5 Formulation, optimization and evaluation of immediate release layer of salbutamol sulphate Salbutamol is moderately selective beta (2)-receptor agonist similar in structure to terbutaline and widely used as a bronchodilator to manage asthma and other chronic obstructive airway diseases. In addition, lower mean peak plasma concentration and longer time to reach the peak level were observed with salbutamol sustained-release tablets as compared with salbutamol tablets USP. The single-dose study results also showed that food decreases the rate of absorption of salbutamol USP from salbutamol sustained-release tablets without altering the extent of bioavailability. In addition, the study indicated that food causes a more gradual increase in the fraction of the available dose absorbed from the sustained-release formulation as compared with the fasting condition. Salbutamol is rapidly and well-absorbed following oral administration. After oral administration of 10 ml of salbutamol syrup (4 mg salbutamol) in normal volunteers, maximum plasma salbutamol concentrations of about 18 ng/ml are achieved within 2 hr, and the drug is eliminated with a half-life of about 5 to 6 hr. 1,2 By considering the all above aspects it is very clear that the drug is stable in g.i.tract and very well absorbed. It has also half life of only 1.6 hr. So it is the most suitable and rational to prepare the immediate release of the same drug which produces very quick onset of action. The reference suggests that sustain release of Salbutamol Sulphate is less effective than immediate release formulation. 3 5.1 Experimental materials Salbutamol sulphate was received as gift sample from Nucare laboratories (India), starch, dibasic calcium phosphate (DCP), micro crystalline cellulose powder (MCCP), sodium starch glycolate (SSG) and cross carmellose sodium (CCS) were received as gift sample from Texas Laboratories. Kyron T 314 and pregelatinised starch were received as gift sample from Corel Pharmachem. Other ingredients were of specified laboratory grade. 5.2 Preparation of immediate release tablets of salbutamol sulphate 4 Various formulations were prepared using four different super disintegrating agents in different concentration by direct compression method using MCCP as filler. The detail of composition of each formulation is shown in Table 5.1 After sifting (#) of accurately weighed Salbutamol Sulphate, MCCP and mannitol, they all were mixed for 15 min. To this Mixer, super disintegrating agents, Talcum Modi Darshan A. 82 Ph.D Thesis
and Mg. stearate were added and mixed for 5 min. The prepared blend was passed through # sieve. The prepared blend was compressed using 6mm concave punch in rotary tablet press machine. Table 5.1: Formula of immediate release part using super disintegrating agents Ingredients Batch (mg) Salbutamol Sulphate IP 4.8 4.8 4.8 4.8 4.8 4.8 4.8 4.8 4.8 4.8 4.8 4.8 MCCP IP Mannitol IP 69.2 67.2 65.2 71.2 70.2 69.2 67.2 62.2 57.2 70.2 68.2 66.2 SSG IP 3 5 7 - - - - - - - - - CCS IP - - - 1 2 3 - - - - - - Pregelatinised starch - - - - - - 5 10 15 - - - Kyron 314 - - - - - - - - - 2 4 6 Talcum IP 2 2 2 2 2 2 2 2 2 2 2 2 Mg.stearate IP 1 1 1 1 1 1 1 1 1 1 1 1 Total 100 100 100 100 100 100 100 100 100 100 100 100 5.3 Evaluation of immediate release part of tablets 5, 6 5.3.1 Weight variation Twenty tablets were selected at random and weighed individually. The individual weights were compared with average weight for determination of weight variation. 5.3.2 Hardness The tablets were held between a fixed and a moving jaw of hardness test apparatus. Each sample was put in the dial type hardness tester and rotated the knob in clockwise direction. The reading was noted down on the dial when the tablet got broken. 5.3.3 Friability Friability test was performed using Roche friabilator. Ten tablets weighed and placed in instrument, which was operated at 25 rpm for 4 min i.e.100 revolutions. After completion of revolutions, the tablets were dusted and reweighed. The percentage friability was determined using the formula. Modi Darshan A. 83 Ph.D Thesis
5.3.4 Disintegration time of immediate layer Single dosage unit was placed in each of the six tubes of the basket and added a disk. Operate the apparatus using water as the immersion fluid, maintained at 37 ± 2 o C. Time was noted when disintegration completed for all samples 5.3.5. Dispersion time of immediate layer Dispersion time test was performed by placing 2 tablets in 100 ml of water and stir gently until completely dispersed. A smooth dispersion was obtained which passed through a sieve screen with a nominal mesh aperture of 710 mm (22#). 5.3.6 Wetting time of immediate layer Wetting time was performed by pouring the die solution into the petridish. The four folded tissue paper was placed upon the die solution. The sample was put above the tissue paper and noted down the time required to wet the tablet completely. 5.3.7 Dissolution studies for immediate layer 7 In-vitro dissolution tests were carried out using USP apparatus type II (ELECROLAB TDT 06 T, Bombay). The dissolution medium consisted of 900 ml 0.1N HCl. maintained at 37 ± 0.5 0 C and stirred at 50 RPM. Samples (10 ml) were withdrawn at predetermined time intervals of 5, 10, 15 and min. Equal amount fresh dissolution medium, maintained at same temperature, was replaced immediately. The absorbance of the solution was measured at about 276.5 nm against blank. It was made clear that none of the ingredients used in the matrix formulation interfered with the assay. Percentage drug release was computed from prepared standard curve. The release study was conducted in the triplicate and mean values were plotted. 5.4 Results and discussion 5.4.1 Precompression study The flow properties of powder depend on angle of repose. The less angle of repose indicates the good flow properties. The results show that, the angle of repose between 39.11 o to 46.35 o. The value of Carr s index should be less than 25.72 % for better compressibility. Hausner s ration was found to be in range of 1.16 to 1.19. All batches shows good compressibility. This was also in good correlation with the Hausner s ratio. Modi Darshan A. 84 Ph.D Thesis
Table 5.2: Flow property of salbutamol sulphate IR 8 Batch Angle of Repose* Carr s Index* Hausners ratio* S1 43.52 ± 0.63 23.38 ± 0.77 1.17 ± 0.65 S2 41.85 ± 0.81 21.53 ± 0.68 1.18 ± 0.74 S3 39.11 ± 0.85 21.18 ± 0.72 1.17 ± 0.68 S4 44. ± 0.91 24.34 ± 0.82 1.19 ± 0.72 S5 42.6 8± 0.76 22.58 ± 0.95 1.17 ± 0.81 S6 40.94 ± 0.86 22.21 ± 0.88 1.16 ± 0.75 S7 46.35 ± 0.92 25.72 ± 0.75 1.19 ± 0.75 S8 45.87 ± 0.71 25.23 ± 0.80 1.19 ± 0.68 S9 45.13 ± 0.90 24.81 ± 0.93 1.18 ± 0.73 S10 44.58 ± 0.99 24.87 ± 0.97 1.18 ± 0.82 S11 43.27 ± 0.83 24.55 ± 0.81 1.17 ± 0.80 S12 43.58 ± 0.83 24.32 ± 0.85 1.17 ± 0.66 * All values are expressed as mean ± standard deviation, n=3. 5.4.2 Physical parameters of salbutamol sulphate tablets Table 5.3: Evaluation of pharmacotechnical parameters of salbutamol sulphate IR 9 Av.Wt. Thickness Hardness Friability Disintegration Dispersion Wetting Batch (mg) (mm) (kg/cm 2 ) (%) time(sec) time(sec) time(sec) (n=) (n=10) (n=5) (n=10) (n=6) (n=5) (n=5) S1 101.2±2.1 2.83-2.88 3 ± 0.3 0.82 22±2 136±11 125±9 S2 100.8±1.8 2.81-2.87 3 ± 0.3 0.62 18±2 95±8 97±5 S3 100.3±1.5 2.80-2.86 3 ± 0.2 0.55 16±1 75±6 80±6 S4 99.7±1.8 2.81-2.85 3 + 0.3 0.58 18±2 98±5 94±8 S5 99.9±1.9 2.82-2.87 3 ± 0.3 0.63 15±1 84±6 81±8 S6 99.2±1.8 2.82-2.89 3 ± 0.2 0.72 14±1 76±7 72±6 S7 101.2±2.1 2.61-2.72 3 ± 0.3 0.77 65±4 95±7 65±6 S8 100.5±1.8 2.65-2.75 3 ±0.3 0.65 35±3 70±4 45±4 S9 100.3±1.5 2.66-2.74 3 ± 0.2 0.61 25±2 35±3 32±4 S10 99.8±1.8 2.64-2.75 3 ± 0.3 0.81 23±3 45±3 30±3 S11 100.1±1.9 2.63-2.73 3 ± 0.3 0.75 23±3 30±2 30±3 S12 100.2±1.8 2.61-2.79 3 ± 0.3 0.72 ±2 25±2 28±3 All values are expressed as mean ± standard deviation Modi Darshan A. 85 Ph.D Thesis
Time (sec) 80 70 60 50 40 30 10 0 Batches Time (sec) 160 140 1 100 80 60 40 0 Figure 5.1: Disintegration time profile Batches Time (sec) 160 140 1 100 80 60 40 0 Figure 5.2: Dispersion time profile Batches Figure 5.3: Wetting time profile Modi Darshan A. 86 Ph.D Thesis
All formulations were evaluated for pharmacotechnical parameters like weight variation, hardness, thickness, friability, disintegration time, dispersion time, wetting time and in-vitro dissolution. Data shown in table indicated there was no difference in results of weight variation, hardness and friability as well as in assay The hardness of the tablets was found to be in the range of 3.0 to 3.5 kg/cm 2 whereas the percentage friability of all the formulations was found below 1% indicating that the friability was within the prescribed limits. The tablets were found to contain 97 % to 103 % of the labelled amount of salbutamol sulphate indicating uniformity of drug content. The average percentage deviation of all tablet formulations was found to be within the limit, and hence all the formulation passed the test for uniformity as per official requirements. From the results of disintegration time, it was found that the tablets of batch S12 have minimum disintegration time i.e. ±2 sec. whereas the batch S7 has maximum disintegration time 65±4 sec. From the results of dispersion time and wetting time, it was found that the tablets of batch S12 has minimum dispersion and wetting time i.e. 25±2 sec and 28±3 sec. respectively, where as the batch S1 has maximum dispersion and wetting time 136±11 sec and 125±9 sec. respectively. 5.4.3 In-vitro dissolution profile of preliminary trial formulations Table 5.4: Evaluation of in-vitro drug release of salbutamol sulphate IR Time (min) 5 Drug release (%) 54.48 59.36 62.77 55.65 58.12 59.71 50.24 54.37 56.35 45.87 51.66 59.24 ±0.61 ±0.30 ±0.33 ±0.31 ±0.35 ±0.53 ±0.59 ±0.50 ±0.48 ±0.56 ±0.43 ±0.32 10 86.24 ±0.59 89.54 ±0.33 91.2 ±0.28 75.3 ±0.32 80.l8 ±0.26 82.46 ±0.42 78.54 ±0.46 82.76 ±0.14 84.77 ±0.64 78.82 ±0.65 84.44 ±0.68 91.56 ±0.92 15 100.6 ±0.59 99.47 ±0.41 98.7 ±0.21 98.82 ±0.22 100.2 ±0.72 99.82 ±0.55 99.67 ±0.46 98.24 ±0.61 100.5 ±0.72 98.85 ±0.62 99.25 ±0.38 98.87 ±0.35 100.6 ±0.97 99.47 ±0.66 98.7 ±0.52 98.82 ±0.55 100.2 ±0.22 99.82 ±0.81 99.67 ±0.22 98.24 ±0.32 100.5 ±0.34 98.85 ±0.30 99.25 ±0.36 98.87 ±0.61 The in-vitro dissolution study was carried out according the prescribed method. The results of drug release studies were shown in table. After 10 min of dissolution testing, only batch S3 and S12 released more than 90 % of drug. All other Modi Darshan A. 87 Ph.D Thesis
formulations released the drug within min. Batch was composed of SSG and in highest conc. So it indicates that superdisintegrant as well as its conc. plays an important role to release the drug. Batch S12 was composed of kyron T-315, again in highest conentration. (6% w/w). 1 Cumulative Drug Release (%) 100 80 60 40 0 0 5 10 15 25 Time (min) S1 S2 S3 S4 S5 S6 S7 S8 S9 S10 S11 S12 Figure 5.4: Dissolution profile of salbutamol sulphate Modi Darshan A. 88 Ph.D Thesis
5.4.4 Visualization of dispersion test Non optimized batch Optimized batch (Batch S12) Figure 5.5: Initial time 0 sec Figure 5.6: After 15 sec side view Figure 5.7: After 15 sec top view Images of the dispersion time test were taken of optimized batch S12 and non optimized batch. For better understanding, photographs were taken by two angels i.e. side view and top view. After observing images, it was very clear that batch S12 tablet disperses and burst very quickly. Top view also indicated the cone formation of the granules within 15 sec while other batches were unable to disperse within 15 sec and no cone formation was found as shown in the above figures 5.5 to 5.7. Modi Darshan A. 89 Ph.D Thesis
5.5 Conclusion Salbutamol sulphate immediate release tablets were prepared by direct compression technique using four super disintegrants i.e sodium starch glycolate, croscarmelose sodium, pregelatinized starch and kyron-314. All formulations were subjected to various physical and pharmacotechnical paramaters. Enhanced dissolution of immediate release tablets of salbutamol sulphate (batch S12) led to improved dissolution which released more than 90% drug within 10 min, the least dispersion time (25 sec), wetting time (28 sec) and considerable disintegrating time ( sec). Batch S12 was formulated using kyron-314 (6%). Batch S12 showed best results and was used for further formulation of dual retard tablet in combination. 5.6 References 1. Sweetman S. Martindale. The Extra Pharmacopoeia. The Pharmaeutical Press, London. 34: 791-794. 2. http://www.drugbank.com/ Salbutamol sulphate. 3. http://www.wikipedia.com/salbutamol sulphate. 4. Lachman L, Liberman H. 09. The theory and practice of Industrial Pharmacy. CBS publishers and distributors pvt. Ltd, New Delhi: 344. 5. Rajeev Garg. 08. Pre-formulation: A need for dosage form design. Pharmainfo.net 6. Banker G, Rhodes CT. 00. Modern Pharmaceutics. Marcel Dekker Inc, New York. 7. Redmington, 05. The science and practice of pharmacy. Welfqrs Kluwer (India) Pvt. Ltd; New Delhi: 916-918. 8. C.V.S. Subramaniam. 05. Text book of Physical Pharmaceutics. Vallabha Prakashan, New Delhi: 224. 9. Indian Pharmacopoeia.1966. Ministry of Health and Family Welfare Govt. of India. The Controller of Publication, Ghaziabad. 2:740. Modi Darshan A. 90 Ph.D Thesis