INTRODUCTION:

Oral bioavailability of a drug depends on its solubility and/or dissolution rate, and dissolution may be rate determining step for appearance of medicinal effect, therefore efforts to increase dissolution of drug with limited water solubility is often needed. Many methods are available to improve these characteristics, including salt formation, micronization and addition of solvent or surface active agents. Solid dispersion (SD) is one of these methods, and involved a dispersion of one or more active ingredients in an inner carrier or matrix in solid state prepared by melting, dissolution in solvent or melting solvent method.¹ Solid dispersion technique has been used for a wide variety of poorly aqueous soluble drugs such as nimesulide,² ketoprofen,³ tenoxicam,⁴ nifedipine,⁵ nimodipine.⁶

Furosemide (FRMD) is 5-(aminosulphonyl)-4-chloro-2-[(2-fuanyl-methyl) amino] benzoic acid, a potent high ceiling (loop) diuretic, mainly used in the treatment of hypertension.⁷ The drug has been classified as class IV drug as per the biopharmaceutical

classification system (BCS) and having low solubility and oral bioavailability, one of the major cause of the low oral bioavailability of FRMD is its solubility.^{8, 9}CPV has been used for the preparation of solid dispersion as a component of the binary system for various drugs such as tenoxicam, ⁴ tacrolimus,¹⁰ and indomethacin,¹¹ ibuprofen,¹⁴ nilvadipine.¹⁵

The present work aims to evaluate the potential of the solid dispersion technique for development of fast-dissolving tablets of FRMD using CPV as the hydrophilic carrier. Furthermore, the study undertakes to investigate kneading as a method for preparation of such binary systems, their solid state characterization, by applying analytical tools like FTIR, XRD and DSC, and attempts to see the possible mechanism of improved dissolution rate.

MATERIALS AND METHODS:

Materials

Furosemide (FRMD) was gift sample from Samruddha Pharmaceuticals, Thane, Mumbai, and Crospovidone (CPV) from ISP Technologies, INC. Wayane, NJ. All reagents and solvents used were of analytical grade.

Methods

Preparation of Furosemide-CPV Solid Dispersion

A mixture of Furosemide and CPV (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. Physical mixtures (PM) were obtained by pulverizing in a glass mortar and carefully mixing accurately weighed (1:1 and 1:2 by weight) amounts of FRMD and CPV. For convenience, all binary systems were given a code name, which is summarized in Table I.

Table I. Percentage Dissolution and Dissolution Efficiency of Furosemide from Different Binary Systems in Comparison With Original Drug*

System	DP60^†	DE30^†	DE60^†
FRMD	17.28 ± 0.09	2.93 ± 0.16	6.91 ± 0.19
PM1	25.707 ± 0.10	4.09 ± 0.34	8.69 ± 0.47
PM2	39.24 ± 0.15	17.33 ± 0.53	25.21 ± 0.33
SD1	69.25 ± 0.49	37.33 ± 0.43	45.21 ± 0.23
SD2	88.36 ± 0.13	58.79 ± 0.57	69.23 ± 0.26

*FRMD indicates furosemide; DP60, % dissolved at 60 minutes; DE30 and DE60, dissolution efficiency at 30 and 60 minutes). ^†All values are mean of 3 readings ± SD.

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.

Table II. Formulation Variable for the SD2-containing Tablets

Ingredients	MD1	MD2	MD3
SD2	80 mg	80 mg	80 mg
Avicel PH102	119 mg	99 mg	89 mg
Croscarmellose sodium	--	20 mg	40 mg

Each tablet contains 1mg magnesium stearate.

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.

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

Tablet Preparation and Characterization

Tablets containing equivalent of 40 mg of Furosemide (SD2 product) were compressed on a 16- station single rotary tabletting press (Type – CMD3 – 16. Cadmach Machinery Pvt. Ltd., Ahamadabad) using an 8-mm standard flat punch by direct compression technique. All the formulations are reported in Table 2. Prepared tablets were evaluated for hardness (Tablet Tester Model No. C – WWTDH 500N Campbell Electronics, Mumbai.), friability (Roche Friabilator), weight variation, and drug content. In vitro dissolution studies of MD2 (tablets containing solid dispersion SD2) and 2 commercial tablets of Furosemide (containing 40mg), Lasix (Sanofi Aventis) and Salinex (IDPL), respectively, were carried using 900-mL SGF (pH-1.2) as the dissolution media.

RESULTS AND DISCUSSION:

Fourier Transform Infrared (FTIR) Spectroscopy

IR spectra of FRMD and its binary systems with CPV 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.

Table III. Percentage Dissolution and Dissolution Efficiency of Furosemide from Fast-Dissolving Tablets Containing solid dispersion (MD3) and Commercial Formulation

Formulations	DP60*	DE60*
MD3	84.519 ± 0.28	63.91 ± 0.54
Salinex	25.707 ± 0.10	18.44 ± 0.21
Lasix	37.709 ± 0.14	28.68 ± 0.53

*All determinations are mean of 3 readings ± SD. DP60, % dissolved at 60 minutes respectively, DE60, dissolution efficiency in 60 minutes.

Differential Scanning Calorimetry (DSC)

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

FRMD 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, ⁸ the degradation product shows an endothermic peak at 280.2^oC. The disappearance or shifting of endo- or exothermic peaks of drug is indication of change in crystalline structure of furosemide in solid dispersion.

X-ray Diffractometry

The X-Ray diffraction pattern of FRMD 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. The X-Ray diffraction pattern of physical mixture was simply a superimposition of each component with peaks of frusemide. In case of solid dispersion prepared with crospovidone in 1:2 w/w ratio disappearance of peaks below 20⁰ was observed and the peaks between 20-30⁰ are broadened, indicating the conversion of crystalline structure to the amorphous one and hypothesis was supported by DSC study.

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 has improved the dissolution rate of FRMD to a great extent. Table 1 summarizes % drug dissolved in 60 minutes (DP60), 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 1 indicate that SD2 (DE60 = 69.23) shows maximum enhancement in dissolution rate. However, SD1 also produces comparable results on terms of dissolution efficiency (DE60 = 45.21). Physical mixtures (PM) 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 is SD2 > SD1 > PM2 > PM1 > FRMD.

Figure 1. FTIR Spectra of furosemide and various binary systems with CPV

This enhancement of dissolution of Furosemide from drug carrier systems can be ascribed to several factors. Ford¹², Martinez-Oharriz¹³ 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 as well as change in crystalline structure during preparation of solid dispersion which is supported by DSC and XRD study. Dry mixing of drug with a hydrophilic carrier result increase in wetting and increased 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 2. DSC curves of furosemide and various binary systems.

Tablet Preparation and Characterization

To formulate a tablet of FRMD, the SD2 binary mixture was selected based on its in vitro dissolution performance. The use of super-disintegrants for preparation of fast-dispersing tablets is highly effective as well as commercially feasible. These super- disintegrants accelerate disintegration of tablets by virtue of their ability to absorb a large amount of water when exposed to an aqueous environment. The absorption of water results in breaking of tablets and therefore faster disintegration. This disintegration is reported to have effect of dissolution characteristics as well.

Figure 3. XRD spectra of furosemide and various binary systems

The formula of different tablets prepared is summarized in Table II. However, tablets showed the fastest disintegration (95 seconds). To improve the disintegration, crosscarmellose sodium was included in the formula, which results in a very fast dispersion (25 seconds). Tablet characteristics of optimized tablet MD3 are tabulated in Table III. In vitro dissolution studies for MD3 confirmed the results obtained with solid binary mixtures. MD3 tablets showed good dissolution efficiency (DE60 = 63.91 ± 0.54) and rapid dissolution (DP60 = 84.51 ± 0.28%). When compared with commercial formulations in the Indian market (Figure 5), tablets formulated with the binary mixture (SD2) clearly perform better (Table 2) and a significant enhancement in dissolution characteristics was observed (P < 0.05). Significant increase in DP60 (% dissolved in 60 minutes) was found with MD3 with respect to commercial formulation Salinex (3.28-fold) and Lasix (2.24-fold).

Figure 4. Dissolution profile of furosemide and its binary systems with crosPVP

Figure 5. Dissolution profile of tablets containing solid dispersion and comparison with commercial tablets

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-cros PVP binary systems along with use of super-disintegrants could be considered for formulation of fast dissolving tablets of furosemide.

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Received on 24.07.2008 Modified on 10.10.2008

Research J. Pharm. and Tech. 1(4): Oct.-Dec. 2008;Page 386-389