1996_intjourpharma_137

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E L S E V I E R International Journal of P harmaceutics 137 (1996) 255-259

i n t e m a t i o n a lj o u r n a l o fp h a r m a c e u t i c s

S o m e o b s e r v a t i o n s o n t h e c ry s ta l st ru c tu r e o f (R , S ) - p r o p r a n o l o l

h y d r o c h l o r i d e

K. Shankland* , K.S . KnightIS IS Facility, RutherJbrd Appleton Laboratory, C hilton, Didcot, Oxon, O XI I OQX , UK

Received 6 February 1996; accepted 11 March 1996

A b s t r a c t

A r e ce n t pa pe r a dd r e s s ing a n a p pa r e n t d i s c re pa nc y in t he s t r uc tu r e o f ( R , S ) - p r op r a no lo l h yd r oc h lo r ide ( R obe r t s

a nd R owe , 1994 ; In t . J . P har m. , 109 (1994) 83-87) i s shown to be redundant . Er rors in comprehension of bas ic

c rys ta l log raphy a re h ighl ighted .

K e y w o r d s : P owd e r X- r a y d i f fr a c tion ; ( R , S ) - P r op r a no lo l hy d r oc h lo r ide ; P o lym or ph i sm ; I nde x ing

A c r y s t a l l i n e s o l i d i s e s s e n t i a l l y a s o l i d w h o s e

a t o m s a r e d i s p o s e d i n a r e g u l a r t h r e e - d i m e n s i o n a l

p e r i o d i c a r r a y . S u c h s o l i d s c a n b e d e s c r i b e d a t a

m o l e c u l a r l e v e l b y : ( a ) a u n i t c e l l s p e c i f i e d b y

t h r e e l i n e a r l y i n d e p e n d e n t b a s i s v e c t o r s ; ( b ) a s e t

o f s y m m e t r y o p e r a t o r s ; ( c ) a s e t o f f r a c t i o n a l

c o o r d i n a t e s w h i c h s p e c i f y t h e l o c a t i o n o f t h e s y m -

m e t r y i n d e p e n d e n t a t o m s r e l a t i v e t o t h e u n i t c e l l

e dge s .

A l l t h e s e p a r a m e t e r s c a n g e n e r a l l y b e d e t e r -

m i n e d b y s i n g l e c r y s t a l X - r a y c r y s t a l l o g r a p h y . I t

i s o f t e n t h e c a s e t h a t s e v e r a l X - r a y d a t a s e t s a n d

c o r r e s p o n d i n g s t r u c t u r e s a r e r e p o r t e d i n t h e l i t e r -

a t u r e f o r t h e s a m e c h e m i c a l e n t i t y . I n s u c h c a s e s ,

t h e q u e s t i o n t o b e a s k e d i s n o t , a s h a s b e e n

s u g g e s t e d ( R o b e r t s a n d R o w e , 1 9 94 ), ' w h i c h s e t i s

* Corresponding author.

c o r r e c t ? '. R a t h e r , t h e q u e s t i o n s h o u l d b e , ' a r e th e

d i f fe r e n t d a t a s e ts in d i c a t i v e o f p o l y m o r p h i s m , o r

d o t h e y s i m p l y r e p r e s e n t t h e s a m e s t r u c t u r e m e a -

s u r e d w i t h a g r e a t e r d e g r e e o f p r e c i s i o n / a c c u r a c y ,

o r t h e s a m e s t r u c t u r e v i e w e d w i t h a d i f f e r e n t

l a t t i c e b a s i s a n d / o r o r i g i n ? ' .

( R , S ) - P r o p r a n o l o l h y d r o c h l o r i d e i s a n e x a m p l e

o f t h e l a t t e r c a s e . T a b l e 1 s h o w s t h e u n i t c e ll s a n d

s p a c e g r o u p s p r e v i o u s l y r e p o r t e d f o r t h i s c o m -

p o u n d . I n a r e ce n t p a p e r ( R o b e r t s a n d R o w e ,

1 9 94 ), w h i c h s e ts o u t t o d e t e r m i n e w h i c h o f t h e

t w o s t r u c t u r e s ' i s c o r r e c t ' , t h e a u t h o r s h a v e f a i le d

t o r e c o g n i s e t h a t t h e s p a c e g r o u p P 2 ~ /n i s m e r e l y

a d i f fe r e n t b a s i s s e t t i n g o f th e s p a c e g r o u p P 2 ~ /c

( H a h n , 1989 ) , a f a c t c l e a r ly i l l u s t r a t e d in F ig . 1 . I t

i s a s t r a i g h t f o r w a r d m a t t e r , u s i n g t h e s e d i a g r a m s

a n d e l e m e n t a r y t ri g o n o m e t r y , t o s h o w t h a t t h e

P 2 1 / n c e l l ( A m m o n e t a l . , 1 9 7 7 ) c a n b e t r a n s -

f o r m e d i n t o a ce l l i n P 2 1 / c w i t h d i m e n s i o n s a =

0378-5173/96/$15.00 © 1996 Elsevier Science B.V. All righ ts reservedP H S0378-5173(96)04517-6



256 K. Shankland, K.S. K night / International Journal of Pharmaceuties 137 (1996) 255 259

Tab le 1

C e ll d im ens ions and space g roups r epo r t ed fo r (R , S ) -p rop rano lo l hydroch lo r ide

Space grou p a (A) b (A) e (A) [~, (o) Volum e (A 3) Referenc e

P2U n 14.017 8.285 14.005 98.76 1607 A mm on et al . (1977)

P2~/c 13.932 8 .327 18.240 130.81 1602 Co tra i t and Da ng ou ma u (1971)

14.005A , b = 8 .285 A, c = 18.243A , /1 =

130 .59 ° . T h i s i s s i mi l a r t o t he c e ll p re v i ou s l y

r e p o r t e d i n P 2 j / c ( C o t r a i t a n d D a n g o u m a u ,

1 97 1) . N e g l e c t i n g t h e d i s o r d e r o f t h e h y d r o x y l

o x y g e n h i g h l i g h t e d b y A m m o n e t a l . ( 1 9 7 7 ) , t h e

s t r u c t u r e s r e p o r t e d b y t h e t w o g r o u p s a r e e f f e c -

t i v e ly id e n t i c a l (s e e F i g . 2 ) a n d s o n o c o n f i r m a t o r yp o w d e r o r s i n g l e c r y s t a l e x p e r i m e n t i s n e e d e d .

G i v e n t h e u n i t c el l a n d s p a c e g r o u p o f a c o m -

p o u n d , i t i s s t r a i g h t f o r w a r d t o p r e d i c t w h e r e

r e f l e ct i o n s w i ll a p p e a r i n a p o w d e r d i f f r a c t i o n

p a t t e r n . I f t h e a t o m i c c o - o r d i n a t e s a r e a ls o a v a i l-

a b l e , t h e n t h e f u l l d i f f r a c t i o n p r o f i l e c a n b e s i m u -

l a t ed . I n F i g . 2 o f t h e i r p a p e r , R o b e r t s a n d R o w e

( 1 9 9 4 ) s h o w o n l y t h e p r e d i c t e d p e a k p o s i t i o n s f o r

t he t wo s i ng l e c rys t a l s t ruc t u re s . As t he un i t c e l l s

a r e v e r y s i m i l a r , t h e p l o t s o u g h t t o b e v i r t u a l l y

s u p e r i m p o s a b l e , y e t t h e y a r e n o t . T h e p e a k p o s i -

t io n s t h e y s h o w b a s e d o n t h e c el l o f A m m o n e t a l.

( 1 9 7 7 ) a r e c e r t a i n l y i n c o r r e c t a s t h e r e s h o u l d b e

n o p e a k s i n t h e p a t t e r n a r o u n d --~ 6 . 38 ° 2 0 f o r a

c el l o f t h e s e d i m e n s i o n s i f t h e s p a c e g r o u p s y m m e -

t ry i s c o r re c t l y spe c i f i e d . I t i s i ron i c t ha t t h i s

i n c o r r e c t p a t t e r n w a s t h e o n e c h o s e n a s s h o w i n g

' t h e b e s t a g r e e m e n t ' w i t h t h e m e a s u r e d p o w d e rp a t t e r n . C o r r e c t s i m u l a t e d p a t t e r n s i n t h e r a n g e s

5 - 3 0 ° 2 0 a n d 1 2 . 3 - 1 3 ° 2 0 f o r b o t h c el ls a t 2 =

1 . 5 4 0 6 A a r e s h o w n i n F i g . 3 . T h e p a t t e r n s a r e

e s se n t i a l l y ide n t i c a l , w i t h t he sm a l l d i f f e re nc e s i n

p e a k p o s i t i o n s a t t r i b u t a b l e t o t h e d i f f e re n c e s i n

t h e e x a c t d i m e n s i o n s o f t h e m e a s u r e d u n i t c e ll s.

I t i s n o g r e a t s u r p r i s e t h a t ( R , S ) - p r o p r a n o l o l

h y d r o c h l o r i d e c a n b e in d e x e d f r o m a l a b o r a t o r y

X - r a y m e a s u r em e n t - - m a n y h u n d r e d s o f c o m -

p o u n d s o f t h is c el l s iz e a n d b e y o n d h a v e b e e n

i n d e x e d o n l a b o r a t o r y s o u r c e s . H o w e v e r , t o s t a t e

c

P 2 1 / c P 2 1 / n

Fig. 1 . Two cel l choices for space group number 14, P2dc and P2~/n. Each diagram shows four adjacent uni t ce l l s v iewed down the

un ique ax i s b (b po in t i ng ou t o f t he pape r ) w i th t he chosen un i t c e l l s h igh l igh t ed .



K. Shankland, K.S. Knight / International Journal of Pharmaceutics 137 (1996) 255-259 25 7

a

" " " , * ° C

¢

/

o

Fig . 2 . The s ing le c ryst a l s t r uc tu r e s r epo r t ed fo r (R , S ) -p ro p ra -

no lo l hydroch lo r ide . Four ad j acen t un i t c e l l s a r e show n in

p ro j ec t i on dow n the b ax i s f o r each s t ruc tu r e . N o te t ha t t he

s t ruc tu r e s have been r epor t ed i n d i f f e r en t handed coord ina t e

sys t em s and so t he P21 /n ce l l i s show n he re w i th t he b ax i s

po in t i ng i n to t he pape r .

t h a t t h e a c c u r a c y a t t a i n a b l e w i t h l a b o r a t o r y

b a s e d p o w d e r X - r a y d i f f r a c t o m e t e r s " o b v i a t e s

t h e n e e d t o u s e s y n c h r o t r o n X - r a y s t o g e n e r a t e

a c c u r a t e p o w d e r p a t t e r n s t o e n a b l e d e f i n it i o n o fl a t t i c e p a r a m e t e r s ( a s r e c e n t l y d e t e r m i n e d f o r

c i m e t i d i n e ) " ( R o b e r t s a n d R o w e , 1 9 9 4 ) i s o v e r -

s ta t in g the cas e . In th e s pec i f ic cas e o f c ime-

t i d i n e , d a t a w e r e c o l l e c t e d a t a s y n c h r o t r o n

s o u r c e w i t h a v i e w t o a t t e m p t i n g t o s o l v e t h e

c r y s t a l s t r u c t u r e a b i n i t i o , n o t o n l y i n d e x t h e c e l l

(Cern ik e t a l . , 1991) . Th i s i s no t a t r iv ia l t a s k

a n d r e q u i re s d a t a o f t h e h i g h e s t q u a l i t y . In t h e

g e n e r a l c a s e , i t i s t h e h i g h i n s t r u m e n t a l r e s o l u -

t i o n a s w e l l a s t h e p o s i t i o n a l a c c u r a c y a t t a i n a b l ea t s y n c h r o t r o n s o u r c e s t h a t i s o f b e n e f i t w h e n

i n d e x i n g p a t t e r n s . F o r e x a m p l e , w i t h o u t a n a

p r i o r i k n o w l e d g e o f t h e c e ll , i t w o u l d b e d i f f ic u l t

t o d e d u c e t h a t t h e p e a k s a t ~ 1 2 .4 ° 20 a n d12 .8 ° 20 s h ow n in c los e -up in F ig . 3 bo t h con-

t a i n i n te n s i t y c o n t r i b u t i o n s f r o m m o r e t h a n o n e

r e f le c t i on . T h u s t w o o r m o r e r e f le c t i o n s c a n e a s -

i l y b e m i s t a k e n f o r o n e . T a b l e 2 s h o w s h o w

s u c h p e a k o v e r l a p a f f e c t e d t h e a c c u r a c y o f t h e

r e fl e c ti o n p o s i ti o n s u s e d b y R o b e r t s a n d R o w e

a s i n p u t t o th e T R E O R i n d e x in g p r o g r a m . E a c h

o f t h e n i n e m e a s u r e d p e a k s w e r e t r e a t e d a s i n d i-

v i d u a l r e f l e c t i o n s f o r t h e p u r p o s e s o f i n d e x i n g ,

y e t p e a k s 3 , 4 , 8 a n d 9 a c t u a l l y c o n s i s t o f p a ir s

o f r e f l ec t ions , w h i l s t peak 7 i s a t r ip le t o f r e f l ec -t i o n s . T h e t w o w e a k s i n g l e t s i g n o r e d i n t h e i n -

d e x i n g p r o c e s s d o c o r r e s p o n d t o r e a l r e f l e c t i o n s .

A l l i n a l l , t h e f i r s t 7 l i n e s i n p u t i n t o T R E O R

c o n s t i t u t e l e ss t h a n h a l f t h e t r u e n u m b e r o f l in e s

i n t h i s r e g i o n . T h e f a c t t h a t a c o r r e c t s o l u t i o n

w a s o b t a i n e d i s t e s t a m e n t t o t h e p o w e r o f th e

s e m i - e x h a u s t i v e t r i a l a n d e r r o r p o w d e r i n d e x i n g

m e t h o d i m p l e m e n t e d i n T R E O R r a t h e r t h a n t h e

q u a l i t y o f t h e i n p u t d a t a . I n c a s e s s u c h a s t h i s ,

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

r e s o lu t i o n p o w d e r d i f f r a c t o m e t e r s u c h a s t h e o n es i te d in s t a t i o n 9 .1 o f t h e D a r e s b u r y S y n c h r o -

t r o n R a d i a t i o n S o u r c e , p r o v i d e d t h a t i n s t r u m e n -

t a l r e s o l u t i o n ( a n d n o t i n t r i n s i c p e a k w i d t h ) i s

t h e l i m i t i n g f a c t o r . M a n y o v e r l a p p i n g p e a k s w i l l

b e s p l i t a n d t h e a d d i t i o n a l i n f o r m a t i o n g l e a n e d

m a y m a k e t h e d i f f e r e n c e b e t w e e n s u c c e s s a n d

f a i l u r e w h e n i n d e x i n g a p a t t e r n , p a r t i c u l a r l y o n e

a s s o c i a t e d w i t h a l a r g e u n i t c e l l a n d a l o w s y m -

m e t r y s p a c e g r o u p .

I t i s i m p o r t a n t t o r e m e m b e r t h a t e v e n w i t h a

h i g h r e s o l u t i o n d i f f r a c t o m e t e r , i t m a y s t i l l b e

d i ff i c u lt t o a s se s s h o w m a n y r e f le c t i o n s a c t u a l l y

c o n t r i b u t e t o a n y g i v e n m e a s u r e d p e a k . A p r o b -

a b i l i s t i c b a s i s f o r m a k i n g s u c h a j u d g e m e n t h a s

been ou t l ined (S iv ia e t a l . , 1993) and s ucces s fu l ly

u s e d t o d e t e r m i n e t h e u n i t c e l l o f s o t a l o l h y -

d r o c h l o r i d e u s i n g l a b o r a t o r y X - r a y d i f f r a c t i o n

d a t a ( S h a n k l a n d a n d S i v i a , 1 9 9 6 ) . T h e m e t h o d

h e l p s b r id g e s o m e o f t h e g a p s i n t h e c o m p l e x i t y

o f i n d e x in g p r o b l e m s t h a t c a n c u r r e n t l y b e t a c k-

l e d u s i n g l a b o r a t o r y a n d s y n c h r o t r o n X - r a y s .



K . S h a n k l a n d , K .S . K n i g h t / I n t e r n a ti o n a l J o u r n a l o f P h a r m a c e u t i c s 1 3 7 ( 1 99 6 ) 2 5 5 - 2 5 9 259

T a b l e 2

A com par i son o f t he pos i t i ons o f t he f i r s t n ine peaks g iven i n

Tab le 1 o f t he pape r o f R obe r t s and R ow e (1994) w i th t he

co r r ec t r e f l ec ti on pos i t i ons ca l cu l a t ed us ing t he ce l l de t e rm ined

by A m m o n e t a l. (1977). N o te t h a t t he ( - 1 1 2 ) re f l ec t i on i s

ve ry w eak an d i s un l ike ly to be v i s ib l e ad j acen t t o t he s t r ong

( - 2 1 1) reflection.

M easu red l i ne pos i t i ons C a l cu l a t ed r e f lec t ion pos i t i ons

L ine num ber Pos i t i on R e f l ec ti on Pos i t i on ( ° 20 )

( ° 20 )

1 8.317 -- 1 0 1 8.307

2 9.736 l 0 1 9.688

3 12.471 --1 1 0 12.438

0 1 1 12.441

4 12.777 2 0 0 12.769

0 0 2 12.7805 (no t used in 13.555 - 1 1 1 13.537

T R E O R )

6 (no t used in 14.466 1 1 1 14.431

T R E O R )

7 16.664 - 2 0 2 16.658

- 2 1 0 16.669

0 1 2 16.677

- 2 1 1 17.146

- 1 1 2 17.152

2 1 1 18.555

1 1 2 18.561

8 17.150

9 18.576

R e f e r e n c e s

A m m on, H . L . , H ow e , D -B . , E rha rd t , D . , B a l sam o , A . , M ac -

chia , B . , Macchia , F . and Keefe , W.E. , The crys ta l s t ruc-

tu r e s o f d i ch lo ro i sop ro t e r eno l , p rop rano lo l andproprano lo l hydroch lo r ide . A c ta Crvs ta l logr . , B33 (1977)

21 29.

C e rn ik , R . J , C hee tham , A . K . , P rou t , C . K . , Wa tk in , D . J . ,

Wi lk inson , A . P . an d W i l li s , B . T . M . , The s t ruc tu r e o f c im e-

t i d ine (C IoH I6N 6S) so lved f rom synchro t ron - r ad i a t i on X -

ray pow de r d i f f r ac t i on da t a . J . Appl . Crys ta l logr . , 24 (1991)

2 2 2 - 2 2 6 .

C o t r a i t , M . an d D ango um a u , J . , S t ruc tu r e c ri s t a ll i ne du

ch lo rhydra t e de p rop rano lo l . C. R. Acad. Sci . Par is Ser.

C., 272 (1971) 2057 2060.

H ahn , T . (Ed . ), In terna t iona l Tab les fo r X -ray Crys ta l lography ,

V ol . A , (Space G roup Sym m et ry ) , K luw er A cadem ic Pub-

l ishers , Dordrecht , 1989.R obe r t s , R . J . and R ow e , R . C . , The un i t c e l l d im ens ions o f

(R , S) -p rop rano lo l hydroc h lo r ide a C onf i rm a to ry s tudy

us ing da t a f rom pow der X - r ay d i f f r ac t i on . In t . J . Pharm. ,

109 (1994) 83-87.

Shank land , K . an d S iv i a , D .S ., U n i t ce ll de t e rm ina t ion o f

so t a lo l hydroch lo r ide by pow der X - r ay d i f f r ac t i on . Int . J .

P h a r m . , 00 (1996) 00 -00 .

Sivia , D.S. , David, W. I .F, Knight , K.S. and Gul l , S .F. , An

in t roduc t ion t o B ayes i an m ode l s e l ec t i on . Phys . D . , 66

(1993) 234 242.

1996_intjourpharma_137

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