Unit 7-Modified Release Dosage Forms.pptx

industrial pharmacy

1. In t r oduction  Dosage f o r m ca n be classifi e d in t o i m m ed i at e -re l e a s e and m od i fi e d- rel e ase dosage for m s . Imm e diate - r e l ease (I R )/ conve n ti o n al’ drug del i very : The s e provide rap i d onset of e f fe c t , fol l owing absorp t ion i n the gas t roi n t e st i nal tr a c t . Lim i tation s : a. Drugs with s hort ha l f-l i f e -- - - requ i re f requent ad m i nistr a t i o n -- - which in c reases c h anc e s of m i s sing dose o f dr u g l e ad i ng t o po o r p a t i e nt co m pl i ance and sub th e rapeu t ic l e vel i n blood. A t y pi c al pea k - va l l e y pl a sma con c . t i m e profi l e i s obt a in e d which m ak e s a t t a in m ent of ste a dy sta t e con d i t ion di f fi c ult (Cs s ) The unavo i dab l e fluc t uations i n the drug conc e ntra t ion m a y l e ad to under m ed i ca t ion or over m ed i ca t ion. 2 b. c.

2. Modif i e d - r e l ease drug del i ver y : refers to the m anipula t ion or m od i fi c a t ion of drug re l e a se from a dosage form wi t h res p e c t t o time, cours e , and /or lo c at i on  In con t rast t o con v en t io n al for m s, m od i fi e d re l e a se produ c ts prov i de are de l a y ed rel e ase, ex t ended rel e ase (ER) and t a r ge t ed-rel e ase s y ste m s .  Can be designed for a l l route of drug ad m in i stra t ion l i ke oral, paren t era l , top i cal rout e . 1. Delayed- r e l ease dosage form : do n ot rel e ase t h e drug i m m e di a t e ly aft e r ad m inistrat i on thr o ugh oral ( m e ans have l a g ti m e bet w een a pa t i e nt t a king a m ed i c i ne, and drug be i ng de t ec t ed i n the blood).  Gast r o- r esi s ta n t dosage form s : start t o rel e ase the drug w h en a cer t a i n env i ron m en t al pH i s m e t . E g. En t eric coa t ed formu l a t io n : design to pass th r ough the stomach una l t e r e d , l a t e r t o re l e a se th e ir m ed i c a t i on wi t hin the in t est i nal tra ct . 3

3. The purpo s e s of such pr e par a t i ons a re t o pr e v e n t s ide e f fec t s rel a ted to the dr u g presence in t h e s t o m ach , prote c t the d r ug f rom deg r ada t ion i n the high l y ac i dic pH of the gas t r i c fluid 2. Extended - r elease ( E R) : r e l e a s e t h e drug i n a co n t r o l l ed manner , at a p r ed e t ermined ra t e , dura t ion and loc a ti on t o ac h ie v e and m a i nt a in opt i m um conc e nt r at i on of drug i n bloo d . at l e ast a t w o - fold r e duction in d ose as well as frequency as co m pared t o an i m m edia t e re l ease (convent i ona l ) dosage f or m . Extende d - r e le a se dosage form m ay be a. b. c. Sust a in e d/ Pro l onged r e l e ase drug de l iv e ry sys t em (SR - D D S) C o ntro l led re l ease drug del i very system (C R - D D S) Repea t ed ac t ion dosage for m s ( m ay be conven t ion a l ) 4

4. ( a ) Sust a ined / Pro l o n ged rel e ase (SR) DDS dr u g rel e a s e o v er a sustained period ( r el e ase not definite us u ally with first o r der rele a se k i netic s .  Preferably desi g n f o r o r al d o sage f o r m s  Drug is rel e a s ed slowly and rate o f absor p tion is slo w .  Onset o f action is dela y e d . (b) Co n tro l led rel e ase (CR) DDS per u n it ti m e) deli v er a co n stant su p ply o f t h e active i n g r edie n t, us u al l y a t a zer o -o r d e r rat e , dr u g r e l e a se a t a pre d et e r mined ra t e ( r el e a s e de f ini t e per u n it t i m e) for a specific peri o d o f ti m e .  Co n tains l o adi n g d o se + m ainte n ance d o se .  L o adi n g d o se is i m m ediately rele a sed to p r o d uce q u ick o n set o f actio n .  Mai n tena n ce d o se is rele a sed a t a c o n tr o lled rate so t h at t h e p l a s m a co n centrati o n r e m ains co n stant above Mi n i m u m E f f e ctive Co n centrati o n (M E C ) . Pla s ma co n cent r ation comes d o wn ac c o r d i ng to first o r der eli m i n ation k i netic s . 5

5. M S C P l a s m a c on c . o f d r u g M E C T i m e M S C P l a s m a c on c . o f d r u g M E C 6 T i m e M S M E E n t e r i c c o a t e d t a b l e t M S M E R e p ea t ac t i o n t a b l e t

6. (c) Repeat action tablet:  m ore th a n one i m m edia t e rel e ase un i ts are in c or p orat e d in t o a single dosage for m .  A dose of ad m in i stratio n , the drug in i t i a l ly i s rel e ased i m m e di a tely aft e r whi c h is usua l ly e q ui v a l ent to a sing l e do s e of the conven t ion a l drug for m ul a t i o n .  After a cer t a i n period of t i m e , a second single dose i s rel e ased. A d vantage: No need of r e -ad m in i stra t ion. Disadva n tage: th a t t he b l ood l e ve l s sti l l e xhib i t t he “ Peak and va l l e y ” char a c t eris t i c . T arget e d - r e l ease sy s tem s : Acts a t part i cu l ar t a r ge t . May be site speci f ic ta r ge t ing as we l l as r ec e p tor ta r ge t ing, may be con t r ol l ed and s u stain e d 7 r e l ease

7. The rationa l e for e x tende d - r e l ease ( E R D F ) pharmaceutica l s  T o redu c e dose and hen c e redu c e the side e f fe c t  D osing frequen c y and i m prove pa t i e nt co m pl i ance  E l i m in a t e the fluc t ua t ions i n blo o d conc e ntra t i on associa t e d with conven t ion a l de l iv e ry  T o t a r get the drug t o a specif i c site i n the body Disa d v a nt a ges of Exten d e d - r elease d o sa g e f o r m s  High cost  Dose d u m p i ng  Pr o m pt ter m i n ation o f t h erapy is no t p o ssible  Less flexi b ility in adjusti n g d o s a ge regi m ens (ERDF)  Ne e d f o r additi o nal patient ed u cation E . g : “ Do not chew o r crush t h e d o sage f o r m , sw a ll o w f u lly wit h o u t b r eaki n g  Drug abs o r b ed a t t h r o u g h specific a b sor p ti o n window in GIT cann o t 8 ERDF

8. 9 Design of Modi f i e d Drug Del i very Syst e m T h e perf o r m ance o f a d r ug de p en d s upo n its: 1 . Rele a se o f d r ug fr o m t h e d o sage f o r m . 2 . Mo v e m ent o f the dr u g (Absor p tio n ) within the bod y . Rate l i m i ted step in a bs orp t i o n in c ase o f co n tr o lled DDS is rele a se of d r ug fr o m f o r m u l ation and in case of co n ve n tional it is pe r m e atio n / abs o r p t o in

9. Desi r ed c h a r a c teri s ti c s of dr u g su i t ab l e f or d e si g ni n g Su st a i ned and con t r olled r e l ease DDS A . Biop h armac e utical characte r istics 1 . Molecul a r weig h t o f t h e dr u g : Less t h an 60 daltons (400 d o p ti m u m) are sui t able f o r passive d i f f u sio n . La r ger m o l ecules are no t sui t able e .g . pe p ti d es and p r o t ein s . 2 . A q ue o us sol u b i lity o f t h e dr u g :  Go o d aq u e o us solub i li t y w ith p H i n d e pe n de n t so l u b il i ty serves a s a g o od cand i date f o r o r al co n tr o lled DD S . E.g . pe n t o x i f y lli ne .  Drug with p H depen d ent aqueous s olubility (e. g . p h e n y toi n ) o r dr u g sol u b l e i n nona q ueous s o l ve n ts (e .g . steroi d s) is sui t able candidates f o r pare n teral co n tr o lled DDS ( e .g . i n tra m usc u lar de p o t ) .  P o o r ly wate r -sol u b l e d r ugs are no t s u i t able cand i dates f o r o r al b e cause t h eir d i ssol u ti o n is rate li m ite d . 3. Io n izati o n ( pK a ) o f the d rug  Drug t h at re m ains is u n i o n ized state a t abs o r p t i on site is a g o od cand i date li k e very we e k a c i d ic d r ug (pKa < 5 ) alo n g enti r e len g th o f GIT and are design for oral deli v ery > 8.0 ) and V ery we a k b a ses (pKa sui t able f or CR/SR f o r m u l ation 10

10.  Drug t hat r e m a i ns i n ion i zed sta t e ( e .g. hexa m e t honi u m ) are poor c a nd i da t es for oral drug de l iv e r y .  For ac i dic drug hav i ng p Ka va l ue 2. 5 -7.5 , i o ni z a t i on i s p H se n sit i v e . These drug r e m a i n union i zed a t gastric pH but io n i z ed a t intes t in a l p H . S o suit a ble for Gastroret e nt i ve drug de l iv e ry s y stem  For basic d r ug hav i ng p Ka 5 – 1 1 , ion i za t ion i s pH sensit i ve, Ioniz e d i n gastr i c pH, Unioni z ed i n in t est i nal p H, Be t t e r ab s orbed from in t est i ne. Suit a ble for design i ng in t est i nal de l iv e ry s y ste m / c olon de l iv e r y . 4. Part i t i on coe f f i c i ent Part i t i on c o e f fic i ent i s t h e fract i on of drug i n a n oil p h ase t o that o f an ad j acent aqueous phase. The drug s hould be s u f fic i en t ly l i pid soluble and water solubl e . High part i t ion coe f fi c i e nt co m p o und are predo m in a ntly l i pid so l u b le and h ave very low aqueous so l ub i l i ty and thus these co m pound persist i n the body for lo n g period s . 11

11. 5. Drug stab i l i ty : Drugs unstab l e i n gast r o - i n tes t in a l env i ron m ent are poor c andi da tes for oral co n t r o lled DD S be c ause b i oav a ila b il i ty wi l l b e less. D rugs that a re un s t a b le i n the env i ron m e nt of the sto m ac h , en t e ric coated for m ul a t i on can de des i g n . 6. M e chan i sm of absorp t io n : Drugs abso r bed by carrier m edia te d transport and those a bso r bed th r ough an “ absorption windo w ” are poor candid a tes e.g. s ever a l B - vit a m in s . 7. Route of admini s tra t io n : Oral rout e : Duration of action m ay be extend e d t o 12 t o 24 hour s . Maxi m um 1000 m g can be given inc l uding addit i ve s . 8. Intra m uscular / Su b cutaneous rout e : Dur a t i on of acti o n can be pro l on g ed from 24hours t o 12 m onth s . Max i m u m 2 ml ad m ini s te r ed through this rout e . or 2 g m can be 12

12. 9. T ransde rm al route : 12 hours t o several da y s . V e r y low d ose drugs ( e .g. ni t rog l ycer i ne) ca n b e a d m in i s t ered. Drugs w i th ex t ensive first pass m etabol i s m i s suit a bl e . Suit a ble dose 50 m g (opt i m u m upto 20 m g) for pa t ches. Pharmacok i netic charact e r i stics 1. Half l i fe of dru g : Half l i fe of drug i s 3-8 h r , not suit a ble f o r < 2 & > 8 h r . Hal f -l i ves shorter ( P e nec i l l in G ) - th a n 2hrs - p oor cand i da t es of su s t a in e d rel e ase dosage dose size will in c rease t o m a i n t a i n co n stant rel e ase. • Lo n g ha l f l i fe (di a z e pa m ) m ore than 8hrs - su s t a in e d e f fe c t a l re a dy occurs 2. Ra t e of m e t a bol i s m : Drug th a t i s rapid l y m e t a bol i zed i n t h e l i ver are con t rol l ed re l e a se DD S . Th e y are be t t e r rel e ase for m ul a t i on/transder m a l . not good c a nd i da t e for oral giv e n by paren t eral con t rol l ed Even the drug th a t inhibit or indu c e the m e t a b ol i sm a l so not good cand i da t e for oral con t rol l ed rel e ase de l iv e r y . 13

13. Pha r mac o dyna m ic cha r act e r i stics Ther a peu t i c s range of a d rug i s wide  a) Therapeut i c rang e : good cand id a t e for con t r ol l ed DDS. In case of l ow th e rape u t i cs range, can be designed but not very m u c h suit a ble l i ke phe n obar b i t o n , di g ox in . b) Therapeut i c ind e x: i t i s t h e rat i on of MS C to – safer i s the drug - TI > 10. MEC . La r ger the rat i o c) P l as m a co n cen t ration – Response r e l at i on a c t iv i ty ship : Drugs su c h as its reserpine who s e pharm a co l ogi c a l is i n depend e nt of pl a s m a conc e ntra t ion are poor cand i da t e for con t rol l ed DDS . 14

14. Desi g n, forms devel o pment and cha r a c ter i z at i on of mo d ifi e d r e l e a se dosa g e Class i fic a ti o n o f o r al c o n t r o l l e d r e l e a se syste m s A. Contin u ous c o n t r o l l e d r e l e ase s y stem s : su c h dosage fo r m rel e ase t h e dr u g for pr o l ong e d p e riod o f t i m e i n e n t i re t e r m i n al re g i o n o f s m a l l i n t e st i n e ) These a r e f u rther c l ass i fy 1 . Disso l u t i o n c o n t r o l l e d r e l e a se syste m s (a) M a trix (or m o n o l i t h) s y st e m s (b) E n c a ps u l a t i on / C o a t i n g s y st e m s l e n g t h of G I T (esp e c i a l ly u p t o 2 . Dif f usion c o n t r o l l e d r e l e a se syste m s (a) M a trix s y st e m s (b) R e serv o ir s y st e m s 3 . Disso l u t i o n and diff u si o n c o n t r o l l e d r e l e a se syste m s a. b. c. d. e. Io n - e x c h a n ge resin – D r ug c o m p l e x es Os m o t ic pr e ssure c o n t ro l l e d s y st e m s p H i n d e p e n d e n t for m u l a t i o n Sl o w d i sso l v i ng sa l ts a n d c o m p l e x es H y dro d y n a m ic pressure c o n t rol l ed s y ste m . 15

15. B. Delayed transit an d t hen c o n ti n u o us r e l ease sy s tem s : th e se for m ul a t i on are design t o ret a in i n s to m a ch for a durat i on and hence de l a y ed th e ir gastr i c tran s i t . S o the drug should b e stab l e i n s to m a ch and should be be t t e r absorb from upper part of in t est i ne . May be  Alt e red densi t y s y ste m s  Mucoadhesive s y ste m s  Siz e -based s y stem C. Delayed r e l ease sy s tems: th e se s y stem part of in t est i ne . rel e ase the drug in lower  Intes t in a l re l ease s y ste m s  Colon i c re l ease sy ste m s The drug for th i s t y pe of s y stem ar e : a. b. c. d. Gastric l ab i le Produce so m e side e f fect in gastr i c region i. e . gastr i c distr e ss Be t t e r absorb from the in t est i ne Have the lo c al a c t i on in in t est i ne or co l on 16

16. Disso l ution cont r ol l ed r e l ease sys t e m s C o ntrol – Dissolution of the d r ug f r o m t h e poly m er m at r ix or enc a psu l a t e d for m s . • The dis s ol u t i on p ro c e ss at a s t e a dy state i s des c ribed b y Noyes W hi t ney equa t io n : dc / dt = ( D A K o / w / V h) ( C b - Cs )----------- (Mo d i f i e d by Bru n ner) = k (Cs - C b ) .................... ( I nit i al d C/ d t = diss o lut i on rate V = v o lu m e o f the solut i on k = i ntri n sic diss o lut i on rate co n st a nt D = di f f u s ion coe f fic i e n t o f d r ug thr o ugh p o res h = thickness o f the di f f u s ion l a y e r A = s u r f ace area o f the ex p o s ed s o l i d C s = sa t u r a t ed solu b i l i t y o f the drug C b = co n c. o f d r ug i n the b u lk s o lut i on Noyes W hi t ney equa t ion) Noyes- W h itney ‟ s equa t ion repres e nts fir s t o r der d is s ol u tion r a te 17 proces s , f or w h ich the driv i ng f orce i s concent r ation gradi e n t .

17.  T h is is tr u e f o r i n -vit r o d i ssol u tion w h ich is charact e rized b y no n -sink co n d i ti o n s .  In v i tro sink co n d i ti o n ca n b e m aintain if Cb is always less t h an 1 % of Cs. In t h i s s i t u atio n , W h i t ne y ‟ s eq u ation represents zero o r der d i ssol u tion rate (Si n k co n d i ti o n : Co n c entrati o n in r ec e p t or c o m p ar t m e nt is m a i nt a ined a t l o wer level comp a r ed to its co n centrati o n in donor co m part m ent) Dissolu t i o n con t r o l led r elease systems may b e of (a) Matrix ( o r m o n o l it h ) s y ste m s ( b ) E n capsulati o n / C o ating s y ste m s M a trix ( o r mo n o l ith) systems  Si n ce t h e d r ug (wat e r sol u b l e) h o m o g eneo u s l y d i spe r sed t h r o u g h o ut a ra t e co n tr o lli n g m edi u m m atrix s y ste m .  T h e waxes used f o r such s ystem a re beesw a x, carnau b a wax, h y d r o g enated ca s t o r o i l et c .  T h ese waxes co n tr o l t h e d r ug d i sso l u t ion b y c o n t r o lli n g fl u id pe n e trati o n i n to t h e m atr i x, b y alteri n g t h e p o r o si t y o f tablet, d e cre a sing its wettabili t y or by itse l f d i ssol v ed at a slower rat e . Release will be e f fect e d 18 by dissol u tion o r erosion o f p o l y m er m atri x .

18. E n capsula t i o n/Coat i ng Devices ) : disso l u t i o n cont r o l led sys t em ( R es e rvo i r  Encaps u la t i o n invo l v es coating of in d iv i d ua l part i c l e s, or gr a n u l e s of drug with the slow l y dis s olv i ng m a t e r i a l .  The pa rt ic l e s obt a ined a f ter c oa t i ng can be co m press e d d ir e ctly i n to t a b lets as in spa c e t a bs or pl a c ed in cap s u les as in the span s ule produ c t s .  A s the t i m e required f or disso l u t i o n of coat i s a f unction of its t h i c k n ess ( va r y ing t h ickness 1- 200 m i c ron) and t h e aqueous solu b i l ity of the poly m e r .  B y using one of sever a l m ic r o en c apsu l ation t ech n iqu es t he drug part i c l e s are coated or e ncap s u lated with slo w ly disso l v ing ma t e r i a ls l i ke ce l lu l ose, PE G s, poly m e t hac r yla t e s , waxes e tc . 19

19. Several t e chn i que for m i c roenc a psula t ion are a) b) Coa s ervat i on/ pha s e separation: for water soluble pol y m er In t erfa c ial pol y m ers pol y meri z atio n : f o r wate r -insolub l e &wa t er s o lub l e c) d) P r ec i pitation metho d : organic solven t -soluble Pol y m er Solve n t ev a porati o n : for s olv e n t -so l uble po l y m e rs, vol a t i le s olv e nt are used Me c han i s m : Dis s olu t ion fol l owed by er o sion 20

20. 2. Dif f usion cont r ol l ed r e l ease sys t e m s  Rate con t r o ll ing step i s the d i f f usion of disso l ved drug t h r ough a poly m e r ic ba r r i er r a th e r th a n dis s olu t ion r a te  Since t h e di f fusional pa t h len g th i n c r e as e s with ti m e as t h e inso l u b le m atrix i s g r a d ually de p le t ed by t h e d r ug and t h e re l ease of drug i s never zero orde r .  Clas s ified in t o r e se r voir sys t em and m onol i th i c sys t e m . Reservo i r devic e s : -  These syste m s are hollow i n w h ich core of drug i s sur r ounded in W a t er inso l uble p o ly m er m e m br a ne (but pe r m eable) li k e HPC, E C , polyv i nyl ac e t a te  Drug r e lease m ech a nism i s inv o l v e it s pa r t i tion i n t o t h e m embra n e and exchange with f luid sur r ounding the par t ic l e or tab l e t .  Dose du m ping i s the m a j or dr a wbac k .  The pe r m e abi l ity of m e m br a ne depend on t h i c kness of the coa t / c oncen t r a t i on of coa t ing solu t ion & on the na t ure of poly m er 21

21. The r a te of drug r e l ea s e from the r e se r voir sys t em can be exp l a i ned by Fick ‟ s Law of di f fusion as p e r the following equa t ion. d C/ d t = D S K ( C 1- C 2 )/h = D S K Δ C /h W he r e W he r e, S = is the ac t ive di f fusion a r ea. 22

22. D = is t he di f fusion coe f fici e nt of the drug ac r oss the coa t ing m e m brane. h = is t he di f fusional path l e ngth ( t hi c kness of poly m er coa t ) ΔC = i s the conc e nt r ation di f ference ac r oss h. K = is t he pa r t i tion coe f fici e nt of the drug b e tween poly m er and exte r nal m ediu m . t he Coat i ng l i ke Coated Beads / Pel l ets and M i c r oenc a psu l at i on t e chn i que is used f or t he pr e pa r a t i o n. 2. Ma t r i x dif f usion cont r ol l ed sys t em  I n th e se s y st e m t h e d r ug i s disp e r s ed i n swe l lab l e hy d roph i lic subs t ances or i n a m ixture of inso l uble m at r ix of r i gid no n - swella b le hydrophobic m ate r ia l s + swellab l e hydrophil i c  In s olu b le p las t i c s such as PVC ( pol y- v in y l ch l o r i d e) a nd fatty m a t eri a ls li k e stearic ac i d, bee s wax etc are t h e m a t eri a l used for r i gid m at r i x . 23

23.  Hydrophilic gu m s m ay be of na tural origin (G u ar gu m , t ragaca n t h), se m i syn t he t ic (HPMC, CM C , Xanthan gu m ) or syn t he t ic (po l y ac r yl a m id e s) are the m a t e r i a l gene r a l ly used for su c h m a t r i ce s .  The equa t i o n des c ri b ing drug rel e ase for th i s sys t em i s giv e n by T . Higuch i . ½ C = K H t  The re l ease of high l y w ater s o lu b le drug can b e sust a ined by u s i n g swel l ab l e m at r ix sys t e m s . 24

24.  For for m u l ation, gum and drug are g r an u la t ed toge t her and co m press e d into tab l e t . Not pr e f e r a bly used as sho w s v e ry slow r e l e ase 25

25.  The m e chanism of drug r e l ea s e from th i s s y stem invo l ves absorpt i on of water ( r esul t ing hy d rat i on, ge l l i ng and s w e l l ing of gu m ) and desorpt i on of drug via s w e l l i ng con t rol l ed di f fusion m ech a nism .  A s the g um s w e l ls and t he drug d i f f uses out o f i t, the s w ol l e n m ass dev o id of d r ug app e ar tr a nspar e nt or gl a ss l i ke a nd s o the s y stem is so m e t i m es ca l l e d a s gl a s s y h y drogel. 3. Dis s olution and diffusion cont r ol l ed r e l ease sy s tems  Drug i s en c ased i n a par t i a l l y solub l e m e m brane  A s the s y st e m c o m e i n c ont a ct with m ed i u m (water), the sol u ble part of m e m brane get solubi l i z ed and cre a t i ng the pores i n m e m bran e .  The m ed i u m en t er thro u gh th e se po r es and solubi l i z e the dru g . The disso l ved drug di f fused ou t .  P o l y m er l i ke E t h y l ce l lu l ose (water insolub l e) and Meth y l ce l lu l ose or pol y -vi n y l - p yrrol i d o ne (PVP) (water solubl e ) are used tog e t h er t o form the m e m bran e . 26

26. Ion - exchange r es i n – Drug c omp l exes Contr o lled re l ease d e l i v e r y of drug t h at io n ize i n acid i c drug and ba s ic pH can be o btai n ed by for m ing the co m pl e x wi t h insolub l e, nontoxi c , an i onic and ca t ion i c ion exch a nger r e sin ( I E R ), r e spe c t i v e l y . The drug rel e ase s lowly by di f fusion from the r e s in s t r u ctur e . Ba s ic drug l i ke nosc a pin e , pheny l prop a nola m in e , phen t e r i m ine e tc . 27

27.  Ion exch a nge r s a r e deve l oped by poly m e r i z a t ion r e ac t i o ns  Co m plexes betw e en I ER and dr u gs are kn o wn as ion exchan g e r e sona t e s .  A typ i ca l c ation - exchan g e r e s in i s p r epared by t h e cop o ly m e r iz a t i on of sty r ene and d i - v in y l - b en z ene . Sulphon i c a cid /C a rbo x y l ic a c id groups a r e a t t a ched sty r en e- d i- v i ny l - b e nz e ne poly m er .  In c ase of anionic e x c h anger Qua t e r n a r y a m m oni u m / Pol y alk y l a m ine copo l y m e r . gro u ps at t ac h ed t o a s tyrene and d i v i nylbe n ze n e Os m ot i c p r es s u r e cont r ol l ed sys t e m s Th e d i f f usion pressu r e exer t ed by water m ol e cu l es on t h e se m i - pe r m eab l e m e m br a ne i s ca l l e d as os m ot i c pr e ssu r e . 28

28.  O s m ot i c d r ug r e lea s e sys t e m s use os m ot i c pressure as a dr i v ing f orce f or the con t r o lled de l iv e ry of drugs. A si m ple o s m otic pu m p cons i s ts os m ot i c of an agen t ) os m ot i c co r e ( co n ta i ning drug with or wi t hout an and is coa t ed with a se m i- pe r m eab l e m e m br a n e .  The se m iper m eable m e m brane has an o r ifi c e f or drug r elea s e f rom the “pu m p.” The dosa g e for m , water a f ter co m ing in co n tact with t h e aqueous fl u ids, i m bibes at a rate d e te r m in e d by the of fluid co r e 29 pe r m eabi l ity f or m ula t io n . of the me m br a ne a nd o s m ot i c pr e ssu r e

29. O s m ogens a r e dis s o l v ed in the bi o logic a l fl u id, which cre a t e s os m otic pr e ssure bu i ld up outs i d e t h e pu m p th r ough ins i d e t h e pu m p and pushes m e di c a m e n t delive r y or i fi c e . They include i n o r ga n ic salts and c a r bohyd r at e s . Mos t l y , potas s ium chloride ( 2 45 at m ), sodium ch l or i de ( 356 at m ), and manni t ol ( 3 8 at m ), su c r ose ( 150 atm ) , sorbitol ( 84 atm) used as os m ogens. B . Delayed t r ansit and then cont i nuo u s r e l ease sys t e m s : Gas t r o r e t ent i ve drug del i very sys t em  D o sage f orm i s retai ne d i n the s t o m ach so th a t drug abso r p t ion in the upper gas t ro i ntestinal t r act can be m ax i m i z ed  those for l o c al a ction i n t h e s to m ach ( e.g. t o tre a t H . py l o r i ) , drugs which have a na r row a b so r p t ion window i n the s m a l l inte s tine and drugs w h ich are degraded i n the colo n .  Seve r a l a ppro a ch a re u s ed for G a st r o- r e t e n t i o n like Mucoadhes i on, f l oat i ng based, densi t y based e tc . 30

30. High Density Syst e m s : - The s e sy s te m s, which have a d ensity of ~3 g/c m 3 , are r et a ined i n t he rug a e of the s to m ach and are c a pab l e of with s tan d i n g it s peri s ta l tic m ove m e nt s . Above a thresho l d density of 2.4–2.8 g/c m 3 , such s y st e m s can b e re t a i n ed i n the lower p art of the sto m ach . Dilue n ts su c h as bar i um sulph a te ( de nsi t y = 4.9 ) , zinc o x ide, t ita n ium dio x id e , and i r on powder m ust be u sed to m a n u f ac t u r e such hig h - dens i ty for m ul a t i ons 31

31. Mucoadhesive system  Mu c oadh e si v e po l y m ers could th eo ret i c a lly adh e re a dos a ge f o r m t o the sto m a c h m uco s a t o ret a in i t i n the sto m a c h. Po l y c a r b oph i l, ch i tos a n, po l y (ac r y lic a c id) , h y d r o x y p ro p y l c e llu l o s e (HPC ) , and sodi u m c a rbo x y m e th y l c e llu l ose (CMC) are m u co a dhe s ive pol y m ers Floating system  Dosage f o r m should float on the st o m ach con t en t s, t hus avo i di n g ga s tric e m pt y ing. Have den s ity l e ss th a n 1.04 g m /c m 3  S we l l a ble pol y m ers su c h a s M e tho c e l , c a rbopol  Gas gen e rat i ng ag e nts l i ke bi c arbon a te and c i tr i c or t a rtaric a c id are us e d. NaHCO3(aq) + HCl(aq) → Na C l(aq) + CO2(g) + H2O ( l) Si z e inc r e a sing syst e ms  A dos a ge f o r m t h at swe l ls and in c rea s e i n si z e a s s o on a s i t rea c hes the sto m a c h t o avo i d be i ng ab l e t o pa s s through the p y loric sphin c t e r .  S w e l l a ble po l y m ers such a s M e t h oc e l ( h y d r o x y p ro p y l m et h y l c e llu l os e ), inv e st i ga t ed po l y e t h y l e ne oxid e , a n d xan t han g u m have a l l be e n 32

32. C. Delayed r e l ease sys t e m s: th e se sys t em r e l e ase the drug part of int e st i n e . i n lower  In t es t inal r e l e ase sys t e m s ( Gast r or e si s t a nt coa t ings)  Colonic r e l e ase sys t e m s Int e st i nal r e l ease sys t e m s ( Gas t r o- r es i sta n t coa t ings)  Me m br a ne c ont r o lled e x tended rel e ase, e x ce p t that the m e m br a ne is des i gned t o dis i nt e gra t e or dis s olve at a pr e- de t e r m in e d poin t .  The m ost co mm on t r igger f or delayed re l ease coat i ngs i s p H .  Gast ro- r e si s tant coa t ings a r e poly m er coa t ings which a r e inso l uble at low pH, b ut a r e solub l e a t h ig h er pH ( e.g. s o m e where be tween pH 5–7 depend i ng on the poly m e r )  This ap p ro a ch i s m ost co m m only used f or re l ea s ing drug i n the s m a l l in t es t ine.  Gast ro- resi s tant c oa t i ng of fo r m ul a tions has t w o function s : i ) to prote c t the s to m ach from the drug o r ii) t o p rot e ct acid - s ensi t ive drugs f rom the sto m ach environ m en t . 33

33. Colonic drug del i very  Disorders li ke infla m m at o ry bo w el di s eases, ul c era t i v e c o l itis, Chron's disease, infe c ti o us diseases and c o lon c ancer a re u s ing s ite spe c ific drug de l iv e ry sys t e m .  Suitab l e for peptide and pro t e in dr u gs. These drugs a r e des t roy e d and in a cti v a ted i n ac idic en v i r on m ent of sto m ach o r by p ancre a t ic enzy m es (o r ) by paren t eral route wh i ch is in c on v e n i e n t and expensiv e . Poly m er li k e Ce l lu l o s e Aceta t e Phthala t e (C A P/pH 5 ), E u dragit L 100 (pH 6 ) , E u dragit S 100 (pH 7 ) , polys a c char i des 34 l ik e chitosan

34. G e neral m e chanis m s of drug r e l ease f r om dosage fo r ms  Sever a l m a t he m atic a l m odels a re app l i ed on i n - v it r o r e le a se d a ta t o e va luate re l ease ki n e tics as we l l as m ech a nism of drug r e l e ase from m odified r e l e ase dosage for m . 2  Fir s t t o fourth m odel g i v e the va lue of co r re la tion coe f fi c ient ( “ R ” ) and last one give the value of exponent (n ) . 2  Model w i th Highest v a l u e of R ” i s consider a s best f i tted m ode l . The va l ue of exponent (n) ind i ca t e the m ech a nism of drug r e l e as e . 1. 2. 3. 4. 5. Zero Order Release Model Fir s t Oder Rel e ase Model Higuchi R e l ea s e Model Hixso n- Crowell R e l ea s e Model Rele a se kin e t i cs, 2 Co m pa r e R Kors m eye r - Peppas Rele a se m ech a nism Model 35 time Cum. D rug r e l e ase 0.0 1 20 2 35 3 55 4 80

35. Z e r o order r e l ease k ine t i c s  Rel e ase ki n et i cs inde pe ndent of c once n tra t ion of drugs i n t h e dosage form  Re f e r s t o the pro c ess of cons t ant drug r e l e ase  V a l ue of r e lease cons t a n t ( K 0) and co r re la t i on c oe f fici e n t ( R 2) can be d e t e r m i n e by pl o t t i n g a gr a ph be t ween c u m ul a tive amount of drug r e l e as e d vs. t i m e .  A st r a i g h t l i ne wi l l be resu l t whose slope wi l l be K and in t e rcept will be C Zero ord e r r e l e ase can be r e pr e sen t ed as C = C + K t W here C = Ini t i al C o ncen t ra t i on/a m ount of drug ( Q o ) , C = cu m ul a t i ve conc e nt r a t i o n/ a m ount (Q) of drug r e l e ase at t i m e “ t ” K o = Zero ord e r r e l e ase cons t an t , t = t i m e i n hours 36

36. Fir s t order r e l ease k ine t i c s : Rel e ase k i n et i cs depe n dent on t h e conce n t ra t i on of drugs i n dosa g e form V a l ue of re l ea s e consta n t ( K 1 ) and c or r e la t ion c oe f fici e n t ( R 2) can be of be de t er m ine by pl o tt ing a graph b et w een log cu m ul at ive p er c en t age drug r e m a i n ing (log C r ) r e sult whose slope will be log H i guchi ’ s model Cu m ul a t i ve pe r cen t age of t o re l ease vs. t i m e . A st r a ig h t l i n e will - K 1 / 2.303 and in t e r cept will be log C C r = log C – K 1 t / 2 . 303 drug r e l e as e d vs. squa r e root of t i m e . ½ C = K H t Drug r e l e ase r a te is propor t ion a l to t he r e c i pro c al of the squa r e root t i m e. of 37

37.  A st r a i ght l i ne will be r e sult whose slope will be K H H i xso n- C r o w e l l cube r oot l aw T o eva l ua t e the drug r e l ea s e with changes in the su r face a r ea di a m e t er of the pa r t i c l e s/t a ble t s: and t he 3√ C - 3 √C t = k HC . t W he r e C t i s the Concent r a t i o n of drug r e l e as e d i n t i m e t . C i s the ini t ial C o ncent r ation of the drug i n the tab l et K HC i s the ra t e cons t ant for the Hi x so n- Crowell rate equa t i o n, as t h e cube root of the pe r cen t age of drug r e m a i ning i n the m a t r i x v/s t i m e . 38

38. 1 2 120 y = 3 . 6 987x + 19 . 7 43 R ' = 0.8842 j t g ~ 100 ..II 100 80 ~ 80 . 1 . , ! 60 .. . ~ .i 60 · ~ 4 " E ... 40 . . . l . E . 20 20 o ~ • 5 10 15 Ti m e (hr s ) a 20 25 30 5 10 15 Ti m e ( h rs ) b 2 2 5 30 2 . 5 1 20 s: 1 00 v = 20.193 x - 0.4547 R'=0 . 9941 v= -0.0 481 x + 1 .9827 R' =0 . 989 4 .. 2 J " I I . ! . .5 80 6 40 . e 5 1 . 5 - " e ~ ! . ! . ~ ~ " ~ 1 - . . . e . JI " E 20 " .9 0.5 v ... -20 1 2 3 4 5 6 Sq ua r e r oot of t i m e ( h rs] 20 30 l O Ti m e ( h r s ) c d ( a) In v i t r o drug r e l e ase m odif i ed re l e a se for m ul a t i on (b) Z e ro ord e r r e l e ase m odel ( c ) fi r st ord e r rel e ase m odel (d)Higu c hi re l e a se m odel 39

39. Me c hanism of drug r e l ease When a dr u g deli v ery s y s t e m is intr o d uced in the appr o priate dissol u tion m edi u m t h en it sw e ll and exist in f o ll o wing t h ree fr o n t : Swelling f r o n t : T h e b o undary between t h e g l as s y p o l y m er and its r u b b er p h a s e . Diffusi o n f r o n t : T h e b o u n dary between t h e S o lid a s u n d i s s o l ved d r ug and t h e d i ssol v ed d r ug in t h e gel la y e r . E r osi o n f r o nt : m edi u m . The b o u n dary betw e en the m a t r i x and the d issolut i o n In co n tr o lled or sustai n ed rele a se f o r m u l atio n s, di f f u sio n , sw e lli n g and erosion are the three m ost i m p o rtant rate contr o lli n g m e c hanis m s . T h e d r ug rele a se fr o m t h e p o l y m er i c syst e m is m ost l y b y t h e d i f f u sion a n d is best described b y fick i an d i f f u sio n . 40

40.  But i n case of f o r m ulation con t a i ning s w e l l i ng pol y m er s , oth e r proc e ss i n a dd i t i on t o di f f usion pl a y a n i m por t ant role drug rel e ase m ech a nis m s . i n explori n g the  Due t o s w e l l ing consider a ble volu m e expansion t a ke m ov i ng di f f u sion bou n da r i e s co m plicati n g the sol u t i on low of di f fusion pl a ce l eading to of fi c k ‟ s seco n d Ko r smeye r - Peppas model or Po w er low Drug rel e a s e is a fu n ction o f the exp o nent (n) o f ti m e . M t / M ∞ = Kt n W h ere Mt / M∞ is t h e frac t i o n o f d r ug r ele a se, t is t h e ki n etic constan t . rel e ase t i m e , K is a n is a n exp o ne n t t h at character i zes t h e Mecha n ism of rele a se is te r m e d as rele a se ex p o n en t . T h e val u e o f rele a se ex p o n ent c h an g es with chan g e t h e ge o m etry o f tablets . 41

41. To de t er m ine the va l ue Log cu m ul a t i ve % of drug re m a i n ing t o be n can re l e a se v/s log t i m e (hr) was pl o t t ed and from the slop e , va l ue of be ca l cu l a t ed. V a l ue of n will t e ll a bout the m e chan i s m of drug rel e a se form for m ul a t i on l i ke a. b. n = 0.45- ---Fick i an di f fusion, si m ple di f fusion (non- s w e l l i ng) 0.45 < n < 0.8 9 - -- - An o m a l ous or non-fick i an d i f f usion m eans S w e l l i ng (do m in a nt), di f fusion and erosion con t rol l ed rel e ase. both c. n = 0.89 or abov e - ---c a se-2 re l ax a t i on m eans erosion of pol y m eric cha i n . or super c ase tr a nspor t -2 Com p arative drug r e l ease st u dy 1. Model independent model  U s ed i n th i s case, a c o m para t i v e s t u d y be t ween two produc t . of drug rel e ase or dissolved  One i s t a ken as for m ul a t i on ) . refe r enc e /standard or ano t h er a s t e st (design 42

42.  Model ind e pendent m a t h e m a t i cal approa c h t o co m p are the disso l ut i on prof i le using two fa c tors, f1 and f2. (a) Diffe r ence Factor (f1) The d i f fere n ce fac t or ( f 1 ) c al c ulates the and pe r cent ( % ) di f feren c e be t ween the two curv e s a t eac h t i me po i nt rel a t i ve error be t ween the two curves is a m e asure m ent of the W h ere, n = n u m ber o f ti m e p o i n ts Rt = % d i ssol v ed a t ti m e t o f refer e nce p r o d uct ( p re chan g e) Tt = % dissol v ed a t ti m e t o f test pr o d u ct (p o st change) Appl i cati on : F 1 is spec i ally used to c o m pare t w o d i ssol u t i on p r o f iles ( d i f ference) , bei n g neces s ary to co n sider on e o f t h em a s t h e refer e nce stan d ard p r oduc t . T o indicate t h e d i f ferences between two, F 1 value sh o uld b e > 15 - 5 ( F DA g u i d eline ) . T h e val u e ≤ 1 5 i n d i cate s i m ilarit y . Us e f u l when 43 sa m p l e p o i n t are less in n u m ber (t h ree o r less ) .

43. (b) Si m i l arity Factor f 2 is inv e r sely prop o rt ion a l to t he av e ra g e squared d i f f erence be t ween the two r e l e ase profi le . The factor f2 m ea s ur e s the c l osen e ss be t ween the two profi l es.  FDA has set a pu b lic s t a n d a r d of f 2 va l u e b e t w een 50–100 to indic a te si m i l ar i ty between two disso l ution profile s .  The va l ue <50 ind i ca t e di f ferenc e .  Useful when sa m ple point a r e m ore i n nu m ber ( m ore th a n th r ee ) . 44

44. 2.Sta t is t i c al A n alys i s for co m pari s on (a) Student ’ s t- T es t :  Calc u la t ed „t‟ v a lue ( m ean) i s co m pa r ed w i th tabul a ted va l u e of „ t‟ i f t h e calc u la t ed v a l u e exceeds the tab u lated v a l u e, th e n t h e n u ll hypoth e s is s hould be re j ected and i n dic a te the signi f ica n t d i f ferences between the disso l ution profile of two f or m ula t ion or vice vers a .  One cha r ac t er of only two produ c t can be co m pa r ed at one t i m e (b) A N O V A Method (An a lys i s of V ariance)  Dete r m ine t h e F v a lue (cr i ti ca l f a c t o r / v aria nc e ) . Co m pa r e t h e varia n ce of di f ferent gr o ups of da t a and pr e d ict whether the data are co m parab l e or no t .  M i ni m um th r ee s e ts of data are required for co m pa r ison and can co m pa r e o n e c h a r ac t e r ( l ike d is s o lution) i n case of one way AN O V A and two cha r ac t e rs ( i n case of two way A N O V A) 45

45. In v i tr o /In v i vo e v a l uati o n of m od i fied r e l e a se dos a ge fo r ms  I n - vi t r o e v al u at i on p a r a m e t ers o f m o d ifi e d rele a ses d e l i v ery s y st e m d e p e nd s upon t he type o f s y st e m a s well a s ro u te o f d e l i v e r y . We sus t a i n e d rel e ase t a b l e t . are t a k e n a c a se o f or a l  Al m ost al l e v a l u a t i on p a ra m e t ers are simi l ar t o t h at of E v a l uation of m o dified tablets O f fic i al T es t s: c o n v e n t i o n al t a b l e ts . W e i g h t vari a t i on Disi n t e gr a t i on ( not for m o d ifi e d rel e ase for m u l a t i o n e x c e pt c o n v e n t i o n al e n t e ric c o a t ed for m u l a t i o n ) Disso l u t i o n or p erc e nt dr u g rele a se in c a se o f m o d ifi e d rel e ase for m u l a t i o n D r ug c o n t e n t in case o f si n g l e u n it s y st e m a n d dr u g l o a d i n g / e n tra p m e n t e f fici e n c y in case of m u l t i p l e u n it s y ste m . S w e l l i ng index st u dy in c a se o f m o d ifi e d rel e ase for m u l a t i o n sp e c i fic a l l y for S u stained / c ont r o l l e d syste m . Gastric res i d e n c e ti m e in c a se o f Gastrore t e n t i ve s y st e m 46 1. 2. 3. 4. 5. 6.

46. No n - O f f i c i al T es t s: General A p pearanc e , Shape (o f f ic i al Thickne s s of t a bl e ts Hardne s s Friab i lity (o f f ic i al test in IP) Unique id e nt i fi c at i on m a r king in IP) and Size of tab l et 1. 2. 3. 4. 5. 6. O r ganol e pt i c prop e r t i e s 47

47. Dissolu t i o n T est  Rate o f d i ssol u ti o n/ rele a se is d i rectly related to t h e e f fica c y o f t h e d r u g .  Rate o f d i ssol u ti o n is a good i n dex f o r co m p a ri n g t h e b i oa v ailabil i ty o f two tablet p r o d ucts o f t h e sa m e d r u g . Official Dissolu t i o n T est App a rat u s T ype I. P . USP B. P . E. P . T ype 1 Paddle B a sk e t apparatus B a sk e t apparatus Paddle appa r atus apparatus T ype 2 B a sk e t Paddle appa r atus Paddle appa r atus B a sk e t apparatus apparatus T ype 3 R e ciprocating Flow through Flow through c y linder cell apparatus cell apparatus T ype 4 Flow through cell apparatus T ype 5 Paddle over disk T ype 6 Rotating c y linder T ype 7 R e ciprocating holder

48. 49 O f f i cial Disso l ution T est A p paratus and s pec i f i c applica t ion T y p e USP Rot a ti o n s p eed T y p e 1 B a s k et ap p aratus 50- 1 r p m , m ay I m m edia t e d r u g release (IDR) go u p to 1 5 r p m Dela y ed re l ease ( D R) Exten d ed / m o d ifi e d release (ER) T y p e 2 Pad d le ap p aratus 25- 50 r p m I D R, DR, ER T y p e 3 R e c i p r ocat i ng 6- 35 r p m I D R,ER c y l i n d er T ype 4 Flow thr o u g h N/A E R , P o o r ly solu b le API ce l l ap p aratus T y p e 5 Pad d le o v er 25- 50 r p m T ra n s d er m al patches disk T y p e 6 Rota t ing c y l i n d er N/A T ra n s d er m al patches T y p e 7 R e c i p r ocat i ng 30 r p m ER h o lder

49. 1. USP Dis s olut i on apparatus I ( Bas k et m e thod) Design:  V es s e l : - M a de of boro s i l i c a te gl a ss. Se m i h e m isph e r i cal bot t om Capac i ty 1000 m l  Sha f t : - Stain l ess ste e l 316  Speed 50 - 100 rp m .  W a t er ba t h : - M a in t ained at 3 7 ±0.5 º C  Dosage form is kept in bask e t.  Screen: 40x40 m esh (0.015 inches opening), wi r e di a m e t er 0.01 in c h ( s a m e as IP) 20x20 m esh (0.034 i nches open i ng) wi r e di a m e t er 0.016 in c h  U S E: T able t s, capsule s , f loa t ing dosage f or m s  and m odified r e l e ase sys t e m , m ul t ip l e unit sys t e m .

50. 2. U S P Disso l ution apparatus II ( Pad d le Design:  V es s e l : - Sa m e as bask e t appa r a t us  Shaft: - Fused wi t h bl a de at bot t om  Sti r r i ng e l e m ent s : - Coated with t e flon For labora t ory purpose st a in l ess st e el is used  Rotat i on S p eed : - 25 - 50 rpm  W at e r - bath: - Ma i nt a ins at 3 7 ±0.5°C m e thod)  Sinke r s : - Plat i num wire used to prevent  t a bl e t/ c apsule from float i ng.  Dosage form shou l d r e m a i n at the bot t om cen t er of ves s el  U S E: Co n vent i onal as w e l l as m odif i ed r e l ease tab l e. Not suitable for f l oating system

51. Single S t a t ion dissoluti o n a p p a ra t us Pad d le type apparatus (Six sta t ion disso l ution apparatus) 52

52. Disso l ution t e st i ng and i nte r p r e t at i on IP standards * D i s the a m ount of di s so l ved a c t i ve i n g r edi e nt s pec i fi e d in the i n d i vidual m o n o g ra p h ( S u p pose 8 0 % ) , ex p ressed as a pe r centage o f the l a bell e d co n t e n t . * * Pe r cent a ges o f t h e label l ed con t en t . S r .n o . Qu a n t i t y N um b er o f Accep t a n ce cr i teria S t a g e / l e ve t a blets tes t ed l 1 S1 6 Ea c h unit is n o t l e ss than D * + 5 per cent ** . 2 S2 6 A ve r age of 12 u n i t s ( S 1 +S 2 ) is eq u al to or g r ea t er than D, a n d no u n it is l e ss than D – 15 per cent **. 3 S3 1 2 A ve r age of 24 u n i t s ( S 1 +S 2 +S 3 ) is eq u al to or g r ea t er than D, n o t More than 2 u n i t s are l e ss than D – 15 per cent * * and no u n it is l e ss than D – 25 per cent **.

53. Dis i ntegrat i on test ( U .S. P .) :  Dis i nteg r at i on te s t i s not perform e d for cont r ol l ed & s us ta i ned r elea s e tab l et s . Speci f ic test S w el l ing index ( S I ) : O ne t a blet f rom each f o r m ula t ion i s ke pt i n a pet r i di s h conta i n i ng pH 7 .4 p hospha t e bu f f ers . The ta b let was r e m o ved eve r y th r ee hour interval up t o 12 hour a nd excess water blo t t e d c areful l y us i ng f i l ter pape r . % S.I = (final w t- in i t i al wt/ i ni t ial wt) x 100 Float i ng lag t i me and durat i on of f l oat i ng  The bu o ya nc y lag t i m e (second s - exp e cted u p to 30 seco n ds) and Durat i on of f loa t ing we r e de t e r m ined i n the USP Disso l ut i on ap p ara t us I I i n an acid i c envi r on m ent ( 0.1N H C L, 900 m l, 50 RPM ) .  The ti m e interval be t ween in t roduc t ion of the tab l ets i n t o the di s so l ut i on m edium and its buoy a n c y to the top of the di s so l ut i on m edium i s taken as bu o yan c y lag t i m e and du r at i on of b u oyan c y is observed vi s ual l y .

54. In-vivo t e sting 1. Phar m acodyn a m i c study: Ther a peu t ic ac t iv i ty as well as tox i c i ty stu d y . Pe r fo r m on co m m only use d . Phar m acok i ne t ic Stand a rd a s well suit a ble an i m a l m o de l . Mice, rat, rabbit m ode l s are 2. stud y : a s t e st perfor m ed in suit a ble an i m a ls mod el . for m ul a t i on giv e n t o t h e suit a ble a ni m a l group s . Bl o od will wi t hdraw at s pec i fic ti m e in t erval and the conc e ntra t i o n of d r ug i n blood i s de t er m ine by suit a ble a n al y t i cal t e chn i que like H P LC, HP T LC, L C - M S e t c. Plot a graph be t ween tim e and c o ncen t rat i o n . Here y ou w i l l find three para m e t e rs l i ke AUC, T m ax and C m a x . By be us i ng AUC, bi o a v a i l a bi l i t y can be de t er m i n ed. m e t hod), Cut m e t hod . Spec i fic test: AUC can m e a s ured by P l an i m e t e r (ph y sical & weigh m e thod, T rape z oid a l m e t hod and square c ount For ga s t r o r etentive fo r mul a ti o n : R ad i o graphs using X - r a y equ i p m e n t t o see the c o ndi t ion e i ther floa t ing, s wel l ing or set t l i ng due t o high densi t y . Ga m a Sc i nt i grap h y : for t a r ge t ing of a for m ul a t i on a spec i fic o r gans 55

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