INTRODUCTION:

A drug given in an orally administered tablet must undergo dissolution before it can be absorb and transported into the systemic circulation. For many drug, dissolution must be preceded by disintegration of tablet matrix ¹. For tablet dissolution it is necessary to overcome the cohesive strength introduced in to the mass by compression. Therefore, usual practice to incorporate a disintigrant will induce this process. Disintegration is frequently considered a prerequisite for drug dissolution, it is no manner assures that drug will dissolved and hence have the potential for satisfactory bioavailability. Therefore it is important to examine the effectiveness of disintigrant in the context of how the rate of dissolution of drug from a tablet is affected ².

The development of fast dispersible tablet using superdisintegrant has become popular for various reasons. For tablet containing sparingly water soluble drugs, the start of dissolution is often delayed by poor wettability of tablet or slow liquid penetration into tablet matrix ^3,
4.

This causes increase in disintegration time and retards the drug release. This can be overcome by addition of superdisintegrant.

Potential disadvantages of use of disintegrant in tablet formulation, using direct compression as the method of manufacture are – (1) high concentration needed for optimum disintegrating efficiency (2) poor disintegration (3) susceptibility to high compression forces which decrease the efficiency (4) poor compression properties (5) decreased disintegrating efficiency in hydrophobic formulations⁵. A group of superdisintegrants including croscamellose sodium (Ac-Di-Sol) sodium starch glycolate (Primojel and Explotab) and crospovidone (Polyplasdone XL) alleviate most of these problems. Use of the superdisintegrants in fast dispersible tablet is possible as tablet shows optimum physical properties.

The total porosity and pore mean diameter decrease, when applied pressure increase and, consequently, the disintegration time increase, as has been also reported by number of authors ^{6, 7, 8}. Under certain condition, the superdisintegrant makes enough pressure in the pores of the tablets as to produce an efficient disintegration ^{9, 10}. Although the rate of capillary penetration in tablets of narrower pore size distribution are lower than those for structure of wide pore size distribution, larger parts of pore structure participate in liquid uptake. So, the final saturation volume is superior at the intermediate level of disintegrants ¹¹.

Table 1 composition of various solid dispersions

S. No.	Composition	Ratio
1	Frusemide : Crospovidone (SD F-POV1)	1 : 1 (w/w)
2	Frusemide : Crospovidone (SD F-POV2)	1 : 2 (w/w)
3	Frusemide : Croscarmellose sodium (SD F-CAR1)	1 : 1 (w/w)
4	Frusemide : Croscarmellose sodium (SD F-CAR2)	1 : 2 (w/w)
5	Frusemide : Sodium starch glycolate (SD F-SSG1)	1 : 1 (w/w)
6	Frusemide : Sodium starch glycolate (SD F-SSG2)	1 : 2 (w/w)
7	Pure drug (FMRD)	-

Wicking and swelling were found to be the primary mechanism of action for tablet disintegrants, while other mechanisms, such as deformation recovery, particles repulsion theory, heat of wetting and evolution of a gas etc., may play a role in particulate cases of tablet disintegration¹². G.K Bolhuis demonstrated that dissolution from tablets and capsules of poorly soluble, hydrophobic drugs can be improved by solid deposition of the drug upon hydrophilic, strongly swelling carriers like the super disintegrants sodium starch glycolate , crosscarmellose, and crosspovidone. This increased in dissolution is because of micronized drug particles are farily evenly distributed on relatively large hydrophilic carrier particles can prevent reagglomeration and increase the drug dissolution rate as an effect of the large effective surface for dissolution. A prerequisite for fast dissolution from an ordered mixture seemed to be that the carrier particles dissolve rapidly, delivering a fine particulate suspension of drug particles¹³.Te Wierik et al Shown that dissolution from capsules and tablets of poorly soluble and hydrophobic drugs can be strongly improved by solid deposition of the drug upon the surface of the hydrophilic and strongly swelling superdisintegrant sodium starch glycolate than hydrophilic soluble carrier like lactose or with a carrier with a carrier with limited swelling properties, such as potato starch.so, an effect of swelling of the super disintegrant , the ‘wetted’ surface of the carrier increases, which promotes wettability and dispersibility of the particulate system. The crosspovidone is a water in-soluble type of cross-linked polyvinylpyrollidone used as tablet disintegrant at concentration of 5-10%, exhibiting high capacity with little tendency to gel formation¹⁴. It was also reported by Lopez-solis. J et al that Crosscarmellose sodium allow a more effective deployment of its dissolution improvement properties in presence of a dissolving diluent like Pharmatose DCL 11 as compare to more hygroscopic starch superdisintegrants¹⁵ .

SSG prepared from differents native starch had high swelling capacity but the rate of water uptake into the disintregrant particles varied from high for sodium potato starch to low for sodium rice starch glycolate.

Figure 1. FTIR Spectra of furosemide and various binary systems

The present work aims to evaluate the potential of the superdisintegrnt for enhancing the solubility and dissolution characteristics of model drug Furosemide (FRMD) using crosspovidone , crosscarmellose, and sodium starch glycolate as the hydrophilic carrier by solid dispersion

The furosemide was taken as modeldrug for this work because it was proved by several researchers that excipient and processing factors affect the dissolution profile of furosemide. very littele works have been published on the pharmaceutics factors which affect the furosemide tablets dissolution. Since furosemide having low solubility and low bioavailability, hence classified as class IV drug as per biopharmaceutical system^{16, 17, 18.}The purpose of this study was to determine the effect of crospovidone, crosscarmelose, and SSG on solubility, disintegration time and hence dissolution profile of furosemide.

MATERIALS AND METHODS:

Materials:

Furosemide (FRMD) was gift sample from Samruddha Pharmaceuticals, Thane, Mumbai, and Sodium starch glycolate (SSG),cross-povidone, and crosscarmellose from Loba cheime, India. All reagents and solvents used were of analytical grade.

Methods:

Preparation of Furosemide-SSG, Furosemide -crosspovidone and Furosemide- crosscarmellose Solid Dispersion^19-23:

A mixture of Furosemide and sodium starch glycolate, Furosemide and crosspovidone, Furosemide and crosscarmellose (1:1 and 1:2 by weight) was wetted with water-ethanol (in 1:1 ratio) and kneaded thoroughly for 60 minutes in a glass mortar. The paste formed was dried under vacuum for 24 hours. Dried powder was passed through sieve no. 60 and stored in a dessicator until further evaluation. The powered obtained by mixing the Furosemide and crosspovidone in 1:1 ratio was coded as SD F-POV1, while the powder obtained by mixing the Furosemide and Crosspovidone in 1:2 ratio was coded as SD F-POV2. Samelike , the powder obtained with crosscarmellose sodium and sodium starch glycolate in (1:1 and 1:2 by weight) was coded as SD F-CAR1, SD F-CAR2,SD F-SSG1 and SD F-SSG2 respectively. The Physical mixtures (PM) were obtained by pulverizing accurately weighed (1:2 by weight) amounts of Furosemide and sodium starch glycolate, Furosemide and crosspovidone, Furosemide and crosscarmellose in glass mortar and carefully mixing for 1 hr. The physical mixtures were coded as PM F-POV, PM F-CAR and PM F-SSG with crosspovidone, crosscarmellose and sodium starch glycolate respectively. For convenience, all binary systems were given a code name as shown in table 1.

Solid State Studies:

Fourier Transform Infrared (FTIR) Spectroscopy:

FTIR spectra were recorded on samples prepared in potassium bromide (KBr) disks using a Shimadzu Corporation, (Koyto, Japan) Model - 8400S. Samples were prepared in KBr disks by means of a hydrostatic press at 6-8 tons pressure. The scanning range was 500 to 4000 cm^-1.

Differential Scanning Calorimetry (DSC):

DSC analysis was performed using METTLER DSC 30S, Mettler Toledo India Pvt. Ltd., Swizerland, using crucible Al 40µL, at of 10⁰C /min heating rate, under nitrogen environment. The temperature range used was 0 – 400⁰C.

X-Ray Diffraction (XRD):

X-ray powder diffraction patterns were recorded on X-ray powder diffraction system, PANalytical spectris Pvt.Ltd., Singapore using copper target, a voltage of 40 Kv and a current of 30 mA. The scanning was done over 2θ range of 5º to 60º.

Figure 2. DSC curves of furosemide and various binary systems.

Dissolution Rate Studies:

The dissolution was studied using USP apparatus II taking 900 ml of dissolution medium, SGF (pH 1.2) for one hour. The rotational speed of the paddle was set at 50 rpm at 37 ± 0.5º C. The 5 mL of aliquots was withdrawn at predetermined time interval for every 5 min. for 1hr. by maintaining sink condition. The samples were analyzed for drug content using double beam UV spectrophotometer (Model No. UV 2401 PC Shimadzu Corporation, Koyto, Japan) at 274 nm

RESULTS AND DISCUSSION:

Fourier Transform Infrared (FTIR) Spectroscopy:

IR spectra of FRMD and its physical binary systems with SSG, crosspovidone, crosscarmellose are presented in Figure 1. Pure furosemide spectra showed sharp characteristic peaks at 3400.27, 3122.54, 1665, and 1560 cm^–1. All the above characteristic peaks appear in the spectra of all binary systems at same wavenumber indicating no modification or interaction between the drug and carrier.

Differential Scanning Calorimetry (DSC):

DSC thermograms of furosemide, as well as their solid dispersions prepared by kneading method and physical mixture are shown in Figure 2.

Table 2 Dissolution Efficiency of Furosemide from Solid dispersion of crosspovidone(SD F-POV2), crosscarmellose (SD F-CAR2), and SSG (SD F-SSG2)

Formulation	Dissolution Efficiency
Formulation	t₁₀	t₃₀	T₆₀
FMRD	0.95	2.93	6.91
PM F-POV	1.93	4.09	8.69
SD F-POV1	9.89	17.33	25.21
SD F-POV2	29.86	58.79	69.23
PM F-CAR	2.17	4.37	8.86
SD F-CAR1	8.58	13.62	18.44
SD F-CAR2	21.66	49.15	63.91
PM F-SSG	1.90	4.65	9.31
SD F-SSG1	15.28	22.60	28.68
SD F-SSG2	21.18	47.29	61.84

Furosemide exhibits a characteristic, sharp exothermic peak at 224.8 ^oC, which is associated with the decomposition of drug and associated with melting point of the drug and indicates the crystalline nature of the drug, the degradation product shows an endothermic peak at 280.2 ^oC. However, the characteristic exodothermic peak, corresponding to drug melting was broadened and shifted toward higher temperature, with reduced intensity, in both physical mixtures as well as solid dispersions. This could be attributed to higher polymer concentration and uniform distribution of drug in the crust of polymer, resulting in complete miscibility of molten drug in polymer. Moreover, the data also indicate there seems to be no interaction between the components of binary system. No significant difference in DSC pattern of dispersions and physical mixture suggests that even in the kneading process could not induce interaction at the molecular level and solid dispersion formed is a physical mixture with highly dispersed drug crystals in carrier. Hypothesis was confirmed by XRD study

X-ray Diffractometry:

The X-Ray diffraction pattern of furosemide exhibited sharp, highly intense and less diffused peaks indicating the crystalline nature of drug are shown in figure 3. The pure frusemide showed diffraction peaks at 2Ө degree of 12, 18, 18.9, 23, 24.7 and 28.6. However the X-Ray diffraction pattern of physical mixture and solid dispersion was simply a superimposition of each component with peaks of frusemide. Moreover, the relative intensity and 2θ angle of PM peaks remains practically unchanged. Thus it can be clearly suggestive from x-ray data that there is no amorphization of FRMD and it is still its in original crystalline form. IR and DSC studies support the same hypothesis, which is confirmed by x-ray diffractometry.The solid dispersion 1:2(w/w) molar ratios prepared by kneading method showed the reduction in sharpness of peak intensity. The peak intensity in 1:2(w/w) solid dispersion as less as compared to other. This showed that, the drug might be a converted to amorphous state, and hence the dissolution profile of drug was increased.

Fig 3. XRD spectra of furosemide and various binary systems

Dissolution Rate Studies:

Dissolution profiles of original drug crystals and drug carrier binary systems are presented in Figure 4. It is evident that the solid dispersion (SD) technique using super disintegrates has improved the dissolution rate of FRMD to a great extent. Table 2 summarizes dissolution efficiency at 30 minutes (DE30), and dissolution efficiency at 60 minutes (DE60) for FRMD and its binary systems with carriers. The values given in Table 2 indicate that SD2 (SD F-POV2, SD F-CAR2, SD F-SSG2) shows maximum enhancement in dissolution rate. However, SD1 (SD F-POV1, SD F-CAR1, SD F-SSG1) also produces comparable results on terms of dissolution efficiency. Physical mixtures (PM F-POV, PM F-CAR, PM F-SSG) also improve dissolution rate by a significant extent as compared with drug alone (P <0.05). The order of efficiencies of products based on DE values (DE 30 and DE 60) is SD F-POV2>SD F-CAR2>SD F-SSG2>SD F-SSG1>SD F-POV1>SD F-CAR1>PM F-SSG>PM F-CAR>PM F-POV>FMRD.

This enhancement of dissolution of Furosemide from drug carrier systems can be ascribed to several factors ^24,
25 reviewed the mechanism of dissolution rate improvement from solid dispersion. Lack of crystallinity, i.e., amorphization, increased wettability and dispersibility and particle size reduction considered to be important factors for dissolution rate enhancement. As indicative from dissolution data of physical mixtures, improvement could be attributed higher wettability, dispersibility. Dry mixing of drug with a hydrophilic carrier results in greater wetting and increases surface available for dissolution by reducing interfacial tension between hydrophobic drug and dissolution media. During dissolution studies, it was noted that drug carrier systems sink immediately, whereas pure drug keeps floating on the surface for a longer time interval.

Figure 4. Dissolution profile of furosemide and its binary systems

(♦)- SD F-POV2, (▲) – SD F-CAR2, (■) – SD F-SSG2, (*) – PM F-SSG (×) – PM F-CAR, (-) –PM F-POV, (+) – FMRD,

CONCLUSION:

The study shows that the dissolution rate of furosemide can be enhanced to a great extent by solid dispersion technique using an industrially feasible kneading method. Hence furosemide-SSG, furosemide- crosspovidone, furosemide- crosscarmellose binary systems along with use of superdisintegrants could be considered for formulation of fast dissolving tablets of furosemide. They enhanced the solubility characteristics as well as dissolution characteristics of hydrophobic drugs because they acts as hydrophilic carrier, they increase the wettability and dispersibility of poorly water insoluble drugs this is particular importants for hydrophobic drugs. So, superdisintegrants can be used as solubilizing agents for hydrophobic drugs.

ACKNOWLEDGEMENT:

The authors thank Samruddha Pharmaceuticals, Thane, Mumbai, for providing the gift sample of furosemide.

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Received on 17.11.2008 Modified on 15.12.2008

Research J. Pharm. and Tech. 2(2): April.-June.2009,;Page 387-391