EFFECT OF SUPERDISINTEGRATING AGENT ON THE RELEASE OF METFORMIN HCl FROM IMMEDIATE RELEASE TABLETS
Department of Pharmacy, University of Chittagong, Bangladesh. Department of Pharmacy, Jagannath University, Dhaka, Bangladesh. Department of Pharmacy, University of Science and Technology Chittagong, Bangladesh
Keywords: Super disintegration, Metformin, Immediate release tablet
Immediate release tablet of Metformin HCl needs to formulate for emergency treatment of type-II diabetes. The prime objective of the present research was to formulate immediate release tablet of Metformin HCL for rapid action by using Sodium starch glycolate, Collidon CL and Crosscarmellose Na as super disintegrants.Wet granulationmethod was adapted for the tablet preparation, maize starch used as a diluent, Povidone k-30 as a binder, sodium starch glycolate, collidon CL and crosscarmellose Na as super disintegrants in different concentration (2-5%). Aerosol -200 to provide proper flow characteristics and magnesium stearate as a lubricant. Total nine formations were prepared and evaluated for hardness, thickness, diameter, friability, weight variation, disintegration time and in-vitro drug release. All the formulations were compared for disintegration time and % drug release. All formulations are evaluated for pre-compression and post-compression parameters. The result obtained showed that the selected batch of tablet formulations containing sodium starch glycolate provides a short DT between 40 to 22 seconds, with sufficient crushing strength and acceptable friability.
tablets are those intended to be swallowed whole and to disintegrate and
release their medicaments rapidly in the gastrointestinal tract (GIT). The
proper choice of disintegrant and its consistency of performance are of
critical importance to the formulation development of such tablets . The bioavailability of a drug is dependent on
in vivo disintegration, dissolution, and various physiological factors .
Superdisintegrants provide quick disintegration due to the combined effect of
swelling and water absorption of the formulation. Due to swelling of superdisintegrants,
the wetted surface of the carrier increases, this promotes the wettability and
dispersibility of the system, thus enhancing the disintegration, dissolution
and bioavailability .
Metformin hydrochloride is an orally administered
antihyperglycemic agent, used in the management of type II diabetes (NIDDM) and
type I diabetes (IDDM). It is a very bitter drug and highly soluble in water
. This work aims at the design a formulation with the immediate release of
Metformin HCl. Different types of disintigrating agents (Sodium starch glycolate, Collidon CL,
and Crosscarmellose Na) were investigated and evaluated for
their efficacy in formulating such kind of dosage form. Metformin HCI (500mg)
was used as a model drug.
Metformin Hydrochloride, Starch,
k -30, Na-Starch glycolate, Collidon CL, Crosscarmallose-na,
-200 and Mg-stearate from ACI
pharmaceuticals limited, Bangladesh. Potassium Di-hydrogen orthophosphate and Di-Sodium
hydrogen orthophasphate collected from UAP laboratories.
this research work, nine (09) probable formulations were designed to
take Metformin Hydrochloride as a model drug and containing
three super disintegrants such asNa-starch glyccolate,Collidon
CL, Crosscarmalose sodium
formulation design summarized as table 1.
Table 1: Formulations of Metformin HCL immediate
Preparation of granules: 
Granules preparation is done in a series of steps
in the laboratory. At first the active drug (Metformin HCl), diluent (Starch) and
amount of superdisintegrants are passed through a 40 mesh
sieve to obtain fine particles. Then, the active drug,
superdisintegrants and the diluent under
current investigation are appropriately weighed and mixed together for 10
minutes in a mortar. Then the binder solution is prepared by dissolving the
above stated amount of povidone k-30 in sufficient amount of water.This
solution is then added drop by drop to the dry mixture in the mortar. During
this addition the mixture is continuously mixed in a clockwise direction, an
action. This mixing process is continued for a further 10 minutes until all the
binding solution has been added. At the end of this mixing, a uniform mixture
of wet mass is obtained.Then the wet mass is then passed through a 16 mesh
sieve to obtain granules. The granules were dried in an oven to get dry
granules at 600 C. Finally, these granules are mixed with
the above declared quantities of aerosil-200, 1/4
magnesium stearate to obtain granules with the pre-requisite flow properties.
The active drug and all the other excipients were taken in such amounts that at
least 40 tablets of each formulation could be prepared.
Study/ Evaluation of
Prepared Granules: 
After preparation of
granules pre-compression study like the angle of repose, bulk and tapped
densities, Hausner ratio, compressibility index were performed.
Study/ Mesurement of some Physical Parameters: [5, 7]
Post compression evaluation like hardness,
thickness, diameter measurement, friability
variation test and in-vitro dissolution study was performed.
Dissolution: [5, 6, 7]
studies were conducted according to the USP method (USP XXII) using apparatus
2. In all cases the conditions were maintained to be exactly the same, i.e. the
RPM was maintained at 100 while the temperature maintained always at 370±0.5C.
Dissolution medium 900 ml of the prepared buffer was poured. The dissolution was then set
up with paddles and the tablets directly placed in the dissolution vessel. The
example, 5 min, 10 min, 15 min, etc, 10ml of sample was then withdrawn, at each
withdrawal, 10ml of fresh dissolution medium was immediately added to maintain
the sink condition.
The dissolution was carried out for one hour. This was done to get a simulated
picture of drug release in the in-vivo condition. The sample that was collected
was first filtered, and then diluted, being assayed at 233 nm using a UV
spectrophotometer. The amount of drug released was calculated with the help of
a straight line equation obtained from the standard curve of Metformin HCL at
the same?max the
percentage of drug released in thus calculated and plotted against time. This
drug release profile was fitted into several mathematical models to get an idea
of the release mechanism of the drug from the dosage form.
Model Dependent Analysis
of the Dissolution data of the different formolations:
Several kinetic models have been proposed
to describe the release characteristics of a drug from a dosageform.The
dissolution data of all the formulations are treated in these various
pharmacikinetic models to identify the probable mechanism of release of the
drug from the dosage form.The dissolution data,s were fitted in the
following four models like zero order kinetics, first order kinetics, higuchi
plotting, korsmeyer poling etc.
RESULT AND DISCUSSION:
Evaluation of granules: Granules are prepared by wet granules method and all
the granules of 09 formulations were evaluated on different parameters and
results are summarized as table 2. It
is evident from the table 2, that
all the above formulations quite readily meet prerequisite crieteria for
showing good flowability. Formulation F 04 and F
06 showed higher angle of repose, and
lower compressibility index and Hausner ratio.The lowest value of bulk and
tapped densities was given by F 06, the lowest value of compressibility index
and Hausner ratio was given by F 05 and the lowest value of angle of repose was
given by F 07.
Table 2: Evaluation of granules (during
Evaluation of tablets:
All the granules were compressed into tablets and tables are evaluated for
different acceptable parameters and all the results are summarized as table 3.
Table 3: Post Compression
Study/Evaluation of tablets.
578 mg. Average weight
and weight variation analysis follows the standard of pharmacopoeia. The average diameter was also found to be
pretty much consistent varying insignificantly between the ranges of (13.04-13.27)mm.The
average thickness of the tablets also ranged between (3.22-3.69)mm; however the
variations were not alarming, result remained within the acceptable range.
the contrary, friability of the tablets of different formulations varied
greatly range from (0.14-0.32) % but in pharmacopoeial range.The friability was
found to be the greatest for formulations F 09.This indicates maximum loss of
tablets upon attrition. According to some authentic references the maximum
friability range should be in between (0.5-1)%. As the friability values for
none of the formulations exceed 1%, it does not pose any serious problems. Hardness of the
tablets of the different formulations varied widely ranging from (8.42-8.93)kg.Since hardness
greater than 5.10 kg is considered acceptable, all the formulations are
therefore thought to show the desired requisite hardness.
Disintegration test: After
the above study tablet of all formulations were tested for disintegration and
mean dissolution time. Results are summarized as table 4.
Table 4: Disintegration and Successive
Mean Disintegration Time
From the table 4, it was seen that the
lowest disintegration time (1.90) was found when sodium starch glycolate was
used as a disintegrant and the highest
disintegration time (2.60) was found when Crosscarmellose sodium was
used as a disintegrant. All disintegrating agents enhanced
disintegration time. With
respect to disintegration time, the following trend is observed amongst the
starch Glycolate > Collidon CL > Crosscarmellose sodium.
and Drug release Profile: Dissolution and total drug release
profile summerized in figure 1 and table 5.
Figure 1: Drug release pattern of all formulations.
From the figure 1 and table 5, it was
seen that the highest % of drug release (93.81) was found when
sodium starch glycolate was used as a disintegrant and the lowest % of drug
release (79.91) was found when Crosscarmellose sodium was
used as a disintegrant. With respect to % of drug release, same trend
like disintegration is observed amongst thedisintegrants, Sodium starch Glycolate >
Collidon CL > Crosscarmellose sodium.
dependent drug release kinetics analysis was performed and results are
summarized as table 6. The
dissolution data,swere fitted in the following four models like zero
order kinetics, first order kinetics, higuchi plotting, korsmeyer poling etc.
Table 5: Summery of Drug Release Model kinetics
Formulation F 01, F02, F03, F04, F05, F06 and F09 best fits with Higuchi (R2 ) and First order
(R2) kinetic models near to same extent and then with Korsmeyer (R2) model. The value of release exponent obtained
from Korsmeyer model, which indicates that the release pattern of Metformin HCL from F 01, F02, F03, F04, F05,
F06 and F09 was followed Fickian transport mechanism,
which appears to indicate a Class 01 diffusion
F 07 best
fits with Higuchi (R2 = 0.954) and First order (R2 =
0.907) kinetic models to same
extent and then with Korsmeyer (R2 = 0.887) model. The value of release exponent obtained from Korsmeyer
model is 0.481 which indicates that
the release pattern of Metformin HCL from F 07 was followed Anomalous/non-Fickian
transport mechanism. Whereas F 08 follows Higuchi model (R2 = 0.952). The value of n for
Korsmeyer release is 0.431. This value indicates
that the drug was released by Anomalous/non-Fickian transport mechanism.
The in-vitro drug relese profile of all
formulations was evaluated and this in-vitro release studies
demonastrated that, the release of Metformin HCL from all tablet formulations
was generally immediate. The tablets conforming to good quality,displayed
various drug release mechanisms. High concentration of super disintegrants used
in the formulations caused high percent release of drug, while lower
concentration caused low release.Thus, the release characteristics were
significantly influenced by the characteristics and concentration of super
disintegrants used. The release characteristics were also influenced by
changing the type of disintegrants. Most release mechanism could be well depicted
by the Higuchi model with the release from tablets being class1 diffusion. Disintegration
time, % of drug release and dissolution time was also observed for all
formulations.Again, the various mechanical and physical parameters of granules
and tablets such as the flow properties, hardness, friability etc. were seen to
comply with the standards set by the different international organizations e.g.
pharmacopeias. Thus the granules and tablets were found satisfactory in terms
of its physical parameters as well as the drug release profile from the
immediate release tablets.
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