % (w/w). The use of an orthogonal PAT method mitigated the risk of false process adaption. In some experiments where the NIR sensor might have been covered by powder and therefore did not measure accurately, LOD monitoring via MB remained feasible. The developed model effectively predicted LOD or process parameters, resulting in an R2 of 0.882 and a RMSE of 0.475 between predicted and measured LOD using the standard method.
ABSTRACT
Only few excipients are known to be suitable as pelletization aids. In this study, the potential use of croscarmellose sodium (CCS) as pelletization aid was investigated. Furthermore, the impact of cations on extrusion-spheronization (ES) of CCS was studied and different grades of CCS were tested. The influence of different cations on the swelling of CCS was investigated by laser diffraction. Mixtures of CCS with lactose monohydrate as filler with or without the inclusion of different cations were produced. The mixtures were investigated by mixer torque rheometry and consequently extruded and spheronized. Resulting pellets were analyzed by dynamic image analysis. In addition, mixtures of different CCS grades with dibasic calcium phosphate anhydrous (DP) and a mixture with praziquantel (PZQ) as filler were investigated. Calcium and magnesium cations caused a decrease of the swelling of CCS and influenced the use of CCS as pelletization aid since they needed to be included for successful ES. Aluminum, however, led to an aggregation of the CCS particles and to failure of extrusion. The inclusion of cations decreased the uptake of water by the mixtures which also reduced the liquid-to-solid-ratio (L/S) for successful ES. This was shown to be dependent on the amount of divalent cations in the mixture. With DP or PZQ as filler, no addition of cations was necessary for a successful production of pellets, however the optimal L/S for ES was dependent on the CCS grade used. In conclusion, CCS can be used as a pelletization aid.
Subject(s)
Excipients , Particle Size , Excipients/chemistry , Drug Compounding/methods , Calcium Phosphates/chemistry , Lactose/chemistry , Chemistry, Pharmaceutical/methods , Cations/chemistry , Praziquantel/chemistry , Magnesium/chemistryABSTRACT
The influence of hydroxypropyl cellulose type (HPC-SSL SFP, HPC-SSL), concentration (2 %, 3.5 %, 5 %) and filler (lactose, calcium hydrogen phosphate (DCP)/microcrystalline cellulose (MCC)) on twin-screw wet granulation and subsequent tableting was studied. The aim was to identify the formulation of the highest tabletability which still fulfills the requirements of the disintegration. Lactose combined with 5 % binder enabled a higher tabletability and a faster disintegration than DCP/MCC. It was found that tabletability of lactose formulations can be increased by higher binder concentration and higher compression pressure while tabletability of DCP/MCC formulations can be only increased by higher compression pressure. It was observed that batches containing DCP/MCC failed the disintegration test, if the highest binder concentration and the highest compression pressure were used. To ensure a fast disintegration, the compression pressure or at least the binder concentration had to be low. Changing the disintegrant and its localization improved the DCP/MCC formulation, resulting in faster disintegration than lactose tablets. However, it also resulted in a lower tabletability. In this study best tablets were achieved with 3.5 % or 5 % binder and lactose as filler. These tablets presented the highest tabletability but still disintegrated in less than 500 s.
Subject(s)
Cellulose , Drug Compounding , Excipients , Lactose , Tablets , Cellulose/chemistry , Cellulose/analogs & derivatives , Lactose/chemistry , Excipients/chemistry , Drug Compounding/methods , Calcium Phosphates/chemistry , Chemistry, Pharmaceutical/methods , Pressure , SolubilityABSTRACT
The MCS initiative was first introduced in 2013. Since then, two MCS papers have been published: the first proposing a structured approach to consider the impact of drug substance physical properties on manufacturability and the second outlining real world examples of MCS principles. By 2023, both publications had been extensively cited by over 240 publications. This article firstly reviews this citing work and considers how the MCS concepts have been received and are being applied. Secondly, we will extend the MCS framework to continuous manufacture. The review structure follows the flow of drug product development focussing first on optimisation of API properties. The exploitation of links between API particle properties and manufacturability using large datasets seems particularly promising. Subsequently, applications of the MCS for formulation design include a detailed look at the impact of percolation threshold, the role of excipients and how other classification systems can be of assistance. The final review section focusses on manufacturing process development, covering the impact of strain rate sensitivity and modelling applications. The second part of the paper focuses on continuous processing proposing a parallel MCS framework alongside the existing batch manufacturing guidance. Specifically, we propose that continuous direct compression can accommodate a wider range of API properties compared to its batch equivalent.
Subject(s)
Excipients , Technology, Pharmaceutical , Excipients/chemistry , Technology, Pharmaceutical/methods , Pharmaceutical Preparations/chemistry , Chemistry, Pharmaceutical/methods , Drug Compounding/methods , Drug Industry/methodsABSTRACT
Process Analytical Technology (PAT) plays a crucial role in the design of today's manufacturing lines as continuous manufacturing becomes more important. Until now PAT tools to measure the ribbon solid fraction (SFribbon) in-line are not commonly used in roll compaction. The aim of this study was therefore to establish a new approach as PAT for in-line ribbon solid fraction determination. Different placebo formulations with different binders and one formulation containing active pharmaceutical ingredient were investigated using in-line laser triangulation measurement to detect the ribbon thickness after compaction. With this the ribbon elastic recovery was determined in-line (ERin-line) while the ribbons are attached to the roll surface. It was found that the ratio (ERratio) between the total elastic recovery and ERin-line is formulation specific and not influenced by any process parameters. This enables ERratio as prediction tool for SFribbon, if the solid fraction at gap (SFgap) width is known. SFgap was determined with ribbon mass flow measurement or based on the Midoux model, a simplified Johanson model, gaining two prediction models for SFribbon. Both models showed good agreement of the predicted SFribbon and the measured one.
Subject(s)
Lasers , Technology, Pharmaceutical , Drug Compounding , Tablets , Powders , Particle SizeABSTRACT
The tableting process involves the conversion of mechanical to thermal energy. This study evaluated the influence of temperature on the tableting behavior of formulations with different compositions. The tableting machine was equipped with a thermally controlled die to mimic the heat evolution from tableting on an industrial scale. Six formulations containing binders with a comparably low glass transition temperature were examined. Besides the polymer type and concentration, the filler was varied. Paracetamol was chosen as the model active pharmaceutical ingredient. The investigation included alterations in tabletability, disintegration and dissolution. Elevated temperatures led to an enhanced tabletability. The polymer type and concentration were decisive for the extent of alterations. The variation of the filler composition played a minor role due to the high melting points of its components. The results were confirmed in disintegration and dissolution studies. A high binding capacity and a low glass transition temperature resulted in a stronger delay of disintegration. The dissolution was sustained. Increased concentrations of the binding polymer enhanced the effect. If the tableting behavior of a formulation is changed by elevated temperatures during formulation development and production, a change of the binder type or concentration should be considered to ensure a reproducible tablet quality.
Subject(s)
Excipients , Hot Temperature , Temperature , Excipients/chemistry , Tablets/chemistry , PolymersABSTRACT
The focus of this study was to investigate the sensitivity of different drug formulations to differences in process parameters based on previously developed scale-up strategies. Three different formulations were used for scale-up experiments from a QbCon® 1 with a screw diameter of 16 mm and a throughput of 2 kg/h to a QbCon® 25 line with a screw diameter of 25 mm and a throughput of 25 kg/h. Two of those formulations were similar in their composition of excipients but had a different API added to the blend to investigate the effect of solubility of the API during twin-screw wet granulation, while the third formulation was based on a controlled release formulation with different excipients and a high fraction of HPMC. The L/S-ratio had to be set specifically for each formulation as depending on the binder and the overall composition the blends varied significantly in their response to water addition and their overall granulation behavior. Before milling there were large differences in granule size distributions based on scale (Earth Mover's Distance 140-1100 µm, higher values indicating low similarity) for all formulations. However, no major differences in granule properties (e.g. Earth Mover's Distance for GSDs: 23-88 µm) or tablet tensile strength (> 1.8 MPa at a compaction pressure of 200 MPa for all formulations with a coefficient of variation < 0.1, indicating high robustness for all formulations) were observed after milling, which allowed for a successful scale-up independent of the selected formulations.
Subject(s)
Excipients , Technology, Pharmaceutical , Particle Size , Solubility , Tablets , Drug CompoundingABSTRACT
During tablet manufacturing an increase in the production temperature can lead to an alteration of tablet characteristics. In the present study, the influence of the initial particle size on the tableting behavior of ductile polymers upon temperature rise was investigated. Different grades of the respective materials were tableted at temperatures ranging from 22 to 70⯰C. Alterations in tableting behavior were affected by the initial particle size. Smaller particle sizes led to a more pronounced decrease in yield pressure and net work of compaction during compressibility analysis. The results were confirmed in the tabletability studies. Tablets from binary mixtures with lactose containing smaller polymer particles yielded a stronger increase in tensile strength. Differences in the tensile strength increase of two grades from the same material correlated with the ratio of their median particle sizes. The alteration of compactibility profiles was also particle size dependent. The increase in solid fraction was more prominent for binary mixtures containing polymers with smaller particle sizes. However, the ratio of the median particle sizes of the compared grades showed no systematic effect. The results underline the importance of controlling the structural properties of a material carefully during formulation development and production. If a formulation responds to temperature variations, an increase in particle size might be beneficial to decrease its heat sensitivity.
Subject(s)
Excipients , Hot Temperature , Particle Size , Excipients/chemistry , Polymers , Tablets/chemistry , Tensile Strength , Drug CompoundingABSTRACT
Fully automated at-line terahertz time-domain spectroscopy in transmission mode is used to measure tablet porosity for thousands of immediate release tablets. The measurements are rapid and non-destructive. Both laboratory prepared tablets and commercial samples are studied. Multiple measurements on individual tablets quantify the random errors in the terahertz results. These show that the measurements of refractive index are precise, with the standard deviation on a single tablet being about 0.002, with variation between measurements being due to small errors in thickness measurement and from the resolution of the instrument. Six batches of 1000 tablets each were directly compressed using a rotary press. The tabletting turret speed (10 and 30 rpm) and compaction pressure (50, 100 and 200 MPa) were varied between the batches. As expected, the tablets compacted at the highest pressure have far lower porosity than those compacted at the lowest pressure. The turret rotation speed also has a significant effect on porosity. This variation in process parameters resulted in batches of tablets with an average porosity between 5.5 and 26.5%. Within each batch, there is a distribution of porosity values, the standard deviation of which is in the range 1.1 to 1.9%. Destructive measurements of disintegration time were performed in order to develop a predictive model correlating disintegration time and tablet porosity. Testing of the model suggested it was reasonable though there may be some small systematic errors in disintegration time measurement. The terahertz measurements further showed that there are changes in tablet properties after storage for nine months in ambient conditions.
ABSTRACT
The aim of this study was to compare different scale-up strategies in twin-screw wet granulation and investigate the impact of the selected strategy on granule and tablet properties for a defined formulation. For the scale-up, a granulation process was transferred from a QbCon® 1 with a screw diameter of 16 mm to a QbCon® 25 line with a screw diameter of 25 mm. Three different scale-up strategies were introduced based on differences in process parameters and their resulting effects on various aspects. such as the powder feed number as a surrogate for the barrel fill level or the circumferential speed. Both are highly dependent on screw diameter and screw speed (SS), while the barrel fill level also depends on the overall throughput. Granules produced on the larger scale were significantly larger due to the larger gap size in the granulator, however, these differences were eliminated after milling. Despite major differences in powder feed number, circumferential speed, overall throughput and SS, product properties for both tablets and granules were strikingly similar after milling on both scales and with all applied strategies. For the selected formulation the effect of varying liquid to solid ratio at the same scale was much higher than the differences between scale-up strategies. The results of this study are promising for future process scale-up from lab scale to production scale in twin-screw wet granulation, as they are indicating towards a robust granulation process leading to similar tablet properties afterwards.
Subject(s)
Bone Screws , Technology, Pharmaceutical , Powders , Particle Size , Temperature , Tablets , Drug Compounding/methods , Technology, Pharmaceutical/methodsABSTRACT
Twin-screw wet granulation offers the possibility to granulate continuously. A drying step after wet granulation is required to realize a full continuous manufacturing line. Aim of this study was to gain insights into the drying behavior of a continuous vibrated fluidized bed dryer intended for pharmaceutical research and development. A Design of Experiment was conducted to examine the influence of process parameters during the drying of granules using drying temperature, air flow, and vibration acceleration as factors. The obtained temperature and humidity profiles during the drying of lactose-MCC and mannitol granules displayed the first and second drying stage which is spatially resolved. With a higher drying temperature or higher air flow, the second drying stage was achieved earlier. An increase in vibration acceleration shortened the residence time and by this, the second drying stage was reached later at a lower granule temperature and thus higher residual moisture of the granules. Formulation-dependent impact of the drying parameters was observed as lactose-MCC led to smaller granules when increasing the temperature or air flow.
Subject(s)
Lactose , Vibration , Drug Compounding , Particle Size , Temperature , Technology, PharmaceuticalABSTRACT
The thermodynamic analysis of tablet formation includes the thermal and mechanical analysis during compression. The aim of this study was to evaluate alterations of force-displacement data upon temperature rise as an indicator for changed excipient properties. The tablet press was equipped with a thermally controlled die to imitate the heat evolution from tableting on an industrial scale. Six predominantly ductile polymers with a comparably low glass transition temperature were tableted at temperatures ranging from 22-70°C. Lactose served as a brittle reference with a high melting point. The energy analysis included the net and recovery work during compression, from which the plasticity factor was calculated. The respective results were compared to the changes in compressibility obtained via Heckel analysis. Elevated temperatures reduced the necessary work for plastic deformation for the ductile polymers, which was reflected in decreasing values for the net work of compaction and the plasticity factor. The recovery work slightly increased for the maximum tableting temperature. Lactose showed no response to temperature variations. Changes in the net work of compaction showed a linear correlation to the changes in yield pressure, which could be correlated to the glass transition temperature of a material. It is therefore possible to detect material alterations directly from the compression data, if the glass transition temperature of a material is sufficiently low.
Subject(s)
Excipients , Lactose , Temperature , Polymers , TabletsABSTRACT
Numerous studies elucidated material behavior based on compression analyses. Especially compressibility, compactibility and tabletability were in the focus of these investigations. In the present study, a comprehensive multivariate data analysis was performed using principal component analysis method. Twelve pharmaceutically used excipients were selected for direct compression tableting and subsequent evaluation of several compression analyses. Material properties, tablet properties, tableting parameters and parameters from compression analyses were used as input variables. The materials could successfully be grouped using principal component analysis. Of the tableting parameters, the compression pressure showed the greatest influence on the results. The tabletability was found to be the most important compression analysis in the material characterization. Compressibility and compactibility only played a minor role in the evaluation. Some important insights have been gained for a deeper understanding of the tableting process using the multivariate approach to evaluate the variety of compression data.
Subject(s)
Chemistry, Pharmaceutical , Excipients , Chemistry, Pharmaceutical/methods , Pressure , Multivariate Analysis , Tablets , Tensile Strength , Drug Compounding/methods , Particle SizeABSTRACT
The influence of localization (intragranular, split or extragranular) of three superdisintegrants (croscarmellose sodium, crospovidone, sodium starch glycolate) on granules and tablets after twin-screw granulation was studied. The aim was to find a suitable disintegrant type and disintegrant localization for lactose tablets manufactured with different hydroxypropyl cellulose (HPC) types. The disintegrants were found to decrease the particle size in granulation, where sodium starch glycolate had the lowest influence. The tablet tensile strength was not influenced strongly by the disintegrant type or localization. By contrast, the disintegration was dependent on the disintegrant type as well as the localization, where sodium starch glycolate performed worst. Intragranular croscarmellose sodium and extragranular crospovidone were identified as beneficial for chosen conditions because a satisfying tensile strength in combination with the fastest disintegration was found. These findings were achieved for one HPC type and the suitability of the best disintegrant-localization-combinations was confirmed for another two HPC types.
Subject(s)
Chemistry, Pharmaceutical , Povidone , Carboxymethylcellulose Sodium , Solubility , Excipients , TabletsABSTRACT
The determination of particle density is a critical part of material characterization regarding compression analyses. Helium pycnometry as the most commonly used method is criticized for different aspects. Most prominent is the susceptibility to errors when measuring water-containing powders. Alternative methods for determining particle density using compression data have already been described. However, a systematic investigation and evaluation is still missing. In this study, the methods by Sun and Krumme were investigated in detail regarding their robustness against variations in tableting settings. Twelve pharmaceutical excipients were tableted at five different settings to verify the applicability and sensitivity to changes in the experimental set-up. Both methods were found to be robust against influencing parameters from the experiments. A sufficiently high compression pressure to approach a constant density value of the corresponding material during tableting was considered to be an essential requirement for the performance of the methods. Brittle materials with high yield pressure were found to be unsuitable for the application of both methods. The method of Krumme gave small deviations to measurements of helium pycnometry for water-free materials. By using the tablet density after in-die elastic recovery, Krumme's method could be used for water-containing materials as well. The method of Sun was found to give significantly smaller values for particle density due to inclusion of slow elastic recovery.
Subject(s)
Chemistry, Pharmaceutical , Helium , Chemistry, Pharmaceutical/methods , Particle Size , Tablets , Pressure , Powders , Drug Compounding/methodsABSTRACT
Influence of the roll speed (RS) during roll compaction on ribbon, granule, tablet properties and its effect on the prediction of the ribbon solid fraction at-gap is often neglected or controversially discussed. The aim of this study was to investigate the effect of the RS systematically. Microcrystalline cellulose (MCC) and lactose were compressed at several maximum roll pressures (Pmax) and RS combinations using a gap-controlled roll compactor. The ribbon solid fraction after elastic recovery (SFribbon), granule size distribution and tabletability of the granules as well as the ribbon solid fraction at-gap (SFgap) were measured. The Midoux number (Mi), derived from the Johanson model, was used to predict the ribbon solid fraction at-gap (SFMi). The measured SFgap and the predicted SFMi lead to a prediction accuracy (PA) of the Midoux number. The results are highly dependent on the material used and the applied Pmax. Higher plasticity of the material leads to a reduction in SFribbon and granule size with increasing RS. However, this effect can be overcome or reduced by adjusting Pmax above the yield pressure of the used material. These results allow for higher roll speeds as a potential upscaling method in roll compaction. On the other side, the PA of the Midoux number was also reduced with increased RS for MCC and had no effect for lactose. Thus, RS seems to be an important factor in the prediction of roll compaction processes and prediction models should include RS as a parameter to improve their accuracy.
ABSTRACT
Tableting on an industrial scale is characterized by an increase in temperature, which is dependent on numerous factors. The aim of this study was to examine the glass transition temperature of frequently used polymers as a critical parameter on tablet properties. Tablets were produced in a tablet press equipped with a temperature-controlled die at four different temperatures ranging from 22 to 70 °C. While pure polymers were characterized for their temperature-dependent compressibility behavior using Heckel analysis, tableting was performed from binary blends containing lactose as a filler and the polymer to be examined (ratio 9:1). Tablets were characterized in terms of tabletability, compactibility and their correlation with the glass transition temperature. The decrease in mean yield pressure upon temperature rise could clearly be correlated to the glass transition temperature of a given polymer, whereby polymers with low glass transition temperatures proved to be more responsive to temperature changes. Tablet properties were equally affected by the applied temperature despite the low polymer content. Thus, polymers with higher glass transition temperatures should be preferred in a full-production scale to avoid an alteration of tablet characteristics, whereas polymers with lower glass transition temperatures could be advantageous if a change of material properties is desired.
Subject(s)
Excipients , Lactose , Temperature , Tablets , Polymers , Tensile Strength , Drug CompoundingABSTRACT
Continuous Manufacturing (CM) of drug products is a new approach in the pharmaceutical industry. In the presented paper, a GMP continuous wet granulation line for production of solid oral dosage forms was investigated in order to assess the system dynamics of the line and to define the best control and diversion strategy. The following steps were involved in the continuous process: dosing/feeding, blending, twin-screw wet granulation, fluid-bed drying, sieving and tableting. Two drug products with two different drug substances were compared during this study: one drug substance as model drug compound and one formulation of a currently evaluated commercial drug product. Several step tests in API concentration were performed in order to characterize the process flow and assess the process dynamics. API content was monitored in real time by Process Analytical Technologies (PAT) thanks to three Near Infrared (NIR) probes located along the process and measuring the API content after blender, after dryer and in the tablet press feed frame. The process parameter values were changed during production in order to detect the impact on the quality of the final product. An automatic residence time distribution (RTD) computation method has been developed in order automate the RTD calculation on the basis of process data to further define and monitor the system dynamics with the final aim of out of specification material diversion during the continuous production. The RTD has been seen as a process fingerprint: a change in the RTD values implies a change in the process.