Fig. 1. FTIR spectra of Pure drug (TEL), Polymer (PEG 6000), Physical Mixture of Drug and Alkalizer (PM, TEL:NaOH) and TA2 (SD, 10:1:400)

Fig. 2. PXRD patterns of Pure drug (TEL), Polymer (PEG 6000) and TA2 (SD 10:1:400)

TEL is manufactured and supplied in the free acid form and is characterized by a very poor solubility, resulting in low bioavailability⁷.

The aim of this study was to investigate the effect of incorporating alkalizer into PEG 6000 based SDs on the dissolution rate of TEL. The alkalizer NaOH was selected on the basis of their strong alkalinity. PEG 6000 was selected as the carrier in the manufacture of SD using the Hot Melt Method.

The main advantages of this direct melting method is its simplicity and economy. The melting or fusion method was first proposed by Sekiguchi and Obi to prepare fast release solid dispersion dosage forms. The physical mixture of a drug and a water-soluble carrier was heated directly until it melted. The melted mixture was then cooled and solidified rapidly in an ice bath under rigorous stirring. The final solid mass was crushed, pulverized, and sieved. Such a technique was subsequently employed with some modification by Goldberg et al and Chiou and Riegelman. The solidified masses were often found to require storage of 1 or more days in a desiccator at ambient temperatures for hardening and ease of powdering. Some systems, such as griseofulvin and citric acid, were found to harden more rapidly if kept at 37° C or higher temperatures. The melting point of a binary system is dependent upon its composition, i.e. the selection of the carrier and the weight fraction of the drug in the system⁸

Fig. 3. DSC thermograms of Pure drug (TEL), Polymer (PEG 6000) and TA2 (SD 10:1:400)

The drug crystallinity were extensively characterized. The structural behavior and molecular interaction of the SD containing alkalizer was also examined by instrumental characterization using differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and Fourier transform infrared spectroscopy (FTIR).

MATERIAL AND METHOD:

Materials:

TEL was obtained as a gift sample from Ratiopharm Private. Ltd. (Goa, India). PEG 6000 was obtained as gift sample from Colorcon Asia Pvt. Ltd. (Goa, India), Sodium Hydroxide (NaOH), was obtained from Loba Chem. (Mumbai, India). All other chemicals and reagents were of analytical grade.

Preparation of Solid dispersion:

Solid dispersions of Telmisartan and PEG were obtained by the hot melt method [9]. Telmisartan : Alkalizer : PEG mixtures containing 10:1:200, 10:1:400, 10:1:600 ratios (Table 1) were heated to 100°C with constant stirring. The Telmisartan was miscible in the PEG melt in all proportions with alkalizer. The melts were allowed to cool and solidify at room temperature and then stored at 4°C. The solid product was ground in a mortar at room temperature and then sieved (105-250 mm). For dissolution assays, a sufficient amount of molten material (equivalent to 100 mg of Telmisartan) was poured into semi permeable bag (2 cm internal diameter)^9,10.

Fourier Transform Infrared Spectroscopy (FTIR):

The spectra of the samples (again including the raw material of TEL, PEG 6000 and different SD powders) were recorded using an spectrophotometer FTIR-88101A (Shimadzu). KBr pellets were prepared by gently mixing 1 mg of the sample with 200 mg KBr. The wavelength ranged from 400 to 4000 cm−1 with a resolution of 4 cm−1¹¹.

Thermal analysis (DSC):

A TA Instruments differential scanning calorimeter DSC-60 (shimadzu) was used to investigate the thermal behaviors of the raw material of TEL, PEG 6000 and the different SD powders. The amount of sample used ranged from 2-8mg for the SD powder and PEG 6000, and was 0.4 mg for pure TEL¹². The samples were weighed in a standard open aluminum pan, while an empty pan of the same type was used as a reference. The heat running for each sample was set from 30 to 300 °C at 10 °C/min, using nitrogen as a purge gas at heat flow of 40ml/min.^12,13.

Table 1. Compositions (w/w) of Different formulations (Solid dispersion Formulations) of Drug, Polymer and Alkalizer by Hot Melt method

Batch code	Telmisartan	NaOH	PEG 6000
TA1	10	1	200
TA2	10	1	400
TA3	10	1	600

Powder X-ray diffraction (PXRD):

PXRD patterns were obtained with using XRD-COMPACT 3K using Powder X-ray diffractometer, CuKα radiation, a voltage of 40 KV and a current of 20 mA. The samples were scanned at the scanning rate of 0.02° /min over the 5-60° 2θ range.

Scanning Electron Microscopy (SEM) analysis:

The scanning electron microscope is used to study the surface morphology of the samples. Photomicrographs of the sample were taken using the Jeol Model JMS-6300 scanning electron microscope (Jeol Technics Company, Japan). The samples for SEM were mounted on sample stubs with double sided adhesive tape, vacuum coated with gold and photomicrographed at suitable magnification. The SEM uses a beam of electron to scan the surface of the sample to build a three dimensional image of the specimen¹⁴.

In vitro dissolution:

Dissolution studies were conducted using a USP II paddle method (50 rpm, 37 °C, and 900 mL dissolution medium) with a dissolution apparatus (Labinda, India). The SD powder equivalent to 80 mg TEL was exposed for 1 hr to gastric fluid (pH 1.2). Samples were withdrawn from the dissolution medium at predetermined intervals (10, 20, 30, 40, 50, 60, 70, 80 and 90 min) and then drug concentration was determined by UV. An equivalent amount of fresh medium was added to maintain a constant dissolution volume¹⁵.

RESULT AND DISCUSSION:

Fourier Transform Infrared Spectroscopy (FTIR):

Structural changes and the lack of a crystal structure can lead to changes in bonding between functional groups that can be detected by FTIR spectroscopy. The FTIR spectra of Telmisartan, PEG 6000 and their SDs with or without alkalizer (Fig. 1). The spectrum of pure Telmisartan showed a distinct absorption band for the carbonyl group C=O at 1700 cm⁻¹ and the O–H band at 3100 cm⁻¹. Based on the variation of these two FTIR bands, we could classify alkalizer of the SDs into two groups [12]. The spectra of the NaOH, showed a change in the C=O bond and the O–H bond, such that the frequency of C=O was shifted from 1695 cm⁻¹ to 1580 cm⁻¹ and the broad O–H band could hardly be recognized.

It has been described that a lowering of the frequency of the carbonyl stretching band from carboxylic acid is typically indicative of strong hydrogen bonding interactions. Moreover, the disappearance of the O–H peak of carboxylic acid attributable to hydrogen bonding confirmed that this moiety could be protonated by alkalizer mainly via a Lewis acid-base interaction. Therefore, it was evident from FTIR spectra that there was a molecular interaction between Telmisartan and the alkalizer, resulting in enhanced dissolution of Telmisartan in SDs^12,13.

Fig. 4. SEM Photomicrograph of Pure Drug (a) and SD (b)

Powder X-Ray Diffraction Studies (PXRD):

The PXRD patterns of Telmisartan, PEG 6000 and their SDs with or without alkalizer are given in (Fig. 2). The PXRD pattern of PEG 6000 had two characteristic peaks of high intensity at 19.0° and 22.0°. The diffraction pattern of pure Telmisartan was highly crystalline in nature as indicated by numerous peaks. Three peaks at 7.0°, 14.0°, 20.0°, 23.0° and 25.0° were noticeable and the main peak at 7.0° was particularly distinctive. It is known that the lack of a distinctive peak of a drug in SD systems demonstrates that a high concentration of the drug is dissolved in the solid state. Moreover, a large reduction in characteristic peaks indicates an amorphous state. Based on the diffractograms of SDs, we could classify the diffraction patterns into two groups according to the presence or absence of a Telmisartan crystalline peak at 7.0° NaOH were in the group for which there was no distinct Telmisartan crystalline peak at 7.0°¹⁶.

The PXRD patterns of binary SD (Telmisartan and PEG6000) also showed the distinctive peak at 19.0° and 22.0°, indicating that Telmisartan was still in the crystalline form. The results of the PXRD patterns were quite different from that of DSC thermograms In fact, PEG 6000 can play a role as the SD carrier and change the crystalline structure of Telmisartan into a partially crystalline structure. The incorporation of a suitable alkalizer in PEG based SDs can definitely promote the change of a crystalline drug to a totally amorphous form leading to an enhanced dissolution rate^16,17.

Differential Scanning Calorimetry (DSC):

The DSC thermograms of TEL, PEG 6000 and their SDs are given (Fig. 3). The DSC curve of pure TEL and PEG 6000 exhibited single endothermic peaks at 269.06 °C (TEL) and 60.39 °C (PEG 6000), respectively, which corresponded to their intrinsic melting points. The characteristic peaks of PEG 6000 were invariably identified in the DSC curves of SDs, suggesting that PEG was present in the same physical state after making the SD powder by the Hot Melt Method. No characteristic melting peak of TEL was identified in the DSC curves obtained from these PEG 6000 based SD formulations^12,18.

Scanning Electron Microscopy (Sem):

Scanning electron microscopy is very helpful in studying the change in the surface topography and shape of the particles of pure drug and solid dispersions (Fig. 4).

The batches of engineered crystals covering extreme polymer concentrations from the entire range of experimental batches were taken for SEM studies. Photomicrographs of the pure drug (a) and SD (b) were taken. Photomicrographs of the pure drug and the formulated batches reveled the change in particle shape and surface topography.

Fig. 5. Cumulative % Drug Release of TA1, TA2 and TA3.

SEM thus indicates that the polymer has formed a uniform coating over the individual drug particles thus resulting in the formation of spherical particles with improved crystal properties as revealed from later studies^14,19.

In Vitro Dissolution:

The percentage drug release of all solid dispersion batches are shown in (Table 2).

The incorporation of pH modifiers was attempted due to the fact that the chemical structure of TEL is pH-dependent so one can assume that pH modifiers can modulate TEL solubility leading to an increase in the dissolution rate. The effect of alkalizer on TEL release rate in gastric fluid (pH 1.2), (Fig. 5). Since the drug is highly soluble in low pH conditions, the dissolution rate of the drug after 90 min reached almost 100% in gastric fluid with all SDs regardless of the alkalizer and even with the pure drug^15,20.

CONCLUSION:

Notwithstanding the wide application of SDs, an obstacle of the SD method is its limited solubilization capacity. SDs containing alkalizer could be a useful method to increase the dissolution rate of an ionizable drug like TEL in a pH-dependent manner. The NaOH in the SD system significantly increased the drug dissolution rate in gastric fluid (pH1.2)

ACKNOWLEDGEMENTS:

The authors are thankful to Ratiopharm Private. Ltd. (Pune, India) for providing gift sample of Telmisartan. Authors are very much thankful to Prof. R. B. Marathe, India for providing laboratory facilities.

Table 2. Dissolution profile of different formulations

Time (Min)	% Drug Release*
Time (Min)	TA1	TA2	TA3
0	0	0	0
10	34.72±1.34	51.1±2.43	17.18±3.23
20	48.16±1.23	60.02±1.89	24.31±1.45
30	61.02±2.56	72.56±2.67	36.00±2.78
40	70.13±1.39	83.3±1.56	50.44±0.98
50	80.64±1.28	94.92±1.45	59.92±2.56
60	87.08±0.15	96.27±0.34	72.74±1.45
70	96.52±1.57	98.13±1.67	83.99±0.40
80	97.12±2.43	100.34±2.34	93.76±1.53
90	97.89±1.98		99.59±2.38

* Indicates mean three experiments

REFERNCES:

1. Yu Seok Youn, Ju Young Jung, Seung Hyun Oh, Sun Dong Yoo and Kang Choon Lee, Improved intestinal delivery of salmon calcitonin by Lys18- amine specific PEGylation: Stability, permeability, pharmacokinetic behavior and in vivo hypocalcemic efficacy. J. Contr. Release 114, (2006), 334–342

2. Mitsuru Sugawara, Shota Kadomura, Xin He, Yoh Takekuma, Naonori Kohri and Katsumi Miyazaki. The use of an in vitro dissolution and absorption system to evaluate oral absorption of two weak bases in pH-independent controlled-release formulations. Eur. J. Pharm. Sci. 26, (2005), 1–8

3. Teo filo Vasconcelos1, Bruno Sarmento1 and Paulo Costa Solid dispersions as strategy to improve oral bioavailability of poor water soluble, Drug Discovery Today, Vol. 12, Numbers 23/24, December 2007

4. M.Y. Heo, Z.Z. Piao, T.W. Kim, Q.R. Cao, A. Kim, B.J. Lee, Effect of solubilizing and microemulsifying excipients in polyethylene glycol 6000 solid dispersion on enhanced dissolution and bioavailability of ketoconazole, Arch. Pharm. Res. 28 (5) (2005) 604–611.

5. N. Ahuja, P.O. Katare, B. Singh, Studies on dissolution enhancement and mathematical modeling of drug release of a poorly water-soluble drug using water-soluble carriers, Eur. J. Pharm. Biopharm. 65 (1) (2007) 26–38.

6. T. Vasconcelos, B. Sarmento, P. Costa, Solid dispersions as strategy to improve oral bioavailability of poorly water soluble drugs, Drug Discov. Today 12 (23–24) (2007) 1068–1074.

7. Phuong Ha Lien Tran, Huyen Thi Thanh Tran, Beom-Jin Lee, Modulation of microenvironmental pH and crystallinity of ionizable telmisartan using alkalizers in solid dispersions for controlled release, J. of Contr. Release 129 (2008) 59–65

8. Daisy Sharma, Mohit Soni, Sandeep Kumar and GD Gupta, Solubility Enhancement – Eminent Role in Poorly Soluble Drugs, Research J. Pharm. and Tech.2(2): April.-June. 2009

9. S. Anguiano-Igea , F. J. Otero-Espinar, J. L. Vila-Jato, J. Blanco-Mhdez, The properties of solid dispersions of clofibrate in polyethylene glycols, Pharmaceutics Acta Helvetiae 70 (1995) 57-66

10. G.R. Lloyd, D.Q.M. Craig , A. Smith , An investigation into the production of paracetamol solid dispersions in PEG 4000 using hot stage differential interference contrast microscopy, Int. J. of Pharm. 158 (1997) 39-46

11. Yalcın zkan, Nazan Doganay, Necati Dikmen, As¸kın Isımer, Enhanced release of solid dispersions of etodolac in polyethylene Glycol, IL Farmaco 55 (2000) 433–438

12. Jaymin C. Shah, Jivn R. Chen, Diana Chow, Preformulation study of etoposide: II. Increased solubility and dissolution rate by solid-solid dispersions, Int. J. of Pharm. 113 (1995) 103-111

13. Dimitrios Bikiaris, George Z. Papageorgiou, Anagnostis Stergiou, Eleni Pavlidou, Evangelos Karavas, Ferras Kanaze, Manolis Georgarakis, Physicochemical studies on solid dispersions of poorly water-soluble drugs Evaluation of capabilities and limitations of thermal analysis techniques, Thermochimica Acta 439 (2005) 58–67

14. Hirofumi Takeuchi, Shinsuke Nagira, Hiromitsu Yamamoto, Yoshiaki Kawashima, Solid dispersion particles of amorphous indomethacin with fine porous silica particles by using spray-drying method, Int. J. of Pharm., 293 (2005) 155–164

15. Susumu Hasegawa, Takeshi Hamauraa, Naho Furuyama, Akira Kusai, Etsuo Yonemochi b, Katsuhide Terada, Effects of water content in physical mixture and heating temperature on crystallinity of troglitazone-PVP K30 solid dispersions prepared by closed melting method, Int. J. of Pharm.,302 (2005) 103–112

16. R. Jachowicz, E. Nurnberg, B. Pieszczek, B. Kluczykowska, Maciejewska, Solid dispersion of ketoprofen in pellets, Int. J. of Pharm., 206 (2000) 13–21

17. Adamo Finia, Jose R. Moyanob, Juan M. Ginesb, Jose I. Perez-Martinezb, Antonio M. Rabasco, Diclofenac salts, II. Solid dispersions in PEG6000 and Gelucire 50/13, Eur. J. Pharm.and Biopharm. 60 (2005) 99–111

18. A. Forster, J. Hempenstall, I. Tucker, T. Rades, Selection of excipients for melt extrusion with two poorly water-soluble drugs by solubility parameter calculation and thermal analysis, Int. J. of Pharm., 226 (2001) 147–161

19. Fude Cuia, Mingshi Yanga, Yanyan Jianga, Dongmei Cuna, Wenhui Lina, Yuling Fan, Yoshiaki Kawashima, Design of sustained-release nitrendipine microspheres having solid dispersion structure by quasi-emulsion solvent diffusion method, J. Contr. Rel., 91 (2003) 375–384

20. Susana Torrado, Santiago Torrado, Juan Jos Torrado, Rafael Caddrniga, Preparation, dissolution and characterization of albendazole solid dispersions, Int. J. of Pharm., 140 (1996) 247-250

Received on 04.09.2009

Accepted on 10.10.2009

Research Journal of Pharmaceutical Dosage Forms and Technology. 1(3): Nov. – Dec. 2009, 250-253