4. RESULTS AND DISCUSSION
In the present piece of investigation Matrix
tablets of Paracetamol & Bilayer tablets of Paracetamol & Tizanidine
were prepared successfully with hydrophilic polymers like Guar gum, HPMC K100 M
and HPMC K4 M by wet granulation technique. Solubility studies of Paracetamol
& Tizanidine were performed. The solubility of selected drugs was found to
be maximum in 0.1N HCl and minimum in water. The results of Preformulation
studies are depicted in table no 05. The results revealed that all experimental powders exhibited
good flow characteristics. The results of Physical characteristics of matrix
layer tablets and bilayer tablets are presented in table no. 08 & 09. The results of weight variation lie in the
range of 789.2 mg to 927.5 mg for matrix layer tablets & 1150.4mg to
1155.5mg for bilayer tablets indicating that the variation in the weight of the
tablets is within official limits. The hardness test was carried out using
erweka hardness tester. The hardness of the tablets was found to be uniform and
in the range of 151.4 to 158.0 Newtons for matrix layer tablets & 250.0 to
254.4 Newtons for bilayer tablets, indicates that the prepared tablets are
mechanically stable. The friability test was carried out by Roche Friabilator.
The percentage friability of matrix layer tablets are in the range of 0.39% to
0.43% and Bilayer tablets in the range of 0.51% to 0.53%, which is less than
the standard limit of 1% indicating that the prepared tablets are mechanically
stable. The results of percent drug content for Paracetamol is in the range of
97% to 100% for matrix layer tablets & 98% to 99% for bilayer tablets,
respectively and the percent drug content for Tizanidine in Bilayer tablets is
in the range of 98 to 99%, which is within the standard limit of ± 5%. It indicates
uniform distribution of drugs in the tablets of each formulation. The
Paracetamol matrix tablets and Paracetamol & Tizanidine Bilayer tablets
were subjected to in vitro drug release studies in pH 0.1 N Hcl for 8 hours to
assess the ability of the formulation for providing controlled drug delivery.
Drug release studies were carried out in eight stage Type 2 dissolution test
apparatus (Electrolab) using 900ml ml of dissolution medium, maintained at 37±10C
at 100 rpm.
4.1, Matrix tablets
The drug release profiles of
Paracetamol matrix tablets were subjected to study the kinetic behavior using
various mathematical models like Zero order, First Order, Higuchi, Korsemayer
release kinetics. The correlation coefficient values of zero order release
profiles of Guar gum matrix tablets (F1, F2, and F3) are 0.9709, 0.9796 &
0.9539. The first order release profiles of Guar gum matrix tablets are 0.9828,
0.9887& 0.9623.The release kinetic data indicates that drug release from
the formulation follows First order kinetics. The correlation coefficient values of Zero order release profiles
of HPMC K100M matrix tablets (F4, F5, F6 and F7) are 0.9881, 0.9862, 0.9870
& 0.9815.The First order release profiles of HPMC K100M matrix tablets are
0.9945, 0.9949, 0.9975& 0.9968. The release kinetic data indicate that drug
release from the formulation followed First order kinetics. The correlation coefficient values of zero order release profiles
of HPMC K100 M & HPMC K4 M matrix tablets (F8, F9, F10 and F11) are 0.9408,
0.9340, 0.9250, & 0.9294 and first order release profiles of HPMC K100 M
& HPMC K4 matrix tablets are 0.9860, 0.9836, 0.9838 & 0.9931.The
correlation coefficient values indicate that drug release from the formulations
follows First-order kinetics. The
correlation coefficient values of zero order release profiles of HPMC K4 M
matrix tablets (F12, F13 and F14) are 0.9423, 0.9363, & 0.9613 and first
order release profiles of HPMC K4 M matrix tablets are 0.9302, 0.8929 &
0.7724. The correlation coefficient values indicate that drug release from the
formulations follows Zero order kinetics.
The correlation coefficient values of Higuchi plot are 0.9977, 0.9938 &
0.9896 for Guar gum matrix tablets (F1, F2, and F3), 0.9867, 0.9856,
0.9891& 0.9941 for HPMC K100M matrix tablets (F4, F5, F6 and F7), 0.9814,
0.9824, 0.9827 & 0.9898 for HPMC K100 M & HPMC K4 M matrix tablets (F8,
F9, F10 and F11) and 0.9952, 0.9939 & 0.99849941 for HPMC K4 M matrix
tablets. The correlation coefficient values are close to one which indicates
that the drug release is by diffusion mechanism. When the percent of drug
released from formulations F1, F2, & F3 were fitted to the model developed
by Korsmeyer et al. the mean diffusional exponent values (n) ranged from 0.9940
to 0.9998 indicating that Paracetamol release from Guar gum matrix tablets
followed anomalous diffusion. The diffusional exponent values (n) for F4, F5,
F6 and F7 ranged from 0.9792 to 0.9947 indicating that the drug release from
the HPMC K100 MCR matrix tablets followed anomalous diffusion. The diffusional exponent values (n) for
F8, F9, F10 & F11 ranged from 0.9751 to 0.9848 indicating that the drug
release from the HPMC K100 M & HPMC K4 M matrix tablets followed anomalous
diffusion. The diffusional exponent
values (n) for F12, F13 & F14 ranged from 0.9808 to 0.9913 indicating that
the drug release from the HPMC K4 M matrix tablets followed anomalous
The correlation coefficient values of zero order and first
order release profiles of HPMC K4M bilayer tablets (FB1, FB2 and FB3) are
0.9705, 0.9460 & 0.9568 and 0.9417, 0.8701 & 0.7943 respectively. The
correlation coefficient value indicates that drug release from the formulation
followed zero order kinetics. The correlation coefficient values of Higuchi
plot are 0.9934, 0.9970 & 0.9940 for HPMC K4M bilayer tablets. The
correlation coefficient values are close to one which indicates that the drug
release is by diffusion mechanism. The diffusional exponent values (n) for FB1,
FB2 & FB3 ranged from 0.9919 to 0.9950 indicating that the drug release
from the HPMC K4M matrix tablets followed anomalous diffusion. In both the matrix and bilayer tablets
the dissolution rate decreases with an increase in the concentration of the
5.3, Selection of
optimized formulation of Paracetamol Matrix tablets & (Paracetamol &
Tizanidine) Bilayer tablets.
4.3.1, Matrix tablets
The dissolution profile of Paracetamol Matrix
tablets was carried out. From the dissolution data it concludes that, the
tablets prepared from Guar gum, HPMC K100 M, polymers posses a very low drug
release profile. Whereas the tablets prepared from HPMC K4 M polymer (F12, F13
& F14) posses a drug release of more than 95%.Thus, the above mentioned
formulations are chosen as optimized formulation and used for preparation of
4.3.2, Bilayer tablets
The dissolution profiles of Paracetamol &
Tizanidine Bilayer tablets were carried out. In case of Bilayer tablets from all the formulations, the drug was
released at a rate of 22-25% in 1st hour & shows more than 97%
release in 8th hour. From the immediate release layer, the drug was
completely released within 15 minutes. The Bilayer tablets, prepared from HPMC
K4 M showed same release profile as that of F12, F13 & F14 matrix
formulations. So, the Bilayer tablets
corresponding to the Matrix tablets F12, F13 and F14 that are FB1, FB2 and FB3
are considered to be the optimized formulations.
Drug-excipients interaction studies
optimized formulations were subjected to FTIR studies to confirm whether or not
there is drug polymer interaction. The results of the FTIR studies indicate
that there was no interaction between the drug and polymers used in the
stability studies were subjected to optimized matrix formulations as well as
Bilayer formulations for the period of three months in air tighten and closed
containers. The stability studies were performed in humidity chamber
maintaining at 40 °C and 75%RH. The
physical characteristic like weight variation, hardness, friability, percent
drug content and in vitro release profile were determined at 1st,2nd
& 3rd month. The results of weight variation,
hardness, friability and percent drug content during stability studies for
Matrix & Bilayer tablets are shown in the table no. 10 & 11 respectively.
These values indicate that there were no appreciable changes when compared with
original samples. Dissolution study
was carried out at regular time interval for all the optimized formulation
during the stability studies. The cumulative percentage drug released for
Matrix & bilayer tablets were studied. The results indicate that, no
appreciable changes were observed in the release profile of the formulations
during the stability studies. The data obtained from the stability studies of
the optimized formulations indicates that the tablets are physically stable.
A study involving preparation and evaluation of
matrix as well as bilayer tablets
were made. Physicochemical parameters
of matrix & bilayer tablets were performed. In vitro drug release profiles of matrix & bilayer tablets
were performed. The matrix
formulations (F12, F13 & F14) containing HPMC K4 M (60mg), SSG (15mg) &
Lactose (DCL 21) 75,95,103 mg respectively, Exhibited good release profile as
compared to the other formulations. Hence, these formulations are considered to
be optimized formulations. Based on
in vitro drug release profile, it was found that the release of medicaments
from prepared matrix tablets (F12, F13 & F14) follows zero order and the release of
medicaments from prepared bilayer tablets (FB1, FB2 & FB3) also follows Zero order. The IR studies confirmed that, no drug – polymer interactions
exist in Matrix formulations (F12, F13 & F14) as well as in Bilayer
formulations (FB1, FB2 & FB3). In
conclusion, the Bilayer tablets of Tizanidine & Paracetamol could be
formulated using HPMC K4 M polymer, which is much more effective in treating
Rheumatoid arthritis, Osteoarthritis & other severe pain syndromes. However, long term stability studies
are needed to establish stable tablet formulations. Further clinical trials are needed to establish its efficacy in
treatment of Arthritic pain.
CONFLICT OF INTEREST: The author confirms that this
article content has no conflicts of interest.
ACKNOWLEDGEMENTS: Declared none.
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