Drying capacity of a continuous vibrated fluid bed dryer - Statistical and mechanistic model development.

The drying capacity of a continuous vibrated fluid bed dryer was studied using a DoE by varying microcrystalline cellulose content in the formulation, water amount in the twin-screw granulation, inlet air temperature, air flow rate and the acceleration of the horizontal fluid-bed. Temperature and humidity profiles were measured along the dryer using wireless sensors. For the parameter space explored in this study, acceleration was the most influential process parameter of the dryer regarding the resulting granule moisture content. An empirical model was developed that allowed for fast and accurate moisture content prediction that could be incorporated into an enhanced control strategy. In addition, a mechanistic model was formulated that allow for prediction of temperature and moisture profiles, and most importantly the moisture content of the granules inside the dryer. The mechanistic model can be integrated to other unit operation models to provide overall understanding of an integrated continuous process line. The mechanistic model also makes it possible to define the equipment design requirements (e.g., length of the dryer) to meet the specific needs in terms of drying capacity, temperature and moisture profile.

Bench to batch: Linking pharmaceutical powder flow characterisation, intermediate bulk container discharge and video observations.

Five well known excipients and a model drug substance with varied particle properties and bulk behaviour were chosen for the study. Based on the results APAP, NaCMC-XL, mannitol and DCPA were selected for a design to understand the impact of different blends. Two pilot scale unvented IBCs were used in the study. The IBC discharge rates were measured using a catch balance and the mode of flow and powder behaviour inside the IBC was recorded using a camera. The videos inside the IBC showed that regardless of flow mode, for powder to flow from the IBC an air burst was necessary. This was similar to observations when emptying water from a bottle. The extent of the air flow inside the IBC was strong and could possibly result in fluidisation segregation. The discharge curves of 15° and 30° hopper half angles were very similar, which was explained by the vertical air movement in the steeper hopper, which reduces the particle acceleration. Several good indicators of flow/no flow in the IBCs were found. However, for predicting the discharge rate there was a linear correlation between flow through an orifice and IBC discharge rate.

Modelling the effect of L/S ratio and granule moisture content on the compaction properties in continuous manufacturing.

The pharmaceutical field is currently moving towards continuous manufacturing pursuing reduced waste, consistency, and automation. During continuous manufacturing, it is important to understand how both operating conditions and material properties throughout the process affect the final properties of the product to optimise and control production. In this study of a continuous wet granulation line, the liquid to solid ratio (L/S) and drying times were varied to investigate the effect of the final granule moisture content and the liquid to solid ratio on the properties of the granules during tabletting and the final tensile strength of the tablets. Both variables (L/S and granule moisture) affected the tablet tensile strength with the moisture content having a larger impact. Further analysis using a compaction model, showed that the compactability of the granules was largely unaffected by both L/S and moisture content while the compressibility was influenced by these variables, leading to a difference in the final tablet strength and porosity. The granule porosity was linked to the L/S ratio and used instead for the model fitting. The effect of moisture content and granule porosity was added to the model using a 3d plane relationship between the compressibility constant, the moisture content and porosity of the granules. The tablet tensile strength model, considering the effect of moisture and granule porosity, performed well averaging a root mean squared error across the different conditions of 0.17 MPa.

Effect of shape on the physical properties of pharmaceutical tablets.

Despite a well-established process understanding, quality issues for compressed oral solid dosage forms are frequently encountered during various drug product development and production stages. In the current work, a non-destructive contact ultrasonic experimental rig integrated with a collaborative robot arm and an advanced vision system is presented and employed to quantify the effect of the shape of a compressed tablet on its mechanical properties. It is observed that these properties are affected by the tablet geometric shapes and found to be linearly sensitive to the compaction pressures. It is demonstrated that the presented approach significantly improves the repeatability of the experimental waveform acquisition. In addition, with the increased confidence levels in waveform acquisition accuracy and corresponding pressure and shear wave speeds due to improved measurement repeatability, we conclude that pharmaceutical compact materials can indeed have a negative Poisson's ratio, therefore can be auxetic. The presented technique and instrument could find critical applications in continuous tablet manufacturing, and its real-time quality monitoring as measurement repeatability has been significantly improved, minimizing product quality variations.

Faster to First-time-in-Human: Prediction of the liquid solid ratio for continuous wet granulation.

In early development, when active pharmaceutical ingredient (API) is in short supply, it would be beneficial to reduce the number of experiments by predicting a suitable L/S ratio before starting the product development. The aim of the study was to decrease development time and the amount of API needed for the process development of high drug load formulations for continuous twin-screw wet granulation (TSWG). Mixer torque rheometry was used as a pre-formulation tool to predict the suitable L/S ratios for granulation experiments. Three different values that were based on the MTR curves, were determined and assessed for their ability to predict the suitable L/S ratio for TSWG. Three APIs (allopurinol, paracetamol and metformin HCl) were used as model substances in high drug load formulations containing 60% drug substance. The MCC-mannitol ratio was varied to assess the optimal composition for the high-dose formulations. The API solubility affected the mixer torque rheometer (MTR) curves and the optimum L/S ratio for TSWG. The highly soluble metformin needed a much lower L/S ratio compared with allopurinol and paracetamol. A design space was determined for each API based on granule flowability and tablet tensile strength. The flowability of the granules and tensile strength of the tablets improved with an increasing L/S ratio. The MCC-mannitol filler ratio had a significant effect on tabletability for paracetamol and metformin, and these APIs having poor compaction properties needed higher MCC ratios to achieve the 2 MPa limit. The MCC-mannitol ratio had no effect on the granule flow properties. Instead, API properties had the largest influence on both granule flow properties and tensile strength. Based on this study, both the L/S ratio and MCC-mannitol ratio are crucial in controlling the critical quality attributes in high drug load formulations processed by TSWG. The optimum flow and tablet mechanical properties were achieved when using 75:25 MCC-mannitol ratio. Both start of the slope and 2/3 of the L/S ratio at the maximum torque in MTR provided a solid guideline to aim for in a TSWG experiment.

Powder flow from an intermediate bulk container - Discharge predictions and experimental evaluation.

Powders are usually dispensed, blended, and transferred between different manufacturing steps in so-called Intermediate Bulk Containers (IBCs), and discharge from an IBC plays a critical role in the ability to manufacture high-quality tablets. To better understand IBC discharge, the flow behavior of selected excipients was comprehensively characterized using a number of techniques including the Hausner ratio/Carr's index, Erweka flow test, FlowPro flow test, shear test and wall friction test as well as FT4 powder rheometer experiments. Jenike's hopper design methodology was then used to predict the minimum non-arching outlet diameter and the mode of flow. Furthermore, the discharge rate from an IBC was predicted using a simple model that takes into account gravity and aerodynamic drag. The predictions were experimentally verified by measuring the discharge rate from a 20 L IBC using five commonly-used excipients. The small-scale Erweka flow test provided the best prediction of the full-scale IBC discharge experiment. Furthermore, a simple model that relied only on the particle size of the material and the diameter of the discharge opening was found to predict the IBC discharge rate remarkably well.

Optical porosimetry by gas in scattering media absorption spectroscopy (GASMAS) applied to roller compaction ribbons.

Currently, there is a need for new technology for in-line or fast at-line assessment of solid material porosity. One specific gap is a fast technology to be used in connection to roller compaction (RC) manufacturing, where the porosity of the RC ribbons is critical to the manufacturing of tablets of the right tensile strength and disintegration properties. In this paper, the development of an at-line technology for fast, non-destructive assessment of porosity of RC ribbons is reported. The technology is based on a diode laser spectroscopic technique called Gas in scattering media absorption spectroscopy (GASMAS). GASMAS measures the sample voids by laser light, giving the distance through air. The total distance the light travels is measured using time-of-flight spectroscopy (TOFS). The ratio of these measures gives an "optical porosity", which through theory relates to the porosity of the sample. We present a description of the technology, evaluations of measurement robustness and results from an experimental design where roller compactor, roll force, roll gap and formulation were varied. It is concluded that the data from two different pharmaceutical formulations is supported by the same calibration curve, which indicates that optical porosimetry is a general technique for pharmaceutical materials that does not require frequent calibrations.

Twin-screw granulation and high-shear granulation: The influence of mannitol grade on granule and tablet properties.

Granule structure has a key influence on tablet critical quality attributes. The ability to control this structure through excipient choice is an important part of formulation development. Mannitol is a popular diluent and the choice of input grade has been shown to impact granule properties. Allopurinol formulations containing two grades of mannitol (Pearlitol 160C and 200SD) were prepared by wet-granulation (twin-screw and high-shear) at different liquid/solid ratios (0.3 and 0.6 g/g). The particle and bulk properties were characterised by a range of techniques and linked to flow performance and tablet tensile strength during compression on a rotary tablet press. During granulation, 200SD underwent a polymorphic transition from a mixture of α and ß to predominantly ß. This transition was accompanied by a morphology change. Mannitol needles were formed, giving more porous granules with a higher specific surface area, which led to poorer flow properties but higher tablet tensile strength. This study concludes that understanding the effect of mannitol grade is a crucial part of formulation selection.

Characterization of microcrystalline cellulose spheres and prediction of hopper flow based on a µ(I)-rheology model.

The objective of this study was to characterize the rheology of a pharmaceutical material in the context of the µ(I)-rheology model and to use this model to predict powder flow in a manufacturing operation that is relevant to pharmaceutical manufacturing. The rheology of microcrystalline cellulose spheres was therefore characterized in terms of the µ(I)-rheology model using a modified Malvern Kinexus rheometer. As an example of an important problem in pharmaceutical manufacturing, the flow of these particles from a hopper was studied experimentally and numerically using a continuum Navier-Stokes solver based on the Volume-Of-Fluid (VOF) interface-capturing numerical method. The work shows that the rheology of this typical pharmaceutical material can be measured using a modified annular shear rheometer and that the results can be interpreted in terms of the µ(I)-rheology model. It is demonstrated that both the simulation results and the experimental data show a constant hopper discharge rate. It is noted that the model can suffer from ill-posedness and it is shown how an increasingly fine grid resolution can result in predictions that are not entirely physically realistic. This shortcoming of the numerical framework implies that caution is required when making a one-to-one comparison with experimental data.

Continuous Twin Screw Wet Granulation and Drying-Control Strategy for Drug Product Manufacturing.

The use of continuous manufacturing has been increasing within the pharmaceutical industry over the last few years. Continuous direct compression has been the focus of publications on the topic to date. The use of wet granulation can improve segregation resistance, uniformity, enhance density, and flow properties for improved tabletability, or improve stability of products that cannot be manufactured by using a direction compression process. This article focuses on development of appropriate control strategies for continuous wet granulation (especially twin screw wet granulation) through equipment design, material properties and manufacturing process along with areas where additional understanding is required. The article also discusses the use of process analytical technologies as part of the control and automation approach to ensure a higher assurance of product quality. Increased understanding of continuous wet granulation should result in increased utilization of the technique, thereby allowing for an increase in diversity of products manufactured by continuous manufacturing and the benefits that comes with a more complex process such as wet granulation compared with direct compression process.

Tableting performance of various mannitol and lactose grades assessed by compaction simulation and chemometrical analysis.

Mannitol and lactose are commonly used fillers in pharmaceutical tablets, available in several commercial grades that are produced using different manufacturing processes. These grades significantly differ in particulate and powder properties that impact tablet manufacturability. Choice of sub-optimum type or grade of excipient in tablet formulation can lead to manufacturing problems and difficulties, which are magnified during a continuous manufacturing process. Previous characterization of tableting performance of these materials was limited in scope and under conditions not always realistic to the commercial production of tablets. This work seeks to comprehensively characterize the compaction properties of 11 mannitol and 5 lactose grades using a compaction simulator at both slow and fast tableting speeds. These include tabletability, compressibility, tablet brittleness, die-wall stress transmission, and strain rate sensitivity. A chemometrical analysis of data, using the partial least square technique, was performed to construct a model to provide accurate prediction of tablet tensile strength for mannitol grades. Such knowledge facilitates the selection of suitable tablet filler to attain high quality tablet products.

Comparison between integrated continuous direct compression line and batch processing - The effect of raw material properties.

There is a current trend in pharmaceutical manufacturing to shift from traditional batch manufacture to continuous manufacturing. The purpose of this study was to test the ability of an integrated continuous direct compression (CDC) line, in relation to batch processing, to achieve consistent tablet quality over long processing periods for formulations with poor flow properties or with a tendency to segregate. The study design included four industrially relevant formulations with different segregation indices and flow properties induced through different grades of the Active Pharmaceutical Ingredient (API), paracetamol, and major filler as well as varying the amount of API. The performance metrics investigated were content, uniformity of content, tablet weight, and tablet strength. The overall process stability over time was significantly improved with the CDC line as compared to the batch process. For all the formulations with a high API content, the CDC line provided better or equal uniformity of content and tablet weight as compared to batch. The CDC line was especially efficient in providing a stable content and tablet weight for poorly flowing formulations containing the standard, cohesive, grade of API. The only formulation that performed better in the batch process was the formulation with a low API content. Thus, for this formulation, the batch process achieved lower variation in tablet content since maintaining a low feed rate for the API proved challenging in the CDC line. In addition, some of the API became stuck in the CDC line between feeding and tableting, most likely at the funnel in the mixer inlet, highlighting the need for properly designed interfaces between units. The insensitivity of the CDC line towards poor flow indicates that one could use direct compression at high drug load compositions of poorly flowing powder blends that could not be processed via batch manufacturing.

Comparative analyses of flow and compaction properties of diverse mannitol and lactose grades.

Appropriate selection of excipient grade during tablet formulation development depends on thorough knowledge in their compaction and flow properties. Each chemically unique pharmaceutical excipient is usually available in several commercial grades that are widely different in powder properties, which influence their performance for a specific formulation application. In this work, 11 grades of mannitol were systematically characterized, in terms of their particulate, flow and tableting properties, and compared against 5 grades of lactose. Principal component analysis (PCA) identified significant correlations among selected variables, such as particle size, surface area, flowability, wall friction, plasticity parameter, tensile strength, and tablet brittleness. PCA also revealed similar grades of the two excipients, which may be used to select replacement grade, if needed, based on similarity in their overall properties.

Provoking an end-to-end continuous direct compression line with raw materials prone to segregation.

Continuous manufacturing of solid oral dosage forms is promising for increasing the efficiency and quality of pharmaceutical production and products. In this study a whole train continuous direct compression (CDC) line has been provoked using challenging formulations typically prone to segregation in batch powder processing. Industrial compositions including components with variable size, bulk density and cohesive nature were selected. An experimental design, including variables such as API/mannitol particle size, API amount, powder feed rate and mixer speed, enabled the output quality of the provoked process to be assessed. Contrary to previous studies, a broader range of finished tablet quality attributes were probed, including content, uniformity of content, tensile strength as well as release performance. Overall, the continuous direct compression line was found to be a capable and efficient manufacturing process for the challenging compositions studied and surprisingly tolerable to handle the materials susceptible to segregation in typical batch settings. As expected, and given the 'fixed' apparatus configuration used in this study, the particulate material properties were found to have the most significant impact on the finished tablet quality attributes. The results emphasize the importance for taking a holistic approach when developing the operational windows and the strategy for control, e.g. by integrating the appropriate material properties, the actual apparatus design, and the relevant formulation design. The CDC line's ability to handle cohesive materials also seem to be one of the key advantages, thus confirming the recent promising results from other continuous direct compression studies.

Achieving a robust drug release from extended release tablets using an integrated continuous mixing and direct compression line.

In the present work the viability of integrated continuous mixing and compression processes for manufacturing of extended release (ER) matrix tablets was investigated in terms of dissolution behavior. The purpose was also to evaluate the combined effect of processing variables and compositional variables on the release robustness. The continuous process was provoked by a challenging formulation design, including variable powder characteristics and compositions of high and low amount of poorly soluble and poorly flowing drug substance (ibuprofen). Additionally a relatively low amount of two different ER matrix former grades (standard granulation grade CR and direct compression grade DC2 of hydroxypropyl methylcellulose, HPMC) was used to challenge the system. Robust ibuprofen release was obtained faster when HPMC CR was used. However, robust release was also achieved when using HPMC DC2 at high ibuprofen content, even though it took slightly longer time to reach the steady state of the process. Due to its poor flow properties, HPMC CR would be very challenging to use in traditional direct compression. The results showed that by using continuous processing it is possible to manufacture and achieve robust performance of compositions that would not be possible with traditional batch processing due to for instance poorly flowability.

Continuous manufacturing of extended release tablets via powder mixing and direct compression.

The aim of the current work was to explore continuous dry powder mixing and direct compression for manufacturing of extended release (ER) matrix tablets. The study was span out with a challenging formulation design comprising ibuprofen compositions with varying particle size and a relatively low amount of the matrix former hydroxypropyl methylcellulose (HPMC). Standard grade HPMC (CR) was compared to a recently developed direct compressible grade (DC2). The work demonstrate that ER tablets with desired quality attributes could be manufactured via integrated continuous mixing and direct compression. The most robust tablet quality (weight, assay, tensile strength) was obtained using high mixer speed and large particle size ibuprofen and HPMC DC2 due to good powder flow. At low mixer speed it was more difficult to achieve high quality low dose tablets. Notably, with HPMC DC2 the processing conditions had a significant effect on drug release. Longer processing time and/or faster mixer speed was needed to achieve robust release with compositions containing DC2 compared with those containing CR. This work confirms the importance of balancing process parameters and material properties to find consistent product quality. Also, adaptive control is proven a pivotal means for control of continuous manufacturing systems.

Roll compaction process modeling: transfer between equipment and impact of process parameters.

In this study, the roll compaction of an intermediate drug load formulation was performed using horizontally and vertically force fed roll compactors. The horizontally fed roll compactor was equipped with an instrumented roll technology allowing the direct measurement of normal stress at the roll surface, while the vertically fed roll compactor was equipped with a force gauge between the roll axes. Furthermore, characterization of ribbons, granules and tablets was also performed. Ribbon porosity was primarily found to be a function of normal stress, exhibiting a quadratic relationship thereof. A similar quadratic relationship was also observed between roll force and ribbon porosity of the vertically fed roll compactor. The predicted peak pressure (Pmax) using the Johanson model was found to be higher than the measured normal stress, however, the predicted Pmax correlated well with the ribbon relative density/porosity and the majority of downstream properties of granules and tablets, demonstrating its use as a scale-independent parameter. A latent variable model was developed for both the horizontal and vertical fed roll compactors to express ribbon porosity as a function of geometric and process parameters. The model validation, performed with new data, resulted in overall good predictions. This study successfully demonstrated the scale up/transfer between two different roll compactors and revealed that the combined use of design of experiments, latent variable models and in silico predictions result in better understanding of the critical process parameters in roll compaction.

A quality by design approach to investigate the effect of mannitol and dicalcium phosphate qualities on roll compaction.

Roll compaction is a continuous process for solid dosage form manufacturing increasingly popular within pharmaceutical industry. Although roll compaction has become an established technique for dry granulation, the influence of material properties is still not fully understood. In this study, a quality by design (QbD) approach was utilized, not only to understand the influence of different qualities of mannitol and dicalcium phosphate (DCP), but also to predict critical quality attributes of the drug product based solely on the material properties of that filler. By describing each filler quality in terms of several representative physical properties, orthogonal projections to latent structures (OPLS) was used to understand and predict how those properties affected drug product intermediates as well as critical quality attributes of the final drug product. These models were then validated by predicting product attributes for filler qualities not used in the model construction. The results of this study confirmed that the tensile strength reduction, known to affect plastic materials when roll compacted, is not prominent when using brittle materials. Some qualities of these fillers actually demonstrated improved compactability following roll compaction. While direct compression qualities are frequently used for roll compacted drug products because of their excellent flowability and good compaction properties, this study revealed that granules from these qualities were more poor flowing than the corresponding powder blends, which was not seen for granules from traditional qualities. The QbD approach used in this study could be extended beyond fillers. Thus any new compound/ingredient would first be characterized and then suitable formulation characteristics could be determined in silico, without running any additional experiments.

Combining experimental design and orthogonal projections to latent structures to study the influence of microcrystalline cellulose properties on roll compaction.

Roll compaction is gaining importance in pharmaceutical industry for the dry granulation of heat or moisture sensitive powder blends with poor flowing properties prior to tabletting. We studied the influence of microcrystalline cellulose (MCC) properties on the roll compaction process and the consecutive steps in tablet manufacturing. Four dissimilar MCC grades, selected by subjecting their physical characteristics to principal components analysis, and three speed ratios, i.e. the ratio of the feed screw speed and the roll speed of the roll compactor, were included in a full factorial design. Orthogonal projection to latent structures was then used to model the properties of the resulting roll compacted products (ribbons, granules and tablets) as a function of the physical MCC properties and the speed ratio. This modified version of partial least squares regression separates variation in the design correlated to the considered response from the variation orthogonal to that response. The contributions of the MCC properties and the speed ratio to the predictive and orthogonal components of the models were used to evaluate the effect of the design variation. The models indicated that several MCC properties, e.g. bulk density and compressibility, affected all granule and tablet properties, but only one studied ribbon property: porosity. After roll compaction, Ceolus KG 1000 resulted in tablets with obvious higher tensile strength and lower disintegration time compared to the other MCC grades. This study confirmed that the particle size increase caused by roll compaction is highly responsible for the tensile strength decrease of the tablets.