Abstract


Iraqi J Pharm Sci, Vol.19(2) 2010                                                   Tinidazole bioadhesive vaginal gels                                     

 

64 

In vitro Evaluation of Tinidazole Bioadhesive Vaginal Gels 
Zainab T.Salih*

, 1
 

 
*Department of Pharmaceutics, College of Pharmacy, University of Baghdad,Baghdad, Iraq. 

 

Abstract    
         Many trials were made to prepare Tinidazole 2% as bioadhesive vaginal gels using different gel 

bases including hydroxypropyl methyl cellulose (3 and 4% w/w), methylcellulose (3 and 4%w/w) and    

carboxymethylcellulose (2 and 3% w/w) .Swelling index of the polymers,pH , viscosity , bioadhesive 

force , and in-vitro drug release to the simulating vaginal fluid (S.V.F.) were investigated for all the 

prepared bioadhesive gels . The mechanism of drug release from the gel bases was also investigated.  

The results revealed that C MC 3% gave the highest viscosity and bioadhesive strength with the lowest 

release rate while lowest viscosity and bioadhesive force was obtained with HPMC gel base with the 

highest release rate. The mechanism of drug release was affected by the type of gel base. Fickian 

diffusion was obtained with all gel bases. 

Key words:  Tinidazole, bioadhesive polymers, gels 

 الخالصة
بروبيم يثيم  % حضر عهً شكم هالو يهبهي يخاطي االنتصاق باستخداو قىاعد هالييت يختهفت تشًم هيدروكسي2تيُدازول           

تى قياش االش انهيدروجيُي وانهسوجت وقىة  ااالَتفاخ نها. كًسيهيهىز وانكاربىكسي يثيم سيهيهىزوانتي تى قياش َسبت  ,انًثيمسيهيهىز 

.وقد  اظهرث   4.2نهالييت انًحضرة في  انىسظ انًشابه نهًحيظ انًهبهي باش هيدروجيُي  تصاق وتحرر اندواء يٍ انتراكيب ااالن

اعطً اعهً  نسوجت واعهً انتصاق  هيهىزكاربىكسي يثيم سي %3وأٌ ,انُتائج اٌ تحرر اندواء يتاثر بُىع وتركيس انبىنيًر انًستخدو 

واعهً َسبت اَتفاخ وابطا تحرر. ايا انهايدروكسي بروبيم يثيم سيهيهىز فقد  اعطً اعهً تحرر نهدواء ونى يعطي اي َسبت اَتفاخ في  

 انتركيس انًستخدو .
Introduction 
         The vaginal route of administration has 

many advantages compared to other routes 
(1).

 

The vaginal epithelium is permeable to a wide 

range of drugs like hormones, peptides, 

proteins and antimycotics agents that need to 

reside at the site of infection for a prolonged 

period to be more effective. The vagina  

provides a promising  site  of   systemic  drug   

delivery   because of  its  large  surface  area 

and  its  rich  blood   supply.  In  addition , a  

prolonged  contact  of a delivery  system   with  

the  vaginal   mucosa  may   be  achieved  

more easily  than  at   other route of drug 

absorption  site like rectum or intestinal  

mucosa 
(2).

 . Tinidazole ( TND ) is {1- [ 2-

(ethylsulphonyl) ethyl ] – 2 – methyl – 5 -

nitroimidazole} has been proved  to  be very  

effective   for   the  therapy   of   amoebiasis  ,  

trichomonas  ,   lambliasis  and   anaerobic 

infections 
(3)

 .The drug  is  well   tolerated  and 

widely used in clinical practice in  the  form of 

I.V infusion , tablets  and vaginal  pessaries
(4).

 

The   efficacy   of   TND   in  the  treatment  of 

trichomonas vaginalis has  been  well   

documented  
(5)

 . TND   is  similar   to  

metronidazole  intravaginal  gel  can  be used  

to  treat  bacterial vaginosis 
(6,7),

 it  is  effective 

, safe ,  easy  to  apply  and  has  fewer  side  

effect  compared   to  oral dosage  forms  of 

this medication 
(8,9)

 patients    tolerate  gels 

better than vaginal  inserts or ointments. 
(10)

   

This study was conducted to formulate TND in 

a suitable mucoadhesive vaginal gel    through 

studying different variables affecting the  

physicochemical properties and the in vitro 

release of the drug from these preparations.  

  

Materials and Methods 
Materials 

         Tinidazole ( TND ) was  supplied by  

Sigma   chemical co.,   methylcellulose( MC) 

and carboxymethylcellulose(CMC)from(BDH 

limite ( HPMC) from ( Shin-Etsu  chemical 

co.– Germany) . All other materials used were 

of analytical grade.  

Methods 

Preparation of simulating vaginal fluid 

(S.V.F)  
         Simulating vaginal fluid (S.V.F ) was  

prepared  by dissolving 3.51gm  of sodium 

chloride ,1.4gm of potassium hydroxide 

,0.22gm of  calcium hydroxide , 0.018gm of  

bovine serum albumin, 2 gm of lactic acid , 

1gm of  acetic acid   ,0.16gm  of  glycerol 

,0.4gm of  urea and 5gm of  glucose in 1 liter  

distilled water then  the pH was adjusted at 

4.2
(11).

     

 

1Corresponding author E- mail : Zainabthabit@yahoo.com 

Received : 3/5/2010 

Accepted : 18/9/2010 



Iraqi J Pharm Sci, Vol.19(2) 2010                                                   Tinidazole bioadhesive vaginal gels                                     

 

65 

Preparation of TND vaginal aqueous gel 

bases  

         The  tested aqueous  gel  bases were 

prepared   by  dispersing  the polymers    

powder of  3 and 4%(w/w)  MC ,2 and 

3%(w/w) CMC  and 3 and 4%(w/w) HPMC  in 

cold  freshly distilled  water  with the aid  of a 

high speed stirrer , until  a  solutions   were   

complete 
(12)

.The   products   were refrigerated  

for 1hour  before use to obtain a suitable 

consistency .TND gels were prepared by 

dispersing 2% drug in different gel bases as 

shown in table(1).      

Table 1:Composition of TND bioadhesive 

vaginal gel 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

In vitro dissolution of TND from   gel bases 
         The  release  study  was  carried  out  in a  

USP   apparatus  type  І at 100 rpm ,a   basket 

of  2.5 cm  in diameter  was  enclosed  with  a  

multifold  filter paper (dialysis cell) in order to 

be filled with 1gm of each base containing 

2%w/w TND. After   connecting   to  a  stirrer  

motor ,  the   dialysis  cell  was immersed   to 

about 1 cm of   its  surface  in  500 ml  of  

simulating vaginal fluid  pH4.2  at 37
◦
C for 5 

hours .Samples  were  withdrawn    after  

0.5,1,2,3,4 and 5  hours and  replaced   with  

an  equal  volume  of the same fluid  solution  . 

The samples   were analyzed   for   their drug 

content at its λmax 320nm 
(13, 14).

. 

 

The effect of polymer type on the release of 

TND from the gel bases  

         The effect    of    MC, CMC and HPMC 

bases on the release of TND from gel bases 

was studied.  

 

The  effect  of  polymer  concentration  on  

the  release  of T ND  from  the  gel  bases  
         The  effect    of     3 and 4% w/w MC  , 2 

and 3% w/w CMC    and 3 and 4% w/w 

HPMC on  the  release of  TND  from  gel 

bases  were  studied.    

 

Measurement of the   swelling index of   dry 

polymer in   S.V.F  
         The  swelling  index  is  the  volume in  

ml  occupied  by 1 gm  of polymer  after  it  

has  swollen  in  aqueous  liquid  (S.V.F used  

in the study)  for four  hours. The process is 

carried out by placing 1gm of  dry    polymer  

in  25ml  graduated   cylinder , moisten  it with 

1ml (ethanol 96%) and with an  addition of  25 

ml  S.V.F  shaking  vigorously  every 10 

minute  for  one hour ,then allowing   to  stand  

for   three  hours . After1.5houre from 

beginning  the  test  any volume of  liquid  

retained in the layer of  the polymer and  any  

particles of  polymer  floated  at  the surface  

of  the  liquid were released 
(15)

.The swelling 

was  measured    according  to this equation:  

 

                    (final volume- initial volume) 

Swelling = 

                              initial volume 

 

Mechanism of  TND release from gel bases  

         To understand  the  mechanism  of  the  

drug  release , the  release  profiles from 

different  gel bases,  the % fraction drug  

released  verses  time  profiles  were plotted  

using  linear fitted  equations  proposed  by 

Koresmeyer - Peppas 
( 16 )

  

      F = Mt/Mo = ktⁿ      at time t                (1) 

      ln F =  ln k + n ln t                                  (2) 

The equations express the fraction (F) release 

of drug from gel Where  Mt  is the amount 

released at time  t  ,Mo  is the initial amount of 

drug   ,K is the  rate constant and  n  is  the  

releasing  exponent value  indicative  the  

mechanism  of   drug  release( if  n  is   0.5   or   

less   (fickian )  holds   the   release, while 

when   n  greater   than  0.5  this  indicate non-

fickian (anomalous)  releasing    mechanism),  

n    value   could  be result   from the slope 

obtained by  the drawing  of ln. Fraction 

released verses ln. Time. 

 

Viscosity measurement  
A Brook Field digital viscometer with a 

suitable sample adaptor was used to measure 

the viscosity in centipoises of the bioadhesive 

prepared gel. 
(17)

 

 

Determination of pH
 

         The pH of the bioadhesive gels were 

determined by digital pH meter .One gram of 

gel was dissolved in 25 ml of dislilled water 

and the electrode dipped into gel formulation 

for 30 minute..The measurements of pH of 

each system were replicated three times 
(18)

 

 

 

 



Iraqi J Pharm Sci, Vol.19(2) 2010                                                   Tinidazole bioadhesive vaginal gels                                     

 

66 

Determination of mucoadhesive force
 

         The mucoadhesive potential of each 

system was determined by measuring the force 

required to detach the gel from sheep vaginal 

mucosal tissue by using a modified chemical 

balance. Asection of vaginal mucosa was cut 

from the sheeps vaginal cavity and instantly 

fixed with mucosal side out onto each glass 

vial using a rubber band.  The vials with 

vaginal mucosa were stored at 37
◦
C for 5 

minutes .Then next vial with a section of 

mucosa was connected to the balance in 

inverted position, while first vial was placed 

on a height adjustable pan. Fixed amount of 

sample of each gel system were placed onto 

the vaginal mucosa of first vial. Then the 

height of second vial was adjusted so that 

mucosal surfaces of both vials come in 

intimate contact .Five minutes contact time 

was given to ensure intimate contact between 

tissues and the sample. Then weight was kept 

rising in the pan until vials get detached. The  

bioadhesive forces as the detachment stress in 

dyne/cm
2
, was determined from the minimal 

weights that detached the tissues from the 

surface of each gel using the following 

equation
(19): 

Detachment stress(dyne/cm
2
)= m  g/A 

Where, m= weight required for detachment of 

two vials in grams. 

g= Acceleration due to gravity [980cm/s
2
]. 

A=area of tissue exposed. 

The vaginal mucosa was changed for each 

measurement .Measurements were repeated 

three times for each  of the gel system. 

 

Results and Discussion 
         In order to fortify the  adhesion of  

administered  drug  onto  the  mucosal  

surface, TND was  formulated in a suitable 

mucoadhesive  polymers  , MC, CMC and  

HPMC  bases  to take a full advantageous of 

the  contact   time , the  drug   can   be  

dispersed  in  the gel giving a concentration  

that  is higher  than corresponding to the 

solubility of  the drug 
(20)

 ,as well as ,it  can  be 

considered as a way for sustaining  the  release 

of the drugs from gel dosage form . MC, CMC 

and HPMC were   used   as   a gel base 

because of there safety use for vaginal 

application as well as there compatibility with 

TND, with other  vaginal secretion.       

 

The effect of polymer type and concentration 

on the releasing of TND from the gel bases  
         Figures 1, 2 and 3 showed   the   amount 

of   TND  released  from    gel   bases  in  

S.V.F  medium .It was found that the amount 

of TND released  from gel bases were 

significantly influenced  (p<0.05)  by  the type  

of  the base  and  the  concentration the  

polymer  used.
(21)

 In general it was found that 

highest amount of TND was released  from   

CMC gel base and decreased with an 

increasing in  polymer concentration.
(22)

 ,also 

the drug release rate  was decreased with the 

increase in the polymer concentration.
(23)

  

 

Estimation of swelling capacity 

         The swelling index (capacity) for 1gm 

dry  MC and CMC are 50% and 80% 

respectively. HPMC is soluble and non-

swollen polymer at the concentration used  .  

The high swelling % of CMC in S.V.F 

indicates that  the swelling of  this  polymer  

takes place  at a slower rate. The straight lines 

obtained from plotting  of t/v ( t: time in hour ,  

v: volume of aqueous S.V.F absorbed per 

volume of dry polymer) against time t in hour  

as shown in figures (4and 5) were utilized to 

calculate the kinetic  of swelling  including 

initial rate  of swelling (rceiprocal of the 

intercept ) and swelling equilibrium( reciprocal 

of slope)
(24)

, as shown in table 2  

Table 2  : The initial rate of swelling (reciprocal of intercept) and swelling equilibrium 

(reciprocal of slope) 

Correlation 

coefficient    r 

Initial rate of swelling (ml 

of fluid solution /hr.ml of 

dry polymer ) 

Swelling to equilibrium 

size(ml of fluid/ml of dry 

polymer ) 

Polymer 

type 

0.99 74.626 1.797 MC 3% 

0.9885 12.987 1.496 MC 4% 

0.9944 11.454 1.951 CMC 2% 

0.995 14.619 1.500 CMC 3% 

 

 

 

 

 

 

 

 

 

 

 

 

 

 



Iraqi J Pharm Sci, Vol.19(2) 2010                                                   Tinidazole bioadhesive vaginal gels                                     

 

67 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 
 

Figure 1 : The effect of MC Concentration 

on the release profile of TND at pH 4.2 and 

37 

 C 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Figure  2:  The effect of CMC on the release 

profile of TND at pH 4.2 and 37

 C 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Figure 3 :  The effect of HPMC on the 

release profile of TND at pH 4.2 and 37

 C 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 
 

Figure 4 : The swelling mechanism of  3 & 

4% w/w MC in simulating vaginal fluid pH 

4.2 and 37

 C 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Figure  5 : The swelling mechanism of  2 & 

3% w/w C MC in simulating vaginal fluid 

pH 4.2 and 37

 C 

 

Releasing mechanism of TND from  gel bases  
         It was found that formulation with higher 

swelling index retard the release of drugs more 

than those with lower swelling indices , this  

swelling also  depends on the pH of the 

medium  and  the  presence  of  electrolytes ,  

where  the S.V.F pH 4.2 has  a lot of  

electrolytes content such as : sodium chloride , 

potassium hydroxide , calcium hydroxide
(25).

 

This  swelling  is important  since  its  

significantly decreases the releasing rate of the 

drug and increases  in the amount of the drug 

release after five hours ,as shown in table-3-

.The reason behind this increasing in the 

amount released due to erosion of the gel as a 

result of  severe hydration or relaxation of the 

polymer , so interchain intermolecular force 

will no longer be able to resist any external 

forces ,once gel erodes ,it breaks up into 

smaller and smaller particles ,more surfaces 

will be exposed to the fresh swelling medium 

figure-3- The amount released of TND to S.V.F

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0.4

0 100 200 300 400

time(minute)

F
 f
r
a

c
ti
o

n
 r

e
le

a
s
e

d
 

2% w/w CMC 

3% w/w CMC 

figure-4-The amount released of TND to S.V.F

0

0.05

0.1

0.15

0.2

0.25

0.3

0 100 200 300 400

time(minute)

F
 f
r
a

c
ti
o

n
 r

e
le

a
s
e

d
 

3% w/w HPMC

4% w/w HPMC

figure-2- The effect of MC cocentration on the release 

profile of TND atpH 4.2 and 37

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0.4

0 100 200 300 400

time(minute)

F
 f
r
a

c
ti
o

n
 r

e
le

a
s
e

d

3% w/w MC 

4% w/w MC 

0

0.5

1

1.5

2

2.5

3

3.5

1 2 3 4 5
time(hr)

t
/v

 (
h

r
/m

l 
f
lu

id
 s

o
lu

t
io

n
 /

m
l 

C
M

C
 )

3% CMC

2% CMC



Iraqi J Pharm Sci, Vol.19(2) 2010                                                   Tinidazole bioadhesive vaginal gels                                     

 

68 

and hence more drug will be released leads to 

an increasing in the amount of the drug 

released from CMC gel base more than other 

swollen MC  gel base after five hours 
(18)

 .As a 

result , CMC gel bases  hold a Fikian release 

mechanism.   

 

Table 3 :The release rate, amount released and the releasing mechanism of the TND from gel bases 

 

Viscosity measurment 
         Viscosity is an important parameter for 

characterizing the gel as it affects the 

spreadibility ,extrudability and release of 

drug
(26)

 .CMC gel base show the highest  

viscosity, and as the polymer concentration 

increase ,the viscosity will be increased as 

shown in table 4. On the other hand , minimum 

level of  viscosity was seen with F5 and F6  

explain the rapid release of drug from this gel 

system and this due to non swelling property 

of HPMC polymer at these  concentration . 

 

Table 4:The viscosity and pH of the 

prepared  TND bioadhesive vaginal gel 

 

 

Determination of pH   
         The pH of gels were found to be within 

the range of 5-6.2 which is within the limit of 

semisolid specification and at this pH  the gel 

will be non irritant to vagina
.(12).

The physical 

appearance of the gel was evaluated with 

naked eye . The gel was smooth without any 

lumps and of uniform color ,no color change 

/liquification /separation  were observed . 

Determination of mucoadhesive force  
Scheme 1 indicates the vaginal bioadhesive 

properties of the prepared gels in sheep 

vagina,and the resultes showed that all vaginal 

bioadhesive strengths were found in the  

 

following order F2,F4>F3>F1>F6>F5  

Indicating that (F2)and (F4) showed the 

highest bioadhesive properties. 
 
 
 
 
 
 
 
 
 
 

 

Scheme 1: Bioadhesive strength of TND 

Bioadhesive vaginal gels 

 
Conclusion 
         Results of this study confirm that, the 
physical properties of the prepared gel were 

affected by the type and concentration of the 

polymer used in the preparation. The more 

sustained preparation with highest bioadhesive 

force and highest viscosity was obtained by the 

use of 3% CMC as a gel base.In addition to 

that the mechanism of drug release from 

tinidazole 3%CMCgel base was diffusion 

mixed with erosion.  
 
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amount  release 

(mg/5hr) 

(mean±SD,n=3) 

K % minⁿ    

releasing     

rate 

n   exponent 

release value 

Polymer  type  

and  

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Fickian 7.05±0.14 5.3974 0.41 MC 3% 

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Iraqi J Pharm Sci, Vol.19(2) 2010                                                   Tinidazole bioadhesive vaginal gels                                     

 

69 

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