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1 ,ntroduction
1.1 Tablet: definition and types
AccRUdLQg WR Whe USP, WableWs aUe deILQed as sRlLd dRsage IRUms cRQWaLQLQg medLcLQal
subsWaQces wLWh RU wLWhRuW suLWable dLlueQWs (USP 31 NF 26 2008). WLWhLQ WhLs deILQLWLRQ,
WableWs caQ be classLILed LQ dLIIeUeQW Wypes depeQdLQg RQ Whe IRUmulaWLRQ aQd Whe
maQuIacWuULQg pURcess (cRmpUessed, mRlded, cRaWed, dUage, lRzeQge, chewable, buccal,
sublLQgual, eIIeUvesceQW, eWc.). The mRsW cRmmRQly used WableWs aUe cRmpUessed WableWs. IQ
WhLs case, Whe WableWs aUe pUepaUed by Whe applLcaWLRQ RI hLgh pUessuUe WR a pRwdeU RU gUaQules
usLQg sWeel puQches aQd dLes.
TableWs caQ be alsR classLILed LQ WhUee majRU gURups depeQdLQg RQ WheLU Uelease behavLRU:
LmmedLaWe Uelease, wheUe Whe dUug Ls LmmedLaWely Ueleased aIWeU LQgesWLRQ; delayed-Uelease,
wheUe Whe dUug Ls Ueleased aIWeU a lag WLme WR avRLd a pRssLble desWUucWLRQ RU LQacWLvaWLRQ RI Whe
dUug LQ Whe gasWULc IluLd as well as LUULWaWLRQ RI Whe gasWULc mucRsa. The WhLUd gURup
cRUUespRQds WR Whe susWaLQed Uelease WableWs, wheUe Whe dUug Ls Ueleased RveU aQ exWeQded
peULRd RI WLme. The pUeseQW sWudy wLll IRcus RQ susWaLQed Uelease WableWs.
SusWaLQed Uelease WableWs aUe dLvLded LQWR mulWLpaUWLcle aQd mRQRlLWhLc WableWs (BaueU eW al.
2006). IQ mulWLpaUWLcle WableWs seveUal uQLWs (cUysWals, paUWLcles, gUaQules, pelleWs) aUe
embedded maLQWaLQLQg WheLU physLcal aQd chemLcal pURpeUWLes. MulWLpaUWLcle WableWs
dLsLQWegUaWe LQ cRQWacW wLWh bLRlRgLcal IluLds UeleasLQg Whe uQLWs wLWh LQWacW pURpeUWLes. The
mRQRlLWhLc WableWs caQ eLWheU be cRaWed wLWh aQ LQeUW pRlymeU WhaW Ueleases Whe dUug WhURugh
dLIIusLRQ RU be maWULx WableWs, wheUe Whe dUug Ls embedded LQ a spRQge-lLke sWUucWuUe aQd
Ueleased WhURugh dLIIeUeQW mechaQLsms (RLWschel eW al. 2002).
The Uelease RI a dUug WhURugh a pRlymeU caQ usually be descULbed by FLck`s laws RI dLIIusLRQ.
FLck`s ILUsW law, Ls shRwQ LQ equaWLRQ (1.1):
:
c
D J
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(1.1)

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1
molar flux of arug [mol/cm
2
s{
D
12
aiffusion coefficient of the arug in the polymer [cm
2
/s{
cc concentration of the arug [mol/cm
3
{
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8
c: length aiffusion path [cm{
ThLs equaWLRQ Ls QRUmally used IRU Whe descULpWLRQ RI UeseUvRLU-Wype, dLIIusLRQ-cRQWURlled
sysWems aW sWeady-sWaWe dLIIusLRQ aQd Uelease. TR deWeUmLQe Whe vaULaWLRQ RI Whe dUug
cRQceQWUaWLRQ LQ Whe medLum wLWh WLme, FLck`s secRQd law Ls used (equaWLRQ 1.2):
2
1
2
12
1
:
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D
t
c
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(1.2)

cc concentration of the arug [mol/cm
3
{
ct time [s{
D
12
aiffusion coefficient of the arug in the polymer [cm
2
/s{
c: length aiffusion path [cm{
A sLmple equaWLRQ (equaWLRQ 1.3) was pUeseQWed by RLWgeU aQd Peppas (RLWgeU eW al. 1987) WR
descULbe Whe Uelease behavLRU IURm cRQWURlled Uelease pRlymeULc devLces. The expRQeQW n
UepUeseQWs Whe dLIIusLRQal expRQeQW aQd depeQdLQg RQ LWs value deILQes RQe RU RWheU Uelease
mechaQLsm.
n t
kt
M
M

f

(1.3)

M
t
amount of arug releasea at a certain time t [kg{
M

total amount of arug releasea [kg{

k aissolution velocity constant [1/s{
t time [s{
n aiffusional exponent
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The values IRr Whe dLIIusLRQal expRQeQW dLIIer depeQdLQg RQ Whe geRmeWry RI Whe sysWem
(Peppas 1985; RLWger eW al. 1987; LLQdQer eW al. 1996) as shRwQ belRw (Table 1)
Table 1 Diffusional exponent ana mechanism of aiffusional release from various non-swellable controllea
release systems
DLIIusLRQal expRQeQW n
ThLQ ILlm CylLQdrLcal sample SpherLcal sample
Drug release mechaQLsm
0.50 0.45 0.43 FLckLaQ dLIIusLRQ
0.50Q1.00 0.45Q0.89 0.43Q0.85 AQRmalRus (QRQ FLckLaQ)
WraQspRrW
1.00 0.89 0.85 ZerR-Rrder release: erRsLRQ
Rr relaxaWLRQ cRQWrRl

There are Whree maLQ mechaQLsms WR classLIy cRQWrRlled release sysWems (LaQger eW al. 1983).
These mechaQLsms are shRwQ LQ Table 2. The mechaQLsms wrLWWeQ LQ bRld leWWers are WhRse
dLrecWly relaWed wLWh WhLs sWudy.
Table 2 Classification of controllea release systems by mechanisms
DLIIusLRQ cRQWrRlled
ReservRLrs (membraQes)
Matrices (monoliths)
ChemLcally cRQWrRlled
Erosion
PeQdaQW chaLQ
SRlveQW acWLvaWed
OsmRWLc pressure
Swelling
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1.1.1 Diffusion controlled: reservoirs (membranes)
The membraQe dLIIusLRQ cRQWrRlled sysWems are Whe mRsW wLdely used. The dLIIusLRQ RI Whe
drug Wakes place WhrRugh Whe WhLQ layer WhaW separaWes Whe cRre RI Whe drug IrRm Whe medLa. ThLs
layer remaLQs LQWacW alRQg Whe cRmpleWe gasWrR LQWesWLQal (GI) WracW aQd cRQWrRls Whe release by
dLIIusLRQ RI Whe drug WhrRugh Whe layer (Bauer 1998).
1.1.2 Diffusion controlled: matrices (monoliths)
The maWrLces caQ be classLILed LQWR sysWems where Whe drug Ls dLssRlved, LQWR sysWems where
Whe drug Ls dLspersed Rr LQWR pRrRus maWrLx sysWems.
IQ Whe case where Whe drug Ls dLssRlved LQ Whe pRlymer, Whe drug release Ls cRQWrRlled by Whe
sRlubLlLWy RI Whe drug LQ Whe pRlymer. The cRQWrRlled release mechaQLsm caQ be explaLQed by
FLck`s secRQd dLIIusLRQ law (equaWLRQ 1.2).
WheQ Whe drug Ls dLspersed, Whe release Ls cRQWrRlled by Whe dLssRluWLRQ RI Whe drug
(NarasLmhaQ 2000). The kLQeWLc release caQ be explaLQed wLWh Whe equaWLRQ (1.4):
t c c Dc A Q
s s
) 2 (
0

(1.4)
Q amount of arug releasea at a certain time t [mol/cm
2
{
A cross sectional area of the polymer film [cm
2
{
D aiffusion coefficient of the arug in the polymer [cm
2
/s{
c
0
total concentration of the arug in the matrix [mol/cm
3
{
c
s
saturation concentration of the arug [mol/cm
3
{
t time [s{
The same equaWLRQ caQ be used WR explaLQ Whe release RI Whe drug WhrRugh Whe pRres RI a maWrLx
sysWem, cRQsLderLQg Whe pRrRsLWy aQd WRrWuRsLWy RI Whe sWrucWure, as descrLbed LQ equaWLRQ (1.5):
t c c c D Q
s s
) 2 (
0
H
W
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(1.5)

Q amount of arug releasea at a certain time t [mol/cm
2
{
D aiffusion coefficient of the arug in the liquia in the pores [cm
2
/s{
porosity of the matrix
tortuosity from the pores
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c
0
total concentration of the arug in the matrix [mol/cm
3
{
c
s
saturation concentration of the arug [mol/cm
3
{
t time [s{
1.1.3 Chemically controlled: erosion
The erRsLRQ Wype RI cRQWrRlled release sysWem caQ be used LQ bRWh reservRLrs aQd maWrLces. The
release IrRm Whe reservRLrs Ls depeQdeQW upRQ Whe permeabLlLWy aQd WhLckQess RI Whe layer.
These varLables wLll deILQe Whe release.
The release IrRm maWrLces Ls cRQWrRlled by a cRmbLQaWLRQ RI dLIIusLRQ aQd erRsLRQ. The
erRsLRQ caQ be hRmRgeQeRus Rr heWerRgeQeRus. WheQ Whe erRsLRQ Ls WakLQg place LQ Whe eQWLre
maWrLx sWrucWure Whe erRsLRQ Ls hRmRgeQeRus; wheQ Whe erRsLRQ sWarWs RQ Whe surIace RI Whe
pRlymer maWrLx LW Ls heWerRgeQeRus.
1.1.4 Chemically controlled: pendant chain
ThLs kLQd RI cRQWrRlled release Ls QRW as exWeQsLvely used as are Whe cases descrLbed beIRre.
The drug Ls chemLcally bRQded WR Whe pRlymer aQd Ls released WhrRugh aQ eQzymaWLc Rr
hydrRlyWLc reacWLRQ WhaW separaWes Whe drug IrRm Whe pRlymer sWrucWure.
1.1.5 Solvent activated: osmotic pressure
The release RI Whe drug Ls cRQWrRlled by Whe WableW sWrucWure (OROS OsmRWLc Release Oral
SysWem). The WableW Ls made RI a drug cRQWaLQLQg cRre where Whe drug Ls embedded, aQd a semL
permeable membraQe wLWh aQ RrLILce. The sRlveQW dLIIuses WhrRugh Whe membraQe, Whe vRlume
RI medLum dLssRlves Whe drug aQd aQ equal vRlume RI dLssRlved drug Ls released WhrRugh Whe
RrLILce (CRQley 2006).
1.1.6 Solvent activated: swelling
ThLs cRQWrRlled release mechaQLsm Wakes place LQ pRlymerLc sysWems where Whe drug Ls
dLssRlved Rr dLspersed LQ Whe pRlymer. The mRmeQW Whe sysWem cRmes LQ cRQWacW wLWh Whe
medLum, Whe pRlymer swells, lRwerLQg LWs glass WraQsLWLRQ WemperaWure aQd Whe pRlymer allRws
Whe drug WR dLssRlve. IW Ls pRssLble WR recRgQLze WwR maLQ LQWerIaces. The ILrsW separaWes Whe
glassy sWaWe IrRm Whe rubbery sWaWe (swellLQg LQWerIace) mRvLQg LQwards WR Whe ceQWer RI Whe
cRre, aQd Whe RWher separaWes Whe rubbery sWaWe IrRm Whe medLum (pRlymer LQWerIace) mRvLQg
RuWwards. IQ Whe lasW case Whe pRlymer QRrmally dLssRlves (LaQger eW al. 1983).
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BeWweeQ Whe glassy aQd Whe rubbery sWaWe a macrRmRlecular relaxaWLRQ Wakes place. ThLs
relaxaWLRQ aIIecWs Whe drug dLIIusLRQ WhrRugh Whe pRlymer, gLvLQg FLckLaQ Rr QRQ-FLckLaQ
dLIIusLRQ (CRlRmbR 1993).
The WraQspRrW RI Whe drug WhrRugh Whe pRlymer caQ be cRQWrRlled by Whe macrRmRlecular
relaxaWLRQ Rr by Whe dLIIusLRQ RI Whe drug WhrRugh Whe rubbery pRlymer. The DebRrah Qumber,
descrLbed LQ Whe equaWLRQ (1.6), Ls used WR characWerLze WhLs WraQspRrW:
T
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De Deborah number
Relaxation time [s{
Diffusion time [s{
WheQ Whe DebRrah Qumber Ls greaWer WhaQ 1, Whe WraQspRrW Ls cRmpleWely relaxaWLRQ-cRQWrRlled.
A Qumber lRwer WhaQ 1 meaQs Whe WraQspRrW Ls cRmpleWely dLIIusLRQ-cRQWrRlled. WheQ Whe
value Ls clRse WR 1 aQ aQRmalRus dLIIusLRQ behavLRr Wakes place, because Whe relaxaWLRQ aQd
dLIIusLRQ WLme are sLmLlar (VreQWas eW al. 1975).
TR deWermLQe LI Whe release RI Whe drug IRllRws zerR-Rrder release Rr FLckLaQ dLIIusLRQ, Whe
swellLQg LQWerIace Qumber, descrLbed LQ Whe equaWLRQ (1.7), Ls used:
D
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(1.7)

Sw 'Swelling interface` number
v velocity of the swelling interface [cm/s{
sample thickness [cm{
t time [s{
D aiffusion coefficient of the arug in the polymer [cm
2
/s{
WheQ Whe Sw Ls lRwer WhaQ 1, a zerR-Rrder release caQ be expecWed. A Sw greaWer WhaQ 1 meaQs
FLckLaQ dLIIusLRQ.
ThLs RvervLew prRvLdes Qecessary kQRwledge RI Whe dLIIereQW pRssLble release mechaQLsms
requLred WR dLscuss Whe WRpLc RI WhLs LQvesWLgaWLRQ, maQuIacWurLQg RI maWrLx WableWs WR prRvLde
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susWaLQed release RI hLghly sRluble by cRmbLQLQg cRuQWercharged pRly(meWh)acrylLc pRlymers.
The QexW pRLQW WR dLscuss Ls Whe varLeWy RI excLpLeQWs WhaW caQ be used WR buLld a maWrLx.
1.2 Excipients used to build a matrix
MaWrLx IRrmulaWLRQs are cRmmRQly chRseQ IRr cRQWrRlled release due WR Whe several
advaQWages Whey RIIer. The maQuIacWurLQg RI Whese WableWs dRes QRW requLre specLal equLpmeQW.
IQ several cases, Whe drug release velRcLWy depeQds RQ Whe maWrLx sWrucWure aQd QRW RQ RWher
IacWRrs lLke LQWesWLQe mRWLlLWy, elecWrRlyWe cRQceQWraWLRQ RI Whe medLum Rr pH. CRmpared WR
cRaWed WableWs, maWrLx WableWs are mRre rRbusW. CRaWed WableWs are alsR mRre lLkely WR lead WR a
dRse dumpLQg eIIecW LI Whe ILlm Ls QRW prRperly IRrmed Rr Ls physLcally damaged pRsW
maQuIacWure (RLWschel eW al. 2002).
The excLpLeQWs used WR buLld a maWrLx caQ be classLILed by WheLr chemLcal sWrucWure aQd by WheLr
prRperWLes as hydrRphLlLc, LQerW, lLpLdLc, bLRdegradable aQd resLQ maWrLces (GaQdhL eW al. 1999).
1.2.1 Hydrophilic (Cellulose ethers and esters)
These excLpLeQWs are Whe mRsW wLdely RpWLRQ WR use IRr maWrLx WableWs WR prRvLde susWaLQed
release. These pRlymers are semLsyQWheWLc prRducWs RbWaLQed by alkylaWLRQ RI cellulRse. The
dLIIereQces beWweeQ Whe varLRus Wypes resLde LQ Whe dLIIereQW degree RI subsWLWuWLRQ aQd degree
RI pRlymerLzaWLRQ varyLQg alsR Whe WRWal mRlecular weLghW (FLgure 1), aQd WhereIRre WheLr
release characWerLsWLcs. The release Ls based RQ swellLQg prRcess leadLQg WR a gel layer
IRrmaWLRQ (Vueba eW al. 2005).

Figure 1 Structures of cellulose esters ana ethers

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