Enhancement of dissolution of Telmisartan through use of solid dispersion technique - surface solid dispersion.

The present study was aimed to increase the solubility of the poorly water soluble drug Telmisartan by using Surface solid dispersion (SSD) made of polymers like Poloxamer 407, PEG 6000 by Solvent evaporation method. The drug was solubilized by surfactants and/or polymers then adsorbed onto the surface of extremely fine carriers to increase its surface area and to form the SSD which give the more Surface area for absorption of the drug. A 2(2) full factorial design was used to investigate for each carrier the joint influence of formulation variables: Amount of carrier and adsorbent. Saturation solubility studies shows the improvement in solubility of drug batch SSD 8 give more solubility improvement than the other batch, in-vitro dissolution of pure drug, physical mixtures and SSDs were carried out in that SSDs were found to be effective in increasing the dissolution rate of Telmisartan in form of SSD when compared to pure drug. Also FT-IR spectroscopy, differential scanning calorimetry and X-ray diffractometry studies were carried out in order to characterize the drug and Surface solid dispersion. Furthermore, both DSC and X-ray diffraction showed a decrease in the melting enthalpy and reduced drug crystallinity consequently in SSDs. However, infrared spectroscopy revealed no drug interactions with the carriers.

Telmisartan (TEL) is an Angiotensin II Receptor Antagonist, which is used in the prevention and treatment of Hypertension. One of the major problems with it is its low solubility in biological fluids, which results into poor bioavailability after oral administration (~42%) and late onset of action. It also shows high first pass metabolism which further reduces the oral bioavaibility. Surface solid dispersion technique has been used to increase the solubility, dissolution and consequently the bioavailability of many practically insoluble or poorly water soluble drugs. Formation of surface solid dispersions is a strategy that is used to reduce the agglomeration of the drug by increasing its surface area in a way that can help in increasing its dissolution rate. The surface solid dispersions can overcome some of the shortcomings of the conventional solid dispersions. The carriers used in surface solid dispersion are water-insoluble, porous materials and hydrophilic in nature. The release of drug from the carrier material depends on hydrophilic nature, particle size, porosity and surface area of the carrier. Larger the surface area available for surface adsorption of the drug better is the release rate.

Materials and Methods

Materials

TEL was generously provided by Torrent Research Centre, Ahmedabad. PEG 4000, PEG 6000, Poloxamer 407, Poloxamer 188, Dichloromethane (DCM) and Aerosil 200 were obtained from Himedia laboratory.

Methods

Phase solubility study

Excess amount of TEL was added to screw capped vials containing 10 ml of aqueous carrier solution at various concentrations and placed on an Incubator shaker and agitated at room temperature for 48 hours. The solutions were filtered and analyzed at 296 nm by using UV-visible spectrophotometer and stability constants calculated. The study was performed in triplicates. Calculate stability constant by the following equation.

Preparation of surface solid dispersion (SSD)

The drug and carrier were dissolved in DCM in separate beakers. Both solutions were mixed in beaker containing adsorbent and stirred until the solvent (chloroform) evaporated completely. The resulting mass was transferred to desiccators containing CaCl2 and stored until completely dry. The resulting solid mass was then pulverized in a mortar to get dry free-flowing powder. The powder was passed through a no. 60 sieve (50 μm)[Table 1].

Table 1

Preparation of SSD

Evaluation of SSD

Drug content

Equivalent weight of SSD containing 10 mg TEM were weighed accurately and dissolved in 10 ml of methanol. The solution was filtered and TEM content was analyzed.

Saturation solubility studies

Pure drug and SSDs in excess quantity were placed in flasks containing 10 ml of distilled water. The samples were placed in an Incubator shaker at 37°C and 50 rpm for 48 hr. The solutions were analyzed by UV-spectrophotometer.

FTIR spectroscopy

FTIR spectra of the drug, the drug and carriers and the drug carriers and the additives were all carried out. Each formula (5 mg) was mixed with about 100 mg. potassium bromide and compressed into discs under pressure of 10,000 to 15,000 pounds per square inch. The IR spectra were recorded using Infra-red Spectrophotometer (IR435-U-04, Shimadzu and Kyoto, Japan).

Differential scanning calorimetry (DSC)

DSC analysis of the free drug, drug with carrier and the drug with carrier and additives were carried out using DSC (TA-60WSI, Shimadzu, Japan). The instrument was calibrated using purified Indium (99.99%). Samples (5 mg) were sealed in a flat bottomed aluminum pan (Shimadzu DSC-60, Japan). The pan was placed in the DSC instrument and scanned between 30 and 300/C at a rate of 10°C/min. Dry nitrogen was used as a carrier gas to eliminate the oxidative and pyrrolytic effects with a flow rate of 10 ml/min. The melting and transition point measurements were performed using the software provided with the device.

X-ray diffractometry (XRD)

XRD spectra of samples were recorded using a high-power powder x-ray diffractometer. (D2 Phaser, BRUKER, AXS Inc., Germany).

In vitro dissolution studies

Dissolution studies were carried out in triplicate in USP Apparatus 2. SSDs equivalent to 20 mg of drug were added to 900 ml of phosphate buffer pH 1.2 stirred at 50 rpm. Aliquots of 5 ml were withdrawn at specified time intervals and analyzed at 296 nm.

Results and Discussion

Phase solubility study

The results showed that Poloxamer 407 and PEG 6000 showed higher stability constants compared to other carried [Figures 1 and 2].

Figure 1

Phase solubility study

Figure 2

Stability constant of carrier

Drug content

Drug content for all SSDs was in the range of 95–105%, which is in accordance with USP standards [Figure 3].

Figure 3

Drug content

Saturated solubility

SSD 8 showed the highest saturated solubility (0.848±0.008 mg/ml) a 80 fold increase in solubility compared to pure drug (0.0014±0.009 mg/ml) [Figure 4].

Figure 4

Saturated solubility studies

FTIR spectroscopy

FT-IR spectroscopic studies conducted for possible drug:carrier interactions. FT-IR spectra of pure drug Telmisartan, and solid dispersions which are as shown in Figure 2 indicating no significant evidence of chemical interaction between drug and carrier, which confirms the stability of drug with its solid dispersion [Figure 5].

Figure 5

FT-IR spectrum of pure drug and SSDs

Differential Scanning Calorimetry (DSC): The DSC spectra of pure drug and solid dispersions are as shown in Figure 4a and 4b. It revealed complex formation between drug and carriers as all the peaks of drug are disappeared [Figure 6].

Figure 6

DSC Spectrum of pure drug and SSDs

X-Ray diffractometry (XRD)

XRD Spectra of Telmisartan and its solid dispersions are as shown in Figure 3. It shows that degree of crystallinity of Telmisartan was found to be decreased due to complex formation between drug and carrier with the possibility of formation of amorphous solid dispersions [Figure 7].

Figure 7

XRD spectrum of pure drug and SSDs

In vitro dissolution studies

The results showed SSD 8 made up of Poloxamer 407 having higher dissolution rate compared to other dispersions, physical mixtures and pure drug. The dissolution profiles of the solid dispersions are shown in Figure 8. The dissolution rate of TEL in physical mixtures as well as in SSDs was higher for both carriers as compared with plain Telmisartan. Plain TEM showed a poor dissolution profile (i.e., only 19% of drug was released at the end of 90 min), whereas physical mixtures showed slight improvement due to the presence of carrier in the respective mixtures. Dissolution profiles of all the SSDs for both carriers were shows that the Poloxamer 407 shows better improvement in dissolution compare to PEG 6000 and their mixture (i.e., significant improvement in dissolution was observed with an increase in carrier proportion). Surface solid 8 (2:2) dispersions with both carriers showed maximum drug release; the SSD with Poloxamer and aerosil 200 showed almost 89.68±0.26% drug release within 90 min, whereas SSD with PEG 6000 shows almost 53.21±0.71% drug release within 90 min, indicating that SSD with Poloxamer 407 showed better a dissolution profile than PEG 6000 and mixture of both.

Figure 8

In vitro dissolution

Design expert contour graph [Figure 9] shows the as increasing concentration of carrier and adsorbent dissolution were increase respectively.

Figure 9

In vitro dissolution

Conclusion

From, the dissolution data of all formulations developed, solubility of Telmisartan, a poorly water soluble drug was enhanced by the surface solid dispersion technique using PEG 6000 and Poloxamer 407 as a carrier and aerosil 200 as adsorbent. This effect may be due to fine particle size, decrease crystallites of Telmisartan adsorbed over carrier and adsorbent resulting in a higher surface area of drug exposed to the dissolution media and improved wettability of the drug particles. The significant reduction in particle size during the formation of SSDs and the inherently higher rate of dissolution of the soluble component of SDs may also contribute to the increased solubility of Telmisartan. SSDs made of Poloxamer 407 showed better dissolution than other carriers. The solubility of TEL has been significantly been improved by the SSD technique hence the technique can be used to enhance the bioavaibility of Telmisartan.