Lauren Briens

The Effect of Moisture on the Flowability of Pharmaceutical Excipients

The effect of moisture content on flowability of six pharmaceutical powders (microcrystalline cellulose (MCC), hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose (CMC), polyvinylpyrrolidone (PVP), corn starch, and potato starch) was investigated. Powder flowability was measured using established static techniques and emerging dynamic avalanche behavior measurements. Static techniques did not provide enough resolution to clearly identify changes in flowability due to increasing powder moisture content. Avalanche time and its standard deviation showed that flowability of MCC, CMC, PVP, and potato starch decreased after a critical moisture content, flowability of corn starch increased and flowability did not significantly change for HPMC. The moisture decreased flowability by forming stronger interparticle liquid bridges and increased flowability by acting as a lubricant. The dynamic density of the celluloses and PVP decreased linearly with increasing moisture content as the particles swelled with water. The starches also swelled and decreased in dynamic density, but only after a moisture content corresponding to monolayer coverage of water around the particles was reached. As flowability and dynamic density change with moisture content, to ensure consistent production of high-quality tablets, the moisture content of the powders must be measured and controlled.

A review of monitoring methods for pharmaceutical wet granulation.

High-shear wet granulation is commonly used in the pharmaceutical industry to improve powder properties for downstream processes such as tabletting. Granule growth, however, is difficult to predict because the process is sensitive to raw material properties and operating conditions. Development of process analytical technologies is encouraged by regulatory bodies to improve process understanding and monitor quality online. The primary technologies investigated for high-shear wet granulation monitoring include power consumption, near-infrared spectroscopy, Raman spectroscopy, capacitance measurements, microwave measurements, imaging, focused beam reflectance measurements, spatial filter velocimetry, stress and vibration measurements, as well as acoustic emissions. This review summarizes relevant research related to each of these technologies and discusses the challenges associated with each approach as a possible process analytical technology tool for high-shear wet granulation.

Detection of local fluidization characteristics using the V statistic

Abstract Defluidized zones degrade the performance of fluidized beds. Triboelectric currents at the distributor were measured in a variety of gas–solid fluidized beds. A V statistic below 1.5 ms −0.5 indicated a defluidized zone. This criterion allowed detection of defluidized zones in an industrial bed within 100 ms and is thus suitable for process control.

Minimum liquid fluidization velocity in gas-liquid-solid fluidized beds of low-density particles

Phase properties evolve in biological and biochemical three-phase fluidization processes and thus it is essential to continuously monitor the fluidization regime. The density of the solids used in these processes is usually only slightly higher than the liquid density. Many techniques used to determine the minimum liquid fluidization velocity of systems with heavier solids do not work with lower-density solid systems. For gas-liquid-solid systems over a wide range of solid densities, the minimum liquid fluidization velocity can be determined from the coefficient of variation of V-statistic of the integrated-bed pressure gradient and the derivative of local conductivity.

Audible acoustics in high-shear wet granulation: application of frequency filtering.

Previous work has shown analysis of audible acoustic emissions from high-shear wet granulation has potential as a technique for end-point detection. In this research, audible acoustic emissions (AEs) from three different formulations were studied to further develop this technique as a process analytical technology. Condenser microphones were attached to three different locations on a PMA-10 high-shear granulator (air exhaust, bowl and motor) to target different sound sources. Size, flowability and tablet break load data was collected to support formulator end-point ranges and interpretation of AE analysis. Each formulation had a unique total power spectral density (PSD) profile that was sensitive to granule formation and end-point. Analyzing total PSD in 10 Hz segments identified profiles with reduced run variability and distinct maxima and minima suitable for routine granulation monitoring and end-point control. A partial least squares discriminant analysis method was developed to automate selection of key 10 Hz frequency groups using variable importance to projection. The results support use of frequency refinement as a way forward in the development of acoustic emission analysis for granulation monitoring and end-point control.

The Effect of Lubricants on Powder Flowability for Pharmaceutical Application

Pharmaceutical tablets are manufactured through a series of batch steps finishing with compression into a form using a tablet press. Lubricants are added to the powder mixture prior to the tabletting step to ensure that the tablet is ejected properly from the press. The addition of lubricants also affects tablet properties and can affect the behavior of the powder mixture. The objective of this research was to investigate the effect of lubricants on powder flowability as flowability into the tablet press is critical. Four lubricants (magnesium stearate, magnesium silicate, stearic acid, and calcium stearate) were mixed, in varying amounts, with spray-dried lactose. In addition, magnesium stearate was also mixed with placebo granules from a high-shear granulator. Measurements based on avalanche behavior indicated flowability potential and dynamic density and were more sensitive to changes in the mixture and provided a more accurate and reproducible indication of flowability than traditional static measurements. Of the tested lubricants, magnesium stearate provided the best increase in flowability even in the low amounts commonly added in formulations.

A Comparison of Granules Produced by High-Shear and Fluidized-Bed Granulation Methods

Placebo granules were manufactured by both wet high-shear and fluidized-bed techniques. The granules were compared based on size, shape, surface morphology, and a variety of different flowability measurements. This comparison showed that granule formation and growth were different, with induction growth for high-shear granulation and steady growth for fluidized-bed granulation. Final granules from high-shear granulation were more spherical and dense compared with the irregular granules from fluidized-bed granulation. The high-shear granules demonstrated better overall flow properties.

The effect of process parameters on audible acoustic emissions from high-shear granulation

Product quality in high-shear granulation is easily compromised by minor changes in raw material properties or process conditions. It is desired to develop a process analytical technology (PAT) that can monitor the process in real-time and provide feedback for quality control. In this work, the application of audible acoustic emissions (AAEs) as a PAT tool was investigated. A condenser microphone was placed at the top of the air exhaust on a PMA-10 high-shear granulator to collect AAEs for a design of experiment (DOE) varying impeller speed, total binder volume and spray rate. The results showed the 10 Hz total power spectral densities (TPSDs) between 20 and 250 Hz were significantly affected by the changes in process conditions. Impeller speed and spray rate were shown to have statistically significant effects on granulation wetting, and impeller speed and total binder volume were significant in terms of process end-point. The DOE results were confirmed by a multivariate PLS model of the TPSDs. The scores plot showed separation based on impeller speed in the first component and spray rate in the second component. The findings support the use of AAEs to monitor changes in process conditions in real-time and achieve consistent product quality.

Characterization of channelling in multiphase systems. Application to a liquid fluidized bed of angular Biobone particles

Abstract Liquid fluidized beds of angular particles exhibit channelling. Unsteady-state tracer injection experiments do not allow accurate detection of channelling. Two new, more sensitive, techniques to estimate channelling were developed: local conductivity measurements within the bed and cross-sectional averafe conductivity measurements from steady-state liquid tracer injections into the bed. The complete fluidization velocity can be estimated from local conductivity measurements and from the fractal dimension of unsteady-state tracer injections both into the bed and upstream of it. Jet mixing is a practical and effective method for reducing channelling in liquid fluidized beds without increasing particle entrainment.

Passive acoustic emissions from particulates in a V-blender.

Abstract Context: Regulatory agencies are recommending the development of process analytical technologies (PAT) to improve the efficiency and product quality during pharmaceutical manufacturing. Objective: The objective of the research was to investigate the potential application of passive acoustic emission monitoring of a V-blender. Materials and methods: Trials were conducted with sugar spheres, lactose or MCC in a V-blender. Vibrations from acoustic emissions were measured using PCB Piezotronics accelerometers with ICP signal conditioners. Results and discussion: A wavelet filter was applied to the measured acoustic emissions to remove vibrations from the tumbling motion of the V-shell, allowing a focus on information about particle motion and interactions within the V-shell. The ideal sensor location was determined to be the lid of one of the V-shell arms due to the impact of the tumbling particles on the lid and transmission of the vibrations from other particle motion within the V-shell. The amplitude of vibrations increased with particle size due to larger particle momentum before a collision. The fill level and the V-shell scale also influenced the measured vibrations as particle motion was affected which in turn affected momentum. Changes in particle flowability could be detected through variations in the measured acoustic emissions. Conclusion: The measured vibrations from passive acoustic emissions reflected particle motion and interactions within a V-blender demonstrating potential as a monitoring method.