Improvement of Dissolution Characteristics of Meloxicam by Complexation with Cyclodextrins

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1 Research Paper Saurav Nandi : Improvement of Dissolution Characteristics of Meloxicam by Complexation with Cyclodextrins 1263 International Journal of Pharmaceutical Sciences and Nanotechnology Improvement of Dissolution Characteristics of Meloxicam by Complexation with Cyclodextrins Saurav Nandi 1*, Subal Debnath 2, S.Y. Manjunath 2, V. Mallareddy 3, Nilesh P. Babre 2, M. Gopal Rao 1 1 College of Pharmacy, Sri Ramakrishna Institute of Paramedical Sciences, Siddapudur, Coimbatore, Tamil Nadu Srikrupa Institute of Pharmaceutical Sciences, Vil. Velkatta, Kondapak (mdl), Dist. Medak, Siddipet. Andhra Pradesh Volume 3 Issue 4 January March 11 3 Divi s Laboratories Ltd., Divi s Research Centre, B34, Industrial Area, Sanath Nagar Hyderabad500018, A.P. ABSTRACT: The aim of the present study was an attempt to prepare tablets containing inclusion complexes of meloxicam with βcyclodextrins and hydroxypropylβcyclodextrin to improve the aqueous solubility of the drug, thus enhances its dissolution rate to show a faster onset of action. Complexation with cyclodextrins has been used as novel approach for designing drug delivery system because of ability for the noncovalent inclusion complexes formation and it has the ability to molecular encapsulate meloxicam into their hydrophobic cavity without the formation of any covalent bonds. Meloxicam complexation with cyclodextrin enhance the drug solubility and dissolution rate. Also cyclodextrins enhance the bioavailability of insoluble drugs by increasing the drug solubility, dissolution and permeability. The carriers used in this study are βcyclodextrin and hydroxypropylβcyclodextrin. Solid complexes of meloxicam with βcyclodextrin and hydroxypropylβcyclodextrin were prepared by two different methods namely, Kneading and Coevaporation techniques. For kneading method, watermethanoldichloromethane at 2 : 5 : 3 ratio was used as a solvent blend and for coevaporation techniques, methanoldichloromethane was used as solvent blend at 2 : 3 ratio. In each case different proportions of drug and carriers at 90 : 10, :, 50 : 50, :, 10 : 90 were used in the preparation of solid complexes to evaluate the effect of carrier concentrations on the dissolution characteristics. A total of meloxicam solid complexes with different carriers were prepared, found to be fine and free flowing powders. The estimated drug content of the prepared complexes were in the range of 100 ± 5%. The dissolution parameters of T 50 and dissolution rate indicated rapid dissolution of meloxicam from the solid complexes when compared with the pure drug and physical mixture. Meloxicamβ CD (10 : 90) complex gave the highest dissolution rate. KEY WORDS: Meloxicam; βcyclodextrin; Hydroxypropylβcyclodextrin; Complexation; Meloxicam solid complexes Introduction Cyclodextrins, with lipophilic inner cavities and hydrophilic outer surfaces, are capable of interacting with a large variety of guest molecules to form a non covalent inclusion complex. Entrapment of a single guest molecule in the cavity of one host molecule is called as mono molecular inclusion (Jayachandran Babu R et al., 1996). Inclusion complexation occurs when aqueous solution of cyclodextrin is shaken with drug molecule or its solution. In aqueous solution the hydrophobic cavities of * For correspondence: Saurav Nandi, Tel: subal_07@yahoo.co.in cyclodextrins are occupied by water molecules, which can be replaced by appropriate drug molecules that are less polar than water. The solubility of the complex is usually lesser than that of cyclodextrin and hence the complex may be precipitated from its saturated solution (Roger A Rajeswski et al., 1995). In the crystalline state, however the guest molecules may be located not only inside the cyclodextrin cavity but also in between the cyclodextrin rings and thus form a crystal lattice inclusion complex. The crystalline complexes of cyclodextrins with drugs are rarely of strictly stoichiometric composition (Challa R et al., 0506). Since there are no covalent bonds between the host and the 1263

2 1264 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 3 Issue 4 JanuaryMarch 11 guest molecules, the complexes of cyclodextrins under physiological conditions are easily dissociated. When meloxicam molecules are accommodated into cyclodextrin cavities whose outer surface is hydrophilic, they are hydrophilized (Satoskar R S et al., 1993). The solid complexes prepared were found to be fine and free flowing powders. The Xray diffraction and scanning electron microscopy studies revealed that crystalline nature of meloxicam, in pure form was reduced to amorphous form in the complexes. Interaction studies like FTIR, indicated no interaction between the drug and carrier used. Experimental Materials and Equipments used Meloxicam, βcyclodextrin (βcd), hydroxypropylβcyclodextrin, HPβCD, (Burgoyner Burbidges & Co., Mumbai), methanol, dichloromethane, ethanol (Fischer Inorganics, Chennai), dissolution apparatus (Electro Lab. TDT08L), UV/Visible spectrophotometer (Jasco V530), analytical balance (Dhona 0D), FTIR (Jasco 410 series), Xray diffraction diffractometer (Siemens KristallofexD5000), SEM (Hitachi SEM.Model S450). Preparation of meloxicam solution Accurately weighed mg of meloxicam was transferred into a 100 ml volumetric flask and added minimum quantity of methanol to solubilize the drug. The phosphate buffer of p H 7.4 is added to this solution, to make up the volume upto 100 ml, this gives the stock solution (0 µg/ml). From this, pipetted out 0., 0.5, 0., 1.0 and 1. ml and made upto 10 ml in a standard flask with phosphate buffer ph 7.4. This gave 5, 10, 15,, and µg/ml concentration solutions and the phosphate buffer ph 7.4 was taken as blank. The absorbance was measured at 365 nm and the graph was plotted against concentration (µg/ml) Vs. absorbance (Table 1, Fig. 1). Table 1 Standard concentration Vs Absorbance. Sl.No. Concentration in µg/ml Absorbance Absorbance Concentration in mg/ml Fig. 1 Standard graph concentration Vs absorbance. Preparation and evaluation of meloxicam solid complexes Coevaporation method Methanol and dichloromethane was used as a solvent blend. The aqueous solution of cyclodextrin was added to a solution of meloxicam in the solvent blend of methanol and dichloromethane in 2 : 3 v/v ratio (Sajula Baboota et al., 05 and K P R Chowdary et al., 05). The resulting mixture was stirred for 1 hour and evaporated at 55 o C in an hotair oven, until dry. The dried mass was pulverized and sieved through mesh no. 100 (Jain A C et al., 01). Kneading technique A solvent blend of methanol, dichloromethane and water was used, here. Meloxicam and cyclodextrin were triturated in mortar with a small volume of solvent blend of watermethanoldichloromethane in 2 : 5 : 3 v/v ratio. The thick slurry was kneaded for 45 min and then dried at 55 0 C in an hotair oven till it got dried. The dried mass was pulverized and sieved through 100 mesh (Chowdary K P R et al., 00). Charcterization of meloxicam solid complexes XRay diffraction studies The powder Xray diffraction patterns were recorded using Siemens KristallofexD5000 Diffractometer. The samples were analyzed in the 2θ angle range of 0 and The diffraction patterns are shown in Fig. 2 & Fig. 3. Scanning electron microscopy Particle sizes of the prepared solid complexes were analyzed. Samples for SEM analysis were mounted on the specimen stubs using Fevicol adhesive. Small samples were mounted directly on Scotsch double adhesive tape. Samples were coated with gold to a thickness of 100A 0 using Hitachi Scanning Vacuum Evaporator, model HUS 5 GB. Coated samples were analyzed which was operated at 15kv, and photographed (Palmeri G F et al., 1997).

3 Saurav Nandi : Improvement of Dissolution Characteristics of Meloxicam by Complexation with Cyclodextrins 1265 any characteristic peaks which confirmed the absence of chemical interaction between the drug and the carriers used. Evaluation of Meloxicam solid complexe Drug content uniformity Fig. 2 SEM of meloxicam pure drug The prepared meloxicam solid complexes were tested for drug content uniformity. From each batch of solid complexes prepared in different ratios, mg of meloxicam solid complex were taken and analyzed for drug content uniformity (Wehrle P et al., 1993). Estimation of Meloxicam solid complexes by UV spectroscopy Accurately weighed amount of meloxicam solid complex was dissolved in 100 ml of phosphate buffer of ph 7.4 in a 100 ml clear and dry volumetric flask. This solution after suitable dilution, was measured for absorbance at 365 nm in a Jasco V530 UVVisible spectrophotometer (Table 3). Fig. 3 SEM of meloxicamβcyclodextrin complex FTIR studies Using FTIR Jasco 410 series PC spectrophotometer compatibility studies of meloxicam and the carriers were carried out. It was observed that the IR spectra obtained from solid complexes were matching with that of pure drug. Hence there were no apperance or disappearance of Table 2 Drug carrier ratios and respective amounts taken for the preparation of complexes. Sl.No. Drug(mg) Carrier(mg) 90: : : : : Table 3 Drug content uniformity. Meloxicam estimated by spectrophotometer (%) Drug carrier Amount of solid complex taken (mg) Expected amount of meloxicam in SC(mg) Solid complexes Kneading method Coevaporation method Meloxicam Meloxicam Meloxicam Meloxicam βcd HPβCD βcd HPβCD 90: : : : :

4 1266 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 3 Issue 4 JanuaryMarch 11 In vitro dissolution studies The dissolution studies, an important aspect of evaluation were carried out with pure drug and its solid complexes (Moyano J R et al., 1997). The dissolution rate studies of various solid complexes were carried out in 0.1M phosphate buffer p H 7.4, using dissolution rate apparatus (Electro Lab.). Dissolution method The phosphate buffer (900ml of 0.1M; ph 7.4) was used as the dissolution medium. Solid complexes equivalent to mg of meloxicam was taken in a hard gelatin capsule, a stainless steel wire was tied around the capsule to dip it in the dissolution medium. A paddle type stirrer was adjusted to 50 rpm and the temperature was maintained at 37 0 ± C. Aliquot dissolution medium (5ml) was withdrawn at different time intervals while replacing it with the same volume of dissolution medium. The samples were analyzed for meloxicam after suitable dilution by measuring absorbance at 365 nm using JASCO V530 UVVisible spectrophotometer while using the 0.1 M phosphate buffer of ph 7.4, as blank. The percentage of meloxicam dissolved at various time intervals was calculated and plotted against time (PoseVilarnovo B et al., 01). Formulation study of meloxicam solid complex Meloxicam solid complex at a drug carrier ratio of 10 : 90 was formulated into tablet with additives and evaluated for drug release characteristics (Mitrevej A et al., 1996). Direct compression method Powder material was directly compressed into a tablet modifying the physical nature of material itself. This method did not require, any equipment and handling expense required in wetting and drying procedures and could avoid hydrolysis of water sensitive drugs. In this method, no filler and binder was used, only the direct compressible vehicle (DCV) was used for compression. Preprocessing steps such as wet granulation, slugging, spray drying, spheronization or crystallization were carried out. In this drug DCV, disintegrant, lubricant, glidant were blended together in a suitable mixer and compressed to a tablet (Adel M et al., 03). Preparation of tablets Tablets containing 7.5 mg of drug were prepared, using solid complex of drug : βcd (10 : 90) and other additives along with sodium lauryl sulphate as a solubility improving agent. The total weight of the tablet taken was 0 mg. Evaluation of tablets Weight variation tests Twenty tablets were taken and weighed individually. They were evaluated for the weight variations. The weight variation allowed as IP limit is 5%. The weights of all the tablets were observed to be within the IP limits. Hardness test Pfizer hardness tester was used for measuring the hardness of formulated meloxicam tablets. From each batch 5 tablets were taken at a random and subjected to the test. Disintegration test The USP device to test disintegration used 6 glass tubes that are 3 inches long open the top and held against 10 inch screen at the basket rack assembly. One tablet was placed in each tube and the basket was positioned in a 1L beaker of distilled water at 37 ± 2 0 C, such that the tablets below the surface of the liquid on their upward movement and descend not closer than 2.5 cm from the bottom of the tester (Hirasawa N et al., 04). Friability test Friability test was performed with the solid complex tablets. The weight of the tablets after undergoing 100 revolutions was found to be within limits, the weight variation allowed was 0.5 ± 1 %. Results and Discussion The Xray diffraction pattern of pure drug showed intensive peaks indicating the crystalline nature of meloxicam, which was reduced in the solid complexes where the peaks indicated the amorphous nature of the drug. This could be the reason for improved dissolution characteristics of solid complexes. Large prismatic crystals were clearly evident from scanning electron microscopy of pure drug indicating high crystallinity of the active moiety under the magnification of 300X (Fig. 2 and Fig. 3). Solid complexes of meloxicam and pure drug of meloxicam study for FTIR spectral analysis showed no appearance or disappearance of characteristics peaks of meloxicam in the solid complexes. Hence, it showed that there was no interaction between the pure drug and the carrier. The dissolution profile of various tablets formulated namely MelT 1, MelT 2, MelT 3 and marketed sample showed that among the tablets formulated MelT 2 and MelT 3 gave higher dissolution of medicament when compared with marketed product (Table 4). The dissolution of medicament from all the prepared tablets followed first order kinetics (Table 8). The dissolution rate

5 Saurav Nandi : Improvement of Dissolution Characteristics of Meloxicam by Complexation with Cyclodextrins 1267 was found to be high in the case of tablets formulated. MelT 2 and MelT 3 employing solid complex, indicating rapid and higher dissolution of medicament when compared with the marketed product. SLS used as the solubility modifier in the formulation and the increased concentration of SLS (Sodium lauryl sulphate) showed increasing rate of dissolution. The results of hardness, frability test, disintegration test had shown that all the batches fulfill the official (IP) requirements for tablets. Hardness of the tablets in all the batches were found to be 89 kg/sq.cm and was satisfactory. The percentage weight losses in the friability test were found to be less than 1% in all batches. Thus the tables prepared were found to be good quality and fulfilling all official requirements of compressed tablets (Table 5). As the proportion of carrier in the complex increased, the dissolution rate of meloxicam also increased. T 50 values were found to be decreased and K values found to be increased when the carrier concentration was raised, indicating fast dissolution of meloxicam at highest carrier concentration. Among the complexes prepared, meloxicamβcd (10 : 90) was found to show highest dissolution rate. Table 4 Percentage of meloxicam dissolved and undissolved from formulated tablets and marketed product. Time in mins % of meloxicam dissolved % of meloxicam undissolved Marketed product Mel T 1 Mel T 2 Mel T 3 Marketed product Mel T 1 Mel T 2 Mel T ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±0. Table 5 Hardness, friability, disintegration time of meloxicam tablet formulated and marketed product. Formulations Hardness (kg/sqcm) Friability (%) Disintegration (min) Marketed product Mel T Mel T Mel T Table 6 Formulae of the prepared meloxicam tablets with βcd (10 : 90). Ingredients/ Materials Mel T 1 mg/tab Mel T 2 mg/tab Mel T 3 mg/tab Meloxicam βcd Lactose Microcrystalline cellulose (MCC) Sodium lauryl sulphate(sls) Talc 5 5 5

6 Volume 3 Issue 4 JanuaryMarch 11 Table 7 Percentage of meloxicam released from physical mixtures and various solid complexes. International Journal of Pharmaceutical Sciences and Nanotechnology

7 Saurav Nandi : Improvement of Dissolution Characteristics of Meloxicam by Complexation with Cyclodextrins 1269 Table 8 First order rate constant for meloxicam dissolution from various solid complexes. First order rate constant K(min 1 ) Solid complexes 90:10 : 50:50 : 10:90 Pure drug PM with βcd PM with HP βcd Kneading technique Meloxicam: βcd Meloxicam: HP βcd Coevaporation method Meloxicam: βcd Meloxicam: HP βcd Table 9 Relation between percentage carrier and T 50 and T 90 values. % Drug % Carrier Kneading technique Coevaporation method Meloxicamβ CD complex MeloxicamHP βcd complex Meloxicamβ CDcomplex MeloxicamHP βcdcomplex T 50 (min) T 90 (min) T 50 (min) T \90 (min) T 50 (min) T 90 (min) T 50 (min) T \90 (min) Conclusion Results of dissolution studies showed a rapid and fast dissolution of meloxicam from all solid complexes when compared with pure drug and physical mixture. Good correlation was observed between percentage carrier in complexation and T 50 and T 90 values. Among the two carriers used βcd gave the highest dissolution rate in the drug carrier ratio of 10 : 90. The dissolution of meloxicam from tablet formulation based on solid complexation was found to be fast and rapid when compared to the marketed product. SLS added further improved the dissolution of the drug from the formulated tablets but other additives have not hindered the dissolution of meloxicam from the formulation. All the tablet formulations based on the complexation, were found to fulfill the official dissolution requirements. Hence, it could be concluded that the tablet formulations based on complexation are considered as: fast release dosage forms of meloxicam. References Adel M, Aly Mazen, K Qato and Maharous O Ahmed. Enhancement of dissolution rate and bioavailability of glipizide through cyclodextrin inclusion complex. Pharmaceutical technology. 54, (03). Challa R, Ahuja A, Ali J, Khar R. Cyclodextrin in drug delivery : An updated review, AAPS Pharm Sci. (02): , (05 06). Chowdary K P R, Nalluri B N, Nimesulide and betacyclodextrin inclusion complexes : physicochemical characterization and dissolution rate studies. Drug Dev Ind Pharm. 26: (00). Hirasawa N, Ishise S, Miyata H, Danjo J K. Application of nilvadipine solid dispersion to tablet formation and manufacturing using crospovidome and methyl cellulose as dispersion carriers. Chem Pharm Bull. 52(92): (04).

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