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Use of Resonant Acoustic Mixing Technology for Ultra-Low-Dose Blending in a Single-Step Mixing Process

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Abstract

Purpose

To evaluate the use of resonant acoustic mixing (RAM) technology for homogenous blending of a morphologically challenging model API in low-dose concentrations (<0.1% w/w), and assess the potential for blend uniformity (BU) optimization.

Methods

Caffeine (CAF) mixing was carried out using a LabRAM I benchtop mixer. Uniformity was assessed under a range of mixing conditions and sample preparation procedures in order to optimize system performance. The capacity for microscale mixing was evaluated from final parameters for 0.05% and 0.0125% CAF blends.

Results

Upon optimization, RAM was able to accurately prepare homogeneous mixtures of <0.1% CAF in dilutions of up to 1 part per 8,000. Results from a 0.05% blend targeting 125 μg CAF dosage amounts revealed an AV score of 8.8 while a 0.0125% w/w blend accurately prepared 25 μg of CAF with 99.3% accuracy (98.7% label claim) and AV of 10.1. Microscale mixing in the 0.05% w/w blend was confirmed from plots of BU data against sample size demonstrating a slope of 0.05 within the range of 250–10 mg sample (125–5 μg CAF). L1 BU criteria only failed at the level of 2 μg CAF, despite target precision to 26 nanograms (98.7% label claim).

Conclusions

This study presents the first instance of a homogenously mixed <0.1% (w/w) blend using RAM technology and demonstrate the suitability for reproducible dosing of single-digit microgram drug amounts. Uniformity is documented for API amounts 60x smaller than a recent report has shown and 10,000x smaller than achieved previously with CAF.

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Abbreviations

API:

active pharmaceutical ingredient

AV:

acceptance value

BU:

blend uniformity

CAF:

caffeine

CAF-45:

caffeine ground and sieved through a 45 μm screen

HPLC:

high-pressure liquid chromatography

HSM:

hot-stage microscope (hot stage microscopy)

L1/L2:

Level 1/Level 2 [BU testing]

LA:

lactose anhydrous

LM:

lactose monohydrate

PCM:

paracetamol (acetaminophen)

PLM:

polarized light microscope (polarized light microscopy)

PSD:

particle size distribution

RAM:

resonant acoustic mixing (resonant acoustic mixer)

[R]SD:

[relative] standard deviation

SMD:

Sauter mean diameter

S/V:

SMD to VMD ratio

USP :

united states pharmacopoeia

VMD:

volume mean diameter

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Acknowledgements

Emilie Bergstrom, Tobi Williams, Peter Scholes, Mark Egerton

Funding

This project was funded through an Innovation Grant awarded by the Horizons Initiative, Quotient Sciences.

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Authors and Affiliations

  1. Pharmaceutical Sciences, Quotient Sciences, 3080 McCann Farm Dr, Garnet Valley, PA, 19060, USA

    Kyle A. Frey, Helen Baker, Andrew L. Lewis & David A. Engers

  2. Analytical Microscopy and Microanalysis, Chemical Microscopy, West Lafayette, IN, USA

    Dale K. Purcell

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  1. Kyle A. Frey
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Correspondence to Kyle A. Frey.

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Frey, K.A., Baker, H., Purcell, D.K. et al. Use of Resonant Acoustic Mixing Technology for Ultra-Low-Dose Blending in a Single-Step Mixing Process. Pharm Res 41, 165–183 (2024). https://doi.org/10.1007/s11095-023-03629-3

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