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ORIGINAL ARTICLE
a
National Institute of Pharmaceutical Education and Research, Hyderabad 500037, India
b
Blue Birds College of Pharmacy, Hanamkonda 506001, India
c
Department of Pharmacy, Acharya Nagarjuna University, Guntur 522510, India
KEY WORDS Abstract The aim of this study was to improve the dissolution rate of the poorly soluble drug valsartan
Liquisolid compact;
by delivering the drug as a liquisolid compact. Liquisolid compacts were prepared using propylene glycol
Valsartan; as solvent, Avicel PH102 as carrier, and Aerosil 200 as the coating material. The crystallinity of the newly
Dissolution; formulated drug and the interaction between excipients was examined by X-ray powder diffraction and
Poorly soluble drug Fourier-transform infrared spectroscopy, respectively. The dissolution studies for the liquisolid formula-
tion and the marketed product were carried out at different pH values. The results showed no change in
the crystallinity of the drug and no interaction between excipients. The dissolution efciency of valsartan
at 15 min was increased from 4.02% for plain drug and 13.58% for marketed product to 29.47% for the
liquisolid formulation. The increase in the dissolution rate was also found to be signicant compared to
the marketed product at lower pH values, simulating the gastric environment where valsartan is largely
absorbed. The liquisolid technique appears to be a promising approach for improving the dissolution of
poorly soluble drugs like valsartan.
& 2012 Institute of Materia Medica, Chinese Academy of Medical Sciences and Chinese Pharmaceutical
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Corresponding author. Tel.: 91 9949141897.
E-mail address: tadikondarao@yahoomail.com (Rama Rao Tadikonda).
Peer review under responsibility of Institute of Materia Medica, Chinese Academy of Medical Sciences and Chinese Pharmaceutical Association.
2211-3835 & 2012 Institute of Materia Medica, Chinese Academy of Medical Sciences and Chinese Pharmaceutical Association. Production and
hosting by Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.apsb.2012.07.005
Use of the liquisolid compact technique for improvement of the dissolution rate of valsartan 503
2.5. Flow properties of liquisolid powders 1 L dissolution medium and maintained at 3770.5 1C. At
appropriate intervals (5, 10, 15, 20, 25, 30 and 45 min), 5 mL
Fixed funnel and the free-standing cone method were of samples were taken and ltered through a 0.45 mm lter.
employed to measure the angle of repose. A funnel was The samples were analyzed at 250 nm by UVvisible spectro-
secured with its tip at a given height (H) above a graph paper scopy. The mean value of six determinations was used to
placed on a at horizontal surface. The powders were carefully calculate the drug release from each formulation. For the
poured through the funnel until the apex of the conical pile comparison of dissolution data in different media for each
just touches the tip of the funnel. The mean radius (r) of the formulation, percentages of drug dissolved at 10 min (Q10 min),
base of the conical pile was determined and the tangent of 30 min (Q30 min), mean dissolution time (MDT) and dissolu-
angle of repose was given by Tan a H/r, where a is the angle tion efciency (DE) at 15 min were calculated24.
of repose23.
2.10. FTIR spectroscopy
2.6. X-ray powder diffraction (XRD)
FTIR spectra of drug, Avicel PH102, Aerosil, liquisolid
XRD patterns were studied using Philips PW 3710 X-ray placebo and liquisolid tablet were obtained. About 5 mg of
diffractometer. Samples were exposed to 1.540 A Cu radiation sample was mixed thoroughly with 100 mg potassium bromide
wavelength and analyzed over the 2y range of 2801. XRD IR powder and compacted under vacuum at a pressure of
patterns were determined for valsartan, formulation without about 12,000 psi for 3 min. The resultant disk was mounted in
drug (blank formulation) and liquisolid system with drug. a suitable holder in Perkin Elmer IR spectrophotometer and
From the literature, it was evident that Aerosil 200 was a non- the IR spectrum was recorded from 4000 cm1 to 625 cm1 in
gritty amorphous powder22; and from the blank formulation, a scan time of 12 min. The resultant spectra were compared
Avicel PH102 spectra can be evaluated. for any spectral changes.
The prepared liquisolid tablets were evaluated for hardness, Spireas et al.21 suggested that particles with high absorption
friability and disintegration time. Hardness was determined by properties due to a porous surface should be used as the
the Pzer hardness tester and friability by a digital tablet carrier material, such as cellulose, starch and lactose.
friability tester. The disintegration time was measured using a
USP disintegration tester (Electrolab). All the studies were
done in triplicate.
Table 1 Solubility of valsartan in different solvents
(all values are mean7SD; n 3).
2.9. Dissolution studies
Solvent Solubility (mg/mL)
Dissolution studies were performed for liquisolid compacts,
plain drug and marketed product (Valzaar-40 mg). The USP Tween 20 69.7372.38
paddle method was used for all in vitro dissolution studies. Tween 80 76.5772.67
PEG 200 65.4171.23
The dissolution was carried out at different pH values using
PEG 400 69.5771.98
different media, i.e., 0.1 M HCl (pH 1.2), 0.001 M HCl (pH PEG 600 83.9172.89
3.0), acetate buffer (pH 4.5) and phosphate buffer (pH 6.8). PG 109.2373.21
The stirring rate was 5071 rpm. The amount of valsartan was
40 mg in all formulations. The dosage forms were placed in PEG, polyethylene glycol; PG, propylene glycol.
Use of the liquisolid compact technique for improvement of the dissolution rate of valsartan 505
Increasing the moisture content of carrier materials may result load factors. The Lf was greater than 0.25 for formulations
in decreased powder owability. The coating material is F1F8 and F12 (Table 2), showing poor owability and
required to cover the surface, and further, maintain the compressibility12.
powder owability11. Accordingly, the coating material should The angle of repose is a result of internal frictional forces of
be a very ne and highly adsorptive silica powder. From the the particles. The angle of repose will be high if the particles
preliminary binding capacity experiments conducted with are cohesive. Angles of reposer301 indicate free ow while
different excipients, Avicel PH102 was selected as carrier anglesZ401 indicate poor ow23. Powder formulations with angles
and Aerosil 200 as the coat material. Valsartan liquisolid of repose greater than 401 were not acceptable (formulations
tablets (F1F12) were prepared with different excipient ratios F1F8 and F12). Formulations F9, F10 and F11 showed 281, 351
(R) using PG as vehicle (Table 2). The appropriate amounts of and 321, respectively. Formulation F9 showed good owability
the carrier and coating material were derived from their liquid but required a higher amount of carrier material which increased
Figure 1 FTIR spectra of pure drug and different excipients. (a) Aerosil 200, (b) Avicel PH102, (c) valsartan, (d) physical mixture and
(e) LSC formulation (F11).
506 Chella Naveen et al.
the tablet size to 610 mg. Hence formulation F10 and F11 were
selected for compression.
The tablets should have sufcient hardness to resist the
breakage during handling, and at the same time, it should
disintegrate after swallowing. Formulation F11 showed good
compressibility with an acceptable hardness (34 kg). Some
liquid was squeezed out from formulation F10 at the same
hardness. This could be attributed to a lesser quantity of coat
material in F10, which is not sufcient to adsorb liquid on its
surface and maintain sufcient owability and compressibility.
Based on this study, F11 was selected for further evaluation.
Formulation F11 shows satisfactory owability (angle of
repose 321), hardness (3.5 kg) and disintegration time (2 min)
at a total tablet weight of 370 mg.
Figure 3 Dissolution prole of marketed product (MP) and test product (TP) in different dissolution media. (a) Dissolution prole in
0.1 M hydrochloric acid (pH 1.2), (b) dissolution prole in 0.001 M hydrochloric acid (pH 3.0), (c) dissolution prole in acetate buffer
(pH 4.5), and (d) dissolution prole in phosphate buffer (pH 6.8). All values are mean7SD, n 6; Po0.05 vs. marketed formulations.
Use of the liquisolid compact technique for improvement of the dissolution rate of valsartan 507
Dissolution media Q10 min (%) Q30 min (%) DE (%) MDT (min)
MP TP MP TP MP TP MP TP
0.1 M HCl (pH 1.2) 17.59(72.61) 40.6(72.44) 31.04(72.2) 60.20(74.43) 13.58(71.43) 29.47(71.38) 36.24(73.81) 26.49(71.93)
0.001 M HCl (pH 3.0) 23.34(72.27) 70.14(70.49) 37.92(73.57) 86.37 (71.66) 18.33(71.51) 50.91(70.76) 29.94(72.22) 14.15(72.55)
Acetate buffer (pH 4.5) 71.06(79.34) 87.80(73.94) 87.40(74.76) 103.99(76.33) 50.95(74.69) 68.13(72.50) 14.27(73.40) 5.68(70.90)
Phosphate buffer 88.68(77.92) 90.07(74.16) 94.79(75.79) 100.09(72.08) 68.58(75.08) 72.16(72.86) 5.14(70.93) 3.81(70.87)
(pH 6.8)
MP, marketed product; TP, test product. DE, dissolution efciency; MDT, mean dissolution time. Data are expressed as mean (7SD).
11. Tiong N, Elkordy AA. Effects of liquisolid formulations on 19. Raja RK, Abbulu K, Sudhakar M. Development, characterization
dissolution of naproxen. Eur J Pharm Biopharm 2009;73:37384. and solubility study of solid dispersion of valsartan. J Chem
12. Javadzadeh Y, Jafari-Navimipour B, Nokhodchi A. Liquisolid Pharm Res 2011;3:1807.
technique for dissolution rate enhancement of a high dose water- 20. Friedrich H, Fussnegger B, Kolter K, Bodmeier R. Dissolution
insoluble drug (carbamazepine). Int J Pharm 2007;341:2634. rate improvement of poorly water-soluble drugs obtained by
13. Gubbi SR, Jarag R. Formulation and characterization of adsorbing solutions of drugs in hydrophilic solvents onto high
atorvastatin calcium liquisolid compacts. Asian J Pharma Sci surface area carriers. Eur J Pharm Biopharm 2006;62:1717.
2010;5:5060. 21. Spireas S, Wang T, Grover R. Effect of powder substrate on the
14. Karmarkar AB, Gonjari ID, Hosmani AH, Dhabale PN, Bhise dissolution properties of methyclothiazide liquisolid compacts.
SB. Dissolution rate enhancement of fenobrate using liquisolid Drug Dev Ind Pharm 1999;25:1638.
tablet technique. Lat Am J Pharm 2009;28:21925. 22. Fahmy R, Kassem M. Enhancement of famotidine dissolution
15. Ahad A, Aqil M, Kohli K, Sultana Y, Mujeeb M, Ali A. Role of rate through liquisolid tablets formulation: in vitro and in vivo
novel terpenes in transcutaneous permeation of valsartan: effective-
evaluation. Eur J Pharm Biopharm 2008;69:9931003.
ness and mechanism of action. Drug Dev Ind Pharm 2011;37:58396.
23. Banker GS, Anderson NR. Tablets. In: Lachman L, Lieberman
16. Kshirsagar SJ, Bhalekar MR, Madgulkar AR, Sable PN, Gupta
HA, editors. The theory and practice of industrial pharmacy.
SR. Dissolution improvement of poorly water soluble drug valsar-
New Delhi: CBS Publishers; 2009. p. 293345.
tan and improving ow properties of solid dispersion. Lat Am J
24. Javadzadeh Y, Rezasiahi MD, Asnaashari S, Nokhodchi A.
Pharm 2010;29:393400.
Liquisolid technique as a tool for enhancement of poorly water-
17. Ibrahim HK, El-Setouhy DA. Valsartan orodispersible tablets:
formulation, in vitro/in vivo characterization. AAPS PharmSciTech soluble drugs and evaluation of their physicochemical properties.
2010;11:18996. Acta Pharm 2007;57:99109.
18. Dixit AR, Rajput SJ, Patel SG. Preparation and bioavailability 25. Griesser UJ, Stowell JG. Solid state analysis and polymorphism.
assessment of SMEDDS containing valsartan. AAPS Pharm In: Lee DC, Webb ML, editors. Pharmaceutical analysis. Oxford:
SciTech 2010;11:31421. Blackwell publishing; 2008. p. 240294.