Optimizing Formulation Development: Understanding Viscosityโs Role in the Formulation Process and How to Create a Measurement Plan Zachary Imam Stacey Elliott 20 January 2021
Optimizing Formulation Development: Understanding Viscosityโs Role in the Formulation Process and How to Create a Measurement Plan
Zachary Imam
Stacey Elliott
20 January 2021
Formulation โexcipient,
temperature
Interactions &Microstructure
Viscosity
2L
h
แถ๐พ
ho
แถ๐พ๐
Viscosityโs Role in Formulation Development
hrel
๐Tm
D
Na+
Cl-
Viscosity Review โ Resistance to FlowSteady Shear
๐ โก๐ โ๐๐๐ ๐ ๐ก๐๐๐ ๐
๐ โ๐๐๐ ๐๐๐ก๐=๐
แถ๐พ
๐ = ๐ ๐, แถ๐พ, ๐, ๐ก แถ๐พ
โข Velocity gradient perpendicular to flow
โข Shearing motion โ adjacent fluid elements forced to slide past each other
โข Shear viscosity ยบ internal or molecular friction
โข Reflects molecular level behavior
โข Size, shape, interactions
โข Microstructure
x
y
๐ข๐ฅ ๐ฆ = 0 = 0
๐ข๐ฅ ๐ฆ = โ = ๐ข๐๐๐๐ก๐
h
แถ๐พ =๐๐ข๐ฅ๐๐ฆ
=๐ข๐๐๐๐ก๐โ
๐น๐๐๐๐
๐ด๐๐๐
๐
Viscosity โ how can it help you?
1. Practical application โ injectability, processing, blinking, topical, ageing, aggregationโฆโฆโฆโฆ
โข Predict performance & processability
2. Investigative tool โ reflects microscopic behaviorโข Individual molecules โ size, shape
โข Pair interaction
โข Complex structure formation
โข Impact of solution environment on all above
โข Intelligent formulation โ work smart, not hard!
Formulation โexcipient,
temperature
Interactions &Microstructure
Viscosity
VROC - Viscometer/Rheometer-on-a-Chip
Microfluidics and MEMS (Micro-Electro-Mechanical Systems)
MEMS Sensors โ Silicon (Si) Pressure Sensor Array
Microfluidics โ Precision Glass Micro-Channel
โrectangular-slit methodโ (USP, chapter 914)
๐ ~๐๐
๐๐ฅ
แถ๐พ ~ ๐
๐ =๐
แถ๐พ
Control
Measure
Dynamic
Viscosity
10
20
30
40
50
60
70
80
90
2 4 6 8 10
Pre
ssu
re (
kP
a)
Sensor Position (mm)
๐๐
๐๐ฅ
How do I start a measurement plan?
Before you start anything ask: โWhat do I want to learn about my sample?โโWill this study be narrow and specific?โโAm I performing a broad characterization study?โ
โข Performance under high shear or low shear?
โข Performance at high or low temperature?
โข Fluid Structure?
โข Molecular Structure?
โข Differentiation?
Knowing this information will help with generating a measurement plan and experimental design
vs
2L
1
10
100
10 100 1000 10000 100000
vis
co
sity
(c
P)
shear rate (sec-1)
0.50%
0.25%
0.125%
Performance at high and low shear rateโข Not universal, but sample dependent
Xanthan Gum
MW = 1,000,000+
Possibly entangled polymer network
๐ผโ
๐ผ๐~๐ผ แถ๐ธ โ ๐๐โ๐๐๐๐โ๐
30
32
34
36
38
40
42
44
100 1000 10000 100000
h(c
P)
shear rate (sec-1)
250 mg/mL BgG Phosphate buffer saline (PBS), pH7.4
250 mM Arg-HCl
w/o Arg-HCl
๐ผ๐
Bovine Gamma Globulin (BgG)
MW = 150,000
Inherently attractive colloid
40
45
50
55
60
65
100 1000 10000 100000 1000000 10000000
h
แถ๐พ
ho
แถ๐พ๐ hโ
Viscosity vs. Shear Rate โ Qualitative InterpretationLow shear plateau
โข Restorative mechanism
โข Near equilibrium
โข Generates thermodynamic stress
High shear plateau
โข Far from equilibrium
โข Hydrodynamics dominate
โข ๐๐ โ ๐โ โ degree of structure & thermodynamic forces
Critical shear rate
โข Non-Newtonian onset
โข Shear flow overcoming
๐โ๐โ
๐๐โ๐โโ
๐โ๐
๐๐โ๐
Viscosity scaling
Non-Newtonian Viscosity250 mg/mL BgG (Bovine g-Globulin)
15
25
35
45
55
65
75
85
95
100 1000 10000 100000
h(c
P)
shear rate (sec-1)
30
32
34
36
38
40
42
44
100 1000 10000 100000
h(c
P)
shear rate (sec-1)
25ยฐC
Phosphate buffer, 150 mM NaCl, pH7.2 Phosphate buffer saline (PBS), pH7.4
10ยฐC
18ยฐC
25ยฐC
37ยฐC
250 mM Arg-HCl
w/o Arg-HCl25ยฐC
25C
h0 = 44 cP
h0 = 38 cP
h0 = 35 cP
Shear Rate ScalingPeclet Number
๐๐ =๐๐ต๐๐
=๐ฟ2 แถ๐พ
๐ท๐ ๐ =
6๐๐๐๐ฟ3 แถ๐พ
๐๐
๐๐ต =๐ฟ2
๐ท๐ ๐
๐๐ =1
แถ๐พ
๐ท๐ ๐ =
๐๐
6๐๐๐๐ฟ
Peclet number โ ratio of characteristic time scales
Brownian motion โ restoring equilibrium structure
Shear flow โ perturbing equilibrium state
Effective self
diffusion
Increasing time/length scale
Designate thinning onset to
๐๐ แถ๐พ๐ = 1 to estimate L
0.75
0.8
0.85
0.9
0.95
1
100 1000 10000 100000
(h-
m)/
(ho-m
)
0.85
0.9
0.95
1
100 1000 10000
(h-
m)/
(ho-m
)
shear rate (sec-1)
10ยฐC 18ยฐC
25ยฐC
37ยฐC
250 mM
Arg-HCl
w/o
?
Scaled Viscosity vs. Peclet Number Master Curve
rh~5 nm from [h]
Rg=5.3 nm monomer (*)
Rg=7.6 nm dimer (*)
โข Temperature โ no significant change in interactions & clustering
โข Arginine (excipient)
โข Decreases L, consistent with reduced cluster size
โข Supports idea of reversible cluster formation increasing viscosity
T (ยฐC) ho (cP) L (nm)
10 91 10
18 54 9.8
25 35 9.8
37 18 9.9
2L
*S. Da Vela et al., Effective Interactions and Colloidal Stability of Bovine g-Globulin in Solution, J. Phys. Chem. B, 2017, 121, 5759-5769.
0.75
0.8
0.85
0.9
0.95
1
0.01 0.1 1 10(h
-m
)/(h
o-m
)๐ท๐ =
๐๐ ๐ผ๐๐ณ๐ แถ๐ธ
๐๐ปArg
(mM)ho (cP) L (nm)
0 44 9.1
250 38 8.1
temperature
excipient
= 25ยฐC
80
90
100
110
120
130
140
150
160
170
10 100 1000
vis
co
sity
(c
P)
shear rate (sec-1)
Sample Differentiation
Real Maple Syrup
Pancake Syrup(Xanthan Gum)
Mix (80/20)
โข Initially explore broad range of shear ratesโข Narrower range possible for QC analysis
1
10
100 1000 10000 100000
vis
co
sity
(c
P)
shear rate (sec-1)
Hydroxypropyl guar
Sodium hyaluronate
Revitalift Prism Maran
Sample Differentiationโข Initially explore broad range of shear ratesโข Narrower range possible for QC analysis
0
5
10
15
20
25
30
35
40
100 1000 10000 100000
Vis
co
sity
(c
P)
Shear Rate (sec-1)
0
2
4
6
8
10
12
14
100 1000 10000
Vis
co
sity
(c
P)
shear rate (sec-1)
Whole Milk Skim Milk Oat Beverage
Unsweet
Almond
Beverage
Almond
BeverageCoconut
Milk
Temperature Sensitive Polymeric Excipients
โข Poloxamer (Lutrolรข)โข Amphiphilic triblock copolymer
โข Poly(propylene oxide) midblock more hydrophobic than poly(ethylene oxide)
โข Form complex microstructures dependent on temperature and concentrationโข Dependent on MW of each block (a,b)
โข Reversible
โข Applicationsโข Rheology/viscosity modifies
โข Solubilizers
โข Sedimentation inhibitors
Increasing Concentration, Temperature
Poloxamer Solutions โ Type & Concentration
โข Not simple Arrhenius behavior โindicates complex reversible microstructure
โข Highly sensitive to concentration
โข Dependent on Poloxamer type โ MW & block ratio
โข Detects phase boundaries โ fluid-gel (15% P407, 30 โ 45ยฐC)
Poloxamer a b MW a/b
188 80 27 7680 โ 9510 3
407 101 56 9840 โ 14600 1.8
10
30
50
70
90
110
130
150
15 20 25 30 35 40 45 50 55 60 65 70 75
rela
tiv
e v
isc
osi
ty
Temperature (ยฐC)
10
20
30
40
50
60
70
80
90
100
0 20 40 60
rela
tiv
e v
isc
osi
ty
Temperature (ยฐC)
P407 in DI H2O P188 in DI H2O
13%
24%
15%
22%
20%
14%
0
5
10
15
20
0 5 10 15 20
Sh
ea
r Str
ess
(P
a)
Time (s)
400 sec-1
Poloxamer Solutions โ Yield Stress
โข Can determine whether material is yielding
โข We cannot calculate yield stress, but we can determine where we are in the materialโs phase diagram
Poloxamer a b MW a/b
407 101 56 9840 โ 14600 1.8
0
10
20
30
40
0 5 10 15 20
Sh
ea
r Str
ess
(P
a)
Time (s)
30ยฐC
0
50
100
150
200
0 20 40 60
Sh
ea
r Str
ess
(P
a)
Time (s)
P407 in DI H2O
40ยฐC 50ยฐC
400 sec-1
80 sec-1
300 sec-1
โข Can probe different regions of phase diagram with different temperatures.
โข At 40ยฐC material is still yielding at 80 and 300 sec-1
Poloxamer SolutionsCombine Temperature/Shear Rate Sweeps
โข Rate sweeps at temperatures along profile (20, 25, 30, 45, 70 ยฐC)
โข Transitions from Newtonian ยฎ Non-Newtonian ยฎ Newtonian
โข Non-Newtonian profiles merge at high shear rates
10
20
30
40
50
60
70
15 20 25 30 35 40 45 50 55 60 65 70 75
rela
tiv
e v
isc
osi
ty
Temperature (ยฐC)
10
20
30
40
50
60
70
100 1000 10000 100000
rela
tiv
e v
isc
osi
ty
shear rate (sec-1)
20 ยฐC
70 ยฐC
45 ยฐC
30 ยฐC
25 ยฐC
14% (wt) P407 in DI H2O
Shear rate sweeps at specified
temperatures
Summary
โข Rheological measurements are iterative
โข Ask good questions at the beginning leads to good experiments later
โข Let the data guide you
โข Make educated guesses on what experiment to run and dive in
โข Rheology is a broad field
โข Applicable to many industries and applications
โข Contact us with questions!
โข Weโre here to help you develop your techniques0
10
20
30
40
100 1000 10000 100000
Vis
cosi
ty (
cP)
Shear Rate (s-1)
10
60
110
15 20 25 30 35 40 45 50 55 60 65 70 75rela
tive
vis
cosi
ty
temperature (ยฐC)
Thank You!Dr. Zachary ImamResearch ScientistRheoSense, [email protected]+1 (925) 866-3801 ext. 1013
Grace BaekMarketing & Sales RheoSense, [email protected]+1 (925)-866-3801 ext. 1013
Dr. Stacey ElliottPrincipal ScientistRheoSense, [email protected]+1 (925) 866-3801 ext. 1013
Eden ReidSenior Marketing AssociateRheoSense, [email protected]+1 (925)-866-3801 ext. 1013