co.

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1
1

THE RECRYSTALLIZATION AND DISSOLUTION OF

ACETYLSALICYLIC ACID

by

Fakhreddin Jamali

Pharm. D., U n i v e r s i t y o f Tehran, I r a n , 1969

A THESIS SUBMITTED' IN PARTIAL FULFILMENT OF

THE REQUIREMENTS FOR THE DEGREE OF

MASTER OF SCIENCE IN PHARMACY

i n the D i v i s i o n

of

Pharmaceutics

of the

F a c u l t y of P h a r m a c e u t i c a l Sciences

We a c c e p t t h i s t h e s i s as conforming t o the

required standard.

THE UNIVERSITY OF BRITISH COLUMBIA

SPRING 1973
In p r e s e n t i n g t h i s t h e s i s i n p a r t i a l f u l f i l m e n t of the requirements f o r

an advanced degree at the U n i v e r s i t y of B r i t i s h Columbia, I agree that

the L i b r a r y s h a l l make i t f r e e l y a v a i l a b l e f o r r e f e r e n c e and study. I

f u r t h e r agree t h a t p e r m i s s i o n f o r e x t e n s i v e c o p y i n g of t h i s t h e s i s f o r

s c h o l a r l y purposes may be granted by the Head of my Department or by

his representatives. I t i s understood t h a t copying or p u b l i c a t i o n of

t h i s thesis for f i n a n c i a l gain s h a l l not be allowed without my written

permission.

Faculty of P h a r m a c e u t i c a l S c i e n c e s

The University of B r i t i s h Columbia

Vancouver 8, Canada

Date:
 ABSTRACT

O b s e r v a t i o n s that some samples of commercial a c e t y l s a l i c y l i c

a c i d had different dissolution r a t e s were f o l l o w e d by reports that

a c e t y l s a l i c y l i c acid exists i n more than one polymorphic form. The

evidence f o r polymorphism has been q u e s t i o n e d by a number of authors

and the e f f e c t s of such f a c t o r s as c r y s t a l habit, particle size,

c r y s t a l i m p e r f e c t i o n , the presence of s a l i c y l i c a c i d and spherulites

of a c e t y l s a l i c y l i c a c i d have been d i s c u s s e d i n an attempt to explain

the anomalous b e h a v i o u r . T h i s work attempts to r e s o l v e the

c o n f l i c t i n g p o i n t s of view.

A c e t y l s a l i c y l i c a c i d was r e c r y s t a l l i z e d from e t h a n o l i n a

c r y s t a l l i z e r which p e r m i t t e d c o n t r o l of the degree of supersaturation

and, therefore, growth r a t e . In a d d i t i o n , a number of other

r e c r y s t a l l i z a t i o n techniques and s o l v e n t s were used t o produce a c e t y l -

salicylic a c i d c r y s t a l s w i t h a wide v a r i e t y of h a b i t s and varying

amounts of s a l i c y l i c a c i d . The c r y s t a l s were compressed i n t o discs

both w i t h and w i t h o u t p r i o r s i z e r e d u c t i o n and sieving. Intrinsic

d i s s o l u t i o n r a t e s , measured u s i n g a r o t a t i n g d i s c t e c h n i q u e showed that

the r a t e s were independent of c r y s t a l growth r a t e , crystal size and

habit, the content of s a l i c y l i c acid (up to 3.8% w/w) and the presence

of s p h e r u l i t e s of a c e t y l s a l i c y l i c a c i d . X-ray d i f f r a c t i o n p a t t e r n s

r e v e a l e d no differences between the v a r i o u s c r y s t a l s and the original

commercial m a t e r i a l . Melting points, however, were dependent on the

method of measurement and the c r y s t a l s i z e and habit. Using the

h o t - s t a g e method and h e a t i n g at a r a t e of 0.2 per minute from a

s t a r t i n g temperature of 2° below the approximate m e l t i n g point

 II

(previously determined), a c e t y l s a l i c y l i c a c i d melted, with

d e c o m p o s i t i o n , i n the range of 128.3 to 132.7°, ( e x c l u d i n g spherulites).

When h e a t i n g was started at 100° the m e l t i n g range became v e r y broad

w i t h s m a l l unaggregated p a r t i c l e s s t a r t i n g to melt at temperatures

between 103° and 112°. Analysis of the melt showed that the

p r o p o r t i o n of s a l i c y l i c a c i d i n c r e a s e d w i t h decrease i n p a r t i c l e

s i z e of the o r i g i n a l a c e t y l s a l i c y l i c acid crystals. Hence, the

d e p r e s s i o n of the m e l t i n g p o i n t of i n d i v i d u a l c r y s t a l s i s related

to the i n c r e a s e d s u s c e p t i b i l i t y of s m a l l p a r t i c l e s to thermal

decomposition w i t h the f o r m a t i o n of s a l i c y l i c acid.

Evidence f o r the e x i s t e n c e of m e t a s t a b l e polymorphs of

a c e t y l s a l i c y l i c a c i d r e s t s on the reported properties of needle-like

c r y s t a l s r e c r y s t a l l i z e d from n-hexane and spherulites grown i n t h i n

f i l m s from s a t u r a t e d a l c o h o l i c s o l u t i o n . The needle-like crystals

m e l t e d over the range 123.9° t o 130.1° u s i n g a h e a t i n g r a t e of 0.2°

per minute from a s t a r t i n g temperature 2° below the approximate

melting point. The wide m e l t i n g range i s p r o b a b l y due to decomposition

of the f i n e n e e d l e s and the f o r m a t i o n of s a l i c y l i c a c i d as discussed

above. Spherulites of a c e t y l s a l i c y l i c a c i d underwent a thermal trans-

f o r m a t i o n over the range 104° to 128° to form e l o n g a t e d prisms and a

s o l u t i o n phase t r a n s f o r m a t i o n i n t o w e l l d e f i n e d prisms when i n c o n t a c t

with a saturated solution of a c e t y l s a l i c y l i c acid i n various alcohols.

The i n t r i n s i c d i s s o l u t i o n rates of compressed d i s c s prepared from the

needle-like c r y s t a l s a n d t s p h e r u l i t e s were the same as the other acetyl-

s a l i c y l i c acid crystals. Moreover, X-ray d i f f r a c t i o n p a t t e r n s of the

needle-like c r y s t a l s , the spherulites and the c r y s t a l s formed from the

spherulites a f t e r thermal and s o l u t i o n phase t r a n s f o r m a t i o n were

i d e n t i c a l w i t h each o t h e r and the o r i g i n a l a s p i r i n . Hence, the

needle-like c r y s t a l s and s p h e r u l i t e s are not m e t a s t a b l e polymorphic

forms o f a c e t y l s a l i c y l i c a c i d . I t i s suggested t h a t both the

thermal and s o l u t i o n phase t r a n s f o r m a t i o n are growth p r o c e s s e s .

SUPERVISOR
 IV

LIST OF CONTENTS
Page

1. INTRODUCTION; 1

2. LITERATURE SURVEY 2

2-1. C r y s t a l and Amorphous S t a t e s 2

2-2. C r y s t a l Growth 4

I. S o l u b i l i t y and Supersolubility 4

II. T h e o r i e s of C r y s t a l Growth 7

2-3. D e n d r i t e Growth 15

2-4. Polymorphism 18

I. Microscopic Optical Crystallography ; 20

II. X-Ray D i f f r a c t i o n 21

III. Infrared Spectroscopy 21

IV. Differential Thermal A n a l y s i s 22

2-5. D i s s o l u t i o n of C r y s t a l l i n e Compounds 22

I. D i s s o l u t i o n Phenomenon 22

II. Reciprocity of Growth and Dissolution 23

III. D i s s o l u t i o n Models 25

IV. D i s s o l u t i o n Measurement Methods 28

V. Factors A f f e c t i n g D i s s o l u t i o n Rate. 30

2- 6. The Polymorphism Q u e s t i o n of A c e t y l s a l i c y l i c A c i d 37

3. EXPERIMENTAL 42

3- 1. Apparatus 42

3-2. Materials 43

3-3. Methods 44

I. Solubility of A c e t y l s a l i c y l i c A c i d in
Absolute Ethanol 44
II. R e c r y s t a l l i z a t i o n of A c e t y l s a l i c y l i c A c i d 46
III. D e t e r m i n a t i o n of S a l i c y l i c A c i d i n A c e t y l s a l i c y l i c
Acid 52
IV. Measurement of the M e l t i n g P o i n t of A c e t y l -
s a l i c y l i c Acid 65
V. X-Ray D i f f r a c t i o n of A c e t y l s a l i c y l i c A c i d 65

VI. D i s s o l u t i o n of A c e t y l s a l i c y l i c A c i d 65

a. Intrinsic Dissolution....... 65

b. Bulk D i s s o l u t i o n 72
 VII. E f f e c t of V a r i o u s Factors on I n t r i n s i c
D i s s o l u t i o n Rate

a. E f f e c t of P a r t i c l e S i z e

b. E f f e c t of S a l i c y l i c A c i d

c. E f f e c t of S u p e r s a t u r a t i o n

d. E f f e c t of H a b i t

e. E f f e c t of R e c r y s t a l l i z a t i o n S o l v e n t

f. D i s s o l u t i o n Rate of S p h e r u l i t e s
g. D i s s o l u t i o n Rate o f M i x t u r e s of P r i s m a t i c
C r y s t a l s and S p h e r u l i t e s

RESULT AND DISCUSSION..

4-1. E q u i l i b r i u m S o l u b i l i t y of A c e t y l s a l i c y l i c A c i d i n
Absolute Ethanol
4-2. C r y s t a l s of A c e t y l s a l i c y l i c Acid
I. S a l i c y l i c A c i d Content
II. Melting Point.....
III. Solution-Phase Transformation
IV. X-Ray D i f f r a c t i o n
4-3. D i s s o l u t i o n of A c e t y l s a l i c y l i c A c i d
I. I n t r i n s i c D i s s o l u t i o n Rate
II. Bulk D i s s o l u t i o n
III. E f f e c t of Various F a c t o r s on D i s s o l u t i o n Rate...
a. P a r t i c l e Size
b. S a l i c y l i c Acid
c. Supersaturation
d. Habit
e. R e c r y s t a l l i z a t i o n Solvent
f. D i s s o l u t i o n Rate of S p h e r u l i t e s and M i x t u r e
of S p h e r u l i t e s and P r i s m a t i c C r y s t a l s

SUMMARY AND CONCLUSION

REFERENCES
 VI

LIST OF TABLES

Page

2-1. The seven c r y s t a l systems 3

2-2. R a t i o of v e l o c i t i e s of d i s s o l u t i o n over those of

growth f o r some g i v e n substances 24

2-3. Variation of growth of K^SO^ i n presence of

some s a l t s 24

4-1. S a l i c y l i c a c i d content of d i f f e r e n t samples of

a c e t y l s a l i c y l i c a c i d c r y s t a l s d u r i n g the m e l t i n g

process. 86

4-2. R e c r y s t a l l i z a t i o n c o n d i t i o n s and p r o p e r t i e s o f

a c e t y l s a l i c y l i c acid crystals 93

4-3. I n t r i n s i c d i s s o l u t i o n r a t e of a c e t y l s a l i c y l i c

a c i d w i t h d i f f e r e n t p a r t i c l e s i z e a t 37* and 300

r.p.m 101
 VII

LIST OF FIGURES

Page

2-1. Theoretical s o l u b i l i t y - s u p e r s o l u b i l i t y diagram 6

2-2. S t r u c t u r e of a low-index f a c e (001) f o r a p e r f e c t crystal

on K o s s e l - S t a n s k i model 9

2-3. C l a s s i f i c a t i o n of c r y s t a l i m p e r f e c t i o n s 12

2-4. The s t r u c t u r e of an edge d i s l o c a t i o n 14

2-5. The end of a screw d i s l o c a t i o n , 14

2- 6. T y p i c a l d e n d r i t e i n two dimensions 16

3- 1. S o l u b i l i t y Apparatus 45

3-2. Crystallizer... 47

3-3. Standard curve f o r the c o l o r i m e t r i c d e t e r m i n a t i o n of

s a l i c y l i c acid 53
3-4. G a s - l i q u i d chromatographic i n t e r n a l s standard ca-Mbratibn
curve" f o f . i s a l i c y l i e d a e i d 56

3-5. G a s - l i q u i d chromatogram of s a l i c y l i c a c i d in commercial

a c e t y l s a l i c y l i c acid 58

3-6. G a s - l i q u i d chromatogram of a c e t y l s a l i c y l i c a c i d i n mixture

of s a l i c y l i c a c i d (1%) and a c e t y l s a l i c y l i c a c i d 59

3-7. Standard c u r v e f o r d e t e r m i n a t i o n of s a l i c y l i c a c i d i n
a c e t y l s a l i c y l i c a c i d u s i n g absorbance r a t i o method 60

3-8. Standard c u r v e f o r s p e c t r o p h o t o f l u o r o m e t r y d e t e r m i n a t i o n

of s a l i c y l i c a c i d . . 62

3-9. M e t a l mold to make a compressed d i s k 67

3 - 10. I n t r i n s i c d i s s o l u t i o n a p a r a t u s 69

3- 11. Standard c u r v e f o r a c e t y l s a l i c y l i c a c i d i n 0.1 N

hydrchloric acid 70
4 - 1. S o l u b i l i t y s u p e r s o l u b i l i t y diagram f o r the a c e t y l s a l i c y l i c

acid - a b s o l u t e e t h a n o l system 76

4- 2. Comparison of s o l u b i l i t y - s u p e r s o l u b i l i t y 77

4 - 3. A c e t y l s a l i c y l i c acid c r y s t a l habits 79
 VIII

Page

4-4. N e e d l e - l i k e c r y s t a l s of a c e t y l s a l i c y l i c a c i d from

n-hexane 80

4-5. Hexagonal p l a t e s of a c e t y l s a l i c y l i c a c i d from e t h a n o l 95% 80

4-6. Spherulites of a c e t y l s a l i c y l i c a c i d 82

4-7. Spherulites of v a n i l l i n 82

4-8. Thermal transformed c r y s t a l s from s p h e r u l i t e s 90

4-9. Solution transformed c r y s t a l s from s p h e r u l i t e s 90

4 - 10. X-ray d i f f r a c t i o n p a t t e r n of a c e t y l s a l i c y l i c a c i d 92

4 - 1 1 . Rotating d i s k d i s s o l u t i o n of a c e t y l s a l i c y l i c acid i n
0.1 N HC1 a t 37* and 300 r.p.m 95
4-12. F i n i t e d i f f e r e n c e s diagram f o r t h e d i s s o l u t i o n of
a c e t y l s a l i c y l i c a c i d i n 0.1 N HC1 a t 37* and 300 r.p.m... 96

4-13. I n i t i a l d i s s o l u t i o n c u r v e of a c e t y l s a l i c y l i c a c i d i n
0.1 N HC1 a t 37* and 300 r.p.m 97

4 - 14. B u l k d i s s o l u t i o n of a c e t y l s a l i c y l i c a c i d i n 0.1 N HC1.... 99

 IX

ACKNOWLEDGEMENTS

The author i s indebted t o Dr.A/.G:Mitchel'l^fchesis s u p e r v i s o r f o r

his guidance and g e n e r a l p e r s o n a l a t t e n t i o n throughout t h e course

of t h i s work and wishes t o express h i s a p p r e c i a t i o n to the

following people:

Dr. F.S.Abbott f o r h i s s c i e n t i f i c a d v i c e and h e l p w i t h t h e

a n a l y t i c a l aspects of t h i s investigation.

Dr. M.Pernarowski f o r h i s academic a d v i c e and c o n s i d e r a t i o n .

Mr. B.G.Butters, Department o f M e t a l l u r g y , for his helpful

a s s i s t a n c e and guidance i n p r e p a r i n g X-ray d i f f r a c t i o n

patterns.

Mr. K.Kent, Department o f M e t a l l u r g y , for his assistance

w i t h p r e p a r i n g comoressed d i s k s .
TO
 1

1. INTRODUCTION.

A c e t y l s a l i c y l i c a c i d was first synthesized i n 1853 by

G e r h a r d t , but the f i r s t s y n t h e t i c e s t e r of s a l i c y l i c a c i d t o be introduced

i n t o m e d i c i n e was p h e n y l s a l i c y l a t e (Menchi, 1886). Meanwhile Hoffman,

a chemist at Bayer's chemical works i n Germany, had found a simpler

method of a c e t y l a t i n g s a l i c y l i c a c i d and had recognized the advantages

of the a c e t y l a t e d compound over s a l i c y l i c a c i d i n the treatment of

rheumatism. Dreser (1899) i n v e s t i g a t e d the pharmacology of t h i s compound

and e v e n t u a l l y Bayer marketed a c e t y l s a l i c y l i c a c i d under the t r a d e name

of " A s p i r i n " . Hence a c e t y l s a l i c y l i c a c i d was one of the f i r s t chemothera-

p e u t i c agents and i t s p r o p e r t i e s have been s t u d i e d s t e a d i l y over the

years.

A c e t y l s a l i c y l i c a c i d has a l o n g h i s t o r y of g i v i n g t r o u b l e i n

melting point determination. Reported v a l u e s range from 100 to 144°. The

anomalous p h y s i o c h e m i c a l behavior of t h i s compound has been s u b j e c t of many

recent papers. Reported d i f f e r e n c e s i n the d i s s o l u t i o n r a t e of commercial

a c e t y l s a l i c y l i c a c i d were f o l l o w e d by r e p o r t s t h a t t h i s compound e x i s t s i n

more than one polymorphic form. The evidence f o r polymorphism has been

questioned by a number of authors, and the e f f e c t s of such f a c t o r s as crystal

habit, particle size, c r y s t a l imperfections, the presence of salicylic

a c i d and s p h e r u l i t e s of a c e t y l s a l i c y l i c a c i d have been d i s c u s s e d i n an attempt

to e x p l a i n the anomalous behavior.;'

T h i s work attempts to r e s o l v e the c o n f l i c t i n g p o i n t s of view by

recrystallizing a c e t y l s a l i c y l i c a c i d u s i n g d i f f e r e n t methods and conditions

of r e c r y s t a l l i z a t i o n f o l l o w e d by a study of the p h y s i c b c h e m i c a l p r o p e r t i e s of

the crystals.
 2

2 - LITERATURE SURVEY

2-1. C r y s t a l and Amorphous S t a t e s .

Most s o l i d drugs are c r y s t a l l i n e i n n a t u r e , i . e . , the

m o l e c u l e s o f which they are composed a r e packed t o g e t h e r i n a r e g u l a r

manner, forming a t h r e e - d i m e n s i o n a l p a t t e r n . S o l i d drugs which appear

as a powder or as i r r e g u l a r lumps c o n s i s t of s m a l l c r y s t a l s as seen

by microscope or examined by X-ray methods. A t y p i c a l c r y s t a l has a

r e g u l a r g e o m e t r i c form w i t h s h a r p , s t r a i g h t edges and p l a n e s u r f a c e s .

When f r a c t u r e d , i t breaks i n t o p i e c e s w i t h p l a n e f a c e s meeting i n

sharp edges.

The r e g u l a r e x t e r n a l form of a c r y s t a l i s determined by a

r e g u l a r assembly o f s m a l l e r u n i t s having a u n i f o r m g e o m e t r i c a l form.

The arrangement of these u n i t s i s the most important c h a r a c t e r i s t i c of

a c r y s t a l , f o r , even i f the e x t e r n a l form i s d e s t r o y e d by powdering,

the i n t e r n a l s t r u c t u r e remains. C r y s t a l s may vary i n s i z e and i n the

development of d i f f e r e n t f a c e s owing to the c o n d i t i o n s under which

they a r e formed (habit m o d i f i c a t i o n ) . The c o n s t a n t g e o m e t r i c a l form

of the u n i t s composing the c r y s t a l i s e x h i b i t e d i n the constancy of

the a n g l e s between s i m i l a r f a c e s (law of constancy o f i n t e r f a c i a l

angles).

The symmetry p o s s e s s e d by c r y s t a l s i s expressed i n terms of

t h e i r symmetry about c e r t a i n p l a n e s and axes o f the c r y s t a l . An " a x i s

of symmetry" i s an a x i s on which the c r y s t a l can be r o t a t e d through

360° and occupy the same p o s i t i o n more than once. If a crystal

p o s s e s s e s a s u i t a b l e number of axes of symmetry, t h r e e of them may be

chosen as " c r y s t a l l o g r a p h i c axes"; i n c r y s t a l s p o s s e s s i n g l e s s than

Table 2 - 1 . The Seven C r y s t a l Systems.

System Axes Angles Example

Cubic a = b = c = p = * = 9Q C
Sodium C h l o r i d e

Tetragonal a = b ; c <* = ft = * = 90 Calcium Oxalate

Orthorhombic a ; b ; c 90^ Acetanilid;',

V a n i l l i n - (I)

Monoclinic a ; b ; c <*= (i= 90 ; * V i t a m i n A (m) ,

A c e t y l s a l i c y l i c Acid.

Rhombohedral a = b = c Cortisone

Hexagonal a = b ; c /3 = 90 ; *=120 Styphnic acid

Triclinic a ; b ; c ai; (i ; V Vitamin A

* m, metastable

** 2, 4, 6. trinitroresorcinal.
 4

t h r e e axes of symmetry, o t h e r axes are chosen as the crystallographic

axes. For c l a s s i f i c a t i o n , a l l c r y s t a l s are r e f e r r e d to seven groups

(Table 2 - 1), e.g. c u b i c (alum), t r i c l i n i c (copper s u l p h a t e ) ,

monoclinic ( a c e t y l s a l i c y l i c a c i d ) , which are d e f i n e d by the p o s i t i o n

of the c r y s t a l l o g r a p h i c axes.

C r y s t a l shapes are o f t e n d e s c r i b e d i n g e n e r a l terms which

are almost s e l f - e x p l a n a t o r y ; needle-shape c r y s t a l s are o f t e n termed

a c i c u l a r and p l a t e - l i k e c r y s t a l s , l a m i n a r . Such terms g i v e no i d e a of

the c r y s t a l l o g r a p h i c axes; f o r example, the p r i s m o c c u r s i n s e v e r a l

groups.

C e r t a i n s o l i d s u b s t a n c e s , e.g. g l a s s and colophony, which

do not e x h i b i t a l l the p r o p e r t i e s of c r y s t a l s , are regarded as "super-

c o o l e d l i q u i d s " or "amorphous s u b s t a n c e s " . Supercooled l i q u i d s have

a v e r y h i g h v i s c o s i t y , but are n e v e r t h e l e s s capable of f l o w i n g v e r y

slowly. Under c e r t a i n c o n d i t i o n s , c r y s t a l l i z a t i o n of the s u p e r c o o l e d

l i q u i d may occur; old glass w i l l crystallize ( d e v i t r i f y ) when rendered

l e s s v i s c o u s by h e a t i n g . The m o l e c u l e arrangements of such substances

are v e r y complex and do not u s u a l l y a c q u i r e the order necessary f o r a

c r y s t a l l i n e form. However, w i t h amorphous s u b s t a n c e s , i t i s by no

means c e r t a i n t h a t o r d e r i s e n t i r e l y l a c k i n g , and the word amorphous

has t h e r e f o r e to be used w i t h c a u t i o n .

2-2. C r y s t a l Growth.

I. S o l u b i l i t y and Supersolubility.

I t was known to e a r l y c r y s t a l l o g r a p h e r s t h a t a c r y s t a l would

not develop i n a j u s t - s a t u r a t e d s o l u t i o n . " S u p e r s a t u r a t i o n " was

 5

recognised as the s t a t e i n which the s l i g h t e s t shock or disturbance

w i l l b r i n g about immediate c r y s t a l l i z a t i o n ; the r e g i o n i n which this

state exists i s called the "metastable r e g i o n " and i s bounded by the

s o l u b i l i t y and s u p e r s o l u b i l i t y curves.

Fig. 2-1 shows a s o l u b i l i t y - s u p e r s o l u b i l i t y diagram.

A represents a p o i n t i n the r e g i o n of u n s a t u r a t i o n which, i f undisturbed,

would remain as a s i n g l e phase i n d e f i n i t e l y . A c r y s t a l placed i n such

a s o l u t i o n would d i s s o l v e . There are two ways i n which we can b r i n g

s o l u t i o n A to the e q u i l i b r i u m " s a t u r a t i o n " c o n d i t i o n ( i . e . , the region

i n which c r y s t a l s n e i t h e r grow nor d i s s o l v e ) . F i r s t by l o w e r i n g the

temperature to the p o i n t B o r , second, by evaporating o f f some of the

s o l v e n t at constant temperature, when the c o n d i t i o n s r e p r e s e n t e d by

p o i n t B ' w i l l be reached. With e i t h e r s o l u t i o n , at B or E*', a c r y s t a l

c o u l d remain i n d e f i n i t e l y w i t h o u t growth or d i s s o l u t i o n t a k i n g place.

T h e o r e t i c a l l y any f u r t h e r c o o l i n g below p o i n t B or w i t h d r a w a l o f solvent

beyond p o i n t B ' should r e s u l t i n the s e p a r a t i o n of s o l i d (i.e., crystal-

l i z a t i o n ) , but i t i s a matter of common experience t h a t t h i s never occurs.

Further c o o l i n g w i l l b r i n g us to a p o i n t C, when the s l i g h t e s t shock or

disturbance w i l l cause immediate c r y s t a l l i z a t i o n . The moment t h i s occurs,

the heat of c r y s t a l l i z a t i o n w i l l p r e v e n t any f u r t h e r drop i n temperature

u n t i l the c r y s t a l s have gathered to themselves most of the a v a i l a b l e

excess r e p r e s e n t e d by the d i s t a n c e from the e q u i l i b r i u m curve.

P r a c t i c a l l y speaking i t i s i n c o n v e n i e n t to b r i n g a s o l u t i o n to the

s u p e r s o l u b i l i t y point f o r c r y s t a l l i z a t i o n . A s l i g h t disturbance or

seeding with a few c r y s t a l s i n the " m e t a s t a b l e " r e g i o n w i l l b r i n g about

immediate r a p i d c r y s t a l l i z a t i o n . The heat of c r y s t a l l i z a t i o n r e s u l t s i n

a notable r i s e i n temperature. T h e o r e t i c a l l y the f u r t h e r t h i s region,

 Temperature, C"

Theoretical solubility-supersolubility diagram.

 7

called by Ostwald (1900) " l a b i l e " , i s p e n e t r a t e d the more and more

u n s t a b l e i t becomes and the g r e a t e r i s the tendency to crystallize.

Opposing t h i s , however, i s the p o s s i b i l i t y of a b i g i n c r e a s e i n the

viscosity of the s o l u t i o n which i n time might o v e r r u l e the tendency

to crystallize (Buckley 1951). L i n e AB'C' .(Fig.

;
2-1) represents

withdrawal of s o l v e n t . As s t a t e d above, n o t h i n g w i l l happen to the

s o l u t i o n a t B' , but on e v a p o r a t i o n to p o i n t C ' c r y s t a l l i z a t i o n

1 1
will

occur spontaneously. I t i s l i k e l y , however, t h a t the s u r f a c e of

the s o l u t i o n w i l l approach p o i n t C* , w h i l e the r e s t of the solution

still remains i n the " m e t a s t a b l e " r e g i o n , so t h a t the b u l k never

reaches the c o n c e n t r a t i o n , C .. T h i s process o c c u r s i n most cases of

crystallization by e v a p o r a t i o n a t c o n s t a n t temperature.

II T h e o r i e s of C r y s t a l Growth

Verma & K r i s h n a (1966) have reviewed and classified the

t h e o r i e s of c r y s t a l growth i n t o two parts: the theory of the growth

of an i d e a l l y perfect crystal arid the t h e o r y of growth of an imperfect

(i.e., real) crystal. Gibbs (1928) compared the growth of a l i q u i d

drop from a m i s t w i t h the growth of a c r y s t a l . The f a c e energy t h a t

r e s i d e s on the s u r f a c e s e p a r a t i n g the two phases r e t a r d s the formation

of the second phase i n s i d e the f i r s t . T h e r e f o r e the s t a b i l i t y of an

isolated drop i s maximum when i t s s u r f a c e f r e e energy and hence i t s

a r e a are m i n i m a l . For a c r y s t a l i n e q u i l i b r i u m w i t h i t s surroundings

at c o n s t a n t temperature and p r e s s u r e , this c o n d i t i o n implies that

Gibbs f r e e energy must be minimum f o r a g i v e n volume. It therefore

f o l l o w s t h a t , f o r a g i v e n volume, those f a c e s which l e a d to a minimum

 8

t o t a l s u r f a c e f r e e energy w i l l develop. However, the atoms or

m o l e c u l e s i n a l i q u i d a r e randomly a r r a n g e d , whereas i n a c r y s t a l the

structural u n i t s have a r e g u l a r arrangement. This e s s e n t i a l difference

between l i q u i d drops and crystals was recognized by G i b b s . Curie (1885)

c a l c u l a t e d the shape and end forms of a c r y s t a l w h i l e Wulff (1901)

deduced t h a t the v e l o c i t i e s of growth of d i f f e r e n t faces are

p r o p o r t i o n a l to the a p p r o p r i a t e s p e c i f i c s u r f a c e f r e e e n e r g i e s .

Real c r y s t a l s a r e not ideally perfect. An ideally perfect

c r y s t a l c o n s i s t s o f a p e r i o d i c a r r a y of atoms or m o l e c u l e s whose

arrangement would conform w i t h the symmetry of one of the 230 space

groups. The atomic theory of c r y s t a l growth can e x p l a i n the formation

of an i d e a l l y p e r f e c t c r y s t a l . Kossel (1927) and Stanski (1928) took

a simple c u b i c model ( F i g . 2 - 2 ) to i l l u s t r a t e the growth of an ideally

perfect c r y s t a l . The atoms or m o l e c u l e s are r e p r e s e n t e d as cubes. The

cubes a r e p l a c e d f a c e to f a c e and each of these i s attached e q u a l l y by

a l l s i x neighbors. The energy r e q u i r e d to s e p a r a t e two neighbors i s

called the " b i n d i n g " energy. Unless the number of c u b i c b r i c k s happens

to be the exact number of s i x t h a t w i l l complete a l l the s i x f a c e s of

the c r y s t a l , at l e a s t one of the f a c e s w i l l be incomplete. This s i t u a t i o n .

produces a "monomolecular s t e p " or simply a " s t e p " on the c r y s t a l surface.

T h i s step i t s e l f i s l i k e l y to be incomplete, having a "kink".

At a b s o l u t e zero temperature, t h e r e i s no thermal v i b r a t i o n

i n c r y s t a l molecules. I f the temperature i s r a i s e d , the m o l e c u l e s start

to v i b r a t e r e l a t i v e to one another. On i n c r e a s i n g the temperature, some

m o l e c u l e s a c q u i r e enough energy to overcome the b i n d i n g energy. They

w i l l then break away from the body of the c r y s t a l , e n t e r the space

Figure 2 - 2. S t r u c t u r e of a low-index f a c e (001) for a perfect
c r y s t a l on K o s s e l S t a n s k i model.
surrounding i t and i n c r e a s e the c o n c e n t r a t i o n of the surrounding vapor

or l i q u i d . Molecules at a k i n k p o s i t i o n are more l i k e l y to l e a v e the

c r y s t a l , though t h i s w i l l a l s o happen f o r some m o l e c u l e s at other

positions. The m o l e c u l e s at the k i n k p o s i t i o n are bound by only

three neighbors, while o t h e r s have more n e i g h b o r s and t h e r e f o r e more

energy i s r e q u i r e d to break the b i n d i n g energy. T h i s e x p l a n a t i o n shows

t h a t k i n k s a c t as "exchanging s i t e s " f o r m o l e c u l e s on the crystal

s u r f a c e and those i n the surrounding phase. The departure of

m o l e c u l e s from the c r y s t a l s u r f a c e c o n t i n u e s u n t i l an e q u i l i b r i u m i s

reached between the c r y s t a l s u r f a c e and the surrounding phase. At

e q u i l i b r i u m , the r a t e s at which m o l e c u l e s j o i n and l e a v e the crystal

s u r f a c e are e q u a l . When the c o n c e n t r a t i o n of the s u r r o u n d i n g phase

exceeds the e q u i l i b r i u m c o n c e n t r a t i o n c r y s t a l s w i l l s t a r t to grow.

Volmer (1922) e x p l a i n e d t h a t between the time a m o l e c u l e h i t s

the s u r f a c e of a c r y s t a l and the time i t evaporates a g a i n i n t o the vapor,

the adsorbed molecule d i f f u s e s a c o n s i d e r a b l e d i s t a n c e . He found t h a t

the growth r a t e c o u l d be e x p l a i n e d only i f t h e r e was considerable surface

d i f f u s i o n of adsorbed m o l e c u l e s d u r i n g t h e i r l i f e t i m e on the s u r f a c e of

the crystal.

Verma & K r i s h n a (1966) e x p l a i n e d t h a t the p r o c e s s of growth on

a p e r f e c t c r y s t a l whose s u r f a c e has steps w i l l be the r e s u l t of three

processes: ( i ) a t r a n s p o r t of m o l e c u l e s from the surrounding phase to

the s u r f a c e to form the adsorbed l a y e r (only one face i n contact);

( i i ) the d i f f u s i o n of the adsorbed m o l e c u l e s on the c r y s t a l s u r f a c e , some

of which i n t h e i r l i f e t i m e on the s u r f a c e meet a step (two faces i n

contact); and ( i i i ) the d i f f u s i o n of such adsorbed m o l e c u l e s along the

edge of the step u n t i l they reach a k i n k (three f a c e s i n c o n t a c t ) . A

 11

m o l e c u l e which reaches a k i n k i s taken i n t o the body of the crystal

f o r the growth of the incomplete layer.

In c o n t i n u e d c r y s t a l growth, new l a y e r s must be initiated

a f t e r completing each l a y e r . B u r t o n and others (1951) c a l c u l a t e d

t h a t new s t e p s w i l l not be c r e a t e d by thermodynamic f l u c t u a t i o n s on

a low-index f a c e u n l e s s the temperature of the c r y s t a l i s r a i s e d t o

i t s melting point. Therefore, surface nucleation i s required to

continue the growth. Gibbs (1928) e x p l a i n e d t h a t a s m a l l i s l a n d of

m o l e c u l e s may collect on the s u r f a c e of the c r y s t a l . The island spreads

r a p i d l y across the whole f a c e and the process o f growth i s h e l d up until

a new nucleus i s formed. The s i z e of the nucleus p l a y s an important

r o l e i n growth. When the n u c l e u s i s s m a l l e r than a c e r t a i n c r i t i c a l

s i z e , the chances of new molecules being added are l e s s than the chances

of a m o l e c u l e b e i n g evaporated from the nucleus.

As i n d i c a t e d above a r e a l c r y s t a l has imperfections (Fig. 2-3).

Imperfections are the r e s u l t of c r y s t a l d e f e c t s . I f the d e v i a t i o n from

a p e r i o d i c arrangement i s l o c a l i z e d t o the v i c i n i t y of o n l y a few atoms,

it i s c a l l e d a p o i n t i m p e r f e c t i o n or p o i n t d e f e c t . Point imperfection

may be e i t h e r a vacancy i n the r e g u l a r arrangement or an e x t r a atom i n

an i n t e r s t i t i a l s i t e . Ion v a c a n c i e s are c a l l e d "Schottky defects", and

it i s presumed t h a t e q u a l numbers of anion and cation vacancies are

generated i n a c r y s t a l . In c e r t a i n c r y s t a l s an i o n can leave i t s regular

p o s i t i o n and take up an i n t e r s t i t i a l p o s i t i o n . Such a combination of

i n t e r s t i t i a l i o n and the consequent i o n vacancy i s c a l l e d a " F r e n k e l

defect". I t i s a l s o p o s s i b l e f o r i m p u r i t y atoms to s u b s t i t u t e f o r the

normal atoms. I t should be noted t h a t a p o i n t d e f e c t produces strain

o n l y i n i t s neighborhood and does not a f f e c t the p e r f e c t i o n of more

 IMPERFECTIONS

POINT LATTICE

IMPERFECTIONS IMPERFECTIONS

LINE DEFECTS

VACANCIES EXTRA ATOMS

PLANE DEFECTS

SAME
SCHOTTKY FRANKEL IMPURITIES
SUBSTANCE

Fig. 2-3. C l a s s i f i c a t i o n of c r y s t a l imperfections.

d i s t a n t p a r t s of the c r y s t a l (Verma & K r i s h n a 1966).

Sometimes the i m p e r f e c t i o n extends to the l a t t i c e of the

c r y s t a l and r e s u l t s i n l i n e and p l a n e d e f e c t s . L i n e d e f e c t s or

d i s l o c a t i o n s o c c u r when an i n t e r r u p t i o n o c c u r s along a c e r t a i n

d i r e c t i o n and d i s t o r t s the atomic l a t t i c e a r r a y . When l i n e d e f e c t s

c l u s t e r t o g e t h e r i n one p l a n e , they can form a p l a n e u n i t or "plane

defect". L i n e a g e b o u n d a r i e s , g r a i n boundaries and s t a c k i n g faults

are examples o f p l a n e d e f e c t s .

The concept o f d i s l o c a t i o n s a r i s e s from a c o n s i d e r a t i o n of

p l a s t i c flow i n a c r y s t a l . C o n s i d e r a p l a n e o f atoms s l i d i n g i n a

c e r t a i n c r y s t a l l o g r a p h i c d i r e c t i o n across a neighboring plane. If

b o t h p l a n e s were r i g i d , the s l i p would be u n i f o r m over the e n t i r e plane

( l i k e the s l i p p i n g of a pack of c a r d s ) . However, the atoms i n a c r y s t a l

are not r i g i d l y bound to each o t h e r . They are e l a s t i c a l l y c o u p l e d , so

t h a t thermal v i b r a t i o n and l o c a l i r r e g u l a r i t i e s make the f o r c e s acting

over the g l i d e p l a n e s nonuniform. T h e r e f o r e , d i f f e r e n t p o r t i o n s of a

s l i p p l a n e , i n g e n e r a l , s l i p over the n e i g h b o r i n g p l a n e by different

amounts. A boundary may be p i c t u r e d such t h a t the two p l a n e s have s l i p p e d

by d i f f e r e n t amounts on e i t h e r s i d e . The t r a n s i t i o n r e g i o n s e p a r a t i n g the

two areas t h a t have s l i p p e d w i l l extend over a few atomic d i a m e t e r s o n l y

(Verma & K r i s h n a , 1966) and the l i n e d i s c o n t i n u i t y may be regarded as a

dislocation.

D i s l o c a t i o n s occur i n two s t a n d a r d o r i e n t a t i o n s : I, d i s l o c a t i o n s

i n the edge o r i e n t a t i o n s (Fig. 2 - 4 ) ; and I I , d i s l o c a t i o n s i n the screw

orientations (Fig. 2 - 5 ) . Other i n t e r m e d i a t e cases can be regarded as

combinations of edge and screw d i s l o c a t i o n s . Thomas (1970) e x p l a i n e d

t h a t , i f a c r y s t a l s u r f a c e has an emergent screw d i s l o c a t i o n , a permanent

s t e p i s a v a i l a b l e f o r n u c l e a t i o n i n s u p e r s a t u r a t e d s o l u t i o n s , and a

s p i r a l growth f e a t u r e r e s u l t s . In g e n e r a l , the s t e p s of the s p i r a l are

monoatomic or monomolecular. Conversely, c r y s t a l d i s s o l u t i o n or

v a p o r i z a t i o n at low u n d e r s a t u r a t i o n s , i s enhanced a t an emergent

screw d i s l o c a t i o n , a s p i r a l d e p r e s s i o n b e i n g thereby formed.

D i s l o c a t i o n s c r e a t e a g r e a t d i s c r e p a n c y between the

t h e o r e t i c a l l y c a l c u l a t e d r a t e of growth of a p e r f e c t c r y s t a l and t h a t

observed for real crystals (Verma & K r i s h n a , 1966). Thomas (1970)

explained that q u a n t i t i v e s t u d i e s o f the a c t i v a t i o n energy of

d i s s o l u t i o n , at i d e a l and d i s l o c a t e d s i t e s , i n d i c a t e t h a t the e n e r g e t i c s

of d i s s o l u t i o n a r e s i g n i f i c a n t l y m o d i f i e d by the dislocation.

2-3. D e n d r i t i c Growth.

C r y s t a l s grown from s o l u t i o n , melt, and vapor can e x i s t i n

almost e n d l e s s v a r i a t i o n s of t r e e - l i k e f o r m a t i o n s called dendrites.

These incude s p h e r u l i t e s and s p h e r i c a l bodies (Buckley 1951). The first

t h i n g observed on the c r y s t a l l i z a t i o n of a s a l t from an aqueous

s o l u t i o n p l a c e d on a microscope s l i d e i s the f o r m a t i o n of n e e d l e - l i k e

or f i b r o u s c r u s t s at the p e r i p h e r y of the drop. Once seeded, some of

the c r y s t a l s develop inwards, and, as t h i s s o l u t i o n i s m e t a s t a b l e , uniform

c r y s t a l l i z a t i o n proceeds. At a l a t e r stage, the drop i s wearing t h i n by

e v a p o r a t i o n and the i n c r e a s e i n c o n c e n t r a t i o n due to e v a p o r a t i o n over-

takes the slower d e p l e t i n g process of m e t a s t a b l e growth. Hence the

s o l u t i o n i n s i d e suddenly becomes l a b i l e (Fig. 2 - 1 ) . At c e r t a i n spots

where t h i s occurs f i r s t , c r y s t a l a p i c e s j u t i n t o the l a b i l e l i q u i d and

r a p i d d e p o s i t i o n takes p l a c e , so t h a t e x t e n s i o n occurs i n the direction

6. T y p i c a l d e n d r i t e i n two dimensions.
of the outward-pushing p o i n t . The s o l u t i o n on e i t h e r s i d e o f the p o i n t

from which m a t e r i a l has been e x t r a c t e d i s only m e t a s t a b l e , and slow

growth i s e x p e r i e n c e d at r i g h t angles t o t h e r a p i d l y e x t e n d i n g point.

Some d i s t a n c e away, a s i m i l a r p r o c e s s i s o c c u r r i n g , and we get a s e r i e s

of l o n g , p a r a l l e l n e e d l e s advancing a t r a t e s c l e a r l y v i s i b l e t o the eye,

w i t h gaps i n between where l i t t l e appears t o be happening. Soon the

l i q u i d between the limbs becomes i t s e l f l a b i l e again due t o f u r t h e r

evaporation, and the r e s u l t i s a s u c c e s s i o n o f b r a n c h i n g s from the main

stems. Under optimum c o n d i t i o n s , these primary b r a n c h i n g s may be

followed by secondary b r a n c h i n g s , as shown i n F i g . 2 - 6 . This

d e s c r i p t i o n r e f e r s t o the almost two-dimensional s i t u a t i o n o f a f l a t

drop o f s o l u t i o n . The f r o s t i n g o f windows i s a f a m i l i a r i l l u s t r a t i o n of

t h i s phenomenon.

Dendrites a r e c r y s t a l l i n e i n the sense that a t c e r t a i n p l a c e s ,

e s p e c i a l l y the e x t r e m i t i e s , they a r e u s u a l l y bounded by p l a n e f a c e s . As

far as t h e i r p h y s i c a l p r o p e r t i e s can be a s c e r t a i n e d , each s m a l l portion

i s s i m i l a r t o a normal c r y s t a l , and they i n v a r i a b l y g i v e i d e n t i c a l X-ray

diffraction patterns.

Dendrite s t r u c t u r e s can be found w i t h a degree o f complexity

ranging from those w i t h p r a c t i c a l l y p a r a l l e l l i m b s , so t h a t r e f l e c t i o n s

of images o f a s l i t from one o f t h e i r f i n e l y s u b d i v i d e d faces are true

to a minute o f a r c , down t o hedgehog d e n d r i t e s which a r e d i f f i c u l t t o

r e c o n c i l e w i t h any g e o m e t r i c a l r e l a t i o n s h i p of the p a r t s . There a r e

many other a s p e c t s o f growth where d e v i a t i o n from the normal mode takes

up i n t e r e s t i n g forms. Some o f these a r e o f a r e p e t i t i v e c h a r a c t e r and

are c a l l e d " s p h e r u l i t e s " . F i g . 4 - 6 i s a spherulite of a c e t y l s a l i c y l i c

a c i d developed a f t e r a s o l u t i o n was poured on the s u r f a c e o f a microscope

s l i d e as a t h i n film.

Popoff (1927) c o n s i d e r e d t h a t the arrangement of the

orientated portions of s p h e r u l i t e s i s only a consequence of t h e i r

common dependence upon an o r i g i n a l c e n t r a l seed. Buckley (1951)

believed t h a t , a l t h o u g h s p h e r u l i t e s may c o n s i s t of a pure substance

grown from s o l u t i o n and perhaps can be e x p l a i n e d on p u r e l y physical

grounds, such as a p e r i o d i c change i n the c o n c e n t r a t i o n o f the

s u r r o u n d i n g s o l u t i o n as above, they a l s o r e q u i r e o t h e r f a c t o r s , such

as the presence of i m p u r i t i e s , e s p e c i a l l y those which can form a s o l i d

s o l u t i o n or o r i e n t a t e d f i l m w i t h the main substance.

Shaftal (1968) e x p l a i n e d that spherulites are formed on

the c r y s t a l l i z a t i o n of many s u b s t a n c e s ; they are s p e c i a l l y character-

istic of substances c o n s i s t i n g of l a r g e m o l e c u l e s , p a r t i c u l a r l y polymers.

Tawashi (1971) grew s p h e r u l i t e s of a c e t y l s a l i c y l i c a c i d and suggested

that substances o f low m o l e c u l a r weight like a c e t y l s a l i c y l i c acid do

not normally give spherulites. However, s p h e r u l i t e s of a c e t y l s a l i c y l i c

a c i d and o t h e r low m o l e c u l a r weight substances l i k e v a n i l l i n (Fig. 4 - 7 ) ,

a c e t a n i l i d , benzocaine and p h e n a c e t i n have been grown i n t h i s work.

2-4. Polymorphism.

Just as any substance, i n g e n e r a l , can e x i s t i n the s o l i d , the

liquid, or the gaseous s t a t e , depending on the c o n d i t i o n s of temperature

and p r e s s u r e , so a l s o a s o l i d formed from s o l u t i o n , m e l t , or vapor phase

can c r y s t a l l i z e i n more than one p o s s i b l e s t r u c t u r e , depending on the

conditions of temperature and p r e s s u r e p r e v a i l i n g a t the time of

crystallization. T h i s phenomenon o f the same c h e m i c a l substance

c r y s t a l l i z i n g i n more than one s t r u c t u r e i s known as "polymorphism".

The d i f f e r e n t s t r u c t u r e s are c a l l e d "polymorphs" or "polymorphic m o d i f i -

cations". There are a l s o cases o f polymorphic m o d i f i c a t i o n s t h a t are

not o b t a i n e d d i r e c t l y from the s o l u t i o n , m e l t , or vapor phase by

c r y s t a l l i z a t i o n , but are o b t a i n e d by phase t r a n s f o r m a t i o n s i n the

s o l i d phase. Polymorphism t h e r e f o r e i n c l u d e s every p o s s i b l e difference

i n the c r y s t a l l i n e s t r u c t u r e of a substance of c o n s t a n t c h e m i c a l

composition ( B a r t h , 1934) except homogenous d e f o r m a t i o n s .

S i n c e the d i f f e r e n t m o d i f i c a t i o n s have the same c h e m i c a l

c o m p o s i t i o n they have s i m i l a r c h e m i c a l p r o p e r t i e s . However, t h e i r

p h y s i c a l p r o p e r t i e s , such as d e n s i t y , s p e c i f i c h e a t , c o n d u c t i v i t y ,

m e l t i n g p o i n t , o p t i c a l b e h a v i o r and X-ray d i f f r a c t i o n s , which depend

on the arrangement of atoms i n the s t r u c t u r e , may be w i d e l y d i f f e r e n t .

Polymorphs o f some compounds d i f f e r i n t h e i r degree of

stability. Under c e r t a i n c o n d i t i o n s the l e s s s t a b l e forms tend to

c o n v e r t to the s t a b l e form. T r a n s i t i o n from one form t o the other takes

p l a c e at a f i x e d temperature when observed under c o n s t a n t p r e s s u r e . This

temperature i s c a l l e d the " t r a n s i t i o n " temperature and i s one of the most

important c h a r a c t e r i s t i c s o f polymorphs. When the t r a n s i t i o n o c c u r s i n

one d i r e c t i o n ( i . e . , t h e m e t a s t a b l e to the s t a b l e form) i t i s s a i d t o be

"monotropic"; when the t r a n s i t i o n i s r e v e r s i b l e , i t i s s a i d t o be

"enantiotropic".

T r a n s i t i o n can take p l a c e i n s o l u t i o n or i n the s o l i d state.

T r a n s i t i o n phenomena i n b o t h media can be used to i d e n t i f y polymorphism

as w i l l be d i s c u s s e d later.

The p h a r m a c e u t i c a l a p p l i c a t i o n s of polymorphism have been

reviewed by H a l e b l i a n and McCrofte (1969) and the s u b j e c t i s covered i n

s e v e r a l t e x t s i n c l u d i n g those by Verma & K r i s h n a (1966), O'Connor

(1960) and McCrone (1957; 1965).

The polymorphism o f a c e t y l s a l i c y l i c a c i d has been the s u b j e c t

of many r e c e n t a r t i c l e s i n c l u d i n g those by Tawashi (1968, 1969, 1971) who

r e p o r t e d t h e e x i s t e n c e o f two polymorphs o f a c e t y l s a l i c y l i c acid

( d e s i g n a t e d Form I and I I ) , and Summers & o t h e r s (1970) who r e p o r t e d

s i x polymorphisms of a c e t y l s a l i c y l i c a c i d (designated Form I t o V I ) .

However no d e f i n i t e evidence has been p u b l i s h e d t o c o n f i r m t h e p o l y -

morphism o f a c e t y l s a l i c y l i c a c i d . The q u e s t i o n o f the polymorphism o f

a c e t y l s a l i c y l i c a c i d i s d i s c u s s e d i n d e t a i l i n p a r t 2 - 6 o f t h i s work.

Haleblian & McCrone (1969) reviewed the methods used t o i d e n t i f y

polymorphism. These methods a r e : o p t i c a l c r y s t a l l o g r a p h y , X-ray diffraction,

i n f r a r e d spectroscopy, d i f f e r e n t i a l thermal analysis, dilatometry, proton

magnetic resonance spectroscopy, n u c l e a r magnetic resonance spectroscopy,

e l e c t r o n spectroscopy and magnetic a n i s o t r o p y . Of these methods ,\ ;only

m i c r o s c o p y , X-ray d i f f r a c t i o n , i n f r a r e d s p e c t r o s c o p y , and d i f f e r e n t i a l

thermal a n a l y s i s have been w i d e l y used.

I. Microscopic Optical Crystallography - Different polymorphs

of a c r y s t a l may belong t o one or two c l a s s e s depending on the e f f e c t o f

the t r a n s m i s s i o n o f l i g h t i n d i f f e r e n t d i r e c t i o n s through t h e c r y s t a l s .

These c l a s s e s a r e i s o t r o p i c and a n i s o t r o p i c . I n i s o t r o p i c c r y s t a l s the

v e l o c i t y o f l i g h t , or the r e f r a c t i v e index which depends on the v e l o c i t y

of l i g h t , i s the same i n a l l d i r e c t i o n s . In a n i s o t r o p i c c r y s t a l s there

may be two o r t h r e e d i f f e r e n t v e l o c i t i e s or r e f r a c t i v e i n d i c e s . Different

polymorphs having different i n t e r n a l s t r u c t u r e s w i l l belong to d i f f e r e n t

c r y s t a l systems and have d i f f e r e n t s e t s o f r e f r a c t i v e indices.

 Hot Stage Method - The p o l a r i z i n g microscope f i t t e d w i t h a

hot stage (or c o l d stage) i s a very u s e f u l t o o l f o r i n v e s t i g a t i n g p o l y -

morphism. With t h i s combination an e x p e r i e n c e d m i c r o s c o p i s t can

q u i c k l y t e l l whether polymorphism e x i s t s , the degree of s t a b i l i t y of

the m e t a s t a b l e forms, the t r a n s i t i o n temperature and m e l t i n g p o i n t s ,

the r a t e of t r a n s i t i o n under a l l temperatures and p h y s i c a l c o n d i t i o n s

and whether to pursue polymorphism as a r o u t e to an improved dosage

form. These methods have been d i s c u s s e d by McCrone (1968) i n a

technical bulletin.

II. X-Ray D i f f r a c t i o n - C r y s t a l l i n e m a t e r i a l s i n powder

form g i v e c h a r a c t e r i s t i c X-ray d i f f r a c t i o n p a t t e r n s made up of peaks

i n c e r t a i n p o s i t i o n s and v a r y i n g i n t e n s i t i e s . From the 2 l v a l u e of

these peaks, the s p a c i n g v a l u e s (d: d i s t a n c e ) f o r the d i f f e r e n t planes

of the c r y s t a l can be c a l c u l a t e d u s i n g the Bragg equation,

n X = 2d s i n $

where the wavelength of the X-ray s o u r c e , X i s known, d i s the s p a c i n g

of u n i t s i n a p e r i o d i c arrangement and 9 i s the angle between the X-ray

beam and the p l a n e of the crystal.

III. I n f r a r e d Spectroscopy - In the i d e n t i f i c a t i o n of

d i f f e r e n t polymorphs w i t h IR s p e c t r o s c o p y , o n l y s o l i d samples (as m i n e r a l

o i l m u l l s , potassium bromide p e l l e t s or a t t e n u a t e d t o t a l r e f l e c t a n c e ) can

be used, s i n c e i n s o l u t i o n the polymorphs of a compound have identical

spectra. Many authors have used IR s p e c t r o s c o p y to study polymorphism.

Kendall (1953) c l a i m e d t h a t , i n a d d i t i o n to being r a p i d , the technique

i s b o t h q u a n t i t a t i v e and qualitative. Smakula & o t h e r s (1957) r e p o r t e d

t h a t when d i f f e r e n t polymorphs of e s t r a d i a l -17/3 were t r i t u r a t e d as a

m u l l f o r d i f f e r e n t time i n t e r v a l s the IR a b s o r p t i o n s p e c t r a f o r these

phases were changed t o a common spectrum.

 22

IV. D i f f e r e n t i a l Thermal A n a l y s i s - In d i f f e r e n t i a l thermal

analysis (DTA), the heat l o s s or g a i n r e s u l t i n g from p h y s i c a l or

c h e m i c a l changes o c c u r r i n g i n a sample i s r e c o r d e d as a f u n c t i o n of

temperature as the substance i s heated at a u n i f o r m r a t e . Enthalpic

changes, b o t h exo- and endothermic, are caused by phase t r a n s i t i o n s .

For example f u s i o n , b o i l i n g , s u b l i m a t i o n , vaporization, c r y s t a l l i n e

structure immersion, s o l i d - s o l i d t r a n s i t i o n and water l o s s are

generally endothermic r e a c t i o n s whereas c r y s t a l l i z a t i o n i s exothermic.

One of the advantages of DTA i s the a b i l i t y to c a l c u l a t e the heats of

t r a n s i t i o n from one polymorph t o the other.

2-5. D i s s o l u t i o n of C r y s t a l l i n e Compounds.

I. D i s s o l u t i o n Phenomenon.

C r y s t a l s d i s s o l v e , when c o n d i t i o n s are r e v e r s e d from those of

growth. C r y s t a l d i s s o l u t i o n takes p l a c e s i n a manner s i m i l a r to c r y s t a l

growth. The atoms or m o l e c u l e s are l o s t p r e f e r e n t i a l l y from the kink

p o s i t i o n s where the b i n d i n g i s weakest. Continuous d i s s o l u t i o n requires

successive nucleation of kinks.

The r a t e of d i s s o l u t i o n i s a f f e c t e d by many f a c t o r s which are

discussed later. In a d d i t i o n , under c o n s t a n t e x p e r i m e n t a l c o n d i t i o n s , the

d i s s o l u t i o n r a t e can v a r y due to the presence of c r y s t a l i m p e r f e c t i o n s and

the presence of i n h i b i t o r s . The free surface energy i n the imperfection

s i t e s i s d i f f e r e n t from other spots (Thomas, 1970). The e f f e c t of

impurities on the d i s s o l u t i o n and habit modification of c r y s t a l l i n e m a t e r i a l s

has been the subject of a number of papers i n c l u d i n g those by Buckley (1951)

and Ives & Plewes (1965). P i c c o l o & Tawashi (1970) s t u d i e d the i n h i b i t i n g

effect of FD&C b l u e No. 1 on the d i s s o l u t i o n r a t e s of s u l f a t h i a z o l e , s u l f a -

g u a n i d i n e and p h e n o b a r b i t a l monohydrate. They suggested t h a t the dye molecules

 23

tend t o d e p o s i t on the k i n k s and reduce the k i n k n u c l e a t i o n r a t e .

I n h i b i t i o n caused by p o i s o n s t h a t are c l o s e l y r e l a t e d c h e m i c a l l y , e.g.

c h o l e s t e r o l - s o d i u m c h e l a t e r e p o r t e d by Saad & H i g u c h i (1965), and the

s u c r o s e - r a f f i n o s e system r e p o r t e d by A l b o n & Dunning (1962) suggest that a

s t e r i c f i t of the p o i s o n m o l e c u l e s on the c r y s t a l f a c e i s n e c e s s a r y .

II. R e c i p r o c i t y of Growth and Dissolution.

Noyes & Whitney (1897) proposed an e q u a t i o n f o r c r y s t a l

dissolution

|| = KS (Co-Ct) (1)

Nerst (1904) m o d i f i e d the mentioned e q u a t i o n to i n c l u d e the

p r o c e s s of growth

• £ , J£ „-ct)<C (2)

where Co i s the s a t u r a t i o n c o n c e n t r a t i o n , Ct the c o n c e n t r a t i o n i n the

b u l k of the s o l u t i o n , dc the amount detached or a t t a c h e d i n a time dt,

S the a r e a of the c r y s t a l - l i q u i d i n t e r f a c e , h the t h i c k n e s s of q u i e s c e n t

l a y e r through which d i f f u s i o n must take p l a c e , and D the diffusion

coefficient. U s i n g t h i s e x p r e s s i o n as a b a s i s f o r t h e i r experiments,

s e v e r a l workers have t e s t e d the v a l i d i t y of the assumption t h a t S(Co-Ct)

s h o u l d be equal but of o p p o s i t e s i g n , f o r growth and d i s s o l u t i o n , D/h

s h o u l d be the same i n both d i r e c t i o n s . Buckley (1951) reviewed many papers,

most of which i n d i c a t e t h a t these phenomena are not r e c i p r o c a l . The

v e l o c i t i e s of growth are u s u a l l y much l e s s f o r any g i v e n substance than

those of d i s s o l u t i o n (Table 2 - 2 ) .
 24

Table 2 - 2 . Ratio of v e l o c i t i e s of d i s s o l u t i o n over those o f growth

f o r some g i v e n substances.

Velocity of d i s s o l u t i o n
Substance Velocity o f growth Temperature

NH4 - alum 4.3 0

K S04
2 7.7 0

K S04
2 10.0 9

K2Cr 07 2 5.7 0

The addition o f another s a l t has a v a r i a b l e effect on the

velocity of growth. The v e l o c i t i e s o f growth of K S04 a r e v a r i e d

2 i n the

presence of added substance i n t h e manner shown i n T a b l e 2-3.

Table 2 - 3 . Variation o f growth o f K S04 i n presence

2 o f some s a l t s .

Substance Added Velocity Factor

KC1 2.05

K C0
2 3 1.66

Na C0 2 3 1.14

K Cr04
2 0.75

KN0 3 0.65

A few substances showed an approximate r e c i p r o c i t y i n having

e q u a l growth and d i s s o l u t i o n v e l o c i t i e s but o n l y a t v e r y h i g h r a t e s o f

stirring (e.g., o x a l i c acid and KCIO3).

The term r e c i p r o c i t y i t s e l f needs c l a r i f i c a t i o n . For complete

reciprocity, t h e growth v e l o c i t i e s should be i d e n t i c a l (but i n the o p p o s i t e

s e n s e ) t o the d i s s o l u t i o n velocities. In a d d i t i o n , t h e same f a c e s should

be m o d i f i e d i n an i d e n t i c a l but opposing manner by the two p r o c e s s e s .

The first of these c o n d i t i o n s n e c e s s i t a t e s the same c o e f f i c i e n t of

d i f f u s i o n i n the two d i r e c t i o n s (an e a s i l y u n d e r s t a n d a b l e c o n d i t i o n ) ,

whereas the second r e q u i r e s t h a t , over a g i v e n area of the crystal

f a c e , the atoms w i l l be l a i d down on the s u r f a c e , or escape o f f again,

with i d e n t i c a l readiness when the same degree of o v e r , or under-

s a t u r a t i o n p r e v a i l s i n the a d j a c e n t solution. T h i s i s an u n l i k e l y

c o n d i t i o n , however. During growth, many atoms or i o n s of i m p u r i t i e s ,

even i n a h i g h l y p u r i f i e d s o l u t i o n , must be p r e s e n t and attached to

the s u r f a c e (e.g.,H or OH i o n s or H2O m o l e c u l e s i n a pure aqueous

solution). T h e i r p r e s e n c e , even i f they are u l t i m a t e l y r e j e c t e d during

growth, w i l l tend to slow down the l a t t e r p r o c e s s , whereas, during

d i s s o l u t i o n they w i l l be the l o c a t i o n s of the more u n s t a b l e parts of

the s u r f a c e and, f a r from h e l p i n g to slow down the d i s s o l u t i o n o f the face,

may a c t u a l l y provide f o c a l spots where the excess df s o l v e n t m o l e c u l e s

can p r i s e open the l e s s - y i e l d i n g l a t t i c e surface. Moreover, as stated

by Buckley (1951), the growth of c r y s t a l s i s s e r i o u s l y m o d i f i e d by

proportions of i m p u r i t y as low as one p a r t i n 30,000 up to one part i n

70,000 of the c r y s t a l l i n e compound. Q u a n t i t i e s of hundreds or thousands

of times these amounts would be needed to produce an e f f e c t on the

dissolution process.

III. D i s s o l u t i o n Models.

In a d i s s o l u t i o n process, s o l u t e m o l e c u l e s must f i r s t be

released from the s u r f a c e of the s o l i d and then t r a n s f e r r e d i n t o the bulk

of the s o l v e n t . . Depending on the r e l a t i v e s i g n i f i c a n c e of these two

p r o c e s s e s and the means by which the t r a n s p o r t i s e f f e c t e d , three physical

models have been s e t up. Higuchi (1967) d e s c r i b e d these models as

follows: a. d i f f u s i o n l a y e r model, i n which i t i s assumed t h a t there i s

a static l i q u i d f i l m adjacent to the s o l i d surface. The r e a c t i o n at the

interface (i.e., solid/liquid f i l m ) i s assumed to be r a p i d , so t h a t the

r a t e of d i s s o l u t i o n i s governed e n t i r e l y by the d i f f u s i o n a l t r a n s p o r t of

the s o l u t e molecule through the liquid film. Once the s o l u t e m o l e c u l e s

pass the l i q u i d f i l m i n t e r f a c e ( i . e . , film/bulk) r a p i d mixing occurs, and

the c o n c e n t r a t i o n gradient i s destroyed; b. i n t e r f a c i a l b a r r i e r model,

i n which the r e a c t i o n at the s o l i d s u r f a c e i s not instantaneous, due to

the f a c t that a high f r e e energy of a c t i v a t i o n i s r e q u i r e d . This process

at the s o l i d / l i q u i d i n t e r f a c e now becomes r a t e l i m i t i n g with respect to

the t r a n s p o r t p r o c e s s ; c. Danckwerts' model. Danckwerts (1951) assumed

t h a t t r a n s p o r t of s o l u t e away from the s o l i d s u r f a c e i s achieved by means

of m a c r o s c o p i c packets of s o l v e n t which a t t a c h themselves to the surface,

absorb s o l u t e by normal d i f f u s i o n and are then r e p l a c e d by f r e s h packets

of s o l v e n t . Assuming the s o l i d s u r f a c e r e a c t i o n to be instantaneous, the

r a t e at which the p r o c e s s occurs i s r e l a t e d to the s o l u t e t r a n s p o r t rate.

The r a t e laws p r e d i c t e d by the d i f f e r e n t mechanisms, both alone

and i n combination, have been d i s c u s s e d by H i g u c h i (1967) i n an extension

review of drug r e l e a s e r a t e p r o c e s s e s . The simplest case i s t h a t of a

s i n g l e component, s i n g l e phase, n o n - d i s i n t e g r a t i n g solid dissolving into

a chemically non-reactive s o l v e n t under m i l d to h i g h agitation condition.

Under such c i r c u m s t a n c e s , the d i f f u s i o n l a y e r r e a c t i o n obeys Nerst

equation (Eq. 2).

|f = ^ (Co-Ct) (2)

When the d i s s o l u t i o n p r o c e s s i s c o n t r o l l e d by the interfacial

r e a c t i o n , one can write:

|| = k i S (Co-Ct) (3)

when k i i s the e f f e c t i v e i n t e r f a c i a l transport rate constant.

 F i n a l l y , under s i m i l a r c o n d i t i o n s to those s p e c i f i e d e a r l i e r ,

the Danckwerts model i s :

|| = K Vs
g (Co-Ct) (4)

where i s the mean r a t e at which f r e s h s u r f a c e i s produced. The

resemblance between the Noyes-Whitney e q u a t i o n (Eq. 1) and equations (2)

through (4) i s obvious, i n that a l l four p r e d i c t a f i r s t order

dependence on (Co-Ct).

In the Noyes-Whitney's e x p r e s s i o n , i t was assumed t h a t a t h i n

l a y e r of a s a t u r a t e d s o l u t i o n of the s o l u t e was formed at the s u r f a c e of

the s o l i d and t h a t the r a t e of d i s s o l u t i o n was governed by the r a t e of

d i f f u s i o n from t h i s s a t u r a t e d l a y e r i n t o the b u l k of the s o l u t i o n . This

concept was very c l o s e to t h a t f o r the d i f f u s i o n model ( e q u a t i o n 2) .

However, r e c e n t l y , S z i n a i & Hunt (1972) p o i n t e d out t h a t as the r a t e of

transport increases (e.g., by change of a g i t a t i o n ) or as the r a t e of

d i s s o l u t i o n decreases a stage i s reached when t r a n s p o r t ( d i f f u s i o n ) to

the b u l k s o l u t i o n i s no longer the r a t e d e t e r m i n i n g p r o c e s s . I t seems

u n l i k e l y t h a t compounds of very low solubility could s u s t a i n a saturated

l a y e r even a t low r a t e s of a g i t a t i o n . In these cases the removal of solute

m o l e c u l e s from the s o l i d must become the rate determining step. Thus one

should consider a whole range of c o n d i t i o n s g o v e r n i n g d i s s o l u t i o n . At one

end of the range are s o l i d s of such h i g h s o l u b i l i t y i n a g i v e n solvent that

they can i n fact sustain a saturated layer. In such cases the r a t e limiting

step i s governed by d i f f u s i o n as d e s c r i b e d by the c l a s s i c a l model. At the

other end of the range are the much l e s s s o l u b l e compounds (e.g., s t e r o i d s ,

many a l k a l o i d s and most s y n t h e t i c drugs i n aqueous systems) where the rate

of d i s s o l u t i o n i s governed not by d i f f u s i o n but by the energy changes of

the p r o c e s s e s at the i n t e r f a c e . T h e s e f l a t t e r are not covered by the

assumptions i n h e r e n t i n the Nbyes-Whitney type e q u a t i o n s even i f the

expressions f i t some of the e x p e r i m e n t a l curves.

IV. D i s s o l u t i o n Measurement Methods.

D i s s o l u t i o n procedures can be classified i n a v a r i e t y of ways.

The c l a s s i f i c a t i o n g i v e n below i s based on i n t r i n s i c and bulk d i s s o l u t i o n

methods.

An i n t r i n s i c d i s s o l u t i o n method i s a procedure whereby the

s u r f a c e a r e a of the pure drug i s kept c o n s t a n t . T h i s method uses non-

d i s i n t e g r a t i n g t a b l e t s t h a t have been compressed at very h i g h pressure.

In t h i s c a t e g o r y a number of methods have been employed such as the

beaker method (Levy & Hayes, 1960), the hanging d i s k method (Nelson, 1958),

the s t a t i c d i s k method (Levy, 1963) and the r o t a t i n g d i s k method (Levy

& S a h l i , 1962; Nogami & o t h e r s , 1966). The beaker method and the r o t a t i n g

d i s k method w i l l be discussed i n more d e t a i l .

a. Beaker Method. P a r r o t t & others (1955) r e p o r t e d on the use

of a t w o - l i t r e three-necked, round bottomed f l a s k to f o l l o w the d i s s o l u t i o n

of n o n - d i s i n t e g r a t i n g spherical tablets. At the s t i r r i n g r a t e used (550

r.p.m.), the t a b l e t r o t a t e d f r e e l y i n the l i q u i d , r a t h e r than remaining

on the bottom of the flask.

N e l s o n , i n 1957, described a d i s s o l u t i o n apparatus i n which a

non-disintegrating drug p e l l e t , mounted on a g l a s s s l i d e so that o n l y the

upper f a c e was exposed, was placed at the bottom of a 600 ml. beaker i n

such a manner t h a t i t c o u l d not r o t a t e when the d i s s o l u t i o n medium was

s t i r r e d at 500 r.p.m. Using t h i s apparatus, N e l s o n was a b l e to r e l a t e

the b l o o d l e v e l s of s e v e r a l o r a l l y a d m i n i s t e r e d theophylline salts to

their i n vitro dissolution rates.

 29

M i t c h e l l & S a v i l l e (1967) a p p l i e d t h i s method t o determine the

intrinsic d i s s o l u t i o n of a c e t y l s a l i c y l i c a c i d . They used d i s k s o f 400 mg.

and 1.3 cm. diameter of sample. Each d i s k was mounted on a microscope

cover s l i p w i t h a s u i t a b l e water i n s o l u b l e a d h e s i v e such as f l e x i b l e

collodion or hard p a r a f f i n , so t h a t o n l y one f a c e remained exposed.

b. R o t a t i n g D i s k Method. T h i s method was developed by Nelson

and d e s c r i b e d by Levy & S a h l i (1962). Non-disintegrating tablets

are mounted i n a p l e x i g l a s h o l d e r , so t h a t o n l y one s u r f a c e i s exposed

to the d i s s o l u t i o n medium. The h o l d e r i s a t t a c h e d through a m e t a l shaft

f r e e from v i b r a t i o n and any n o n - c o n c e n t r i c movement t o a v a r i a b l e speed

precision stirring motor; the motor must be capable of m a i n t a i n i n g a

given rate of r o t a t i o n f o r extended p e r i o d s of time. I n the o r i g i n a l

work o f Levy & S a h l i , the t a b l e t was immersed to a depth o f one i n c h

below the s u r f a c e o f 200 ml. o f d i s s o l u t i o n f l u i d , m a i n t a i n e d a t 37° i n

a 500 m l . three-necked, round bottomed f l a s k . The r a t e o f r o t a t i o n was

555 r.p.m. Samples were removed a t a p p r o p r i a t e time i n t e r v a l s f o r

analysis. Somewhat s i m i l a r c o n d i t i o n s were employed by N e l s o n (1962) i n

a dissolution study of e r y t h r o m y c i n and i t s e s t e r s .

The stirring mechanism was l a t e r m o d i f i e d by Levy & T a n s k i (1964) ,

so as t o a f f o r d precisio.n c o n t r o l o f r o t a t i o n , anywhere from approximately

3 to 400 r.p.m. A range o f t h i s magnitude i s n e c e s s a r y i n o r d e r t o

determine the d i s s o l u t i o n r a t e at various rates of a g i t a t i o n and, t h e r e b y ,

characterize and e l u c i d a t e the d i s s o l u t i o n mechanism. A further

modification was proposed by Wood & o t h e r s (1965), who used the compression

d i e as t h e r o t a t i n g h o l d e r . I n o r d e r t o prevent the d i s k or t a b l e t from

falling o u t , t h e bottom o f the d i e was threaded. I n t h i s manner, as much

as 75% o f the d i s k can be d i s s o l v e d without i t f a l l i n g o u t .

 M i t c h e l l & S a v i l l e (1967) s t u d y i n g the dissolution rate of

a c e t y l s a l i c y l i c a c i d u s i n g the r o t a t i n g d i s k method of Wood & o t h e r s (1965)

showed that i n t r i n s i c d i s s o l u t i o n r a t e s were independent of p r e s s u r e over

2

the compression range 2,000 to 13,000 Kg/cm , and were independent of the

p a r t i c l e s i z e of a c e t y l s a l i c y l i c a c i d used i n p r e p a r i n g the compressed

disks. Nogami & o t h e r s (1966) used a d i s k of 3 cm. diameter to study

the d i s s o l u t i o n r a t e of a number of drugs.

Bulk d i s s o l u t i o n methods have been used by many a u t h o r s . Excess

compound i s added t o the s t i r r e d d i s s o l u t i o n medium and the amount

dissolved i s measured at s u i t a b l e time i n t e r v a l s . The change i n s u r f a c e

a r e a p r e c l u d e s measurement of i n t r i n s i c d i s s o l u t i o n r a t e s but the method

is useful f o r the study of phase t r a n s f o r m a t i o n s (Nogami & o t h e r s , 1969;

G r i f f i t h s & M i t c h e l l , 1971).

V. Factors A f f e c t i n g Dissolution Rate.

The physiochemical factors that control the r a t e of dissolution

include temperature, degree of a g i t a t i o n , pH, s o l u b i l i t y and concentration

g r a d i e n t , c o m p o s i t i o n and v i s c o s i t y of the d i s s o l u t i o n medium and its

potential for micellar s o l u b i l i z a t i o n , the presence of a c t i v e or inactive

additives, polymorphism, c r y s t a l mass, and e f f e c t i v e surface. These

f a c t o r s , which must be taken i n t o account when attempting to modify drug

dissolution so as t o enhance, d e l a y , or s u s t a i n b i o l o g i c a l availability,

have been reviewed i n p a r t by Wurster & T a y l o r (1965), Levy (1966), and

Wood (1967).

Of the many p h y s i o c h e m i c a l f a c t o r s involved, consideration will

be r e s t r i c t e d to the e f f e c t s of a g i t a t i o n i n t e n s i t y , drug solubility,

temperature, s u r f a c e a r e a , polymorphism and h y d r a t e and solvate.

 a. A g i t a t i o n Intensity: It i s probably true to say that (

one of the most important v a r i a b l e s to c o n s i d e r i n d i s s o l u t i o n i s the

degree of a g i t a t i o n . From the e a r l i e r discussion on dissolution

mechanisms, i t i s apparent that agitation conditions w i l l most p r o f o u n d l y

a f f e c t d i f f u s i o n controlled d i s s o l u t i o n , since the thickness of the

layer i s inversely proportional to the a g i t a t i o n or s t i r r i n g speed.

Levich (1942) c a l c u l a t e d that for a disk rotating in a

volume where w a l l e f f e c t s are m i n i m a l , the t h i c k n e s s of the diffusion

l a y e r , h, s h o u l d be r e l a t e d to the a n g u l a r v e l o c i t y of the d i s k , w, by

the expression

h = 1.612D /3 V /6 1 X
W- ^
-
(5)

where D i s the s o l u t e molecule d i f f u s i o n c o e f f i c i e n t and V the v i s c o s i t y .

T h e r e f o r e , f o r l a m i n a r flow

K CW^
t 0 (6)

where Kt, the r a t e c o n s t a n t f o r the transport p r o c e s s , = ^V^* For other

types of stirring

K ocW
t
a
(7)

where the v a l u e of a, which l i e s between 0 and 1, depends on the type

of a g i t a t i o n (laminar or t u r b u l e n t ) , the geometry of the stirrer and

vessel and the p o s i t i o n of the; s t i r r e r w i t h r e s p e c t to the dissolving

substance (Bircumshaw & R i d d i f o r d 1952).

Levich (through Cooper & K i n g e r y , 1962) derived an equation,

r e l a t i n g i n t r i n s i c d i s s o l u t i o n r a t e , DR, and r o t a t i o n r a t e RR. Levy &

Procknal (1964) expressed t h i s i n the form:

LogDR = a l o g RR + C (8)

where a and c are constants. In d i f f u s i o n - c o n t r o l p r o c e s s e s , a = 1. If

the r a t e of the i n t e r f a c i a l reaction i s the rate determining step, the

 32

o v e r a l l d i s s o l u t i o n r a t e w i l l be independent of a g i t a t i o n and a = 0.

A d i s s o l u t i o n system p r o c e e d i n g i n accord w i t h Danckwerts' model may

be expected to show some dependence on a g i t a t i o n i n t e n s i t y , s i n c e the

d i s s o l u t i o n r a t e w i l l be f u n c t i o n of the r a t e of t r a n s f e r of the

m a c r o s c o p i c packets of s o l v e n t and the g e n e r a t i o n of new surface.

Presumably, a w i l l have a v a l u e approaching unity.

The value of a may a l s o vary w i t h the type of a g i t a t i o n used

(Wurster & T a y l o r , 1965). I t should a l s o be borne i n mind t h a t

a g i t a t i o n w i l l a f f e c t the degree of d i s p e r s i o n of a c o l l e c t i o n of

p a r t i c l e s , and hence the t o t a l s u r f a c e exposed t o the d i s s o l u t i o n medium.

b. Drug S o l u b i l i t y . The Noyes-Whitney e q u a t i o n (Eq. 1) shows

a f i r s t - o r d e r dependence on the d i f f e r e n c e i n s o l u b i l i t y , (Co-Ct). Any

means whereby Co can be i n c r e a s e d a n d / o r c t reduced w i l l cause a c o r r e s -

ponding i n c r e a s e i n dissolution„rate. When Co i s much g r e a t e r than Ct, the

i n i t i a l d i s s o l u t i o n r a t e , DR, w i l l be d i r e c t l y p r o p o r t i o n a l to Co. This

b e h a v i o r was confirmed by Hamlin & o t h e r s (1965), who showed t h a t , f o r

55 s e t s of d a t a obtained from suspended p e l l e t s i n b o t t l e s undergoing

r o t a t i o n at 6 r.p.m. i n a Wruble (1930) apparatus:

DR = (2.24+0.10) Co (9)
-2 -1 -1
where DR i s mg. cm. hr , Co i s mg. ml and the constant (2.24) i s

cm. hr ^. The value of +0.10 i s the 95% confidence internal for the

constant. However, d e v i a t i o n s from t h i s r u l e have been r e p o r t e d (Hamlin

& Higuchi, 1966).

The s a t u r a t i o n s o l u b i l i t y of a weak a c i d or base i s not an

i n v a r i a n t property of t h a t compound, but w i l l vary w i t h the pH of the

d i s s o l u t i o n medium. In b o t h cases i t i s p o s s i b l e to i n c r e a s e Co and,

c o n s e q u e n t l y , the r a t e of d i s s o l u t i o n .
 33

The pH-dependence of Co has been used to enhance the d i s s o l u t i o n

r a t e of b u f f e r e d a c e t y l s a l i c y l i c a c i d t a b l e t s . The a d d i t i o n of a s m a l l

amount o f b u f f e r t h a t w i l l r a i s e the pH of the environment immediately

adjacent to the p a r t i c l e d i s s o l v i n g i n the media r e s u l t s i n an effective

i n c r e a s e i n Co i n the s a t u r a t i o n l a y e r surrounding the particle.

S u r f a c e a c t i v e agents, at s t r e n g t h s i n excess of the critical

m i c e l l e c o n c e n t r a t i o n enhance the d i s s o l u t i o n r a t e due to increase i n

Co (Bates & o t h e r s , 1966; Wurster & P o l l i , 1961; T a y l o r & Wurster, 1965;

Singh & others, 1968).

According to the Noyes-Whitney e q u a t i o n , i n c r e a s e i n the

c o n c e n t r a t i o n i n the d i s s o l u t i o n medium, C t , r e s u l t s i n a decrease i n

the d i s s o l u t i o n r a t e . The c o n c e n t r a t i o n Ct can be m a i n t a i n e d at a v e r y

low v a l u e by: a. s t u d y i n g o n l y the i n i t i a l d i s s o l u t i o n ; b. using very

l a r g e volume of d i s s o l u t i o n f l u i d ; ' o r c. maintenance of s i n k c o n d i t i o n s .

Under these conditions

j± = k Co = K (10)

and the p r o c e s s i s pseudo zero order.

According to G i b a l d i & Feldman (1967), s i n k c o n d i t i o n can be

assumed i f the t o t a l amount of drug i n s o l u t i o n does not exceed 10 to 20%

of the s a t u r a t i o n c o n c e n t r a t i o n . With drugs having only a very low

solubility i n the d i s s o l u t i o n medium, t h i s can r e s u l t i n the use of very

l a r g e volumes of f l u i d . G i b a l d i & Feldman (1967) superimposed an organic

phase on the aqueous d i s s o l u t i o n medium to a c t as a r e s e r v o i r to maintain

the s i n k c o n d i t i o n s f o r the d i s s o l v e d drug. Another approach, used by

Wurster & P o l l i (1961), i s the a d d i t i o n of absorbent m a t e r i a l s to the

aqueous phase. Hersey & B a r z i l a y (1969) have advocated the use of dialysis
as a s u i t a b l e technique t o a c h i e v e s i n k c o n d i t i o n s i n the d i s s o l u t i o n

medium without r e s o r t i n g t o the use o f l a r g e volumes o f f l u i d .

c. Temperature: An i n c r e a s e i n temperature w i l l i n c r e a s e the

r a t e o f both the i n t e r f a c i a l r e a c t i o n and t h e t r a n s p o r t processes

(Bircumshaw & R i d d i f o r d , 1952). For a transport c o n t r o l l e d dissolution

process the dependence o f k fc on temperature can be expressed by the

Arrhenius equation

. „ -Et/RT
k t = Z e t (11).

where k t i s g i v e n by t h e r a t i o o f the d i s s o l u t i o n r a t e , DR, and s o l u b i l i t y ,

Co, p r o v i d e d t h e e x p e r i m e n t a l c o n d i t i o n s a r e such t h a t the c o n c e n t r a t i o n

of d i s s o l v e d s o l u t e i s n e g l i g i b l e compared w i t h Co, Z t i s a c o n s t a n t

a s s o c i a t e d w i t h the entropy o f the r e a c t i o n and/or c o l l i s i o n factors,

and i s c a l l e d t h e frequency f a c t o r , E t energy o f a c t i v a t i o n , R gas constant

and T, a b s o l u t e temperature.

For i n t e r f a c i a l r e a c t i o n s , t h e dependence o f c h e m i c a l velocity

constant p e r u n i t a r e a a t u n i t volume, kc on temperature may be a l s o

expressed by means o f the A r r h e n i u s equation

k c = z e-
c
E C / R T
(12)

where Z c i s the c o l l i s i o n frequency and Ec t h e energy o f a c t i v a t i o n .

d. Surface Area: The Noyes-Whitney e q u a t i o n shows t h a t t h e

d i s s o l u t i o n r a t e i s d i r e c t l y p r o p o r t i o n a l t o t h e s u r f a c e a r e a , S.

Reduction i n p a r t i c l e s i z e b r i n g s about an i n c r e a s e i n s u r f a c e a r e a and

hence enhances the d i s s o l u t i o n rate.

Enhanced d i s s o l u t i o n r a t e s i n the presence o f s u r f a c t a n t s below

the c r i t i c a l m i c e l l e c o n c e n t r a t i o n have been a t t r i b u t e d t o an i n c r e a s e i n

e f f e c t i v e s u r f a c e a r e a , r e s u l t i n g from a l o w e r i n g of interfacial

t e n s i o n and i n c r e a s e d w e t t i n g (Wurster & S e i t z , 1960; Levy & Gumtow,

1963; Weintraub & Gibaldi, 1969).

e. Polymorphism: Many drugs e x i s t i n a number of polymorphic

forms. The c o r r e c t c h o i c e o f polymorphic form may be important from the

p o i n t of view of c h e m i c a l and p h y s i c a l s t a b i l i t y and a l s o clinically.

Polymorphs are e i t h e r s t a b l e or m e t a s t a b l e . The metastable

forms are u n s t a b l e and tend t o change to the more s t a b l e crystalline

form. The m e t a s t a b l e polymorphs u s u a l l y have h i g h e r s o l u b i l i t i e s and

f a s t e r d i s s o l u t i o n r a t e s than the s t a b l e form. In the p r o c e s s of

d i s s o l u t i o n the m e t a s t a b l e form may be transformed t o s t a b l e form and

result i n a decreased d i s s o l u t i o n r a t e . I n t h i s case the l i n e a r curve

of the i n i t i a l d i s s o l u t i o n p r o c e s s may be preceded by a s t e e p e r p o r t i o n

which i s due to simultaneous phase change. Nogami & o t h e r s (1969)

showed t h a t the f i n a l s l o p e of the d i s s o l u t i o n curve i s r e l a t e d t o the

s o l u b i l i t y o f the s t a b l e form (A) by e q u a t i o n (13)

|f = k Co
t A (13)

and the i n i t i a l s l o p e i s r e l a t e d t o the s o l u b i l i t y of the more s o l u b l e

form (B) by

|f = k Co
t B (14)

where C o A and COB are the r e s p e c t i v e s o l u b i l i t i e s and the o t h e r terms

have been d e f i n e d p r e v i o u s l y .
 f. Hydrate and S o l v a t e : Many drugs a s s o c i a t e w i t h solvent

m o l e c u l e s t o produce c r y s t a l l i n e forms, termed " s o l v a t e s " . When water

is the s o l v a t e , the s o l v a t e formed i s c a l l e d a " h y d r a t e " . The

solubility and t h e r a t e o f d i s s o l u t i o n of a s o l v a t e may be

s i g n i f i c a n t l y d i f f e r e n t from the n o n - s o l v a t e d form of the drug (Shafter

& Higuchi, 1963). Whether the drug s o l v a t e demonstrates enhanced

d i s s o l u t i o n c h a r a c t e r i s t i c over t h e n o n - s o l v a t e d form o f the drug depends

on the n a t u r e o f the s o l v a t e and t h e n a t u r e o f the d i s s o l u t i o n medium.

For example, P o o l e & o t h e r s (1968) noted t h a t the anhydrous form o f

0

a m p i c i l l i n was more b i o l o g i c a l l y a v a i l a b l e when o r a l l y a d m i n i s t e r e d to

human s u b j e c t s , and produced h i g h e r peak b l o o d l e v e l s of the a n t i b i o t i c

than d i d the t r i h y d r a t e . However, r e c e n t l y H i l l & others (1972) found

no s i g n i f i c a n t d i f f e r e n c e s i n d i s s o l u t i o n r a t e o f anhydrous and t r i h y d r a t e

forms o f a m p i c i l l i n when measured i n s o l u t i o n o f 0.53 N HC1. They

postulated t h a t t h e d i s s o l u t i o n r a t e s of these two forms should n o t be

r a t e - l i m i t i n g i n g a s t r o i n t e s t i n a l absorption and suggested t h a t t h e

reported differences i n bioavailability from o r a l p r o d u c t s c o n t a i n i n g the

two forms a r e r e l a t e d t o f o r m u l a t i o n f a c t o r s , and n o t t o t h e h y d r a t i o n

s t a t e o f the raw m a t e r i a l . Poole & Bahal (1968) a l s o s t u d i e d the d i s s o l u t i o n

and s o l u b i l i t y c h a r a c t e r i s t i c s o f the anhydrous and h y d r a t e forms o f an

e x p e r i m e n t a l a m i n o a l i c y c l i c p e n i c i l l i n and found r e s u l t s s i m i l a r t o t h a t

reported forampicillin. In c o n t r a s t , B a l l a r d & B i l e s (1964) determined

the a b s o r p t i o n r a t e of o r g a n i c s o l v a t e s o f the t e r t i a r y b u t y l a c e t a t e esters

of p r e d n i s o l o n e and h y d r o c o r t i s o n e following pellet implantation i n rats.

They found t h a t the a b s o r p t i o n r a t e o f t h e monoethanol s o l v a t e o f t h e

prednisolone e s t e r was 4.7 times t h a t o f the anhydrous form.

 37

2-6 The Polymorphism Q u e s t i o n of A c e t y l s a l i c y l i c Acid.

Mitchell & Saville (1967) r e p o r t e d d i f f e r e n c e s i n the

d i s s o l u t i o n r a t e s of s i x d i f f e r e n t samples of commercial acetylsalicylic

acid (ASA). The lowest d i s s o l u t i o n r a t e was 0.995 and the h i g h e s t was

-2 -1

1.75 mg.cm. min. using the r o t a t i n g d i s k method of Wood & others

(1965) at 37 and 430 r.p.m. The ASA w i t h the lowest d i s s o l u t i o n r a t e

was a f r e e flow ASA g r a n u l e and t h a t w i t h the h i g h e s t d i s s o l u t i o n rate

was a c r y s t a l l i n e ASA. I.R. and X-ray d i f f r a c t i o n s t u d i e s showed no

evidence of polymorphism.

Tawashi (1968) r e p o r t e d the e x i s t e n c e of two polymorphs of

ASA. The s t a b l e form I (m.p. 143° t o 144°) was obtained by slow

r e c r y s t a l l i z a t i o n at room temperature, and the l e s s s t a b l e form I I

(m.p. 123° to 125°) was obtained by slow r e c r y s t a l l i z a t i o n at room

temperature from n-hexane. He claimed to have found d i f f e r e n c e s i n

the I.R. and X-ray s p e c t r a , but no e v i d e n c e was produced t o support

this claim. In a d d i t i o n to measuring the i n t r i n s i c d i s s o l u t i o n r a t e s

using a compressed d i s k t e c h n i q u e , Tawashi used the s i n g l e c r y s t a l

d i s s o l u t i o n method of H i g u c h i & others (unpublished work). He measured

the d i s s o l u t i o n r a t e s o f t h r e e d i f f e r e n t f a c e s (Tawashi uses

the term axes) of form I (a hexagonal p l a t e ) and one f a c e of form I I (a

thin needle-like crystal). The d i s s o l u t i o n r a t e of the n e e d l e crystal

was greater than from any face of the hexagonal p l a t e and Tawashi accepted

t h i s as e v i d e n c e of polymorphism. However, i t i s l i k e l y t h a t Tawashi

measured the d i s s o l u t i o n r a t e s of f a c e s (110), (100) and (010) for the

p l a t e whereas f o r the n e e d l e c r y s t a l the d i s s o l u t i o n r a t e of f a c e (001)

o n l y was measured. L a t e r , G r i f f i t h s & M i t c h e l l (unpublished work) and

M i t c h e l l & others (1971) found no d i f f e r e n c e s i n the I.R. spectra, ATR

 38

s p e c t r a , X-ray d i f f r a c t i o n p a t t e r n s , m e l t i n g point, thermograms

( d i f f e r e n t i a l scanning calorimeter) or i n t r i n s i c d i s s o l u t i o n r a t e s o f

ASA r e c r y s t a l l i z e d from e t h a n o l 95% and n-hexane. These f i n d i n g s were

confirmed by Schwartzman (1972) who, i n a d d i t i o n , found e t h a n o l i n the

ASA recrystallized from t h i s s o l v e n t . I t was not e s t a b l i s h e d whether

the e t h a n o l was p r e s e n t on the s u r f a c e o f the c r y s t a l , was trapped

interstitially o r was due t o hydrogen bonding.

Tawashi (1969) r e p o r t e d a d i f f e r e n c e i n the g a s t r o - i n t e s t i n a l

absorption o f forms I and I I when g i v e n t o human s u b j e c t s as a d i s p e r s i o n

i n water. The d i f f e r e n c e was a t t r i b u t e d t o polymorphism. However, i t i s

p o s s i b l e t h a t the d i f f e r e n c e s i n a b s o r p t i o n a r i s e from the marked

d i f f e r e n c e s i n h a b i t which occur when ASA i s r e c r y s t a l l i z e d from e t h a n o l 95%

and n-hexane. Tawashi s t a t e d t h a t both forms were o f about the same

p a r t i c l e s i z e , but even i f one c r y s t a l dimension., was-., o f about the same

s i z e , the d i f f e r e n c e s i n the o t h e r dimensions would l e a d t o s i g n i f i c a n t

d i f f e r e n c e s i n d i s s o l u t i o n r a t e s and t h e r e f o r e absorption rates.

The question o f polymorphism was f u r t h e r c o m p l i c a t e d by the

r e p o r t by Summers, C a r l e s s & Enever (1970) t h a t there are s i x polymorphs

of ASA. These were d i s t i n g u i s h e d on t h e b a s i s of m e l t i n g point (DSC and

h o t - s t a g e microscopy) and d e n s i t i e s but o n l y minor d i f f e r e n c e s were found

in the X-ray d i f f r a c t i o n p a t t e r n s . They found t h a t t h e l e a s t s t a b l e form

m e l t e d a t 100° and the most s t a b l e one melted a t 133° t o 135°. A sample

which was s u b l i m a t e d under vacuum had a m e l t i n g point of 108°. They a l s o

c l a i m e d t o have noted s o l u t i o n - p h a s e transformation o f some o f the forms

at 20°C i n n - p e n t a n o l u s i n g m i c r o s c o p i c method.

G r i f f i t h s & M i t c h e l l (1971) r e p o r t e d a solution-phase trans-

f o r m a t i o n i n the p r o c e s s o f b u l k d i s s o l u t i o n o f ASA. They showed t h a t

the c o n c e n t r a t i o n i n the b u l k i n c r e a s e d r a p i d l y and showed an initial

peak b e f o r e the e q u i l i b r i u m s o l u b i l i t y was reached. They p o s t u l a t e d

t h a t the peak i s due to an abrupt t r a n s f e r of s o l u t e from the large

s u r f a c e a r e a of a more s t a b l e form. The bulk l i q u i d becomes super-

saturated with respect to the more s t a b l e c r y s t a l l i n e form which

c r y s t a l l i z e s out on the s u r f a c e of the s o l i d . They a l s o r e p o r t e d in

the i n t r i n s i c d i s s o l u t i o n process from a compressed d i s k of ASA, the

l i n e a r curve was preceded by a steeper p o r t i o n . They accepted that as

a simultaneous phase change. They found t h a t ATR s p e c t r a and X-ray p a t t e r n

of the s u r f a c e of the ASA d i s k , commercial ASA and c r y s t a l s before and

a f t e r the b u l k d i s s o l u t i o n experiment were i d e n t i c a l .

Kildsig & others (1971) claimed to have found d i f f e r e n t pKa

values f o r form I (pKa 8.99) and form I I (pKa 9.19) i n dimethylformamide

using tetrabutyl-ammonium h y d r o x i d e as the t i t r a n t . They a s c r i b e d the

pKa values to d i f f e r e n c e s i n i n t r a and i n t e r m o l e c u l a r hydrogen bonding.

Pfeiffer (1971) q u e s t i o n e d the evidence f o r the e x i s t e n c e of

polymorphs of ASA. He suggested t h a t , d i f f e r e n c e s i n s i z e and h a b i t might:

a. affect the d i s s o l u t i o n r a t e from a compressed d i s k through d i f f e r e n c e s

in c a p i l l a r i t y or w e t t i n g ; b. a f f e c t the d e t e r m i n a t i o n of m e l t i n g point

and heat o f f u s i o n through d i f f e r e n c e s i n r a t e s of s u b l i m a t i o n and

decomposition; c. affect d e n s i t y measurement by v a r i o u s l y i n t e r f e r i n g

with the complete f i l l i n g of c a v i t i e s by the displacement f l u i d . He also

proposed t h a t , c r y s t a l s somehow d i f f e r w i t h regard to imperfection,

s t r e s s e s or f i n e r s t r u c t u a l d e t a i l s , but these d i f f e r e n c e s a l s o would not

justify the use of polymorphic d e s i g n a t i o n s . Whatever the source of

apparent e x t r a thermodynamic a c t i v i t y e x h i b i t e d by some of the ASA crystals,

exposure to heat, u l t r a s o u n d , s o l v e n t , e t c . , c o u l d cause them to anneal,

 40

grow or r i p e n ; they would thus mimic polymorphic b e h a v i o r by reverting

to a "more s t a b l e " form but would not undergo changes in their routinely

determined X-ray d i f f r a c t i o n properties.

M u l l e y & o t h e r s (1971) showed t h a t even ASA recrystallized

from nonaqueous s o l v e n t s c o n t a i n e d from 0.10% (recrystallized from

e t h a n o l 96% at 20 ) t o 2.4% (recrystallized from a s a t u r a t e d solution

i n n-hexane a t 68°, a f t e r s t a n d i n g f o r f o u r t e e n hours a t 0°) salicylic

acid (SA) as a r e s u l t o f h y d r o l y s i s . They showed t h a t samples of ASA

which were s u b l i m a t e d a t atmospheric p r e s s u r e s from 0.05 t o 12 mm Hg

c o n t a i n e d from 1.3 t o 60% SA and melted from 136.6 to 115° respectively

u s i n g d i f f e r e n t i a l thermal a n a l y s i s method. He concluded t h a t the

phenomena a t t r i b u t e d to polymorphism c o u l d be e x p l a i n e d by the presence

of s a l i c y l i c a c i d i n the samples p a r t i c u l a r l y as s i g n i f i c a n t differences

i n X-ray d i f f r a c t i o n s were not found.

Tawashi (1971) demonstrated the e x i s t e n c e o f ASA spherulites.

On h e a t i n g to 124° the s p h e r u l i t e s were t r a n s f o r m e d t o n e e d l e - l i k e crystals

which m e l t e d a t 125°. Borka (1972) c o n s i d e r e d t h a t , s p h e r u l i t e s are

s t r o n g e v i d e n c e f o r the e x i s t e n c e o f Tawashi's polymorphic form, form I I .

In h i s work s p h e r u l i t e s m e l t e d at 125° o n l y when t h i s temperature was

maintained. No i n f o r m a t i o n was g i v e n r e g a r d i n g the time r e q u i r e d . He

was unable t o reproduce the thermal t r a n s f o r m a t i o n o f s p h e r u l i t e s to

n e e d l e - l i k e prisms as d e s c r i b e d by Tawashi.

Borka (1972) determined the m e l t i n g p o i n t o f ASA crystals

c o n t a i n i n g d i f f e r e n t amounts of s a l i c y l i c a c i d , u s i n g open and closed

c a p i l l a r y tube methods. He showed t h a t the decrease i n m e l t i n g p o i n t

from 131° (0% SA) t o 114° (18% SA) i s almost l i n e a r when p l o t t e d against

the percentage of SA i n ASA. He c o n s t r u c t e d a phase diagram f o r the

 41

binary system of ASA arid SA which showed t h a t a p p r o x i m a t e l y 17 or 72%

of SA i s required to y i e l d a melting p o i n t of 123-125° which i s the melting

point of the n e e d l e - l i k e c r y s t a l s and spherulites. Since the SA content

of the s p h e r u l i t e s i s i n s u f f i c i e n t to depress the m e l t i n g p o i n t to 123-125°,

Borka argued t h a t , the d e p r e s s i o n of the m e l t i n g p o i n t of ASA i s not due

to the presence of SA i m p u r i t i e s but i s e v i d e n c e f o r the e x i s t e n c e of

polymorphic form I I . Borka a l s o showed an almost l i n e a r r e l a t i o n s h i p

between the h e a t i n g r a t e and m e l t i n g p o i n t of ASA. He reported a change

i n melting p o i n t from 130° to 139° when u s i n g r a t e s of 0.2° and 10° min

r e s p e c t i v e l y and he showed t h a t the c h o i c e of s t a r t i n g temperature a l s o

affects the m e l t i n g point. At constant c o n d i t i o n s , a sample of ASA

m e l t e d at 135.4° and 137.3° when s t a r t i n g temperatures were 130° and 135°

respectively. Hence i t i s c l e a r t h a t p u r i t y , r a t e of h e a t i n g and s t a r t i n g

temperature p l a y •- v e r y important r o l e s i n the m e l t i n g p o i n t of ASA.

Borka (1972) a l s o demonstrated a s o l u t i o n - p h a s e transformation

from ASA s p h e r u l i t e s to ASA prisms. He covered the ASA spherulites with

a cover s l i p and allowed a drop of s a t u r a t e d s o l u t i o n of ASA i n isoamyl

a l c o h o l to flow under the cover s l i p . Spherulites changed to prismatic

c r y s t a l s of ASA. He d i d not mention the time r e q u i r e d for this trans-

formation to take p l a c e and accepted t h i s phenomenon as a p h a s e - t r a n s -

formation and strong e v i d e n c e of the e x i s t e n c e of polymorphism.

 42

3. EXPERIMENTAL.

3-1. Apparatus.

Solubility Measurement Apparatus (see 3 - 3, I ) :

Waterbath (50 L., O r d i n a r y f i s h tank).

Circulatory Crystallizer (see 3 - 3 , I I ) :

ISCO Model 310 M e t e r i n g Pump.

Mansostat V a r i s t a l t i c Advanced Model Pump.

Haake Thermoregulator Type FE.

Haake Thermoregulator Type R21.

F i s h e r Dyna Mix S t i r r e r .

Gas D i s p e r s i o n Tubes, Kimble // 28630.

H i t a c h i Colman 124, Spectrophotometer.

Micro-Tek 220 G a s - L i q u i d Chromatography equipped w i t h

Flame I o n i z a t i o n D e t e c t o r and a 5% ov-210,

Gas Chrom. Q. (6 f t . x 2 mm.) Column.

Aminco-Bowman S p e c t r o p h o t o f l u o r o m e t e r .

Buchi Rotavapor "R".

M e t t l e r FP2 and FP1 M e l t i n g P o i n t Apparatus.

P h i l l i p s High Angle X-ray D i f f r a c t o m e t e r w i t h Tennelac TC-124

Counter Recorder.

M e t a l Mold Punch and D i e ^See 3 - 3 V I I , a ( i ) J

U.S. Gauge Co. H y d r o l i c P r e s s .

R o t a t i n g D i s k D i s s o l u t i o n Apparatus JSee 3 - 3, V I I , a ( i i ) )

E l e c t r o n i c A p p l i c a t i o n s Group F l a s k - Tac T r a n s i s t o r i s e d Stroboscope.

F i s h e r Steadi-Speed A d j u s t a b l e S t i r r e r .
 Materials.

Acetylsalicylic A c i d B.P. (ASA), B.D.H. Canada L o t s 34755

and 27648, May and Baker L o t 27648, and Monsanto Granules

S a l i c y l i c Acid (SA) Reagent Grade, B.D.H. Canada L o t 32533.

Sodium Carbonate, Anhydrous Reagent.

Absolute Ethanol, Reagent Grade.

E t h a n o l 95%, Reagent Grade.

Acetone, Reagent Grade.

C h l o r o f o r m , Reagent Grade.

Chloroform, C e r t i f i e d Spectroanalyzed.

Amyl A l c o h o l , Reagent Grade,

n-hexane, Reagent Grade.

F e r r i c Ammonium S u l f a t e B.P.

D i l u t e N i t r i c A c i d B.P.

Diazomethane Solution.

T e t r a h y d r o f u r a n ' , Reagent Grade.

M e t h y l 0-methoxybenzoate, Eastman, H i g h e s t Purity.

Hydrochloric A c i d 0.1 Normal.

G l y c e r i n , Reagent Grade.

Solvent E t h e r U.S.P.
3-3. Methods.

I. S o l u b i l i t y of A c e t y l s a l i c y l i c A c i d i n A b s o l u t e Ethanol.

The apparatus shown i n F i g . 3 - 1 c o n s i s t s of two 150 ml.

flasks containing g l a s s wool. A narrow bore g l a s s tubing bent at each

end j o i n s the two flasks.

Excess ASA* was added to a g i v e n volume of a b s o l u t e ethanol

in 'a'. The f l a s k s were connected and fastened on a r o t a t o r i n a

temperature c o n t r o l l e d water b a t h . In o r d e r t o a c c e l e r a t e the approach

to s a t u r a t i o n , the apparatus was i n v e r t e d at s u i t a b l e time i n t e r v a l s ,

so t h a t s o l u t i o n passed through the g l a s s wool i n t o the other f l a s k .

The g l a s s wool p r e v e n t s the passage of ASA crystals into flask 'b',

w h i l e the g l a s s tubing p e r m i t s displacement of a i r . Finally the

saturated s o l u t i o n was t r a n s f e r r e d to the f l a s k 'li* ( p r e v i o u s l y weighed),

the a l c o h o l evaporated u s i n g a r o t a r y e v a p o r a t o r and the f l a s k and contents

d r i e d to constant weight. At l e a s t three replicate gravimetric

d e t e r m i n a t i o n s were made and the r e s u l t s averaged.

* B r i t i s h Drug Houses, Canada, L o t 34755.

 45

Figure 3 - 1 . SOLUBILITY APPARATUS.

a and b, 150 ml. f l a s k s ; c, c o n n e c t i n g tube;
d, narrow g l a s s tube; e, g l a s s wool; f, solvent;
g, powder.
 46

II. R e c r y s t a l l i z a t i o n of A c e t y l s a l i c y l i c Acid.

a. R e c r y s t a l l i z a t i o n from A b s o l u t e E t h a n o l : A crystallizer

was designed s i m i l a r to t h a t d e s c r i b e d by Bujac (1970) on the b a s i s of

producing a saturated s o l u t i o n i n two s e p a r a t e but interconnected

v e s s e l s , and then making a s u p e r s a t u r a t e d s o l u t i o n by decreasing the

temperature i n one of the vessels.

A diagram of the apparatus i s shown i n F i g . 3 - 2 . Excess ASA

was added to a b s o l u t e ethanol at the d e s i r e d temperature i n one of the

jacketed beakers ( r e s e r v o i r ) and stirred continuously. The solution was

pumped through a f i l t e r s t i c k i n t o the other jacketed beaker (crystallizer),

and repumped i n t o the r e s e r v o i r through another f i l t e r stick. After

reaching equilibrium, the temperature i n the c r y s t a l l i z e r was decreased

slowly to produce a s u p e r s a t u r a t e d solution. Some ASA c r y s t a l s were

added as seeds. The r e s u l t i n g c r y s t a l s were removed from the crystallizer,

washed w i t h s o l v e n t ether and dried i n a desiccator.

The c i r c u l a t o r y c r y s t a l l i z e r proved s u i t a b l e f o r the production

of l a r g e amounts of ASA crystals. The equilibrium s o l u b i l i t y curve was

determined t o g e t h e r w i t h the s u p e r s o l u b i l i t y curve and therefore the

metastable region. C r y s t a l s were grown at d i f f e r e n t degrees of super-

s a t u r a t i o n a f t e r seeding (see 3-3, c). The degree of supersaturation,Ac,

was c a l c u l a t e d from e q u a t i o n (15).

Ac = (Ct-Co) (15)

where Ct i s the p e r c e n t ASA i n s o l u t i o n and Co i s the e q u i l i b r i u m solubility

of ASA at the same temperature.

The many f a c t o r s which c o u l d affect nucleation and the rate

o f c r y s t a l growth are beyond the scope of the p r e s e n t work. However, i t

i s w e l l known t h a t n u c l e a t i o n v a r i e s w i t h change i n a g i t a t i o n speed

 47

Figure 3 - 2 . ^CRYSTALLIZES..
a, r e s e r v o i r ; j , c r y s t a l l i z e r v e s s e l ; b and i , thermometers;
c and h , s t i r r e r s ( 3 cm. p o l y e t h y l e n e , Nalgene); d and g,
g l a s s tubes; e and f , f i l t e r s t i c k s ; k and 1 , pumps;
m, l a b o r a t o r y j a c k .
 48

(Bujac, 1970). The main purpose o f a g i t a t i o n i n a c r y s t a l l i z e r i s t o

suspend t h e c r y s t a l s . I f some o f t h e c r y s t a l s remain on the v e s s e l

bottom, the o v e r a l l growth r a t e i s reduced as a l l the c r y s t a l surfaces

are n o t exposed t o the mother l i q u o r . Crystals lying s t a t i o n a r y on

the bottom not o n l y grow a t a slow r a t e , but they a l s o tend t o form

agglomerates o r , worse, compact i n t o a s o l i d cake. Hence t h e type o f

s t i r r e r and i t s p o s i t i o n were chosen to ensure t h a t t h e c r y s t a l s were

suspended a t low speeds (60-70 r.p.m.).

The n u c l e a t i o n p o i n t s o f A S A i n a b s o l u t e e t h a n o l a t a g i v e n

c o n c e n t r a t i o n l i e a p p r o x i m a t e l y 3.-5° below the e q u i l i b r i u m solubility

point (see F i g . 4 - 1 ) . Because o f t h i s narrow m e t a s t a b l e r e g i o n ,

c r y s t a l growth under c o n d i t i o n s i n which t h e r e was a p r e c i s e difference

i n the degree o f s u p e r s a t u r a t i o n was d i f f i c u l t , s i n c e the apparatus

r e q u i r e d a degree o f temperature c o n t r o l beyond the c a p a b i l i t y o f the

apparatus used.

b. R e c r y s t a l l i z a t i o n from E t h a n o l 9 5 % : The apparatus

d e s c r i b e d i n I I , a , was employed t o r e c r y s t a l l i z e A S A from e t h a n o l 9 5 %

u s i n g t h e same method.

c. R e c r y s t a l l i z a t i o n a t D i f f e r e n t Degrees o f S u p e r s a t u r a t i o n :

Excess A S A was added t o a g i v e n volume o f a b s o l u t e e t h a n o l i n the

c r y s t a l l i z e r v e s s e l and a s a t u r a t e d s o l u t i o n o f ASA was p r e p a r e d a t 25.8°.

The temperature i n the c r y s t a l l i z e r v e s s e l was reduced to 24.8°

(Ac = 1 . 1 % w/w) and some A S A c r y s t a l s were added as seeds. The c r y s t a l

growth p r o c e s s was c o n t i n u e d f o r t h i r t y minutes. The r e s u l t i n g crystals

were removed, washed w i t h s o l v e n t e t h e r and d r i e d i n a d e s i c c a t o r .

In another experiment the-.same p r o c e s s was f o l l o w e d but seeds were

added t o t h e s u p e r s a t u r a t e d s o l u t i o n a t 23.5° (Ac = 2.5% w/w).

 d. Slow R e c r y s t a l l i z a t i o n from a S t i r r e d S o l u t i o n : Excess

ASA was added t o a g i v e n amount o f a b s o l u t e ethanol a t 35° and s t i r r e d .

The temperature was i n c r e a s e d slowly t o 43° t o o b t a i n a c l e a r s o l u t i o n ,

and then decreased g r a d u a l l y t o 20° w i t h i n three hours and the c r y s t a l s

were removed from the s o l u t i o n , washed w i t h s o l v e n t ether and d r i e d i n

a desiccator.

e. Fast R e c r y s t a l l i z a t i o n : Excess ASA was added t o a g i v e n

amount o f a b s o l u t e ethanol i n a jacketed beaker at 35° and s t i r r e d . The

temperature was i n c r e a s e d t o 45° t o o b t a i n a c l e a r s o l u t i o n , and then

reduced t o 20° w i t h i n twenty minutes. The r e s u l t i n g c r y s t a l s were

c o l l e c t e d and washed w i t h s o l v e n t ether and d r i e d i n a d e s i c c a t o r .

f. M i c r o c r y s t a l l i z a t i o n of A c e t y l s a l i c y l i c Acid: Microcrystalline

ASA was prepared f o l l o w i n g the method o f A f f o n s o & Naik (1971).

50 g. o f ASA was d i s s o l v e d i n 1120 m l . o f g l y c e r i n a t 80° to

obtain a saturated s o l u t i o n o f ASA i n g l y c e r i n . The c l e a r s o l u t i o n was

t r a n s f e r r e d to a glass v e s s e l . Stirring and e x t e r n a l c o o l i n g were s t a r t e d

immediately and f o l l o w e d by the q u i c k a d d i t i o n o f i c e water. The

temperature was dropped t o 5° w i t h i n f i f t e e n minutes.

The m i c r o c r y s t a l s were f i l t e r e d under vacuum through Whatman No. 42

f i l t e r paper. F i l t r a t i o n was a c c e l e r a t e d by the a d d i t i o n of i c e water.

The product was washed w i t h i c e water, and d r i e d i n a d e s i c c a t o r . The s i z e

of the c r y s t a l s was measured u s i n g a microscope f i t t e d w i t h a c a l i b r a t e d

e y e - p i e c e micrometer.

g. R e c r y s t a l l i z a t i o n of S p h e r u l i t e s : 20 g. o f ASA was d i s s o l v e d

i n 100 m l . o f e t h a n o l 95% a t room temperature t o make a c o n c e n t r a t e d s o l u t i o n .

One drop o f s o l u t i o n was spread as a t h i n f i l m on a microscope slide

( p r e v i o u s l y washed w i t h e t h a n o l ) . The s p h e r u l i t e s were observed t o grow

 50

a f t e r a few seconds, f i l l i n g the microscope f i e l d . Growth s t a r t s from

the c e n t e r o f the s p h e r u l i t e s .

T h i s experiment was a l s o c a r r i e d out f o l l o w i n g the method

of Tawashi (1971) u s i n g saturated solutions, One drop o f a f r e s h ,

f i l t e r e d , saturated s o l u t i o n o f ASA i n e t h a n o l 95% was spread on a

c l e a n g l a s s s l i d e , p r e v i o u s l y washed w i t h e t h a n o l . The s p h e r u l i t e s

grew from the c e n t e r and r a p i d l y f i l l e d t h e microscope f i e l d . Small,

w e l l d e f i n e d p r i s m s , l o c a t e d mostly on the edges o f the s l i d e , were

a l s o observed.

h. R e c r y s t a l l i z a t i o n o f C r y s t a l s from Spherulites:

S p h e r u l i t e s were grown on a microscope s l i d e and covered w i t h a cover

glass. One drop of a f r e s h , f i l t e r e d , s a t u r a t e d s o l u t i o n o f ASA i n

„^namyl a l c o h o l was allowed to flow under t h e cover g l a s s . A f t e r a few

minutes a l l the s p h e r u l i t e s changed t o s m a l l , w e l l - d e f i n e d prisms.

i. R e c r y s t a l l i z a t i o n from a S o l u t i o n o f 0.1 N H y d r o c h l o r i c

Acid: A concentrated s o l u t i o n o f ASA i n 0.1 N h y d r o c h l o r i c a c i d was

p r e p a r e d by c o n t i n u i n g the r o t a t i n g d i s k d i s s o l u t i o n experiment a t 37°

for t h r e e hours ( a s o l u t i o n of 380 mg./lOO m l . o f ASA). The s o l u t i o n

was kept i n a r e f r i g e r a t o r f o r e i g h t e e n hours. Resulting c r y s t a l s were

removed and washed w i t h e t h e r s o l v e n t and d r i e d i n a d e s i c c a t o r .

In another experiment, excess ASA was added to a g i v e n volume

of 0.1 N h y d r o c h l o r i c a c i d a t 3 7 ° , s t i r r e d r a p i d l y f o r t h i r t y minutes.

The s o l u t i o n was f i l t e r e d u s i n g a Whatman No. 1 f i l t e r paper and kept i n

a r e f r i g e r a t o r f o r eighteen hours. The r e s u l t i n g c r y s t a l s were removed,

washed w i t h s o l v e n t e t h e r and d r i e d i n a d e s i c c a t o r .
 j. Slow R e c r y s t a l l i z a t i o n a t Room Temperature: Excess ASA

was added t o e t h a n o l 95 % a t room temperature, and s t i r r e d to obtain a

saturated solution. The s o l u t i o n was f i l t e r e d through a Whatman No. 1

f i l t e r paper, and kept a t room temperature for forty-eight hours. The

resulting c r y s t a l s were removed and washed w i t h s o l v e n t e t h e r and d r i e d

in a desiccator.

k. • R e c r y s t a l l i z a t i o n from n-hexane: Excess ASA was added t o

1000 m l . n-hexane at 6 0 ° , s t i r r e d well and f i l t e r e d . The c l e a r solution

was kept i n a r e f r i g e r a t o r f o r s i x hours. R e s u l t i n g c r y s t a l s were

collected and washed w i t h s o l v e n t e t h e r and d r i e d in a desiccator.

 III. Determination of S a l i c y l i c Acid i n A c e t y l s a l i c y l i c Acid.

The pharmacopeial l i m i t s f o r s a l i c y l i c a c i d (SA) i n commercial

ASA a r e 0.1% USP 18 r e v i s i o n and 0.05% B.P. 1968. Hence t h e method

used t o measure the amount of SA i n ASA should be s e n s i t i v e enough to

d e t e c t these l e v e l s or p r e f e r a b l y l e s s , since i t i s possible that SA

can be i n c o r p o r a t e d i n t o the ASA c r y s t a l l a t t i c e as an i n t e r s t i t i a l

defect.

S a l i c y l i c a c i d p r e s e n t i n ASA was determined u s i n g colorimetry,

gas-liquid chromatography, spectrophotometry, and absorbance r a t i o

methods.

a. Coloriimetry.

In the presence o f a c i d f e r r i c ammonium s u l f a t e , SA produces

a v i o l e t c o l o r which absorbs a t 530 nm.

P r e p a r a t i o n o f Standard Curve ( F i g . 3 - 3 ) - 100 mg. SA,

accurately weighed, was d i s s o l v e d i n 10 ml. o f e t h a n o l 95%, t r a n s f e r r e d

to a 100 m l . v o l u m e t r i c f l a s k and water added t o volume. 10 m l . o f t h i s

s o l u t i o n was t r a n s f e r r e d t o another 100 ml. v o l u m e t r i c f l a s k and d i l u t e d

to volume w i t h water. 0.5, 1, 2 and 3 m l . o f t h i s l a t t e r s o l u t i o n were

transferred t o f i v e 100 m l . v o l u m e t r i c f l a s k s and 2 ml. o f a c i d ferric

ammonium s u l f a t e s o l u t i o n B.P. was added t o each f l a s k , d i l u t e d t o volume

w i t h water, and a l l o w e d t o s t a n d f o r one minute. The i n t e n s i t y o f the

c o l o r produced was measured a t 530 nm and p l o t t e d versus concentration

on l i n e a r graph paper. The s l o p e o f the curve was 1.85 u s i n g regression

analysis.

P r e p a r a t i o n o f Sample S o l u t i o n - Approximately 1.0 g. o f ASA

accurately weighed was d i s s o l v e d i n 10 m l . o f e t h a n o l 95% and t r a n s f e r r e d

t o a 100 m l . v o l u m e t r i c f l a s k . Two m l . of a c i d f e r r i c ammonium sulfate

 53

F i g u r e 3 - 3. Standard curve f o r the c o l o r i m e t r i c d e t e r m i n a t i o n

of s a l i c y l i c a c i d .
 54

s o l u t i o n was added and water t o make up to volume. The i n t e n s i t y o f

t h i s s o l u t i o n was measured at 530 nm a f t e r a l l o w i n g to stand f o r one

minute.

In t h i s method the amount of ASA r e q u i r e d i s more than the

e q u i l i b r i u m s o l u b i l i t y o f ASA i n the s o l v e n t . Hence t h i s method i s

u n s a t i s f a c t o r y f o r the d e t e r m i n a t i o n of s m a l l amounts o f SA i n ASA.

b. G a s - L i q u i d Chromatography Determination of S a l i c y l i c Acid

in A c e t y l s a l i c y l i c Acid: The procedure i n v o l v e s the c o n v e r s i o n of the

two a c i d s t o t h e i r m e t h y l e s t e r s w i t h diazomethane i n tetrahydrofuran

(THF) s o l u t i o n and subsequent i s o t h e r m a l e l u t i o n o f the components

from the column f o l l o w i n g the method o f Watson and o t h e r s (1971)•

i P r e p a r a t i o n o f Diazomethane S o l u t i o n - The method of De Baer

& Backer (1956) was followed*.

A 125 ml. d i s t i l l i n g f l a s k w i t h a condenser s e t f o r d i s t i l l a t i o n

was f i t t e d w i t h a long-stem d r o p p i n g f u n n e l . The condenser was connected

by means of an adaptor t o a s t o p p e r e d 250 ml. Erlenmeyer f l a s k . Through

a second h o l e i n the s t o p p e r of the Erlenmeyer f l a s k an o u t l e t tube was

p l a c e d which was bent so as t o pass i n t o and n e a r l y to the bottom o f a

second unstoppered Erlenmeyer f l a s k . Both r e c e i v e r s were c o o l e d i n an

i c e - s a l t mixture; i n the f i r s t and second r e c e i v e r s r e s p e c t i v e l y , 2 ml.

THF and 7 ml. of THF were p l a c e d . The i n l e t tube passed below the s u r f a c e

of the THF i n the second flask.

In the d i s t i l l i n g f l a s k , a s o l u t i o n o f 1.29 g. o f potassium

h y d r o x i d e d i s s o l v e d i n 2 ml. o f water, 7.0 ml. o f 2 - e t h o x y - e t h a n o l ,

2.0 m l . of THF, and a " T e f l o n " - c o a t e d magnetic s t i r r i n g bar were p l a c e d .

* 2-ethoxy-ethanol was used i n s t e a d of C a r b i t o l i n t h i s experiment.

 55

The dropping f u n n e l was a t t a c h e d and a d j u s t e d so t h a t t h e stem was j u s t

above the s u r f a c e o f the s o l u t i o n i n the d i s t i l l i n g flask. A s o l u t i o n of

4.3 g. (0.02 M.) o f p - t o l y l s u l f o n y l m e t h y l n i t r o s a m i d e i n 2.5 m l . o f THF

was p l a c e d i n the dropping funnel. The d i s t i l l i n g f l a s k was heated i n a

water b a t h a t 70-75°, the s t i r r e r was s t a r t e d , and n i t r o s a m i d e s o l u t i o n

was added a t a r e g u l a r r a t e f o r f i f t e e n t o twenty minutes. As soon as

all the n i t r o s a m i d e s o l u t i o n had been added, a d d i t i o n a l THF was t r a n s -

f e r r e d i n t h e dropping f u n n e l and added u n t i l the d i s t i l l a t e was c o l o r l e s s .

P r e p a r a t i o n o f Standard Curve o f S a l i c y l i c A c i d ( F i g . 3 - 4) -

A s t o c k s o l u t i o n o f 5 mg./ml. o f SA i n THF was prepared; 0.2, 0.3, 0.4,

0.5 and 0.6 m l . o f t h i s s o l u t i o n were t r a n s f e r r e d t o f i v e 5 ml. v o l u m e t r i c

flasks respectively. A s t o c k s o l u t i o n o f 5 mg./ml. o f ortho-metoxybenzoate

(OMBA) i n THF was a l s o prepared f o r use as an i n t e r n a l s t a n d a r d . One m l . o f

t h i s s o l u t i o n was t r a n s f e r r e d t o each o f the above 5 m l . v o l u m e t r i c flasks.

Diazomethane was added t o the s o l u t i o n u n t i l a permanent y e l l o w c o l o r

appeared, and then THF was added t o volume. One^l. o f s o l u t i o n s o f 0.2,

0.3 and 0.4 m l . o f SA i n 5 ml. and 0.8^<1. o f s o l u t i o n s o f 0.5 and 0.6 m l .

of SA i n 5 m l . THF were i n j e c t e d by means o f a m i c r o s y r i n g e i n t o a GC

equipped w i t h a f l a m e - i o n i z a t i o n d e t e c t o r u n i t and f i t t e d w i t h a 5% 0V-210

GasChrom Q (100-120 mesh) U-shaped g l a s s column (6 f t . x 2 mm.). The drugs

were i s o t h e r m a l l y e l u t e d as t h e i r m e t h y l a t e d compounds under t h e f o l l o w i n g

conditions: inlet temperature 180°, column temperature 90°, detector

temperature 255°. Gas flows were: Ng 25 ml./min.; H£ 30 ml./min.;

a i r 12 ml./min. The d e t e c t o r s i g n a l was r e c o r d e d by a r e c o r d e r w i t h a

2

c h a r t speed o f 15 inches/hour, input attenuator 10 and output a t t e n u a t o r 32.

The r e t e n t i o n ' t i m e f o r SA.was 3.5 minutes.

 56

Figure 3 - 4 . Gas-liquid chromatographic internal standard calibration

curve for salicylic acid.
 57

The a r e a r a t i o s o f the methylated compound t o i n t e r n a l standard

were p l o t t e d a g a i n s t the weight r a t i o s o f t h e drug to internal standard,

F i g . ( 3 - 4) • The s l o p e o f t h e curve was o b t a i n e d from r e g r e s s i o n a n a l y s i s

and was 1.070 which i s i n agreement w i t h the v a l u e o f 1.069 r e p o r t e d by

Watson & o t h e r s (1971).

Sample S o l u t i o n - 298 mg. of powdered c r y s t a l l i n e ASA was

a c c u r a t e l y weighed and t r a n s f e r r e d t o a 5 ml. v o l u m e t r i c f l a s k . 1 ml.

of OMBA s t o c k s o l u t i o n and s u f f i c i e n t diazomethane were added t o produce

permanent y e l l o w c o l o r , and then THF was added t o volume. One jil. o f t h i s

s o l u t i o n was i n j e c t e d i n t o instrument by means o f a m i c r o s y r i n g e and the

r e s u l t was c a l c u l a t e d ( F i g s . 3 - 5 and 3-6).

T h i s method i s a time consuming procedure and t h e s m a l l amounts

of SA n o r m a l l y found i n commercial ASA cannot be determined. A chromato-

gram o f the e l u t i o n o f SA from ASA i s shown i n F i g . 3 - 5 . The sample

was a commercial ASA c o n t a i n i n g 0.09% SA ( s p e c t r o p h o t o m e t r i c determination).

SA has a v e r y s m a l l peak l y i n g on t h e t a i l o f t h e s o l v e n t peak. The

isothermal e l u t i o n of a s y n t h e t i c mixture o f ASA c o n t a i n i n g 1% SA* shown

i n F i g . 3 - 6 shows t h a t a l t h o u g h t h i s l e v e l o f SA can be determined t h e

method i s u n s a t i s f a c t o r y f o r s m a l l amounts o f SA.

c. Determination of S a l i c y l i c A c i d i n A c e t y l s a l i c y l i c A c i d using

Absorbance R a t i o Technique.

The absorbance o f sample o f ASA c o n t a i n i n g SA a t 276 and 303 nm.

303

was measured and absorbance r a t i o ("275") c a l c u l a t e d .

P r e p a r a t i o n of Standard Curve ( F i g . 3 - 7 ) : Stock s o l u t i o n s of

ASA (1 g./lOO ml. o f e t h a n o l 95%) and SA (0.1 g./lOO ml. o f e t h a n o l 95%)

were p r e p a r e d . 1, 5, 10, 15 and 20 ml. o f SA s t o c k s o l u t i o n were added t o

five different 100 ml. v o l u m e t r i c f l a s k s c o n t a i n i n g 10 ml. o f ASA s t o c k

*The same e x p e r i m e n t a l c o n d i t i o n s except, output a t t e n u a t o r = 16.

 58

Fig. 3 - 5 . G a s - l i q u i d chromatogram of s a l i c y l i c a c i d i n commercial

a c e t y l s a l i c y l i c a c i d . T h e peak due to i s o t h e r m a l e l u t i o n
of a c e t y l s a l i c y l i c ( r e t e n t i o n time 37 minutes) i s not
shown i n t h i s f i g u r e .
 59

Fig. 3-6. G a s - l i q u i d chromatogram o f a c e t y l s a l i c y l i c a c i d i n

m i x t u r e of s a l i c y l i c a c i d (1%) and a c e t y l s a l i c y l i c
a c i d . The peak due to i s o t h e r m a l e l u t i o n of a c e t y l -
s a l i c y l i c a c i d ( r e t e n t i o n time 37 minutes ) i s not
shown i n t h i s f i g u r e .
 60

l.o r-

10 15 20

S a l i c y l i c Acid (per cent)

Figure 3 - 7. Standard curve for determination of s a l i c y l i c acid i n

a c e t y l s a l i c y l i c acid using absorbance r a t i o method.
solution. E t h a n o l 95% was added t o volume, and absorbance o f each o f

the s o l u t i o n s was measured a t 276 and 303 nm. r e s p e c t i v e l y . The

303

absorbance r a t i o (^^^) was c a l c u l a t e d , and p l o t t e d as f u n c t i o n o f

SA%. The s l o p e o f the curve c a l c u l a t e d u s i n g regression analysis

was 0.0415.

Preparation o f Sample S o l u t i o n : A g i v e n sample o f ASA was

transferred i n t o a f l a s k and d i s s o l v e d i n e t h a n o l 95%. The absorbance

at 303 and 276 was measured and t h e absorbance r a t i o c a l c u l a t e d . No

sample weighing o r volume c o r r e c t i o n i s r e q u i r e d i n t h i s method.

T h i s method was used to measure the SA i n ASA melt a f t e r

melting point determinations. T h i s method cannot d e t e c t SA i n amounts

l e s s than 0.1%, because the amount of sample r e q u i r e d exceeds the

s o l u b i l i t y o f ASA i n e t h a n o l . I t i s v e r y r a p i d and no volume c o r r e c t i o n

or weighing a r e r e q u i r e d .

d. Spectrophotofluorometric Determination of S a l i c y l i c Acid

i n A c e t y l s a l i c y l i c A c i d : A cihlorof ormic s o l u t i o n o f SA has a t y p i c a l

fluorescence which i s d e t e c t a b l e a t an e x c i t a t i o n wavelength o f 310 nm.

and an e m i s s i o n wavelength o f 450 nm.

The method o f Shane & S t i l l m a n (1971) was followed.

Preparation of Standard Curve ( F i g . 3 ^ 8 ) - 100 mg. o f SA was

accurately weighed and t r a n s f e r r e d t o a 100 ml. v o l u m e t r i c f l a s k and

dissolved i n chloroform.* S u f f i c i e n t c h l o r o f o r m was added t o make up

to volume. One m l . o f t h i s s o l u t i o n was d i l u t e d w i t h c h l o r o f o r m t o

100 m l . i n a 100 m l . v o l u m e t r i c f l a s k . Ten ml. o f t h i s l a t t e r solution

was transferred t o another 100 m l . v o l u m e t r i c f l a s k and made up t o volume

* U n l e s s o t h e r w i s e s t a t e d c h l o r o f o r m C e r t i f i e d S p e c t r o a n a l y z e d was
used i n t h i s experiment.
 62

Figure 3 - 8 . Standard curve f o r spectrophotofluorometry determination

of s a l i c y l i c a c i d . ,
 63

with chloroform. One, 5, 10, 15 and 25 ml. of t h i s s o l u t i o n were t r a n s -

f e r r e d to f i v e 100 ml. v o l u m e t r i c f l a s k s and diluted to volume w i t h

c h l o r o f o r m t o make s o l u t i o n s of 0.001, 0.005, 0.010, 0.015 and 0.025 mg.

SA p e r 100 ml. The r e l a t i v e f l u o r e s c e n c e i n t e n s i t y of these s o l u t i o n s

was o b t a i n e d a t e x c i t a t i o n and e m i s s i o n wavelengths of 310 and 450 nm.

respectively. The s l o p e of the curve was 4.4 using regression a n a l y s i s .

The instrument was l o c k e d at a s e n s i t i v i t y of 30. The slit arrangement

was 3, 2, 2, 3, 0.5 and the instrument was c a l i b r a t e d using a s o l u t i o n

of 0.1^g./ml. q u i n i n e s u l f a t e i n 0.1 N sulphuric acid*'.

P r e p a r a t i o n of Sample S o l u t i o n - 100 mg. of ASA was

a c c u r a t e l y weighed and t r a n s f e r r e d t o a 100 ml. v o l u m e t r i c flask,

d i s s o l v e d i n and d i l u t e d to volume w i t h c h l o r o f o r m . Ten ml. of this

s o l u t i o n was d i l u t e d to 100 ml. w i t h c h l o r o f o r m i n a 100 ml. volumetric

f l a s k and i t s r e l a t i v e f l u o r e s c e n c e i n t e n s i t y was measured at excitation

and e m i s s i o n wavelengths of 310 and 450 nm. r e s p e c t i v e l y .

The f l u o r e s c e n c e i n t e n s i t y i s due to the p r e s e n c e of o n l y SA,

because ASA does not f l u o r e s c e . " ' I t i s a one-step o p e r a t i o n ; the complete

a n a l y s i s , e x c l u s i v e of c a l i b r a t i o n , r e q u i r e s l e s s than t e n minutes. The

fluorometer i s e s p e c i a l l y u s e f u l i n the d e t e r m i n a t i o n of v e r y s m a l l amounts

of SA i n the presence of a l a r g e amount of ASA, because the fluorescence

per u n i t weight i s very s t r o n g and g i v e s l a r g e peaks. Using t h i s method i t

is p o s s i b l e to d e t e c t as l i t t l e as 0.001% of SA i n a s o l u t i o n , and because

* At the b e g i n n i n g and the end of each experiment the xenon lamp

i n t e n s i t y was checked by remeasuring and comparing the r e l a t i v e
f l u o r e s c e n c e i n t e n s i t y of a s o l u t i o n of O.lyyg./ml. q u i n i n e s u l f a t e
i n 0.1 N s u l p h u r i c a c i d a t e x c i t a t i o n and e m i s s i o n wavelengths of
350 and 450 nm. r e s p e c t i v e l y .

** ASA does not e x h i b i t f l u o r e s c e n c e a c t i v i t y i n t h i s experimental -condition,

of the h i g h s o l u b i l i t y of ASA i n c h l o r o f o r m , t h e r e i s no s o l u b i l i t y

problem.

The o n l y disadvantage i s the p o s s i b l i t y o f a change i n the

i n t e n s i t y o f the xenon lamp. The i n t r o d u c t i o n o f e r r o r s due t o t h i s

cause was avoided by u s i n g a s o l u t i o n of q u i n i n e s u l f a t e as a s t a n d a r d

s o l u t i o n to c a l i b r a t e the instrument b e f o r e each a n a l y s i s . In o r d e r

to remove any background i n t e r f e r e n c e , h i g h l y pure c h l o r o f o r m * w i t h

almost zero f l u o r e s c e n c e a c t i v i t y was used.

T h i s method was c o n s i d e r e d to be the most s u i t a b l e and

c o n v e n i e n t , and was used t o determine s m a l l amounts o f SA i n ASA.

* Chloroform Certified Spectroanalyzed, Fisher S c i e n t i f i c Company.

 IV. Measurement of the M e l t i n g P o i n t of the Acetylsalicylic

Acid Samples.

The m e l t i n g p o i n t of d i f f e r e n t samples of ASA was determined

using open c a p i l l a r y tube and hot stage methods. The sample was

ground and filled i n t o a c a p i l l a r y tube and/or was placed on a m i c r o -

scope s l i d e and covered w i t h a cover s l i p . S p h e r u l i t e s were scraped from

the s l i d e on which they were grown, f i l l e d into a capillary tube and/or

covered w i t h a cover s l i p and placed on the hot stage and the melting

p o i n t determined. Melting p o i n t of a l l samples determined under constant

c o n d i t i o n s , i . e . , a s t a r t i n g temperature of 2° below the e s t i m a t e d melting

point (determined i n a p r e l i m i n a r y experiment u s i n g a heating rate of

10°/min)i and heating r a t e of 0.2°/min. (Table 4-2).

V. X-Ray D i f f r a c t i o n of the A c e t y l s a l i c y l i c A c i d Samples.,

Approximately 300 mg. of the ASA sample was filled into a

sample s l i d e and exposed to CuKot r a d i a t i o n i n an X-ray diffractometer.

The l o c a t i o n and i n t e n s i t y of the peaks at d i f f e r e n t v a l u e s of 29 were

studied.

In the case of s p h e r u l i t e s , the samples were scraped from

the m i c r o s c o p e s l i d e and placed i n the sample s i t e i n the instrument.

Compressed d i s k s were used f o r X-ray a n a l y s i s directly.

VI. D i s s o l u t i o n of A c e t y l s a l i c y l i c Acid.

a. I n t r i n s i c D i s s o l u t i o n Rate: The i n t r i n s i c d i s s o l u t i o n rate

of ASA was measured u s i n g the r o t a t i n g d i s k method of Nogami & o t h e r s (1966)

as d e s c r i b e d p r e v i o u s l y by G r i f f i t h s & M i t c h e l l (1971).

Xi) Preparation of Compressed D i s k : A m e t a l punch and die

 66

(Nogami & o t h e r s 1966) shown i n F i g . 3 - 9 was employed to compress the

d i s k of ASA. I t c o n s i s t s of a d i e , 'a', upper punch, 'b', lower punch, ' c ' ,

base w i t h three nuts, 'd', r i n g w i t h a top f o r e x h a u s t i o n , 'e', adaptor

w i t h two s m a l l p l a s t i c 0 - r i n g s i n the c e n t e r h o l e , ' f ' , and two plastic

0-rings, 'g'. The 0 - r i n g s i n the c e n t e r h o l e , ' f ' , make the assembly

a i r t i g h t when 'b' i s i n s e r t e d i n t o the h o l e . The 0-rings 'g' make the

assembly a i r t i g h t between 'd' and 'e'. and 'e' and 'f' respectively.

After 'c' and 'a' were a t t a c h e d t o 'd'. 3 g. of sample was put i n 'd'

and then 'b' was inserted into ' d', as shown i n F i g . 3 - 9 , 2. Finally

the punch and d i e was assembled as i n F i g . 3 - 9 , 3, and put on a h y d r a u l i c

press*. The i n s i d e of the assembly was exhausted under reduced pressure

of about 2 mm. Hg f o r f o u r minutes. C o n t i n u i n g the e x h a u s t i o n , the powder

sample was compressed by upper punch 'b' u n t i l the compression a r r i v e d at

2

approximately 3 .' 6 ' tons per cm **. Compression was continued f o r

e i g h t minutes i n t h a t s t a t e . In o r d e r to remove the compressed d i s k ,

parts ' f , 'e', 'd' and 'c' were taken o f f from the assembly. Die 'a'

and upper punch 'b' c o n t a i n i n g the compressed d i s k were p l a c e d above

a 10 cm. m e t a l t u b i n g shown i n F i g . 3 r 9, 4, which was cut v e r t i c a l l y .

H y d r a u l i c p r e s s u r e was a p p l i e d manually and the d i s k was carefully

f o r c e d out of the d i e .

* U.S. Gauge Company.

2
** The gauge p r e s s u r e i s c a l i b r a t e d i n Kg./cm .
 1

4-

Fig. 3-9. M e t a l mold to make a compressed disk,

d i e ; b, upper punch ; c, lower punch . d, base

p l a s t i c 0-rings.
 (ii) I n t r i n s i c D i s s o l u t i o n Apparatus and Procedure - The

apparatus shown i n F i g . 3 - 1 0 was used f o r the measurement of d i s s o l u t i o n

rate. A 3 cm. diameter compressed d i s k of sample 'q' was a f f i x e d to the

s t a i n l e s s s t e e l holder of the same diameter, 'p', using n a i l polish*as

an a d h e s i v e . So t h a t o n l y the bottom f a c e of the d i s k was exposed t o the

liquid, the edges of the d i s k were covered w i t h the a d h e s i v e . The

s t a i n l e s s s t e e l h o l d e r was connected to a motor, 'm'. The holder, 'p',

with disk, 'q', was mounted above the j a c k e t e d beaker, 'n', which contained

250 ml. of 0.1 N hydrochloric acid solution. The jacketed beaker was

placed on a l a b o r a t o r y j a c k . When the temperature i n the beaker, 'n',

a r r i v e d a t an e q u i l i b r i u m temperature of 37°, the d i s k was rotated at

300 r.p.m. (checked w i t h an e l e c t r o n i c s t r o b o s c o p e ) and the beaker was

r a i s e d on the l a b o r a t o r y j a c k to immerse the d i s k to a f i x e d depth i n the

solution. Care was taken to ensure t h a t no a i r bubbles adhered t o the

disk surface.

At a p p r o p r i a t e i n t e r v a l s , 2 ml. samples we're taken from the

beaker and d i l u t e d v o l u m e t r i c a l l y to 10 or 25 ml. w i t h 0.1 N hydrochloric

acid. The a n a l y s i s was c a r r i e d out spectrophotometrically at 276 nm.

A c a l i b r a t i o n curve of c o n c e n t r a t i o n o f ASA i n 0.1 N hydrochloric acid

v e r s u s absorbance at 276 nm. ( s l i t width 0.5) was used to c a l c u l a t e the

amount of ASA dissolved ( F i g . 3 - 11). The a b s o r p t i v i t y value of ASA in

0.1 N h y d r o c h l o r i c a c i d from the s l o p e of the r e g r e s s i o n analysis

was 6.45 when c o n c e n t r a t i o n was considered as grams per liter. Dissolution

r e s u l t s were p l o t t e d as mg. ASA d i s s o l v e d ( c a l c u l a t e d using equation (16)1

* Cutex S p i l l p r u f P o l i s h .
F i g u r e 3 - 10. INTRINSIC DISSOLUTION APPARATUS.
1, t h e r m o m e t e r ; m, s t i r r e r m o t o r ; n , j a c k e t e d b e a k e r ;
o, l a b o r a t o r y j a c k ; p, sample h o l d e r ; q, compressed d i s k .
Figure 3 - 11. Standard curve f o r d e t e r m i n a t i o n of a c e t y l s a l i c y l i c acid
i n 0.1 N HC1.
 71

versus time

A x Vd x 250 i - . ,., „
Ct = — = mg. ASA d i s s o l v e d a t time t (16)
Vs x a

where A i s absorbance, Vs the volume o f sample, Vd t h e volume t o which

sample i s d i l u t e d and a i s the a b s o r p t i v i t y v a l u e . The d i s s o l u t i o n r a t e

was c a l c u l a t e d from e q u a t i o n (17)

D i s s o l u t i o n rate = s
l°P e
. ,. .
surface area of d i s k (17)

= slope -2 . -1
-j mg. cm . mm

D i s s o l u t i o n r a t e o f s i x d e t e r m i n a t i o n s f o r the ASA c o n t r o l were

-2 -1
1.13, 1.15, 1.16, 1.20, 1.20 and 1.22 mg. cm . min ; mean v a l u e , = 1.18
-2 -1

mg. cm .min . The c o n f i d e n c e l i m i t , CL, f o r t h e mean v a l u e was

c a l c u l a t e d u s i n g e q u a t i o n (18)
CL = t _ ( S E )
n 1 (18)

where t (2.571) i s the v a l u e o b t a i n e d from t a b l e s o f t - d i s t r i b u t i o n f o r

a p r o b a b i l i t y o f 0.05, n number o f d e t e r m i n a t i o n s and degrees o f freedom n-1.

_2
Standard e r r o r , SE (1.452 x 10 ) , was c a l c u l a t e d u s i n g e q u a t i o n (19)

SE = y V a r i
; n C £
(19)

_3
and v a r i a n c e (1.264 x 10 ) c a l c u l a t e d from e q u a t i o n (20)

Variance = 1X
* J
(20)
n—1

where x i s the mean v a l u e . The mean v a l u e f o r the i n t r i n s i c dissolution

r a t e o f ASA from a 3 cm. diameter compressed d i s k , r o t a t i n g a t 300 r.p.m.

i n 0.1 N HC1 a t 37° was 1.18 ± 0 . 0 3 7 mg. c m , m i n -2 - 1

( c o n f i d e n c e l i m i t = 0.95)
 b. Bulk D i s s o l u t i o n .

Excess ASA* (5-10 times the e q u i l i b r i u m s o l u b i l i t y ) was added

to 250 ml. 0.1 N HC1 i n a j a c k e t e d beaker, m a i n t a i n e d a t a c o n s t a n t

temperature (30 or 37°) and s t i r r e d r a p i d l y (300 o r 500 r.p.m.) w i t h a

3 cm.Nalgene s t i r r e r . Samples were removed a t s u i t a b l e time i n t e r v a l s ,

using a pipet f i t t e d with a f i l t e r s t i c k , d i l u t e d and a n a l y z e d spectro-

photometrically a t 276 nm. The amount of ASA d i s s o l v e d was calculated

using the method d e s c r i b e d for intrinsic d i s s o l u t i o n and p l o t t e d v e r s u s

time ( F i g . 4 - 14).

I n another experiment a m i x t u r e of commercial ASA and spherulites

(15% s p h e r u l i t e s ) was p r e p a r e d and the b u l k d i s s o l u t i o n s t u d i e d a t 37° and

300 r.p.m.

VII. E f f e c t of V a r i o u s F a c t o r s on the I n t r i n s i c D i s s o l u t i o n Rate,

a. P a r t i c l e Size.

(i) E f f e c t o f P a r t i c l e S i z e Using Unground C r y s t a l s : 100 g.

of commercial ASA was s i e v e d through s t a n d a r d mesh s i e v e s . Crystals which

passed through mesh s i z e s 25, 35 and 45, and were r e t a i n e d by mesh s i z e s

35, 45 and 60 r e s p e c t i v e l y , were compressed and t h e i r d i s s o l u t i o n rates

determined.

C r y s t a l s r e s u l t i n g from d i f f e r e n t c o n d i t i o n s of r e c r y s t a l l i z a t i o n

(i.e., solvent, temperature, and e t c . ) had d i f f e r e n t s i z e s . The d i s s o l u t i o n

rates of these c r y s t a l s were a l s o determined and compared (Table 4 - 2).

(ii) P a r t i c l e Size A f t e r Grinding: The method d e s c r i b e d i n

3-3, V I I , a ( i ) , was employed, but the c r y s t a l s were ground i n t o a f i n e

powder by means o f a p e s t l e and mortar b e f o r e compressing. Crystals which

* B.D.H., Canada, L o t s 27648, mesh s i z e 40, and 34755, mesh s i z e 40.

 73

passed through mesh, s i z e s 25,45 and 60 and were r e t a i n e d by mesh s i z e s

35, 60 and 85 r e s p e c t i v e l y , were used i n t h i s experiment.

b. Salicylic Acid.

The SA p r e s e n t i n d i f f e r e n t samples o f ASA was determined

spectrophotometrically, and the d i s s o l u t i o n r a t e was measured.

The d i s s o l u t i o n r a t e o f a p a r t i a l l y h y d r o l y s e d sample which had

been kept a t 37° i n an oven:, c o n t a i n i n g a beaker o f water f o r f i f t y hours

was a l s o determined.

c. Supersaturation.

C r y s t a l s which were grown i n t h e c r y s t a l l i z e r u s i n g d i f f e r e n t

degrees o f s u p e r s a t u r a t i o n were compressed and t h e i r d i s s o l u t i o n r a t e s

determined and compared (see 3 - 3 , II, c).

d. Habit.

ASA samples w i t h d i f f e r e n t h a b i t s were p r e p a r e d , i . e . prisms,

p l a t e s and s p h e r u l i t e s (Table 4 - 2 ) . The samples were compressed w i t h o u t

g r i n d i n g and the d i s s o l u t i o n r a t e o f t h e compressed d i s k s was measured.

e. R e c r y s t a l l i z a t i o n Solvent.

C r y s t a l s grown from d i f f e r e n t s o l v e n t s ( i . e . , absolute ethanol,

ethanol 95% and 0.1 N HC1) were c o l l e c t e d , compressed and the d i s s o l u t i o n

r a t e s o f the d i s k s were measured.

f. D i s s o l u t i o n Rate o f S p h e r u l i t e s .

S p h e r u l i t e s o f ASA which were grown from e t h a n o l 95% on s e v e r a l

20 x 20 cm. s l i d e s were s c r a p e d , compressed and the d i s s o l u t i o n r a t e

measured.
 74

g. D i s s o l u t i o n Rate of a M i x t u r e of P r i s m a t i c Crystals and

Spherulites.

A m i x t u r e c o n s i s t i n g o f 80% c r y s t a l s grown from slow

r e c r y s t a l l i z a t i o n from e t h a n o l 95% a t room temperature and 20% spherulites

was p r e p a r e d , compressed and d i s s o l u t i o n r a t e measured.

 75
4. RESULTS AND DISCUSSION.

4-1. Equilibrium Solubility of A c e t y l s a l i c y l i c Acid i n Absolute Ethanol.

Absolute e t h a n o l was used as the r e c r y s t a l l i z a t i o n solvent i n

most o f the r e c r y s t a l l i z a t i o n s , t h e r e f o r e the s o l u b i l i t y of ASA in this

s o l v e n t was required.

The r e s u l t s from the e q u i l i b r i u m s o l u b i l i t y gravimetric

determination of ASA i n absolute ethanol are shown i n F i g . 4 - 1 . During

the r e c r y s t a l l i z a t i o n experiments, c o n d i t i o n s were a t t a i n e d , at constant

temperature, where n e i t h e r growth nor d i s s o l u t i o n o c c u r r e d . The

c o n c e n t r a t i o n of ASA i n s o l u t i o n under these c o n d i t i o n s was a l s o taken

as the e q u i l i b r i u m s o l u b i l i t y (Fig. 4*1).

From the n u c l e a t i o n o b s e r v a t i o n s and the d e t e r m i n a t i o n of

c o n c e n t r a t i o n and temperature at which no crystal growth or d i s s o l u t i o n

took p l a c e , a s o l u b i l i t y - s u p e r s o l u b i l i t y diagram was constructed

(Fig. 4 - 1 ) . The m e t a s t a b l e r e g i o n l i e s between the s o l u b i l i t y and

the spontaneous n u c l e a t i o n lines.

Results obtained u s i n g the c r y s t a l l i z e r and the e q u i l i b r i u m

s o l u b i l i t y apparatus are i n agreement. Fig. 4 - 2 compares the

s o l u b i l i t y and s u p e r s o l u b i l i t y curves of ASA i n absolute ethanol found

i n t h i s work w i t h v a l u e s determined by Glasby & Ridgway (1968) u s i n g a

fluidized bed c r y s t a l l i z e r as w e l l as a s o l u b i l i t y apparatus. Results

from t h i s work are c o n s i d e r a b l y g r e a t e r than those r e p o r t e d by G l a s b y &

Ridgway.
 76

Figure 4 - 1 . S o l u b i l i t y - s u p e r s o l u b i l i t y diagram of the a c e t y l s a l i c y l i c acid-

ethanol system. O , s o l u b i l i t y determination i n c r y s t a l l i z e r ;
A s o l u b i l i t y determination i n s o l u b i l i t y apparatus;
t

<3, nucleation.
 77

F i g u r e 4 - 2. Comparison of s o l u b i l i t y - s u p e r s o l u b i l i t y of a c e t y l s a l i c y l i c

i n -absolute -ethanol., Sthis work; , Glasby &

Ridgway(1968)
 78

4-2. C r y s t a l s of A c e t y l s a l i c y l i c A c i d .

In o r d e r t o study the e f f e c t o f h a b i t , s i z e , s a l i c y l i c acid

content and the r a t e o f growth on the p h y s i c o - c h e m i c a l p r o p e r t i e s o f

ASA c r y s t a l s , a v a r i e t y o f methods o f r e c r y s t a l l i z a t i o n were employed.

These r e s u l t e d i n a s e r i e s o f c r y s t a l s w i t h d i f f e r e n t h a b i t s , s i z e s

and p e r c e n t SA. No attempt was made t o i d e n t i f y or count the type and

number o f i m p e r f e c t i o n s i n the r e s u l t i n g crystals.

A s i n g l e c r y s t a l o f ASA grown by suspending a small c r y s t a l

i n a s a t u r a t e d s o l u t i o n o f ASA i n a b s o l u t e e t h a n o l was a t e t r a g o n a l

prism ( F i g . 4 - 3, a) w i t h two each o f the f o l l o w i n g f a c e s : (100), (010)

and (001). C r y s t a l s from n-hexane were v e r y t h i n n e e d l e s (Fig. 4 - 4 )

and those from e t h a n o l 95% o b t a i n e d by slow r e c r y s t a l l i z a t i o n a t room temper-

ature ( e v a p o r a t i o n ) were sometimes hexagonal p l a t e s ( F i g . 4 - 5 and 4 - 3, c)

and sometimes t a b u l a r due t o exaggerated growth o f f a c e s (110) ( F i g . 4 - 3 , f ) .

C r y s t a l s grown i n a b s o l u t e e t h a n o l and e t h a n o l 95% u s i n g the c i r c u l a t o r y

c r y s t a l l i z e r were hexagonal prisms ( F i g . 4 - 3, b) which i n d i c a t e t h a t

plane (110) i n s t i r r e d suspended c r y s t a l s has a slower r a t e o f growth

than i n a s i n g l e suspended c r y s t a l . I n some c r y s t a l s , p l a n e (110) has a

v e r y slow r a t e o f growth so t h a t the c r y s t a l appears as a t e t r a g o n a l p r i s m

w i t h two (110), two (110), one (001) and one (OOl) f a c e s ( F i g . 4 - 3 , d ) .

C r y s t a l s from an u n s a t u r a t e d s o l u t i o n o f ASA i n 0.1 N HC1 (0.38 g./lOO ml.)

were o c t a h e d r a l pyramids, which have 8 (111) f a c e s ( F i g . 4 - 3, e ) . When

ASA was grown from a s a t u r a t e d s o l u t i o n of ASA i n 0.1 N HC1, i t appeared

as hexagonal p l a t e s ( F i g . 4 - 3, c ) .

S p h e r u l i t e s o f ASA ( F i g . 4 - 6 ) r e c r y s t a l l i z e d i n a v e r y thin

layer. M i c r o s c o p i c o b s e r v a t i o n o f t h e s p h e r u l i t e growth p r o c e s s showed t h a t

growth occurs r a d i a l l y outward from the c e n t e r .

 79
c

O p t i c a l axes o f the m o n o c l i n i c system

or \001)

(110)
(010)

(100)

(110). (100)
(110)

(010)

(111) (111)

(111) (111)

(001)

Figure 4-3. ACETYLSALICYLIC ACID CRYSTAL HABITS.

a, t e t r a g o n a l p r i s m ; b, hexagonal p r i s m ; c, hexagonal p l a t e ;
d, t e t r a g o n a l p r i s m ; e, o c t a h e d r a l pyramid; f, plate. A l l
h a b i t s belong to'-the m o n o c l i n i c system.
Fig. 4-4. N e e d l e - l i k e c r y s t a l s of a c e t y l s a l i c y l i c acid
from n-hexane (X100).

Fig. 4-5. Hexagonal p l a t e of a c e t y l s a l i c y l i c acid

from e t h a n o l 9 5 % (X 10).
 I

81.

Tawashi (1971) s t a t e d t h a t the growth of ASA i n t o two-dimensional

s p h e r u l i t e s i s an unusual phenomenon, and t h a t substances of low molecular

weight l i k e ASA do not n o r m a l l y c r y s t a l l i z e i n t h i s way. He argued t h a t

s p h e r u l i t e formation i s formed by c o n d i t i o n s of h i g h s u p e r s a t u r a t i o n and

a h i g h v i s c o s i t y of the c r y s t a l l i z a t i o n medium. These c o n d i t i o n s are

l i k e l y t o be met when a s a t u r a t e d s o l u t i o n of ASA i n e t h a n o l i s spread

as a t h i n f i l m on a g l a s s s l i d e . The a v a i l a b l e surface f o r evaporation

is l a r g e and the s o l v e n t mass t r a n s f e r r a t e becomes an important factor

in crystallization. Tawashi (1971) p o s t u l a t e d t h a t , the r e p o r t e d variation

i n thermal and d i s s o l u t i o n c h a r a c t e r i s t i c s of commercial ASA and the

s u r f a c e phase t r a n s f o r m a t i o n r e p o r t e d by G r i f f i t h s & M i t c h e l l (1971) c o u l d

be a t t r i b u t e d to the presence of ASA s p h e r u l i t e s on the s u r f a c e of commercial

ASA crystals. However, Borka (1972) p o i n t e d out that s p h e r u l i t e formation

on a c r y s t a l s u r f a c e i s u n l i k e l y s i n c e preformed c r y s t a l s dominate and

direct a d d i t i o n a l c r y s t a l growth; t h i s i s the b a s i s of a l l c r y s t a l

seedings.

In our l a b o r a t o r y s p h e r u l i t e s of p h e n a c e t i n , vanillin (Fig. 4-7),

a c e t a n i l i d and benzocainehave been grown from a b s o l u t e e t h a n o l u s i n g the

same method d e s c r i b e d f o r the growth of ASA spherulites. Hence the

e x i s t e n c e of s p h e r u l i t e s i s a normal phenomenon even f o r m o l e c u l e s w i t h

low m o l e c u l a r weight.

I. S a l i c y l i c A c i d Content. ." . - :.. *~ -

M i t c h e l l & others (1971) suggested t h a t the v a r i a t i o n i n the

d i s s o l u t i o n r a t e s of d i f f e r e n t samples of commercial ASA reported by

Mitchell & Saville (1967) may be due to d i f f e r e n c e s i n the number and type

of c r y s t a l i m p e r f e c t i o n s . The most l i k e l y i m p u r i t y to cause c r y s t a l defects

Fig. 4-6. S p h e r u l i t e s of a c e t y l s a l i c y l i c acid (X100)

Fig. 4-7. S p h e r u l i t e s of v a n i l l i n ( X 3 5 ) .
i n ASA c r y s t a l s i s the SA m o l e c u l e , which by s u b s t i t u t i n g i n the lattice

s t r u c t u r e f o r an ASA m o l e c u l e would g i v e r i s e to a p o i n t imperfection

(substitutional defect). Mulley & others (1971) demonstrated t h a t i t i s

almost i m p o s s i b l e to r e c r y s t a l l i z e ASA from even nonaqueous s o l v e n t without

producing a s m a l l amount of SA. Thomas (1971) p o i n t e d out that q u a n t i t a t i v e

s t u d i e s of a c t i v a t i o n energy of d i s s o l u t i o n at i d e a l and imperfect sites,

indicate,:; t h a t the e n e r g e t i c s of d i s s o l u t i o n are s i g n i f i c a n t l y modified

by the i m p e r f e c t i o n s . M i t c h e l l & others (1971) suggested t h a t , f u r t h e r

work to c l a r i f y the e f f e c t of c r y s t a l d e f e c t s on the d i s s o l u t i o n r a t e of

ASA is necessary.

In t h i s work, c r y s t a l s of ASA were d e l i b e r a t e l y prepared so as

to c o n t a i n SA i n d i f f e r e n t amounts (Table 4 - 2 ) . The SA content of these

c r y s t a l s a f t e r thorough washing w i t h s o l v e n t e t h e r ranged from 0.01 to

3.87%.

II. M e l t i n g P o i n t of A c e t y l s a l i c y l i c A c i d C r y s t a l s .

The term m e l t i n g p o i n t d e s c r i b e s the temperature at which the

s o l i d and l i q u i d forms of a substance are i n e q u i l i b r i u m . A pure substance

m e l t s s h a r p l y and completely over a narrow temperature range, w h i l e a

m i x t u r e or a compound c o n t a i n i n g i m p u r i t i e s m e l t s g r a d u a l l y over a wide

temperature range.

A c e t y l s a l i c y l i c a c i d has a long h i s t o r y of g i v i n g t r o u b l e i n

melting point determinations (Hayman & o t h e r s , 1925). The reported values

range from 100 (S ummers & o t h e r s , 1970) to 144 (Tawashi, 1968).. This i s

not a normal phenomenon f o r a pure monotropic substance. For more d e t a i l s

on the m e l t i n g p o i n t of ASA see 2-6.

 In t h i s work, the m e l t i n g p o i n t of ASA was determined using

b o t h h o t - s t a g e and c a p i l l a r y tube methods, under constant conditions,

i . e . , a s t a r t i n g temperature of 2° below the e s t i m a t e d m e l t i n g point

(determined i n a p r e l i m i n a r y experiment u s i n g a heating r a t e of 10°/minute)

and h e a t i n g r a t e of 0.2°/minute. As T a b l e 4 - 2 shows, c r y s t a l s with

d i f f e r e n t s i z e s , h a b i t s and SA content were examined. The melting points

of a l l the samples were between 128.1° and 132.7° ( e x c l u d i n g spherulites)

where the m e l t i n g point i s regarded as the temperature at which the

c r y s t a l s melt completely.

Tawashi's polymorphs (1968) (see 2 - 6 ) m e l t e d at 143-144°

(form I , hexagonal p l a t e s ) and 123-124° (form I I , n e e d l e - l i k e ) . No

information was given regarding the s t a r t i n g temperature and the rate

of h e a t i n g . Schwartzman (1972) r e p o r t e d m e l t i n g p o i n t s of 126-137° f o r

the p l a t e s (Tawashi's form I) and 127-133° f o r the n e e d l e - l i k e c r y s t a l s

(Tawashi's form I I ) u s i n g h o t - s t a g e a p p a r a t u s . H i s r e p o r t was also

w i t h o u t any information about the s t a r t i n g temperature and the r a t e of

heating. In our work hexagonal p l a t e s from 95% ethanol (Fig. 4-5)

(Tawashi's form I) and n e e d l e - l i k e c r y s t a l s from n-hexane ( F i g . 4-4)

(Tawashi's form I I ) m e l t e d at 130.3° and 130.1° r e s p e c t i v e l y under the

experimental conditions described above. Even though the m e l t i n g points

of t h e s e two d i f f e r e n t c r y s t a l s were q u i t e c l o s e , the n e e d l e - l i k e c r y s t a l s

m e l t e d over a v e r y broad range (123.9 - 130.1°) when h e a t i n g was s t a r t e d at

121°, w h i l e the p l a t e s were observed to m e l t over the range 128.8 - 130.9°

under the same c o n d i t i o n s .

Borka (1972) showed t h a t , the m e l t i n g p o i n t o f ASA depends on the

r a t e of h e a t i n g and the s t a r t i n g temperature. He constructed a phase

diagram f o r the b i n a r y system of ASA and SA which showed t h a t approximately

17 or 72% of SA i s r e q u i r e d to y i e l d a m e l t i n g p o i n t of 123-125° which i s

the m e l t i n g p o i n t of Tawashi's form I I . S i n c e the SA content of the

form I I i s i n s u f f i c i e n t to depress the m e l t i n g p o i n t to 124°, Borka argued

t h a t the d e p r e s s i o n of the m e l t i n g p o i n t i s not due to the presence of SA

i m p u r i t i e s but i s evidence f o r the e x i s t e n c e of p o l y m o r p h i c form I I .

However, Borka was dealing with e u t e c t i c mixture. Mulley & others (1971),

however, had suggested p r e v i o u s l y t h a t , i n a d d i t i o n to the e f f e c t s of

separate c r y s t a l s of SA, v a r i a t i o n i n the amount, l o c a t i o n and bonding of

SA w i t h i n the ASA c r y s t a l c o u l d i n f l u e n c e the m e l t i n g p o i n t . P f i e f f e r (1971)

p o i n t e d out t h a t d i f f e r e n c e s i n s i z e and h a b i t might a f f e c t the determination

of m e l t i n g p o i n t and heat of f u s i o n through d i f f e r e n c e s i n r a t e s of

s u b l i m a t i o n and decomposition.

In t h i s work, when h e a t i n g was s t a r t e d at a low temperature,

e.g., 100°, o b s e r v a t i o n under the h o t - s t a g e apparatus showed t h a t v e r y

s m a l l unaggregated p a r t i c l e s s t a r t to m e l t at a temperature between 103°

and 112°. T h i s process o c c u r r e d at a v e r y slow r a t e and was f o l l o w e d by a

f a s t and sharp m e l t i n g at a temperature between 128° and 132°, which

corresponds to t h a t o b t a i n e d u s i n g the c a p i l l a r y tube method. It i s

suggested that s m a l l p a r t i c l e s of ASA c r y s t a l s are more s u s c e p t i b l e to decomp-

o s i t i o n d u r i n g the h e a t i n g process than the l a r g e r p a r t i c l e s and form a

mixture of ASA and SA which m e l t s over the temperature range of 103 - 128°.

In o r d e r to c o n f i r m t h i s h y p o t h e s i s , the t r u e m e l t i n g range of three

d i f f e r e n t samples of ASA was measured ( s t a r t i n g temperature 100° and

h e a t i n g r a t e of 2°/min.) T h i s range was c o n s i d e r e d t o be the range i n

which c r y s t a l s melt s h a r p l y and completely. The SA content was measured

at the lower l i m i t of the m e l t i n g range and i n the melt.

As shown i n Table 4 - 1 , the SA content of n e e d l e s and s p h e r u l i t e s

 86

Table 4 - 1 . S a l i c y l i c acid content o f d i f f e r e n t samples o f

acetylsalicylic a c i d c r y s t a l s d u r i n g the m e l t i n g process.

Approximate % Initial % s a l i c y l i c a c i d formed

Sample
m e l t i n g range* .
s i z e range salicylic ° i n t h e h e a t i n g p e r i o d W/W
I 1 / T T

° —
(/O acid W/W c

lower l i m i t upper limit

Commercial 800-1000 0.10 130.1-131.2 2.50 8.80

Needle-like 100-500 0.92 125.2-130.1 4.80 11.40

Spherulites 0.10 127.7-130.7 5.12 12/90

* The range i n which c r y s t a l s m e l t s h a r p l y and c o m p l e t e l y . The t r u e

m e l t i n g p o i n t i s the p o i n t a t which a l l the c r y s t a l s melt completely

(upper l i m i t o f the m e l t i n g range).

of ASA was c o n s i d e r a b l y h i g h e r than t h a t of commercial ASA. These t h r e e

samples of ASA were chosen i n t h i s experiment s i n c e they are d i f f e r e n t i n

the h a b i t and size. C r y s t a l s of commercial ASA were prisms which were

fairly u n i f o r m i n a l l of t h e i r dimensions (800 - 1000^1) w h i l e the needle-

like c r y s t a l s were v e r y t h i n i n one dimension (5 - 8 ) and v e r y long i n

the o t h e r (100 - 500^*); s p h e r u l i t e s were i n a v e r y t h i n c r y s t a l l i n e layer.

T h i s experiment r e v e a l e d t h a t the m e l t i n g range pf ASA depends indirectly

on the s i z e and h a b i t of the sample through the d i f f e r e n c e i n s u s c e p t i b i l i t y

to decomposition. Although the lower l i m i t s of the m e l t i n g ranges are

v a r i a b l e from one sample t o another, the h i g h e r l i m i t s are i n good

agreement; t h e r e f o r e i t i s recommended t h a t , i n the m e l t i n g p o i n t study

of ASA, the temperature at which a l l c r y s t a l s melt completely be considered

as the t r u e m e l t i n g p o i n t .

The m e l t i n g of s m a l l p a r t i c l e s o f ASA at temperatures between

103 - 128° cannot be d e t e c t e d by means of the M e t i e r FP1 C a p i l l a r y - t u b e

apparatus. The capillary tubes are scanned by a l i g h t source which i s

s e n s i t i v e to changes i n the l i g h t t r a n s p a r e n c y of the samples which occurs

d u r i n g the m e l t i n g p r o c e s s . Apparently the amount of sample melted and/or

becoming t r a n s p a r e n t at low temperatures does not permit the passage of

sufficient light t o operate the automatic i n d i c a t o r and indicate the

melting point. However, the m e l t i n g range o f 128.1 - 132.7° was always

fairly constant. T h i s range i s i n agreement w i t h t h a t o f 130.9° r e p o r t e d

by Borka (1972) u s i n g a M e t i e r FP1 and starting temperature of 130° and

a h e a t i n g r a t e of 0.2°/minute.

Tawashi (1971) showed t h a t ASA s p h e r u l i t e s underwent a t r a n s -

f o r m a t i o n to n e e d l e - l i k e c r y s t a l s a t 124° and melted a t 125° (see 2 - 6 ) .

Borka (1972) however was not a b l e t o reproduce this.

 In t h i s work, the m e l t i n g p o i n t of s p h e r u l i t e s was not always

constant and v a r i e d from b a t c h t o b a t c h . They melted between 126.5 & 131.4°

and underwent a thermal t r a n s f o r m a t i o n to p r i s m a t i c c r y s t a l s ( F i g . 4 - 8) at

a temperature between 104° to 128° r a t h e r than 124° reported by Tawashi (.1970)

As described before (see 4 - 4 ) the X-ray p a t t e r n o f the s p h e r u l i t e s ,

t r a n s f o r m e d s p h e r u l i t e s and the ASA c o n t r o l were i d e n t i c a l . Therefore the

thermal t r a n s f o r m a t i o n phenomenon i s not a p o l y m o r p h i c phase transformation

and can be explained i n terms of c r y s t a l growth or c r y s t a l ripening.

S p h e r u l i t e s are an u n s t a b l e form of c r y s t a l which grow from a t h i n f i l m of

solution. Tawashi (1971) c o n s i d e r e d them to be a mesomorphic phase.

Buckley (1951) d e s c r i b e d s p h e r u l i t e s as c r y s t a l l i n e i n the sense t h a t , at

c e r t a i n p l a c e s , e s p e c i a l l y the e x t r e m i t i e s , they are u s u a l l y bounded by

plane faces. So f a r as t h e i r p h y s i c a l p r o p e r t i e s can be ascertained, each

s m a l l p o r t i o n i s s i m i l a r to a c r y s t a l , and they i n v a r i a b l y g i v e X-ray

d i f f r a c t i o n patterns. They a r e , i n f a c t , c r y s t a l s which have run r i o t under

the p e c u l i a r c o n d i t i o n of growth. S h a f t a l (1968) demonstrated t h a t the

s i n g l e c r y s t a l d i f f r a c t i o n p a t t e r n g i v e n by the t h i n n e s t and smallest c r y s t a l s

show t h a t a s p h e r u l i t e a r i s e s from f o l d i n g i n a s i n g l e - c r y s t a l p l a t e l e t .

Pfeiffer (1971) p o i n t e d out t h a t exposure to h e a t , u l t r a s o u n d , solvent, etc.,

could cause c r y s t a l s to a n n e a l , grow or r i p e n ; they would thus mimic p o l y -

morphic b e h a v i o u r by r e v e r t i n g to a "more s t a b l e " form but would not undergo

changes i n t h e i r r o u t i n e l y determined X-ray d i f f r a c t i o n p r o p e r t i e s . Therefore

it i s suggested t h a t , thermal t r a n s f o r m a t i o n of ASA s p h e r u l i t e s to prismatic

c r y s t a l s i s a growth p r o c e s s which o c c u r s when some of the thinner portions

of a s p h e r u l i t e m e l t , and the melt flows towards the n e i g h b o r i n g portions of

the s p h e r u l i t e where i t r e c r y s t a l l i z e s to b u i l d the p r i s m a t i c c r y s t a l s of

ASA.
III. Solution-Phase Transformation of A c e t y l s a l i c y l i c A c i d C r y s t a l s .

An easy way t o determine which of two forms of a compound i s

s t a b l e at a g i v e n temperature i s to observe the r e l a t i o n s o l u b i l i t y of

the two i n a solvent. T h i s i s best and most r a p i d l y done by observing

c r y s t a l s of both t o g e t h e r i n a drop of s a t u r a t e d s o l u t i o n under the

microscope. The l e s s s o l u b l e form w i l l grow and the more s o l u b l e w i l l

dissolve. T h i s i s c a l l e d a s o l u t i o n phase transformation.

Borka (1972) a p p l i e d a method s i m i l a r to t h a t mentioned t o

d e t e c t the s o l u t i o n phase t r a n s f o r m a t i o n of the ASA s p h e r u l i t e s (see 2 - 6 ) .

He allowed a drop of s a t u r a t e d s o l u t i o n of ASA i n isoamyl a l c o h o l to flow

under a cover s l i p p l a c e d over s p h e r u l i t e s of ASA grown on a m i c r o s c o p e

slide. S p h e r u l i t e s changed to p r i s m a t i c c r y s t a l s o f ASA. He d i d not

mention the time r e q u i r e d f o r t h i s change to take p l a c e . He suggested

t h a t t h i s was s t r o n g evidence f o r the e x i s t e n c e of the form I I polymorph

of ASA d e s c r i b e d by Tawashi (1968). T h i s experiment was repeated i n this

work and the same phenomenon was observed.(Fig. 4-9). However, no

d i f f e r e n c e s were noted i n the X-ray d i f f r a c t i o n p a t t e r n s of the s p h e r u l i t e s

and n e e d l e - l i k e p r i s m s . Hence t h i s phenomenon cannot be due to a polymorphic

phase t r a n s f o r m a t i o n . The s p h e r u l i t e s changed i n t o the prisms a f t e r two to

f i v e minutes. In t h i s p e r i o d of time, e v a p o r a t i o n takes p l a c e . Hence the

c o n c e n t r a t i o n of the s a t u r a t e d s o l u t i o n i n c r e a s e s and the s o l u t i o n becomes

supersaturated. I t i s suggested t h a t under these c o n d i t i o n s the small

c r y s t a l l i n e p o r t i o n s of a s p h e r u l i t e w i l l a c t as seeds and normal c r y s t a l s

w i t h w e l l d e f i n e d f a c e s are b u i l t up. Therefore, the s o l u t i o n phase t r a n s -

formation d e s c r i b e d by Borka (1972), l i k e thermal t r a n s f o r m a t i o n , is a

growth process r a t h e r than a r e v e r s i o n from a m e t a s t a b l e to a s t a b l e

polymorphic form.
 90

F i g . 4-9. Solution transformed c r y s t a l s from s p h e r u l i t e s (X100).

IV. X-Ray D i f f r a c t i o n o f A c e t y l s a l i c y l i c A c i d Crystals.

The most c o n c l u s i v e p r o o f of polymorphism i s a difference i n

the X-ray d i f f r a c t i o n p a t t e r n of the v a r i o u s forms. Each crystalline

form has i t s own c h a r a c t e r i s t i c X-ray d i f f r a c t i o n pattern.

The X-ray d i f f r a c t i o n p a t t e r n o f the ASA c o n t r o l shown i n

F i g . 4 - 10, agrees w i t h t h a t r e p o r t e d by Wheatley (1964). I t shows s i x

sharp and many s m a l l e r peaks which are l o c a t e d between 7.8° and 44° 2$.

Hence ASA c o n t r o l belongs t o the m o n o c l i n i c system w i t h the same c r y s t a l

s t r u c t u r e as d e s c r i b e d by Wheatley.

D i f f r a c t o g r a m s were prepared from c r y s t a l s and the compressed

d i s k of a l l the samples shown i n T a b l e 4 - 2 ( i n the case of o c t a h e d r a l

pyramids and t r a n s f o r m e d s p h e r u l i t e s o n l y powder was examined) and also

samples of ground ASA control with higher d i s s o l u t i o n rate £ see 4 - 3 III,

a, ( i i ) j and compared w i t h t h a t o f the ASA control. A l l the p a t t e r n s

were i d e n t i c a l .

The absence of d i s t i n c t d i f f e r e n c e s i n the X-ray diffractograms

i s c l e a r e v i d e n c e t h a t ASA does not e x i s t i n polymorphic forms. In

p a r t i c u l a r , the s u g g e s t i o n of Borka (1972) t h a t s p h e r u l i t e s correspond

to the form I I polymorph d e s c r i b e d by Tawashi (1968) cannot be s u p p o r t e d .

F i g u r e 4 - 10. X-ray d i f f r a c t i o n p a t t e r n of a c e t y l s a l i c y l i c acid.
Table 4 - 2 . RECRYSTALLIZATION CONDITIONS AND PROPERTIES OF ACETYLSALICYLIC ACID CRYSTALS.

Crystals Approximate* Salicylic M e l t i n g Point° D i s s o l u t i o n Rate

s i z e range0/0 acid % Hot-stage C a p i l l a r y mg.i cnr^min -'-.
-

800 - 1000 0.10 130.0 130.7 1.18

Hexagonal prisms from e t h a n o l (Ac 1.1% w/w
at 24.8 ) ; c i r c u l a t o r y c r y s t a l l i z e r 200 — 300 0.14 130.2 130.8 1.17
Hexagonal prisms from e t h a n o l (Ac 2.5% w/w
at 23.5 ) ; c i r c u l a t o r y c r y s t a l l i z e r 200 _ 300 0.14 130.4 129.9 1.19
Hexagonal prisms from e t h a n o l (fast
150 _ 200 0.01 132.7 132.7 1.19
Hexagonal prisms from e t h a n o l (slow
300 _ 400 0.10 132.0 131.8 1.18
Hexagonal prisms from 95% e t h a n o l . . 300 - 400 0.12 131.8 131.8 1.18
N e e d l e - l i k e c r y s t a l s from n-hexane 100 - 500 0.92 130.1 - 11.21
Hexagonal p l a t e s from 95% e t h a n o l (slow r e -
c r y s t a l l i z a t i o n at room temperature) 1000 _ 2000 1.40 130.3 131.2 1.19
Microcrystalline hexagonal p l a t e s from glycerin 80 - 100 3.87 129.1 - 1.21
Hexagonal p l a t e s r e c r y s t a l l i z e d at 3° from
s a t u r a t e d s o l u t i o n i n 0.1 N'HC1 1300 _ 1600 1.20 131.7 131.1 1.19
O c t a h e d r a l pyramids r e c r y s t a l l i z e d at 3° from
a s o l u t i o n o f 0.38 g./lOO ml. of 0.1 N HC1 800 _ 2500 128.1
0.83 128.3
Spherulites from 95% e t h a n o l 20 - 40 0.10 126.5-131.4 126.5-130.8 1.18
Prisms from s p h e r u l i t e s (saturated
s o l u t i o n added) . . . . 5 _ 50 0.12 128.1 130.8 _

Prisms from s p h e r u l i t e s (after heating) .. 5 - 50 12.50 126.5-131.4 129.8 -

* The l o n g e s t c r y s t a l a x i s .

** A c = (Ct - Co) w h e n & c i s a measure o f the degree o f s u p e r s a t u r a t i o n , Ct i s t h e % a c e t y l s a l i c y l i c a c i d i n

s o l u t i o n and Co i s the e q u i l i b r i u m s o l u b i l i t y of a c e t y l s a l i c y l i c a c i d a t the same temperature. ^,
CO
4-3. D i s s o l u t i o n of A c e t y l s a l i c y l i c A c i d .

I. Intrinsic Dissolution Rate.

A t y p i c a l c o n c e n t r a t i o n - t i m e curve f o r the d i s s o l u t i o n of ASA

up t o 74% of the s o l u b i l i t y o f ASA i n 0.1 N HC1 i s shown i n F i g . 4-11.

The d i s s o l u t i o n curve was used t o c o n s t r u c t a f i n i t e d i f f e r e n c e s diagram

(Fig. 4 - 12), from which the s a t u r a t e d c o n c e n t r a t i o n , Co, was estimated

as d e s c r i b e d by Nog ami & o t h e r s (1966). The equilibrium s o l u b i l i t y , Co,

determined from the b u l k d i s s o l u t i o n experiment was 5.7 mg./ml. w h i l e Co

e s t i m a t e d k i n e t i c a l l y from the f i n i t e d i f f e r e n c e s diagram was 5.5 mg./ml.'

The v a l u e s c a l c u l a t e d by G r i f f i t h s & M i t c h e l l (1971) were 5.7 and 5.8 mg./ml.

for the b u l k d i s s o l u t i o n and f i n i t e d i f f e r e n c e s methods r e s p e c t i v e l y .

Fig. 4-13 shows a c o n c e n t r a t i o n - t i m e curve f o r the dissolution

of ASA c o n t r o l over the i n i t i a l time p e r i o d a t 37° and 300 r.p.m. i n

0.1 N HC1 solution. The r a t e c o n s t a n t s f o r the t r a n s p o r t c o n t r o l l e d process,

kt and the o v e r a l l d i s s o l u t i o n r a t e c o n s t a n t , FCj., were c a l c u l a t e d u s i n g

equation (21) which i s developed from the Noyes-Nenst equation

|f = k t (Co-Ct) = | K t (Co-Ct) = | | (Co-Ct) (21)

where V i s the volume of the s o l u t i o n and the o t h e r terms have been d e f i n e d

in equation (2) (see 2 - 5 , II). C t , the c o n c e n t r a t i o n a t time t , can be

n e g l e c t e d over the s h o r t time i n t e r v a l of the experiment. The r a t e constant

for the t r a n s p o r t c o n t r o l l e d p r o c e s s c a l c u l a t e d from e q u a t i o n (10)

f = k
t C o
< >
10

was 1.50 x 10 2
min "'" a t 37° and 300 r.p.m. u s i n g the e q u i l i b r i u m solubility

o b t a i n e d from the b u l k d i s s o l u t i o n experiment (5.7 mg./ml.). The overall

d i s s o l u t i o n r a t e c o n s t a n t c a l c u l a t e d from e q u a t i o n (22)

= (22)

was 2.12x10-3 c m m i n - l _ '

 1.25

Time (min.)

Figure 4 - 11. R o t a t i n g d i s k d i s s o l u t i o n of a c e t y l s a l i c y l i c a c i d i n 0.1 N HC1

at 37 and 300 r.p.m.
 96

tod

Csl
U

C 1 (mg./ml.)

Figure 4 - 1 2 . F i n i t e d i f f e r e n c e s diagram f o r the d i s s o l u t i o n o f a c e t y l -

s a l i c y l i c a c i d i n 0.1 N HC1 at 37° and 300 r.p.m.
C-p c o n c e n t r a t i o n a t time t-^; C^, c o n c e n t r a t i o n a t time
t£ = t^+ 10 mins.; -0-, C2 VS. C-^ and, , C-^ = C2.
 250h

0 5 10 15 20 25

Time (min.)

F i g u r e 4 - 13. I n i t i a l dissolution curve o f a c e t y l s a l i c y l i c acid

i n 0.1 N.HC1. a t 37° and 300 r.p.m.
 II. Bulk Dissolution.

The c o n c e n t r a t i o n of ASA i n the b u l k i n c r e a s e d r a p i d l y and

reached the equilibrium s o l u b i l i t y as shown i n F i g . 4-14.

Griffiths & Mitchell (1971) r e p o r t e d an i n i t i a l peak b e f o r e

the equilibrium s o l u b i l i t y was reached. I t was suggested t h a t , this

was due to an abrupt t r a n s f e r of s o l u t e from the large s u r f a c e a r e a of

a more s t a b l e form. The b u l k l i q u i d became s u p e r s a t u r a t e d w i t h

r e s p e c t to the more s t a b l e form which c r y s t a l l i z e d out on the surface

of the solid.

In t h i s work no initial peak was observed d u r i n g the bulk

dissolution experiment.

In o r d e r to study the possible e f f e c t of the presence of

spherulites on-the d i s s o l u t i o n b e h a v i o u r of ASA crystals (see 4-2)

a m i x t u r e of s p h e r u l i t e s and ASA crystals (the same ASA as i n the

above experiment) was prepared and the b u l k d i s s o l u t i o n was studied.

A g a i n no initial peak was observed.

III. E f f e c t of V a r i o u s F a c t o r s on D i s s o l u t i o n Rate of

Acetylsalicylic Acid,

a. Particle Size.

(i) E f f e c t of P a r t i c l e S i z e U s i n g Unground C r y s t a l s : No

significant differences i n d i s s o l u t i o n r a t e were found u s i n g commercial

ASA* s i e v e d into different p a r t i c l e sizes (Table 4 - 3 ) nor when u s i n g

c r y s t a l s which were grown i n d i f f e r e n t s i z e s (Table r;4 - 2 ) . Hence the

r e s u l t s o b t a i n e d u s i n g the rotating d i s k method c o n f i r m the previous

findings of M i t c h e l l & o t h e r (1971) t h a t , the dissolution rate is

independent of p a r t i c l e s i z e .

* B.D.H., Canada, Lot 27648

F i g u r e 4 - 14. Bulk d i s s o l u t i o n o f a c e t y l s a l i c y l i c a c i d i n 0.1 N. HC1.
O.at 37° and 500 r.p.m.; A,at 37° and 300 r.p.m.;
O, a t 30 and 300 r.p.m.
 100

(ii) P a r t i c l e Size After Grinding: Disks prepared after

grinding and s i e v i n g ASA* i n t o v a r i o u s s i z e ranges showed no differences

i n dissolution rate. The d i s s o l u t i o n r a t e was i n agreement w i t h that of

the ASA control (Table 4 - 3).

Some powder of ASA which was ground by means of a p e s t l e and

mortar showed a remarkable r a i s e on d i s s o l u t i o n r a t e of ASA (DR = 1.55 mg.

-2 -1

cm min ). Despite four reproducible determinations, further attempts to

c o n f i r m t h i s u n u s u a l b e h a v i o u r were u n s u c c e s s f u l .

T h e r e f o r e , p a r t i c l e s i z e and grinding do not a f f e c t the intrinsic

d i s s o l u t i o n of ASA. T h i s i s important s i n c e P f e i f f e r (1971) suggested

differences i n s i z e might a f f e c t the dissolution rate from a compressed

disk through d i f f e r e n c e s in capillarity or w e t t i n g , and Summers & o t h e r s

(1970) r e p o r t e d a t r a n s f o r m a t i o n of form I I I to form I I i n the process

of grinding.

b. Salicylic Acid.

S i n c e the SA content of ASA c r y s t a l s a f f e c t s the m e l t i n g point

of t h i s compound s i g n i f i c a n t l y (Mulley & o t h e r s , 1971; Borka, 1972) it

seemed n e c e s s a r y t o study the e f f e c t of the SA content on the intrinsic

d i s s o l u t i o n r a t e of ASA.

I m p u r i t i e s l i k e SA may be i n c o r p o r a t e d i n t o the crystal lattice

as a s u b s t i t u t i o n a l d e f e c t or as a s o l i d s o l u t i o n leading to d i s t o r t i o n of

the h o s t l a t t i c e (Khamskii, 1969). The most l i k e l y i m p u r i t y i n the case

of ASA i s SA which may be adsorbed onto the i n t e r n a l and external surface of

the ASA c r y s t a l s or be p r e s e n t as s e p a r a t e c r y s t a l s . The SA content of the

ASA c r y s t a l s produced i n t h i s work, a f t e r thorough washing w i t h s o l v e n t ether

ranged from 0.01 t o 3.87% but as shown i n T a b l e 4 - 2 was without any

e f f e c t on the i n t r i n s i c d i s s o l u t i o n rate of ASA.

* B.D.H., Canada, Lot 27648.

Table 4 - 3 . I n t r i n s i c d i s s o l u t i o n rate of a c e t y l s a l i c y l i c acid

w i t h d i f f e r e n t p a r t i c l e s i z e a t 37° and 300 r.p.m.

-2 -1
Mesh S i z e D i s s o l u t i o n Rate (mg.cm .min )
(see 3 - 3 , V I I , a ( i ) ) ground unground

25 1.19 1.18

35 - 1.18

45 1.20 1.17

60 1.18
 102

c. Supersaturation.

M i t c h e l l & others (1971) s p e c u l a t e d t h a t the anomalous

behavior of ASA may result from d i f f e r e n c e s i n the number and type of

c r y s t a l imperfections. C r y s t a l imperfections are p r e s e n t in a l l crystals

and are thermodynamically u n s t a b l e . Thomas (1970) has emphasized the

important, often crucial, r o l e played by d i s l o c a t i o n s i n the reactivity

of c r y s t a l l i n e s o l i d s i n c l u d i n g such p r o p e r t i e s as c r y s t a l growth and

dissolution. V a r i a t i o n i n the c o n d i t i o n s of c r y s t a l growth w i l l affect

the type and number of d e f e c t s i n a crystal.

G l a s b y & Ridgway (1968) have shown, under the c o n d i t i o n of their

experiment, t h a t i n c o r p o r a t i o n of m o l e c u l e s i n t o the c r y s t a l l a t t i c e i s

the r a t e l i m i t i n g step i n the growth of ASA i n a f l a i d i z e d bed crystallizer.

When i n c o r p o r a t i o n i s r a p i d i t i s r e a s o n a b l e to expect t h a t a l a r g e number

o f i m p e r f e c t i o n s w i l l be b u i l t into a crystal. By growing c r y s t a l s under

different c o n d i t i o n s of temperature and degree of s a t u r a t i o n , i t i s

p o s s i b l e to e v a l u a t e the e f f e c t s of growth r a t e , and hence i n d i r e c t l y

v a r i a t i o n i n the number of i m p e r f e c t i o n s , on the i n t r i n s i c d i s s o l u t i o n

and other properties.

As mentioned i n the e x p e r i m e n t a l p a r t of t h i s work, ASA was

r e c r y s t a l l i z e d under a v a r i e t y of c o n d i t i o n s . Two b a t c h e s of c r y s t a l s were

grown i n the c i r c u l a t o r y c r y s t a l l i z e r at d i f f e r e n t growth r a t e s by varying

the temperature and degree of s u p e r s a t u r a t i o n under c o n t r o l l e d c o n d i t i o n s

(4C 1.1% w/w at 24.8° a n d & C 2.5% w/w at 23.5°). A l s o c r y s t a l s were

grown from s a t u r a t e d s o l u t i o n s of ASA i n d i f f e r e n t solvents and

different temperatures. Growth rates/were c o n t r o l l e d i n an approximate

manner by changing the r a t e of c o o l i n g .

The n u c l e a t i o n p o i n t s o f ASA i n absolute ethanol at a g i v e n

 103

concentration l i e a p p r o x i m a t e l y 3.5° below t h e e q u i l i b r i u m solubility

( F i g . 4 - 1 ) . The m e t a s t a b l e r e g i o n i s therefore v e r y narrow and c r y s t a l

growth under c o n d i t i o n s i n which t h e r e was p r e c i s e c o n t r o l o f the degree

of supersaturation was d i f f i c u l t to achieve. N e v e r t h e l e s s , no s i g n i f i c a n t

d i f f e r e n c e s were noted i n the d i s s o l u t i o n r a t e s o f c r y s t a l s grown i n

absolute ethanol under c o n t r o l l e d c o n d i t i o n s o f temperature and super-

s a t u r a t i o n arid ASA r e c r y s t a l l i z e d from o t h e r s o l u t i o n s under a v a r i e t y o f

conditions. Although no attempt was made t o measure t h e a c t u a l growth

r a t e s o r count the number o f i m p e r f e c t i o n s , i t i s apparent t h a t differences

i n growth r a t e a r e w i t h o u t e f f e c t on subsequent d i s s o l u t i o n r a t e s .

d. Habit.

The d i s s o l u t i o n r a t e o f ASA w i t h d i f f e r e n t h a b i t s , i . e . t e t r a -

g o n a l p r i s m s , hexagonal prisms and hexagonal p l a t e s ( F i g . 4 - 3 ) were

examined (Table 4-2). C r y s t a l s were compressed w i t h o u t g r i n d i n g and

the i n t r i n s i c d i s s o l u t i o n r a t e s were determined. No s i g n i f i c a n t d i f f e r e n c e s

were noted. This'.is important s i n c e Wood ( p e r s o n a l communication through

M i t c h e l l & others, 1971) p o i n t e d out t h a t f a i l u r e to a c h i e v e a r e q u i s i t e

degree o f s i z e r e d u c t i o n may be r e s p o n s i b l e f o r the v a r i a t i o n i n

d i s s o l u t i o n r a t e s o f compressed d i s k s p r e p a r e d from c r y s t a l s o f d i f f e r e n t

habit.

e. R e c r y s t a l l i z a t i o n Solvent.

A c e t y l s a l i c y l i c a c i d grown from d i f f e r e n t s o l v e n t s , i.e. absolute

ethanol, ethanol 95%, g l y c e r i n and 0.1 HC1, were compressed and the

d i s s o l u t i o n r a t e determined (Table 4 - 2). Again no s i g n i f i c a n t

d i f f e r e n c e s were n o t e d .
 104

Schwartzman (1972) found e t h a n o l i n the ASA recrystallized

from t h i s s o l v e n t . I t was not e s t a b l i s h e d whether the e t h a n o l was present

on the s u r f a c e of the c r y s t a l s , was trapped i n t e r s t i t i a l l y or was due to

hydrogen bonding. I t i s concluded t h a t the e x i s t e n c e of e t h a n o l in

c r y s t a l s of ASA does not a f f e c t the d i s s o l u t i o n r a t e .

f. D i s s o l u t i o n Rate of S p h e r u l i t e s and a Mixture of

S p h e r u l i t e s and Prismatic Crystals.

Tawashi (1971) p o s t u l a t e d t h a t , the r e p o r t e d variation in

thermal and d i s s o l u t i o n b e h a v i o r o f ASA c o u l d be due to the p r e s e n c e of

s p h e r u l i t es on the s u r f a c e of commercial ASA crystals. Borka (1972)

showed t h a t , s p h e r u l i t e s cannot grow on the s u r f a c e of c r y s t a l s . He

pointed out t h a t , preformed c r y s t a l s dominate and direct additional crystal

growth. T h i s i s the b a s i s of a l l c r y s t a l s e e d i n g . In t h i s work,

s p h e r u l i t e s were added d e l i b e r a t e l y to p r i s m a t i c , c r y s t a l s (see 3 - 3 , VII, g)

but no s i g n i f i c a n t d i f f e r e n c e s were noted i n the subsequent d i s s o l u t i o n

- 2 - 1 - 2 - 1
r a t e s of the m i x t u r e (1.19 mg. cm min ) , s p h e r u l i t e s (1.18 mg. cm min )

and the ASA control.

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5. Summary and Conclusions.

I. A c e t y l s a l i c y l i c a c i d r e c r y s t a l l i z e s i n d i f f e r e n t habits

a l l of which belong t o the m o n o c l i n i c system.

I I . S p h e r u l i t e s of ASA e x h i b i t the same X-ray diffraction

p a t t e r n s as o t h e r forms of ASA.

I I I . The e x i s t e n c e of s p h e r u l i t e s i s not an unusual phenomenon.

S p h e r u l i t e s of o t h e r low m o l e c u l a r weight o r g a n i c compounds, i . e . , phen-

a c e t i n , acetanilidv. , v a n i l l i n and benzocaine, were grown i n t h i s work.

IV. D i f f e r e n t methods of r e c r y s t a l l i z a t i o n g i v e ASA crystals

w i t h d i f f e r e n t amounts of SA.

V. The m e l t i n g p o i n t of ASA depends on the experimental

conditions. A c e t y l s a l i c y l i c a c i d m e l t s between 128.3 and 132.7°

( e x c l u d i n g s p h e r u l i t e s ) u s i n g a s t a r t i n g temperature 2° below the

e s t i m a t e d m e l t i n g p o i n t and a h e a t i n g r a t e of 0.2°/min.

V I . Very s m a l l unaggregated p a r t i c l e s of ASA start t o melt

at a temperature between 103 and 112° a t a v e r y slow r a t e . Melting

c o n t i n u e s w i t h i n c r e a s e d temperature up t o 128° when f a s t and sharp

m e l t i n g of a l l the remaining c r y s t a l s occurs between 128 and 132°.

T h i s range i s always f a i r l y constant. The s u s c e p t i b i l i t y of ASA towards

thermal decomposition becomes g r e a t e r w i t h decrease in particle size

and the d e p r e s s i o n of the m e l t i n g p o i n t of i n d i v i d u a l c r y s t a l s i s r e l a t e d

to the amount of SA formed.

V I I . S p h e r u l i t e s of ASA melt between 126.5 and 131.4° and

produce more SA i n the p r o c e s s of m e l t i n g than the o r i g i n a l commercial

ASA.

VIII.The thermal and s o l u t i o n t r a n s f o r m a t i o n observed with

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s p h e r u l i t e s a r e p r o c e s s e s o f c r y s t a l growth.

IX. No s u r f a c e transformation was noted d u r i n g the b u l k

d i s s o l u t i o n process.

X. The i n t r i n s i c d i s s o l u t i o n r a t e o f r e c r y s t a l l i z e d ASA i s

independent o f the c o n d i t i o n s o f r e c r y s t a l l i z a t i o n , the SA c o n t e n t ,

at l e a s t up t o 3.87%, h a b i t and s i z e o f the c r y s t a l s .

XI. No s i g n i f i c a n t d i f f e r e n c e s were found i n the i n t r i n s i c

d i s s o l u t i o n r a t e of any commercial or r e c r y s t a l l i z e d ASA.

XII. The low i n t r i n s i c d i s s o l u t i o n r a t e o f a f r e e flow-granular

ASA reported by M i t c h e l l & S a v i l l e (1967) was confirmed u s i n g the same

sample. Other p r o p e r t i e s o f t h i s sample were i d e n t i c a l . It i s

suggested t h a t the low d i s s o l u t i o n r a t e may be due t o the e f f e c t o f

g r a n u l a t i n g agents used i n the m a n u f a c t u r i n g p r o c e s s .

XIII. I t i s suggested t h a t , t h e observed d i f f e r e n c e between the

two forms o f ASA r e p o r t e d by Tawashi (1968) i s s i m p l y the r e s u l t o f an

attempt t o compare t h e d i s s o l u t i o n r a t e s from d i f f e r e n t f a c e s .

XIV. The d i f f e r e n c e s i n g a s t r o - i n t e s t i n a l a b s o r p t i o n of d i f f e r e n t

c r y s t a l l i n e forms when g i v e n t o human s u b j e c t s as a d i s p e r s i o n i n water

(Tawashi, 1969) i s most l i k e l y due to the ' d i f f e r e n c e s i n c r y s t a l h a b i t

which occurs when ASA i s r e c r y s t a l l i z e d from e t h a n o l and n-hexane. The

c r y s t a l grown from e t h a n o l i s a tabular c r y s t a l w h i l e the one from

n-hexane i s n e e d l e - l i k e . Hence, even though t h e i r l o n g e s t dimensions may

be the same s i z e , the d i f f e r e n c e s i n o t h e r dimensions o f the c r y s t a l

w i l l l e a d t o s i g n i f i c a n t d i f f e r e n c e s i n d i s s o l u t i o n r a t e s and t h e r e f o r e

absorption rates.
 107

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