|Year : 2012 | Volume
| Issue : 5 | Page : 64-68
Enhancement of dissolution of Telmisartan through use of solid dispersion technique surface solid dispersion
Bhumika Patel, RH Parikh, Deepali Swarnkar
Department of Pharmaceutics and Pharmaceutical Technology, Student and Faculty of Ramanbhai Patel College of Pharmacy, Charotar University of Science and Technology Education Campus Changa, Gujarat, India
|Date of Web Publication||21-Mar-2012|
Department of Pharmaceutics and Pharmaceutical Technology, Student and Faculty of Ramanbhai Patel College of Pharmacy, Charotar University of Science and Technology Education Campus Changa, Gujarat
| Abstract|| |
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.
Keywords: Surface solid dispersion, Poloxamer 407, PEG 6000, solvent evaporation method
|How to cite this article:|
Patel B, Parikh R H, Swarnkar D. Enhancement of dissolution of Telmisartan through use of solid dispersion technique surface solid dispersion. J Pharm Bioall Sci 2012;4:64-8
|How to cite this URL:|
Patel B, Parikh R H, Swarnkar D. Enhancement of dissolution of Telmisartan through use of solid dispersion technique surface solid dispersion. J Pharm Bioall Sci [serial online] 2012 [cited 2014 Mar 7];4:64-8. Available from: http://www.jpbsonline.org/text.asp?2012/4/5/64/94142
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|| |
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.
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].
Evaluation of SSD
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 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 [Figure 1] and [Figure 2].
Drug content for all SSDs was in the range of 95-105%, which is in accordance with USP standards [Figure 3].
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].
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].
Differential Scanning Calorimetry (DSC): The DSC spectra of pure drug and solid dispersions are as shown in [Figure 4]a and b. It revealed complex formation between drug and carriers as all the peaks of drug are disappeared [Figure 6].
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].
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.
Design expert contour graph [Figure 9] shows the as increasing concentration of carrier and adsorbent dissolution were increase respectively.
| 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.
| Acknowledgement|| |
The authors are thankful to Ramanbhai Patel College of Pharmacy fraternity for providing all the assistance needed for accomplishing this project.
| References|| |
|1.||Kiran T, Surface solid dispersion of Glimepiride for enhancement of dissolution rate. International Journal of PharmTech Research 2009;3:822-831. |
|2.||Elbary AA, In vitro and in vivo Evaluation of Glibenclamide using Surface Solid Dispersion (SSD) Approach. British Journal of Pharmacology and Toxicology 2011;1:51-62. |
|3.||Parikh B N, Formulation, Optimization and Evaluation of Immediate release Tablet of Telmisartan. Journal of Global Pharma Technology 2010;2:79-84. |
|4.||Beom Jin Lee, P. H. L. T., Huyen Thi Thanh Tran, Modulation of Microenvironmental pH and Crystallinity of Ionizable Telmisartan using alkalizers in Solid dispersions for controlled release. Journal of Controlled Release 2008;129:59-65. |
|5.||Gosse P, A review of Telmisartan in the treatment of Hypertension: Blood pressure control in the early morning hours. Vascular Health and Risk Management 2006;2:195-201. |
|6.||J. Kausalya, Solubility and Dissolution Enhancement Profile of Telmisartan using various techniques. International Journal of PharmTech Research 2011; 3: 1737-1749. |
|7.||Yanzhuo Zhang, Spherical mesoporous Silica Nanoparticles for loading and release of the Poorly water-soluble drug Telmisartan. Journal of Controlled Release 2010;145:257-263. |
|8.||Murthy, Studies on Dissolution rate enhancement of Telmisartan with Hydrorxy propyl β Cyclodextrin complexes. Asian journal of pharmaceutical sciences and research 2011;1:73-85. |
|9.||Micardis® , Telmisartan - A over view. Boehringer Ingelheim Pharmaceuticals, INC, 11-19. |
|10.||Patil M, Characterization and formulation of Solid dispersion of Telmisartan using NaHCO 3 by Hot Melt method. IJPI's Journal of Pharmaceutics and Cosmetology 2011;1:21-33. |
|11.||Kothawade S. N., Formulation and characterization of Telmisatan solid dispersions. International Journal of PharmTech Research 2010;2:341-347. |
|12.||Sekar V., Immediate Release Tablets of Telmisartan Using Superdisintegrant- Formulation, Evaluation and Stability Studies. Department of Pharmaceutics, College of Pharmacy, Sri Ramakrishna Institute of Paramedical Sciences 2008;56:575-577. |
|13.||Patil A. B., Formulation and Evaluation of Solid dispersion of Telmisartan with KOH as alkaliser by hot melt method. Journal of Pharmaceutical and Biomedical science 2010;1:1-7. |
|14.||Shilpi Sinha, Solid Dispersion as an Approach for Bioavailability Enhancement of Poorly Water-Soluble Drug Ritonavir. AAPS PharmaSciTech 2010;1:518-527. |
|15.||Nakatani M. H., Solid Pharmaceutical Formulations comprising Telmisartan. Boehringer Ingelheim International 2005;545:1-19. |
|16.||Shinde S. S, An approach for solubility enhancement: Solid dispersion. International Journal of Advances in Pharmaceutical Sciences 2010;.1:299-308. |
|17.||Daisy Sharma, Solubility Enhancement - Eminent Role in Poorly Soluble Drugs. Research Journal of Pharrmacy and Technology 2009;2:220-224. |
|18.||Serajuddin, Solid Dispersion of Poorly Water-Soluble Drugs: Early Promises, Subsequent Problems, and Recent Breakthroughs. Journal of Pharmaceutical Sciences. 1999;88:1058-1066. |
|19.||Aly A. M., "Preparation of Rapidly Disintegrating Glipizide Tablets by Surface Solid Dispersion through Superdisintegrants". International Journal of Pharmaceutical Sciences and Nanotechnology 2008;233-242. |
|20.||Suporn Charumanee, "Improvement of the Dissolution Rate of Piroxicam by Surface Solid Dispersion". CMU. 2004;77-83. |
|21.||lalitha Y., Enhancement of dissolution of Nifedipine by Surface solid dispersion technique. International Journal of Pharmacy and Pharmaceutical Sciences 2011;41-46. |
|22.||Rao M., Dissolution Improvement of Simvastatin by Surface Solid Dispersion Technology Near RTO, Kennedy Road, Pune-411001, Maharashtra, India Department of Pharmaceutics, AISSMS College of Pharmacy 2010;27-34. |
|23.||Santanu Chakraborty, Comparative study on effect of natural and synthetic Superdisintegrants in the formulation of Fast dissolving tablets. International Journal of Green Pharmacy 2008;22-25. |
|24.||Rouchotas C., Comparison of Surface modification and solid dispersion techniques for drug dissolution". International Journal of Pharmaceutics 2000;1-6. |
|25.||Shrivastava, Design, Optimization, Preparation and Evaluation of Dispersion Granules of Valsartan and Formulation into Tablets. Current Drug Delivery 2009, 28-37. |
|26.||Niharika A., Enhancement of solubility and dissolution rate of Meloxicam by solid dispersions in superdisintegrants. Research Journal of Pharmaceutical, Biological and Chemical Sciences 2010;655-671. |
|27.||Gohel M. C., Jani G. K., Evaluation of synthesized cross-linked Tragacanth as a potential disintegrant. Indian Journal of Pharmaceutical Science 2011;113-118. |
|28.||Nakanishi S., Evaluation of the physicochemical characteristics of crospovidone that influence Solid dispersion preparation. International Journal of Pharmaceutics 2011;119-125. |
|29.||Chaulang G., Formulation and Evaluation of Solid Dispersions of Furosemide in Sodium Starch Glycolate. Tropical Journal of Pharmaceutical Research 2009;43-51. |
|30.||Na Zhao, Functionality Comparison of 3 Classes of Superdisintegrants in Promoting Aspirin Tablet Disintegration and Dissolution. AAPS PharmSciTech 2005;E634-E640. |
|31.||Shibata Y., The preparation of a solid dispersion powder of Indomethacin with crospovidone using a twin-screw extruder or kneader. International Journal of Pharmaceutics 2009;53-60. |
|32.||Bhise S., Review Article-Superdisintegrants as Solubilizing Agent. Journal of Pharmaceutical Science and technology 2009;387-391. |
|33.||Srinarong P., Strongly enhanced dissolution rate of Fenofibrate solid dispersion tablets by incorporation of superdisintegrants. European Journal of Pharmaceutics and Biopharmaceutics 2009;154-161. |
|34.||Mohanachandran P. S., Superdisintegrants: An overview. International Journal of Pharmaceutical Sciences Review and Research 2011;105-109. |
|35.||J. Balasubramaniam Effect of Superdisintegrants on Dissolution of Cationic Drugs. Dissolution Technologies 2008;19-25. |
|36.||Adel M. Aly, Superdisintegrants for Solid Dispersion - To Produce Rapidly Disintegrating Tenoxicam Tablets via Camphor Sublimation. Pharmaceutical Technology 2005;68-78. |
|37.||Nayak A. K., Current developments in Orally disintegrating tablet technology". Journal of pharmaceutical education research 2011;21-34. |
|38.||Khan Arshad Ahmed, Design and evaluation of Aceclofenac fast dissolving tablets prepared by crystallo-co-agglomeration technique. International Journal of Pharmacy and Pharmaceutical Sciences 2011;116-123. |
|39.||Xiaorong Hea, Development of a rapidly dispersing tablet of a poorly wettable compound-formulation DOE and mechanistic study of effect of formulation excipients on wetting of Celecoxib. Indian Journal of Pharmaceutical Science 2008;176-186. |
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9]