Enhancement of Dissolution Rate of Telmisartan by Solid Dispersion Technique

 

M. Chinna Eswaraiah, S. Jaya*

Department of Pharmaceutics, Anurag Pharmacy College, Ananthagiri, Kodad, Suryapet-508206, Telangana, India.

*Corresponding Author E-mail: jayamay24@gmail.com

 

ABSTRACT:

Telmisartan is an angiotensin II type -1 receptor antagonist, used in the treatment of essential hypertension. Telmisartan belongs to class II under biopharmaceutical classification system, characterized by low solubility and high permeability. Oral absorption of Telmisartan is dissolution rate limited and it requires enhancement of solubility and dissolution. The main objective of the present study is to increase the solubility and dissolution rate of telmisartan through solid dispersion technology using various concentrations of water soluble carriers such as poly vinyl pyrrolidone, polyethylene glycol 4000 and poloxomer 407. Solid dispersions were prepared by solvent evaporation technique using methanol as solvent. The enhancement of dissolution rate depends on the nature and concentration of the carrier. The order of increasing dissolution rate with water soluble carriers was poloxomer 407 > polyethylene glycol 4000 > polyvinyl pyrrolidone. Increasing dissolution may be due to the reduced particle size of the drug, enhanced wettability of the drug by hydrophilic carriers. The formulations were evaluated by fourier transform infrared spectroscopy. Telmisartan tablets formulated employing selected solid dispersions gave higher dissolution than the plain tablets.

 

KEYWORDS: Solid dispersion, Telmisartan, poloxomer 407, PEG 4000 and PVP.

 

 


INTRODUCTION:

Most of the newly discovered chemical entities exhibit low and variable bioavailability due to their poor aqueous solubility at physiological pH and consequently low dissolution rate. These drugs are classified as class II under BCS- biopharmaceutical classification system with poor solubility and high permeability characteristics1. Oral bioavailability of a drug depends on its solubility and dissolution rate, is the rate limiting step for the therapeutic activity. The bioavailability of poorly water soluble drug is limited by its dissolution rate, which is controlled by the surface area available for dissolution, larger the surface area, higher will be the dissolution rate.

 

Particle size is inversely proportional to the surface area. Since the surface area increases with decreasing particle size, decrease in particle size can be accomplished by conventional methods like micronization and nanonization. There are several techniques to enhance the dissolution of poorly water soluble drugs such as salt formation, cyclodextrin complexation, use of surfactants and superdisintegrants2,3. The formulation of low aqueous soluble drugs using solid dispersion method has been an active area of research. The term solid dispersion refers to the dispersion of one or more active ingredients in a hydrophilic inert carrier or matrix at molecular level. Carrier may be water soluble or water dispersible. Polymers with high glass transition temperature are used because the glassy state is the desirable state for solid dispersion. At the glass transition temperature, the glassy material has higher internal pressure and increased specific volume relative to crystalline state, responsible for its increased solubility and dissolution rate. The principle involved in formulation of solid dispersions is achievement of the amorphous state which is more soluble than the crystalline state. Solid dispersions are prepared by melting (fusion), solvent evaporation methods4.

 

Angiotensin is a vasoconstrictor. Telmisartan is an angiotensin II type -1[AT-1] receptor antagonist, used in the treatment of essential hypertension. Telmisartan acts by binding to the angiotensin II type-1 receptors, resulting in the inhibition of angiotensin II effect on vascular smooth muscles, results in decrease in systemic vascular resistance5. Telmisartan is a partial agonist of peroxisome proliferator activated receptor gamma (PPARγ), a well known target for insulin sensitizing antidiabetic drugs. This suggests that Telmisartan can improve carbohydrate and lipid metabolism and control insulin resistance without causing the side effects that are associated with full PPARγ activators6. Telmisartan is practically insoluble in water belongs to BCS class II7. There is a need to increase the solubility of the drug. To enhance solubility, dissolution and bioavailability of telmisartan can be achieved via solid dispersion technology by using hydrophilic carriers.

 

MATERIALS AND METHODS:

Materials:

Temisartan was purchased from Yarrow chemical Ltd., Mumbai (India). Polyvinyl pyrrolidone, polyethyleneglycol 4000, poloxomer 407, microcrystalline cellulose, mannitol, magnesium stearate and talc were purchased from Aman scientific traders Vijayawada (India). All other reagents used were of analytical grade.

 

METHODS:

Analytical method for calibration curve of telmisartan:

 Maximum wavelength of telmisartan was found to be 296nm using UV-visible spectroscopy. Standard solution (100µg/ml) was prepared from stock solution (1mg/ml) in a 0.1N hydrochloric acid. Aliquotes of standard drug solution ranging from 0.2 to 1.8ml were transferred into 10ml volumetric flask and were diluted up to the mark with 0.1N hydrochloric acid. The absorbance of each solution was measured at 296nm against 0.1N hydrochloric acid. A plot of concentration of drug versus absorbance was plotted8.

 

Fourier transform infrared spectroscopy (FT-IR)

FTIR spectroscopy was used to study the structural changes and possible interactions between drug and carrier in the solid dispersion. Infrared spectra of pure drug, solid dispersions were scanner over the frequency range 4000-400 cm-1. The resultant spectra were compared for any changes9.

Preparation of telmisartan solid dispersions by solvent evaporation method:

Telmisartan solid dispersions were prepared by solvent evaporation method using carriers (PVP PEG 4000 and poloxomer 407) in proportions viz 1:1 and 1:2 (drug: carrier). The drug and carrier were dissolved in methanol in a china dish and the mixture was heated until the solvent evaporated. The resultant solid dispersion was collected, pulverized and passed through sieve no.60, store in a dessicator for further use10.

 

Preparation of telmisartan tablets:

Compressed tablets each containing equivalent of 20mg of telmisartan was prepared employing selected solid dispersions by direct compression methods. For direct compression microcrystalline cellulose was used as directly compressible vehicle. Solid dispersion containing the medicament, microcrystalline cellulose and other excipients were blended thoroughly in a closed polyethene bag and were directly compressed into tablets on a rotary 12-station tablet punching machine (M/s. Cemach Machinery Co. Pvt. Ltd., Mumbai) using 9 mm round and flat punches.

 

Table 1: Formulation of Telmisartan tablets with selected solid dispersions by direct compression method

Ingredients

( mg/tab)

Formulation

TF7

TF8

TF9

TF10

Telmisartan

20

 

 

 

SDF2

-

60

-

-

SDF4

-

-

60

-

SDF6

-

-

-

60

Microcrystalline cellulose

68

68

68

68

Mannitol

68

68

68

68

Magnesium stearate

2

2

2

2

Talc

2

2

2

2

Total weight

200

200

200

200

 

Evaluation of Tablets:

All the tablets prepared are evaluated for weight variation, content of active ingredient, hardness, friability, disintegration time and dissolution rate.

 

Weight variation:

Twenty tablets of each formulation were weighed using an electronic weighing balance. The average weight was calculated and individual tablet weight was compared with average weight.

 

Hardness and friability:

The hardness of three tablets was measured by Monsanto hardness tester. Hardness of tablets was measured in terms of kg/cm 2. Friability of tablets was measured by using Roche friabilator. Ten tablets were accurately weighed and placed in the friabilator and operated for 100 revolutions. The tablets were dedusted and reweighed and friability was calculated using following equation.

 

Drug content:

Ten tablets were weighed and powdered using a mortar and pestle. An accurately weighed quantity of powder equivalent to 20mg of Telmisartan was taken into 100 ml volumetric flask, dissolved in 0.1 n hydrochloric acid and the solution was filtered through whattman filter paper. The filtrate was collected and suitably diluted with 0.1 N hydrochloric acid and assayed for telmisartan using UV- Visible spectrophotometer.

 

Disintegration time:

Disintegration times of the tablets were determined using tablet disintegration test apparatus employing distilled water as test fluid.

 

In-vitro dissolution study:

Dissolution rate of telmisartan as such and from various telmisartan solid dispersions and tablets was studied using 8 station dissolution rate test apparatus (DBK) with paddle. The dissolution rate was studied in 900ml 0.1N hydrochloric acid telmisartan (20mg) or solid dispersion equivalent to 20mg of telmisartan at a speed of 50rpm and a temperature of 370C ± 0.20C were used in each test. Samples of dissolution medium (5ml) were withdrawn through a filter (0.45μ) at different time intervals, suitably diluted, and assayed for telmisartan by measuring absorbance at 296nm. The dissolution experiments were conducted in triplicate11.

 

RESULTS AND DISCUSSION:

Analytical method for calibration curve of telmisartan:

Maximum wavelength of telmisartan was found to be 296nm using UV-visible spectroscopy. The standard regression equation for telmisartan obtained was y = 0.054x+0.002 with a coefficient of regression (R 2) of 0.999.

 

Solid dispersions of telmisartan in three water soluble polymers namely PVP, PEG 4000 and poloxomer 407 were prepared by common solvent evaporation method employing methanol as solvent. In each case solid dispersions were prepared at two different ratios of drug: carrier namely 1:1 and 1:2. All the solid dispersions prepared were found to be fine and free flowing powders. All the tablets prepared contained telmisartan 98.12 to 99.35%. Hardness of the tablets was in the range 3.21 -3.46kg/sq.cm and was satisfactory. The percentage weight loss in the friability test was less than 0.86 in all the tablet formulations prepared. All the tablets formulated disintegrated rapidly within 6 min. Thus all the tablets formulated employing solid dispersions were found to be of good quality, fulfilling all official (I.P) and other requirements of compressed tablets. The dissolution rate of telmisartan as pure drug and from various solid dispersions was studied in 0.1N hydrochloric acid. The dissolution of telmisartan from all solid dispersions was rapid and several times higher than the dissolution of telmisartan as such. The dissolution data were fitted into zero order and first order kinetic models to assess the kinetics of dissolution. The dissolution of telmisartan as such and from all solid dispersions followed first order kinetics. Plots of log percent remaining versus time were found to be linear with all the products. First order rate constant (k1 min-1) was calculated in each case from the slope of first order linear plots. The dissolution parameters of various solid dispersions prepared are given in Table 2.

 

Table 2: Dissolution parameters of solid dispersions

Solid dispersion

Drug : polymer ratio

% of drug dissolved in 10 min.

k1 (min -1)

Increase in k1 no. of folds

Telmisartan

-

9.25

0.0092

-

SDF1

1:1

38.40

0.030

3.33

SDF2

1:2

57.86

0.046

5.12

SDF3

1:1

48.63

0.039

4.35

SDF4

1:2

62.66

0.055

6.14

SDF5

1:1

85.45

0.111

12.28

SDF6

1:2

90.94

0.159

17.66

 

Fig. -1: Comparative dissolution profile of pure Telmisartan and its solid dispersions

 

All the dissolution parameters (percent dissolved in 10 min and K1 values) indicated rapid and higher dissolution of telmisartan from solid dispersions than that of telmisartan as such. Among the three carriers tested (PVP, PEG 4000 and poloxomer 407), poloxomer 407 solid dispersions gave higher dissolution rates than the other two solid dispersions. The dissolution rate of Telmisartan in solid dispersion was strongly dependent on the relative concentrations of the carrier. As the concentration of carrier in the solid dispersion increased, the dissolution rate also increased. At 1:2 ratio of drug carrier, PVP, PEG 4000 and poloxomer 407 solid dispersions gave 5.12, 6.41 and 17.66 fold increases in the dissolution rate of telmisartan respectively. With all the three soluble carriers the dissolution rate was increased as the carrier concentration was increased. The order of increasing dissolution rate observed with various polymers was poloxomer 407 > PEG 4000 > PVP. Thus the dissolution rate and dissolution efficiency of telmisartan were markedly enhanced by solid dispersion of telmisartan in water soluble carriers. The observed increase in the dissolution rate of telmisartan from its solid dispersions is due to the possible reduction in particle size, increased wettability of drug particles when they are dispersed in the hydrophilic water soluble polymers. Solid dispersions in PVP (1:2) SDF2, PEG 4000 (1:2) SDF4 and Poloxomer 407 (1:2) SDF6 exhibited a marked enhancement in the dissolution rate and efficiency of telmisartan. The feasibility of formulating these solid dispersions into compressed tablets with enhanced dissolution rate was evaluated. These solid dispersions were formulated into tablets with usual tablet additives by direct compression methods as per the formulae given in Table 2. All the tablets formulated employing solid dispersions gave rapid and higher dissolution of telmisartan. Telmisartan dissolution from all the tablets prepared by direct compression method followed first order kinetics with correlation coefficient “R2” above 0.910.

 

Fig. -2: Comparative dissolution profile of pure Telmisartan and its solid dispersions

 

Drug and carrier interactions in the solid dispersions prepared were evaluated by FTIR spectral study. The FTIR spectra of pure telmisartan and TF10, which gave highest enhancement in the dissolution rate of telmisartan containing poloxomer (1:2) shown in fig. 3. Telmisartan exhibits characteristic peaks at indicated characteristic peaks at 3,433 cm−1 (N–H stretch), 3059 cm -1 (aromatic C-H stretch), 2956 cm-1 (aliphatic C-H stretch), 1691 cm-1 ( carbonyl group) and the peak at 1454 cm-1 indicated the presence of C= C aromatic group. All the above characteristic peaks appear in the spectra of best formulation at same wave number indicating no significant evidence of chemical interaction between drug, carrier and other excipients.

 

CONCLUSION:

The study shows that the dissolution rate of telmisartan can be enhanced to a greater extent by solid dispersion technique. The dissolution of telmisartan from all the solid dispersions was several times higher than the pure telmisartan. Among the three water soluble carriers poloxomer 407 solid dispersions gave highest enhancement in the dissolution rate of telmisartan. This may be due to the increase in drug wettability, conversion to amorphous form in the solid dispersion. The order of increasing dissolution rate was poloxomer 407 > PEG 4000 > PVP. Higher dissolution rate of telmisartan was found in formulations containing 1:2 ratios of water soluble carriers. The selected solid dispersions could be formulated into tablets by direct compression method. Telmisartan tablets formulated employing solid dispersions gave higher dissolution rate than plain telmisartan tablets.

 

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Received on 19.07.2019            Modified on 25.09.2019

Accepted on 16.11.2019           © RJPT All right reserved

Research J. Pharm. and Tech 2020; 13(5): 2217-2220.

DOI: 10.5958/0974-360X.2020.00398.4