Mary T. am Ende

Process Modeling in the Pharmaceutical Industry using the Discrete Element Method

The discrete element method (DEM) is widely used to model a range of processes across many industries. This paper reviews current DEM models for several common pharmaceutical processes including material transport and storage, blending, granulation, milling, compression, and film coating. The studies described in this review yielded interesting results that provided insight into the effects of various material properties and operating conditions on pharmaceutical processes. Additionally, some basic elements common to most DEM models are overviewed. A discussion of some common model extensions such as nonspherical particle shapes, noncontact forces, and interstitial fluids is also presented. While these more complex systems have been the focus of many recent studies, considerable work must still be completed to gain a better understanding of how they can affect the processing behavior of bulk solids.

A Thermodynamic Model for Organic and Aqueous Tablet Film Coating

A tablet film-coating model for aqueous- and/or organic-based systems is shown to predict exhaust stream conditions thereby facilitating process optimization and scale-up. This coating model uses the First Law of Thermodynamics and conservation of mass principles to complete a material-energy balance on the coating unit operation for a closed, non-isolated system. Heat loss from the coating pan is incorporated into the model through a parameter called a heat loss factor (HLF) that is directly related to the heat transfer coefficient and pan surface area. For a mixed organic-aqueous coating formulation, the outlet air temperature and humidity are most notably affected by the coating composition and the inlet drying air temperature, which controls the evaporative cooling rate. The coating solution temperature and inlet air relative humidity do not significantly influence the exhaust air temperature, Tair,out. The HLF was determined to be 24 to 62 cal/min°C for the LDCS-20 to HCT-30, 360 cal/min°C for the HCT-60, 0 cal/min°C for the HC-130L and 945 to 1322 cal/min°C for the Accela-Cota-48 to Compulab-36 coating pans. This model successfully predicts Tair,out within 3°C for a given coating pan, and within 6°C scaling up from one to 220 kg pans for both organic- and aqueous-based coatings. The model is also useful for probing process and formulation variable sensitivity critical to establishing process robustness.

Improving the Content Uniformity of a Low-Dose Tablet Formulation Through Roller Compaction Optimization

In this investigation, the potency distribution of a low-dose drug in a granulation was optimized through a two-part study using statistically designed experiments. The purpose of this investigation was to minimize the segregation potential by improving content uniformity across the granule particle size distribution, thereby improving content uniformity in the tablet. Initial operating parameters on the Gerteis 3-W-Polygran 250/100/3 Roller Compactor resulted in a U-shaped potency function (potency vs. granule particle size) with superpotent fines and large granules. The roller compaction optimization study was carried out in two parts. Study I used a full factorial design with roll force (RF) and average gap width (GW) as independent variables and Study II used a D-optimal response surface design with four factors: RF, GW, granulating sieve size (SS), and granulator speed (GS). The planned response variables for Study I were bypass weight % and potency of bypass. Response variables for Study II included mean granulation potency with % relative standard deviation (% RSD), granulation particle size, sieve cut potency % RSD, tablet potency with % RSD, compression force at 7 kP crushing strength, and friability of 7-kP tablets. A constraint on GW was determined in Study I by statistical analysis. Bypass and observations of ribbon splitting were minimized when GW was less than 2.6 mm. In Study II, granulation potency, granulation uniformity, and sieve cut uniformity were optimized when the SS was 0.8 mm. Higher RF during dry granulation produced better sieve cut uniformity and tablets with improved uniformity throughout the run, as measured by stratified tablet samples taken during compression and assayed for potency. The recommended optimum roller compaction and milling operating parameters that simultaneously met all constraints were RF = 9 kN, GW = 2.3 mm, SS = 0.8 mm, and GS = 50 rpm. These parameters became the operating parameter set points during a model confirmation trial. The results from the confirmation trial proved that the new roller compaction and milling conditions reduced the potential for segregation by minimizing the granulation potency variability as a function of particle size as expressed by sieve cut potency % RSD, and thus improved content uniformity of stratified tablet samples.

Diffusion-Controlled Delivery of Proteins from Hydrogels and Other Hydrophilic Systems

The short in vivo half-life of many pharmaceutically active proteins necessitates the need for multiple administrations to produce a therapeutic response, emphasizing the applicability of controlled release formulations (Lee, 1992). The key variables that affect protein transport through hydrophilic polymers depend on the delivery mechanism and device properties, in a similar manner as in the case of lower-molecular-weight drug substances. However, in the case of proteins, the role of solute molecular size is much more dramatic in hindering the diffusion and release from hydrophilic polymers (am Ende, 1993). Another critical consideration in protein delivery from hydrogel systems is the potential for protein denaturation in the device. For diffusion-controlled delivery systems, where water is the main transporting medium, the protein solution stability governs the type of device. Extended releasing times can be achieved with reservoir systems (Fig. 1) for highly stable proteins (Langer, 1990). Alternatively, dehydrated delivery systems

Verification of Design Spaces Developed at Subscale

Recent concerns about the applicability of design space boundaries developed on small scale to commercial manufacturing processes have been raised by regulators worldwide. These concerns center around the scalability of unit operations and their corresponding process parameters, and the impact this has on the desired attributes of the drug substance or product. Requests have been made to verify design space boundaries with data generated at commercial scale. Because it is not always feasible to manufacture large-scale batches, alternative approaches to verification are necessary. The following article discusses various science-based strategies that could be used to verify design space boundaries. These approaches balance the requirements to address regulatory concerns and ensure that quality standards are maintained for both drug substances and products, within the operating constraints currently facing the pharmaceutical industry.

In-depth experimental analysis of pharmaceutical twin-screw wet granulation in view of detailed process understanding

Twin-screw wet granulation is gaining increasing interest within the pharmaceutical industry for the continuous manufacturing of solid oral dosage forms. However, limited prior fundamental physical understanding has been generated relating to the granule formation mechanisms and kinetics along the internal compartmental length of a twin-screw granulator barrel, and about how process settings, barrel screw configuration and formulation properties such as particle size, density and surface properties influence these mechanisms. One of the main reasons for this limited understanding is that experimental data is generally only collected at the exit of the twin-screw granulator barrel although the granule formation occurs spatially along the internal length of the barrel. The purpose of this study is to analyze the twin-screw wet granulation process using both hydrophilic and hydrophobic formulations, manufactured under different process settings such as liquid-to-solid ratio, mass throughput and screw speed, in such a way that the mechanisms occurring in the individual granulator barrel compartments (i.e., the wetting and different conveying and kneading compartments) and their impact upon granule formation are understood. To achieve this, a unique experimental setup was developed allowing granule characteristic data-collection such as size, shape, liquid and porosity distribution at the different compartments along the length of the granulator barrel. Moreover, granule characteristic information per granule size class was determined. The experimental results indicated that liquid-to-solid ratio is the most important factor dictating the formation of the granules and their corresponding properties, by regulating the degree of aggregation and breakage in the different compartments along the internal length of the twin-screw granulator barrel. Collecting appropriate and detailed experimental data about granule formation along the internal length of the granulator barrel is thus crucial for gaining fundamental physical understanding of the twin-screw wet granulation process.

CFD-DEM Modeling of an Industrial-Scale Wurster Coater

Large-scale fluid bed coating operations using Wurster coaters are common in the pharmaceutical industry. Experimental measurements of the coating thickness are usually analyzed for just few particles. To better predict the coating uniformity of the entire batch, computational techniques can be applied for process understanding of the key process parameters that influence the quality attributes. Recent advances in computational hardware, such as graphics processing unit, have enabled simulations of large industrial-scale systems. In this work, we perform coupled computational fluid dynamics-discrete element method simulations of a large-scale coater that model the actual particle sizes. The influence of process parameters, inlet air flow rate, atomizing air flow rate, bead size distribution, and Wurster gap height is studied. The focus of this study is to characterize the flow inside the coater; eventually, this information will be used to predict the coating uniformity of the beads. We report the residence time distribution of the beads inside the Wurster column, that is, the active coating zone, which serves as a proxy for the amount of coating received by the beads per pass. The residence time provides qualitative and quantitative measurements of the particle-coating uniformity. We find that inlet air flow rate has the largest impact on the flow behavior and, hence, the coating uniformity.

Detailed modeling and process design of an advanced continuous powder mixer

ABSTRACT A vertical in‐line continuous powder mixing device (CMT – Continuous Mixing Technology) has been modelled with the discrete element method (DEM) utilizing a calibrated cohesive contact model. The vertical design of the mixing device allows independent control of mean residence time (MRT) and shear rate. The hold‐up mass and outlet flow are controlled by an exit valve, located at the bottom of the in‐line mixer. A virtual design of experiments (DoE) of DEM simulations has been performed and parameters such as particle velocities, powder bed shape, residence time distribution (RTD), travel distance, and mixing quality are evaluated for the complete operating space. The RTD of the DEM model has been validated with tracer experiments. The resulting RTD has been fitted with an analytical form (generalized cascade of n continuous stirred tank reactors) and utilized to study the downstream response of the continuous mixing device to upstream fluctuations in the inlet material stream. The results indicate a high mixing quality and good filtering properties across the operating space. However, the combination of low hold‐up mass and high impeller speeds leads to a reduced filtering capability and wider exit valve openings, indicating a less desirable operating point.