Effects of tableting process parameters and powder lubrication levels on tablet surface temperature and moisture content.

Punch sticking is a recurrent problem during the pharmaceutical tableting process. Powder moisture content plays a key role in the buildup of sticking; it evaporates due to increased tablet temperature, accumulates at the punch-tablet interface, and causes sticking through capillary force. This study investigated the effects of compaction pressure (CP), compaction speed (CS), and lubrication level (magnesium stearate (MgSt) ratio) on tablet surface temperature (TST) and tablet surface moisture content (TSMC). TST and TSMC were measured with an infrared thermal camera and near-infrared sensor, respectively. Microcrystalline cellulose was used as the tableting powder and MgSt as the lubricant. The low range of CS values (16-32 mm/s) considered in this study did not have significant effects on TST and TSMC. MgSt ratio had a significant positive effect on TST; this may be explained by the increase in powder blend effusivity with the addition of MgSt. However, MgSt ratio did not have a significant effect on TSMC. CP had a significant positive effect on both TST and TSMC. Increased CP induced higher heat generation through particle deformation and friction during the compaction phase, leading to increased TST. Furthermore, the water vapor diffusion rate through the powder bed might have increased due to the rise in thermal energy and led to further moisture accumulation at the tablet-punch interface, causing the significant positive effect of CP on TSMC. This result may explain the occurrence of sticking regardless of the CP applied during the tableting process.

Moisture Behavior of Pharmaceutical Powder during the Tableting Process.

The moisture content of pharmaceutical powder is a key parameter contributing to tablet sticking during the tableting process. This study investigates powder moisture behavior during the compaction phase of the tableting process. Finite element analysis software COMSOL Multiphysics® 5.6 was used to simulate the compaction microcrystalline cellulose (VIVAPUR PH101) powder and predict temperature and moisture content distributions, as well as their evolution over time, during a single compaction. To validate the simulation, a near-infrared sensor and a thermal infrared camera were used to measure tablet surface temperature and surface moisture, respectively, just after ejection. The partial least squares regression (PLS) method was used to predict the surface moisture content of the ejected tablet. Thermal infrared camera images of the ejected tablet showed powder bed temperature increasing during compaction and a gradual rise in tablet temperature along with tableting runs. Simulation results showed that moisture evaporate from the compacted powder bed to the surrounding environment. The predicted surface moisture content of ejected tablets after compaction was higher compared to that of loose powder and decreased gradually as tableting runs increased. These observations suggest that the moisture evaporating from the powder bed accumulates at the interface between the punch and tablet surface. Evaporated water molecules can be physiosorbed on the punch surface and cause a capillary condensation locally at the punch and tablet interface during dwell time. Locally formed capillary bridge may induce a capillary force between tablet surface particles and the punch surface and cause the sticking.

Insights into tablet sticking: a quantitative case study with an ibuprofen and methocarbamol-based formulation.

OBJECTIVES AND METHODS: Tablet sticking is a continuous accumulation of pharmaceutical powder onto tooling surfaces during compression. Its occurrence greatly impacts tablet productivity, quality attributes, and tooling age. In a previous study, the authors proposed a multivariate data analysis approach to gain insights into tablet sticking directly on the industrial stage. The objective was to determine the combination of factors that could help distinguish between batches affected and unaffected by sticking. The present study aims to generalize this approach by extending it to quantitative predictions of punch sticking intensity. A total of 345 variables was gathered on 28 industrial batches of an ibuprofen and methocarbamol-based formulation. RESULT AND CONCLUSION: Using PLS regression models, it was shown that the association of granulation duration and compression force allows to significantly explain ∼60% of sticking variations of studied formulation. In addition, unlike the classification models developed in the earlier work, the validation residues in the present study were found to be normally distributed (Shapiro-Wilks p value = 0.96) and independent from the target variable (R2 = 9.5%).

A multivariate data analysis approach to tablet sticking on an industrial scale: a qualitative case study of an ibuprofen-based formulation.

OBJECTIVES: Sticking is one of the most common and damaging issues that occur during tablet manufacturing. Sticking is the adhesion of powder onto tooling surfaces during compression. Because of the numerous factors involved in its occurrence, understanding tablet sticking requires the simultaneous investigation of these factors to clarify their possible interactions. However, conducting such a study experimentally can present a significant financial and technical burden. In this study, we aimed to leverage the large amount of data that is usually generated during industrial manufacturing to gain insights into sticking. METHODS: This was achieved by collecting and analyzing a total of 71 historical batches that used an ibuprofen-based formulation. We associate each batch with a hundred parameters, including a qualitative descriptor of sticking, and employ a predefined methodology based primarily on multivariate data analysis. RESULTS AND CONCLUSIONS: Our results highlight the role of lubrication, water content, and the low melting point of ibuprofen in its sticking tendency. Based on these findings, we propose and discuss an industrial manufacturing data analysis approach to sticking and its associated systematic methodology, consisting of collection, exploration, and data modeling.

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.

Proven Anti-Wetting Properties of Molybdenum Tested for High-Temperature Corrosion-Resistance with Potential Application in the Aluminum Industry.

The behavior of Mo in contact with molten Al was modelled by classical molecular dynamics (CMD) simulation of a pure Mo solid in contact with molten Al at 1200 K using the Materials Studio®. Results showed that no reaction or cross diffusion of atoms occurs at the Mo(s)-Al(l) interface, and that molten Al atoms exhibit an epitaxial alignment with the exposed solid Mo crystal morphology. Furthermore, the two phases {Mo(s) and Al(l)} are predicted to interact with weak van der Waals forces and give interfacial energy of about 203 mJ/m2. Surface energy measurements by the sessile drop experiment using the van Oss-Chaudhury-Good (VCG) theory established a Mo(s)-Al(l) interface energy equivalent to 54 mJ/m2, which supports the weak van der Waals interaction. The corrosion resistance of a high purity (99.97%) Mo block was then tested in a molten alloy of 5% Mg mixed in Al (Al-5 wt.%Mg) at 1123 K for 96 h, using the ALCAN's standard "immersion" test, and the results are presented. No Mo was found to be dissolved in the molten Al-Mg alloy. However, a 20% mass loss in the Mo block was due to intergranular corrosion scissoring the Mo block in the ALCAN test, but not as a result of the reaction of pure Mo with the molten Al-Mg alloy. It was observed that the Al-Mg alloy did not stick to the Mo block.

Wet granulation end point prediction using dimensionless numbers in a mixer torque rheometer: Relationship between capillary and Weber numbers and the optimal wet mass consistency.

The optimal wet mass consistency during wet granulation is often determined using the hand squeezing test. In this study, torque values recorded inside the wet mass were measured using a mixer torque rheometer (MTR) via multiple additions of liquid. The main objective of this work was to predict the optimal wet mass consistency of pharmaceutical powders using the modified capillary (Ca∗) and Weber (We∗) dimensionless numbers. The results show that the optimal wet mass consistency versus Ca∗ (or We∗) can be fitted with a power-law function, whereas the improved capillary number Ca' proposed in this work gives different relationships and behaviors depending on the spreadability and wettability of the blend. The wettability was obtained by measuring the contact angle between the liquids and the pharmaceutical powders. The surface free energy and the polar and dispersive parts of a liquid's surface energy were obtained from Young's equation and the Owens-Wendt-Rabel-Kaelble (OWRK) model. This study demonstrated the importance of the interfacial energy σb-s and the pore radius, Rpore in the establishment of a dimensionless number, Ca∗, that can satisfactorily predict with an R2 of 0.80, the optimal wet mass consistency of pharmaceutical powders measured by the MTR.

Non-invasive detection technologies of solid foreign matter and their applications to lyophilized pharmaceutical products: A review.

Good Manufacturing Practice Regulations, under the Food and Drug Administration (FDA), stipulate that all pharmaceutical products must be free of any contaminants, including, namely, any foreign solid objects. Lyophilization is a common manufacturing method that consists of several steps where foreign materials may enter the product. The presence of unintended particles in freeze drying, which will herein be referred to under the term 'Lyophilization', is of great concern to the authorities responsible for drug safety and effectiveness. In the pharmaceutical industry, presently, the inspection of lyophilized products for foreign matter particulates relies on visual inspection where only the outer surface of the lyophilized cake is visible. This review is motivated by the need for new control strategies for foreign matter (FM) detection in lyophilized products; more specifically, it assesses the reliability of non-destructive technologies for FM detection in dried samples. Emerging technologies applied in other industries, such as various types of spectroscopies and imaging (e.g. chemical, X-ray, ultrasound, thermal and terahertz), are evaluated based on compatibility with the intended application, with identification of the possible technical challenges.

Stability of Extemporaneously Prepared Acetazolamide Oral Suspensions at Two Temperatures.

OBJECTIVES: Some drugs need to be compounded by the pharmacist before being administered to the patient. A study was conducted to determine the stability of acetazolamide suspensions in 2 different vehicles (Oral Mix and Oral Mix Sugar Free [SF]) from bulk drug and tablets at 2 different temperatures and in 2 different containers (amber plastic bottles and clear plastic syringes). METHODS: Acetazolamide suspensions (25 mg/mL) were prepared from bulk drug or tablets. Each suspension, using Oral Mix or Oral Mix SF, was split between 2 types of containers-amber plastic bottles and clear plastic syringes-and stored either at room temperature (23°C-27°C) or under refrigeration (3°C-7°C). Samples were drawn from the suspensions right after preparation and on days 7, 14, 30, 45, 60, 75, and 90. They were then analyzed by high-performance liquid chromatography (HPLC) using a reverse-phase column. A validated stability-indicating HPLC with ultraviolet detection method was developed. A visual inspection and a pH measurement were also completed at each time point. Stability was defined as retention of at least 90% of the initial concentration of acetazolamide suspension. RESULTS: At least 91.2% of the initial acetazolamide concentration in suspensions remained throughout the 90-day study period for both vehicles, both containers, and both temperatures. Assays varied between 91.2% and 105.0% of the initial concentration for all 112 tested conditions but 2 (105.2% and 109.0%). Linear regression was calculated for each time profile and remained above 95.0% at the end of the study in all cases. Similarly, pH remained within 0.1 unit of the initial pH, which was 4.2 for Oral Mix and 4.3 for Oral Mix SF. Furthermore, no changes in organoleptic properties were observed because the preparations remained as white fluid suspensions without sedimentation. CONCLUSIONS: Acetazolamide suspensions were stable for at least 90 days in all tested conditions because the average drug concentration was not less than 90% of the initial concentration. The beyond-use date could be extended from 60 to 90 days.

Validation of a stability-indicating HPLC-UV method for the quantification of acetazolamide in Oral-Mix and Oral-Mix SF.

This manuscript details the modifications made to the HPLC assay method described in the USP monograph for Acetazolamide Compounded Oral Suspension.•The method was modified to allow the quantification of acetazolamide in two new suspension vehicles: Oral Mix and Oral Mix SF;•It was validated for linearity, accuracy, precision and specificity;•It was demonstrated stability-indicating and suitable for use in a stability study using these vehicles.

In-line monitoring of Ibuprofen during and after tablet compression using near-infrared spectroscopy.

Near infrared spectroscopy (NIRS) used as process analytical technology tool to monitor Active Pharmaceutical Ingredient concentrations during tablet manufacturing has been reported to enhance overall product quality assurance. NIRS applications in different manufacturing stages are facilitated by their ability to handle different sample presentations - be it solids, liquids, gels or powders. The present study evaluates NIRS suitability for monitoring Ibuprofen concentrations (coated pellets form) inside the feed frame of a tableting press as well as in output tablets. Process monitoring was undertaken with quantitative chemometric analysis. NIRS-based predictions of concentrations both inside the feed frame and in tablets were compared to ultraviolet (UV) spectroscopy assays of temporally stratified tablet samples. Process dynamics were also compared in terms of concurrent concentrations change kinetics in the feed frame and in output tablets. NIRS showed good sensitivity to Ibuprofen concentrations despite the use of coated pellets. Ibuprofen contents as low as 1.7% w/w were detected effectively. NIRS-based quantitative predictions in the feed frame and in tablets closely matched the UV assay values of sampled tablets. As anticipated from the 2-wheel feed frame geometry, upon the addition of each consecutive blend, results show that the predicted concentration inside the feed frame were delayed compared with that of the tablets exiting the tablet press. For these tests, the delay was estimated to be 1.25 min. This finding highlights the importance of NIRS probe position inside the feed frame as a function of its geometry. Successive feed frame and tablet monitoring by NIRS could prove beneficial for real time release testing of tablet formulations.

Specificity of process analytical tools in the monitoring of multicomponent pharmaceutical powders.

The application of Process Analytical Technologies in pharmaceutical manufacturing has been the subject of many studies. Active pharmaceutical ingredient monitoring in real time throughout the manufacturing process is commonly the target of many such implementations. The tools in place must be sensitive to, and selective of, the parameter(s) to be monitored, i.e. in the case of component quantification, they must respond to the component in question and be robust against all others. In this study, four different ingredients (riboflavin, ferrous fumarate, ginseng, and ascorbic acid) in a multi-component blend were monitored by three different tools (near infrared spectroscopy, laser-induced fluorescence and red-green-blue camera) using a full factorial design. The goal was to develop efficient and robust concentration-reading/prediction models able to assess and monitor component interference. Despite relatively high complexity of the blend studied, the three tools demonstrated reasonable specificity for the tracked ingredients (and showed advantages when combined), taking into account larger acceptance criteria typical of dietary products. In certain cases, some interference might lead to biased predictions, highlighting the importance of good calibration. The tools tested and the methodology proposed has divulged their potential in monitoring these components, despite the complexity of the 31-component blend.

Use of Plasma-Synthesized Nano-Catalysts for CO Hydrogenation in Low-Temperature Fischer⁻Tropsch Synthesis: Effect of Catalyst Pre-Treatment.

A study was done on the effect of temperature and catalyst pre-treatment on CO hydrogenation over plasma-synthesized catalysts during the Fischer⁻Tropsch synthesis (FTS). Nanometric Co/C, Fe/C, and 50%Co-50%Fe/C catalysts with BET specific surface area of ~80 m² g⁻1 were tested at a 2 MPa pressure and a gas hourly space velocity (GHSV) of 2000 cm³ h-1 g-1 of a catalyst (at STP) in hydrogen-rich FTS feed gas (H2:CO = 2.2). After pre-treatment in both H2 and CO, transmission electron microscopy (TEM) showed that the used catalysts shifted from a mono-modal particle-size distribution (mean ~11 nm) to a multi-modal distribution with a substantial increase in the smaller nanoparticles (~5 nm), which was statistically significant. Further characterization was conducted by scanning electron microscopy (SEM with EDX elemental mapping), X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS). The average CO conversion at 500 K was 18% (Co/C), 17% (Fe/C), and 16% (Co-Fe/C); 46%, 37%, and 57% at 520 K; and 85%, 86% and 71% at 540 K respectively. The selectivity of Co/C for C5+ was ~98% with 8% gasoline, 61%, diesel and 28% wax (fractions) at 500 K; 22% gasoline, 50% diesel, and 19% wax at 520 K; and 24% gasoline, 34% diesel, and 11% wax at 540 K, besides CO2 and CH4 as by-products. Fe-containing catalysts manifested similar trends, with a poor conformity to the Anderson⁻Schulz⁻Flory (ASF) product distribution.

Developing a quality by design approach to model tablet dissolution testing: an industrial case study.

This study applied the concept of Quality by Design (QbD) to tablet dissolution. Its goal was to propose a quality control strategy to model dissolution testing of solid oral dose products according to International Conference on Harmonization guidelines. The methodology involved the following three steps: (1) a risk analysis to identify the material- and process-related parameters impacting the critical quality attributes of dissolution testing, (2) an experimental design to evaluate the influence of design factors (attributes and parameters selected by risk analysis) on dissolution testing, and (3) an investigation of the relationship between design factors and dissolution profiles. Results show that (a) in the case studied, the two parameters impacting dissolution kinetics are active pharmaceutical ingredient particle size distributions and tablet hardness and (b) these two parameters could be monitored with PAT tools to predict dissolution profiles. Moreover, based on the results obtained, modeling dissolution is possible. The practicality and effectiveness of the QbD approach were demonstrated through this industrial case study. Implementing such an approach systematically in industrial pharmaceutical production would reduce the need for tablet dissolution testing.

Using multiple Process Analytical Technology probes to monitor multivitamin blends in a tableting feed frame.

As Process Analytical Technology (PAT) implementation grows in the pharmaceutical industry, more studies are being performed to evaluate its suitability in new applications and processes within the manufacturing chain. As the last step in tablet production, the compression stage represents a critical phase that ensures product quality. In-line control put in place at this stage has the potential to detect powder blends that are out of specification limits and, thus, help to improve product quality. The objectives of the present project are to quantify the composition of a commercial 31-component multivitamin powder blend in real time on an industrial feed frame, using 3 different PAT tools: light-induced fluorescence spectroscopy, near infrared spectroscopy and red, green and blue color imaging. To do so, the concentrations of 5 components (Beta-Carotene, Riboflavin, Ferrous Fumarate, Ginseng and Ascorbic Acid) were alternately changed and monitored with one or many probes. Transition periods between batches served to quantify different powder flow dynamics with sequential composition step changes. The results showed that 4 out of 5 components, each present in commercially-relevant concentrations, could be monitored by one or more tools. Flow dynamics were measured and found to vary significantly in different powder blends.

Monitoring the concentration of flowing pharmaceutical powders in a tableting feed frame.

The use of process analytical technology (PAT) tools is increasing steadily in the pharmaceutical industry. Such tools are now located throughout the process. When producing tablets, the tableting step itself may be the ideal moment to assess final product composition. Being the last unit operation in tablet production where the elements are still free flowing, it is relatively straightforward to ascertain the composition of the blend in real time. However, a single probe cannot be expected to monitor the composition of every component of a multicomponent blend. In this study, three PAT tools (light-induced fluorescence spectroscopy, near-infrared spectroscopy and color (RGB) imaging) simultaneously checked the composition of powder blends flowing through the feeding unit (feed frame) of a tablet press. The results demonstrate the potential of these tools in monitoring changes in the concentration of a multicomponent mixture in real time, providing users with means to both scrutinize the process and better understand phenomena occurring inside the feed frame.

Predicting the dissolution behavior of pharmaceutical tablets with NIR chemical imaging.

Near infrared chemical imaging (NIRCI) is a common analytical non-destructive technique for the analysis of pharmaceutical tablets. This powerful process analytical technology provides opportunity to chemically understand the sample, and also to determine spatial distribution and size of ingredients in a tablet. NIRCI has been used to link disintegrant, excipients and active pharmaceutical ingredient (API) to tablet dissolution, as disintegrants play an important role in tablet disintegration, resulting in API dissolution. This article describes a specific methodology to predict API dissolution based on disintegrant chemical information obtained with NIRCI. First, several tablet batches with different disintegrant characteristics were produced. Then, NIRCI was successfully used to provide chemical images of pharmaceutical tablets. A PLS regression model successfully predicted dissolution profiles. These results show that NIRCI is a robust and versatile technique for measuring disintegrant properties in tablet formulations and predicting their effects on dissolution profiles. Thus, NIRCI could routinely complement and eventually replace dissolution testing by monitoring a critical material attribute: disintegrant content.

Development of a multivariate light-induced fluorescence (LIF) PAT tool for in-line quantitative analysis of pharmaceutical granules in a V-blender.

Process analytical technologies (PAT) enable process insight, process control and real-time testing. Light-induced fluorescence (LIF) spectroscopy is especially well suited for low-concentration ingredients as, in many cases, it is the most sensitive probe of the in-line PAT toolbox. This study is aimed at verifying the applicability of a multivariate LIF analyzer to monitor granulated powder blends in industrial settings. Its targets are to: (1) evaluate the critical parameters of powders to obtain robust, precise and accurate concentration predictions and (2) assess technology performance for in-line monitoring of blending operations. Varying dye properties, moisture levels and particle sizes have been shown to have the most significant impact on fluorescence emission. Reliable quantitative models can be obtained by controlling and/or mitigating these factors.

Prediction of segregation tendency in dry particulate pharmaceutical mixtures: Application of an adapted mathematical tool to cohesive and non-cohesive mixtures.

The measurement of average residence times and their variance, used to calculate the deviation of chemical reactors from the ideal behaviour of a perfectly-mixed vessel, or a plug flow pattern, has already been proposed in the literature to evaluate the segregation tendency of granular mixtures. The method consists of introducing pulse perturbation (of another material) to the established regular flow of a single granular material or a granular mixture and to assess the response of the system in terms of pulsed material concentration at the process outlet. The particles' average residence time and its standard deviation are then related to segregation tendency. Results from the application of this new method are useful when compared to those obtained from a reference mixture to be chosen according to a particular formulation development or process understanding need. This work applies the proposed method for various mixtures, both cohesive and non-cohesive, and derives phenomenological mathematical models expressing segregation tendency as a function of the parameters shown to be critical (i.e. statistically significant) to component segregation. The models were shown to be statistically and experimentally robust in the case of non-cohesive to slightly cohesive mixtures. Although the mathematical models are phenomenological, the findings allow for deriving mechanistic explanations on segregation tendency.

Agglomeration tendency in dry pharmaceutical granular systems.

The agglomeration tendency of dry pharmaceutical mixtures containing various concentrations of Xylitab 100 (Xylitol), calcium carbonate precipitated (CCP) and magnesium stearate (MgSt) was evaluated statistically as a function of mixing time. A Ro-Tap tester was employed to mix the three pharmaceutical components, and the agglomerates formed were measured with respect to their weight and size. An experimental design was devised and applied to structure and then statistically analyze the results. Xylitab was found not to be influential in the formation of agglomerates, but aided in deagglomeration when mixed with other components. CCP and MgSt formed agglomerates over time and showed positive interactions favouring agglomeration. The agglomerates started to fracture when they reached a critical size, at which stage the particles' attraction forces (cohesion forces) were weaker than both gravity and inertia. It has been shown and quantitatively demonstrated that the mixing time and ingredient concentrations of a three-component pharmaceutical mixture can affect agglomeration tendency.