continuous flow nanoparticles using afa

C O V A R I S P R O C E S S T E C H N O L O G I E S COVARIS | PROPRIETARY Carl Beckett | [email protected]

Crystal nanoparticles with

Covaris Adaptive Focused

Acoustics (AFA)

Take control of nucleation and crystal growth

C O V A R I S P R O C E S S T E C H N O L O G I E S

Create API nanoparticles

Control API nucleation and crystal growth in a continuous

process stream.

Improve yield of difficult reactions

Integrate PAT for automated, real time feedback and Quality

Control

Adaptive Focused Acoustics™ (AFA)

enables you to:

2 COVARIS | PROPRIETARY


2mL batch formulation shows AFA enables nanoparticle formation for a

formulation that would otherwise yield large and varied particle sizes

3

700nm w/AFA

Covaris Proprietary|Confidential

No AFA yields large chunks

Ibuprofen

DMA solvent

PVP stabilizer

500mM concentration


AFA 2mL batch scale impact


Drug Cinnarzine

Solvent Dimethylacetamide (DMA)

Drug solvent concentration 125 mM

Stabilizer 0.2% PVP30 and 0.25 mM SLS

Stabilizer percentage 0.2%

Solvent:Anti-solvent ratio 1:29, 1:14, 1:6.6

S220x Covaris Focused-ultrasonicator

300 W Peak Incident Power (PIP)

50% Duty Factor (DF)

1,000 Cycles Per Burst (CPB)

12x24 2 mL process vessel

300 processing time (seconds)

6°C water bath temperature

125mM-

Control

Ratio d10-

Control d50-

Control d90-

Control Span 1:6.6 9.0 29.9 1730.0 57.5 1:6.6 8.0 26.8 66.5 2.1 1:6.6 8.0 26.5 64.2 2.1

Average 8.3 27.7 620.2 20.6 SD 0.45 1.54 784.70 26.1

125mM-

AFA Ratio d10-AFA d50-AFA d90-AFA Span

1:6.6 0.0406 0.122 0.325 2.335 1:6.6 0.0406 0.122 0.333 2.387 1:6.6 0.0407 0.123 0.334 2.395

Average 0.041 0.122 0.331 2.372 SD 0.000 0.000 0.004 0.027

All values are in microns

Stir bar control

AFA

• Smaller particles (d50 from 27.7 to 0.122 micron)

• Dramatically improved distributions

All values are in microns


Scalable to continuous process streams


to/from

chiller

Feed 1

Feed 2

Flow Cell

PVP30, SLS, and water

API and Solvent

water bath

AFA

collection reservoir

AntiSolvent pump

Solvent pump

Schematic of Flow Apparatus


Nanoparticles in a continuous flow process


Sample 9 Sample 10 Sample 11 Sample 12

d10 0.085 0.091 0.098 0.090

d50 0.180 0.191 0.202 0.187

d90 0.415 0.409 0.423 0.399

Span 1.834 1.663 1.611 1.654

PIP = 500 W. All values are in microns

Sample 5 Sample 6 Sample 7 Sample 8

d10 2.15 1.79 1.89 1.78

d50 3.48 3.23 3.03 2.86

d90 5.55 5.01 4.95 4.73

Span 0.98 1.32 1.01 1.03 PIP = 300 W. All values are in microns

Production rate = 36.5 mg/min

Cinnarizine

Drug solvent concentration 125 mM (46 mg/mL)

Solvent flow rate 800 µL/min

Anti-solvent flow rate 10 mL/min

Stabilizer 0.2% PVP30 and 0.25 mM SLS

Stabilizer percentage 0.2%

Solvent:Antisolvent ratios 1:12.5 (10 mL/min anti-solvent, 800 µL/min solvent)


Particle size determined via computer control


• Particle size can be computer

controlled by the acoustical settings

• Allows real time PAT monitoring and

feedback control


Technology Overview



“Controlled” Cavitation

• Under appropriate conditions, acoustic waves traveling through a liquid medium may

cause the dissolved gasses to come out of solution as microscopic bubbles that then

collapse generating shearing forces as the fluids rush back in to fill the void.

• Covaris technology controls cavitation which enables control over shear forces

• Cumulative effect of hundred of thousands of cavitation bubbles



Covaris Adaptive Focused Acoustics (AFA):

based on Highly Developed Biophysical Technologies

Therapeutic Ultrasound:

Since1980, Extracorporeal Shockwave Lithotripsy (ESWL)

treatments apply non-contact acoustic properties to break down

kidney and gall stones. Also known as, High Intensity Focused

Ultrasound (HIFU)

Diagnostic Ultrasound:

imaging also uses related technology (low intensity, high frequency

focused ultrasound)

Covaris’ Adaptive Focused Acoustics (AFA) is

optimized for biomolecule processing

30 Patents granted, 20 Pending



Technology overview

Acoustic frequency spectrum



AFA Technology

High frequency >

Short wavelength >

Allows focusing >

High energy density >

Highly controllable


• Non contact

• Isothermal

• Repeatable

• Efficient


A few of the locations of the > 3,000 systems placed worldwide

COVARIS | PROPRIETARY 13

http://www.bing.com/images/search?q=Purdue+University&FORM=KADOMI

http://www.gsk.com/index.htm

http://mlnm.com/index.asp

http://www.bing.com/images/search?q=Johns+Hopkins+University&FORM=KADOMI

http://www.princeton.edu/main/

http://www.sanger.ac.uk/

http://www.broadinstitute.org/




http://www.nih.gov/

http://www.bayercropscience.com/

http://en.wikipedia.org/wiki/File:JohnsonandJohnsonLogo.svg

http://www.merck.com/

http://www.aacr.org/default.aspx

http://www.harvard.edu/index.php

http://www.novartis.com/

http://www.lanl.gov/


High performance water conditioning system (hpWCS) High volume, continuous processing • Permits max power processing

• Maintains water quality

• Ultimate in thermal control

Continuous operation, AFA Flow Process Vessels Intermediate, preclinical development • Stainless steel design specifically for high power

applications

• Jacketed vessels for improved thermal control

Small scale batch processing, early formulation & process

screening • Precisely controlled, isothermal processing to

18 mL

S220x Focused-ultrasonicator

Flow System example configuration



Computer defined acoustical settings


• Repeatable methods

• Operator independent

• Full acoustic control

• Saved method file

• Multistep processing

C O V A R I S P R O C E S S T E C H N O L O G I E S COVARIS | PROPRIETARY

17

SUMMARY

Control of nucleation and crystal growth allows precise, stable

production of crystalline API.

Enables nanoparticle formation.

Scalable from 100µL to continuous flow manufacturing.

Automated, computer control maintains Quality real time.

C O V A R I S P R O C E S S T E C H N O L O G I E S COVARIS | PROPRIETARY

18

Questions

continuous flow nanoparticles using afa

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