Liquid Transport Rates during Binary Collisions of Unequally-sized Particles

In this paper, we study the liquid transport between particles of different sizes, as well as build a dynamic liquid bridge model to predict liquid transport between these two particles. Specifically, the drainage process of liquid adhering to two unequally-sized, non-porous wet particles is simulated using direct numerical simulations (DNS). Same as in our previous work (Wu et al., AIChE Journal, 2016, 62:1877–1897), we first provide an analytical solution of a proposed dynamic liquid bridge model. We find that such an analytical solution also describes liquid transport during collisions of unequally-sized particles very well. Finally, we show that our proposed model structure is sufficient to collapse all our direct numerical simulation data. Our model is hence able to predict liquid transport rates in size-polydisperse systems for a wide range of parameter

Numerical study on the effect of particle shape on mixers

Homogenization of particulate systems is a critical part in the processing of particulate materials to achieve consistency and ensure product quality. Homogenization is achieved by mixing, the aim is to obtain a final mixture that is homogeneous when mixing individual particulate constituents, in the sense of a uniform spatial mass distribution. Although there is always some measure of heterogeneity in a mixture this can be quantified by Gys sampling theory. This is critical for pharmaceutical industries in which it is essential that the variance of the active ingredients between tablets are within specified bounds. Although there have been numerous numerical studies on mixing using the Discrete Element Method (DEM), most studies to date have incorporated significant simplifications to reduce the computational time such as using mono-disperse size distributions, scaling up of particle size and spherical estimations of shape. The development of GPU based DEM simulations in the past few years significantly increased the number of spherical particles however most often at the expense of simplifying the physical interaction between particles. This oversimplification of particle shape has much wider primary implications as primary contact mechanisms such as angularity and locking are omitted. This is important in the pharmaceutical industry where the feed powders are often made from crystalline solids in which the shape of the individual particles are polyhedral. As this study demonstrates, this is significant in that the underlining dynamics of polyhedral particles is vastly different to that of spherical particles, resulting in tighter packing fractions different flow patterns, and percolation. In this paper we use the GPU based DEM code BlazeDEM3D-GPU to study and quantify the effect of particle shape in a high shear blade mixer

Characterization of the coating and tablet core roughness by means of 3D optical coherence tomography

This study demonstrates the use of optical coherence tomography (OCT) to simultaneously characterize the roughness of the tablet core and coating of pharmaceutical tablets. OCT is a high resolution non-destructive and contactless imaging methodology to characterize structural properties of solid dosage forms. Besides measuring the coating thickness, it also facilitates the analysis of the tablet core and coating roughness. An automated data evaluation algorithm extracts information about coating thickness, as well as tablet core and coating roughness. Samples removed periodically from a pan coating process were investigated, on the basis of thickness and profile maps of the tablet core and coating computed from about 480,000 depth measurements (i.e., 3D data) per sample. This data enables the calculation of the root mean square deviation, the skewness and the kurtosis of the assessed profiles. Analyzing these roughness parameters revealed that, for the given coating formulation, small valleys in the tablet core are filled with coating, whereas coarse features of the tablet core are still visible on the final film-coated tablet. Moreover, the impact of the tablet core roughness on the coating thickness is analyzed by correlating the tablet core profile and the coating thickness map. The presented measurement method and processing could be in the future transferred to in-line OCT measurements, to investigate core and coating roughness during the production of film-coated tablets

At-line validation of optical coherence tomography as in-line/at-line coating thickness measurement method

Optical Coherence Tomography (OCT) is a promising technology for monitoring of pharmaceutical coating processes. However, the pharmaceutical development and manufacturing require a periodic validation of the sensor's accuracy. For this purpose, we propose polyethylene terephthalate (PET) films as a model system, to periodically validate the measurements during manufacturing. This study proposes a new approach addressing the method validation requirement in the pharmaceutical industry and presents results for complementary methods. The methods investigated include direct measurement of the layer thickness using a micrometer gauge as reference, X-ray micro computed tomography, transmission and reflectance terahertz pulsed imaging, as well as 1D- and 3D-OCT. To quantify the significance of OCT for pharmaceutical coatings, we compared the OCT results for commercial Thrombo ASS and Pantoloc tablets with direct measurements of coating thickness via light microscopy of microtome cuts. The results of both methods correlate very well, indicating high intra- and inter-tablet variations in the coating thickness for the commercial tablets. The light microscopy average measured coating thickness of Thrombo ASS (Pantoloc) was 71.0 µm (83.7 µm), with an inter-coating variability of 8.7 µm (6.5 µm) and an intra-coating variability of 2.3 µm to 9.4 µm (2.1 µm to 6.7 µm)

Predicting capsule fill weight from in-situ powder density measurements using terahertz reflection technology

The manufacturing of the majority of solid oral dosage forms is based on the densification of powder. A good understanding of the powder behavior is therefore essential to assure high quality drug products. This is particularly relevant for the capsule filling process, where the powder bulk density plays an important role in controlling the fill weight and weight variability of the final product. In this study we present a novel approach to quantitatively measure bulk density variations in a rotating container by means of terahertz reflection technology. The terahertz reflection probe was used to measure the powder density using an experimental setup that mimics a lab-scale capsule filling machine including a static sampling tool. Three different grades of α-lactose monohydrate excipients specially designed for inhalation application were systematically investigated at five compression stages. Relative densities predicted from terahertz reflection measurements were correlated to off-line weight measurements of the collected filled capsules. The predictions and the measured weights of the powder in the capsules were in excellent agreement, where the relative density measurements of Lactohale 200 showed the strongest correlation with the respective fill weight (R 2 =0.995). We also studied how the density uniformity of the powder bed was impacted by the dosing process and the subsequent filling of the holes (with excipient powder), which were introduced in the powder bed after the dosing step. Even though the holes seemed to be filled with new powder (by visual inspection), the relative density in these specific segments were found to clearly differ from the undisturbed powder bed state prior to dosing. The results demonstrate that it is feasible to analyze powder density variations in a rotating container by means of terahertz reflection measurements and to predict the fill weight of collected capsules

Crystal shape modification via cycles of growth and dissolution in a tubular crystallizer

Besides size and polymorphic form, crystal shape takes a central role in engineering advanced solid materials for pharmaceutical and chemical industry. This work demonstrates how multiple cycles of growth and dissolution can manipulate the habit of an acetylsalicylic acid crystal population. Considerable changes of the crystal habit could be achieved within minutes due to rapid cycling, i.e., up to 25 cycles within <10 min. The required fast heating and cooling rates were facilitated using a tubular reactor design allowing for superior temperature control. The face specific interactions between solvent and the crystals’ surface result in face specific growth and dissolution rates and hence alterations of the final shape of the crystals in solution. Accurate quantification of the crystal shapes was essential for this work, but is everything but easy. A commercial size and shape analyser had to be adapted to achieve required accuracy. Online size, and most important shape, analysis was achieved using an automated microscope equipped with a flow-through cell, in combination with a dedicated image analysis routine for particle tracking and shape analysis. Due to the implementation of this analyser, capable of obtaining statistics on the crystals’ shape while still in solution (no sampling and manipulation required), the dynamic behaviour of the size shape distribution could be studied. This enabled a detailed analysis of the solvent’s effect on the change in crystal habit

Simulation Aided Pharmaceutical Hot Melt Extrusion Process Understanding, Setup and Scale-up

During the pharmaceutical product development it is important, especially in the early phases, on get a good idea on the processability of the candidate formulations. Especially for hot melt extrusion (HME) based formulations choosing the appropriate equipment and process setup that will result in the desired product quality is not trivial. Especially significant in the early phases of the product development cycle, where typically only small amounts of active pharmaceutical ingredients (API) are available (often in the rage of couple of grams only), it is crucial to still be able to give educated guesses on the processability of the formulation, the expected product quality and, ideally, being able to propose candidate process setups. In order to fulfil the goals mentioned above, development of formulation and process specific knowledge is required, as well as development of potent in silico methodologies capable of mirroring the actual process itself. This work focuses on the development of suitable in silico tools for the accurate HME process capturing, extended experimental investigations and product quality correlation and prediction.DiV2-(03) page 1DiV2-(03) page 5

The Future of Pharmaceutical Manufacturing Sciences

ABSTRACTThe entire pharmaceutical sector is in an urgent need of both innovative technological solutions and fundamental scientific work, enabling the production of highly engineered drug products. Commercial-scale manufacturing of complex drug delivery systems (DDSs) using the existing technologies is challenging. This review covers important elements of manufacturing sciences, beginning with risk management strategies and design of experiments (DoE) techniques. Experimental techniques should, where possible, be supported by computational approaches. With that regard, state-of-art mechanistic process modeling techniques are described in detail. Implementation of materials science tools paves the way to molecular-based processing of future DDSs. A snapshot of some of the existing tools is presented. Additionally, general engineering principles are discussed covering process measurement and process control solutions. Last part of the review addresses future manufacturing solutions, covering continuous processing and, specifically, hot-melt processing and printing-based technologies. Finally, challenges related to implementing these technologies as a part of future health care systems are discussed

The effect of liquid bridge model details on the dynamics of wet fluidized beds

Wet fluidized beds of particles in small periodic domains are simulated using the CFD-DEM approach. A liquid bridge is formed upon particle-particle collisions, which then ruptures when the particle separation exceeds a critical distance. The simulations take into account both surface tension and viscous forces due to the liquid bridge. We perform a series of simulations based on different liquid bridge formation models: (1) the static bridge model of Shi and McCarthy, (2) a simple static version of the model of Wu et al., as well as (3) the full dynamic bridge model of Wu et al. We systematically compare the differences caused by different liquid bridge formation models, as well as their sensitivity to system parameters. Finally, we provide recommendations for which systems a dynamic liquid bridge model must be used, and for which application this appears to be less importan

Relative Contributions of Solubility and Mobility to the Stability of Amorphous Solid Dispersions of Poorly Soluble Drugs: A Molecular Dynamics Simulation Study

Amorphous solid dispersions are considered a promising formulation strategy for the oral delivery of poorly soluble drugs. The limiting factor for the applicability of this approach is the physical (in)stability of the amorphous phase in solid samples. Minimizing the risk of reduced shelf life for a new drug by establishing a suitable excipient/polymer-type from first principles would be desirable to accelerate formulation development. Here, we perform Molecular Dynamics simulations to determine properties of blends of eight different polymer–small molecule drug combinations for which stability data are available from a consistent set of literature data. We calculate thermodynamic factors (mixing energies) as well as mobilities (diffusion rates and roto-vibrational fluctuations). We find that either of the two factors, mobility and energetics, can determine the relative stability of the amorphous form for a given drug. Which factor is rate limiting depends on physico-chemical properties of the drug and the excipients/polymers. The methods outlined here can be readily employed for an in silico pre-screening of different excipients for a given drug to establish a qualitative ranking of the expected relative stabilities, thereby accelerating and streamlining formulation development