INTRODUCTION:

In recent years, the orodispersible tablet has attracted the interest of many researchers. Many elderly patients have difficulty swallowing tablets, capsules, or powders. To alleviate this problem, these tablets are expected to dissolve or disintegrate in the oral cavity without drinking water. The disintegrated mass can slide down smoothly along the esophagus with the help of saliva, so even people who have swallowing or chewing difficulties can take it with ease. The basic approach used in the development of fast-dissolving tablets is the use of superdisintegrants. Another approach used in developing such tablets is maximizing pore structure of the tablets. Drying was adopted after the compression of tablets with addition of a subliming agent to increase porosity of the tablets. It is likely that a porous hydrophilic matrix will easily pick up the disintegrating medium and break quickly^1-5.

The application of an optimization technique consisting of statistical design to pharmaceutical formulation development would provide an efficient and economical method to acquire the necessary information to understand the relationship between controllable (independent) variables and performance or response (dependent) variables⁶. In addition, the optimization process provides a method to develop an empirical model equation to characterize the response as a function of the different independent variables.

The technique of optimization is well reported in the literature for the development of tablet formulations^7-9, micro-capsules¹⁰.

Telmisartan chemically is 2-[4-[[4-methyl-6-(1-methylbenzoimidazol-2-yl)-2-propyl-benzoimidazol-1-yl] methyl] phenyl] benzoic acid, an angiotensin receptor blocker used over cardiovascular diseases. Telmisartan was selected as a model candidate drug because of its poor solubility and less bioavailability (42%) ^11-13.

The objective of the study was to formulate and evaluate orodispersible tablets of Telmisartan. A 3² full factorial design and Response Surface Methodology (RSM) were used to study the effect of formulation variables on the performance of these tablets.

MATERIALS AND METHODS:

Materials:

Telmisartan was obtained as a gift sample Lupin Pharmaceuticals, Aurangabad (M.S), Polacrilin Potassium (PK) was gifted by Themax, Pune, (M.S), Microcrystalline Cellulose (MCC), Camphor, Sodium Lauryl Sulphate (SLS), Magnesium Stearate and Lactose were procured from Lobachemie, Mumbai. Other reagents and organic solvents used were of analytical grade. Buffer and its dilutions were prepared with double-distilled water.

Methods:

Preparation of Telmisartan Orodispersible Tablets:

The tablets were prepared as follow according to the proportion given in the Table 1. The raw materials were passed through a no. 100 sieve. All materials mixed in polybag for 20 min and then mixture was lubricated by magnesium stearate before compression. The tablets were compressed using six station rotary tablet compression machine (JM-6, JMC) equipped with 8 mm punch. The tablet weight was adjusted to 150 mg. Sublimation of camphor was done at 60⁰C¹⁴. Preliminary trials were carried out for selection of superdisintegrants and subliming agent.

Table 1: Composition of Orodispersible Tablets

Ingredients	Amount (mg)
Telmisartan	50
Polacrilin Potassium	5-15
Camphor	0-30
MCC	50
SLS	1.0
Magnesium Stearate	2.0
Lactose	q.s. 150

Full Factorial Design:

A3² full factorial design was used in the present study. In this design 2 factors are evaluated, each at 3 levels, and experimental trials are performed at all 9 possible combinations. The amount of superdisintegrant (PK, X₁) and the subliming agent (camphor, X₂) were chosen as independent variables. As shown in equation (1), a statistical model incorporating interactive and polynomial terms was used to evaluate the responses.

Y = β₀– β₁ X₁ - β₂ X₁²- β₃ X₂+ β₄ X₂² + β₅ X₁ X₂- β₆ X₁² X₂+ β₇ X₁ X₂²+ β₈ X₁²X₂²-----(1)

Where, Y are the dependent variables, namely, disintegration time (Y₁) and percentage friability (Y₂); b₀ is the arithmetic mean response of the 9 runs; and b₁-b₈ are the estimated coefficients for the factors X₁ and X₂, respectively. The main effects (X₁ and X₂) represent the average result of changing one factor at a time from its low to high value. The interaction term (X₁X₂) shows how the response changes when 2 factors are simultaneously changed. The polynomial terms (X₁₂ and X₂₂) are included to investigate nonlinearity. The simplified models were then utilized to produce three-dimensional response surface plots and contour plots to analyze the influence of disintegration time and percentage friability^15,16.

Table 2.a: Design matrix of Dependent and Independent Variables

Run	Coded levels		Disintegration time DT± SD (Sec)	% Friability % F± SD
Run	X₁ (mg)	X₂ (mg)	Disintegration time DT± SD (Sec)	% Friability % F± SD
T₁	-1	-1	185±2.5	0.245±0.0042
T₂	-1	0	160±3.8	0.175±0.0023
T₃	-1	+1	137±4.7	0.148±0.0054
T₄	0	-1	130±6.4	0.280±0.0034
T₅	0	0	110±2.5	0.225±0.0065
T₆	0	+1	88±3.4	0.210±0.0023
T₇	+1	-1	70±4.5	0.485±0.0043
T₈	+1	0	40±2.6	0.288±0.0025
T₉	+1	+1	25±5.6	0.260±0.0018

Table 2.b: Coded levels in actual values

Independent Variable	Coded Levels and Actual Values
Independent Variable	-1	0	1
X1- Polacrilin K	5	10	15
X2- Camphor	0	15	30

Optimization Model Validation:

Various feasibility and grid searches were conducted to find the composition of optimized formulations. The checkpoint formulation was prepared and evaluated for various response properties.

The design matrix for independent variables and dependent variables with coded levels are mentioned in actual values as shown in Table 2 a and Table 2 b.

Evaluation of Tablet Properties^{17, 18}:

The crushing strength of the tablets was measured using a Monsanto hardness tester. The friability of a sample of 20 tablets was measured using a Roche Friabilator (Jashbin). Twenty preweighed tablets were rotated at 25 rpm for 4 minutes. The tablets were then reweighed after removal of fines (using no. 60 mesh screen), and the percentage of weight loss was calculated.

Disintegration test:

Disintegration test (n=5) was carried out on the Disintegration test apparatus (Electrolab). Tablets were placed in the dissolution medium 0.1 N HCl.

Dissolution Studies:

Dissolution experiments(n=6) were performed with a USP XXVII dissolution test apparatus, type II (Electrolab) in pH 1.2 a simulated gastric fluid (SGF) at 37±0.5⁰C at a rotation speed of 100 rpm. At appropriate time intervals, 10ml of the sample was withdrawn and filtered. The removed samples were analyzed at 292 nm by UV-Vis spectrophotometer (UV 530 JASCO).

RESULTS AND DISCUSSION:

On the basis of the results obtained in the preliminary screening studies, the batch containing PK showed the fastest disintegration. Hence, it was selected for further studies. The crushing strength of the tablets was adjusted to 5 kilopound (kp) and tablets diameter was 8 mm and the thickness were ~1.8mm.

In order to investigate the factors systematically, a factorial design was employed. The disintegration time and percentage friability for the 9 batches (T₁ to T₉) showed a wide variation from 185 to 25 seconds and from 0.485 to 0.148 percentage loss, respectively (Table 2.a). The data clearly indicate that the disintegration time and percentage friability values strongly depend on the selected independent variables. The polynomial equations can be used to draw conclusions after considering the magnitude of coefficient and the mathematical sign it carries (positive or negative).

Computed results to describe the relationships among the factors on dependent variables are expressed by Equations. (2) and (3).

Y₁(DT) = +106.67 –58.17 X₁ -2.50 X₁²-20.72 X₂+1.28 X₂² + 0.000 X₁ X₂-1.78 X₁² X₂+0.67 X₁ X₂²+0.22 X₁²X₂²------------------------------------------------------------------ (2)

Y₂(%F) =+0.26 +0.078 X₁+9.481E-003 X₁²-0.066X₂+0.014 X₂² - 0.032X₁X₂-0.015 X₁²X₂+0.010 X₁X₂²+3.519E-003X₁²X₂² -------------------------------- (3)

Concerning disintegration time, the results of multiple linear regression analysis showed that both the coefficients b₁and b₂ bear a negative sign. Therefore, increasing the concentration of either camphor or PK is expected to decrease the disintegration time. When higher percentage of camphor is used, higher porosity is expected in the tablets. The water uptake and subsequent disintegration are thus facilitated. On the other hand, an increase in the concentration of camphor leads to an increase in friability because the coefficient b₁bears a positive sign. When a higher percentage of camphor is used, more porous and mechanically weak tablets are produced. As indicated by negative sign of the coefficient b₂, the increase in the incorporated amounts of PK resulted in decrease in the friability.

Two-dimensional contour plots and three-dimensional response surface plots are presented in Figs.1.a and b, Figs.2.a. and b. , which are very useful to study the interaction effects of the factors on the responses. These types of plots are useful in study of the effects of two factors on the response at one time. In all the presented figures, the third factor was kept at a constant level. All the relationships among the three variables are non-linear.

Table 3 shows the composition of optimum check-point formulations, their predicted and experimental values for all the response variables, and the percentage error in prognosis. Percentage prediction error is helpful in establishing the validity of generated equations and to describe the domain of applicability of RSM model. The low magnitudes of error in the present study prove the high prognostic ability of the RSM.

All tablet formulations were completely dissolved in 45 minutes showing 100% drug release.

CONCLUSION:

The results of a 3² full factorial design revealed that the amount of PK and camphor significantly affect the dependent variables, disintegration time, and percentage friability. The significant effects of the interaction and polynomial variables on the investigated characteristics of Telmisartan orodispersible tablets were verified. Compared with the experimental optimized preparation, the observed responses were in close agreement with the predicted values of the optimized one, thereby demonstrating the feasibility of the optimization procedure in developing Telmisartan orodispersible tablets. It is thus concluded that by adopting a systematic formulation approach, an optimum point can be reached in the shortest time with minimum efforts.

ACKNOWLEDGEMENT:

The authors are grateful to Lupin Pharmaceuticals, Aurangabad (M.S), for providing gift sample of Telmisartan and Thermax Ltd (Pune) for providing PK.

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Received on 24.03.2009 Modified on 22.05.2009

Research J. Pharm. and Tech.2 (3): July-Sept. 2009,;Page 548-551