Ir aq i J.Pharm.Sc i., Vol.15 (1 )  ,2006 49

In Vitro Release Study on Capsules and Tablets Containing  
Enteric - Coated Granules Prepared by Wet Granulation 

Eman B. H. Al-Khe dairy* 
Received   27-4-2004          Accepted    21-10-2004  

ABSTRACT 
       We t granulation metho d was  used instead of conventional pan c oating  or fluidized  – bed coa ting  
te chnique  to  p repare e nteric -coate d diclofenac sodium granules , us ing ethano lic s olutio n of EudragitTM 
L10 0 as coating, b inding  and granula ting a ge nt .Add ition of PEG400  o r di-n-b utyl phthalate as  a 
plas ticizer was found to imp ro ve the  e nteric  p rope rty of the coat. 
Part o f the re sulted  granules  was fille d in ha rd  gelatin c apsules (s ize 0), while the o ther p art was 
co mpressed into  tab le ts with a nd without disinte grant. 
The  releas e profile of these two dos age fo rms  in 0 .1 N HCl (pH 1.2)fo r 2 ho urs, and  in p hos phate buffer 
(p H 6.8) for 45 minutes  as  we ll as  the  re lease kine tic we re  c omp ared with that o f the  e nteric  film c oated 
Voltadin (R)  SDI tab le ts . 
The  results of this  s tudy s ho w tha t, the prepared  dos age  forms  have  a  goo d ente ric property, with fa ster 
re lease of drug fro m e nc aps ulated  enteric-coated granules  in c ompa ris on with comp ress ed  tab le ts. 

 

  الخالصة
ة لتحضيرحبيبات      خدام الطريقةالرطب ست وفي تم ا كل ى لتحضيرعقار صوديوم داي شائعة األخر ال من الطرق ال ة معويا بد غلف ناك و ذلك م

مادة اليودراجيت ا ل ولي ل وب في  ۱۰۰باستخدام محلول كح ث انها التذ حي ة  غلف كونها مادة م كمادة رابطة لتكوين الحبيبات باألضافة الى 
جيني اعلى من ولكن تذوب في أس هيدرو عدة  ولي اثيلين  ٦الم مثل الب ة  غلف زيد من مرونة المادة الم خدام مواد ت ست وقد وجد ان ا

ول معوي  ٤۰۰كاليك غليف ال حسن من عملية الت وتيل فثاليت ت مادة ثنائي بي   .و
ة وسرعة       كيفي ة  رن مقا ب٬ حيث تم  وتحويله الى حبو ما تم ضغط الجزء اآلخر  ة جزء من هذه الحبيبات في كبسوالت ك وقد تم تعبئ

هيدروجيني هذه األشكال الصيدالنية في وسط ذي اس  ن  عقار م رر ال ري( ۱‚۲تح مض الهيدرو كلو هاحا رية قيمت ۰ك ذي عيا لمدة ) ٫۱
جيني  ي اس هيدرو عتين وفي وسط ذ ة معويا( دقيقة مع حبوب  الفولتادين ٤۵لمدة  ٦٫۸سا غلف راء )  الم وية سام عمل اد   .من ا نتاج م

ة على      وي حضرة٬ وأ ن تحرر العقار من الكبسوالت الحا ة الم الني ي لألشكال الصيد ودة التغليف المعو الحبيبات  وقد اظهرت النتائج ج
وب حب رره من ال ويا كان أسرع من تح ة مع غلف  .الم

 
INTRODUCTION 
      En te ric co ated  granules  e nc apsulated in hard 
ge la tin caps ules  as a p harmaceutica l d osa ge  form 
were us ed to  ge t products with fa st o ns et of 
absorption and be tter pha rmaco kine tic properties 
(1-3), s ince  this  dosa ge  form is  less influenc ed  by 
fo od intake  due to  faster gas tric e mptying  of 
granules after diss olving of hard gelatin s he ll 
co mpared  with the retentio n o f re la tiv ely la rge 
ente ric coated  ta blet in the  s to mac h. 
 In a dditio n, patients  p re fe rred  the easily 
swa llowed ge latin c apsules on tab le ts  (4). 
Different tec hniques  were used  to  prepa re 
ente ric-co ated  granules  or pellets, s uc h a s pan 
coating and fluidize d bed coating ap paratus  (5-8). 
The  a im of this  study is  to investigate whe ther 
ente ric-co ated  granules  co uld be p repa red by 
ordina ry we t granulatio n metho d using ethanolic 
solution of EudragitTM  L 1 00  as  coating and 
granulating agent.  

 
 
 

The  non-steroida l anti-infla mma to ry d rug 
(NS AID) Dic lo fe na c s od ium is      us ed  as  a 
mode l d rug fo r this stud y. 
MATERIALSand METHOD 
Mater ials:- 
       The  following ma te rials  we re  us ed , 
Dic lofenac so dium (Bio Gena.Ita ly), EudragitT M 
L 10 0 (Rhö m pharma ,GMBH, Weiterstadt, 
Germany) ,Ethanol 95% ,Polyethylene  glycol 
400  (BDH chemica ls  Ltd ,Pool Engla nd ), 
Lac to se  ,Hyd rochloric acid, (Rieda l-De  Hae n, 
AG Seelze-Ha nno ve r, 
Germany) ,Microcrys ta lline  c ellulose  (Av icel P H 
102 ) (F MC Co rp oratio n,Pe nsylvania 
USA.) ,Trisod ium pho sp hate  (Hopkins  and 
Willia ms Ltd . ,En gland), Di-n-butyl p htha la te 
(US B ,B. Brus sels  ,Be lgium), Magnes ium 
stea ra te (Me rc k ,Darms ta dt ,Ge rmany), and  
ente ric film c oated Vo lta din(R) S DI  tab le t as  a 
re fe re nce. 

 
 
 

    *De partment of Pharmaceutics ,College of Pharmacy, Univers ity o f Bag hdad,Bag hdad- Ir aq 
 

 
 
 
 

 
 
 
 



Ir aq i J.Pharm.Sc i., Vol.15 (1 )  ,2006 50

Method:- 
 Preparation of Enteric-Coated    
  Granules:- 
        Diclofenac  sod ium was mixed with 
lactose and the  powde r mass was  mo is te ned 
with 2 % e thanolic  s olution of Eud ra gitT M L100 
as  a  gra nulating , b inding and ente ric coating 
agent (6, 9) until the p ro pe r consistency was 
obta ined. The  a moun t of enteric polyme r was 
about 1.25% base d o n the to ta l weight of the 
powder mixture. The moist ma ss  was  the n 
granulated by passing through a 0.8 mm mes h 
size  s ieve . The  gra nules  we re  the n dried o n 
trays. Part o f the  res ulte d granules  was filled in 
ha rd  gelatin capsules   size 0 (25 mg ⁄ c aps ule) 
while the  othe r p art was  co mpressed  into 
ta blets (25 mg      ⁄ ta blet). 

 Dissolution:- 
      The dissolution c harac te ris tics  of the 
encapsula ted ente ric-coated  gra nules, the 
co mpressed ta blets fro m the  prep ared  gra nules 
and  Vo ltad in(R)SDI ta blets as  a  refere nce  were 
stud ied using USP XXIV metho d for enteric 
coated products a t 50 r.p.m and c ons tant 
te mpe ra ture  (37±  0.5 °C ). One capsule  or 
ta blet of e ach was  p la ced in 7 50 ml 0 .1  N HCl 
(p H 1 .2 )a nd samples  were ta ken for 2  hours, 
fo llowed b y add ition o f 250  ml of 0.2M 
trisodium p hos phate to the same jar to get 
phosp ha te  buffer o f p H 6 .8 , then sa mpling 
were co ntinue d fo r 45  minutes (10). 
         Sa mples  were taken at certain ti me 
intervals and assayed fo r diclofena c so dium 
spec trophtometric ally a t its  λ max 27 3 nm fo r 
the ac id  me dium and at λ max 27 6 nm for the 
buffer medium. 

 
 Factors Affe cting the 

Preparation:-   
1. Effec t of Addit io n of Pla stic iz er:- 
     Two d iffe re nt typ es  of p la stic izers were 
us ed to  s tudy their effect o n imp rov ing the 
co ating prope rty of Eud ra gitT M L1 00. A wa te r-
so luble type  (PEG 40 0) a nd  non wa te r-so luble 
(Di-n-butyl phtha la te). 10% of e ithe r type  of 
plas ticize r ca lc ulated  on the amo unt o f dry 
la cq uer s ub stance was  a dde d to the co ating 
so lution (9).  
2. Effec t of Comp ressing  the  Granules:- 
     P art o f the  res ulted ente ric-co ated  gra nules 
was  compres sed into  tablets . The  res ults  of 
diss olution o f these tab le ts we re  co mpa red 
with tha t o f encapsula ted e nteric -c oated 
granules. 

                   
 

3. Effec t of Additio n of Disinteg ra nt : 
     10 % Av icel P H 1 02  c alcula te d on the total 
amount o f granules  was added  e xtragranularly 
(11) to the  ente ric c oa ted gra nules  be fo re 
comp re ssio n. The results of d isso lution we re 
comp ared  with tho se  of enc apsula ted ente ric-
coa ted gra nules  as  well as with tab le ts 
prepa re d from the same gra nules but witho ut 
disintegra nt. 
RESULTS and DISCUSSION  
 Dissolution in Acid   Medium:- 
1. Effe ct of Addition of  Plas ticiz e r:- 
          The  e ffec t of pla sticize r was  s tudied  by 
comp aring the  re le as e of drug from the  
enc aps ulated  gra nule s co ated with EudragitT M 
L100  in ac id  med ium with a nd  witho ut 
add ition of plas ticize r. 
      The  res ults show that 15% of the drug was  
re le ase d from the  coa ted gra nule s in the  
abs ence of p la sticize r in the  c oa ting s olutio n, 
which is not a cc epted  a cco rd ing to  the  US P 
re quire ments  fo r the e nteric -c oate d 
pre pa ra tions, whic h state that not mo re  than 
10% of drug diss olve s at the end of 2  hours  (10). 
          Additio n of e ither P EG 400  o r di-n-b utyl 
phtha la te to  the  c oa ting s olution de crea sed  the  
re le ase  of the  d rug afte r 2 ho urs of d is so lution 
in a cid med ium to 6 .2 % a nd 8.5% res pec tive ly 
in co mpa riso n with 1 0% relea se d from the  
re fe re nce  Voltadin(R) SDI ta blets (Fig. 1 ), 
which a re a ll acc ep ta ble. 
          The se re sults indica te  tha t add ition of 
either o f the  p la stic izer can imp ro ve the  e nteric  
pro pe rty of the coa ting polyme r whic h may be  
due  to increa sing the  mo bility of the  chain of 
the polyme r at the surfac e of the  gra nules , so  
they fa cilitate the  filming p ro perty o f the  
polyme r (12,13),but since  d i-n-butyl phthalate is  
non water so luble, it will de creas e the  
permea bility of film to  mo is ture  a nd  enha nce  
the stability of the pro duct, so  it is pre ferred  
fo r the  prepa ra tion of this prod uct on P EG 400  
(14),the re fo re the granules  prep ared  with P EG 
400  we re  negle cted. 
2. Effec t of Compressing  the  Granule s:- 
     Co mpress ing of the granules  p re pared  using 
di-n-butyl phtha la te as  plas tic izer fo r the  
coa ting ma te rial to tablets  with and witho ut 
add ition of disintegra nt, resulte d in decreasing 
the release  of d rug in the a cid medium of 
diss olutio n to  7.4% and 6 .3% respe ctively in 
comp aris on with the e nc aps ulated granules 
(Fig. 1). The  decrease  in the re lease of drug 
may be  d ue to the sma ller s urface  a rea of the  
ta blets comp ared  to the  gra nules , while the  
slight d ifference in the re leas e be tween the two 
ta blet p repa ra tions, may be  d ue  to the effec t of 
disintegra nt. 



Ir aq i J.Pharm.Sc i., Vol.15 (1 )  ,2006 51

 
 
 

                       
 
 
 
 
 
 
 
 
 
 
 
 

                                                  
    Acid me dium               Buffe r 
       pH(1.2)               me dium pH(6.8)   
   
  

 
Fig. (1 ) Dissolutio n profile  of e ncaps ulate d 
e nteric-coa te d granule s ta ble ts Pre pa re d 

with  and  wit hout ad dition o f disinte g rant in 
c ompa riso n with Vo ltadin(R)S DI table ts 

 

 Dissolution in Buffer Medium:- 
       As s hown in Fig. 1, highe r and fa ster 

re lease was ob tained from e nc apsulated 
enteric-co ated granules  in comp arison with 
Volta din(R)SD I ta blets and  tab le ts  p repared 
with and without add ition of d is inte grant, 
where ab out 90% of the  d rug was  released 
fro m these  gra nules within 2 0 minutes  (8) 
comp ared  to 72%, 57.5% and  49.7% from 
the othe r tablets , respec tive ly.            
This high a nd fas t re le ase of d rug is  ma inly 
due  to the  large r surface area  o f the  gra nules 
comp ared  to the  tab le ts . 
In  ad dition, bo th the encapsula ted ente ric-
coa ted granules  and  tablets containing 
disintegra nt a s well a s Vo ltad in(R)SDI tab le ts 
met the  USP spec ifications  for the re lease of 
drug in buffe r solutio n (not less than 7 5%of 
drug dissolves at the end  o f 45  minu te s) (10) 
in c ontras t to ta blets without dis inte grant.   

Kine tics of Dissolution:- 
     The release charac te ris tics  o f the  d rug fro m 
encapsula ted ente ric-coated  gra nules and 
ta blets prepa red from the se  gra nules in 
presence of disintegra nt a s well as that of 
Voltadin(R) S DI ta ble ts, fo llow firs t order 

kinetics , since p lo tting the lo garith m of the  
perce nt rema ining versus ti me gav e straight 
lines with good  corre latio n (r-value range  fro m 
-0 .94 to -1 .01) for the  acid me dium and the  
two  p hases in the  buffe r me dium of d isso lution 
as  s how n in F ig.2 . 

 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

                   Acid me dium              Buffe r 
                         pH(1.2)            me diu m 
pH(6 .8) 
                                           
Fig . (2)  Plot o f the  log % re ma in ing ve rs us 

time  for the  re lease  o f drug fro m 
e nca psulate d e nte ric-coate d granule s and 

table ts   pre pa re d with addition o f 
disintegrant in co mparis on with 

Vo ltadin(R) S DI ta ble ts. 
 

       The s mall value of the release  ra te 
constant in the ac id  me dium(pH 1.2) (Table 1) 
gives  a n indication that the c oating mate rial 
(EudragitTM  L1 00) when used  as gra nula ting 
and  b inding a gent is effec tive  in preventing  the  
re lease of d rug in acidic  p H.  
However, the  s mall a nd s low release of d rug at 
this  p H ma y be either due  to the presence of 
sma ll-unc oated d rug or due to  the release of 
drug through the c oating  and its  po ss ib le 
discontinuitie s (15). 
       As the  pH of the d isso lution med ium 
reaches  the level critica l for the  coa ting p H 6 .8 
(b uffe r me dium) the  fil m s ta rts  to d isso lve, 
thereby inc reas ing the re leas e of d rug (9, 15) as 
shown in Fig.2 and Tab le  1 , in which the re  is  a 
great increase in the rele ase  rate co ns ta nts of 
the two  dosa ge fo rms  in the buffer med ium 
mainly at the firs t p hase (more than 1 00 time s) 
comp ared  to tha t at ac id  me dium. 
   In  a dditio n, the  res ults  o f diss olution at the  
buffer med ium give  an indica tion tha t the  
re lease of d rug is  a ffec te d by the  d osa ge  form 

0

10

20

30

40

50

60

70

80

90

100

0 20 40 60 80 100 120 140 160 180

Time (minutes)

%
 D

ru
g 

re
le

as
ed

Encapsulated enteric-coated
granules using di-n- butyl
phthalate as a  plasticizer

Voltadin(R)  tablets

Tablets with disintegrant

Tablets without disintegrant

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

2

0 20 40 60 80 100 120 140 160 180

Time (minutes)

L
o

g 
%

 r
em

a
in

in
g

Encapsulated enteric coated granules
using di-n-butyl phthalate as a
plasticizer

Voltadin (R) tablets

Tablets with disintegrant



Ir aq i J.Pharm.Sc i., Vol.15 (1 )  ,2006 52

as  well as  b y the surfa ce area, s ince  the  rele ase 
ra te  cons ta nts fo r the e ncaps ulated  ente ric-
coated gra nules are  highe r tha n that of 
co mpressed ta blets. 
 
 

Table  (1) 
Re le ase  rate co ns ta nts  (K) min-1.o f the  Pre pare d 
Do sage  Fo rms  in Comparis on with Vo lta din(R) 

SDI Tab le ts 
Voltad in(  R ) 
 SDI 
Tablets   

Tab le ts   
with 
Dis inte -
grant  

Enc apsulated  
Enteric-coa ted  
Gra nules using  
di-N-Butyl  
Phtha la te as   
Plasticize r  

p H The 
Dissol-  
ution 
Me dium 

88.3*10-5 5 7.5*10-5 7 6.75 *10 -5 1.2 
      6.8 

0.098 0 .143 0 .309 K1 
0.017 0 .020 0 .031 K2 

 
Abbre viations:- 
K1: re fe rs  to the dissolutio n ra te  cons ta nt for 
the  
      first pha se  in the  b uffe r med ium 
 K 2 : re fe rs  to the  d isso lution rate cons tant fo r   
        the  s econd phase  in the  b uffe r med ium    

Refe rences:- 
1. Anslow -J A.;Gree ns -DS.; Ho ope r,-JW.and 

Wa gner-GS. Fa ster and mo re  re liable 
d elivery o f salicylic acid from e nteric 
asp irin granules  versus enteric -c oated 
ta blets. Curr-Ther-Res ., 1984 , 36(Nov ), 
8 11 -818.  

2. Gams t-ON. Enteric-coated nap ro xe n 
ta blets. Eur-J -Rheumatol-Inflamm., 19 92, 
1 2 (2 ), 5-8. 

3. P ondey- VP.; Pha nindrud u- A.; 
Ma na valan- R. a nd  Livingstan- J. In v itro 
s tudy o n c apsule formulatio ns  of 
o mep ra zole  co ntaining enteric -c oated 
gra nule s. Boll-Chim-Farm., 20 02, 141 (6 ), 
4 19 -422. 

4. Overga ard A-B; Hojsted-J ; Ha nsen-R; 
Mo ller-Sonnergaard-J and Chris turp  L-L. 
P atie nt’s e va luatio n o f s hape , s ize  and 
c olor o f so lid do sa ge form. Parm- Wo rld-
S ci., 20 01, 23 (5) 185-1 88 . 

5. Hosney-EA; el-Ma hrouk, GM. and 
Goud a-MW. Formula tion a nd in vitro and 
in vivo  availability of d ic lo fe nac sodium 

e nteric -coa ted beads . Drug – Dev - Ind 
P harm. ,1 998 , 24 (7 ), 661 -6 66    

6. Ma rv ola-M; Nykänen -P; Rautio-S; 
Iso ne n-N. and Autere-A.-M. Enteric 
p olyme rs as binders and coa ting materia ls 
in mul tip le -unit s ite-spec ific drug de live ry 
s ys te ms. Eur-J -P harm-Sci., 1999, 7, 25 9-
2 67. 

7.  Oba ra-S ; Maruyama -N; Nis hya ma-Y and 
Ko kubo-H. Dry co ating a n innova tive 
e nteric  coating me thod  us ing c ellulose 
d erivative. Eur- J -Pharm-Bio pha rm., 1999, 
4 7(1), 51 - 59 . 

 
8. Cla udio-N; Rita-C; Elisabetta-E; Albe rto-

G; Alrs sa nd ro; Ca rlo-V and Enea -M. 
Infl uence  of formulation a nd  process 
p arame te rs  on pe lle t prod uction by powd er 
layering technique. P hrm-Sc i-Tech., 2000, 
1 (2 ) artic le  9 . 

9. P roduc t info rma tion bulletin Eudragit ś  
Rö hm Pha rm, GMBH, Weiterstad t -
Ge rmany. 

10.  USP  XXIV 20 00, p.547, p .1 94 7. 
11.  Ka ssab-H.J. M.Sc. thes is, College  of 

p harma cy, Unive rsity o f Baghd ad  1999. 
12.  Ka rl Toma  a nd Ka ro line  Bec htold. 

Infl uence  of aqueo us  coa tings on the      
s tability o f e nteric -c oated pe llets and 
tab le ts.                                        

      Eur-J-Parm-Bio pharm., 199 9, 47, 39-50 . 
13.  Ra ymond-C. Rowe. Ma teria ls  used in the 

film co ating of oral                                  
d osage  form in F lo re nce-A.T. Ma te rials 
used in p harmaceutica l formulatio n. 
Blackwell sc ie ntific p ub lica tions. Oxford 
Lond on Ed inburgh. 1 985   p.16. 

14. S tuart C. Po rter ; Charles-H.Bruno . and 
Ge ra ld J .Jac kson. Pan coating o f tab le ts 
a nd granules in Lie be rma n H.A. and 
Lachman L. pha rmace utical dos age fo rm: 
Tablets  Vol.3 Ma rc el De kker, INC.New 
Yo rk Bas el.1982  p.96-97 . 

15. Muskó -Zs; Pintye-Hó di k.;Gá spár R.; 
P itye  J .; Szab ó -Révés z P .; Erős  I. and 
F alka y G. S tudy o f in vitro  and in vivo 
d isso lution of theo phylline from fil m 
c oa ted pe llets . Eur-J -Pharm-Biopha rm., 
2 001 , 51, 143-14 6.