Seán McSweeney

Blend uniformity analysis of pharmaceutical products by Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS).

Blend uniformity analysis (BUA) is a routine and highly regulated aspect of pharmaceutical production. In most instances, it involves quantitative determination of individual components of a blend in order to ascertain the mixture ratio. This approach often entails the use of costly and sophisticated instrumentation and complex statistical methods. In this study, a new and simple qualitative blend confirmatory test is introduced based on a well known acoustic phenomenon. Several over the counter (OTC) product powder blends are analysed and it is shown that each product has a unique and highly reproducible acoustic signature. The acoustic frequency responses generated during the dissolution of the product are measured and recorded in real time. It is shown that intra-batch and inter-batch variation for each product is either insignificant or non-existent when measured in triplicate. This study demonstrates that Broadband Acoustic Resonance Dissolution Spectroscopy or BARDS can be used successfully to determine inter-batch variability, stability and uniformity of powder blends. This is just one application of a wide range of BARDS applications which are more cost effective and time efficient than current methods.

HfO 2 high-k dielectric layers in air-coupled capacitive ultrasonic transducers

For air-coupled applications, broadband capacitive ultrasonic transducers (CUTs) at the mm to cm scale are often desirable. Improved device performance may be obtained by etching well-defined geometric features into a silicon backplate electrode, then using a metallized polymer film as the other electrode. The use of additional dielectric coatings for devices at this scale may have a number of beneficial effects. This work investigates the use of HfO2 high-k dielectric coatings on the backplate electrodes of air-coupled CUTs. A range of such devices was constructed and used in a through-transmission configuration. Different thickness HfO2 layers were investigated at different bias voltages, and the effects on the sensitivity and bandwidth of the devices were analyzed. The predicted capacitance of each device was within 7% of the measured capacitance, with variations due to additional trapped air and manual assembly. Increasing the HfO2 layer thickness decreased the overall capacitance of the CUT as expected, but produced significant improvements in device sensitivity and bandwidth at certain bias voltages. A strong correlation between HfO2 high-k dielectric layer thickness and peak-to-peak amplitude was observed. The variation in device operation after successive bias charge/discharge cycles also become consistently less as the HfO2 layer thickness was increased.

A tethered front-plate electrode CMUT for broadband air-coupled ultrasound

Capacitive micromachined ultrasonic transducers (CMUTs) typically consist of a back-plate electrode on a substrate wafer, separated from a front-plate electrode by a small cavity. The electrode structures are usually sealed and when operating in air the majority of these CMUTs are highly resonant. However, for air-coupled applications, this sealing is not strictly necessary allowing other more open electrode structures to be explored. A CMUT structure specifically for air-coupled operation was investigated, consisting of a front-plate electrode that was tethered at only a few points around its periphery. The front-plate was also perforated to increase the overall squeeze-film damping and hence the bandwidth of the device. A series of CMUTs up to 800 μm by 800 μm square was manufactured in a standard CMOS process, using a sacrificial polyimide etch to leave a free-standing aluminum front-plate electrode 1.0 μm thick with a nominal electrode gap of 1.5 μm. A number of thin tethers along the device edges attached the front-plate electrode to the substrate, producing a CMUT structure that was completely open at the edges, with low front-plate stiffness and high squeeze-film damping. A one-dimensional analytical model was formulated to predict the response of the devices, and compared to the measured response of the manufactured CMUTs. The structures were not optimized, but initial results on the prototypes were promising. The devices had a pull-in voltage of only 5 V and a nominal capacitance of 70 pF. The devices were tested as transmitters and receivers over a 15 mm path in air, using a well-characterized broadband transducer as a standard transmitter or receiver. The tethered CMUTs had a center frequency of 400 kHz with a usable bandwidth of over 1 MHz in air, giving a Q-factor of less than 1. However, the devices were not very efficient, with an insertion loss of almost 70 dB and highly damped, as expected. The analytical model also gave reasonably good agreement with the experimental measurements.

A parallel-architecture parametric equalizer for air-coupled capacitive ultrasonic transducers

Parametric equalization is rarely applied to ultrasonic transducer systems, for which it could be used on either the transmitter or the receiver to achieve a desired response. An optimized equalizer with both bump and cut capabilities would be advantageous for ultrasonic systems in applications in which variations in the transducer performance or the properties of the propagating medium produce a less-than-desirable signal. Compensation for non-ideal transducer response could be achieved using equalization on a device-by-device basis. Additionally, calibration of ultrasonic systems in the field could be obtained by offline optimization of equalization coefficients. In this work, a parametric equalizer for ultrasonic applications has been developed using multiple bi-quadratic filter elements arranged in a novel parallel arrangement to increase the flexibility of the equalization. The equalizer was implemented on a programmable system-on-chip (PSOC) using a small number of parallel 4th-order infinite impulse response switched-capacitor band-pass filters. Because of the interdependency of the required coefficients for the switched capacitors, particle swarm optimization (PSO) was used to determine the optimum values. The response of a through-transmission system using air-coupled capacitive ultrasonic transducers was then equalized to idealized Hamming function or brick-wall frequency-domain responses. In each case, there was excellent agreement between the equalized signals and the theoretical model, and the fidelity of the time-domain response was maintained. The bandwidth and center frequency response of the system were significantly improved. It was also shown that the equalizer could be used on either the transmitter or the receiver, and the system could compensate for the effects of transmitter-receiver misalignment.

pH Dependence of the Dissolution Rate of Enteric- Coated Drug Spheres Determined by Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS)

Enteric coatings are widely used in formulations of drug delivery spheres. The coating protects an active pharmaceutical ingredient (API) from acidic conditions in the low pH environment of the stomach. The coating breaks down readily at higher pH in the lower intestine to allow absorption of the API. The thickness of the enteric coating is one of the factors that determine the release rate of the drug in the gastrointestinal tract. It is difficult to determine the loading of the drug layer and enteric coating on the core support sphere without conventional dissolution testing during and post manufacture. Broadband acoustic resonance dissolution spectroscopy (BARDS) potentially offers a new, rapid approach to characterizing enteric coatings during their manufacture. BARDS applications are based on reproducible changes in the compressibility of a solvent during dissolution, which is monitored acoustically via associated changes in the frequency of induced acoustic resonances. Two drug sphere formulations that yield characteristic and reproducible data were investigated. A steady-state acoustic lag time is associated with the disintegration of the enteric coating and drug layer in basic solution. This lag time is pH dependent and is indicative of the rate at which the coating and layers dissolve. BARDS analysis has the potential to characterize drug sphere formulations at-line in very short timescales. BARDS represents a complementary technique to conventional dissolution testing that could be used in precompliance testing for quality assurance during manufacture. BARDS data, in the future, may also be indicative of the likely performance of a formulation under USP dissolution testing.

Improving the bandwidth of air coupled capacitive ultrasonic transducers using selective networks

One of the key limitations on using CUT (capacitive ultrasonic transducers) and cMUTs (capacitive micromachined ultrasonic transducers) in air is their relatively narrow bandwidth which although superior to that of current piezoceramic devices could be improved. Most air coupled capacitive devices could benefit hugely through the use of selective networks for bandwidth expansion, resonance reinforcing, or a combination of both. This work has investigated the application of pole/zero manipulation techniques to modify and enhance the transmission characteristics of capacitive transducers through front end mounted components. The main objective was to positively enhance the performance characteristics of capacitive transducers. A modified electrical equivalent circuit for CUTs to include the selective networks used was developed. The work assessed the effects of a tuned amplifier on the passband of the devices studied and then focused on more complicated network designs for enhancement. Simulations of the effects of the networks on the devices using equivalent circuit models were carried out and the response curves to pulsed operation were calculated and compared to experimental measurements from a pair of fixed CUTs with a combined centre frequency of 280 kHz and 3 dB bandwidth of 160 kHz. Increases in centre frequency of 25% and 3 dB bandwidth of 77% using a single tuned amplifier were obtained. Resonance reinforcing, resonance shifting and ripple suppression were also studied through the manipulation of the q factor and pole location of such an amplifier. Performance enhancements were studied for a number of CUT aperture sizes and membrane thicknesses and a comparative study of the theoretical and experimental effect of these variations was conducted. With the appropriately designed network, enhancement of peak resonance with a simultaneous bandwidth expansion was obtained at the expense of other operating parameters such as stopband ripple. Simulations of more complicated circuit designs using equivalent circuit models of capacitive devices showed that the maximum level of passband ripple observed for the bandwidth expansion method using a single tuned amplifier was reduced while achieving simultaneously the same 3 dB results. The implication for bandwidth expansion of a capacitive transducer through selective network design is significant, allowing increased resolution in imaging systems, ultrasonic ranging and non destructive evaluation. Significant improvements have been observed without additional signal manipulation, through digital means or otherwise, in certain transmission properties of the devices. Future work will expand on the enhancement of capacitive transducers through the use of hybrid resonator circuits and other related methods.

Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS) – A novel approach to investigate the wettability of pharmaceutical powder blends

The ability of broadband acoustic resonance dissolution spectroscopy (BARDS) to assess the wettability of powder blends is investigated. BARDS is a novel analytical technology developed on the basis of the change in acoustic phenomena observed when material is added into a solvent under resonance. Addition of solid material to the solvent results in the introduction of gas (air) into the solvent, changing the compressibility of the solvent system, and reducing the velocity of sound in the solvent. As a material is wetted and dissolved, the gas is released from the solvent and resonance frequency is altered. The main purpose of this work is to demonstrate the ability of BARDS to assess differences in the wetting behavior of tablet excipients (microcrystalline cellulose (MCC) and magnesium stearate (MgSt)) and a model drug (metoclopramide hydrochloride) as single component powders and multicomponent powder blends. BARDS acoustic responses showed a prolonged release of gas for the powdered blends with lubricant compared to unlubricated blends. As the elimination of gas from the solvent was assumed to follow first order elimination kinetics, a compressible gas elimination rate constant was calculated from the log plots of the gas volume profiles. The gas elimination rate constant was used as a parameter to compare the release of gas from the powder introduced to the solvent and hence the powder wetting behavior. A lower gas elimination rate constant was measured for lubricated blends compared to nonlubricated blends, suggesting the prolonged hydration of lubricated blends. Standard wetting techniques such as contact angle measurements and wetting time analysis were also used to analyze the blends and confirmed differences in wetting behavior determined by BARDS. The study results demonstrate the capability of BARDS as a rapid, analytical tool to determine the wetting behavior of the pharmaceutical powder blends and the potential of BARDS as a process analytical technology (PAT) tool.

Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS): A Rapid Test for Enteric Coating Thickness and Integrity of Controlled Release Pellet Formulations.

Graphical abstract Figure. No Caption available. Abstract There are no rapid dissolution based tests for determining coating thickness, integrity and drug concentration in controlled release pellets either during production or post‐production. The manufacture of pellets requires several coating steps depending on the formulation. The sub‐coating and enteric coating steps typically take up to six hours each followed by additional drying steps. Post production regulatory dissolution testing also takes up to six hours to determine if the batch can be released for commercial sale. The thickness of the enteric coating is a key factor that determines the release rate of the drug in the gastro‐intestinal tract. Also, the amount of drug per unit mass decreases with increasing thickness of the enteric coating. In this study, the coating process is tracked from start to finish on an hourly basis by taking samples of pellets during production and testing those using BARDS (Broadband Acoustic Resonance Dissolution Spectroscopy). BARDS offers a rapid approach to characterising enteric coatings with measurements based on reproducible changes in the compressibility of a solvent due to the evolution of air during dissolution. This is monitored acoustically via associated changes in the frequency of induced acoustic resonances. A steady state acoustic lag time is associated with the disintegration of the enteric coatings in basic solution. This lag time is pH dependent and is indicative of the rate at which the coating layer dissolves. BARDS represents a possible future surrogate test for conventional USP dissolution testing as its data correlates directly with the thickness of the enteric coating, its integrity and also with the drug loading as validated by HPLC.

Studies of air-coupled capacitive ultrasonic transducers with TiO 2 high-k dielectric backplate electrode coatings

Capacitive ultrasonic transducers for operation in air typically consist of a rigid backplate electrode and a movable flexible membrane electrode. The backplate is often contoured or textured to modify the frequency response and sensitivity of the device, and the membrane electrode is typically a metallized dielectric polymer film. The compliance of the air in the gap between the two electrodes provides the restoring force for the membrane. The sensitivity of these devices would be increased if the dielectric constant k of the membrane electrode could be increased, but suitable high-k materials are often not found in membrane form. Also, most polymer membrane materials are relatively fragile; metal foils may be used as membrane electrodes in harsh environments, but lack the additional dielectric effect of the polymer membranes. Hence, the inclusion of a high-k dielectric layer on the backplate electrode should increase the device capacitance and hence its sensitivity. Earlier work investigated the use of HfO2 high-k layers in this regard. This latest work has investigated the effect of using TiO2 high-k layers on the backplate electrode of an air-coupled capacitive ultrasonic transducer for enhanced operation in air. A series of reproducibly textured backplate electrodes were micromachined, consisting of a regular array of small pits etched into a silicon substrate, and then electroded with platinum. A layer of TiO2 high-k dielectric material was then deposited to different depths on a selection of backplates. A metallized 5 μm PET membrane electrode was then used to produce a range of capacitive ultrasonic transducers for operation in air. These devices were then tested and characterized as transmitters and receivers, and the effects of the TiO2 layers investigated. The capacitance of the devices was modeled to include the capacitances of the active pits and the parasitic capacitance of the intermediate areas, and measurements were in good agreement with the predicted values. The effect of TiO2 high-k layer thickness on device sensitivity and fractional bandwidth was investigated experimentally, and both were seen to increase with the TiO2 layer thickness, as expected. These latest devices with a TiO2 layer were less sensitive than earlier devices with equivalent layers of HfO2 high-k dielectric due to the lower breakdown voltage and dielectric characteristics of TiO2.