Table
No. 2 Properties of
the Prepared Granules
|
Properties
|
Result
|
|
Angle of Repose
|
28.70 0
|
|
Bulk Density
|
0.641
|
|
Tapped Density
|
0.781
|
|
Carr’s Index (%)
|
15.492
|
|
Hausner’s
Ratio
|
1.18
|
MATERIALS
AND METHODS:
Materials:
Salbutamol
sulphate and Theophylline are obtained as a
gift sample (Cipla pharmaceutical Ltd., Kurkum MIDC, Pune), Other
polymers and chemicals such as HPMC K4M,K15M (Colorcon
Asia Ltd.,Goa,India),Carbapol
934P, colloidal silicon dioxide (Aerosil), magnesium stearate, sodium bicarbonate (New Life Pharmaceuticals,Pune,India). Remaining all the materials were obtained
commercially and used as such.
Fabrication
of floating matrix tablets: 9
Tablets
containing Salbutamol sulphate
and Theophylline as a pure drug were prepared by wet
granulation method. The matrix tablet contains uniform mixture of drug, polymer
and other excipients. Weighed quantities of drug,
polymer, diluents and other excipients as given in a
Table No.1were mixed properly in a mortar. Weight granulation was made by using
7.5 % ethanolic solution of Polyvinyl Pyrolidone. Wet mass was passed through sieve (16#)
and prepared granules were air dried and kept in desiccators for 1 day. Dried
granules were again passed through sieve (40#).Finally
tablets were lubricated by adding magnesium stearate
and glidant (each 1%) and compressed in to tablets
weighing 500 mg maintaining all the physical parameters constant through all
the batches.
Evaluation of Granules:
Angle of Repose10:
The angle of repose of granules was determined by the
funnel method. The accurately weighed granules were taken in a funnel. The
height of the funnel was adjusted in such a way that the tip of the funnel just
touched the apex of the heap of the granules. The granules were allowed to flow
through the funnel freely onto the surface. The diameter of the powder cone was
measured and angle of repose was calculated using the following equation2:
Where, h and r are the height and radius of the powder cone.
Figure No.1:
Swelling and Erosion study
Bulk Density11:
Both
loose bulk density (LBD) and tapped bulk density (TBD) were determined. A
quantity of 2 g of powder from each formula, previously lightly shaken to break
any agglomerates formed, was introduced into a 10-mL measuring cylinder. After
the initial volume was observed, the cylinder was allowed to fall under its own
weight onto a hard surface from the height of 2.5 cm at 2-second intervals. The
tapping was continued until no further change in volume was noted. LBD and TBD
were calculated using the following formulas3:
Compressibility Index12:
The
compressibility index of the granules was determined by Carr’s compressibility
index7:
Total Porosity13:
Total
porosity was determined by measuring the volume occupied by a selected weight
of a powder (Vbulk) and the true volume of granules (the space
occupied by the powder exclusive of spaces greater than the intermolecular
space, V)
Evaluation of Tablets:
Thickness:
The
thickness of the tablets was determined using a thickness gauge (Mitutoyo, New Delhi, India). Five tablets from each batch
were used, and average values were calculated.
Weight Variation Test9:
To
study weight variation, 20 tablets of each formulation were weighed using an
electronic balance (Denver APX-100, Arvada, Colorado), and the test was
performed according to the official method.10
Hardness and Friability:
For
each formulation, the hardness and friability of 6 tablets were determined
using the Monsanto hardness tester (Cadmach, Ahmedabad, India) and the Roche friabilator
(Campbell Electronics, Mumbai, India), respectively.
Determination of swelling and erosion behavior:14
The swelling and eroding behavior of matrix tablet was determined,
reported by Al-Taani and Tashoush.
Matrix tablet was introduced into the dissolution apparatus containing 900 ml
of 0.1 N HCl (pH 1.2 at 37 0C) at 100 rpm. The tablets
were removed using a small basket and swollen weight of each tablet was
determined. To determine matrix erosion, swollen tablets were placed in a
vacuum oven at 40 0C and after48 hours
tablets were removed and weighed. Swelling (%) and erosion (%) was calculated
according to the following formula, where S is the weight of the matrix tablet
after swelling; R is the weight of the eroded matrix tablet; and T is the
initial weight of the matrix tablet:
Swelling Index = S − T / T
% Erosion = (T – R) / T ×100.
Fig.No.2
Showing % Release of all the Prepared Formulations (F1-F11). (Theophylline)
In Vitro Release Studies:
The
in vitro dissolution studies were carried out using USP apparatus type II
(Tab-Machines, Mumbai, India) at 75 rpm. The dissolution medium consisted of
0.1N hydrochloric acid for the first 2 hours and the phosphate buffer pH 7.4
from 3 to 24 hours (900 mL), maintained at 37°C ±
0.5°C. The drug release at different time intervals was measured by UV-visible
spectrophotometer (1600 Simatzu) at 270 nm and 276
for theophylline and salbutamol
respectively. The release studies were conducted in
triplicate.
Fig.No.5 Showing % Release of all the
Prepared Formulations (F1-F11). (Salbutamol Sulphate)
Kinetic analysis of the dissolution data:14,15
In order to study the exact mechanism of drug release from the
matrix floating tablets, the release data were fitted to zero-order,
first-order and higuichi equation. These models fail
to explain drug release mechanism due to swelling (upon hydration in contact
with dissolution medium) along with gradual erosion of the matrix. Therefore,
the dissolution data was also fitted to the well-known exponential equation (Korsmeyer equation), which is often used to describe the
drug release behavior from polymeric systems:
Log (M t / M f ) = Log k + n Log t
Where, Mt is the amount of drug release at time t; M f is the amount of drug
release after infinite time’s is a release constant incorporating structural
and geometric characteristics of the tablet; and n is the diffusion exponent
indicative of the mechanism of the drug release.In order to make sure the release exponent for different batches of
floating matrix tablets, the log value of % drug dissolved was plotted against
log time for each batch according to the Equation. Value of n = 0.45 indicates Fickian (Case I) release ;> 0.45 but <0.89 for non-fickian (anomalous) release; and >0.89 indicate super case II type of release. Case II generally refers to the
erosion of the polymeric chain and anomalous transport (non-fickian)
refers to a combination of bothdiffusion and erosion
controlled-drug release. Mean dissolution time (MDT) was calculated from dissolution
data using the following equation (Mockel and Lippold):
MDT
= (n / n + 1). k – 1 / n
Where, n =release exponent and k = release rate constant.
RESULT and DISCUSSION:
In
the present study, HPMC K4M, K15M, K 100M, HPC and Carbapol
934P, sustained release tablets of Theophyline and salbutamol sulphate was prepared
accurately according to the formula given in the Table No.1.Swelling (%) and erosion (%) was calculated given in
the Table No.8 and 9Formulation
with Carbapol retards the release of the drug because
of its cross-linked polymeric nature which hold the water inside its microgel network. This results in a dramatic increase in
the density of the Tablet. In the present studies of dissolution given in the Table No.10,11formulation of the
batches 1,2,3,4 and 5 were shown the release of Theophyline,
96.89%,94.33%,91.25%, 81.54%,69.66% at the end of 12th hours, respectively and
that of salbutamolSulphate 95.48%,93.66%,91.88%,83.54%,67.59%at the
end of 12th hours, respectively. Further the result of dissolution studies of
formulation batches 6,7 and 8 with
different fillers showing release of drug, 95.33%,96.56%,93.56%at the end of
12th hours for Theophylline, respectively that of salbutamol Sulphate
94.68%,94.85%,92.65% at the end of 12th hours, respectively.
In further dissolution studies of
formulations 9, 10 and 11 with different fillers released the Theophyline, 90.88%, 79.65and 67.69%at the end of 12 hours,
respectively that of salbutamol
sulphate89.58%77.68%and 66.67%at the end of 12th hours, respectively. We have
Optimized Formulations with various concentrations but only the Formulation
with 50% concentration shows maximum release of drug at the end of 12th hr.
CONCLUSION:
Overall,
this study concludes that from all formulations, formulation 1 shown the
highest release followed by 7, 6, 2, 8, 3, 9, 4, 10, 5, and 11 at the end
of12th hours for Theophyline and salbutamol
Sulphate.There was not significant difference in all
the formulation batches despite different molecular sizes of polymers for Theophyline and salbutamol Sulphate. Relaese of the drug as
delayed to same extent, except the formulations with Carbapol
934P which was also observed by some other investigators where Carbapol 934P was found to compromise the release of the
drug (retard the release) with no significant difference in the release of the
drug with the different types of fillers. Optimized Formulations containing 50%
concentrations of polymers were shown the maximum release of the drug at the
end of 12th hour. Further erosion along with diffusion was the mechanism of the
release.
ACKNOWLEDGEMENT:
The
author would like to sincerely gratitude to the New Life Pharmaceuticals,
Pune, India.Colorcon Asia
Ltd., Goa, India, for providing all requirements for
this project work. Also very thankful to all those who have help directly or
indirectly to carry out the research work successfully.
REFRENCES:
1.
Rowland M, Tozer TN. Clinical Pharmacokinetics:
Concepts and Applications, Ed 3(First Indian Edition) 1996, Lea and Febiger, Philadelphia, pp 1.Cooper J, Gunn C. Powder flow
and compaction. In: Carter SJ, eds. Tutorial
Pharmacy.New Delhi, India: CBS Publishers and
Distributors; 1986:211-233.
2.
Amperiadou A, Georgarakis
M. Controlled release salbutamol sulphate
microcapsules prepared by emulsion solvent-evaporation technique and study on
the release affected parameters. International Journal of Pharmaceutics
1995; 11: 1-8
3.
Rowland M, Tozer TN. Clinical Pharmacokinetics:
Concepts and Applications, ed 3(First Indian Edition) 1996, Lea and Febiger, Philadelphia, pp1.
4.
Nishimura K, Koyama H, Ikeda A, Sugiura
N,Kawakatsu K, Izumi T. The additive effect oftheophylline on a high- dose combination of inhaled Salbutamol and Ipratropium
bromide instable COPD - chronic obstructive pulmonary disease. Chest 1995; 107:
718-723.
5.
Murthy SN, Hiremath SR.
Formulation and Evaluation of Controlled-Release Transdermal
Patches ofTheophylline-Salbutamol Sulfate. Drug Dev Ind Pharm 2001; 27: 1057-1062.
6.
Dandagi PM, Mastiholimath VS, Patil MB, Manvi FV,Gadad AP, Ruchi Sharma.
Development and Evaluation of Theophylline and Salbutamol sulphate Sustained
Release Matrix Tablets.Indian Journal of
Pharmaceutical Sciences2005; 67(5): 598-602.
7.
Prabakaran D, Paramjit Singh, Parijat Kanaujia,Jaganathan KS, Amit Rawat, Suresh P Vyas. Modified push-pull osmotic system for simultaneous
delivery of theophylline and Salbutamol: development and in vitro characterization.Int.
Journal of Pharmaceutics 2004; 284: 95-108.
8.
Sweetman SC. ed. Martindale: The
Complete Drug Reference. ed 33, Pharmaceutical Press,London,
2002, pp 757 – 786.
9.
Pharmacopoeia of India. New Delhi: Ministry of Health and Family Welfare,
Government of India, Controller of Publications; 1996.
10.
Cooper J, Gunn C. Powder flow and compaction. In: Carter SJ, eds.
Tutorial Pharmacy. New Delhi, India: CBS Publishers and Distributors;
1986:211-233.
11.
Shah D, Shah Y, Rampradhan
M. Development and evaluation of controlled release diltiazem
hydrochloride microparticles using cross-linked
poly(vinyl alcohol). Drug Dev Ind Pharm.
1997;23(6): 567-574.
12.
Aulton ME, Wells TI. Pharmaceutics: The Science of Dosage
Form Design. London, England: Churchill Livingstone; 1988.
13.
Martin A. Micromeritics.
In: Martin A, ed. Physical Pharmacy. Baltimore, MD: Lippincott Williams and
Wilkins; 2001:423-454.
14.
Al-Tanni BM, Tashtoush
BM,Effect of microenvironment pH of swellable and erodable buffered
matrices on the release characteristics of the diclofenac
sodium. AAPS PharmSciTech; Vol. 4 Number 3, Sep 2003;
Published Date: 08/31/2003; DOI: 10.1208/pt040343.
15. Korsemeyer R, Gurny R, Peppas N. Mechanisms of solute release from porous
hydrophilic polymers. Int J Pharm. 1983; 15:25–35.