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.

Quantification of surface composition and surface structure of inhalation powders using TOF-SIMS.

A multivariate TOF-SIMS methodology has been developed and applied to quantify surface composition and chemical distribution for dry powder blends. Surface properties are often critical to the behavior of powder formulations, especially in the case of dry powders for inhalation, as surface properties directly affect inter-particulate forces and, hence, the dispersibility of the formulation. The mass spectrum at each pixel was fit to a linear combination of reference spectra obtained by non-negatively constrained alternating least squares. From the pixel compositions, average surface coverage and a range of other image features were calculated. Two kinds of systems have been examined: 1) binary blends of lactose particles and coating agents, and 2) blends of different inhalation drugs with carrier lactose. For both kinds of systems, detailed insight into the surface composition and structure could be derived. For the former study, TOF-SIMS results were compared with a complementary surface analysis technique, XPS.

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.

Real time MRI to elucidate the functionality of coating films intended for modified release.

Polymer films based on mixtures of ethyl cellulose (EC) and hydroxypropyl cellulose (HPC) have been widely used to coat pellets and tablets to modify the release profile of drugs. For three different EC/HPC films we used 1H and 19F MRI in combination with a designed release cell to monitor the drug, polymer and water in 5 dimensional (5D) datasets; three spatial, one diffusion or relaxation and a temporal dimension, in real time. We observed that the water inflow through the films correlated with the initiation of the dissolution of the drug in the tablet beneath the film. Leaching of the pore forming HPC further accelerated water penetration and resulted in a drug release onset after a hydrostatic pressure was generated below the film indicated by positional changes of the film. For the more permeable film, both water ingress and drug egress showed a large variability of release over the film surface indicating the heterogeneity of the system. Furthermore, the 1H diffusion dataset revealed the formation of a gel layer of HPC at the film surface. We conclude that the setup presented provides a significant level of details, which are not achieved with traditional methods.

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.

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.

Imaging of Crystalline and Amorphous Surface Regions Using Time-of-Flight Secondary-Ion Mass Spectrometry (ToF-SIMS): Application to Pharmaceutical Materials.

The structure of a material, in particular the extremes of crystalline and amorphous forms, significantly impacts material performance in numerous sectors such as semiconductors, energy storage, and pharmaceutical products, which are investigated in this paper. To characterize the spatial distribution for crystalline-amorphous forms at the uppermost molecular surface layer, we performed time-of-flight secondary-ion mass spectroscopy (ToF-SIMS) measurements for quench-cooled amorphous and recrystallized samples of the drugs indomethacin, felodipine, and acetaminophen. Polarized light microscopy was used to localize crystallinity induced in the samples under controlled conditions. Principal component analysis was used to identify the subtle changes in the ToF-SIMS spectra indicative of the amorphous and crystalline forms for each drug. The indicators of amorphous and crystalline surfaces were common in type across the three drugs, and could be explained in general terms of crystal packing and intermolecular bonding, leading to intramolecular bond scission in the formation of secondary ions. Less intramolecular scission occurred in the amorphous form, resulting in a greater intensity of molecular and dimer secondary ions. To test the generality of amorphous-crystalline differentiation using ToF-SIMS, a different recrystallization method was investigated where acetaminophen single crystals were recrystallized from supersaturated solutions. The findings indicated that the ability to assign the crystalline/amorphous state of the sample using ToF-SIMS was insensitive to the recrystallization method. This demonstrates that ToF-SIMS is capable of detecting and mapping ordered crystalline and disordered amorphous molecular materials forms at micron spatial resolution in the uppermost surface of a material.

Investigation of the Effect of the Tortuous Pore Structure on Water Diffusion through a Polymer Film Using Lattice Boltzmann Simulations.

Understanding how the pore structure influences the mass transport through a porous material is important in several applications, not the least in the design of polymer film coatings intended to control drug release. In this study, a polymer film made of ethyl cellulose and hydroxypropyl cellulose was investigated. The 3D structure of the films was first experimentally characterized using confocal laser scanning microscopy data and then mathematically reconstructed for the whole film thickness. Lattice Boltzmann simulations were performed to compute the effective diffusion coefficient of water in the film and the results were compared to experimental data. The local porosities and pore sizes were also analyzed to determine how the properties of the internal film structure affect the water effective diffusion coefficient. The results show that the top part of the film has lower porosity, lower pore size, and lower connectivity, which results in a much lower effective diffusion coefficient in this part, largely determining the diffusion rate through the entire film. Furthermore, the local effective diffusion coefficients were not proportional to the local film porosity, indicating that the results cannot be explained by a single tortuosity factor. In summary, the proposed methodology of combining microscopy data, mass transport simulations, and pore space analysis can give valuable insights on how the film structure affects the mass transport through the film.

Novel method for visualizing water transport through phase-separated polymer films.

Drug release from oral pharmaceutical formulations can be modified by applying a polymeric coating film with controlled mass transport properties. Interaction of the coating film with water may crucially influence its composition and permeability to both water and drug. Understanding this interaction between film microstructure, wetting, and mass transport is important for the development of new coatings. We present a novel method for controlled wetting of polymer coating films in an environmental scanning electron microscope, providing direct visual information about the processes occurring as the film goes from dry to wet. Free films made of phase-separated blends of water-insoluble ethyl cellulose (EC) and water-soluble hydroxypropyl cellulose (HPC) were used as a model system, and the blend ratio was varied to study the effect on the water transport properties. Local variations in water transport through the EC/HPC films were directly observed, enabling the immediate analysis of the structure-mass transport relationships. The leaching of HPC could be studied by evaporating water from the films in situ. Significant differences were observed between films of varying composition. The method provides a valuable complement to the current approach of making distinct diffusion and microscopy experiments for studying the dynamic interaction of polymer films with water.

Effect of the manufacturing conditions on the structure and permeability of polymer films intended for coating undergoing phase separation.

The major aim of this work was to study the effect of two process parameters, temperature and coating flow, on permeability to water and structure of free films sprayed from mixtures of ethyl cellulose (EC), hydroxypropyl cellulose (HPC), and ethanol. The films were sprayed in a new spraying setup that was developed to mimic the film coating process in a fluid bed and to provide well controlled conditions. EC and HPC phase separated during the film drying process, and EC- and HPC-rich domains were formed. The process parameters had a great impact on the structure and the permeability to water of the films. The longer the time before the film structure was locked by a high film viscosity, that is, the lower the temperature and the higher the coating flow, the larger the domains and the lower the film permeability. The effective diffusion coefficient of water in the films varied by about six times within the range of the process parameters studied. Structures of sprayed films and water effective diffusion coefficients in sprayed films were compared to those of cast films. For the cast films, the domains were bigger, and the permeability to water was significantly lower compared to those of the sprayed films. The results indicate that the process parameters can be used as a mean to regulate structure and permeability of coating films undergoing phase separation.

Study of pharmaceutical coatings by means of NMR cryoporometry and SEM image analysis.

Nuclear magnetic resonance (NMR) cryoporometry and scanning electron microscopy (SEM) image analysis have been used to investigate the size and shape distribution of pores in pharmaceutical coatings. The coatings were made from a mixture of hydroxypropylcellulose (HPC) and ethylcellulose (EC). Upon solvent evaporation from a solution consisting of both the polymers, a solid polymer film is formed, which after removal of the water-soluble HPC consists of a skeleton of EC. A change in the amount of HPC enables modification of the water permeability through the films. By means of NMR cryoporometry, the presence of small pores (radius below 400 nm) was revealed with no significant change in the pore size distribution (PSD) as the HPC content in the films were changed. NMR cryoporometry showed the presence of channels of a characteristic 30-nm length scale in the films that contained more than 22% HPC. Below this threshold, the lack of interconnecting channels seems to prevent complete HPC dissolution and thereby the water permeability. SEM image analysis showed pore sizes that ranged from hundreds of nanometers up to few micrometers. Above the 22% threshold, further increase of HPC in the films resulted in an increased pore volume and wider PSD.

Water-based latex dispersions 4. Exchange dynamics and residence times of nonylphenol ethoxylate in concentrated latex dispersions.

The equilibrium residence times of the nonionic surfactant nonylphenol ethoxylate (NP100) in a latex dispersion were determined using NMR diffusometry. At 16% w/w particle concentration and 0.12, 0.43 and 0.81% w/w NP100, the residence times of the surfactant were 0.16, 1.02 and 4.73 s in solution (tau(A)) and 0.3, 0.37 and 0.61 s on the surface of the particles (tau(B)), respectively. At even higher particle concentration (>45% w/w), tau(A) and tau(B) were 1.47 and 2.2 s. Calculating the number of collisions that ought to result in adsorbed species, at 16% w/w, only 2, 5 and 2 per thousand (corresponding to 0.12, 0.43 and 0.81% w/w NP100) resulted in adsorption, whereas at >45% w/w, only 12 per thousand resulted in adsorption, which suggested that the surfactant was irreversibly adsorbed on the particles. The small increase in collision frequency with increased particle concentration could be a result of a diffusion controlled adsorption, while an energy barrier for desorption controlled the overall exchange dynamics in the dispersion. The slow dynamics in the dispersion was controlled, mainly by the nonylphenol group, which gave NP100 a strong preference to surfaces. In addition, the chain length of the poly(ethylene glycol) (PEG) group changed the solution behavior from being that of a typical surfactant to that of a polymer.

Evaluation of solid dispersion particles prepared with SEDS.

Formation of solid solution particles in the Solution Enhanced Dispersion by Supercritical fluids (SEDS) process from a model drug and two different types of carriers, mannitol and Eudragit E100 was evaluated. The crystal properties of samples and molecular interactions were investigated with DSC and FTIR, respectively. The effect of co-crystallisation of drug and mannitol on dissolution rate was studied. Even if a true one-phase solid dispersion was not obtained, the crystal structure of both drug and mannitol was mutually affected by the presence of the other. The drug was not in highly crystalline form in the co-precipitates. The interactions between the drug and mannitol could also be identified as hydrogen bonding between the amine or hydroxyl groups of the drug and the hydroxyl groups of mannitol. These interactions and changes in the crystal structure are probably directly related to the increase in the dissolution rate observed. A true solid solution was obtained when the drug was co-processed with Eudragit E100. A clear interaction between the acid hydroxyl group of the drug and the basic carbonyl group on the Eudragit E100 was observed. SEDS was shown to be an effective process for forming intimate blends and solid solutions for the drug and two different types of carriers.