INTRODUCTION:

Therapeutic effectiveness of a drug depends upon the bioavailability and ultimately upon the solubility of drug molecules. Solubility is one of the important parameter to achieve desired concentration of drug in systemic circulation for pharmacological response to be shown. Currently only 8% of new drug candidates have both high solubility and permeability^.1

The bioavailability can be increased by changing disintegration and dissolution, the aqueous solubility lesser than 1 μg/ml will definitely create a bioavailability problem and thereby affecting the efficacy of the drug.

There is number of methods through which aqueous solubility of the drug can be increased in which solid dispersion is one of the effective and accepted techniques in the pharmaceutical industry. The solid dispersion was defined as the dispersion of one or more active ingredients in an inert carrier or matrix at solid state by using melting solvent systems. The drug is dispersed in molecular form of carriers which are pharmacologically inert. A number of freely water soluble materials with intrinsic rapid dissolution properties have been used to formulate solid dispersion various formulate solid dispersion.

Gatifloxacin is a broad-spectrum fluoroquinolone which is used in the treatment of acute sinusitis, community-acquired pneumonia, complicated and uncomplicated urinary tract infections. The aqueous solubility of Gatifloxacin is 40-60 mg /ml when determined at pH 2-5. The peak plasma concentration is reported 0.75-2.0 hours after oral dosing. Gatifloxacin having a protein binding of 20% and high bioavailability of 96%. The dose of the drugs 400 mg and is depends upon the condition. The objective of the present study was the preparation of solid dispersion of gatifloxacin using mannitol¹. It may improve the solubility of practically water insoluble drugs like gatifloxacin it may helps as to overcome limited dissolution rate and formulation difficulties².

MATERIALS AND METHODS:

Gatifloxacin was purchased from (Reddy’s laboratories, Hyderabad), mannitol, Hydrochloric acid (Universal Laboratories, Mumbai), Sodium hydroxide (Burgoyne Burbidges & Co, Mumbai), Methanol (SD Fine-chem. Limited, Mumbai) and all other required chemicals were analytical grade.

Preparation of solid dispersion:

Physical mixture^3,4 (pm) :

Drug carrier ratio of 1:1, 1:2, 1:3, 1:4 was used to prepare physical mixture. The drug and carrier were mixed thoroughly in a mortor. This was done by geometric dilution technique to ensure homogenous distribution.

Solvent evaporation^3,4,5 (se) :

Gatifloxacin and mannitol in different proportions were dissolved in sufficient volume of methanol with continuous stirring. The solvent was completely evaporated at 40-45⁰ C with continuous stirring to obtain the dry granules.

Kneading Method⁵ (KM):

Gatifloxacin and mannitol in different ratios (1:1, 1:2, 1:3, 1:4) were taken. Mannitol was added to the mortar, small quantity of 0.1N NAOH was incorporated while triturating to get wet mass. Then slowly drug was incorporated into the slurry and triturating was further continued for 1h. Wet mass was further air dried at 45°C for 24 hours, pulverized and passed through sieve No.100 and stored in desiccators over fused calcium chloride for further study.

Fig.1: High Resolution Photograph Of Solid Dispersions

Evaluation of solid dispersions:

Estimation of drug content in solid dispersion⁷:

50ml solid dispersions or physical mixture were weighed accurately and transferred in to a 50ml volumetric flask. The volume was made up to the mark with sodium hydroxide and kept for 2hrs with occasional shaking and filtered. Then the drug content was analyzed spectrophotometrically at 286 nm using a single beam visible U.V Spectrophotometer.

Invitro dissolution studies^{2-6,
8 :}

The release of gatifloxacin from solid dispersion was investigated in 0.1N HCL as a dissolution medium (900ml) using the paddle method specified in USP XXIV (model TD T6P-Electrolab).sample of 100mg solid dispersions were taken in the basket. A speed of 75rpm and temperature 37+ 0.5⁰C was maintained throughout the experiment. At fixed intervals, aliquots (5ml) were withdrawn and replaced with fresh dissolution media. The concentration of drug released at different time intervals was then determined by measuring the Absorbance using UV spectrophotometer at 286 nm against blank.

IR Studies⁹ :

FTIR Spectroscopy was performed on each at the samples to determine the structure of the organic compounds and to identify the presence of specific functional groups within a sample. Furthermore drug polymer interactions were examine using the resulting spectra. The infrared spectra were obtained using a scale of wave numbers (cm-1). The analysis were performed by using a thermo nicolet nexus 286 FTIR ESP.3-5mg of sample was added to approximately 100mg of KBr .The mixture was then ground to a fine powder using a mortar and pestle and transparent discs formed using a pellet press. The discs were placed in FTIR spectroscopy apparatus and spectra were collected. The range of the collected spectra was 4000-400cm^-1.

Fig.2: FT-IR of gatifloxacin

Fig.3:FT-IR of mannitol

Fig.4: FT-IR Of Solid Dispersion By Kneading (1:4)

RESULTS AND DISCUSSION:

Solid dispersion of Gatifloxacin containing varying concentration of mannitol was improved in an attempt to improve the solubility and dissolution rate of Gatifloxacin. The Gatifloxacin and solid dispersion were investigated by analytical method and IR spectra.

Drug Content:

The drug content of different concentrations of drug and polymer was estimated spectrophotometrically at 286nm and was tabulated (Table. 1).

Table 1: Effect of concentration of Drug:Carrier ratio on % Drug content of Gatifloxacin from prepared solid dispersions

Method	1:1	1:2	1:3	1:4
Physical mixture	82.03%	89%	94.42%	97.6%
Solvent evaporation	84.42%	90.19%	95.76%	99.42%
Kneading method	87.6%	94.03%	96.5%	99.92%

In-vitro dissolution studies:

The dissolution profiles of Gatifloxacin solid dispersion were studied. The dissolution rate was significantly increased when the Gatifloxacin : mannitol ratio was at 1:4. The mean percentage of drugs for physical mixture was 87.82, 93.01, 95.71and 96.321. But in the solvent evaporation method increase in release rate was observed 90.56, 93.50, 96.821 and 98.813 respectively. In the kneading method increase in release rate as compared to solvent evaporation and physical mixture. It 97.80, 99.20, 99.77 and 99.85 respectively .The % drug release of Gatifloxacin prepared from different methods of solid dispersions was observed and tabulated (Table-2)

Table 2: Comparison of in-vitro release of gatifloxacin solid dispersions

Method	1:1	1:2	1:3	1:4
Physical mixture	87.82%	93.01%	95.71%	96.31%
Solvent evaporation	90.56%	93.50%	96.821%	98.813%
Kneading method	97.80%	99.20%	99.77%	99.85%

Fig 1: In-Vitro Dissolution Profile of Gatifloxacin Solid Dispersions By Physical Mixture Method

Fig 2: In-Vitro Dissolution Profile of Gatifloxacin Solid Dispersions By Solvent Evaporation Method

Fig 3: In-Vitro Dissolution Profile of Gatifloxacin Solid

Dispersions By Kneading Method:

Kinetics:

When data was plotted according to first order kinetics, a linear plot was obtained with their high regression coefficient value -0.34, suggesting that the rate of release from solid dispersions was followed as per “first order kinetics”.

The data fitted with Higuchi equation yields a linear plot with their high regression coefficient values 0.924,indicating that mechanism of release from solid dispersions was diffusion controlled .To know precisely whether Fickian’s or non Fickian’s diffusion exists the data was plotted according to Korsemeyer equation . The plot showed the slope value n=0.807,this shows that mechanism of release was “super case II”

Table: 3 Kinetics of Gatifloxacin from prepared Solid dispersions by kneading method

Formulation	Parameters	Zero order	First order	Higuchi’s	Korsmeyer-Peppas
Kneading (1:4)	k	8.711	0.229	27.05	2.139
Kneading (1:4)	R²	0.944	-0.34	0.924	0.807

CONCLUSION:

The prepared solid dispersions were extended to various characterizations. IR shows there was no degradation of drugs. The solubility and dissolution studies showed there is a possibility of improved solubility of gatifloxacin through solid dispersion with mannitol. A maximum increase in dissolution rate was obtained with gatifloxacin:mannitol solid dispersion with a weight ratio of 1:4 though mannitol dispersion by kneading showed faster dissolution rate when compared with that of pure drug.

REFERENCES:

1. Masataka saito, Takasthi Ugajin, Yasuo Nozawa, Int. J. Pharm Sci; 2002, 249, 71.

2. Phole J; U.S. Patt; 1967, 3,325-362

3. Himasankar, K; Murali Mohan Babu,G.V, Indian J. Pharm.Sci;2002,64(5),629.

4. Gowthamrajan. K, Giriraj Kulkarni.T, Int. J. Pharm Sci; 2002,64(6),525.

5. Saha,R.N; Sajeev, C;Padma Priya, K, Int. J. Pharm Sci; 2002,64(6),529.

6. Madhusudhan. B, Ranbhau. D, Gudsoorkar. V.R, Int. J. Pharm Sci; 2002,64(3),233.

7. Madhusudhan. B, Ranbhau.D, Gudsoorkar. V.R, Int. J. Pharm Sci; 2002,64(3),233.

8. Kusum Devi, V; Vijayalakshmi, P and Avinash, M, Int. J. Pharm Sci;2003,542.

9. Dr. David L. Tomasko et.al. Analysis is of pharmaceutical/polymer solid dispersions produced by supercritical carbon dioxide – Assisted Techniques –2005

Received on 14.05.2012 Accepted on 28.05.2012

Asian J. Res. Pharm. Sci. 2(2): April-June 2012; Page 58-61