| Abstract|| |
The purpose of the present work was to develop an optimized immediate release tablet for hypertensive patients using amlodipine besylate as a model drug candidate by optimization technique to produce the intended benefits. A 3 2 factorial design was employed in formulating immediate release tablet. The independent variables selected were superdisintegrants such as sodium starch glycolate and in addition to that, effect of microcrystalline cellulose was studied. The dependent variables considered for study was DT and DP 60 . The tablets prepared were evaluated for thickness, uniformity of weight, hardness, friability, wetting time, in vitro disintegration time, and in vitro drug release study. The response surface plots differentiate the results between the independent and dependent variables. Apart from fulfilling all official and other specifications, the tablets exhibited higher rate of release.
Keywords: Amlodipine besylate, factorial design, immediate release tablet
|How to cite this article:|
Atram SC. Formulation and evaluation of immediate release tablet using response surface methodology. Asian J Pharm 2011;5:46-51
| Introduction|| |
Amlodipine is a prototype second-generation dihydropyridine calcium channel blocker. They have a longer duration of action and can be given once daily. Amlodipine is used in the treatment of mild to moderate hypertension, chronic stable angina pectoris, or vasopastic angina (prinzmetal's or variant). In these conditions, it may be employed as monotherapy or in combination with other antihypertensives or antianginals. Amlodipine can be safely combined with ί blockers, ACE inhibitors, thiazides, and nitrates. It has a half-life of 40 hours and the initial effects are cumulative over many days. ,,
Various techniques can be used to formulate immediate release tablets; direct compression is one of the techniques that require the incorporation of a superdisintegrants into the formulation. Direct compression does not require the use of water or heat during the formulation procedure and is very sensitive to changes in the type and proportion of excipients and the compression forces, when used to achieve tablets of suitable hardness without compromising the rapid disintegration characteristics. ,
The present work carried out for development of immediate release tablet amlodipine besylate by using the 3 2 factorial design method and studying the effect of independent variable on dependent variable to produce an effective formulation. The 3 2 factorial designs were applied for the effect of independent variable such as sodium starch glycolate and microcrystalline cellulose on the dependent response such as DT and DP 60 , respectively.
| Material and Methods|| |
Amlodipine besylate was received as a gift sample from Concept Pharmaceutical Pvt. Ltd., Aurangabad, India. Microcrystalline cellulose was received as a gift sample from Colorcorn Asia Pvt. Ltd., Goa, India. Starch 1500, sodium starch glycolate was received as a gift sample from Concept Pharmaceutical Pvt. Ltd., Aurangabad, India. All other chemicals and reagents are of analytical grades.
Preparation of immediate release tablet of amlodipine besylate
The super disintegrants (sodium starch glycolate and microcrystalline cellulose PH102) were used to formulate the tablets. All the ingredients, as shown in [Table 1], were co-ground in a pestle and motor and then aerosil and magnesium stearate were added and mixed for 10 minutes. The mixed blend of drug-excipient was compressed using a LABPRESS compression machine (Cadmach, Machineries Ltd. Ahmadabad, Gujarat, India) to produce tablets with 2.75-mm thickness and 9.28 mm in diameter. The tablet press setting was kept constant across all formulations. Details are mentioned in [Table 1].
|Table 1: Generalized formulation of amlodipine besylate immediate release tablets |
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Optimization by 3 2 factorial design,,,
A 3 2 randomized full factorial design was used in the present study. In the design, two factors each were evaluated at three levels and experimental trials were performed. Details are mentioned in [Table 2] and [Table 3]. The amount of superdisintegrant, sodium starch glycolate (A), and microcrystalline cellulose (B) were selected as independent variables. In vitro DT and DP 60 were selected as dependent variables.
|Table 3: Formulation design of amlodipine besylate immediate release layer tablet per design (32) layout |
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Evaluation of blend,,,,,
The prepared blends were evaluated for parameters like bulk density, tap density, Carr index, Angle of repose, and Hausner ratio.
The bulk density was calculated using the equation,
Bulk density = Weight of sample/Bulk volume
The tap density was calculated by the following equation,
Tap density = Weight of drug sample/Tapped volume
It is calculated by the formula,
C = VT-VB/VT
Where, VB is the freely settled volume of a given mass of powder, and VT is the tapped density of the same mass of powder.
Angle of repose
The angle of repose is calculated by,
Tan θ = h/r
Where, h is height of the pile and r is the radius of the pile.
It is calculated by the formula,
Where, ρB is the freely settled bulk density of the powder and ρT is the tapped density of the powder.
Evaluation of tablets ,,,,,,,,
Thickness and diameter
and diameter of tablets were determined using vernier caliper. Five tablets from each batch were used, and an average value was calculated.
The crushing strength of the tablets was measured using a Monsanto hardness tester. Three tablets from each formulation batch were tested randomly and the average reading noted.
Ten tablets were weighed and placed in a Roche friabilator and the equipment was rotated at 25 rpm for 4 minutes. The tablets were taken out, dedusted, and reweighed. The percentage friability of the tablets was measured as per the following formula:
Randomly, 20 tablets were selected after compression and the mean weight was determined. None of the tablets deviated from the average weight by more than ±4.5% (USP XX).
Twenty tablets were weighed and powdered. An amount of the powder equivalent to 10 mg of amlodipine besylate was dissolved in 50 ml of 0.1N HCl, filtered, diluted suitably, and analyzed for drug content at 240.80 nm using UV-visible spectrophotometer (UV 1600-Shimadzu, Japan).
A piece of tissue paper (12 Χ 10.75 cm) folded twice was placed in a Petri dish More Details (Internal diameter = 9 cm) containing 10 ml of buffer solution simulating saliva pH 6.8. A tablet was placed on the paper and the time taken for complete wetting was noted. Three tablets from each formulation were randomly selected and the average wetting time was noted.
Water absorption ratio
The procedure of water absorption ratio without Rosaline dye powder was followed for determining the water absorption ratio (R) which was determined according to the following equation:
R = [(Wa - Wb)/Wb] Χ 100
Where, Wb and Wa were the weights of the tablet before and after use.
Disintegration time for fast dissolving tablet (FDTs) was determined using united state pharmacopoeia (USP) disintegration apparatus with simulated gastric fluid (SSF) (pH 6.8, 900 ml at 37ºC) as the disintegrating medium. To comply the test, all tablets should disintegrate within 3 minutes.
In vitro dissolution studies
vitro drug release studies were carried out using USP dissolution rate test apparatus (apparatus 2, 50 rpm, 37±0.5ºC) for 2 hours in 0.1N HCl (900 ml). At the different time interval, 5 ml of the sample was withdrawn and replaced with 5 ml of the 0.1N HCl. The dissolution samples were obtained at different time interval replacing with drug-free dissolution medium. The samples withdrawn were analyzed by a UV spectrophotometer at 240.80 nm.
| Result and Discussion|| |
Evaluation of prepared blend of amlodipine besylate
Before formulation, blends of API and excipients were prepared and evaluated for various parameters, as explained earlier. Bulk density was found in the range of 0.2941 to 0.3846 g/cm 3 and tapped density between 0.3773 and 0.4347 g/cm 3 . Using the above two density data, Hausner ratio and compressibility index were calculated. The powder blends of all formulations with Hausner ratio <1.25 indicated better flow properties. The compressibility index was found to be between 7.68 and 22.05% and the compressibility-flowability correlation data indicated an excellent flowability of all powder blends. The better flowability of all powder blends was also evidenced from the angle of repose (in the range of 31.75-34.16 o ), which is below 40 o , indicating good flowability. Details are mentioned in [Table 4].
Evaluation of prepared tablets of amlodipine besylate
The prepared tablets of amlodipine besylate were evaluated for appearance, weight variation (±%), hardness (kg/cm 2 ), thickness (mm), friability (%), drug content (%), water absorption ratio, content uniformity (%), and wetting time (sec). The results were acceptable and within limits. The cumulative drug release was shown. Details are mentioned in [Figure 1] and [Table 5].
A 2-factor, 3-level factorial experimental design technique was employed to investigate the dependent variables like disintegration time and percent drug dissolved using the Design Expert Software (Version 7.1.4). The responses given by the software are expressed in terms of the quadratic polynomial equations which are given below
Final equations in terms of coded factors (Disintegration time)
DT = 22.25 + 3.76 A + 1.48 B - 0.305 AB + 8.05 A 2 - 0.44 B 2
The r 2 (0.9976) was high indicating the adequate fitting of the quadratic model. The polynomial equations can also be used to draw conclusions considering the magnitude of coefficient and the mathematical sign it carries, that is, positive or negative. The positive coefficient of variable A, that is, sodium starch glycolate in case of response i.e. disintegration time indicates that as the sodium starch glycolate concentration was increased, the DT was increased. The relationship between the variables was further elucidated by using the response surface plot shown in [Figure 2]. A high level of factor A gave a least disintegration time. The "Pred R-Squared" of 0.9703 is reasonable agreement with "Adj R-Squared" of 0.9935. This may indicate a good fitting of the model. "Adeq Precision" measures the signal to noise ratio. A ratio greater than 4 is desirable. Ratio of 40.059 indicates an adequate signal. This model can be used to navigate the design space. The PRESS value shows 6.8025. The Model F value of 245.14 implies that the model is significant. The VIF value is 1. Details are mentioned in [Table 6].
Final equations in terms of coded factors (percent drug dissolved)
DP = 97.9589 - 2.9116A - 2.8466B + 0.155AB - 9.3879 A 2 + 1.2766 B 2
The r 2 (0.9937) was high indicating the adequate fitting of the quadratic model. The polynomial equations can also be used to draw conclusions considering the magnitude of coefficient and the mathematical sign it carries, that is, positive or negative. The negative coefficient of variable A, that is, sodium starch glycolate in case of response % drug dissolved indicates that as the sodium starch glycolate concentration was increased, the percent drug dissolved value was also decreased. The relationship between the variables was further elucidated by using the response surface plot shown in [Figure 3]. A high level of factor A gave a low value of % drug dissolved at all the levels of factor B, which indicated that the factor A has a significant negative effect on % drug dissolved. The "Pred R-Squared" of 0.9242 is in reasonable agreement with the "Adj R-Squared" of 0.9832. "Adeq Precision" measures the signal to noise ratio. A ratio greater than 4 is desirable. Ratio of 41.007 indicates an adequate signal. This model can be used to navigate the design space. The PRESS value is 21.2629. The Model F value of 94.84 implies the model is significant. The VIF value is 1. Details are mentioned in [Table 7].
| Conclusion|| |
In the present study, amlodipine besylate 10 mg tablets have been formulated and developed using direct compression technique, to provide a safe, highly effective method for treating severe hypertension while reducing undesirable adverse effects. The results suggest that suitably formulated immediate release tablets of amlodipine besylate with a superdisintegrants (sodium starch glycolate and microcrystalline cellulose) can be achieved by factorial design method.
The independent variables exhibited a good response on the dependent variables to produce an effective formulation. Thus, the present study demonstrated potentials for rapid absorption, improved bioavailability, effective therapy, and patient compliance.
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Sandeep C Atram
Vidyabharati College of Pharmacy, CK Naidu Marg, Camp Road, Amravati - 444 602, (MS)
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]