G o in g in t o d e ta i l

T h e o r i t ic a l C o n c e p t o f ,

T a b le t t in g p r o c e s s , P r o c e d u r e s a n d C h a r a c te r is t ic

A C T IV E IN G R E D IE N T

T a b le t s : A c t iv e In g r e d ie n t s

2 b r o a d c la s e s o f d r u g , a d m in is t e r e d o r a l ly in fo rm o f ta b le t s :

• (a ) Insoluble drugs in t e n d e d fo r lo c a l e f f e c t o n G ITe g ., a b s o r b e n t a n d a n ta c id

• (b ) S oluble drugs in t e n d e d fo r s y s t e m ic e f f e c t f o l lo w in g d is s o lu t io n in G IT a n d s u b s e q u e n t a b s o r p t io n

T h e g o a ls in ta b le t d o s a g e fo rm d e s ig n fo r th e 2 c la s s e s d i f f e r .

• Insoluble drugs - a c t io n a r e s t r o n g ly e f f e c t e d b y s u r f a c e p h e n o m e n a s o th e p r o d u c t d e s ig n s h o u ld c o n s id e r a fo rm u la t io n o f r e a d i ly d is p e r s ib le w i t h f in e p a r t ic le s a n d la r g e s u fa c e a r e a .

• S oluble drugs - fo r s y s t e m ic e f f e c t p r o d u c t n e e d s to d is in t e g r a te a n d d is s o lv e fo r th e r e le a s e o f d r u g in a n a v a i la b le fo rm a t o r a b o v e a b s o r p t io n s i t e . E g .,f o r a d r u g l ik e ly t o b e a b s o r b e d h ig h in th e u p p e r p a r t o f G IT --- d is s o lu t io n n e e d to b e r a p id . F o r p r o d u c t n e e d to d e a b s o r b e d in th e in t e s t in e , i t n e e d to s k ip th e s to m a c h . E g .,a c id la b i le d r u g s ---e n te r ic c o a te d o r o th e r f o rm o f g a s t r ic p r o t e c t io n .

C h e m ic a l c h a r a c te r is t ic o f a c t iv e in g r e d ie n t is c r i t ic a l t o p r o d u c t d e s ig n . E g ., I b u p r o fe n :

• E ta n o l c r y s t a l is e d (e th y l) Ib u p r o fe n w a s in i t ia l ly d e v e lo p e d b u t th is c h e m ic a l f o rm is p o o r ly c o m p r e s s ib le , n e e d w e t g r a n u la t io n , te n d e n c y to s t ic k la m in a te d u r in g c o m p r e s s io n .

• M e ta n o l c r y s t a l l is e d (m e th y l) Ib u p r o f e n w a s s u b s e q u e n t ly d e v e lo p e d a n d th is fo rm c a n b e e a s i ly d i r e c t c o m p r e s s w i t h o u t p ic k in g , s t ic k in g a n d la m in a t in g .

I n f lu e n c e o f P h y s ic a l P r o p e r t ie s

• s m a l l b a t c h o f s a m p le g iv e n e a r l ie r t o a fo rm u la t o r m a y f r e q u e n t ly d i f f e r f r o m th e la r g e b a t c h m a n u fa c t u r e d la t e r .

• A lm o s t a l l t a b le t s w i l l r e q u i r e d t h e a d d i t io n o f e x c ip ie n t . O th e r th a n fo r t h e p u r p o s e o f s a t is f a c t o r y d r u g r e le a s e a n d fa c i l i t a t e m a n u fa c t u r in g , th e a d d i t io n o f s u c h e x c ip ie n t is to a c h iv e a c c e p t a b le f iz ik a l a n d m e c h a n ic a l p r o p e r t ie s

• T h e C r y s t a l l in e s t r u c t u r e ; f r o m m a n u fa c t u r in g (ta b le t t in g ) a s p e c t , i f a s u b s t a n c e p o s s e s th e p r o p e r crystalline structure i t c a n b e c o m p r e s s e d d i r e c t ly w i t h o u t f u r t h e r t r e a tm e n t . R e la t iv e ly v e r y f e w o f s u c h m a te r ia o (a c t iv e o r e x c ip ie n t) is a v a i la b le .

• E g .N a C l :h a v in g c u b ic c r y s t a l l in e s t r u c t u r e , w h e r e u p o n c o m p r e s s io n , th e c r y s t a l l a r e f r a c t u r e d a n d f r a g m e n t fo rm a c lo s e -p a c k a r r a n g e m e n t w h ic h r e a d i ly c o n s o l id a t e s o n c o m p r e s s io n . T h e c u b e s t r u c t u r e e n s u r e th a t s t r u c t u r e a lo n g e a c h a x is is th e s a m e th e r e f o r e n o a l l ig n m e n t is n e c e s s a r y fo r io n ic o r v e n d e r w a a ls b o n d in g to o c c u r b e tw e e n in d iv id u a l p a r t ic le .

W h e r e a s e fo r N o n -C u b ic c r y s t a l l in e s t r u c t u r e , r e a l ig n m e n t is n e c e s s a r y , e g ., K C l, w h e r e p a r t ic le s iz e d is t n .,c r y s t a l l s h a p e , b u lk d e n s i t y & m o is t u r e c o n te n t a r e in f lu e n c in f f a c t o r

B io a v a i la b i l i t y C o n s id e r a t io n

G e n e r a l ly , t h e r a n k o r d e r o f

v a r io u s d o s a g e fo rm in d e c r e a s in g o r d e r o f d r u g a v a i la b i l i t y is :

T h e r e f o r e , i f a l l f a c t o r b e in g e q u a l, t a b le t s is o n e o f t h e

le a s t b io a v a i la b le fo rm

o f d r u g .

Solution

Fine suspension(dispersion)

Micronised drugsin capsule

UncoatedTablet

Coated Tablet

Factor effecting the release of drug from tablets(confine to formulation and process)

Drug Particle sizePotent drug of

limitedsolubility

need to be insmaller size

Granulation processesmethod, type &

amount of granulating agent

& granule size

Tabletdisintegration

mechanism andrate

Disintegrants& Lubricants

type,amount & method of

incorperation

Plus otherformulation

and processingfactor

Effect of granule size on the dissolution rate of salicylic acid contained in compressed tablet

020406080

100120140160180

0 10 20 30 40 50TIME (min)

AM

OU

NT

DIS

SOL

VE

D

(mg) 60- to 80- mesh

40- to 60- mesh

C o n to h -C o n to h• T h e e f f e c t o f g r a n u le s iz e o n D r u g R e le a s e c le a r ly

s h o w n b y fa c t t h a t s a l ic y l ic a c id g r a n u le s c a n b e in tw o d i f f e r e n t m e s h r a n g e smesh size vs. Particle size range

• T h e e f f e c t o f C o n t r o l R e le a s e ta b . O f T r ip e le n n a m in e H C l (a n t ih is t .) w h e r e th e crystal size have more impact o n g r a n u le s iz e a l t h o u g h b o t h h a v e a f f e c t o n D r u g R e le a s e .

• D r u g s l ik e N i t r o f u r a n t o in (a n t ib io t ic ) n e e d to h a v e o p t im a l p a r t ic le s iz e ~ 1 5 0 m e s h fo r a d e q u a te r e le a s e o f d r u g a n d to minimise the side effect of emesis

T h e e f f e c t o f th e p a r t ic le s iz e o f D i lu e n t s

• P a r t ic u la r ly w h e n la r g e a m o u n t a r e u s e d , d i lu e n t s c a n s ig n i f ic a n t ly a f f e c t t h e b io p h a rm a c e u t ic , c h e m ic a l a n d p h y s ic a l p r o p e r t ie s o f t h e f in a l t a b le t

e g ., * in t e r f e r e n c e w i t h d r u g a b s o r p t io n -C a s a l t in t e r a c t w i t h T e t r a c y c l in e

* d is c o lo r a t io n o f t a b le t -a m in e b a s e s /s a l t s in t e r a c t w i t h la c t o s e in th e p r e s e n c e o f a lk a l in e lu b r ic a n t

• T h e r e f o r e d i lu e n t s h a v e to b e s c r e e n e d f o r in te r a c t io n w i t h in th e ta b le t

M o is t u r e C o n te n t a n d U p ta k e b y ta b le t

T h e ty p e o f D i lu e n t s u s e d in a ta b le t w i l l d e te rm in e

• I n i t ia l m o is t u r e le v e l

• T e n d e n c y to r e t a in e d o r p ic k u p m o is t u r e

T h e s e c o n t r ib u t e to p r o d u c t s ta b i l i t y

F ig . 2 :

% m o is t u r e u p ta k e b y ta b le t s c o n t a in in g v a r io u s e x c ip ie n t s

H o w th e h y g r s c o p ic n a tu r e o f e x c ip ie n t c a n a f f e c t t h e ta b le t f o rm u la t io n

• W a te r s o r p t io n o r d e s o r p t io n b y d r u g s a n d e x c ip ie n t s is n o t a lw a y s r e v e r s ib le . A b s o r b e d m o is t u r e m a y n o t b e e a s i ly r e m o v e d d u r in g d r y in g .

• M o is t u r e c a n e f f e c t t b e w a y in w h ic h a s y s t e m a c c e p t s e q u o u s g r a n u la t in g s o lu t io n s

• T h e m o is t u r e c o n te n t a n d r a t e o f m o is t u r e u p ta k e a r e fu n c t io n s o f t e m p e r a t u r e a n d h u m id i t y a n d s h o u ld b e c o n n s id e r e d .

• M o is t u r e c o n te n t in a g r a n u la t io n a f f e c t s th e t a b le t in g c h a r e c t e r is t ic o f t h e g r a n u la t io n ,

• H y g r o s c o p ic i t y d a ta c a n a id in th e d e s ig n o f t a b le t-m a n u fa c t u r in g a r e a s .

• M o is t u r e s e n s i t iv e d r u g s s h o u ld n o t b e c o m b in e d w it h h y g r o s c o p ic e x c ip ie n t s ,

• P a c k a g in g m a te r ia l s h o u ld b e c h o s e n to s u i t t h e p r a d u c t .

C o n t… .M o is t u r e C o n te n t a n d U p ta k e b y ta b le t

• M o is t u r e is h e ld in a m a te r ia l e i t h e r in a - b o u n d

o r - u n b o u n d m a n n e r

• T h e c o n d i t io n s u n d e r w h ic h th is w a te r is r e le a s e d f r o m a m a te r ia l s h o u ld b e c o n s id e r e d in th e s e le c t io n o f d i lu e n t s

• e g ., C a S u lp h a te d ih y d r a t e h a s 1 2 % m o is t u r e o n a m o le fo r m o le b a s is (b o u n d m o is t u r e a s w a te r o f c r y s t a l l iz a t io n -le b e r a t e d o n ly a t m o r e th a n 8 0 °C) a n d a b s o r p l i t t le m o is t u r e . S o C a S u lp h a te is w id e ly u s e d in v i t . T a b . A n d o th e r m o is t u r e s e n s i t iv e ta b s .

O th e r p r o p e r t ie s o f d i lu e n t s to b e c o n s id e r e d

• Degree of Cohesiveness - w h ic h a d i lu e n t im p a r t w h e n c o m p a c t e d e s p . w h e n s iz e o f t a b le t is a l im i t in g fa c t o r

• S ensitivity to Physiochemical c h a n g e s a r is in g f r o m m a n u fa c t u r in g o r p r o c e s s in g

e g ., im p a c t o f a p p l ie d fo r c e (c o m p r e s s io n ) o n d is in t e g r a t io n & h a r d n e s s ~ f ig .3 & 4Ideal property of a diluent ~ not sensitive to physicochemical changes during manufacturing such that it will affect tab. Quality adversely

• Cost - per kg• taste & mouth-feel e s p .c h e w a b le ta b le t : w h e r e ”a g in g ” e f f e c t s le a d in g to r e d u c e d c h e w a b i l i t y a n d in c r e a s e h a r d n e s s a r e to b e e x a m in e .