Pharmaceutica Analytica Acta

The aim and objective of the present study is to develop and evaluate FDT of Telmisartan and enhance the onset of action of Telmisartan and also to study the influence of excipients on the physical characteristics of the tablets by applying three level two factor factorial designs taking Telmisartan as model drug which is used in the treatment of the hypertension. The study was intended to select the best possible diluents and the superdisintegrants combination to formulate the dispersible tablets among all the diluents and disintegrants used. Finally the impact of the diluents ratio and superdisintegrants on various properties of the tablet were also determined [1].

The basic approach in the development of the fast dissolving tablet is the use superdisintegrants. Croscarmellose, sodium starch glycolate, crospovidone, polacrallin potassium are the best used superdisintegrants globally. In this study all the above mentioned superdisintegrants are selected and best one is selected for further studies. Another approach used in developing FDT’s is freeze drying and vacuum drying, but both are cumbersome and they yield a fragile and hygroscopic product. Therefore it was decided to adopt the Direct Compression Technique to prepare FDT in an easy and comfortable way as it requires less number of unit operations. Additionally a wetting agent is used to increase the wicking nature of the tablet.

Factorial designs allow for the simultaneous study of the effects that several factors like concentration of superdisintegrants and diluent concentration may have on the physical characteristics of the tablets [2].

Contour plot helps in visualizing the response surface. Contour plots are useful for establishing desirable response values and operating conditions [3].

Using a surface plot one can visualize the response surface. Surface plots are useful for establishing desirable response values and operating conditions.

Electronic digital balance-Sartorious BT 323S, Tapped density apparatus-Electrolab USP ETD 1020, Rotary tablet punching machine- Elit Jemkay Pvt Lt, Ahmedabad, Friability test apparatus-Electrolab, EF 2, Mumbai, Disintegration apparatus-Electrolab ED 2AL, Helium lamp (LOD)-Mettler-Toledo, Thickness (Vernier Calipers)-Mitutogo Vernier Calipers, Sieves, Jayanth test sieves, Mumbai, Hardness tester, Monsanto hardness tester, UV-Visible spectrophotometer-Shimadzu (uv-1601), Vernier calipers-Mitutoyo, Japan, Monsanto hardness tester-Scientific Eng Corp Delhi, Stability chamber-Neutronics, HPLCShimadzu, FTIR-Shimadzu, X-ray diffractor-Philips, DSC (Differential Scanning Colorimetry)-Shimadzu.

Telmisartan, Kyron T-314, Crosspovidone, XL 10, SSG, Croscarmellose, Strawberry Flavour, Aerosil, Neotame, Microcrystalline cellulose, Mannitol SD, Magnesium stearate, Glycine, Methanol (HPLC Grade), HCl, TEA(tri ethyl amine), Acetonitrile (HPLC Grade). All the chemicals were provided by KAPL Bangalore [4].

The plan of work is to perform pre-formulation studies of the prepared formulation with excipients for their compatibility by FTIR studies and screening of various disintegrating agents for the preparation of rapidly integrating tablets. The best disintegrating agent was used and further evaluated by 3² factorial design and regression analysis. Dispersible tablets were prepared by direct compression technique for a model antihypertensive drug, telmisartan. Formulation of rapidly disintegrating tablets was carried out using different diluents ratio. The prepared dosage form was subjected to pre- and post- compression parameters. Selection and optimization of the best formulation was carried out based on the above results. The results were subjected to ANOVA after the development of polynomial models. The optimized formulation was compared with the reference product by using similarity factor to assess the bioequivalence between the two products. Compatibility studies were performed for the final formulation by using DSC and also stability studies were performed on the most satisfactory formulation as per ICH guidelines [5].

The disintegration and solubilisation of directly compressed tablets depends on action of the disintegrant and other excipients used like wetting agents. Disintegrant efficacy is strongly affected by tablet size and hardness. Large and hard tablets will have more disintegration time than usually required. As a consequence low values in hardness may lead to increased friability. This will affect the physical resistance on the tablet. Disintegrants have major role in the disintegration process of the mouth dissolving tablets made by direct compression. To ensure high disintegration rate, choice of suitable type and optimal amount of the disintegrant is important. All the ingredients were passed through #30 meshes separately. The drug and the diluents were mixed in small portions of both at each time and blended to get a uniform mixture. The ingredients are weighed and mixed in geometrical order. Flavouring agents followed by the lubricants were added at the end and were mixed thoroughly. The blend was compressed using 10 mm flat punch to get a tablet of 300 mg using 16-stationary rotary punching machine. Elit Jemkay Pvt Ltd., Ahmedabad [6].

The aim of the study is to formulate fast dissolving tablets of Telmisartan by direct compression technique using a wetting agent for fast wicking action and for the solubility enhancement of Telmisartan. Different disintegrants were selected for this study following literature survey. Superdisintegrants used are Croscarmellose sodium, Sodium starch glycolate, Crospovidone, Crospovidone XL 10 and Polacrallin potassium.

Since Telmisartan had poor solubility and less bioavailability. Therefore, Addition of different Superdisintegrants were added to decrease the disintegration time thereby increasing the bioavailability and wetting agent was employed to enhance its solubility [7-21].

For the drug Telmisartan, Superdisintegrants were added in different percentage concentrations. The Superdisintegrants and other excipients were mixed thoroughly. The blend was then compressed directly. All the Superdisintegrants were screened and the final formulations with favorable disintegration time and friability results were taken into account for solubility enhancement studies. Since it is already proved that addition of a wetting agent like Glycine will increase the solubility of water insoluble drugs, Glycine is added at a concentration of 3%w/w of the total tablet. The process for the formulation of Telmisartan fast dissolving tablets was developed in a systematic way. Trials were taken by conducting the dissolution studies of the tablets with Glycine, with 1% SLS and 3% SLS in which the drug is intended to show greater solubility (Tables 1-4).

Table 1: Working formula of the preliminary batches from f1-f15 batches.

Table 2: Factorial design studies: 3² Full factorial design lay out.

Table 3: Coded values and actual values of X₁and X₂ variables.

Table 4: Analysis of factorial formulation: Working formula of factorial formulation.

NOTE: X₁ and X₂ are independent variable representing the concentration of Kyron and diluents ratio in the coded values. Y₁ and Y₂ are the dependent variables representing the responses like Disintegration time in seconds and % Friablilty. All the values of Y₁ and Y₂ are the taken from the following table.

Compatibility analysis by FTIR spectrophotometer was performed.

Pre-compression parameters

It contains Bulk density, Tapped density, Compressibility index and hausner’s ratio, Angle of repose.

Post-compression parameters include

Weight variation, Thickness and diameter, Apparent density, Physical appearance, Hardness, Friability, Disintegration Time, Wetting Time and Water Absorption Ratio, Assay [22-30].

In vitro dissolution studies: In vitro dissolution studies for fabricated Mouth Dissolving tablet is carried out by using USPXX III Type II (Electro Lab dissolution tester) dissolution apparatus at 75 rpm in 900 ml of 0.1 N HCl as dissolution media, maintained at 37 ± 0.5°C. Mouth dissolving tablet of desired formulation were taken and placed in the vessels of dissolution apparatus. Sample of 10 ml were collected from the vessels at specified time intervals 10, 20, 30, and 60 min filtered and determined by liquid chromatography as described in the following procedure. Drug concentration was calculated from the standard and expressed as percentage of drug dissolved or released [9].

The purpose of stability testing is to provide evidence of the quality of the drug substance or drug product, and how it varies with time under the influence of a variety of environmental conditions (heat, humidity, light, air etc). The choice of test conditions defined in the guideline ICH – Q1A (R2) is based on an analysis of the effects of climatic conditions in the three regions of the EC, Japan and the United States [31-39].

Dissolution profiles may be considered similar by virtue of (1) overall profile similarity and (2) similarity at every dissolution sample time point. The dissolution profile comparison may be carried out using model independent or model dependent method [40].

A simple model independent approach uses a difference factor (f1) and a similarity factor (f2) to compare dissolution profiles (Moore 1996). The difference factor (f1) calculates the percent (%) difference between the two curves at each time point and is a measurement of the relative error between the two curves [41-47].

Standard plot of telmisartan

Regression analysis: Absorbance Y vs. Conc X (mcg/ml): The regression equation is Absorbance (Y)=0.01136(c)+0.05292 (m). Conc X (mcg/ ml). Where, c=y intercept, m=slope of the regression equation; r2=0.9993; R-Sq=99.93%; R-Sq (adj)=99.9% (Figures 1-15) (Tables 5-22).

Table 5: Peak list.

Table 6: Pre-Formulation Studies: Drug-excipient compatibility studies.

Table 7: Principal Peaks in FTIR spectrum.

Table 8: Pre-compression parameters of the preliminary batches F1-F15.

Table 9: Effect of the Disintegrating Agent with the Disintegration Time and % Friability.

Table 10: Post-compression parameters of the preliminary batches F1-F15.

Table 11: Screening the effect of glycine, 1% SLS and 3% SLS on solubility by dissolution apparatus.

Table 12: Pre-Compression parameters of factorial formulations.

Table 13: Evaluation of factorial formulations.

Table 14: Dissolution data of the optimized batch and comparison with the marketed product.

Table 15: Multiple regression analysis for response factor y1 (Disintegration time).

Table 16: Summary of results of regression analysis for response factor y1 (Disintegration time):

Table 17: Results of ANOVA for dependent variables.

Table 18: Multiple Regression Analysis for Response Factor Y₂ (% Friability):

Table 19: Summary of results of regression analysis for response factor Y₂ (% Friability).

Table 20: Results of ANOVA of Full and Reduced Model for Dependent Variable.

Figure 1: Standard plot of Telmisartan.

Figure 2: X-ray of pure API: (sample)

Figure 3: X-ray of reference API.

Figure 4: DSC Thermogram of pure API.

Figure 5: Compatibility studies by FTIR.

Figure 6: Left: Radar plot showing the effect of the Disintegrant on the Disintegration time.
Right: Radar plot showing the Effect of the Disintegrant on the % Friability.

Figure 7: Effect of various wetting agents on the dissolution of the Telmisartan FDT’s and comparative dissolution profile Telmisartan tablets with two different wetting agents.

Figure 8: Comparative dissolution profile solubility enhancer vs. without enhancers.

Figure 9: Comparative dissolution profile of Marketed batch vs. P6 Batch.

Figure 10: Right: Plot showing the level of interactions between the X₁ and X₂ at various concentrations. Left: Plots showing the effect of individual concentration of X₁, X₂ on the % Friability.

Figure 11: Right: Plot showing the level of interactions between the X₁ and X₂ at various concentrations. Left: Plots showing the effect of individual concentration of X₁, X₂ on the % Friability.

Figure 12: Right: Contour plot showing the effect of X₁ and X₂ on the % Friability. Left: Contour plot showing the effect of X₁ and X₂ on the % Friability.

Figure 13: Right: Response Surface Plot of Y₁ vs. X₁ and X₂; Left: Response Surface Plot of Y₂ vs X₁ and X₂.

Figure 14: Diagramatic representation of invitro dispersion time of dispersible tablets: (P6 optimized batch).

Figure 15: Final compatibility studies of telmisartan fast dissolving tablets using differential scanning colorimetry.

Polymorphism studies by x-ray diffraction

S=3.66035 ; R-Sq=99.6%; R-Sq(adj)=98.9%; Regression Analysis: Y₁ versus X₁, X₂, X₁ X₂, X₁², X₂²; The regression equation is Y₁=26.1-30.7X₁+19.7X₂- 15.7X₁X₂+11.3 X₁²+14.3X₂².

Y₂ (Fraibility) vs. X₁ and X₂

S=0.0650285; R-Sq=99.5%; R-Sq(adj)=98.6% {FULL MODEL}

Regression Analysis: Y₂ versus X₁, X₂, X₁ X₂, X₁², X₂² {FULL MODEL}. The regression equation is Y₂=0.321-0.193 X₁+0.455 X₂-0.147X₁X₂-0.0367 X₁²+0.628X₂²

S=0.0619980; R-Sq=99.3%; R-Sq(adj)=98.7% {REDUCED MODEL}

Regression Analysis: Y₂ versus X₁, X₂, X₁ X₂, X₂² {REDUCED MODEL}. The regression equation is Y₂=0.297-0.193X₁+0.455X₂-0.147 X₁X₂+0.628X₂²

Stability data:

Melting point determination

By using melting point determination apparatus, the preliminary physical characteristics of the pure API like melting point, Telmisartan was found to be 255°C complies with literature standards.

X-ray diffraction studies and DSC studies

The X-ray Studies revealed that the API sample is only of pure polymorph A and there was no contamination of polymorph B which has less stability, poor flow than polymorph A which may cause degradation during the compression stages of tablets.

FT-IR studies

The excipient compatibility studies were conducted with the pure API and it was found to be compatible by comparative studies. Results revealed that there was no disturbance in the pure API.

HPLC studies

The solubility studies between without solubility enhancer, glycine and 1% SLS, 3% SLS were conducted. There was huge indirect relationship was observed that, increase in the concentration of SLS from 1% to 3% causes decrease in the solubility from 98% to 85%. And glycine has showed very good solubility of 99.97% which is comparatively higher than SLS which was observed by HPLC chromatograms.

DSC studies

Final compatibility studies of Telmisartan with all the excipients are performed and analyzed. The comparative thermogram of API and final blend results revealed that that there was no incompatibility between them. The clear peak at 252°C in the pure API thermogram was not disturbed after final blending was completed.

Experimental design

In the present study, a three level two factorial design was used to evaluate the effects of the selected independent variables on the responses, to characterize the physical properties of the tablet like disintegration time, the % friability and to optimize the procedure. This design is suitable for exploration of the quadratic responses and the second order polynomial models, thus helping to optimize the process by using a small number of experimental runs. This design resolves the two factor interaction effects of the individual terms and allows the mid-level setting (0) for the combination of factors.

Optimization results

The formulation was designed using 3² factorial design, the materials and compositions used are presented in table 4. In this study, formulation variables i.e,

Independent variables: X₁=Disintegrant Concentration (Kyron T-314)

X₂=Diluent ratio (MCCP: MANNITOL)

Dependent variables: Y₁=Disintegration time,

Y₂=% Friability.

Influence of independent variables on the final formulation

The preliminary trails were conducted by using five different Superdisintegrants like Croscarmellose, sodium starch glycolate, Crospovidone, XL-10 and kyron T-314. Three batches were using a single superdisintegrant. On the basis of the results obtained in the preliminary studies, the batch containing the Kyron T-314 is showing good correlation % friability and disintegration time. Hence it was selected for further studies. The hardness was adjusted to the 4 kg/cm². Wetting agent like glycine is used to increase the water availability for the superdisintegrant by its wicking action. The table of post compression parameters of F1 to 15 indicates that the concentration dependent disintegration was observed in the batches prepared by the different Superdisintegrants at different concentrations. Tablets with lower friability (≤ 0.5%) may not break during handling on machines and or shipping. In the first few attempts in preliminary batches a change in the filler ratio of (MCCP: Mannitol) causes changes in the friability values were observed and hence it is also considered as one of the important factor that effect friability. The use of superdisintegrant at varied concentrations {along with change in the filler concentration/ratio} effecting the friability was also observed. Addition of colloidal silicon dioxide results in decreased friability and marginal effect on the disintegration time. As the magnesium stearate will form a layer around the tablet that may decrease the wicking action of the other excipients. It was decided to add the colloidal silicon dioxide that helps to restore the bonding properties of the other excipients. So, based on the observation it was decided to take superdisintegrant concentration and MCCP: MANNITOL (filler ratio) as the two independent variable that effecting the friability and disintegration time taken as the dependent variables. The disintegration time and % friability for the 9 batches from P1 to P9 showed wide range of variation (i.e., 8 sec to 119 sec and 0.16% to 1.71%) respectively. This indicates the disintegration time and friability are strongly dependent on the selected independent variables. The fitted equation (full and reduced model) relating the disintegration time and friability is shown in the table. The polynomial equation can be used to draw the conclusion after considering the magnitude of the coefficient and the mathematical sign it carries (positive or negative). Table 27 shows results of analysis of variance (ANOVA), which was performed to identify the insignificant factors. The high values of the correlation coefficient for disintegration time and % friability indicates a good fit.

Estimation of quantitative effects of the factors

A response regression analysis for each factor was performed by using the coded values of the factor levels (-1, 0, 1). In the table 18, 19, 21 and 22, the factor effects and associated p-values for the responses were presented. A factor is considered to influence the response if the effects significantly differ from zero and the p-value is less than 0.05. A positive sign indicates a synergistic effect, while a negative sign represents an antagonistic effect of the factor on the selected response.

Analysis of fitted data

Combinational effect on disintegration time: The results of linear multiple regression analysis reveal that on increasing the concentration of the superdisintegrant i.e. Kyron T-314, there is decrease in the disintegration time is observed as the coefficient of the X₁ bears the negative symbol. This may be due to an increase in the concentration might cause the increase in the water uptake by the superdisintegrant in the formulation causing the tablet to disintegrate rapidly by swelling. Similarly the X₂ coefficient positive symbol indicates that increase in the concentration of MCCP in the diluents ratio will increase the disintegration time was observed.

Y₁=26.1-30.7X₁+19.7X₂-15.7X₁X₂+11.3 X₁²+14.3X₂²

The factor X₁, and interaction term X₁ X₂ has antagonistic effect on the Y₁ response and these factors are found to be significant with a p-value of 0.0002 and 0.003. The factor X₂, and the nonlinearity factors X₁², X₂² have synergetic effect on the Y₁ and found to be significant with p-values of 0.001, 0.022 and 0.012. For estimation of the significance of the model, the analysis of variance ANOVA was applied. Using the 5% significance level, a model is considered to be significant if its p-value (significant probability value) is less than the 0.05. From the table 19, the value of p was found to be less than 0.05 and hence the model is considered was found to be significant to predict the influence of the independent variables on the responses or dependent variables i.e. disintegration time (Y₁).

Combination effect on % friability: As the concentration of the superdisintegrant led to decrease in the friability values because the coefficient of X₁ indicates negative sign. When an higher amount of the superdisintegrant is used, the adhesive nature may result in the increase in the inter particulate bonding strength such that decrease in the friability is achieved. Thus addition of polacrallin potassium not only favors the disintegration time but also the friability values. Tablets of low friability of 0.16% may not break during the handling, packing and shipping. Thus polacrallin potassium helps in producing the mechanically strong Fast Dissolving Tablets. In the same manner, the coefficient of the X₂ bears positive symbol indicating that increase in the MCCP in the filler ratio causes increase in the friability value. But from the graph the effect is in sigmoid fashion. This indicates that decrease in the concentration of MCCP will decrease the friability values up to certain extent i.e. when the MCCP: MANNITOL is 2:2. But the proportionality is observed up to the certain level i.e. up to the MCCP: Mannitol ratio is 2:2, after that again the reverse is observed because the X₂² nonlinearity factor was found to be more significant.

Y₂=0.321-0.193 X₁+0.455 X₂-0.147 X₁ X₂-0.0367 X₁²+ 0.628 X₂² {Full model}

Y₂=0.297-0.193 X₁+0.455 X₂-0.147 X₁ X₂+0.628 X₂² {Reduced Model}

The factor X₁ and interaction term X₁ X₂ have antagonistic effect on the Y₁ response and these factors are found to be significant with a p-value of 0.005 and 0.02. The factor X₂ , and the nonlinearity factor X₂² have synergetic effect on the Y₁ and found to be significant with p-values of 0.001 and 0.001. The nonlinearity factor X₁² was to found to be insignificant in predicting the % friability because its p-value is 0.483 and hence it was excluded in estimating the ANOVA of the model. For estimation of the significance of the model, the analysis of variance ANOVA was applied. Using the 5% significance level, a model is considered to be significant if its p-value (significant probability value) is less than the 0.05. From the tables 2 and 3, the value of p was found to be less than 0.05 and hence the model is considered was found to be significant to predict the influence of the independent variables on the responses or dependent variables i.e. % friability. The reduced model was tested to determine whether X₁² variable contribute significantly to predict the % friability or not. Since the p-value is <0.05, it was conclude that X₁² does not contribute significantly to predict the % friability.

Analysis of contour plots and response surface plots

Three-dimensional (3D) plots and Contour plots for the measured responses were formed, based on the model polynomial functions to assess the change of the response surface. Also the relationship between the dependent and independent variables can be further understood by these plots. Since the model has two factors, one factor was held constant for each diagram; therefore, a total of 2 response surface diagrams was produced one for each response. Response surface plots are presented using optimal levels of the factors studied. Considering the greatest difference in model polynomial functions response, the surface plots for responses Y₁ and Y₂ are further presented (Figures 13 and 14). In Figure 14 (Right), response surface plots (3D) showing the effect of concentration of superdisintegrant (X₁) and ratio of diluents (X₂) on the response Y₁ (Disintegration time of Telmisartan) and in figure 14 (Left), response surface plots (3D) showing the effect of concentration of superdisintegrant (X₁) and ratio of diluents (X₂) the response Y₂ (% Friability), respectively are presented. The influence of concentration of superdisintegrant (X₁) and ratio of diluents (X₂) are presented.

Oral disintegrating tablets (ODT) of TELMISARTAN was successfully prepared by using direct compression method The optimal batch P6 exhibited the disintegration time of 8 sec and friability of 0.16%. The method for immediate release of Telmisartan tablets with optimal release properties was determined using experimental design methodology. After determination of significant parameters by using three-level two-factorial design was applied. Analytical parameters investigated in this study were: concentration of superdisintegrant (X₁), ratio of diluents (X₂). The chosen responses were disintegration time and the % friability. The model reliability and estimation of quantitative effects of different levels of investigated factors was performed using the Minitab System statistical software, Release 16.0. The levels of these factors were predicted to obtain an optimal response with reference to set constraints. The observed responses were close to the predicted values for the optimized drug release method. From the above results, it can be concluded that characterization and optimization of the Telmisartan immediate release tablets was performed in a very short time period and with a small number of experimental runs. It is essential that experimental design methodology is a very economical way for extracting the maximum amount of complex information, a significant experimental time saving factor and moreover, it saves the material used for analyses and personal costs as well. The results of 3² factorial design revealed that the amount of superdisintegrant and the filler ratio significantly affect the dependent variables disintegration time and % friability. It is concluded that by adopting a systematic formulation approach, an optimum can be reached in the shortest time with minimum efforts.