INTRODUCTION:

The formulation of poorly soluble drugs for oral delivery now presents one of the major challenges to formulation scientists in the industry^1-4. Various formulation parameters that play a crucial role for successful formulation are aqueous solubility, stability at ambient temperature and humidity, photo stability, compatibility with solvents and excipients etc. Of these, solubility is the most important property for developing formulations. Compounds exhibiting dissolution rate limited bioavailability are considered class II according to BCS classification⁵. As per recent report⁶, 46% of the total NDAs filed between 1995 to 2002 were BCS class IV, while only 9% were BCS class I drugs, revealing that a majority of approved new drugs were water insoluble. There are drug candidates that have poor solubility in water but can be dissolved by suitable conventional formulation strategies which include, Co-solvents⁷, Milling techniques⁸, super critical processing⁹, Solid dispersions¹⁰ including complexation¹¹, and precipitation techniques¹².

Solid dispersion technique has often proved to be the most commonly used in improving dissolution and bioavailability of poorly soluble active pharmaceutical ingredients because it is simple, economic and advantageous.

In solid dispersion technique, water soluble carriers are used to improve dissolution characteristics of poorly water soluble drugs. Valsartan is 3-methyl-2-[pentanoyl-[[4-[2-(2H-tetrazol-5- yl) Phenyl] methyl] amino]- butanoic acid. It is white fine powder having poor aqueous solubility. The present study is an attempt to overcome the poor aqueous solubility of VALSARTAN by solid dispersion technique using sodium starch glycollate (SSG) as carrier.

MATERIALS AND METHODS:

Valsartan was obtained as gift sample from Rubicon Reseacrh limited, Mumbai, Sodium starch glycollate (SSG) was obtained from Loba Chem, Mumbai. All other solvents and reagents used were of analytical grade.

METHODS:

Phase Solubility Study:

Phase Solubility study was conducted as per the method reported by M. Cirri et.al¹³ .Drug and carrier as per the specified drug: carrier ratio were weighed accurately and added to pure drug with 25 ml of water in screw capped bottles. All the bottles were shaken in Remi orbital incubator shaker at 37°C and 24°C for 24 h. The container with drug and water was used as control. After 24 h the solutions were filtered using (0.4 nm) filter paper and the filtrate was diluted. The absorbances were measured in spectra at 250 nm. From the absorbance the solubility of the drug were calculated.

Table: 1 Phase Solubility data of Valsartan with SSG:

Temp

°C

Slope

Intercept

∆G

kJ/mol

∆H

kJ/mol

∆S

kJ/mol

46.211

-1.216

0.841

-5.743

-5.724

47.566

-0.845

1.209

-8.635

-8.607

Fig: 1 In vitro release pattern of Solid dispersions and Pure drug

♦-VALSARTAN; ■-SD1; ▲- SD2; ×- SD3; *- SD4

Preparation of Solid dispersions:

Four formulations of Solid dispersions containing Valsartan with sodium starch glycollate (SSG) as carrier in ratios of 1:1, 1:3, 1:5 and 1:9 were prepared by Dispersion method as proposed by KPR Chowdary et.al¹⁴. The drug and carrier were weighed accordingly to the specified drug: carrier ratio. Valsartan was dissolved in ethanol and the carrier was taken in mortar. The carrier was triturated slowly with ethanol i.e. drug solution and it was dispersed till a porous mass was formed. The mass was dried in Vaccum oven maintained at -1kg/cm² at room temperature. Solid mass was pulverized and passed through sieve no.-80 to get uniform sized particles. The corresponding physical mixtures were also prepared as reported by Sudha. R. Vippagunta et.al¹⁵.

Estimation of Drug content:

The Physical mixture and Solid dispersions equivalent to 50 mg of model drug was taken and dissolved separately in 50 ml of 0.1N NaOH. The solution was filtered and was further diluted such that the absorbance falls within the range of standard curve. The absorbances of solutions were determined at 250 nm. From the absorbance total drug content in the batches was calculated and given in table 4.

Dissolution studies:¹⁶

The in vitro dissolution study was performed in USP XIX Dissolution rate test apparatus (Campbell, Mumbai) using 900 ml of Phosphate buffer pH 6.8. Amount of SD and PM equivalent to 80 mg of the solid dispersions and physical mixtures were weighed and kept in the dissolution flask. Samples were withdrawn at pre determined time interval and the same volume was replaced immediately to maintain sink condition. The withdrawn samples were suitably diluted and the absorbance of the solution was determined at specified wavelength of 250 nm.

Fig: 2 XRD Pattern of SD4 and PM4 compared with pure drug.

SD4 (1:9)

PM4 (1:9)

Saturation solubility study:

The Solid dispersions, Physical mixtures and pure drug Saturation solubility study was performed as reported by J.Hecq et.al¹⁷. Weighed amount of Valsartan (pure drug) and solid dispersions equivalent to 40 mg of the drug were separately introduced into 25- ml stoppered conical flasks containing 10 ml of distilled water. The sealed flasks were agitated on a rotary shaker for 24 h at 27° C and equilibrated for 2 days. An aliquot was passed through 0.45-μm membrane filter and the filtrate was suitably diluted and analyzed on a UV Spectrophotometer at 250 nm. The same procedure was followed for Valsartan physical mixture and absorbance was taken at 250 nm.

Wettability study:

The pure drug and formulations were subjected to wettability studies by Buchner funnel method as proposed by M.C. Gohel et.al¹⁸ and Water absorption method as per the method reported by Sunil Kumar Battu et.al¹⁹.

Permeation study:

The permeation study of the pure drug, solid dispersions and the physical mixtures were carried out using two different membranes viz .Egg membrane and Cellulose nitrate membrane. The diffusion of the drug through the membranes was analyzed in a diffusion cell and the procedure was followed as proposed by Mehdi Ansari et.al²⁰ for egg membrane and Giovanna Corti et.al²¹ for cellulose nitrate membrane.

Fig: 3. IR Spectrum of SD4 and PM4 compared with pure drug

SD4 (1:9)

PM4(1:9)

VALSARTAN

X-ray Diffraction study²²:

All the selected formulations and pure drug were subjected to X-ray diffraction study. The XRD patterns were recorded on a PW1729, Philips diffractometer (Eindhoven, The Netherlands) using Ni-filtered, CuKα radiation, a voltage of 40kV and a 25-mA current. The scanning rate employed was 10 min^-1 over the 10 to 30⁰ diffraction angle (2θ) range.

Drug-Polymer Interaction analysis:

The drug-polymer interaction studies were performed with IR study, TLC analysis and UV overlay spectra. IR spectrum of pure drug, solid dispersions and physical mixtures were taken in Double beam IR spectrophotometer (Shimadzu, Japan) using KBr pellet technique.

TLC analysis was done by applying the test solution and the reference solution (both 20mg/5ml) on the plate coated with silica gel and allowing the mobile phase containing Chloroform: Ethyl acetate: Acetic acid. The spots were visualized under UV scanner at 248nm and the Rf values were calculated.

The overlay spectra of pure drug and the formulations dissolved in 0.1N Sodium hydroxide were taken in UV-Visible Spectrophotometer (Shimadzu, Japan) by scanning from 200-400nm and the λ max was found out.

RESULTS AND DISCUSSIONS:

The objective of this work is an attempt to increase the aqueous solubility and dissolution rate of Valsartan by solid dispersion techniques²³ using sodium starch glycollate as hydrophilic carrier.

Phase solubility study:

Phase solubility study of Valsartan was conducted as per the method reported by M. Cirri et.al¹³. Table: 1 gives the phase solubility data. The solubility of Valsartan was found to be increasing constantly on increasing the concentration of the carrier (SSG) when physically mixed with the drug. The negative ∆G, ∆H, ∆S values of the formulations indicate the spontaneity of the process at low temperature. The thermodynamic Parameters results proved the solubilization effect of the carrier on the drug.

Drug Content of Solid dispersions and Physical mixtures:

Valsartan assay data was given in Table: 3. From the data it was clearly evident that the assayed drug content in the formulated solid dispersions and physical mixtures was found to be with in the range of +5% of the theoretical amount indicating the method used for formulation was suitable and reproducible in nature.

In vitro Release studies¹⁶:

Table: 2 show the release data and profile of Valsartan–SSG Solid dispersions. The interpretation of the data and the profile showed that the percentage cumulative release (%CR) from Valsartan-SSG Solid dispersion was higher than pure drug. It was also postulated that batch SD4 showed a CR of 87.18% where as pure drug gave CR of 34.92%. The CR from the batches was also found to be increased on increasing the concentration of the carrier incorporated in formulations.

Table: 2. In vitro Drug release parameters for Valsartan-SSG Solid dispersions and Physical mixtures.

Sample	D:C	%CR 10	%CR 30	%CR 60	%DE 60	MDT 60	T50
Pure Drug	-	2.878	22.163	34.919	16.50	31.65	63.6
Solid Dispersions	1:1	36.838	42.082	48.455	38.16	12.75	95.1
	1:3	39.675	44.953	49.287	40.62	10.55	76.0
	1:5	57.920	67.417	86.435	59.649	27.944	5.4
	1:9	80.918	83.200	87.188	76.60	7.28	0.5
Physical mixtures	1:1	30.322	34.431	44.656	33.53	14.95	0.2
	1:3	35.955	42.007	45.624	38.06	9.95	111.6
	1:5	45.497	56.511	67.055	51.20	14.18	18.3
	1:9	59.219	63.416	77.790	60.44	13.38	3.9

(%CR – cumulative release, %DE – Dissolution efficiency, MDT – Mean

TABLE: 3. Selection Parameters for Formulations

Formulation	Drug Content (%)	Solubility (mg/ml)	Permeability (mg/ml/hr)		Wettability
Formulation	Drug Content (%)	Solubility (mg/ml)	Egg Membrane	Cellulose Nitrate Membrane	Buchner Funnel Method (Min)	Water absorption Method (R)
Pure Drug	100.00	0.0278	0.0030	0.0137	80	3.904
SD4	102.40	0.0444	0.0103	0.0328	30	18.92
PM4	95.40	0.0402	0.0079	0.0284	42	14.40

Saturation solubility studies:

Saturation solubility studies were conducted as per the method reported by J.Hecq et.al¹⁷and was shown in Table: 3. Valsartan was found to have saturation solubility of 0.0278 mg/ml. Batches SD4 and PM4 gave a solubility value of 0.0444 mg/ml and 0.0402mg/ml respectively. The results proved that the carriers SSG was able to enhance the solubility of Valsartan in water.

Wettability studies:

The Buchner funnel method and water absorption method of Valsartan and selected batches were investigated as per the method reported by M .C. Gohel et.al¹⁸and Sunil Kumar et.al¹⁹ respectively and findings are shown in Table 3. The wetting time and water absorption ratio of the pure drug was found to be 80 minutes and 3.904 respectively its indicating poor wettability of the drug. The wetting time of samples was found to be very less (30 min) and water absorption ratio was more (18.92) than pure drug. This behavior may be attributed to increased wettability by the action of hydrophilic carrier used in the formulation.

Permeation study:

Permeation study through Egg membrane was done as per the method reported by Mehdi Ansari et.al²⁰ and Giovanna Corti et.al²¹. The data for Egg membrane and Cellulose nitrate membrane was given in the Table 3. It was observed that the amount of drug permeated from selected batches in both membranes was found to be higher than pure drug. Permeation through Cellulose nitrate membrane shows better result when compared with Egg membrane. The results can be considered as the evident for increase in release rate of Valsartan from Solid dispersions.

XRD analysis²²:

XRD analysis of the pure drug and selected batches were performed at CECRI, Karaikudi. It is generally stated that if three consecutive Relative intensity percentage values in XRD pattern decreases it can be confirmed as decrease in crystallinity had occurred in samples. The base foot of the peak and the FWHM (Full Width Half Maximum) values of the intense peaks are compared with that of the standard patterns. If the base of the peaks is broader in nature and its FWHM values decreases it indicates significant reduction in crystallinity. The observations were reported by Yuichi Tokuza et al and Center for Computational Project.

XRD Patterns of Valsartan and selected formulations were given in Fig: 2 XRD pattern of Valsartan showed numerous sharp, narrow and intense peaks, claiming its high crystallinity. The patterns of formulations showed no/little peaks indicating its amorphous nature. On comparison of selected samples patterns with that of pure drug, it was observed that the number and intensity of peaks were found to be less in samples, and Relative Intensity Percentage values were also found to be well correlating with interpretation guidelines. The bases of peaks in the sample were broader in nature confirming the reduction in crystallinity in samples. The decreased FWHM value of intense peaks in the samples than pure drug also confirms the reduction in crystallinity in samples. These observations from comparison of XRD pattern can be treated as confirmation tool for reduction in crystallinity and phase transition (from crystalline to amorphous form) had occurred in the samples.

Interaction Analysis:

I R Studies:

The I.R Spectrum of Valsartan along with selected formulations was taken and the characteristic peaks were shown below in Fig.3. The characteristic peaks were noted down and positions of the peaks were compared with the I.R spectrum of the selected samples. The results of the I.R analysis revealed that no interaction between drug and carriers.

TLC data:

Rf values of Valsartan and formulations are shown in the Table 4. It was noticed that there was no significant change in Rf value of pure drug and selected samples. The results of the TLC analysis revealed that no interaction between drug and carriers.

UV-Visible Spectroscopy:

The λmax of the sample and pure drug was found to be similar proving that no interaction between drug and carriers. (Data not shown)

Table: 4 TLC Analysis Data:

S. no	Sample	Rf value
1	PURE DRUG	0.51
2	SD4	0.50
3	PM4	0.53

CONCLUSION:

The objective of the present study was to improve the solubility and dissolution behaviour of the poorly soluble drug, Valsartan by solid dispersion technique using SSG as carrier. The dispersion method of preparing solid dispersions was found to be satisfactory as it produced good product with high drug content. Out of the four formulations prepared formulation SD4 showed marked increase in the solubility as well as the dissolution when compared to pure drug. The IR study, TLC analysis and the UV overlay spectra of the formulations showed no signs of interactions of the drug with the carrier. Further the XRD analysis showed that there was a considerable decrease in the crystallinity of the drug which increases the surface area thereby increasing the dissolution. Thus it can be concluded that the solubility of the poorly soluble drug, Valsartan can be improved markedly by using solid dispersion technique and the carrier SSG has increased the dissolution of the drug without any interaction.

ACKNOWLEDGEMENTS:

We thank M/s. Rubicon Research Limited, Mumbai for providing pure drug sample of Valsartan and CERTI, Karaikudi for helping in getting the XRD patterns for our formulations. We also thank the management of KMCH educational trust for giving permission to conduct this research work.

REFERENCES:

1. Craig DQM. The mechanisms of drug release from solid dispersions in water-soluble polymers. Int J Pharm . 2002; 231: 131 - 144.

2. Ford JL. The current status of solid dispersions. Pharm Acta Helv .1986; 61: 69 - 88.

3. Nakamichi K, Yasuura H, Kukui H, et al. New preparation method of solid dispersion by twin screw extruder. Pharm Technol Jpn .1996; 12: 715 - 729.

4. Breitenbach J, Berndl G, Neumann J, Rosenberg J, Simon D, ZeidlerJ. Solid dispersions by an integrated melt extrusion system. Proc Control Rel Soc. 1998; 25: 804 – 805

5. The Biopharmaceutics Classification System (BCS) Guidance, Office of Pharmaceutical Science, http://www. fda.gov/cder/OPS/BCS_guidance.htm (accessed 12.01.08)

6. Clew low PJ. Survival of the smartest. Scrip’s Target world drug delivery news. 2004; 35: 316-323,

7. Seedher N, Kaur J. Solubilization of nimesulide; use of co-solvents. Indian J Pharm. Sci. 2003; 65(1): 58-61

8. Mersiko-Liversidge E, MGurk SL, Liversidge GG. Insulin nanoparticles: a novel formulation approach for poorly water soluble Zn-Insulin. Pharm Res. 2004; 21(9): 1545-1553

9. Benjamin C-Y.Lu, Dingan Zang, Wei Sheng, Solubility enhancement in supercritical fluids. Pure and Appl.Chem. 1990; 62(12): 2277-2285

10. Abu T.M.Serajuddin. Solid dispersion of poorly soluble drugs-Early promises, subsequent problems, and recent breakthroughs. J. Pharm Sci. 2000; 88(10): 1058-1066

11. Frömming K-H. Cyclodextrine-eine vielseitig verwendbare Gruppe neuer Hilfsstioffe. In Muller RH, Hildebrand, G.E. (eds), Pharmazeutische Technologie; Modern Arzneiformen, 2^nd ed. WVG, Stuttgart, 1998.

12. Sucker, H. Hydrosole, eine Alternative für die parenterale Anwendung von schwer wasserlöslichen Wirkstoffen. In Muller RH, Hildebrand, G.E. (eds), Pharmazeutische Technologie; Modern Arzneiformen, 2^nd ed. WVG, Stuttgart, 1998

13. Cirri M, Mura P, Rabasco A.M, Gines J.M, Moyano J.R, Gozalez Rotriguez. Characterization of Ibuproxam binary and ternary dispersion with hydrophilic carriers. Drug Devel. Ind. Pharm. 2004; 30: 65-74.

14. Chowdary KPR, Srinivasa Rao S. Investigation of dissolution enhancement of Itraconazole in Superdisintegrants. Drug Devel. Ind. Pharm. 2000; 26: 1217-1220.

15. Sudha RV, Karin AM, Siva T, David JW. Solid state characterization of nifedipine solid dispersions. Int. J. Pharmaceutics. 2002; 236: 111-123.

16. www.cder.com/valsartan (accessed on 23.12.08)

17. Hecq J, Deleers M, Fanara D, Vranckx H, Amighi K. Preparation and characterization of nanocrystals for solubility and dissolution rate enhancement of Nifedipine. Int. J. Pharmaceutics. 2005; 299: 167-177.

18. Gohel M.C, Patel L.D. Processing of Nimesulide-PEG 400-PEG-PVP solid dispersions: Preparation, Characterization and In-vitro dissolution. Drug Devel. Ind. Pharm. 2003; 29: 299-310.

19. Sunil K.B, Michael A.R, Soumyajit M, Rao.Y. Formulation and evaluation of rapidly disintegrating Fenoverine tablets: Effect of superdisintegrant. Drug Devel. Ind. Pharm. 2007; 33:1225-1232.

20. Mehdi A, Maryam K, Monireh A. The study of drug permeation through natural membrane. Int. J. Pharmaceutics. 2006; 327: 6-11.

21. Giovanna C, Francesca M, Marzia C, Sandra F, Paola M. Development and evaluation of an in vitro method for prediction of human drug absorption 1. Assessment of artificial membrane composition. European J Pharm. Sci. 2006; 27: 346-353.

22. Yuichi T, Atsutoshi I, Hiiroko S, Toshio O, Keiji Y. Characterization and quantitation of Clarithromycin polymorphs by powder X-Ray diffractometry and solid state NMR spectroscopy. Chem Pharm Bull .2002; 50:1128-1130.

23. Tejal J.S, Avani F.A, Jolly R.P, Rajesh H.P. Process optimization and Characterization of Poloxamer solid dispersions of a poorly water soluble drug. Pharm Sci Tech. 2007; 89: E1-E7.

Received on 04.03.2009 Modified on 12.05.2009

Research J. Pharm. and Tech.2 (3): July-Sept. 2009,;Page 502-506