Tablet Press Research Articles

Digital twin of a continuous direct compression line for drug product and process design using a hybrid flowsheet modelling approach

The pharmaceutical industry is continuously overcoming ways to reduce its development times to market and bring new medicines to patients with the highest quality standards faster. This can be achieved with continuous manufacturing and digital design by minimising the amount of active pharmaceutical ingredient (API) needed in drug product design, early project de-risking, and reducing the use of clinical manufacturing equipment, rework, and quality investigations. This paper presents the digital twin of a continuous direct compression line combining first-principles models, residence time distribution (RTD) models obtained from discrete element method (DEM) simulations, science of scale tools and data-driven models from process data in a hybrid flowsheet approach. The flowsheet predicts critical process parameters in the feeders, blender, and tablet press, and critical quality attributes, like tablet composition, weight, thickness, and hardness. It allows the study of the steady state operation in the design space, the impact of operating conditions, material and process parameters, and the dynamic response to disturbances. This is used to de-risk and optimise drug product and process development while reducing the number of experiments. The digital twin also has the potential to guide manufacturing runs and respond to new drug product market approval queries using flowsheet modelling.

Influence of temperature on the compression behavior of pharmaceutical excipients

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.

Automatic system dynamics characterization of a pharmaceutical continuous production line

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.

Effect of roll compaction pressure on the properties of high drug-loaded piracetam granules and tablets

Objective The aim of this study was to use an alternative granulation technique, solventless roll compaction, and to investigate the effect of the roll compaction pressure on the properties of granules and high-drug-loaded (80%, w/w) immediate release piracetam tablets. Significance Piracetam is commonly manufactured as high drug-loaded tablets by wet granulation with an aqueous binder solution. Due to its high solubility in water, the wet granulation process is largely susceptible to processing methods and can induce the uncontrolled polymorphic transition of piracetam as well as convert it into mono- and di-hydrates. Methods The blends, comprising piracetam, Kollidon® 30, and Avicel® PH-101 were roll compacted at 4, 5 and 13 MPa hydraulic pressure and calibrated using an industrial roll compactor. The resultant granules milled and raw piracetam was investigated with DSC. The resultant granules are mixed with Ac-Di-Sol®, Aerosil® 200 Pharma, and magnesium stearate to prepare tablets using an industrial tablet press at the same compression force and 25, 65, and 100 rpm. The obtained tablets were film coated with an aqueous dispersion of Opadry® II using a pilot-scale solid-wall pan coater. Results Roll compaction pressure influenced the polymorphic composition of piracetam, the granule properties and tablet mixture in relation to morphology, particle size, flowability, bulk and tapped density, as well as tablet hardness, tablet friability, disintegration, and dissolution. Conclusion This study showed that roll compaction can be successfully used for the preparation of highly water-soluble, highly drug-loaded piracetam film-coated tablets avoiding wet granulation pitfalls.

The Effect of Cellulose Nanofibers on the Manufacturing of Mini-Tablets by Direct Powder Compression.

Mini-tablets (MTs) contain a small amount of active pharmaceutical ingredients in one small tablet. MTs are advantageous because they can be fine-tuned according to the age and weight of pediatric patients and they are easy for children and the elderly to swallow. However, there are manufacturing concerns such as the difficulty in achieving both hardness and disintegration of a small tablet and it is difficult to keep the tablet weight and drug content consistent in MTs because the mold used for its production is special. In this study, we aimed to determine if an additive such as cellulose nanofibers (CNF), which has been studied in various fields in recent years, could be used to manufacture MTs without difficulties. In this study, an MT was manufactured using a rotary tableting press with a compression force of 2, 5, and 8 kN, and the weight variation, drug content variation, tensile strength, friability, disintegration time, and drug dissolution were evaluated. Of note, the tensile strength of MTs produced with a compression force of ≥5 kN was ≥1.3 MPa, which was comparable to that of an ordinary tablet with an 8 mm diameter and a hardness of ≥30 N. The disintegration time of the MT which was 20-30% CNF was ≤30 s at any compression force. MTs with CNF showed similar disintegration to MTs with other common disintegrants. Therefore, we found that CNF is a functional additive capable of manufacturing MTs by direct powder compression which has both strength and disintegration.

Slow-release agricultural pesticide formulations: state of the art

The need for a long-term sustaining of optimal concentrations of applied pesticides in the soil in agriculture resulted in the development of systems for controlled release of active substances. Such systems are based on the use of eco-friendly carrier materials that are harmless to plants, humans and environment. Inorganic substances (e.g., clays or alike substances), biodegradable polymers of natural or synthetic origin, blends of such polymers and their composites with inorganic fillers can be used as carriers. The deposited pesticides are released by diffusion or, in the case of systems based on biodegradable polymers, by degradation of the carrier. Inorganic carriers are usually impregnated with a pesticide. As for polymers, there is a wide range of methods for obtaining forms. Namely, these are the microsphere and nanoparticle formation, film casting, tablet pressing, form gelatinizing, and coprecipitation of a pesticide and a polymer from a solution. Co-extrusion of pesticides with polymers or their composites at temperatures below the degradation temperature of the components is another promising method for obtaining pesticide carriers.

Differentiating analytical error from sampling errors in PAT methods through variographic analysis

In variographic analysis the nugget effect provides an estimate of the total process measurement system error. The value of variographic analysis can be further increased by differentiating the analytical error from the sampling errors. The ratio of the minimum practical error (MPE) to the analytical error provides an estimate of the suitability and performance of a sampling system since the analytical error would still remain even if sampling errors could be completely eliminated. The sampling and analytical errors for four systems used to obtain 1-D lots of pharmaceutical powder blends is presented. The first studies were conducted with blends moving over a conveyor belt and with the feed-frame of a tablet press. The researchers then developed and patented a new stream sampler and chute for sampling and analysis of pharmaceutical powder blends. Near Infrared or Raman spectra were obtained as the powder blends flowed or moved and used to determine the drug concentration in the blends. Even though these methods do not require sample extraction and sample preparation in a laboratory, they are still subject to sampling errors which were estimated through the variographic analysis. The MPE was compared to the analytical error for these four systems. The results obtained show that it is often possible to reduce sampling errors to less than ten times the analytical error. These studies represent the first efforts to estimate and reduce sampling errors in the analysis of the powder blends used to manufacture the tablets that many patients take daily.

Experimental and numerical investigations of the RTD in a GEA ConsiGma CTL25 tablet press

A discrete element model (DEM) for the prediction of residence time distributions (RTD) in a tablet press operation is validated. To this end, a Design-of-Experiment (DoE) study was performed on the Courtoy Modul P tablet press, and RTD data was gathered using optical measurement of a tracer for various process conditions. Flowability and compressibility of the powder were measured and used for DEM calibration. DEM predictions for RTD exhibit an overall good agreement with DoE ground truth data. The highest relative error for mean residence time amounted to 10% and was observed for the low mass flow edge case. Further, a detailed investigation of the granular flow was carried out with a focus on dead flow regions and mixing behavior in the feed paddle region.

Pharmaceutical tablet compression: measuring temporal and radial concentration profiles to better assess segregation

Concentration monitoring inside a tablet press feed frame is important not only to assess the composition of the powder blend compressed into tablets but also to detect quality affecting phenomena such as powder segregation. Near infrared spectroscopy has been successfully used to monitor powder concentration inside the feed frame; however, so far, this methodology does not provide information on local spatial variability, since it probes a very small area of powder sample. Near infrared chemical imaging (NIR CI) has the potential to improve process monitoring because it can simultaneously acquire a plurality of spectra covering nearly the entire width of the feed frame, thereby making it possible to detect local variations in powder concentration. The present work uses both NIRS and NIR CI to monitor the concentration of Ibuprofen and Ascorbic acid in multi-component mock pharmaceutical blends flowing through the feed frame of an industrial tablet press. The concentrations of Ibuprofen and Ascorbic acid were successfully monitored in multi-component powder blends. NIR spectral wavelength ranges and pre-treatments were simultaneously optimized via a genetic algorithm. N-way PLS approach for concentration monitoring was found to be more suitable than regular PLS when analyzing spectral images and provided the ability to visualize spatial segregation.

RATIONALE OF THE COMPOSITION OF THE TABLET MASS FOR THE CREATION OF DISPERSIBLE TABLETS WITH BIOFLAVONOIDS

Abstract. In recent years, with diseases associated with chronic venous insufficiency, people have resorted to medications created on the basis of bioflavonoids and flavonoid complexes. However, most oral phleboprotectors, including flavonoids such as rutin, hesperidin, diosmin, have low biological availability, which is due to their low solubility in water. It is possible to increase bioavailability by using substances with a higher degree of micronization, as well as by complexing and using dosage forms with increased bioavailability. In this regard, the purpose of this work was to create a drug in the form of dispersible tablets containing rutin and hesperidin in combination with ascorbic acid as active components. Substances of rutin and hesperidin, ascorbic acid, a PE-5300V spectrophotometer, a stopwatch, scales, buckets, a manual press with pressure gauges of various sensitivity, a tablet press RTM-12, punches and a matrix with a diameter of 10 and 20 mm were used in the work. To determine the main indicators of tablet mixtures for dispersible tablets, 6 model compositions of tablet mixtures with different contents of gas-forming components, fillers, binders, moisture stabilizers, lubricants and flavor additives were made. In the course of a step-by-step study of technological, physico-chemical and organoleptic indicators of 6 model formulations, the approximate composition and technology of dispersible tablets were selected. The obtained results were recalculated taking into account the ranking of the measurements made. The integrated weighted average assessment of disintegration, crushing strength, ejection pressure, moisture resistance, organoleptic properties and sedimentation stability made it possible to select the final composition of the dispersed tablets. It is established that the maximum weighted average score belongs to the dispersed tablets obtained from tablet mixture No. 6.

The Development of Innovative Dosage Forms of the Fixed-Dose Combination of Active Pharmaceutical Ingredients.

The development of innovative forms of combination drugs is closely related to the invention of the multilayer tablet press, polymers for pharmaceutical applications, the hot-melt extrusion process, and 3D printing in the pharmaceutical industry. However, combining multiple drugs within the same dosage form can bring many physicochemical and pharmacodynamic interactions. More and more new forms of fixed-dose combinations (FDCs) have been developed due to work to overcome the incompatibility of active substances or to obtain different drug release profiles in the same dosage form. This review provides discussions of the application of various innovation formulation technologies of FDC drugs such as bilayer system, multilayer tablet, active film coating, hot-melt extrusion, and 3D printing, taking into account the characteristics of the key ingredients in the FDC formulation and presenting technological problems and challenges related to the development of combination drugs. Moreover, the article summarizes the range of dosage forms that have been made using these technologies over the past 30 years.

Use of Thermal Boron Technique to Determine Optimum Synthesis Parameters for Zirconium and Hafnium Diborides

Zirconium and hafnium diborides were synthesized. The process of obtaining zirconium and hafnium diborides was carried out by reduction of zirconium and hafnium dioxides with amorphous boron at high temperature in a vacuum furnace with a residual pressure of 10 Pa. The synthesis of metal diborides included the following stages: preparation of charge, pressing, annealing of tablets, milling, and classification. The initial components were mixed in a drum-type apparatus; an aqueous solution of polyvinyl alcohol was used as a plasticizer. Tableting was performed on an OYSTAR Manesty FlexiTab tablet press with a punch diameter of 13 mm at a pressure of 218.7 MPa. The thickness of the obtained tablets was 3 mm. The obtained tablets were annealed in a Nabertherm VHT/GR vacuum furnace. A graphite crucible with zirconium oxide or hafnium oxide backfill, respectively, was used for annealing. The furnace was vacuumized with a forevacuum pump to a residual pressure of 10 Pa. The morphology of ZrB2 and HfB2 particles was investigated using the QUANTA 200 3D electron and focused-beam system. The phase composition and structural parameters of the samples were investigated on a Shimadzu XRD-6000 diffractometer with Cu Kα radiation. We determined the optimal parameters for the synthesis of zirconia and hafnium diborides: the optimal temperature for the synthesis of zirconia diboride was 1800 оС, for the synthesis of hafnium diboride — 1850 оС, the heating rate was 8.5 оС/min. The highest yield of zirconium and hafnium diborides was achieved in samples with a molar ratio of MeO2:B = = 1:6 at a synthesis time of 60 minutes. The yield of metal diborides was 99%.The authors who contributed to this paper include V. I. Sachkov, R. A. Nefedov, R. O. Medvedev, A. S. Sachkova, D. A. Biryukov.The authors would like to thank the Tomsk Regional Centre of Shared Knowledge for their support of this research work. This research was funded by the Ministry of Education and Science of the Russian Federation under the Governmental Assignment no. FSWM-2020-0028.

Modelling the Compaction Step of a Platform Direct Compression Process

The ability to predict formulation behaviour at production scale during formulation design can reduce the time to market and decrease product development costs. However, it is challenging to extrapolate compaction settings for direct compression formulations between tablet press models during scale-up and transfer from R&D to commercial production. The aim of this study was to develop statistical process models to predict tablet tensile strength, porosity and disintegration time from compaction parameters (pre-compression and main compression force, and press speed), for three formulations, with differing deformation characteristics (plastic, brittle and elastic), on three tablet press models (one pilot-scale tablet press (KG RoTab) and two production-scale presses (Fette 1200i and GEA Modul P)). The deformation characteristics of yield pressure and elastic recovery were determined for the model placebo formulations investigated. To facilitate comparison of dwell time settings between tablet press models, the design of experiments (DoE) approach was 9 individual 16-run response surface DoEs (3 formulation × 3 press models), whose results were combined to create a polynomial regression model for each tablet property. These models predicted tablet tensile strength, porosity and disintegration time and enabled the construction of design spaces to produce tablets with specified target properties, for each formulation on each press. The models were successfully validated. This modelling approach provides an understanding of the compaction behaviour of formulations with varying deformation behaviour on development and commercial tablet press models. This understanding can be applied to inform achievable production rates at a commercial scale, during the formulation development.

Simulation of Powder Flow Behavior in an Artificial Feed Frame Using an Euler‐Euler Model

AbstractThe Eulerian approach is an alternative numerical method to the traditionally used discreet particle techniques for modeling powder flow, avoiding limitations on particle number and diameter. The feasibility of an Euler‐Euler simulation in a pharmaceutical application was investigated. In two‐ and three‐dimensional flow simulations, computational fluid dynamics models and parameters were determined and verified based on comparison with experiments. Residence time distributions were calculated to show the applicability of the Eulerian model with two granular phases under the constraint of a continuous setup. Finally, this model was implemented to improve the process understanding of the powder flow in an artificial feed frame of a rotary tablet press.

Effect of feed frame on lubricant sensitivity during upscaling from a compaction simulator to a rotary tablet press

Internal lubrication can be associated with reduced tabletability. Deformation mechanism, lubricant type, lubricant blending time and paddle speed (PS) of the forced feeder are known to be influenceable factors. This study investigated the effect of lubricant blending time and PS of forced feeders on the tensile strength of lubricated microcrystalline cellulose (MCC) and lactose tablets. Magnesium stearate (MgSt), sodium stearyl fumarate (SSF) and stearic acid (SA) were used as lubricants. Tablets were produced on a compaction simulator and a rotary tablet press to investigate lubricant sensitivity during upscaling. Lubricant sensitivity was found higher for MCC compared to lactose which was attributed to the higher plasticity of MCC. The reduction in tensile strength upon lubricant addition followed the order: MgSt > SSF > SA; which could be linked to particle size, specific surface area and particle shape of the lubricants. Although differences in tensile strength were observed between the lubricant types, comparable ejection forces were obtained. The impact of PS on tensile strength was higher compared to lubricant blending time for both tableting machines. A good correlation of tensile strength and lubricant sensitivity between the compaction simulator and rotary tablet press was observed based on the calculation of paddle passes (NPP).

Tracking raw material flow through a continuous direct compression line Part I of II: Residence time distribution modeling and sensitivity analysis enabling increased process yield

Continuous manufacturing (CM) offers advantages in quality and space–time yield compared to common batch manufacturing. However, higher yield losses due to the start-up procedure make a broad application uneconomical. This work discusses the possibility of reducing yield losses by adjusting the degree of back-mixing. Back-mixing of nonconforming material from disturbances or start-up will result in the contamination of subsequent material. Therefore, higher degrees of back-mixing cause the discharge of additional material. Choosing an advantageous setting of operational parameters may be a simple way to change the degree of back-mixing. Based on direct compression, this work demonstrates the identification of promising parameters. Therefore, step-change experiments using color-marked material in the feeder, blender, and tablet press quantify the impact of three operational parameters per device. Models for the devices and the entire process result from those measurements. Subsequently, a global variance-based sensitivity analysis identifies the most influential parameters. As a result, adjusting the minimal filling level of the feeder and the rotational feed frame speed of the tablet press reduces back-mixing by more than 30 %. At high costs of the raw materials, the resulting savings can significantly improve the economic performance of CM compared to batch manufacturing.

Application of MHE-based NMPC on a Rotary Tablet Press under Plant-Model Mismatch

Active control strategies play a vital role in modern pharmaceutical manufacturing. Automation and digitalization are revolutionizing the pharmaceutical industry and are particularly important in the shift from batch operations to continuous operation. Active control strategies provide real-time corrective actions when departures from quality targets are detected or even predicted. Under the concept of Quality-by-Control (QbC), a three-level hierarchical control structure can be applied to achieve effective setpoint tracking and disturbance rejection in the tablet manufacturing process through the development and implementation of a moving horizon estimation-based nonlinear model predictive control (MHE-NMPC) framework. When MHE is coupled with NMPC, historical data in the past time window together with real-time data from the sensor network enable model parameter updating and control. The adaptive model in the NMPC strategy compensates for process uncertainties, further reducing plant-model mismatch effects. The frequency and constraints of parameter updating in the MHE window should be determined cautiously to maintain control robustness when sensor measurements are degraded or unavailable. The practical applicability of the proposed MHE-NMPC framework is demonstrated via using a commercial scale tablet press, Natoli NP-400, to control tablet properties, where the nonlinear mechanistic models used in the framework can predict the essential powder properties and provide physical interpretations.

FORMULATION AND DEVELOPMENT OF SUSTAINED RELEASED GLICLAZIDE TABLETS WITH THE DIFFERENT HYDROPHILIC POLYMER BY USING DIRECT COMPRESSION

To effectively manage the diabetic mellitus type-II hyperglycemic problem, Gliclazide tablet is the sustained- release tablet that has been designed and fabricated for years. This research evaluated the effects of different grades of hydrophilic polymers in sustained release of Gliclazide tablets made with direct compression technique. HPC GF GRADE, HPMC K4M, and PARTECK® SRP 80 were used as the polymer, Avicel pH 101 (MCC) was used as the highly compressible diluent and Starch 1500 was used as insoluble tablet filler. Aerosil 300 and Magnesium Stearate was used as a Glidant and lubricant for improving the flow property of powder and to decrease the friction between dying wall and punches. Pre-compression characteristics were evaluated for angle of repose, bulk density, compressibility, tapped density, and Hausner's ratio and DSC, XRD, FT-IR. Tablets were prepared on a rotary tablet press machine (Eliza press) and after compression tablets were evaluated for weight variation, thickness, hardness, friability, drug content, and in-vitro drug release study. The physico-chemical properties of blends were estimated accelerated stability study was also developed formulations were kept for stability study for three months as per ICH guidelines and found to be stable. Advantages of formulating insoluble drugs such as Gliclazide is that if it is used in the preparation of capsules or tablets of the drug,its dose might be reduced which is economically beneficial.

Study of the technological properties of excipients in the development of the composition of orally dispersible tablets

Introduction. The article presents the results of studying the technological properties of individual excipients widely used in the compositions of existing orally dispersed tablets (ODT) for subsequent planning a multifactorial experiment. Samples of excipients were analyzed according to such pharmacopoeial indicators as description, flowability, bulk density, compressibility, fractional composition, solubility in water.Aim. The aim of the work is to create a list and study the technological properties of candidate substances for the role of auxiliary substances in the composition being developed by the ODT.Materials and methods. The technological properties of excipient samples were studied according to the methods of the State Pharmacopoeia of the XIV edition using the flowability tester GTL (ERWEKA, Germany), the bulk density tester SVM 221 (ERWEKA, Germany), the tablet press PGR-10 (LabTools, Russia) and the tablet hardness tester TBH 125 TDP (ERWEKA, Germany).Results and discussion. As a result of the study, experimental data on the technological properties of excipient samples were collected, and the selected samples were compared according to pharmaceutical and technological indicators.Conclusion. In the course of the study, a list of auxiliary substances for the development of the composition of ODT was formed and studies of their technological properties were carried out. The obtained experimental data will allow to develop an optimal matrix of a multifactorial experiment for the development of the composition of ODT and justify the choice of excipients.

NIR spectroscopic methods for monitoring blend potency in a feed frame - calibration transfer between offline and inline using a continuum regression filter

A material sparing method for near-infrared (NIR) calibration was developed using an offline apparatus coupled with a calibration transfer method to enable a partial least squares (PLS) model to monitor the concentration of active pharmaceutical ingredients (API) in the feed frame of a rotary tablet press. The offline apparatus was designed to simulate the powder flow dynamic and NIRS measurement environment of a tablet-press feed frame. A comprehensive experimental design, including calibration and testing, was employed to determine blend inhomogeneity. NIR spectra were collected at both the feed frame (inline) conditions and the simulator (offline) conditions. The simulator conditions were designed to mimic the density and powder flow in the feed frame during the actual tableting process. The offline data were pretreated by an orthogonalization-based calibration transfer algorithm, a continuum regression filter (CR filter), before being subjected to PLS modeling. This study demonstrated: (1) calibration for inline application can be generated using an offline apparatus, and (2) the CR filter, as an innovative calibration transfer method, can generalize the offline method for multiple feed frame conditions.