Broadband Acoustic Resonance Dissolution Spectroscopy Research Articles

Broadband acoustic resonance dissolution spectroscopy of natural edible salts: Visualization and interpretation for descriptive and diagnostic analysis

Broadband acoustic resonance dissolution spectroscopy (BARDS) has been recently introduced as a low-cost method for the analysis of powdered materials. In this study, ten Iranian natural table salts, each separated into five particle size fractions, were analyzed with BARDS. The compositions and crystalline structure of samples were investigated with inductively coupled plasma optical emission spectroscopy, flame photometry, and X-ray diffraction methods. Moreover, different linear and nonlinear dimensionality reduction methods were used to visualize the ten salt types. The analyses revealed the presence of halite, sylvite, and anhydrite in the rock salts, and halite, bischofite, and periclase in the sea salts. Subjecting bubble volume spectra to nonlinear dimensionality reduction using the t-distributed stochastic neighbor embedding algorithm, the salts were clearly distinguished in a two-dimensional space with the distances and positions relative to their composition, crystalline structure, and particle morphology. The results of this study provide a roadmap toward unraveling the underlying mechanisms behind the BARDS spectra for further applications in characterizing natural edible salts.

Sounding out falsified medicines from genuine medicines using Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS)

The trade in falsified medicine has increased significantly and it is estimated that global falsified sales have reached $100 billion in 2020. The EU Falsified Medicines Directive states that falsified medicines do not only reach patients through illegal routes but also via the legal supply chain. Falsified medicines can contain harmful ingredients. They can also contain too little or too much active ingredient or no active ingredient at all. BARDS (Broadband Acoustic Resonance Dissolution Spectroscopy) harnesses an acoustic phenomenon associated with the dissolution of a sample (tablet or powder). The resulting acoustic spectrum is unique and intrinsic to the sample and can be used as an identifier or signature profile. BARDS was evaluated in this study to determine whether a product is falsified or genuine in a rapid manner and at lower cost than many existing technologies. A range of genuine and falsified medicines, including falsified antimalarial tablets from south-east Asia, were tested, and compared to their counterpart genuine products. Significant differences between genuine and falsified doses were found in their acoustic signatures as they disintegrate and dissolve. Principal component analysis was employed to differentiate between the genuine and falsified medicines. This demonstrates that the tablets and capsules included here have intrinsic acoustic signatures which could be used to screen the quality of medicines.

Sounding out stability of enteric coated dosage forms using Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS)

Stability testing is essential in the pharmaceutical industry to determine product shelf- life and the conditions under which drug products should be stored. Stability testing involves a complex set of procedures, considerable cost, time, and scientific expertise to build quality, efficacy and safety in a drug formulation. This paper highlights a new complementary approach to stability testing called Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS). BARDS measurements are based on reproducible changes in the compressibility of a solvent during dissolution. It is monitored acoustically via associated changes in the frequency of induced acoustic resonances. This study presents a novel approach to track the change of various drug formulations to determine the formulation's stability. Pellets, tablet and multiple-unit pellet system (MUPS) formulations were investigated to examine the effect of polymer coating and formulation core degradation over time. In combination with minimal usage of Ultra Violet - Visible Spectroscopy, BARDS can effectively track these changes. The technique offers a rapid approach to characterizing pharmaceutical formulations. BARDS can enable rapid development of solid drug formulation dissolution and disintegration testing as an In-Process Control test and drug stability analysis. The data show that a solid oral dose formulation has an intrinsic acoustic signature specific to the method of manufacture, excipient composition and elapsed time since the production of a product. BARDS data are also indicative of which aspect of a formulation may be unstable, whether a coating, sub-coating or core. It is potentially a time-efficient, cost-effective and greener approach to testing coating stability, disintegration and overall formulation stability.

Modelling of gas evolution during powder rehydration for Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS)

As a powder wets and dissolves in a liquid, trapped gas bubbles are released and the measurement of the evolution of gas volume versus time can be used to quantify the ease with which powder wets and dissolves in the liquid. This phenomenon forms the basis of the BARDS analytical measurement technique. To complement this experimental approach, a model of the evolution of gas bubbles from a powder into a liquid during powder dispersion and solubilisation is presented. The model is validated against experimental data from the rehydration of Milk Protein Isolate (MPI) powder; both in its original state, and in the agglomerated state and is shown to match the experimental data with good accuracy. Use of the model facilitates a fuller interpretation of the experimental BARDS data and the values of dispersion and solubilisation rate constants can be applied for quantitatively comparing the behaviour of powders. It also permits development of robust rehydration parameters from the experimental BARDS signal.

Broadband acoustic resonance dissolution spectroscopy as a rapid tool for the compositional analysis of food powders: A case study of edible salts

Broadband acoustic resonance dissolution spectroscopy (BARDS) is a novel method that can be used for the analysis of food-based powders, which are mainly characterized by their composition and particle morphology. This study aimed to evaluate BARDS for the compositional analysis of food powders. The changes in the BARDS spectra due to the changes in composition and particle morphology of fifteen salt mixtures (constituting of NaCl, KCl, and MgCl2) in five particle size ranges were comprehensively studied. Moreover, different regression methods were utilized to estimate each mixture component content. The results revealed that the average time–frequency spectra of each mixture in a certain particle size class were highly distinct and allowed discrimination from others. The unique spectra of each salt mixture originated from the specific dissolution rate and degassing effect of each constitutive compound. Finally, the accurate prediction of each mixture component content confirmed the consistency and efficiency of the method.

The sound of tablets during coating erosion, disintegration, deaggregation and dissolution.

This research aims to address a gap in our understanding of the mechanisms by which pharmaceutical tablets achieve highly reproducible and predictable drug release. The present industrial and regulatory practice is centred around tablet dissolution, i.e. what follows disintegration, yet the vast majority of problems that are found in formulation dissolution testing can be traced back to the erratic disintegration behaviour of the medicinal product. It is only due to the distinct lack of quantitative measurement techniques for disintegration analysis that this situation arises. Current methods involve costly, and time-consuming test equipment, resulting in a need for more simple, green and efficient methods which have the potential to enable rapid development and to accelerate routine solid drug formulation dissolution and disintegration testing. In this study, we present a novel approach to track several sequential tablet dissolution processes, including coating erosion, disintegration, deaggregation and dissolution using Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS). BARDS, in combination with minimal usage of UV spectroscopy, can effectively track these processes. The data also show that a solid oral dose formulation has an intrinsic acoustic signature which is specific to the method of manufacture and excipient composition.

Effects of spraying surfactants in a fluidised bed on the rehydration behaviour of milk protein isolate powder

Milk protein isolate (MPI) powder is a difficult to rehydrate powder displaying poor wettability and slow dissolution. In this study, MPI powder was top-sprayed with surfactants (Tween 80 and lecithin) in a fluidised bed to investigate the effect of surfactants on the rehydration behaviour. The wetting behaviour of MPI covered by the surfactants was greatly improved except for 4% lecithin. The wetting time of lecithinated MPI decreased to 42 s compared with MPI of 36 min. The Tween coated powders and larger size fractions displayed faster wetting attaining a minimum wetting time of 15 s. The rate of dissolution was not influenced by the presence of the surfactants as the particles continued to slowly dissolve. Broadband acoustic resonance dissolution spectroscopy (BARDS) showed that the gas release behaviour of surfactant covered MPI was totally altered and accelerated in comparison to the MPI powder, especially for Tween 80.

A rapid in-process control (IPC) test to monitor the functionality of taste masking polymer coatings using Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS).

Monitoring of the coating end-point of functional coatings during the coating application process is desirable. Since currently available PAT methods require expensive test equipment, there is a need for a rapid test that can easily be applied without major investment. BARDS is a novel technique that has the potential to economise the production process of these kinds of pellet and tablet formulations. The thickness of a controlled release coating is a key factor that determines the release rate of the drug in the gastro-intestinal tract or other targeted functionalities such as taste masking or moisture protection. Correspondingly, the amount of drug per unit mass of pellets decreases with increasing thickness of the functional coating. In this study, the functional polymer loading of the coating process is investigated by testing pellets via BARDS technology (Broadband Acoustic Resonance Dissolution Spectroscopy). The technique offers a rapid approach (<200 s) to characterising functional coatings at-line during their manufacture. Measurements 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. In case of enteric coatings a steady state acoustic lag time is associated with the erosion of the enteric coatings in acidic dissolution test media. This lag time is indicative of the coating layer thickness, assuming that the quality of the film coating is high. BARDS represents a possible future surrogate test for IPC testing, as a PAT method and possibly also for conventional USP dissolution testing. BARDS data correlate directly with the thickness of the functional coating, its integrity and also with the drug loading as validated by UV-Vis spectroscopy.

Application of broadband acoustic resonance dissolution spectroscopy (BARDS) to the gas release behaviour during rehydration of milk protein isolate agglomerates

The BARDS technique was applied in this study to acoustically assess the rehydration behaviour of milk protein isolate (MPI) agglomerates and to compare with regular MPI powder. The results showed that BARDS has potential to monitor the rehydration behaviour of agglomerates. The greater porosity (>70%) of agglomerated powders introduced more compressible gas into the water. The BARDS profile showed that there was faster initial gas release from the agglomerates, indicating better wetting and dispersion ability of the agglomerates with shorter tM (time of maximum gas volume in solution). At 0.10% powder addition, agglomerated MPI reached tM within 109 s, which was significantly less than the control MPI at 140 s. MPI with lactose binder (MPI-L) had a tM of 80 s at 0.10% powder addition and, larger size MPI-L had a tM of 60 s. At 0.20% and 0.30% powder addition, more time was required to wet and disperse the powders.

The sound of salts by Broadband Acoustic Resonance Dissolution Spectroscopy

Salts are available in different grades and in a wide price range. Some contain more impurities than others, while some have special culinary traits that determine their identity. Acoustic profiling, which is based on the ‘hot chocolate effect’, may provide an interesting strategy to characterise salts of various origins to underpin their identity. In this study, the link between the identity of 60 food grade and technical salts and their acoustic properties was examined by Broad Acoustic Resonance Dissolution Spectroscopy. In particular, the influence of the composition of the salts and the impact of the salts' particle size distributions on their acoustic profiles were examined. Sodium and potassium contents were measured by flame photometry and the salts' particle size distributions by laser light diffraction. Reference salts (NaCl, KCl, MgCl2) and mixtures thereof were analysed for comparison, as well as intact and ground versions of the salt samples. The results show that both the composition and morphology of the salt crystals determine the down-slope of the resonance frequency, which is caused by the rate of release of entrained and dissolved gas. Coarse salts with high levels of non-NaCl constituents showed a rapid decline in sound frequency, which corresponds to a high gas release rate. On the other hand fine salts composed of pure NaCl revealed a slower change in sound frequency and thus lower gas release rates. The frequency minimums were however not affected by the salts' compositions nor particle size distributions. It is primarily the particle size distribution that affects the rate at which gas is released, and thus the change in sound frequency. Only when the particles are more similar in size, the composition also starts playing a role. Since both particle size distribution and composition is unique for each salt, the various salts show distinct acoustic profiles. Evidently, the current study shows that ‘listening’ to the sound of salts reveals interesting information about their identity and origin.

Tracking Cocrystallization of Active Pharmaceutical Ingredients with Benzoic Acid Coformer Using Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS)

This study investigates the use of Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS) as a detection method for the formation of cocrystals. BARDS is a novel approach that uses reproducible changes in the compressibility of a solvent as a sample dissolves to characterize and differentiate between materials and in this case cocrystallization. Two cocrystal systems with a 1:1 stoichiometry were examined, which used benzoic acid as a coformer with isonicotinamide and with theophylline. Cocrystals were prepared using dry and wet milling for periods from 1 to 40 min, and samples were analyzed using infrared spectroscopy, powder X-ray diffraction, and BARDS. Comparison of the BARDS data with the IR and PXRD data cross-validated the BARDS results. This study shows that BARDS can be used to rapidly assess the formation of these cocrystals at-line when milling or as a relatively low cost tool in preformulation product development. The data can also be used to gauge the unique entrained gas and gas volum...

Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS): A rapid test for enteric coating thickness and integrity of controlled release pellet formulations

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.

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.

Sustained-release multiparticulates for oral delivery of a novel peptidic ghrelin agonist: Formulation design and in vitro characterization

There is an impetus to provide appropriate sustained release oral delivery vehicles to protect biofunctional peptide loads from gastric degradation in vivo. This study describes the generation of a high load capacity pellet formulation for sustained release of a freely water-soluble dairy-derived hydrolysate, FHI-2571. The activity of this novel peptidic ghrelin receptor agonist is reported using in vitro calcium mobilization assays. Conventional extrusion spheronization was then used to prepare peptide-loaded pellets which were subsequently coated with ethylcellulose (EC) film coats using a fluid bed coating system in bottom spray (Wurster) mode. Aqueous-based EC coating dispersions produced mechanically brittle coats which fractured due to osmotic pressure build-up within pellets in simulated media. In contrast, an ethanolic-based EC coating solution provided robust, near zero-order release in both USP Type 1 and Type 4 dissolution studies. Interestingly, the functionality of aqueous-based EC film coats was restored by first layering pellets with a methacrylic acid copolymer (MA) subcoat, thereby hindering pellet core swelling in acidic media. Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS) was utilised as a complementary technique to confirm the results seen in USP dissolution studies. Retention of activity of the ghrelinergic peptide hydrolysate in the final encapsulated product was confirmed as being greater than 80%. The described pellet formulation is amenable to oral dosing in small animal studies in order to assess in vivo efficacy of the whey-derived ghrelinergic hydrolysate. In more general terms, it is also suitable as a delivery vehicle for peptide-based bioactives to special population groups e.g paediatric and geriatric.

New insights into the mechanism of rehydration of milk protein concentrate powders determined by Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS)

This study investigated the transfer of water into milk protein concentrate (MPC) powder particles using Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS) as a detection method for the first time. BARDS analysis is based on an acoustic phenomenon which occurs during powder rehydration. Release of air from the powder into the solvent during rehydration leads to outgassing in the solvent, which results in changes in solvent compressibility that are monitored through accompanying changes in induced resonance frequencies in the dissolution vessel. BARDS confirmed that water transfer into MPC particles became increasingly inhibited as protein content of the powder increased. The reproducibility of the data indicates that air release from internal vacuoles within powder particles in high-protein MPCs is a highly ordered process, occurring over a protracted time scale. Kinetic modelling of gas volume data from BARDS confirmed that the release of occluded air caused the changes in solvent compressibility during rehydration. The physicochemical properties of solubilised protein had a slight inhibitory effect on escape of bubbles from the solvent, but the primary factor limiting gas release from high-protein MPCs was water transfer into powder particles and the concomitant release of occluded air into the solvent. In agreement with many previous studies, cryo-SEM analysis showed that particles in high-protein MPCs were slow to disperse; the current study, in addition, highlights inhibited water transfer into particles as another factor which may contribute to their poor rehydration properties. A potential link between inhibited water transfer and poor dispersibility is proposed.

PH Dependence of the Dissolution Rate of EntericCoated 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.

Rapid profiling of enteric coated drug delivery spheres via Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS)

There is an increased trend towards the use of drug and enteric coated sugar spheres for controlled oral delivery of active pharmaceutical ingredients (API). This trend is driven by increased efficacy and ease of formulation of different dosage levels. However, difficulties exist in determining the thickness of drug and enteric coatings in a time efficient manner during manufacture, quality assurance and stability testing. The thickness of the coating determines the dosage of the API and the thickness of the enteric coating determines the release rate of the drug in the gastro-intestinal tract. Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS) offers a rapid new approach to characterising the enteric coating thickness and the raw materials used in their manufacture. BARDS applications are based on reproducible changes in the compressibility of a solvent during dissolution which is monitored acoustically due to associated changes in the speed of sound in solution. It is demonstrated how core delivery sugar spheres have unique acoustic spectra attributable to the mean size distribution of the spheres. A steady state acoustic lag time is associated with the disintegration of the enteric coating, in basic solution. This lag time can be manipulated by varying the concentration of the base which affects the rate at which the coating dissolves. It is anticipated that the thickness/loading of the spheres can be estimated from the lag time.

The relationship between dissolution, gas oversaturation and outgassing of solutions determined by Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS)

The addition of a solute to a solvent is known to reduce the solubility of dissolved gases in solution which leads to gas oversaturation and outgassing of the solvent. The importance of the processes involved have received relatively little attention due to a limited capacity to elucidate their effects in real time. Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS) is a recently introduced acoustic approach which can monitor changes in the compressibility of a solvent due to outgassing. BARDS spectra show that a time dependent and quantitative reduction in gas oversaturation, following the dissolution of a simple salt, takes place over several hours. It is shown how vigorous agitation quickly equilibrates a solution, post dissolution, by removing gas oversaturation consistently. The level of oversaturation can be elucidated by further dissolving a marker compound into a solution consecutively. BARDS spectra indicate that the dissolution of a compound produces a consistent and quantifiable oversaturation of a solvent and a consistent and quantifiable outgassing. Low frequency sonication in an immersion bath is also shown to play no significant role in removing gas oversaturation post dissolution.

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.

Principles and Applications of Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS): A Sound Approach for the Analysis of Compounds

The dissolution of a compound results in the introduction and generation of gas bubbles in the solvent. This formation is due to entrained gases adhered to or trapped within the particles. Furthermore, a reduction in gas solubility due to the solute results in additional bubble generation. Their presence increases the compressibility of the solvent with the added effect of reducing the velocity of sound in the solvent. This effect is monitored via the frequency change of acoustic resonances that are mechanically provoked in the solvent and are now used as an insightful analytical technique. An experimental set up was designed to study a large number of compounds as a function of time, concentration, and solvent system. This revealed the role of the various physical and chemical mechanisms in determining the observed response. It is also shown that this response is strongly dependent on the physical and chemical characteristics of the solute compound used, therefore resulting in a method for the characterization of compounds and mixtures. Additional factors such as morphology (polymorphism), particle size, and dissolution rate are shown to be key in the variation of the resulting response. A mathematical model has also been developed in parallel, which inter-relates the various processes involved in the observed response. It is anticipated that BARDS will open up a new window into transient dissolution processes and compound characterization.