Nucleation Control via the Rational Design of Immiscible Polymer/Surfactant Thin Films

Importance of Crystallization Properties can be used to change

manufacturing process (filtration, milling, drying, etc.) and dissolution rates

Streamlining the manufacturing process means less expensive drugs for consumers

milling

granulation

What is Crystallization? Two step process

1. Nucleation- creation of new phase (i.e. liquid to solid)

2. Crystal growth

Crystal Growth

Saturated solution

Create supersaturation and formation of nuclei One of the most important means of controlling

crystallization is nucleation

NucleationNucleati

on

Primary Secondary (crystal induced)

Homogenous(spontaneous)

Heterogeneous

(foreign surface)

Methods to control nucleation

Supersaturation state of solution that contains more dissolved solute than could be dissolved under normal circumstances

Super cooling process of lowering temperatures below freezing without solvent solidifying

Heterogeneous nucleation the method used in our experiments

Heterogeneous Nucleation Almost all crystallization processes occur

heterogeneously

What has been done before: SAM (self-assembled monolayer)▪ Inefficient method

homhet

evaporation

The Advantages of Our Method Biocompatibility

Easy manufacturing

Polymeric films contain immiscibility caused by micelle formation Micelles act as nucleation sites for

acetaminophen

Methodology (Film Preparation and Drop Crystallization on Films)

Drop crystallization

Cast film

Polymer solution

Supersaturated AAP

PET substrate

Nucleation Mechanism Determination Nucleation mechanism was elucidated by

identifying which crystal face was in contact with the polymer surface.

Preferred orientation exhibited in the PXRD imply preferential nucleation face

(022)

AAP Form I ( No Preferred Orientation)

AAP Form I Preferred Orientation in the presence of Na CMC film with SPAN 80

Probability of Nucleation Mechanisms on PET Substrate

[10-1] [022] BothNa ALG F108

21% 17% 62%

Na ALG PAA 10% 21% 69%Na CMC 7% 54% 39%Na CMC

F10848% 0% 51%

Na CMC SPAN 80

0% 93% 7%

Surface Chemistry Characterization (EDX)

Na CMC

Na CMC F108

Na CMC SPAN80

Na ALG F108

Na ALG PAA

Surface Chemistry of Polymeric Film

Theoretical C/O Ratio

Experimental C/O Ratio

Na ALG F108 1~1.09 1.70±0.07

Na ALG PAA 1~1.03 1.94±0.1

Na CMC 1 1.54±0.05

Na CMC F108 1~1.45 2.16±0.12

Na CMC SPAN 80 1~1.52 (FLAT)

2.67±0.41(Grey Patch)

4.65±1.59

C/O Ratio

CMC 1

F108 2-3

SPAN 80 4

ALG 1

PAA 1.5

Nucleation Mechanism Study Influence Factor-- Concentration of SPAN 80

SPAN 80 Concentration

(g/100g)

[10-1] [022]

Both

0.405 0% 100% 0%0.2025 0% 99% 1%0.102 0% 93% 7%

0.0506 0% 99% 1%0.038 0% 98% 2%0.032 2% 79% 19%0.018 0% 80% 20%0.008 0% 76% 24%

0.0054 2% 63% 35%

0.0054 0.008 0.018 0.032 0.038 0.0506 0.102 0.2025 0.4050

10

20

30

40

50

60

70

80

90

100

63

7680 79

98 9993

99 100

SPAN Concentration (g/100g)

Prob

abili

ty o

f Nuc

leat

ion

Plan

e at

(022

)

Na CMC F127

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.90

102030405060708090

100

Probability of Nucleation on (022) Face

Concentration of F127 (g/100g)Prob

abili

ty o

f Nuc

leat

ion

on (0

22)

Face

0 0.01 0.02 0.03 0.04 0.05 0.060

102030405060708090

100

Probability of Nucleation on (022) Face

Concentration of F127 (g/100g)Prob

abili

ty o

f Nuc

leat

ion

on (0

22)

Face

[10-1] [022] Both

0.81 25 24 51

0.05 1 80 19

0.01 3 92 5

0.005 0 94 6

0.001 12 39 49

Probably, there are four phases in F127 controlling nucleation • Phase 1: after initial addition of small

amount of F127, it starts to lose selectivity

• Phase 2: selectivity begins to increase via the addition of more F127.

• Phase 3: shows exclusive control of nucleation within a range

• Phase 4: when the concentration of micelle is too high, it starts to loose the selectivity.

SEM OF F1270.81 0.05 0.01

0.005 0.001

EDX of F127

C/O Ratio0.81 1.91±0.03

0.05 1.40±0.04

0.01 1.48±0.05

0.005 1.36±0.01

0.001 1.33±.0.02

Microscope Image of Na CMC F127

0.81 0.05 0.01

0.005 0.001

F127 forms globular micelle in size range of 68-70 nm

Difficult to see under the microscope

Conclusion Size of the micelle formed by F127 and SPAN 80 are

different. Micelle size of F127 is much smaller than SPAN 80. So we rarely can see under microscope.

F127 and F108 have similar structures, but F127 can control the nucleation mechanism because F127 has a lower critical micelle concentration so that F127 can form micelle at a concentration we can use.

The ability to form micelles and the number of micelles that can be formed by the surfactant is critical to control the nucleation mechanism.

Future Work

Methodology for analyzing critical micelle concentration

Choose another surfactant to test our hypothesis

Acknowledgement

Supervisor: Dr. Keith Chadwick

Graduate student: Jing Ling

Chadwick Lab group

Questions?