8 Formulaton, evaluation and optimization of immediate release layer of amlodipine besylate

Transcription

1 8 Formulaton, evaluation and optimization of immediate release layer of amlodipine besylate Amlodipine besylate is antihypertensine and also used in angina. Conventional tablets are requiring to be administered three to four times daily. The formulation is developed to reduce frequency of administration and for patient compliance, a bilayer floating tablet of amlodipine besylate and atenolol were prepared. In which one layer made up of immediate release (IR) layer with help of super disintegrating agents which acts as loading dose. Tablets were prepared by direct compression method using different super disintegrating agents like kyron T-314, croscarmellose sodium, sodium starch glycolate etc. Finally one super-disintegrating agent was selected in terms of its concentration. Amlodipine is a prototype second generation dihydropyridine calcium channel blocker that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. It has a longer duration of action i.e. half life of 40 hr as well as more absorption through upper gastro instetinal tract and the initial effects are cumulative over many days and more over for patient compliance in case of anti-angina patients, a rapid onset of action is necessary for immediate pain relief. Hence amlodipine can be given as a single immediate release dose Experimental material Amlodipine besylate was a gift sample from Zydus Cadila HealthCare Ltd, Ahmedabad. Sodium starch glycolate and cross carmellose sodium were procured from Chemdyes Corporation, Ahmedabad. Kyron T-314 was obtained from Corel Laboratories, Ahmedabad. All other chemicals and reagents used were of analytical grade. 8.2 Preparation of immediate release tablets of amlodipine besylate. 2, 3 Various formulations were prepared using different super disintegration agents in different concentrations by direct compression method using Micro Crystalline Cellulose and Mannitol. After sifting (20#) of accurately weighed amlodipine besylate, MCCP and mannitol, they all were mixed for 15 min. To this mixer, super disintegrating agents, talcum and mg. stearate were added and mixed for 5 min. The prepared blend was passed through 20# sieve. The prepared blend was punched using 6 mm flat punch in rotary tablet press machine. Modi Darshan A. 117 Ph.D Thesis

2 Table 8.1: Formulation of immediate release layer of amlodipine besylate of dual retard tablet Ingredients Batches (mg) A1 A2 A3 A4 A5 A6 A7 A8 A9 A10 A11 A12 Amlodipine besylate Kyron T SSG CCS Lactose Talcum Mg. stearate MCC Total weight Evaluation of immediate release part of tablets Physical parameters of immediate release tablets of amlodipine besylate 4-6 As per I.P, prepared immediate release tablets of amlodipine besylate were evaluated for various parameters like weight variation test, hardness, friability, disintegration time, dispersion time and wetting time as per procedure described in sections 5.3. Results are shown in table 8.3 and Dissolution studies for immediate layer 7 In-vitro dissolution tests were carried out using USP apparatus type II (ELECROLAB TDT 06T, Bombay). The dissolution medium consisted of 900 ml 0.1N HCl. maintained at 37 ± C and stirred at 50 RPM. Samples (10 ml) were withdrawn at predetermined time intervals of 5, 10, 15 and 20 min. Equal amount fresh dissolution medium, maintained at same temperature, was replaced immediately. The absorbance of the solution was measured at about 239 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. 8.4 Results and discussion Precompression study For each designed formulation, blend of drug and excipients was prepared and evaluated for precompression properties. Data revealed that angle of repose of all Modi Darshan A. 118 Ph.D Thesis

3 formulations lied between 24.2 o to 27.3 o which indicated good flow of the powder and eased for compression without weight variation. While carr s index falled between to That region was quite good for compression properties. Data of all the batches reveals that the all batches possess the good flow property as well as compression quality. Table 8.2: Evaluation of precompression properties of batches A1-A12 Batches Angle of repose(θ) Bulk density (gm/cm 3 ) Tapped density(gm/cm 3 ) Carr s index (%) Hausner s ratio A1 27.2± ± ± ± ±0.2 A2 25.3± ± ± ± ±0.2 A3 26.0± ± ± ± ±0.1 A4 24.2± ± ± ± ±0.2 A5 27.2± ± ± ± ±0.2 A6 26.4± ± ± ± ±0.2 A7 27.0± ± ± ± ±0.2 A8 26.5± ± ± ± ±0.3 A9 27.2±2 0.57± ± ± ±0.2 A ± ± ± ± ±0.03 A ± ± ± ± ±0.03 A ± ± ± ± ±0.03 All values are expressed as mean ± standard deviation, n= Physical parameters of amlodipine besylate tablets All the 12 formulations were evaluated for pharmaco technical parameters like weight variation, hardness, thickness and friability. Average weight of the tablet did not deviate more than 7.5% which confirmed IP specification. Friability of all the formulations was below 1% which also confirmed specification. In preliminary study, A1-A4 batch where Kyron T-314 (1-4%) was used as superdisintegrating agent. Hardness, disintegration time, wetting time and friability for preliminary batches A1 to A4 were found between kg/cm 2, sec, sec. and % respectively. Very less disintegration time obtained in batch A4 was due to high concentration of super-disintegrating agent (Kyron T-314) in Modi Darshan A. 119 Ph.D Thesis

4 formulation. A4 batch had given the best results with the disintegration time of 52 sec, friability of 0.57 %, hardness of 4.2 kg/cm 2 with 99.82% drug release within 30 min. Table 8.3: Evaluation of physical parameter of batches A1-A12 Batch No. Av.Wt. (mg) n=20 Thickness (mm) n=10 Hardness (kg/cm 2 ) n=5 Friability (%) n=10 A ± ± ± A ± ± ± A ± ± ± A ± ± ± A ± ± ± A ± ± ± A ± ± ± A ± ± ± A ± ± ± A ± ± ± A ± ± ± A ± ± ± All values are expressed as mean ± standard deviation, n=3. For A5-A8 batches where SSG (2-8%) was used as super-disintegrating agent. Hardness, disintegration time, wetting time and friability for preliminary batches A5 to A8 were found between kg/cm 2, sec, sec. and % respectively. Very less disintegration time obtained in batch A8 was due to high concentration of super-disintegrating agent (SSG) in formulation. Here batch A8 exhibited good result in the term of disintegration time along with friability parameter and dug release. A8 batch had given the desired results with the disintegration time of 48 sec, friability of 0.62 %, hardness of 4.1 kg/cm 2 with 98.85% drug release within 15 min. In formulation of A9-A12 batches, Ac-Di-Sol (1-4%) was used as superdisintegrating agent. Hardness, disintegration time, wetting time and friability for preliminary batches A9 to A12 was found between kg/cm 2, sec, Modi Darshan A. 120 Ph.D Thesis

5 sec and % respectively. Very less disintegration time obtained in batch A12 was due to high concentration of super-disintegrating agent (Ac-Di-Sol) in formulation. Here batch A12 shown a very nice result in the sense of disintegration time along with friability parameter and dug release. A12 batch had given the desired results with the disintegration time of 54 sec, friability of 0.53 %, hardness of 4.2 kg/cm 2 with % drug release within 30 min. Table 8.4: Evaluation of physical parameter of batches A1-A12 Batches Disintegrating time (sec) Wetting time (sec) Drug content (%) A1 74±2 82± A2 66±1 76± A3 58±2 66± A4 52±3 58± A5 79±2 81± A6 68±1 70± A7 56±3 62± A8 48±2 56± A9 77±2 78± A10 68±2 72± A11 61±1 67± A12 54±3 62± All values are expressed as mean ± standard deviation, n=3. From the preliminary trials, 3 formulations i.e. batch A4, batch A8 and batch A12 were selected for optimization study. Considering all physical parameters of immediate release layer of tablet it was concluded that 4% Kyron T-314 was the best amongst all. Modi Darshan A. 121 Ph.D Thesis

6 Time (sec) A1 A2 A3 A4 A5 A6 A7 A8 A9 A10 A11 A12 Batches Figure 8.1: Disintegration time profile of amlodipine besylate Time (sec) A1 A2 A3 A4 A5 A6 A7 A8 A9 A10 A11 A12 Batches Figure 8.2: Wetting time profile of amlodipine besylate Modi Darshan A. 122 Ph.D Thesis

7 8.4.3 In-vitro dissolution profile of optimized formulations of amlodipine besylate. Table 8.5: Evaluation of in-vitro drug release of optimized formulations of amlodipine besylate. Time (min) Cumulative drug release (%) A4 A8 A ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±0.70 All values are expressed as mean ± standard deviation, n=3. Cumulative Drug Release (%) Time (min) Batch A4 Batch A8 Batch A12 Figure 8.3: Dissolution profile of optimized formulations of amlodipine besylate Modi Darshan A. 123 Ph.D Thesis

8 For optimization above three formulations were evaluated for drug release. All the formulations released more than 90% of drug within 10 min. It was quiet good and confirmed the specification of immediate release dosage form. For optimization, physical parameters were also considered along with in-vitro drug release. After considering all parameters on the basis of cosiderable disintegration time, good wetting time and the least concentration of disintegrating agent used, batch A4 containing 4% Kyron T-314 was optimized as immediate later of dual retard tablet. 8.5 Conclusion Amlodipine besylate immediate release tablets were prepared by direct compression technique using three super disintegrants i.e sodium starch glycolate, croscarmelose sodium and kyron-314. All formulations were subjected to various physical and pharmacotechnical paramaters. Enhanced dissolution of immediate release tablets of amlodipine besylate (batch A4) led to improved dissolution which released approx. 90% drug within 5 min, considerable disintegrating time (52 sec) and least wetting time (58 sec). Batch A4 was formulated using Kyron T-314 (4%). Batch A4 showed best results and was used for further formulation of dual retard tablet in combination. 8.6 References 1. Jayaprakash S, Mohamed H, Pillai K, Balasubramaniyam P, Firthouse M, Boopathi M Formulation and evaluation of bilayer tablets of amlodipine besilate and metprolol succinate. Der Pharmacia Lettre 3(4): Pare A, Yadav SK, Patil UK Formulation and Evaluation of Effervescent Floating Tablet of amlodipine besylate. Res. J. Pharm. and Tech. 1(4): Lachman L, Liberman H The theory and practice of Industrial Pharmacy. CBS publishers and distributors pvt. Ltd; New Delhi: The Indian Pharmacopoeia Commission, Central Indian Pharmacopoeia Laboratory, Ministry of Health and Family Welfare, Govt. of India. Ghaziabad: 96-97, , A Lachman L, Lieberman A, Kinig JL The Theory and Practice of Industrial Pharmacy. Varghese Publishing House, Bombay 4: Bhardwaj V, Shukla V, Goyal N, Salim MD, Sharma PK Formulation and evaluation of fast disintegrating sublingual tablets of amlodipine besylate using different superdisintegrants. Int. J. Pharm. Pharm. Sci. 2: Modi Darshan A. 124 Ph.D Thesis

9 7. Rahman Z, Ali M Design and evaluation of bilayer floating tablets of captopril. Acta Pharm 56: Reddy S, Rao Y Formulation and release characteristic of a bilayer matrix tablet containing glimipiride immediate release component and metformin as sustained release component. Ind J Pharm Sci Nano 39: Modi Darshan A. 125 Ph.D Thesis