Formulation and
Evaluation of Taste Masked Sustained Release Dosage Form of Metformin
Hydrochloride Using Indion Resin
Bhoyar PK1*, Biyani DM2, Shahare HV1,
Ikhar PK1,Borkar VS1
1S.S.D.J.
2S.K.B.College of Pharmacy, New Kamptee, Dist:
ABSTRACT
Sustained release formulation of metformin hydrochloride (MTHCL) presents significant
challenges due to its poor inherent compressibility, high dose and high water
solubility. Thus formulating MTHCL into an sustained dosage form would provide
slow release. But, it is bitter in taste and taste should be masked to
formulate it in a palatable form. So in the work undertaken, an attempt was
made to sustained the release as well as to mask the bitter taste by complexation technique using strong cation-exchange
resin, Indion 254 and Indion
264 (Polyacrylic hydrogen with carboxylic
functionality).The drug loading onto ion-exchange resin was optimized for
mixing time, activation, effect of pH, mode of mixing, ratio of drug:resin and temperature.The resinate was evaluated for micromeritic
properties, taste masking and characterized by X-Ray diffraction study and IR.
Using resinate sustained release tablets were
formulated using Hydoxy propyl
methyl cellulose (K100M: HPMC) as binder and microcrystalline cellulose(MCC) as
diluent.The tablets were evaluated for hardness, thickness,friability,drug content, weight variation and invitro drug release.Tablets thus
formulated (Batch B-6) provided sustained release of drug over a period of time
10 hours with First order kinetics. The release of MTHCL from resinate controls the diffusion of drug molecules through
the polymeric material into aqueous medium.The
results showed that MTHCL was successfully taste masked and formulated into an
sustained dosage form as an alternative to conventional tablet.
KEY
WORDS: Metformin hydrochloride, Sustained release, Taste
masking, Indion (254,264).
INTRODUCTION
In
the present study Metformin Hydrochloride was chosen
as a model drug. It is an oral antidiabetic biguinide preparation. It is used in the treatment of type
2 diabetes (NIDDM), type 1 diabetes (IDDM).1-2 It is very strongly
bitter drug. Ion exchange resins are water insoluble cross linked polymers
containing salt forming group in repeating position on polymer chain. The
unique advantage of ion exchange resins for complexation
is due to the fixed positively or negatively charged functional groups attached
to water insoluble polymer backbones. These groups have an affinity for
oppositely charged counter ions, thus absorbing the ions into the polymer
matrix. Since most of drugs posses ionic sites in their molecules, the resin
charge provides means to loosely bind such drugs. The binding is an equilibrium
process, resulting in continuous desorption or elution of drug from the resin
as drug is absorbed into the body.3-4 Several authors have reported
to use ion exchange resinate matrices to controlled
the release of variety of drugs.5-7
Administration
of a drug orally having bitter taste with acceptable level of palatability is a
challenge to the pharmacist in the present world, especially in pediatric and
geriatric formulation.8-9 The complex of cationic drug and strong cation exchange resin does not break at the pH of saliva i.e.
6-7 with cation concentration of 40 meq/lit. This implies that while passing through mouth, the
drug remains in the complex form, thereby imparting no bitter taste in the
mouth.
In the present work
strong cation exchange resins i.e. Indion 254, Indion 264 were
employed. in order to get the sustained release profile of metformin
hydrochloride.
MATERIALS
AND METHODS:
Materials:
Metformin
hydrochloride–IP was a Gift sample from Zim
Laboratories (
Preparation of drug resin Complex (Resinate): 10-12
Resinates were
prepared by Batch process. An accurately weighed amount of drug (100 mg) was
dissolved in 100 ml of distilled water. Then ion exchange resin (100 mg) was
added and stirred on a magnetic stirrer. Resinate
thus formed was filtered and washed with copious amount of deionised
water to remove any uncomplexed drug. It was then
dried at 50oc and the drug content was determined
spectrophotometrically at 233.5 nm.
Determination
of drug content in the resinate: 13
Accurately weigh,100 mg drug equivalent
resinate, added to 100 ml of 0.1N HCl and stirred for
5 hours. Then the suspension was filtered, further dilutions were made &
the drug content was determined at 233.5 nm using 0.1N HCl
as a blank.
Optimization
of Metformin hydrochloride–Indion
resin complexation:
The drug loading on to resin was
optimized for various parameters such as mixing time, activation, effect of pH,
mode of mixing, ratio of drug:resin and effect of
temperature.
Table
1: Formulation Design
Ingradients |
Formulations |
|||||
B-1 |
B-2 |
B-3 |
B-4 |
B-5 |
B-6 |
|
Indion 254 Resinate |
524* |
524 |
524 |
- |
- |
- |
Indion 264 Resinate |
- |
- |
- |
542* |
542 |
542 |
MCC (PH 102) |
54 |
42 |
30 |
36 |
24 |
12 |
HPMC (K100M) |
48 |
60 |
72 |
48 |
60 |
72 |
Mg. Stearate |
12 |
12 |
12 |
12 |
12 |
12 |
Talc |
12 |
12 |
12 |
12 |
12 |
12 |
Total |
650 |
650 |
650 |
650 |
650 |
650 |
* Containing 300 mg of
drug
Optimization for mixing time on drug loading:11
Separate batches of indion
254 and indion 264 (100mg) were soaked in 100 ml of
distilled water in a beaker and about 100mg of drug was added and stirred for 5 hrs and the drug content was determined
as mentioned previously.
Effect of activation of resin on drug loading:
Resins were washed
with distilled water and subsequently with 1N HCl.
The resins were rewashed with water until neutral pH was reached. Drug: resin
complexes were prepared by placing 100mg of acid-activated resins, in a beaker
containing 100 ml distilled water and about 100mg of drug and stirred for 5 hrs
& drug content was determined. Similarly, alkali activation of all resins
were performed, replacing 1 N HCl with 1 N NaOH.
Effect
of pH, mode of mixing, ratio of drug: resin and temperature on drug loading: 10-12
For optimization of pH, weighed, 100 mg
of drug was added to 100mg of activated Resins in 100 ml of distilled water.
The pH of solutions were adjusted at 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0 and 6.5
and stirred for 5 hrs and the drug content was determined. For optimization of
mode of mixing, Rotary shaker & Magnetic stirrer were used. All activated
resins (100mg) in 100 ml of distilled water and about 100mg of drug. The pH
were adjusted at 3.5 & drug content was determined. For ratio of drug:resin, three batches were prepared containing
drug-resin in the ratio of 1:1, 1:2, 1:3. The pH was maintained at 3.5.The
solution was stirred for 5 hrs. To study the effect of temperature, separate
batches were prepared containing drug-resin in the ratio of 1:1 was taken. The
pH was maintained at 3.5 and were stirred at 300C,350C,400C,450C,500C,600C,700C
and the drug content was
determined .
Evaluation of micromeritic properties of resinates:14-16
The different properties of resinates like shape, flow properties, bulk density, tap
density, packing ability were
studied.
Characterization
of resinate:
Infrared
(IR) study:
FT-IR spectrum of the drug, resin and resinate were recorded over the wave no 4000 to 400 cm-1
on Jasco Dispersive type FT-IR spectrophotometer
using the KBr disc technique .Then the spectra were
comparatively analysed for drug interaction.
X-ray
diffraction study:
The drug, resins and resinate was subjected to X-ray diffraction study for the
confirmation of complex formation.
Taste evaluation of solid drug: resin complex:
Drug resin complex
(1:1) was subjected to sensory evaluation by a panel of nine members using time
intensity method. Sample equivalent to 100 mg was held in mouth for 10 sec.
Bitterness was recorded instantly and then after 20,30,40,50 and 60 minutes.
The evaluation was performed by classifying bitter taste into five classes.
Level 0: No bitter taste is sensed, 1: Acceptable bitterness, 2: Slightly
bitterness, 3: Moderately bitterness Level 4: strongly bitterness. Descriptive
statistics mean and standard deviation were calculated for all variables.
Paired t test was applied using INSTAT software. Value p< 0.05 has been
considered as statistical significant level.
Formulation
of tablets:
Resinates of drug
(dose of drug 300mg) were formulated into tablet by wet granulation technique
using MCC and HPMC (K100M). Required quantity of resinate,
HPMC (K100M) and MCC were blended in geometric fashion, deionised
water was added to powder blend, disperse thoroughly in order to get the weight
mass. The damp mass was then shift through sieve no-22 to obtain granules. The
granules obtained were lubricated and compressed into tablet on tablet machine.
(Table.1).
Evaluation of tablets:17-19
Tablets
were evaluated for various official and nonofficial specifications.Thickness measured with the help of vernier caliper in micrometer. The hardness of the tablets
were measured with monsanto hardness tester.
For drug
content uniformity,20 tablets were weight and crushed. Weight accurately to get
10 mg drug equivalent resinate powder and transferred
it to 100 ml of 0.1 N HCl. This suspension was
stirred on a magnetic stirrer for 5 hrs. The suspension was then filtered and
the drug content was determined at 233.5 nm by making suitable dilutions.
Table
2: Micromeritic properties of resinates*
Character |
Indion 254 resinate |
Indion 264 resinate |
|
Shape |
Irregular |
Irregular |
|
Angle
of repose |
33.00 |
0.3233 |
|
Bulk
density (gm/cm3) |
0.7552 |
0.6944 |
|
Tap
density (g/cm3) |
0.7812 |
0.7352 |
|
Carr's
index (%cc) |
5.888 |
0.5549 |
|
Housner ratio |
1.0625 |
1.058 |
* Average of three
determinations
Table
3: Volunteers 0pinion test for Metformin
hydrochloride before and after taste masking (n=9)
Time (sec.) |
Before taste masking Mean±SD |
After taste masking with Indion 254 Mean±SD |
After taste masking with Indion 264 Mean±SD |
10 |
4.0±0.00** |
0.2±0.44** |
0.2±0.44** |
20 |
3.3 ±0.50** |
0.1±0.33** |
0.1±0.33** |
30 |
2.55±0.52** |
0 |
0 |
40 |
2.0±0.50** |
0 |
0 |
50 |
1.77±0.44** |
0 |
0 |
60 |
1.22 ±0.44** |
0 |
0 |
P<0.0001**
In-vitro release studies:
Tablets
formulated with resinates were subjected to in-vitro
dissolution studies using USP type II apparatus (paddle type) at 100 rpm with temperature of 370c
± 0.50 C. Dissolution was carried in 900 ml simulated gastric
fluid for 2 hour and for further 8 hours in simulated intestinal fluid.20,21 After 1 hour interval, 5 ml
dissolution medium was withdrawn by pipette. The samples withdrawn were
diluted to 50 ml with buffer and filtered. The filtered samples were analyzed
at 233.5 nm.
Drug release models:
The drug release data of Batch B-6 was fitted
in various release kinetic equations such as Zero Order, First order, Matrix, Peppas, Hix.Crow.
RESULT
AND DISCUSSION:
Optimization
of Metformin hydrochloride-Indion
resin complexation:
Metformin
hydrochloride was loaded on ion exchange resin by batch process. Complexation is essentially a process of diffusion of ions
between the resin and surrounding drug solution. As reaction is equilibrium
phenomenon, maximum efficacy is best achieved in batch process .11
Complexation between
drug and resin increase up to optimum time and then remain almost constant. It
was found to be optimum after 5 hrs of mixing in all the resins investigated.
Highest drug binding on resin was achieved when activated with 1N HCl. The drug loading was found to be 25.61±0.52,
25.32±0.49 for indion 254 and 264 respectively. After
activation with acid treatment, the exchangeable ion on the resin is H+.
Relative selectivity of H+ is least than other ionic form and
therefore it increases percent complexation. Maximum
drug loading on the resin occurs at pH 3.5; a maximum of 30.79±0.73, 29.75±1.16
for indion 254 and 264 respectively. As pH increases
above 3.5, percentage of drug loading decreases. This may be due to fact that the fraction of metformin
hydrochloride (pKa –11.5) protonation decreases as the pH increases and reduces the
interaction with the resin.11- 22 Complexation
was found to be optimum in case of stirring, a maximum of 30.79±0.67,
29.75±0.64 for indion 254 and 264 and in case of
shaking 25.27±0.54, 24.67±0.86 for indion 254 and 264
respectively. This finding may indicate the significant involvement of van der waals forces taking place
along with drug exchange during complexation. 23 Drug resin in the ratio
of 1:1 gives optimum loading. The drug loading was found to be 30.78±0.53,
29.75±0.35 for indion 254 and 264 respectively.
Increase in the amount of resin increases the amount of drug adsorbed from the
solution but decreases the drug content per 100 mg of resinates.
Maximum drug loading on the resin occurs at a temperature of 600C; a
maximum of 58.31±0.74, 56.18±0.74 for indion 254 and
264 respectively. Increased temperature during complexation
increases ionization of drug and resin. Higher temperatures tend to increase
the diffusion rate of ions by decreasing the thickness of exhaustive exchange
zone. 24
Evaluation of physical
properties of resinates:
The different micromeritic
properties resinates like shape, flow properties,
bulk density, tap density, packing ability were studied (Table:2).The results showed that the resinates
have good flow properties and packing abilities.
Evidence
of complex formation:
Infrared
(IR) study:
FT-IR spectra of drug shows peak for
amino group at 1028 cm -1
wave number which is absent in FT-IR spectra of drug : resin complexes of indion
254 and 264 resinate. This gives evidences of complex
formation.Figure:1.
X-ray
diffraction study:
The X-Ray Diffraction study of drug
shows highly crystalline nature. Resins indion 254
and indion 264 showed amorphous nature and the
resinates showed noncrystalline
characteristics. This might be because of entrapment of drug molecule in the
polymer matrix of the resins. From all the evidences it can be concluded that
the drug resinate was a chemical complex (Figure:2).
Studies have shown that the molecules of the entrapped drug changes from
crystalline to amorphous state.25
Panel
evaluation of taste:
Panel of 9 members using time intensity
method determined the threshold bitterness value. From majority of volunteers
it was found that 100 mg/ml was
the threshold concentration of bitter taste of metformin
hydrochloride (Table:3).
Table 4: Evaluation of physical characteristics of tablets (Batch
B1-B6)
Evaluation
parameters |
Formulations |
|||||
B-1 |
B-2 |
B-3 |
B-4 |
B-5 |
B-6 |
|
Hardness (kg) |
4.11±0.64 |
4.25±0.63 |
4.51±0.36 |
4.21±0.68 |
4.41±0.32 |
4.53±0.35 |
Thickness (mm) |
7.55±1.57 |
7.56±0.63 |
7.16±1.23 |
7.53±0.93 |
7.26±0.35 |
7.21±0.46 |
Friability (%w/w) |
0.63 |
0.58 |
0.53 |
0.54 |
0.49 |
0.44 |
Drug Content (%w/w) |
97 |
96.68 |
99 |
98.1 |
97.22 |
99 |
% Weight variation |
3.45 ±0.7 |
4.04 ±0.6 |
1.43 ±0.4 |
2.08±1.6 |
2.78±0.5 |
1.23±0.2 |
Table 5: Cumulative % of drug release from tablets(Batch B-1-B-6)
Figure
1: FT-: IR spectra of A. Metformin hydrochloride, B. Indion 254 resin,
C.Indion-254 resinate,
D Indion 264 resin, E. Indion-264 resinate.
Fig.
2: X-Ray Diffraction pattern of A. Metformin
hydrochloride, B. Indion 254 resin,C.
Indion-254 resinate, D Indion
264 resin, E. Indion-264 resinate.
Formulation
of sustained release tablet using resinate:
The batches
of controlled formulations were designed, using higher and lower concentration
of HPMC (K100M) and MCC (PH-102) and
other excipients and compressed into tableting machine.
Evaluation
of tablets:
The prepared batches
(B1-B6) of tablets were evaluated for various official and
non-official parameters. Tablets were obtained of uniform weight due to uniform
die fill with acceptable variations as per IP specifications, i.e.below 7.5 %.The hardness of tablets for each formulation
was between 4-5 kg/cm2 .Average thickness was found to be in the range of
In-vitro drug release:
Results of the invitro release studies of
various formulations designed and manufactured are presented in Table No 5 and
are shown in Figure.3.The result showed that, in case of indion 254 resinate, more than 95 % of drug released from tablets
formulation with HPMC (K100M)
in 8 to 10 % concentration within 7-8 hrs(Batch B1,B2). By
addition of 12% HPMC does not affect the drug release significantly (Batch B-3). This may be
due to rapid disintegration of tablets in dissolution medium because of larger
particle size of indion 254 resinate.
In case of indion 264 resinate
tablets (Batch B-4, B-5) with 8-10 % HPMC, more than 93 % of the drug released within 8-9 hrs.
Addition of 12 % HPMC, more than 92 % of drug released from tablet for 9 to 10 hrs (Batch
B-6).This may be because of strong binding properties of HPMC which binds the
fine particles of resinate. The drug release from
these tablets was simply due to slow erosion and ion exchange. The B-6 formulation shows precise sustained
release of metfomin hydrochloride with first order
kinetics.
Fig. 3: Cumulative % of drug release from tablets (Batch B-1-B-6)
CONCLUSION:
Metformin hydrochloride a bitter
drug could be successfully sustained released and taste masked using ion
exchange resins. The process of sustained release was optimized with respect to
parameters like mixing time, activation, effect of pH, mode of mixing, ratio of drug: resin
and temperature. The resinate was evaluated for micromeritic properties, taste masking and characterized by
IR and X-Ray diffraction study. Tablets thus formulated with Indion 264 and 12% HPMC (K100M) (Batch B-6) provided
sustained release of drug over a period of time 10 hours. The release of MTHCL
from resinate controls the diffusion of drug
molecules through the polymeric material into aqueous medium. The B-6
formulation shows precise sustained release of metfomin
hydrochloride and follows first order kinetics. Hence it was concluded that,
formulation B-6 was selected as best formulation.
ACKNOWLEDGEMENT:
The author wish to thanks Zim
pharmaceuticals Pvt.Ltd (kalmeshwar),Nagpur,India for providing the gift sample of Metformin hydrochloride.The
authors wish to thanks Ion-Exchange India ltd. Mumbai,India
for providing Indion resin samples and University
department of Physics, Nagpur, India for
providing X-Ray diffraction facility.
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Journal . of Pharmaceutical Dosage Forms and Technology. 1(1): July.-Aug. 2009, 49-54