Restriction lift date: 2027-10-31
Applications of Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS) in pharmaceutical analysis
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University College Cork
Dissolution testing is one of the most time-consuming, costly, and laborious tasks in the pharmaceutical industry, and yet it is a cornerstone of quality control testing and product release. Dissolution testing is a prerequisite for the quality control and release to market of nearly every prescription and over the counter product. It is one of the few technologies which has not undergone disruption of any kind. Practices have changed little in decades, with liquid samples being taken at regular intervals over several hours and tested using expensive analytical instruments. Most routine testing can take upwards of a day to perform. Speeding up these processes is vital. This thesis highlights a modern complementary approach to existing dissolution testing practices for powder, pellet, tablet and liquid formulations called Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS). BARDS is an innovative technique that can economise production processes for drug formulations. BARDS is based on reproducible changes in a solvent's compressibility as a sample dissolves. It is a rapid and straightforward method that utilises a magnetic stir bar to mix added solute and induce a vessel's acoustic resonance containing a fixed volume of solvent. As a sample is wetted and subsequently dissolved, gas is released from the solvent, altering the resonance frequency. Adding a solute to a solvent reduces the solubility of dissolved gases in solution, leading to gas oversaturation and outgassing of the solvent, changing the solvent system's compressibility, and reducing the velocity of sound in the solvent. In the results section of this thesis, Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS) is used to characterise several pharmaceutical formulations, including enteric-coated microspheres, tablets and multiple-unit pellet systems (MUPS). Effervescent tablets, chewable tablets and liquid formulations were also analysed. A single replicate BARDS measurement can provide data relevant to multiple dissolution processes in a time-efficient manner by tracking the Erosion of the enteric coating, Disintegration, Deaggregation and overall Dissolution of the formulations while assessing the formulation's integrity using an EDDDI Plot. BARDS can determine the thickness of the drug and enteric coatings, characterise various dosage forms and test formulation integrity. Ultra Violet -Visable Spectroscopy (UV-Vis) has been used in the cross-validation of the technique. Tablets, pellets, and multiple-unit pellet system (MUPS) formulations were examined to investigate the effect of polymer coating and formulation core degradation over time. BARDS can enable the rapid development of solid drug formulation dissolution and disintegration testing as an In-Process and In-Line Control test and drug stability analysis. In combination with minimal Ultra Violet - Visible Spectroscopy usage, BARDS can effectively track these changes, therefore assessing a formulation's stability. BARDS data also indicates which aspect of a formulation may be unstable, whether a coating, sub-coating or core. Paediatric and geriatric formulations were studied in detail in this thesis. Chewable, effervescent and liquid dosage forms were characterised for formulation attributes using BARDS. Nutraceutical and pharmaceutical chewable and effervescent formulations were investigated in tablet form to examine how the formulation disintegrates and dissolves. The data show that a solid oral dose formulation has an intrinsic acoustic signature specific to the method of manufacture and excipient composition. Effervescent tablets disintegrate rapidly due to a chemical reaction. The reaction causes carbon dioxide gas production and subsequent release, resulting in the characteristic effervescent fizz, which can be tracked acoustically using BARDS. This thesis will highlight BARDS as a rapid characterisation technique to track the chemical reaction associated with effervescent dosage forms. BARDS can be used as an analytical tool to quantify the dissolution of liquid formulations. This has been demonstrated by a test model using two different liquid formulation types, suspension formulations and syrup formulations. Similarities between different brands were apparent when tested. BARDS can qualitatively discriminate between Active Pharmaceutical Ingredient (API) dosage, API type, and discriminate whether an API has been partially dissolved in the suspension media before addition to the BARDS instrument. In conclusion, various applications with the tremendous novelty of this platform technology have been proven. This project can potentially impact the methodology for dissolution testing with a high capability to influence regulatory policies and practices worldwide. BARDS can enable the rapid development of solid drug formulation dissolution and disintegration testing as an in-process control test and drug stability analysis. The data shows that a dosage formulation has an intrinsic acoustic signature specific to the method of manufacture, excipient composition and elapsed time since the production of a product. In addition, BARDS is a time-efficient, cost-effective and green approach to formulation characterisation.
BARDS , Dissolution testing , Drug formulations , Disintegration , EDDDI plot , Enteric coating , Real-time release test , Suspensions , MUPS , Effervescence , Microspheres
O'Mahoney, N. 2022. Applications of Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS) in pharmaceutical analysis. PhD Thesis, University College Cork.