J . MICROENCAPSULATION, 1991, VOL.
8, NO, 4, 4 7 9 4 3 2
Preparation and in vitro evaluation of salbutamol sulphate microcapsules
Journal of Microencapsulation Downloaded from informahealthcare.com by East Carolina University on 04/23/15 For personal use only.
N. R . D H A R A M A D H I K A R I , S. R . JOSH1 and N. C. MANEKART Department of Pharmaceutical Sciences, Nagpur University Campus, Nagpur 440 010, India (Rereiued 7 January 1991; accepted 4 February 1991)
Microcapsules of salbutamol sulphate were prepared using cellulose acetate phthalate as a coating material and by the coacervation phase separation (solvent evaporation) technique for obtaining sustained action. Prepared microcapsules were evaluated for their drug content, physical properties, release characteristics and stability. ‘The effect of coat to core ratio on release pattern was studied and it was found that microcapsules prepared with coat to core ratio 2 : 1 were able to retard the release of drug for 1 2 hours. No significant change was observed in drug content and release pattern even after storage.
Introduction Salbutamol sulphate belongs to t h e class called selective beta-2 adrenergic stimulants. It is used in t h e management of asthma, chronic bronchitis and other bronchopulmonary disorders involving bronchospasm. Salbutamol sulphate is rapidly absorbed after oral administration and has an elimination half-life of 4 hours (Smith and Anderson 1984). T h i s necessitates administration of the d r u g in three o r more divided doses daily. Sustained release formulations can be used to reduce t h e frequency of dosage as well as the fluctuations in plasma level resulting from repeated dosage with conventional products. Microcapsules o r salbutamol sulphate were prepared by phase separation induced by solvent evaporation at room temperature. Various coat to core ratios were employed. Microcapsules were evaluated for their drug content, physical properties, release characteristics and stability. T h e procedure adopted is a modification of the technique described by Kitajima and co-workers (Kitajima et al. 1972). Cellulose acetate phthalate (I.P.) was dissolved in 25 ml of acetone (I.P.) and salbutamol sulphate ( I . P . )was suspended in 3 0 m l of light liquid paraffin (I.P.). Both the phases were mixed together by stirring at l 0 0 0 r p m . Evaporation of acetone was accomplished mostly by the rotation of stirrer. Microcapsules were washed with solvent ether (I.P.) and then with water. T h e d r u g content of microcapsules was determined spectrophotometrically by measuring the absorbance at 2 7 6 n m using 0.1 N hydrochloric acid as a solvent. From the d r u g content of microcapsules ‘per cent d r u g encapsulated’ was calculated by the following formula: Percentage d r u g encapsulated = T o t a l yield of microcapsules wt of d r u g present in microcapsules X
t ’1’0
weight of d r u g used
x 100
w horn correspondence should be addressed. O 2 h S S 2 0 4 X / Y I $3 00
(01 Y 9 1
Tallor
& Francis I,td
N . B . Dharamadhikari et al.
480
In vitro dissolution studies of microcapsules were carried out by the changing p H method (Souder and Ellenbogen 1958). Release characteristics were determined by employing microcapsules equivalent to 8 mg drug and using a standard Dissolution Rate Test Apparatus USP XIX at 37 1°C and 100 rpm. T h e drug content in the filtered samples was determined spectrophotometrically at 276 nm after suitable dilutions. T h e flow properties of the microcapsules was determined by measuring the angle of repose by the funnel and cone method (Barlage et al. 1963). T h e bulk density of the microcapsules was also determined. Stability studies of the microcapsules were carried out by storing the microcapsules at room temperature, 37 1°C and 45 1°C for 8 weeks and evaluated periodically for drug content and for release characteristics.
Journal of Microencapsulation Downloaded from informahealthcare.com by East Carolina University on 04/23/15 For personal use only.
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+
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Table 1. Composition of salbutamol sulphate microcapsules. Code
Coating material quantity in G
Core material quantity in G
% Drug encapsulated
1.o 2.0 3.0 40 5.0 6.0
3.0 3.0 3.0 3.0 3.0 3.0
40.25 42.36 66.00 68.09 75.89 9000
~
s1
s2 s3 s4
s5 S6
TIME
IN H O U R S
Figure 1. In w h o release of salbutamol sulphate from uncoated drug ( 0 )and products S1 (0),S2 ( 0 )and S3 ( A ) .
Evaluation of salbutamol sulphate microcapsules
48 1
100 0 w
r/)
2
80
-I
w
Journal of Microencapsulation Downloaded from informahealthcare.com by East Carolina University on 04/23/15 For personal use only.
K
'3 6 0 a
0
*40
5
V
20
2
4
TIME
6
8
10
12
IN HOURS
Figure 2. In vitro release of salbutamol sulphate from the products S4 (0),S5 ( 0 )and S6 ( A ) .
Table 2.
Physical properties of salbutamol sulphate microcapsules. Product
Angle of repose
Bulk density
Sl s2 s3 s4 s5 S6
39.20 39.00 38.70 38.80 36.00 35.20
00.50 0066 00.42 00.66 00.81 00.5 1
T h e microcapsules obtained were spherical in shape and free flowing. T h e effect of core to coat ratio on the percentage drug encapsulated is reported in table 1. Maximum drug encapsulated was observed at a coat to core ratio of 2 : 1. T h e plot of cumulative percentage drug released versus time is shown in figures 1 and 2. Effect of the coat to core ratio on release pattern was studied and it was found that microcapsules prepared with coat to core ratio of 2 : 1 were able to retard the release of drug for 1 2 hours. Increase in the coat density resulted into more uniform release. T h e angle of repose and bulk density of prepared microcapsules are recorded in table 2. All the microcapsules showed excellent flow properties. No significant change was observed in the drug content after storing at various temperatures for 8 weeks.
482
Evaluation of salbutamol sulphate microcapsules
T h u s the microcapsules of salbutamol sulphate, prepared with coacervation phase separation induced by solvent evaporation, showed good flow properties and those prepared with a coat to core ratio of 2 : 1 were able to retard the release of the drug for up to 1 2 hours. They showed good storage stability with respect to drug content and release pattern.
Journal of Microencapsulation Downloaded from informahealthcare.com by East Carolina University on 04/23/15 For personal use only.
References BARLAGE, H. N., LEE,C. O., and KLAISTHING, L., 1963, Physical and Technical Pharmacy, (New York: The Blackinston Division, McGraw-Hill Book Co.), p. 458. KITAJIMA, M., YAMAGUCHI, T., KONDO,A., and MUROYA, N., 1972, Encapsulation method, U.S. Patent, 3 691 090. J. K., 1984, The Oxford Textbook of Clinical Pharmacology and SMITH, D . G., and ANDERSON, Drug Therapy (Oxford: Oxford University Press), p. 621. SOUDER, J . , and ELLENBOGEN, W., 1958, Laboratory control of d-amphetamine sulfate sustained release capsules. Drug Standards, 26, 77.
8, NO, 4, 4 7 9 4 3 2
Preparation and in vitro evaluation of salbutamol sulphate microcapsules
Journal of Microencapsulation Downloaded from informahealthcare.com by East Carolina University on 04/23/15 For personal use only.
N. R . D H A R A M A D H I K A R I , S. R . JOSH1 and N. C. MANEKART Department of Pharmaceutical Sciences, Nagpur University Campus, Nagpur 440 010, India (Rereiued 7 January 1991; accepted 4 February 1991)
Microcapsules of salbutamol sulphate were prepared using cellulose acetate phthalate as a coating material and by the coacervation phase separation (solvent evaporation) technique for obtaining sustained action. Prepared microcapsules were evaluated for their drug content, physical properties, release characteristics and stability. ‘The effect of coat to core ratio on release pattern was studied and it was found that microcapsules prepared with coat to core ratio 2 : 1 were able to retard the release of drug for 1 2 hours. No significant change was observed in drug content and release pattern even after storage.
Introduction Salbutamol sulphate belongs to t h e class called selective beta-2 adrenergic stimulants. It is used in t h e management of asthma, chronic bronchitis and other bronchopulmonary disorders involving bronchospasm. Salbutamol sulphate is rapidly absorbed after oral administration and has an elimination half-life of 4 hours (Smith and Anderson 1984). T h i s necessitates administration of the d r u g in three o r more divided doses daily. Sustained release formulations can be used to reduce t h e frequency of dosage as well as the fluctuations in plasma level resulting from repeated dosage with conventional products. Microcapsules o r salbutamol sulphate were prepared by phase separation induced by solvent evaporation at room temperature. Various coat to core ratios were employed. Microcapsules were evaluated for their drug content, physical properties, release characteristics and stability. T h e procedure adopted is a modification of the technique described by Kitajima and co-workers (Kitajima et al. 1972). Cellulose acetate phthalate (I.P.) was dissolved in 25 ml of acetone (I.P.) and salbutamol sulphate ( I . P . )was suspended in 3 0 m l of light liquid paraffin (I.P.). Both the phases were mixed together by stirring at l 0 0 0 r p m . Evaporation of acetone was accomplished mostly by the rotation of stirrer. Microcapsules were washed with solvent ether (I.P.) and then with water. T h e d r u g content of microcapsules was determined spectrophotometrically by measuring the absorbance at 2 7 6 n m using 0.1 N hydrochloric acid as a solvent. From the d r u g content of microcapsules ‘per cent d r u g encapsulated’ was calculated by the following formula: Percentage d r u g encapsulated = T o t a l yield of microcapsules wt of d r u g present in microcapsules X
t ’1’0
weight of d r u g used
x 100
w horn correspondence should be addressed. O 2 h S S 2 0 4 X / Y I $3 00
(01 Y 9 1
Tallor
& Francis I,td
N . B . Dharamadhikari et al.
480
In vitro dissolution studies of microcapsules were carried out by the changing p H method (Souder and Ellenbogen 1958). Release characteristics were determined by employing microcapsules equivalent to 8 mg drug and using a standard Dissolution Rate Test Apparatus USP XIX at 37 1°C and 100 rpm. T h e drug content in the filtered samples was determined spectrophotometrically at 276 nm after suitable dilutions. T h e flow properties of the microcapsules was determined by measuring the angle of repose by the funnel and cone method (Barlage et al. 1963). T h e bulk density of the microcapsules was also determined. Stability studies of the microcapsules were carried out by storing the microcapsules at room temperature, 37 1°C and 45 1°C for 8 weeks and evaluated periodically for drug content and for release characteristics.
Journal of Microencapsulation Downloaded from informahealthcare.com by East Carolina University on 04/23/15 For personal use only.
+
+
+
Table 1. Composition of salbutamol sulphate microcapsules. Code
Coating material quantity in G
Core material quantity in G
% Drug encapsulated
1.o 2.0 3.0 40 5.0 6.0
3.0 3.0 3.0 3.0 3.0 3.0
40.25 42.36 66.00 68.09 75.89 9000
~
s1
s2 s3 s4
s5 S6
TIME
IN H O U R S
Figure 1. In w h o release of salbutamol sulphate from uncoated drug ( 0 )and products S1 (0),S2 ( 0 )and S3 ( A ) .
Evaluation of salbutamol sulphate microcapsules
48 1
100 0 w
r/)
2
80
-I
w
Journal of Microencapsulation Downloaded from informahealthcare.com by East Carolina University on 04/23/15 For personal use only.
K
'3 6 0 a
0
*40
5
V
20
2
4
TIME
6
8
10
12
IN HOURS
Figure 2. In vitro release of salbutamol sulphate from the products S4 (0),S5 ( 0 )and S6 ( A ) .
Table 2.
Physical properties of salbutamol sulphate microcapsules. Product
Angle of repose
Bulk density
Sl s2 s3 s4 s5 S6
39.20 39.00 38.70 38.80 36.00 35.20
00.50 0066 00.42 00.66 00.81 00.5 1
T h e microcapsules obtained were spherical in shape and free flowing. T h e effect of core to coat ratio on the percentage drug encapsulated is reported in table 1. Maximum drug encapsulated was observed at a coat to core ratio of 2 : 1. T h e plot of cumulative percentage drug released versus time is shown in figures 1 and 2. Effect of the coat to core ratio on release pattern was studied and it was found that microcapsules prepared with coat to core ratio of 2 : 1 were able to retard the release of drug for 1 2 hours. Increase in the coat density resulted into more uniform release. T h e angle of repose and bulk density of prepared microcapsules are recorded in table 2. All the microcapsules showed excellent flow properties. No significant change was observed in the drug content after storing at various temperatures for 8 weeks.
482
Evaluation of salbutamol sulphate microcapsules
T h u s the microcapsules of salbutamol sulphate, prepared with coacervation phase separation induced by solvent evaporation, showed good flow properties and those prepared with a coat to core ratio of 2 : 1 were able to retard the release of the drug for up to 1 2 hours. They showed good storage stability with respect to drug content and release pattern.
Journal of Microencapsulation Downloaded from informahealthcare.com by East Carolina University on 04/23/15 For personal use only.
References BARLAGE, H. N., LEE,C. O., and KLAISTHING, L., 1963, Physical and Technical Pharmacy, (New York: The Blackinston Division, McGraw-Hill Book Co.), p. 458. KITAJIMA, M., YAMAGUCHI, T., KONDO,A., and MUROYA, N., 1972, Encapsulation method, U.S. Patent, 3 691 090. J. K., 1984, The Oxford Textbook of Clinical Pharmacology and SMITH, D . G., and ANDERSON, Drug Therapy (Oxford: Oxford University Press), p. 621. SOUDER, J . , and ELLENBOGEN, W., 1958, Laboratory control of d-amphetamine sulfate sustained release capsules. Drug Standards, 26, 77.
