Fingerprinting Emulsions and Micro-emulsions using ......Fingerprinting Emulsions and Micro-emulsions using Solvent NMR Relaxation and Diffusion measurements 15th AIChE Annual Meeting

Fingerprinting Emulsions and Micro-emulsions using Solvent NMR

Relaxation and Diffusion measurements

15th AIChE Annual Meeting Salt lake City, UT, November 9th 2015

XiGO Nanotools 2015 1

David Fairhurst, PhD. and

Sean Race XiGo Nanotools, Inc.

Characterization of Emulsions: Limitations of Current Techniques

Though widely used, traditional techniques have limitations that make them unsuitable for analysis of many emulsion systems Light Microscopy, Image Analysis, Confocal Scanning Microscopy q  Small sample size - Time consuming – Can distort droplet shape and size - Cannot

measure nano- and micro-emulsions

Laser Light Scattering q  Dilution step disrupts many emulsions - Cannot distinguish between droplet and

suspended solid particle - Droplet clusters are estimated as large droplets - Cannot measure micro-emulsions

Electrozone Sensing q  Requires dilution - Large number of droplets need to be measured individually -

Limited to O/W emulsion systems - Cannot measure micro-emulsions Acoustic Attenuation q  Signal attenuates drastically with high solid-content samples and the presence of air XIGO Nanotools 2015 2

Micro-emulsions Increase in use in major industrial applications q  enhanced oil recovery q  drug carriers Thorough characterization of colloidal (nano) systems essential q  problems with study of micro-emulsions

q  form spontaneously at specific Oil/Water compositions q  thermodynamically stable q  destroyed on dilution or alteration of composition q  study is difficult – few techniques available

XIGO Nanotools 2015 3

Practical Advantages of NMR Relaxation and Diffusion measurements

q  any liquid (with at least one H atom) q  includes mixtures of (miscible) liquids

q  wide internal phase concentration range: 1% to 70+% (HIPE) q  no dilution, no sample preparation

q  rapid measurements (typically minutes) q  small samples (typically 0.1mL; as little as 200µL) q  non-invasive, non-destructive

q  samples can be stored and re-measured


NMR Gradient Coils

Relaxation: Fixed Uniform field Diffusion: Variable Field Gradient


NMR Relaxation Free Induction Decay

Spin-echo relaxation: T2 method

Spin-lattice relaxation: T1 method

Choice of T1 or T2 depends on specific application


CPMG pulse sequence

Inversion Recovery pulse sequence

Emulsions

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Regular emulsions are two phase systems: O/W or W/O Each phase has an intrinsic relaxation time → composition dependent Single exponential (blue line) to the relaxation data (red dots) not appropriate Requires a double exponential fit → two resultant relaxation times: short T and long T

NMR relaxation can clearly distinguish between the two phases

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Emulsions: Rheology data*

8 XiGO Nanotools 2015

For each emulsion pair: (a) as Viscosity ↑ the long T2 ↓ (b) as Yield ↑ the short T2 ↓

0.01000 0.1000 1.000 10.00 100.0 1000shear stress (Pa)

0.1000

1.000

10.00

100.0

1000

10000

1.000E5

1.000E6

1.000E7

visc

osity

(Pa.

s)Sample 1_O-W lotion_050415-0001f, Steady state flow stepSample 2_O-W emulsion_050415-0006f, Steady state flow step

Emulsion pair 1

NMR relaxation correlates well with emulsion viscoelastic characteristics

Sample Viscosity (Pa.s)

Yield (Pa)

Short T2 (ms)

Long T2 (ms)

Jergens 93,640 20 80 302

Generic** 66,790 10 278 541

Aveeno 280,170 100 256 497

Generic 450,040 170 148 337

Gold Bond 233,700 60 77 251

Generic 280,400 110 47 244

*TA Rheometer Model AR 1000

** Studio 35, Walgreens

Jergens

Generic

Model Micro-emulsions

Formulation Water Composition 1. 47% oil, 53% water 4% surfactant, 2.0% NaCl, 2.5% co-solvent 2. 62% oil, 38% water 4% surfactant, 2.0% NaCl, 5.0% co-solvent 3. 44% oil, 56% water 4% surfactant, 2.2% NaCl, 5.0% co-solvent 4. 77% oil, 23% water 4% surfactant, 1.7% NaCl, 5.0% co-solvent


Oil= n-decane Co-solvent= 2-butanol

Micro-emulsions 1

Oil-rich phase Microemulsion Water-rich phase

1

2 3 4

Relaxation plot for Sample #2 model micro-emulsion

At high magnetization values (short time) single exponential fit (blue line) to the data (red dots) is not good → indicates two phases


** Sudan Red Dye Soluble in oil

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Micro-emulsions 2 Sample Microemulsion

T2 relaxation time (ms)

Short T2 Long T2

1 925 1960

2 510 1400

3 940 1920

4 380 1100

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Short T2 Relaxation Times

NMR short T2 relaxation times track directly with % Oil in microemulsions

0 100 200 300 400 500 600 700 800 900

1000

#1 47% Oil #2 62% Oil #3 44% Oil #4 77% Oil

Double exponential fit to the relaxation curve results in two T2 values

Micro-emulsions 3

Sample 6: Original aqueous phase used to prepare Sample 2: 4% surfactant; 2% NaCl; 5% co-solvent Sample 10: Aqueous phase extracted from 3-phase system of Sample 2

NMR relaxation useful new tool to study the formulation of micro-emulsion systems

0

500

1000

1500

2000

2500

3000

2% NaCl Sample #6 Sample #10

T2 Relaxation times


NMR Diffusion

Signal echo is attenuated as droplets diffuse under the influence of an increasing field gradient

Signal Echo Attenuation and Drop Size

Increasing drop size


.4 µ .5µ .6µ

Validation of NMR Technique Fundamental Measurement is Diffusion

0.01

0.10

1.00

20 200

Diffu

sion/10-

9 /m

2 s-1

Mw/g

Diffusion data for an homologous series of eight n-Alkanols Solid line – literature values Red dots ● Acorn Drop

Methanol

Decanol

Heptanol Pentanol Hexanol

Octanol

Butanol

Ethanol

Comparison Of Droplet Size Monodisperse PDMS-in-Water Emulsions

20µm 74µm

Nominal Size (µm) Visual

Measured Size (µm) NMR

20 19.8 40 38.9 51 49.9 64 62.7

74 71.8


q  Does not require any dilution step, or other pre-treatment prior to measurement q  Bulk measurement of opaque or colored samples q  Highly viscous, semi-solid emulsion systems (butter, asphalt….) q  Presence of solid particles is not misinterpreted as droplets q Wide range of droplet sizes can be quantified including nano- and micro-

emulsions

Advantages of TD-PFG* NMR

q Measure self-diffusion coefficients of molecules q  Emulsion formulation development and performance characterization q Quantify emulsification efficiency q  Determine emulsion stability kinetics q  Study accelerated aging under controlled (e.g. ICH) guidelines


*Time Domain Pulse Field Gradient

Practical Uses of NMR Diffusion

Oil-in-Water Emulsions


Comparison of six commercial lotions Sample Diffusion (m2 s-1)

Jergens 4.01 x 10-10

Generic* 4.46 x 10-10

Aveeno 1.98 x 10-10

Generic* 2.57 x 10-10

Gold Bond 2.12 x 10-10

Generic* 1.04 x 10-10

Attenuation

* Studio 35™, Walgreens, USA Micrograph Image

Virtually impossible to determine a precise droplet size from microscopy or light scattering

NMR easily tracks relative compositional differences

O/W Microemulsions

17 XIGO Nanotools 2015

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9

1

0 0.5 1 1.5 2 2.5

Sample 1

Sample 2

Sample 3

Sample 4

Attenuation functions

13 2

4

Sample Diffusion Coefficient (m2 s-1)

1 9.54 x 10-10

2 6.46 x 10-10

3 8.73 x 10-10

4 8.44 x 10-10

Symbols are experimental data points; lines are the fit Sample 1 and Sample 2 are markedly different Samples 3 and 4 are virtually identical

NMR can be used to easily fingerprint microemulsions

Conclusions q  Controlling and understanding the relative affinities

of components critical for development of useful microemulsion systems

q  NMR measurements can be used to fingerprint

preparation of emulsions and micro-emulsions q  used at any step from R&D through QC and Process

control q  provides insights into complex formulations

q  NMR is non-invasive and non-destructive

q  samples can be stored and re-measured

18 XiGO Nanotools 2015

Acorn Area™

q  Patented*, low-field** (13MHz) NMR device q  R&D and QC/QA laboratory use

q  Batch mode q  Time mode q  Two temperature control options

Acorn Flow™

q  Flow-thru option for the Acorn Area q  Continuous sampling, addition of reactants, etc

q  Heterogeneous and/or settling suspensions

Acorn Drop™

q  Measures droplet size of emulsions without dilution q  Two ranges: 1µm to 100µm (2Q 2015) and 1nm to 500nm (2016)

Acorn Chek™

q  Production and process control in manufacturing (2016) * Patents issued in US, EU, China and Japan

** C.L. Claves et al, Surface Area Determination via NMR: Fluid and Frequency Effects, Powder Technology, 54(4) 261 (1988)


Thank you

www.xigonanotools.com Tel: 844 367 9446

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Fingerprinting Emulsions and Micro-emulsions using ......Fingerprinting Emulsions and Micro-emulsions using Solvent NMR Relaxation and Diffusion measurements 15th AIChE Annual Meeting