(T1130-11-65) Application of Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS) to Investigate Tablet Behaviour in Aqueous Media

Purpose: BARDS is a novel analytical technology based on monitoring the change in acoustic phenomena observed when a material is added into a solvent. Addition of a solid material results in the introduction of air (gas) into the solvent, which changes the compressibility of the liquid system and reduces the velocity of the sound (resonance) therein.^1,2 In its simplest form, a pharmaceutical tablet can be described as a mixture of a compacted solid material and gas. The gas is the air contained within the pores of the tablet. When pharmaceutical tablets are introduced into an aqueous system, the air entrapped within the tablet’s surface pores is displaced into the liquid as the compact is wetted. As the tablet proceeds to disintegrate and dissolve, the gas entrained within the tablet is released into the aqueous system. Therefore, the process of air introduction, from the tablet into the liquid media, would result in a change into the compressibility of the liquid. BARDS is designed in such a way to track and record these changes in compressibility of the aqueous medium in form of acoustic spectra. The main purpose of this study is to demonstrate the capability of BARDS to profile the process of tablet disintegration and subsequent particle wetting behaviour. These BARDS profiles detected differences between tablets produced with and without magnesium stearate and at different tensile strengths and porosities.

Methods: Formulation - Two tablet blend formulations were investigated in this study. The first formulation was composed of MCC (90% w/w) and metoclopramide hydrochloride (10% w/w) and referred to as unlubricated Blend. The second formulation was composed of microcrystalline cellulose (89.5% w/w), metoclopramide hydrochloride (10% w/w) and a powder lubricant Magnesium stearate (0.5% w/w) and referred to as lubricated Blend. For both formulations, the total blend size of 2 kg was blended in a stainless-steel double cone blender (DKM) with an 11.9 litre volume operated with ERWEKA AR402 drive unit at an angle of 900. MCC and API were blended for 30 minutes at 30 rpm for unlubricated blend. Magnesium stearate (0.5% w/w) was added to the unlubricated blend and blended for a further minute at 30 rpm to formulate lubricated blend. Compaction - Unlubricated and lubricated blends were compressed at a range of 30 MPa to 234 MPa compression pressures using 8 mm flat faced round punches on a 10 station Riva Piccola tablet press (Riva, United Kingdom). BARDS - A BARDS Spectrometer consists of a dissolution chamber and a vessel equipped with a magnetic stirrer (source of sound/acoustics in BARDS system) and a microphone set above the dissolution vessel, to receive and record the acoustic responses from the vessel (Figure 1). The glass vessel containing 25 mL of deionised water is placed on the stirrer plate. The stirrer motor underneath is positioned to allow the magnetic stirrer bar to gently tap the inner vessel wall, which will act as the source of broadband acoustic excitation. The audio is sampled at a rate of 44.1 kHz. The resonances of the liquid vessel are recorded in a frequency band of 0-20 kHz, which are called as frequency time profiles.

Results: For both the unlubricated and lubricated blends, tablets were produced at a range of compaction pressures. As anticipated, an increase in compaction pressure showed an increase in the tablet tensile strength and decrease in the tablet porosity as shown in Figure 2. Tablets were analysed using BARDS and frequency time profiles were captured (Figure 1). Frequency-time profiles for unlubricated and lubricated tablets compressed at increasing compaction pressures are shown in Figure 3. Clear differences in the frequency-time profiles can be observed with respect to tablet compaction pressures and the presence or absence of magnesium stearate. Frequency time profiles were converted into gas volume time profiles to estimate the total gas released and escaped in the aqueous medium for unlubricated and lubricated tablets.

Conclusion: This study shows the application of a novel analytical methodology, BARDS, to study the behaviour of tablets in aqueous media in real-time. BARDS was able to detect differences in the behaviour of tablets during disintegration for the formulations studied. Parameters such as ∆t_f(min), ∆T_ss, Area Under Volume Curve and gas elimination rate constants were calculated from BARDS data and identified as useful parameters to understand differences in the tablet disintegration behaviour in aqueous media. This provides greater insights of tablet behaviour in aqueous media than normal disintegration. The study demonstrates the potential of BARDS as a technique to screen tablet formulations in an aqueous media prior to time-consuming dissolution studies.

References: 1. Peddapatla RVG, Ahmed MR, Blackshields CA, et al. Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS): A Novel Approach to Investigate the Wettability of Pharmaceutical Powder Blends. Mol Pharm. 2018;15(1):31-39. doi:10.1021/acs.molpharmaceut.7b00658
2. Fitzpatrick D, Krüse J, Vos B, et al. Principles and applications of broadband acoustic resonance dissolution spectroscopy (BARDS): A sound approach for the analysis of compounds. Anal Chem. 2012;84(5):2202-2210. doi:10.1021/ac202509s

Acknowledgements: This research was funded by the Pharmaceutical Manufacturing Technology Centre (PMTC), an Enterprise Ireland & Irish Development Agency (IDA) funded centre under grant number Project TC 2013-0015 and Synthesis and the Solid State Pharmaceutical Centre (SSPC) and Science Foundation Ireland (SFI) under grant number 12/RC/2275. The authors would like to thank Alltech Ltd. and the Irish Research Council (IRC) for the generous support for Rizwan Ahmed’s studentship and fellowship (EPSPD/2019/198).