Objective: The purpose of the current research work was to study effect of formulation variables in a statistical way for the SR formulations of Valsartan sodium.

Methods: Valsartan sodium is an antihypertensive agent angiotensin‒II receptor blocker belongs to BCS class‒III agent. SR tablet formulations of Valsartan sodium were formulated using variable quantities of HPMCK100M and Xanthan Gum by direct compression method. quantities of polymers was chosen as independent variables, X₁ and X₂ respectively whereas, time required for dissolution 10%(t_10%), 50%(t_50%), 75%(t_75%) and 90%(t_90%) of drug from formulation were chosen as dependent variables. 9 formulations were prepared and evaluated for various pharmacopoeial tests.

Results: The results reveals that all formulations were found to be with in the acceptable limits and release rate profiles of all formulations were fitted to kinetic models. The statistical parameters were determined. Polynomial equations were developed for dependent variables. Validity of them was checked by countercheck formulations (C₁,C₂). According to SUPAC guidelines, formulation (F₄) containing mixture of 12% HPMCK100M and 16% Xanthan gum, was found to be identical formulation (dissimilarity factor f₁=1.763, similarity factor f₂=86.747 & No significant difference, t=0.0478) to marketed product (VALZAAR).

Conclusion: Formulation F₄ follows First order kinetics, Non‒Fickian Diffusion Anomalous Transport. (n=0.826).

Keywords: valsartan sodium, 3² factorial design, sustained delivery, hpmck100m, xanthan gum, first order kinetics, anomalous transport

Oral route is the extensively used mode of administration for both conventional delivery systems and novel drug delivery systems. Tablets are the most famous solid dosage forms sold in the market. For chronic Therapy, immediate release formulations are required to be administered in repetitive mode results patient non‒compliance.¹ However, oral administartion of majority of drugs facilitates hepatic first pass metabolism, results low systemic availability of active ingredient, shorter action and development of non‒active or toxic metabolites.² The aim of developing SR formulations is to maintain sink conditions (C_SS levels for prolonged period). Systems such as modified release/timed release also similar to sustained drug delivery.^3‒5 SR formulations shows reduction in frequency of administration in comparison with prompt release dosage forms.⁶ SR formulations offers advantage over immediate release formulations by optimising characteristics of active ingredients. Polymers plays a key role in the release of drug from formulations. Polymers from natural sources are widely used in product development due to numerous advantages. Gums such as guar, xanthan, tragacanth, alginates, pectin etc. celluloss such as HPMC, HPC, CMC, SCMC extensively used for retarding property.

Formulations processed by Direct Compression (DC) technique, a simple approach because of Easer, rapid production, No degradative effects occurred during manufacturing, compliance.⁶ The suitability of drug candidates for sustained release system based on biopharmaceutical, pharmacokinetic and pharmacodynamic properties of it.

Drug profile and rationality for experimental design

The aim of present research work, stastical study of formulating SR formulation of Valsartan sodium.

Valsartan sodium, antihypertensive agent, angiotensin‒II receptor blocker, belongs to BCS Class‒III agent. It is used for the management of myocardial Infarction, congestive heart failure. The main problem associated with this drug is, its low bioavailability (20‒25%), shorter t_1/2(6hr). conventional tablets should be taken 2‒3times a day to attain C_SS. Administration of Valsartan sodium in a sustained release formulation would be more beneficial for the management of hypertension. Hence, to reduce dosing frequency, improve therapeutic efficacy, patient compliance once daily sustained release Valsartan sodium is desirable.^7‒13 Formulating a dosage form for obtaining a desirable drug release with minimum heuristics is essentilal. RSM with polynomial equation based concept has been efficiently utilised for optimization process. Hence an attempt is made in current work to design SR tablet formulations of Valsartan sodium using HPMCK100M and Xanthan gum by using 3² Factorial design technique. The significant variables such as quantity of HPMCK100M and Xanthan gum and dependent variables, i.e. t_10%, t_50%, t_75%, t_90%, (Time taken for dissolution 10%,50%,75%,90% of drug respectively).^14,15

Materials used in research work were procured from the various sources. Valsartan sodium was a gift sample from Meditech Pharma Ltd, Hyderabad, India. HPMCK100M, Xanthan gum, MCC and Lactose were procured from Loba Chemie Pvt.Ltd, Mumbai. Other excipients such as magnesium stearate, Talc were procured from S.D. Fine Chem. Ltd., Mumbai.

Design, development of valsartan sodium sustained release tablet formulations

3² factorial design, describe the proportion in which the independent variables amounts of HPMCK100M and Xanthan gum were used in current proposal The time required for 10%(t_10%), 50%(t_50%), 75%(t_75%) and 90%(t_90%) dissolution were opted as dependent variables. Significance terms were chosen at 95% confidence interval (p<0.05) for resultant equations. Polynomial equations were developed for dependent variables in accordance with Linear step‒wise backward Regression Analysis Technique. The 3 levels of factor X₁ (HPMCK100M) at 8%, 12%, 16% concentrations. 3 levels of factor X₂ (Xanthan gum) at 8%, 12%, 16% concentrations (%with respect to 250mg). nine formulations were designed and prepared using trail run combinations of the two factors i.e X₁, X₂ as per experimental design and evaluated to check the significance of combined effects of X₁, X₂ to select the best combination and to optimise.

Manufacture of valsartan sodium sustained release tablet fomulations

Valsartan sodium SR Tablets were obtained by utilising Direct Compression method. Composition of each Tablet was shown in Table 2. All ingredients required for formulation were collected and weighed accurately and passed through sieve no 40. They were subjected to polybag mixing for 10‒15min to obtain a uniform powder blend. magnesium stearate was added to the powder blend and then again mix for 4‒5min, Blend was subjected to compression by using tablet Minipress (8mm round punches and same hardness used for required number of tablets). Compressed tablets were evaluated as per official standards and unofficial tests. Tablets were packaged in air tight, light resistance and moisture proof containers.

Experimental design

Experimental design used in experimentation for the optimization of release rate modifiers concentration such as, quantity of HPMCK100M was labelled as X₁ and quantity of Xanthan gum was labelled as X₂. Formulation design was summarized in Table 1. 3 levels for the quantity of HPMCK100M were selected and coded as ‒1= 8%, 0=12%, +1=16%. Three levels for the quantity of Xanthan gum were selected and coded as ‒1= 8%, 0=12%, +1=16%. Formulae for all the factorial batches were given in Table 2.

Mechanical strength

The Mechanical strength of the tablets was determined by diametric breakdown of tablet with the help of Monsanto/ Pfizer’s Hardness Tester, results expressed in terms of kg/cm².

Friability

This test was executed by using Roche friabilator. A sample of 20 tablets are taken weighed (W) and dedusted in a drum for 4minutes at a speed of 25rpm or 100 free falls and weighed (W₁) again. % friability was determined by using following formula. %weight loss should not be more than 0.8.

$Friability\left(\%\right)=\left[(W-W_1)/W)\right]\times 100$

Content uniformity

A sample of 20 tablets was chosen randomly & the % drug content was determined, the tablets content should be in the range of 100±15% of the labelled amount can be considered as the test was passed.

Assay

A sample of 20 tablets collected and subjected to pulverisation. powder equivalent to 80mg was dissolved in 1dL of phosphate buffer pH6.8, subjected to agitation to get more solubilisation. The solution was filtered through a 0.45μ membrane filter, diluted suitably and the absorbance of final solution was measured by using UV‒Visible Spectrophotometer at 251nm by employing phosphate buffer pH6.8 as blank.

Thickness

This test was performed by using vernier calipers by placing the tablet between two arms of the vernier calipers. Final result was recorded

In‒vitro drug release study

The In vitro drug release study was performed by using USP XXIII type‒II dissolution test apparatus (Paddle type) using 900ml of 0.1 NHCl as dissolution medium for initial 2hours followed by phosphate buffer pH6.8 at 50rpm and temperature 37±0.5°C as standard set of conditions specified by monograph for SR Formulations. At predetermined time intervals, 5 ml of the samples were withdrawn by means of a syringe fitted with a pre‒filter, the volume withdrawn at each interval was replaced with same quantity of fresh dissolution medium. The resultant samples were analyzed for the absorbance at 251nm using UV Visible spectrophotometer after appropriate dilutions. The determinations were performed in triplicate (n=3).

Kinetic modeling of drug release

The dissolution profile of formulations was fitted in to zero‒order, first‒order, Higuchi and Korsmeyer‒peppas models to know the pattern, order of drug release and mechanism.^5,16,17

SR Tablet formulations of Valsartan sodium were prepared and optimized by 3² factorial design in order to screen the best combination of different drug release rate modifiers, HPMCK100M, Xanthan gum and also to achieve objective of present research work. The 2 factorial variables utilized in the development of formulations are, quantities of HPMCK100M & Xanthan gum were opted as independent variables (X₁, X₂), and In vitro dissolution characteristics such as t_10%, t_{50% ,} t_75% & t_90% considered as dependent variables_. 9 formulations were deigned and formulated utilizing 3² factorial design and all the formulations containing 80mg of Valsartan sodium as dose. All the tablets were subjected to various official tests such as mean hardness, friability, drug content, mean thickness and results are summarised in Table 3. The hardness of tablets was found to be 4.525±0.43‒5.07±0.42Kg/cm². % Weight loss in for formulations <0.445. Drug content factorial formulations was found to be within acceptable range only. In vitro drug release studies were done for factorial batches using 0.1NHCl for initial 2hours followed by phosphate buffer pH6.8 as a dissolution media at 50rpm and 37±0.5°C. The In vitro dissolution profiles of tablets were shown in Figure 1‒4 (Kinetic Plots) and the Statistical values for kinetic models were tabulated in Table 4. % Cumulative Drug release for trial batches F₁‒F₉ at 12Hr were found to be 89.20‒96.325%. From the result it reveals that the rate of drug release was higher for batches containing Low level of X₁ compared with others, due to High quantity of polymer results drug may have entrapped within a polymer matrix causing a decrease in release rate. Therefore, predicted release of drug can be resulted by manipulating the quantities of X₁,X₂. Formulation F₄ containing 30mg of HPMCK100M, 40mg of Xanthan gum exhibited promising kinetic values (t_10%= 0.384h, t_{50% =} 2.520h, t_{75% =} 5.039h, t_{90% =} 8.370h). The variation in initial rapid release of drug is due to difference in the viscosity of the polymeric mixtures. As we know that viscosity of polymer is inversely proportional to the rate of drug release, variation in the viscosity is due the formation of thicker gel layer in formulation.¹⁸ The In vitro drug release profile of Valsartan sodium trail runs was subjected to goodness of fit test by linear backward step‒wise regression analysis according to kinetic/ mathematical models to know the drug release mechanism. Kinetic plots shown in Figure 1‒4. It was known that from the above results dissolution profile of most of batches follows First order kinetics with co‒efficient of determination (R²) values above 0.972 (0.972‒0.979). The values of r of factorial batches for Higuchi’s kinetics was found to be 0.953‒0.964, which confers that the data fitted well to Higuchi’s square root of time equation confirming the release followed diffusion mechanism. Kinetic data also treated for Peppas equation, the slope (n) values 0.626‒0.887 that proves Non‒Fickian diffusion mechanism (anomalous drug transport). Polynomial equations were derived for dependent variables by backward stepwise linear regression analysis with the help of PCP Disso software and kinetic plots were constructed by using SIGMAPLOT V13 software. Response surface morphology plots were shown in Figure 5‒8 for t_10%, t_50%, t_75% and t_90% using X₁ and X₂ on both the axes respectively. The Kinetic parameters for factorial formulations F₁ to F₉ were shown in Table 5.

Figure 1 Comparative zero order plots for F₁‒F₉.

Figure 2 Comparative first order plots for F₁‒F₉.

Figure 3 Comparative higuchi plots for F₁‒F₉.

Figure 4 Comparative korsmeyer‒peppas plots for F₁‒F₉.

Figure 5 Response surface plots for t_10%.

Figure 6 Response surface plots for t_50%

Figure 7 Response surface plots for t75%.

Figure 8 Response surface plots for t_90%.

Polynomial equation for 3² full factorial designs was explained as follows

$Y=b_0+b_1{X}_1+b_2{X}_2+b_{12}{X}_{{}_1}{X}_2+b_{11}{X}_2^1+b_{22}{X}_2^2\mathrm{.....}$

Where, Y is dependent variable, b₀ is average response of 9 trails, b₁ is estimated co‒efficient for X₁. The main effects (X₁ and X₂) shows the mean result/ impact of changing one factor at a time from proximities of low to high value. The interaction term/ compatibility (X_1,X₂) represents how the response varies when two factors/variables are simultaneously changed. X₁² and X₂² are useful for evaluating non‒linearity. Validity of developed equations was scrutinised by designing 2 check point formulations of intermediate concentration (C₁, C₂).

The polynomial equations for dependant variables developed as follows,

Y₁= 0.377+0.053X₁+0.0219X₂‒0.004X₁X₂+0.0406 X₁²+0.02519X₂² (for t_10%)

Y₂= 2.489+0.356X₁+0.144X₂‒0.026 X₁X₂+0.269 X₁²+0.171X₂² (for t_50%)

Y₃= 4.980+0.721X₁+0.285X₂‒0.051 X₁X₂+0.540 X₁²‒0.333X₂² (for t_75%)

Y₄ = 8.272+1.191X₁+0.485X₂‒0.080 X₁X₂+0.896 X₁²+0.552X₂² (for t_90%)

The +^ve sign for co‒efficient of X₁ in Y_1, Y_2, Y₃ and Y₄ polynomials denotes that, as the quantity of HPMCK100M increases, Y value also increases. In other hand, the represents that both independent variables shows significant impact on dependent variables. From the results it can be concluded that, as the increase in quantity of the retardants leads to decrease in drug release rate and drug release pattern may be changed by appropriate chosen of independent variables. The Drug release kinetic parameters for predicted from the developed polynomial equations and those actual observed from experimental results are presented in Table 6.

The closeness of both values for dependant variables indicates validity of developed equations. The response surface plots were constructed to show the impact of independent variables on dependant variables. F₄ is compared with marketed product (VALZAAR) shows similarity factor (f₂) 86.74712, difference factor (f₁) 1.76296 (There is no significant difference in drug release because t_cal is<0.05).

The current research theme envisions the use of release retardants, HPMCK100M and Xanthan gum in the formulation development of sustained release tablets of Valsartan sodium with the help of 3² factorial statistical design technique. From the results it clears that the amount of polymer is inversely proportional to the rate of drug release. Combination of retardants used since there is no incompatibility with the drug which may be more favourable for obtaining desired prolonged release of the drug. F₄ obeys Higuchi’s square root law, drug release pattern mechanism was found to be Non‒Fickian Diffusion (Anomalous Transport), First order release type. On the basis of kinetic parameters, the optimized formulation F₄ may be used for the effective management of hypertension and to reduce the risk of Low ventricular Dysfunction, cardiovascular disease, Herat attack, stroke. This may improve the patient compliance by reducing the dosing frequency. We could be able to minimize the per oral cost of the Formulation.

The author would like to thank the Management, Principal & Staff of M.A.M College of Pharmacy, Kesanupalli (v) Narasaraopet, Guntur (D.t), A.P., India for facilities granted for the successful completion research work.

Authors declare that there is conflict of interest.

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