Tracking yeast metabolism and the Crabtree effect in real time via CO2 production using Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS)

In this study, a new approach to measure metabolic activity of yeast via the Crabtree effect is described. BARDS is an analytical technique developed to aid powder and tablet characterisation by monitoring changes in the compressibility of a solvent during solute dissolution. It is a rapid and simple method which utilises a magnetic stir bar to mix added solute and induce the acoustic resonance of a vessel containing a fixed volume of solvent. In this study it is shown that initiation of fermentation in a yeast suspension, in aqueous buffer, is accompanied by reproducible changes in the frequency of induced acoustic resonance. These changes signify increased com-pressibility of the suspension due to CO2release by the yeast. A simple standardised BARDS protocol reveals yeast carbon source preferences and can generate quantitative kinetic data on carbon source metabolism which are characteristic of each yeast strain. The Crawford-Woods equation can be used to quantify total gaseous CO2produced by a given number of viable yeast when supplied with a fixed amount of carbon source. This allows for a value to be calculated for the amount of gaseous CO2produced by each yeast cell. The approach has the potential to transform the way in which yeast metabolism is tracked and potentially provide an orthogonal or surrogate method to determining viability, vitality and attenuation measurements in the future

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

Tracking cocrystallization of active pharmaceutical ingredients with Bbenzoic 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 volume generation of the cocrystal samples during dissolution and their dissolution kinetics

Development of low-dose protocols for thin-section CT assessment of cystic fibrosis in pediatric patients.

Purpose: To develop low-dose thin-section computed tomographic (CT) protocols for assessment of cystic fibrosis (CF) in pediatric patients and determine the clinical usefulness thereof compared with chest radiography. Materials and Methods: After institutional review board approval and informed consent from patients or guardians were obtained, 14 patients with CF and 11 patients without CF (16 male, nine female; mean age, 12.6 years ± 5.4 [standard deviation]; range, 3.5–25 years) who underwent imaging for clinical reasons underwent low-dose thin-section CT. Sections 1 mm thick (protocol A) were used in 10 patients, and sections 0.5 mm thick (protocol B) were used in 15 patients at six levels at 120 kVp and 30–50 mA. Image quality and diagnostic acceptability were scored qualitatively and quantitatively by two radiologists who also quantified disease severity at thin-section CT and chest radiography. Effective doses were calculated by using a CT dosimetry calculator. Results: Low-dose thin-section CT was performed with mean effective doses of 0.19 mSv ± 0.03 for protocol A and 0.14 mSv ± 0.04 for protocol B (P < .005). Diagnostic acceptability and depiction of bronchovascular structures at lung window settings were graded as almost excellent for both protocols, but protocol B was inferior to protocol A for mediastinal assessment (P < .02). Patients with CF had moderate lung disease with a mean Bhalla score of 9.2 ± 5.3 (range, 0–19), compared with that of patients without CF (1.1 ± 1.4; P < .001). There was excellent correlation between thin-section CT and chest radiography (r = 0.88–0.92; P < .001). Conclusion: Low-dose thin-section CT can be performed at lower effective doses than can standard CT, approaching those of chest radiography. Low-dose thin-section CT could be appropriate for evaluating bronchiectasis in pediatric patients, yielding appropriate information about lung parenchyma and bronchovascular structures

High-resolution structure of the antibiotic resistance protein NimA from Deinococcus radiodurans

In this paper, the 1.2 Å atomic resolution crystal structure of the 5-nitroimidazole antibiotic resistance protein NimA from Deinococcus radiodurans (DrNimA) is presented

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

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