Formulation and Process Optimization of Solid Dispersion of Meloxicam and PEG8000 Prepared by Spray Drying

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1 Research Paper Patel R.P. et al. : Formulation and Process Optimization of Solid Dispersion of Meloxicam 647 International Journal of Pharmaceutical Sciences and Nanotechnology Formulation and Process Optimization of Solid Dispersion of Meloxicam and PEG8000 Prepared by Spray Drying Volume 2 Issue 3 October December 2009 Patel R.P. *, Patel M. P., Suthar A. M. and Baria A.H. S. K. Patel College of Pharmaceutical Education and Research, Ganpat University, Ganpat Vidyanagar, Kherva, Mehsana, (Gujarat), India. ABSTRACT: The poor solubility and wettability of meloxicam leads to poor dissolution and hence shows poor bioavailability. The present study is aimed at increasing solubility of drug using solid dispersion technique. The solid binary systems were prepared using different drug: polymer ratio (1:1, 1:5 and 1:10) with polyethylene glycol 8000 by different techniques like physical mixing, melting method and spray drying method. The formulations were characterized by differential scanning colorimetry, scanning electron microscopy and in vitro dissolution rate studies. The solubility of drug increased linearly with the increase in polymer concentration. The solid dispersion of drug prepared by spray drying method demonstrated higher drug dissolution rates in comparison to solid dispersion prepared by physical mixtures, melting method and pure meloxicam. Moreover, spray drying process parameters inlet air temperature and feed rate were also optimized to obtain maximum powder yield and satisfactory particle size and compressibility. The outcome indicated that with the increase in feed rate, the powder yield and Carr s index decreases but particle size increases. On the other hand, as the inlet temperature increases, powder yield and Carr s index increases. KEYWORDS: Solid dispersions; Spray drying; Solubility; Meloxicam; Crystallinity 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 (Chiou WL, Riegelman S, 1971). Solid dispersions traditionally have been used as an effective method to improve the dissolution properties and bioavailability of poor water-soluble drugs (Chiou and Riegalman, 1971; Serajuddin, 1999; Leuner & Dressman, * For correspondence: Rakesh P. Patel, raka_77us@yahoo.com 2000) Spray drying is transformation of feed from a fluid state into dried particulate form by spraying the feed into a hot drying medium. In this investigation emphasis is also placed on optimizing spray drying process parameters for preparing solid dispersion (Bataille, et al., 2000; Lee, et al., 2005). Meloxicam (MLX) is a nonsteroidal anti-inflammatory drug used to relieve the symptoms of arthritis, primary dysmenorrhea, fever, and as an analgesic, especially where there is an inflammatory component. It has water solubility of mg/ml. The molecular size of these polymers favors the formation of interstitial solid solutions (Leuner, et al., 2004; Chul Soon, et al., 2008). The present work aims to prepare solid dispersions of MLX with water soluble carrier like Polyethylene Glycol (PEG 8000) to improve poor aqueous solubility and dissolution behavior and to optimize the spray drying process parameters for preparing MLX-PEG 8000 solid dispersion. This study also aims to characterize the prepared solid dispersion by various method like, DSC, SEM and study the In-vitro dissolution behavior of prepared solid dispersions of MLX. 647

2 648 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 2 Issue 3 October - December 2009 Materials and Methods Materials MLX was gift sample from Lincoln Pharmaceuticals Ltd., (Ahmedabad, India). PEG 8000 was obtained as gift sample from Astron pharmaceuticals Ltd., (Ahmedabad, India). Dichloromethane was purchased from S. D. Fine chemicals (Mumbai, India). All other chemicals/solvents were of analytical grade. Preparation of Solid Dispersion (SD) by Spray Drying Method MLX and PEG 8000 were dissolved in dichloromethane to prepare solid dispersions having different weight ratio of MLX: PEG 8000 (W/W) 1:1, 1:5 and1:10 (Table 1) to prepare 5% w/v solution (Shabde, V.S. et al., 2008). The resultant solution was spray dried by using LU-222 ADVANCED Lab Spray Drier (Labultima, Mumbai, India) under following set of conditions: flow rate, 6 ml/min; inlet temperature, 50 C; outlet temperature, 40 C; aspiration 50 mbar and atomization air pressure, 2 kg/cm 2 for preparing solid dispersion (Weuts, et al., 2005). After spray drying, the dispersions were dried at 40 C under vacuum until constant weight. Table 1 Optimization of MLX: PEG 8000 ratio. Batch code MLX: PEG 8000 (W/W) ratio S1 1:1 S2 1:5 S3 1:10 Preparation of Solid Dispersion by Melting Method MLX was added to the melted PEG 8000 at 75 C and the resulting homogeneous preparation was rapidly cooled in a freezing mixture of ice and sodium chloride, and stored in desiccators for 24 h. Subsequently, the dispersion was ground in a mortar and sieved through 100 # (Frances, et al., 1991). Preparation of Physical Mixtures (PMs) Physical mixtures (PMs) were prepared by thoroughly mixing appropriate amounts of MLX or MLX spray dried (MLXSD) and PEG 8000 in a mortar until a homogeneous mixture was obtained (Takeuchi, et al., 2005). The resulting mixtures were sieved through a 100 # sieve. Characterization of Solid Dispersion (a) Compressibility Index (CI) Compressibility is indirectly related to the relative flow rate, cohesiveness and particle size distribution of the powder (Martin A, 2001). Tapped (ρ2) and Apparent (ρ1) Bulk density measurements can be used to estimate the compressibility of a material. CI was calculated using following equation: Compressibility index (%) = (ρ2- ρ1)/ρ2 100 (1) (b) Scanning electron microscopy (SEM) (Carver, et al., 1971; Agbada, et al.,1994). Particles size, shape and surfaces were characterized by surface electron microscope (SEM - Philips XL30 ESEM TMP). (c) Drug - Excipients compatibility study The Drug - Excipients compatibility was evaluated by Differential Scanning Calorimetry (DSC) Analysis (Chauhan, B., et al., 2005). DSC study was performed for pure MLX, PEG 8000 and solid dispersion prepared by different methods. All samples were weighed (8-10 mg) and heated at a scanning rate of 20 C/min under dry air flow (100 ml/min) between 50 and 300 C. Aluminum pans and lids were used for all samples. (d) In-vitro dissolution profile Dissolution studies of above samples were performed using USP XXIII apparatus type 2. Samples equivalent to 15 mg of the drug were added to the dissolution medium (500 ml of phosphate buffer ph 7.4 at a temperature of 37 C ± 0.5 C), which was stirred with a rotating paddle at 50 rpm (Jung, J.Y., et al., 1999). At suitable time intervals, 10 ml samples were withdrawn, filtered (0.22 μm), diluted and analyzed at 363 nm using UV spectrophotometer. Experimental Design The Feed rate (X1) and Inlet temperature (X 2 ) were chosen as independent variables in a 3 2 full factorial design. A statistical model incorporating interactive and polynomial terms was used to evaluate the response. 2 Y = b 0 = b 1 X 1 + b 2 X 2 + b 12 X 1 X 2 + b 11 X 1 + b 22 2 X 2 (2) Where Y is the dependent variable and b 0 is the arithmetic mean response of the 9 runs and b 1 is the estimated coefficient for the factor X 1. The statistical

3 Patel R.P. et al. : Formulation and Process Optimization of Solid Dispersion of Meloxicam 649 analysis of the factorial design batches was performed by multiple linear regression analysis carried out in Microsoft Excel The Carr s index, Powder yield, and Particle size values were the responses. Results and Discussion The results of above evaluation revealed that MLX: PEG 8000 ratio 1:10 gives maximum drug release of 98.7% after 90 mins compare to 1:1 and 1:5 which gave 63.1% and 77.3% of drug release after 90 mins, respectively (Figure 1). Dissolution profiles of pure MLX and SDs prepared by different methods by taking MLX: PEG 8000 (W/W) ratio 1:10. Among the two PMs one was prepared using pure MLX (SD-PM1) and second with the spray dried MLX (SD-PM2), SD prepared by spray drying (SD-SD), and SD prepared by melting method (SD-M). Figure 2 clearly point out that the dissolution rate of pure MLX is very low as 31.59% after 90 mins. SDs of MLX prepared by spray drying significantly enhanced dissolution rate 98.82% in 90 min. PMs with spray dried MLX improve dissolution rate compared to PMs from pure MLX. SD prepared by melting method also gave better dissolution rate, 79.8 % MLX in 90 mins. DSC curves obtained for pure MLX, PEG-8000, and solid dispersion prepared by different methods are shown in Figure 3. Pure powdered MLX showed a melting endotherm at C. DSC scan of PEG showed single sharp endotherm at C due to melting of PEG. DSC thermograms of SD-SD, SD-PM1, SD-PM2, and SD-M showed the little melting peak of the drug at C and sharp endothermic peak at 66.4 C due to melting of PEG. Absence of MLX peak indicates that MLX is present as amorphous or as a solid solution inside the PEG matrix. Scanning Electron microscopy study of MLX (A), PEG (B), SD-SD(C), SD-M (D), SD-PM1 (E), SD-PM2 are shown in Figure 4. The photomicrograph of MLX is characterized by presence of crystalline structures. The spectra shown in these figure showed that degree of crystallinity is decreased by addition of polymers i.e., PEG SD-SD (C), showed absence of well defined crystalline structure of MLX (Paradkar, A., et al., 2004). In case of physical mixtures, SD-PM2 (H) shows less crystalline structures due to spray drying of MLX. Cumulative percent release of MLX Time (min) S1 S2 S3 Fig. 1 In vitro dissolution profile of S1, S2 and S3.

4 650 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 2 Issue 3 October - December 2009 Cumulative percent release of MLX Time(min) SD-SD SD-M SD-PM1 SD-PM2 MLX Fig. 2 In vitro dissolution profiles of pure MLX and its solid dispersions prepared by different methods. Fig. 3 DSC Spectra of MLX (A), PEG-8000 (B), SD-SD (C), SD-PM1 (D), SD-PM2 (E), SD-M (F).

5 Patel R.P. et al. : Formulation and Process Optimization of Solid Dispersion of Meloxicam 651 Fig. 4 Scanning electron microscopy of MLX (A), PEG8000 (B), SD-SD (C), SD-M (D), SD-PM1 (E), SD-PM2 (F). Broadhead et al. suggested that the increase in particle size might be an effect of increased agglomeration at the higher inlet drying air temperatures due to a higher feed rate (required to obtain a constant outlet drying air temperature if the inlet drying air temperature is increased). Lower feed rate, yielded smaller droplets which dried too fast to allow particle agglomeration. Broadhead showed that during spray drying of b-galactosidase the process yield was increased by increasing inlet drying air temperature. Although the effect of temperature on particle size is reported to be dependent on the material being dried. Similar observations have been made by Stahl et al. during spray drying of insulin. Similarly, spray drying of insulin for inhalation resulted in higher process yields at increasing inlet drying air temperature (Gonnissen, Y., et al., 2008). Carrs index is a measure for the flow properties of spray dried powder mixtures. Higher flowability is observed at high inlet air temperatures. The statistical analysis of the factorial design batches was performed by multiple linear regression analysis. The Carr s index, powder yield, and particle size values for the 9 batches are (B1 to B9) shown in Table 2. In case of dependent variable powder yield, particle size and Carr s index, X 1 and X 2 factors showed significant effect where, P < As the feed rate increases, the powder yield and Carr s index decrease. Lower feed rate, yielding smaller droplets which dried too fast to allow particle agglomeration, consequently by increasing feed rate one can increase the particle size. On the other hand, as the inlet temperature increases, powder yield and Carr s index increase. There is no significant effect of inlet temperature on the particle size. The optimized spray drying process had an inlet temperature of 50 C and feed rate of 6 ml/min.

6 652 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 2 Issue 3 October - December 2009 Batch Code Variables levels in coded form X 1 X 2 Table full factorial design layout. Powder yield (%) Median particle size (um) Carr s index (%) B B B B B B B B B Translation of coded levels in actual units Variables level Low (-1) Medium (0) High (+1) Feed rate (ml/min) X Inlet temperature ( o C) X (Air flow rate 400 Nl/h, Aspiration 50 mbar, Outlet temperature 40 o C, Atomization air pressure 2kg/cm 2 ). Conclusion This study clearly revealed that the preparation of solid dispersions of PEG8000 with meloxicam by spray drying, physical mixture, and melting method led to enhanced dissolution properties. The highest improvements in solubility and in-vitro drug release were observed in solid dispersion prepared with PEG-8000 by spray drying method. The dissolution rates of solid dispersion prepared by physical mixtures and melting method were higher than that of pure drug. Thermal analysis indicated that drug is present in an amorphous form at high concentration of PEG Spray drying at low feed rate would be more economical as it increases powder yield, at the same time flowability. At lower feed rate smaller droplets may be produced which dry too fast to allow particle agglomeration, as a result, by increasing feed rate one can increase the particle size. While the inlet temperature increased from 45 C to 55 C powder yield and flow property increased, there is no significant effect of inlet temperature on the particle size. Solid dispersion prepared by spray drying method are extremely important from a commercial point of view as it improves dissolution profile of poorly soluble drug like MLX. References Agbada, C.O., York, P. Dehydration of theophylline monohydrate powder- effects of particle size and sample weight. Int. J. Pharm. 1994, 106: Billon, A., Bataille, B., Cassana, G., Jacob, M. Development of spray-dried acetaminophen Microparticles using experimental designs. International Journal of Pharmaceutics. 2000, 203: Breall, H.D., Getz, J.J., Sloan K.B. The estimation of relative water solubility for pro drugs that is unstable in water. Int. J. Pharm. 1993, 93: Broadhead, J., Rouan, S.K.E., Hau, I., Rhodes, C.T. The effect of process and formulation variables on the properties of spray dried bgalactosidase, J. Pharm. Pharmacol. 1994, 46: Carver, L.D. Particle size analysis. Industrial Research. 1971, Chauhan, B., Shimpi, S., Paradkar, A. Preparation and evaluation of glibenclamide-polyglycolized glycerides solid dispersions with silicon dioxide by spray drying technique. European Journal of Pharmaceutical Sciences. 2005, 26: Chiou WL, Riegelman S. Pharmaceutical applications of solid dispersion systems. J Pharm Sci. 1971, 60: 1281Y1302. E.J. Crosby, W.R. Marshall, Effects of drying conditions on the properties of spray dried particles, Chem. Eng. Prog. 1958, 54: Gonnissen, Y., Goncalves, S.I.V., De Geest, B.G., Remon, J.P., Vervaet, C. Process design applied to optimize a directly compressible powder produced via a continuous manufacturing process. European Journal of Pharmaceutics and Biopharmaceutics. 2008, 68:

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