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1

The effect of Ethanol

• Various solid state composition

• Depends on the spray dry conditions (i.e temperature, humidity)

Polymorphism

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2

Aims

Assess if polymorphic change follows the trend linked tothe particle size distribution that is normally obtainedduring spray dry process.

To investigate the effect of ethanol on drying kinectics,which then affect the crystal growth and dryingbehavior of polymorphs .

Methods

MATERIALS

• D-Mannitol

α,β,δ and

hemihydrate

• Ethanol

DATA INTERPRE-TATION

Identify polymrphic

change according to particle size

4

Raman Microscopy

CHEMO-METRICS

Multivariate Data Analysis

PLS-DA

SPRAY DRY

Mannitol in 10% Ethanol

1

NGI

Separate to different particle

size fractions

(Stage 1 – Stage 8)

2

SOLID STATE ANALYSIS

Characterize mannitol

polymophrs

3

X-RAY Diffracto-

metry

Scanning Electron

Micrograph / Thermogravi-

metric Analysis

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Results – SEM / TGA

Stage 110.9 ± 3.4 µm

Stage 42.7 ± 1.7 µm

Stage 7,81.0 ± 0.4 µm

TGA - No detectable weight loss

Results - XRD

5 10 15 20 25 30 35 40

Offset Y

valu

es

2 Theta

S78

S6

S5

S4

S3

S2

S1

Bulk

10% Ethanol

αα ββ

• All samples contain α and β-mannitol.

• Comparing the ratio of two polymorphs at indicated positions, αcontents increase relatively at smaller particle size.

Bulk

Stage 1

Stage 2

Stage 3

Stage 4

Stage 5

Stage 6

Stage 7,8

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Results – Raman Microscopy

400 600 800 1000 1200 1400

0

5000

10000

15000

20000

25000

30000

Inte

nsity

Wavenumber (cm-1)

alpha mannitol

beta mannitol(a)

400 600 800 1000 1200 1400

-0.15

-0.10

-0.05

0.00

0.05

0.10

0.15

Wavenumber (cm-1)

Loading 1, 86.54%

Loading 2, 13.15%

Loading 3, 0.25%

(b)

• 3 principal components• 100% specificity and sensitivity• 0% misclassification rate

Results – Raman Microscopy

-- Bulk powder -- S 1 S 2 S 3 S 4 S 5 S 6 S 7 S 8

0

10

20

30

40

50

60

70

80

90

100

Perc

en

tag

e o

f b

eta

ma

nn

ito

l (%

)

NGI stage

(c)

• Content of β-mannitoldecreased from NGI Stage 1 to 8

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5

Different drying rates for droplets with various sizes

1 sec 5 secs

• Smaller droplets are likely to dry faster than larger droplets

• Ostwald rules of stages– more meta-stable α-mannitol in small particles

• Moisture as ‘lubricant’ for stable crystal arrangement– more stable β-mannitol in large particles

Conclusions

• Ethanol increases drying rate of mannitol in thespray drying system, leading to the presence ofmeta-stable α-mannitol in addition to stable β-mannitol.

• Polymorphic form of mannitol changes accordingto particle size from spray drying process.