Understanding the role of magnesium stearate in lowering punch sticking propensity of drugs during compression.

The sticking of active pharmaceutical ingredient (API) to the surfaces of compaction tooling, frequently referred to as punch sticking, causes costly downtime or product failures in commercial tablet manufacturing. Magnesium stearate (MgSt) is a common tablet lubricant known to ameliorate the sticking problem, even though there exist exceptions. The mechanism by which MgSt lowers punch sticking propensity (PSP) by covering API surface is sensible but not yet experimentally proven. This work was aimed at elucidating the link between PSP and surface area coverage (SAC) of tablets by MgSt, in relation to some key formulation properties and process parameters, namely MgSt concentration, API loading, API particle size, and mixing conditions. The study was conducted using two model APIs with known high PSPs, tafamidis (TAF) and ertugliflozin-pyroglutamic acid (ERT). Results showed that PSP decreases exponentially with increasing SAC by MgSt. The composition of material stuck to punch face was also explored to better understand the onset of punch sticking and the impact of possible MgSt-effected punch conditioning event.

Magnesium stearate surface coverage on tablets and drug crystals: Insights from SEM-EDS elemental mapping.

Scanning electron microscopy-based energy dispersive X-ray spectroscopy (SEM-EDS) is proposed as a versatile tool for quantifying surface area coverage (SAC) by magnesium stearate (MgSt) on pharmaceutical tablets and particles. Our approach involved fast elemental mapping and subsequent SAC quantitation by image analysis. The study was conducted using a multi-component system, but the particle-level mapping was limited to active pharmaceutical ingredient (API) crystals. For both tablets and API particles, the calculated SAC against MgSt loading afforded a positive linear correlation over the range of MgSt levels examined in this work. On the tablet surface, MgSt was found to be preferentially concentrated at or in the close vicinity of grain boundaries, supporting the idea of compression-driven migration and relocation of MgSt within the tablet. On the particle surface, only discrete aggregates of MgSt were observed, as opposed to the widely accepted phenomenon of the formation of a thin lubricant film around host particles. The selection of proper SEM-EDS operating conditions and the challenges confronted in particle surface mapping are discussed in detail.

Experimental Evaluation of the Impact of Rapid Environmental Changes on Stress Distribution in Tablet Coatings.

Drying-induced cracks in tablet coatings are undesirable as they not only affect tablet's appearance, but they may also interfere with its function. While it is well known that tensile stresses in the coating are responsible for coating failures, few have measured the stress in tablet coatings, especially when exposed to rapid environmental changes. In this study, two commercial tablet coatings based on Hydroxy Propyl Methyl Cellulose (HPMC) and Poly Vinyl Alcohol (PVA) are exposed to rapid variations in temperature and humidity to observe the variation in residual stress. Reducing temperature at a fixed humidity or reducing humidity at fixed temperature, both lead to high residual stresses. When both the humidity and temperature were reduced together, the residual stresses were very high causing delamination in the PVA-based film and cracking in the HPMC-based film. The changes in residual stress are almost instantaneous for the HPMC-based film while it is slower for the PVA-based film. The results highlight the importance of environmental conditions on the residual stress in the film and the resulting coating failure.

Impact of Rapid Environmental Changes on Stress Distribution in Tablet Coatings: Simulations.

Immediate-release film coatings, also known as "non-functional" film coating, are applied to core tablets to improve product appearance and swallowability, impart taste-masking properties, improve handling and stability of the dosage form, and reduce exposure to active drug substance for caregivers. The coatings have no measurable impact on bio-performance of the drug product but they protect tablets from negative effects of environment such as humidity, oxidation, and light. The mechanical stability and integrity of tablet coatings are therefore important to maintain drug product quality attributes such as appearance and stability. Therefore, environmental conditions under which these coatings may crack are important to understand so as to prevent their occurrence. In this work, we present a novel computational framework to assess the mechanical integrity of tablet coatings exposed to rapid variations in environmental conditions. We perform detailed stress and strain analysis of tablet coatings on tablet surfaces with debossed regions and identify conditions for cracking. Coatings with both elastic and viscoelastic properties are considered. Rapid changes in environmental temperature and humidity can cause differential expansion/contraction of coating and tablet core resulting in stresses that are higher than those experienced during the drying process in a coater. Debossed regions on the tablet surface with sharp surface curvatures act as stress concentrators that nucleate cracks. Small changes in the design of the debossed regions lead to modest reductions in the peak stress. Stress calculations show that coatings that are well bonded to tablet surface can crack only under very extreme conditions.

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.

Development of a predictive model for gravimetric powder feeding from an API-rich materials properties library.

A model was developed for predicting the feed factor profile of a powder, processed through a gravimetric feeder, as a function of material properties and process parameters. Predictive models proposed in existing literature have often used excipients and active pharmaceutical ingredients (APIs) with good powder flow characteristics in their development. In this work, a material properties library containing a large proportion of APIs, as well as excipients and co-processed blends, was used to build the model and enhance the prediction of feed factor profile for cohesive powders. Gravimetric feeder trials were performed at varying mass flow rates and screw geometries to determine the feed factor profiles. A semi-empirical exponential model, with parameters fmax, fmin, and ß, was then used to fit the experimental feed factor profiles. Bayesian optimisation and Support Vector Regression (SVR) modelling techniques were utilised to optimise and predict the exponential model parameters as a function of material properties. The parameters found to strongly influence the model were particle size, bulk density, FFC and FT4 rheometer parameters. Results showed low prediction errors between the estimated and experimental data. The final model produces good estimations of the feed factor profile and requires minimal powder consumption.

Continuous Mixing Technology: Characterization of a Vertical Mixer Using Residence Time Distribution.

Continuous powder mixing technology (CMT) application during continuous direct compression has emerged as a leading technology used in the development and manufacture of solid oral dosage forms. The critical quality attributes of the final product are heavily dependent on the performance of the mixing step as the quality of mixing directly influences the drug product quality attributes. This study investigates the impact of blend material properties (bulk density, API particle size distribution) and process parameters (process throughput, hold up mass and impeller speed) on the mixing performance. Mixing of the blend was characterized using the Residence Time Distribution (RTD) of the process by trending the outlet stream of the mixer using a near-infrared (NIR) probe after the injection of a small mass of tracer at the inlet stream. The outcomes of this study show that the RTDs of the mixer with throughput ranging between 15 and 30 kg/h; impeller speed ranging between 400 and 600 rpm and hold up mass (HUM) ranging between 500 and 850 g can be described by a series of two ideal Continuous Stirred Tank Reactors (CSTRs) with different volumes, and correspondingly, different mean residence times. It is also observed that the mixing is mainly occurring in the lower chamber of the CMT and the normalized RTDs of the mixer are similar across the range of process conditions and material attributes studied. The results also showed that the formulation blend with different API particle sizes and bulk properties, like bulk density and flowability, provide insignificant impact on the mixing performance. The CMT allows independent selection of target set points for HUM, impeller rotational speed and line throughput and it shows great robustness and flexibility for continuous blending in solid oral dose manufacturing.

Monitoring blend potency in a tablet press feed frame using near infrared spectroscopy.

A near-infrared (NIR) probe was installed into the feed frame of a rotary tablet press to monitor API concentration as a function of time. A series of step change experimental trials were completed, where a placebo blend was initially charged into the feed frame, and an active blend was layered above. The compression process was initiated, and process parameters, such as mass throughput rate, and feed frame paddle wheel speed were systematically varied. For the range of mass throughput rates studied, excellent correlations were shown between the NIR signal and weight corrected tablet potency from stratified tablet samples. A similar correlation was demonstrated for higher feed frame paddle wheel speeds. However, for lower feed frame paddle wheel speeds, a bias was observed between weight corrected tablet potency and the NIR signal. This finding suggests that compression process parameters, such as paddle wheel rotational speed and NIR probe location, must be optimized for different tablet press geometries to ensure that the NIR process signal can be related to tablet potency. This emerging application of Process Analytical Technology (PAT) may be used to identify powder segregation events during discharge of powder from an intermediate bulk container (IBC) or as a development tool to further understand powder mixing dynamics occurring within the feed frame. This may also be used as a diagnostic tool for fault detection during tablet compression. Finally, this PAT application may also be integrated with the tablet press control system as a gating or reject device for sub or super-potent tablets or enable Real-Time-Release testing (RTRt) through the continuous monitoring of the potency and homogeneity of powder circulating within the feed frame.