Improvement of Physicochemical properties of Mesalamine with Hydrophilic Carriers by Solid Dispersion (kneading) method.
Govt.College of Pharmacy, Karad Pin code- 415124 (Maharashtra). INDIA.
*Corresponding Author E-mail :venkat_yadav3@rediffmail.com
ABSTRACT:
The purpose of the study was to improve the Physicochemical properties of Mesalamine like solubility , dissolution properties and stability of a poorly water-soluble drug like Mesalamine by forming dispersions with polyvinylpyrrolidone (PVP), Polyethylene Glycol (PEG) and β- Cyclodextrine as water-soluble carriers. The solid dispersion of Mesalamine by kneading method were prepared using 1:2 and 1:3 ratios of drug to polymers polyvinylpyrrolidone (PVP), Polyethylene Glycol (PEG) and β-Cyclodextrin. The saturation Solubility study was carried out by using flask shaker method at room temperature. Dissolution study was conducted in 0.1N HCl at 370C ± 0.50C using USP type II (paddle) type dissolution apparatus. The prepared dispersion showed marked increase the saturation solubility and dissolution rate of Mesalamine than that of drug alone. The dispersion with β Cyclodextrine (1:3) showed faster dissolution rate as compared to the other prepared dispersions. Characterization of Mesalamine solid dispersion was performed by Fourier Transform Infrared (FTIR) and X-ray powder diffractometry study. The stability studies performed on the mesalamine pure drug and optimized solid dispersion with β- Cyclodextrins (1:3) in accelerated condition upto six months. The stability study reveals no significant variation in in-vitro dissolution study of optimized solid dispersion β- Cyclodextrins (1:3) up to six month comparative to pure mesalamine drug.
KEY WORDS : Solid dispersion, water-soluble carriers, Mesalamine, β Cyclodextrine.
INTRODUCTION:
Mesalamine is 5-amino salicylic acid, active moiety of sulphasalazine. Its major indications are to treat mild to moderate acute exacerbations of ulcerative colitiss in remission, particularly in patients intolerant of sulphasalazine. It is white to pinkish crystals slightly soluble in water, 20 to 30 % absorbed following oral administrations.
Many technological methods of enhancing the dissolution characteristics of slightly water soluble drugs have been reported in literature such as micronization, formation of solvates, adsorbates, complexes, microspheres or more often solid dispersion. Solid dispersions of drugs that are poorly water soluble with pharmacologically inert water-soluble carriers can be used to increase the dissolution rate of drugs 1, 2. This approach has the potential to improve the bioavailability of drug significantly when absorption is limited by solubility. Some proposed mechanisms of the solid dispersion formulations
including the solubilizing effect of the carrier, decreased agglomeration and aggregation of drug particles, particle size reduction to molecular size, yielding to solid state solution within carriers and increased drug solubility via complex formation or solubilization and improved wettability 3, 4.
Solid dispersions of drugs in water soluble carriers such as PVP, PEG, β Cyclodextrin are known to increase the dissolution rate 5, 6, 7. The rate and extent of dissolution of the active ingredient from any dosage form often determine the rate and extent of absorption of the drug 8. In case of drug that is poorly water soluble, dissolution may be the rate-limiting step in the process of drug absorption. Drugs with poor water solubility have been shown to be unpredictably and slowly absorbed compared with the drugs of higher solubility.
The purpose of this study was to prepare solid dispersion by Kneading method, to improve the dissolution rate of Mesalamine.It was postulated that, if the drug is only slightly soluble in water, the dissolution process could be the rate-limiting step in the absorption of drug thus resulting in poor bioavailability.
In the present study three different compounds were chosen as carriers to prepare solid dispersion systems with the Mesalamine like PVP, PEG, β Cyclodextrin .All solid dispersion systems were prepared in 1:2 and 1: 3 drug to polymer ratio. Studies were initiated to evaluate the saturation solubility, in-vitro dissolution kinetics and assessment stability of the solid dispersions over a 6-month storage period at accelerated condition. Further characterization of a drug-carrier combination was conducted using FTIR and X-ray powder diffraction.
MATERIALS AND METHODS:
Mesalamine was obtained as gift sample from Sun Pharmaceutical Ltd. β-Cyclodextrin was obtained as gift sample from Roquette Fereres, France. All the other chemicals and solvents of analytical grade were purchased from Merck (India) and Loba chemicals.
Methods for Preparations of solid dispersion of Mesalamine (kneading method):
Mesalamine and the various water soluble carriers (PVP, PEG and β Cyclodextrin) were weighed in different ratio 1:2, 1:3 and transferred to mortar for kneading using hot water up to 45 minutes. Sufficient hot water was being added to maintain paste like consistency. The resulting paste was then dried in hot air oven at 45șC for 24 hours. The dried dispersions were milled and passed through sieve No. 18.The prepared dispersions were stored in glass vials and used for further studies.
Detection of drug content in prepared dispersions:
Three samples of prepared Mesalamine dispersions equivalent to 100mg of Mesalamin where accurately weighed, crushed and transferred to 100ml standard conical flask to it add 10ml ethanol and dissolve the drug and polymer. The volume was made up to 100ml with 0.1N HCl, filtered through Whatman filter paper and absorbance was taken at 231.40 nm.
Physicochemical characterization of prepared solid dispersions:
Solubility determination:
Solubility study was carried out by using flask shaker method. Excess Mesalamine and its different dispersions were introduced separately into the bottles with 25 ml capacity, each containing 10 ml of deionized water (pH 7.0+ 0.1). All suspensions were protected from the light by wrapping the bottles with aluminum foil and shaked for 24 hours at room temperature. The content of each bottle was then filtered through a 0.8” membrane. The filtrate was then diluted with distilled water and assayed spectrophotometrically at 230 nm (UV-visible Spectrophotometer-Shimadzu 2401 PC). Solubility of each sample was determined in triplicate.
Table 1: codes for prepared solid dispersions of mesalamine with water-soluble carriers.
Sr.No |
Solid Dispersion System |
Codes for dispersion |
|
1 |
Mesalamine |
M |
|
2 |
Mesalamine + PVP (1:2) |
M2PVP |
|
3 |
Mesalamine + PVP (1:3) |
M3PVP |
|
4 |
Mesalamine + PEG (1:2) |
M2PEG |
|
5 |
Mesalamine + PEG (1:3) |
M3PEG |
|
6 |
Mesalamine + β Cyclodextrin (1:2) |
M2BCD |
|
7 |
Mesalamine + β Cyclodextrin (1:3) |
M3BCD |
Fig.1: Dissolution profile of Mesalamine and its prepared dispersions.
Dissolution Studies:
The dissolution test was carried out by using USP-I (rotating basket). The dissolution conditions includes, Dissolution medium (0.1N HCl.), Temperature (37 ± 0.50 C), Speed of Rotation (75 rpm), Volume of Medium (900 ml.). Mesalamine (50 mg) and 50mg drug containing prepared solid dispersion were placed in the basket of dissolution medium and the apparatus was run. The 10 ml aliquot was withdrawn at interval of every 5 min. up to 30 min. After withdrawing each sample same amount of drug free dissolution medium was replaced so as to maintain sink condition. The samples were filtered through Whatman filter paper and absorbance was recorded at 231.4 nm.
Powder X-ray diffraction:
The cavity of the metal sample holder of x-ray diffractometer was filled with the ground sample powder and then smoothened with a spatula. X-ray diffractograms of Mesalamine and its dispersion samples were obtained using a Philips Analytical X Part PRD / SRS Division, N.B.B.S. and L.U.P, from Nagpur. A scanning rate of 0.04 2θ s-1 over the range of 10-600 2θ by using CuK” as tube anode having wavelength 1.5418A0 was used to record each spectrum
Fourier transforms Infrared spectroscopy (FT-IR):
FTIR was recorded using SHIMADZU Fourier Transform Infrared Spectroscopy Model FTIR 8400S, Sr.No-210141005.38 L P. Supplied by Toshwin analytical Pvt. Ltd. Mumbai using potassium bromide discs.
Fig.2: Dissolution profile of optimized solid dispersion (M3BCD) at initial, three and six months accelerated stability study.
Stability study:
Mesalamine pure drug and optimized sample of solid dispersions prepared with β Cyclodextrin in ratio 1:3 (M3 β CD) was stored at accelerated conditions in glass vials for 6 months. At the three and six months storage period, the appearance, content and dissolution rate of the aged sample was compared with that of initial mesalamine pure drug and optimized M3 β CD solid dispersion.
Table 2: solubility profile of mesalamine and their different dispersions in distilled water.
Sr.No. |
Dispersion Code |
Solubility in distilled water (mg/ml) ± SD* |
|
1 |
M |
0.982±0.028 |
|
2 |
M2PVP |
2.859±0.019 |
|
3 |
M3PVP |
2.964±0.038 |
|
4 |
M2PEG |
3.059±0.055 |
|
5 |
M3PEG |
3.188±0.045 |
|
6 |
M2BCD |
3.289±0.031 |
|
7 |
M3BCD |
3.464±0.026 |
RESULTS AND DISCUSSION:
The drug content of all dispersions was found to be in between 90 to 95 % and the % yield within 90 to 98%. The codes of the prepared dispersions and the solubility profile of Mesalamine and its different dispersions with polymers are shown in table: 1 and 2. The solubility of Mesalamine in water was found to be approximately 0.982 mg/ml. significantly increasing in solubility was obtained for all dispersions of Mesalamine with hydrophilic polymers. Maximum solubility was observed in M3BCD, considered as optimized solid dispersion of drug. Increase in solubility may be due to hydrophilic nature of the polymers, decreased agglomeration and aggregation of drug particles, particle size reduction to molecular size. Another probable theory concerns to an increasing effective solubilization process by carriers in the microenvironment (diffusion layer) immediately surrounding the drug particles. In summary, the order of solubility was found to be M3BCD > M2BCD > M3PEG > M2PEG > M3PVP > M2PVP > M.
Fig.3: Dissolution profile of mesalamine pure drug at initial, three and six months accelerated stability study.
As expected, the dissolution rate of pure Mesalamine was extremely poor with only about 65 % of drug released within 30 min of the dissolution run. As stated this observations might be attributed to poor wettability and particle agglomeration during the run. When incorporated into solid dispersions, the dissolution rate of Mesalamine from all dispersions was significantly higher then that of pure Mesalamine (Fig.1) The most rapid dissolution was observed with the M3BCD solid dispersion in comparison with the other dispersions. The fastest dissolution from M3BCD dispersion might be attributed to the solubilizing effects of β Cyclodextrin on the active drug. It is speculated that β Cyclodextrin favors the entrapment of poorly soluble compounds into its cavity. The hydrophobic part of the drug accommodate in the hydrophobic cavity of β Cyclodextrin and that of hydrophilic part of drug to outer hydrophilic portion of the β Cyclodextrin thus the molecularly encapsulated drug has greatly improved aqueous solubility and dissolution rate. Overall, the increase in dissolution rates of drugs with different carriers and their combinations may be due to lower contact angle, improved wettability and increased surface area.
FTIR study (Fig: 4) of Mesalamine and its different dispersions revealed that there is no chemical interaction between drug and polymers. All prepared dispersions showed no finger print difference and starching of functional groups as compared to the drug Mesalamine.
XRPD study (Fig: 5) reveals the physical interaction between the drug and polymers. All prepared dispersions showed changes in the number of peaks or few diffuse peaks were observed in all dispersions as compared to XRPD spectra of raw Mesalamine drug, which indicate decrease in crystallinlity in dispersed Mesalamine.The decreased drug crystallite size, can explain the faster dissolution and increased solubility, which indicates that there is physical interaction between drug and polymers.
The accelerated stability study of pure mesalamine drug and optimized solid dispersion for the dissolution study profile were mentioned in figure 2 and 3. The stability study reveals no significant variation in in-vitro dissolution study of optimized solid dispersion β Cyclodextrin (1:3) upto six month comparative to pure mesalamine drug.
Fig.4: FTIR spectra of Mesalamine and its different dispersions with hydrophilic polymers.
Fig.5: X-ray diffractograms of Mesalamie and its different dispersions with hydrophilic polymers.
ACKNOWLEDGEMENT:
The authors wish to thank Sun Pharmaceutical Ltd. Gujarat (India) for providing Mesalamine as gift sample for this research work.
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Received on 14.08.2008 Modified on 22.08.2008
Accepted on 10.10.2008 © RJPT All right reserved
Research J. Pharm. and Tech. 1(4): Oct.-Dec. 2008;Page 422-425