Nanosuspension ‘tops down milling’

The majority (~90%) of new chemical entities (NCEs) discovered by the pharmaceutical industry today are poorly soluble or lipophilic compounds; as are about 40% of existing drugs in the market. Consequently, this can create major challenges in drug development due to poor solubility, short biological half-life, poor bioavailability, prominent adverse effects, and stability of NCE’s.

Nanosuspensions have emerged as an effective strategy for the delivery of hydrophobic drugs because of the unique versatility and advantages in formulation. Adaptive Focused Acoustics can be used to create nanosuspensions through the complete life cycle from discovery through first human trials. By enabling closed vessel, contamination free wet milling in a scalable manner, early stage compounds can be dosed and evaluated, without extensive Formulation development, with a very minimal amount of material. Subsequent trials can be completed with the same technology through the preparation of larger volumes of nanosuspension sample material.

The Covaris Focused Ultrasonicator, has successfully demonstrated the ability to mill small volumes of early stage material into nanosuspensions suitable for animal dosing. Volumes as low as 100ul are possible with 100% recovery of the material.


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Features Benefits
Isothermal Eliminates molecular thermal damage by maintaining isothermal sample temperatures during the process
Scalable Scales from bench-top screens through clinical studies (micro-liters to 1,000+ liters)
Compatible with Quality By Design and Process Analytical Technology
Non-contact Enables sterile, closed, single-use fluid circuits which eliminate carryover
Enables disposable wetted surfaces which minimizes impurities
Reproducible Standardizes the process application of industry-proven AFA technology
Automated process by minimizing subjective operator influence
Rapid Improves processing performance (from 2 days to 2 minutes)
Increases solubility and stability

AFA wet milling comparison to bead mill

AFA reference:
Z avg – 227
PDI – .218
(1.3% secondary population)
Bead mill reference:
Z avg – 289
PDI – .293
(9.6% secondary population)


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Covaris S-Series benchtop system
Single vessel processing from 300ul through 18ml sample volumes:
• Discovery
• Animal dosing
• Method development
Covaris E-Series automated processing of individual samples
Automated processing in multi-vessel configurations including 96 well plates
• Screening automation
• Formulation solubility screens
• Method development
Covaris FS-Series Benchtop laboratory system
Processing single vessels up to 18ml. Processing batch material from 22ml through multi-liter
• Discovery to Development
• Larger animal study dosing
• Process method development
Covaris FP-Series Pilot scale system with data acquisition monitoring of continuous process streams
Processing single vessels up to 18ml. Processing batch material from 22ml through multi-liter
Continuous process flow through capability• Discovery to Development
• Larger animal study dosing to First Human trial
• Process method development
• Continuous process with PAT analytical feedback

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Felodipine nanosuspension – 300ul
Cinnarizine nanosuspension – 2ml
Cinnarizine nanosuspension – 250ml

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Drug Development and Delivery Nanosuspension Formulations

Solidification of Nanosuspension via Spray Granulation. Yidan Lan et al,
AAPS 2012 Poster presentation.
Demonstrated the feasibility of combining AFA technology (to produce nanosuspension by Tops down milling) and spray granulation.

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SEM before and after wet milling

Wet milling of 2ml Felodipine

250ml nanosuspension preparation

Bead mill comparative run:
6 hours AFA achieves similar distribution as 24 hour bead milling