Preparation and Characterization of Meloxicam–Myrj-52 Granules Obtained by Melt Granulation

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Pharmaceutical Technology, Pharmaceutical Technology-12-02-2007, Volume 31, Issue 12

Various manufacturing techniques can improve a drug's solubility, thus increasing its bioavailability. The authors examined whether melt granulation can enhance drug solubility using meloxicam as the drug substance and myrj-52 as the binder.

The rate and extent of dissolution of the active ingredient in any dosage form is often considered the rate and extent of absorption of the drug (1). In cases such as poorly water soluble drugs, dissolution may be the rate-limiting step in the absorption process. Drugs with poor aqueous solubility such as piroxicam absorb slowly compared with drugs with higher solubility (2). One can develop formulations to increase a drug's water solubility.


Interest in melt granulation has increased because of the technique's advantage over traditional wet granulation. The melt-granulation process uses a substance that melts at relatively low temperatures (i.e., 50–80 °C). This substance can be added to the molten form over the substrate or to a solid form, which is then heated above its melting point by hot air or by a heating jacket. In both cases, the substance acts like a liquid binder after it melts. Thus, melt granulation does not require organic or aqueous solvents (3). The main advantage of not using organic solvents is the absence of any risk originating from residual solvents. Moreover, the drying step is not necessary in melt granulation, thus the process is less time-consuming and more energy-efficient than wet granulation.

After selecting a suitable binder, one can use melt granulation to prepare controlled-release or improved-release granules. Many hydrophobic excipients have been used to prepare controlled-release granules. Polyethylene glycol is used to improve dissolution because it is hydrophilic in nature (4–7).

Polyoxyl stearates may be considered as potentially useful hydrophilic binders in melt granulation (8). Polyoxyl stearates are a series of polyethoxylated derivatives of stearic acid. They are nonionic, hydrophilic surfactants produced by the polyethoxylation of stearic acid. Polyoxyl-40 stearate is waxy and solid and has a faint odor of fat. Its color ranges from off-white to light tan. It has a particularly low melting point (38 °C) and is mainly used as an emulsifying agent, solubilizing agent, and wetting agent.

Meloxicam [4-hydroxy-2 methyl-N-(5-methyl-2-thiazolyl)-2H-1, 2-benzothiazine-3-carboxamide 1, 1-dioxide] is a nonsteroidal anti-inflammatory drug used to treat rheumatoid arthritis, osteoarthritis, and other joint pains. It is a preferred COX-2 inhibitor with superior gastrointestinal tolerability (9). Meloxicam has poor dissolution in aqueous fluids, especially in acidic mediums. Many studies have been performed to improve meloxicam's dissolution and bioavailability (10–12).

The goal of this investigation was to improve the dissolution rate of meloxicam through melt granulation using water-soluble myrj-52 as a meltable binder. The authors investigated the in vitro release of the drug from granules and studied their morphology using scanning electron microscopy (SEM). The authors also investigated possible interaction between the components using infrared (IR) spectroscopy, differential scanning calorimetry (DSC), and powder X-ray diffractometry (PXRD).


Lupin Research Park (Pune, India) provided a gift sample of meloxicam, Glenmark Pharmaceuticals (Nashik, India) supplied myrj-52, and Signet Chemical (Mumbai, India) provided StarLac. Other ingredients were obtained from Merck (Mumbai). All chemicals used were of analytical grade.


Preparation of the granules. The granules were prepared in the laboratory by adding molten myrj-52 to the physical mixture of the drug and filler. The batch size was 500 g. The granulation process and the formulation were optimized on the basis of preliminary trials. The final formulation contained 10% meloxicam, 25% myrj-52, and 65% StarLac (w/w). The drug and diluent were mixed in the mortar for 15 min. The mixture was then heated to 50 °C on a hot plate. Next, molten myrj-52 was added to prepare the granules. The granulation time was 5 min. At the end of the granulation process, granules were cooled at room temperature by spreading them out on trays, collected, and passed through a #40 sieve.

Preparation of the physical mixture. The physical mixture was prepared by mixing meloxicam, myrj-52, and StarLac with a pestle and mortar for 15 min.

Preparation of the solid dispersion. The solid dispersion was prepared by fusion. First myrj-52 was melted and the mixture of drug and StarLac was added. The mixture was stirred for 5 min at 60 °C and cooled on aluminum foil at room temperature. Next, the solid sample was pulverized in the mortar, sieved, and stored in the dessicator at 25 °C.

Evaluation of melt granules, physical mixture, and solid dispersion

Drug content. The percentage of drug content in the granules and solid dispersion was measured by dissolving the amount of granules or solid dispersion equivalent to 15 mg of meloxicam in 100 mL of ethanol. The drug content in the solution was measured spectrophotometrically (UV-1700 UV–vis spectrophotometer, Shimadzu, Kyoto, Japan) at 363.5 nm.

Solubility studies. Excess amounts of pure meloxicam were added to 30 mL of 0–10% concentrations of myrj-52 solution, sonicated, and agitated for 24 h. The suspension was filtered (0.45-μm filter, Millipore, Billerica, MA), diluted with the same concentration of myrj-52 solution, and analyzed spectrophotometrically at 363.5 nm. The average of three experiments was taken.

Fourier transform infrared spectroscopy. Fourier transform infrared (FTIR) spectra of samples were obtained, after appropriate background subtraction, using an FTIR spectrometer (8400 S, Shimadzu, Kyoto, Japan) equipped with a deuterated triglycine sulfate detector, a diffuse-reflectance accessory, and a data station. About 1–2 mg of the sample was mixed with dry potassium bromide. The sample was then scanned at the 400- and 4000-cm–1 wavelength ranges.

Differential scanning calorimetry. A differential scanning calorimeter (DSC 30, Mettler Toledo, Columbus, OH) was used to obtain the DSC curves representing the rates of heat uptake. About 3 mg of sample was weighed in a standard open aluminum pan. An empty pan of the same type was used as the reference. Samples were heated from 30 to 300 °C at a heating rate of 20 °C/min while being purged with dry nitrogen. Calibrations of temperature and heat flow were performed with indium.

Powder X-ray diffractometry. The solid dispersion, melt granulation, and physical mixture of meloxicam compared with the plain meloxicam were analyzed using a powder diffractometer (PW 1830, Phillips, Eindhoven, the Netherlands). Samples were exposed to CuKα radiation to measure the 2θ at 4–50° with a diffractometer reproducibility of ±0.001. A rate meter with a time constant of 2 × 102 pulses/s and a scanning speed of 2° (2θ)/min recorded the PXRD patterns automatically.

Scanning electron microscopy. The samples were sputter-coated with gold to render them electrically conductive. The samples' morphology was examined using SEM (JEOL-840 SEM, JEOL, Tokyo, Japan).

Granule-size analysis. The size distribution of granules was evaluated by sieve analysis with a vibrating shaker (Labhosp, Mumbai) and #5 sieve in the 75–1400 μm range. The fractions were collected, stored in a dessicator at 25 ± 2 °C, and used for the dissolution.

In vitro dissolution studies. The dissolution of meloxicam alone, from the melt granulation, from the physical mixture (PM), and from the solid dispersion (SD) were determined using a US Pharmacopeia (USP) Type II dissolution apparatus (Veego Scientific, Mumbai). The dissolution medium consisted of phosphate buffer (pH 7.4) maintained at 37 ± 0.5 °C.

Samples equivalent to 15 mg of meloxicam were added to 900 mL of dissolution medium in a 1000-mL cylindrical beaker. The paddle speed was 100 rpm. At intervals of 5, 10, and 15 min, 10-mL samples were withdrawn during a period of 90 min. The same volume of preheated dissolution medium was infused into the medium after each sample was taken, to maintain a constant volume of the dissolution medium throughout the test. The samples were filtered using filter paper (41, Whatmann International, Maidstone, UK), and the meloxicam content was determined spectrophotometrically at λmax 363.5 nm using a Shimadzu UV-1700 spectrophotometer (Shimadzu). Data were analyzed with PCP-Disso software (Poona College of Pharmacy, Pune, India).

Permeation study. Female hairless mice (8–10 weeks old) were killed by cervical dislocation, and their full-thickness skins removed. The adhering fat and visceral tissue were removed. To remove extraneous debris and leachable enzymes, the dermal side of the skin was put in contact with a saline solution for 2 h. The dermal side was then treated with 1-mL phosphate buffer for 6 h to equilibrate the membrane before starting the diffusion experiment. The skin was stretched over the end of an open-ended glass tube. The tube was immersed in a 400-mL beaker containing 100-mL phosphate buffer (pH 7.4) and kept in a vertical position so that the membrane was below the surface of the buffer solution. The surface area available in diffusion was 2.5 cm2. The tube (donor) and beaker (receptor) were maintained at 37 °C and shaken in a thermostatically controlled shaker. A 3-mL aliquot of saturated buffer solutions (pH 7.4) of meloxicam as a pure drug and melt granules prepared with myrj-52 were inserted one by one into the tube. For 6 h, 5-mL samples were removed from the receptor at intervals and analyzed spectrophotometrically at 363.5 nm. The experiment was repeated three times, and the average of the readings was calculated.

Stability studies. For stability studies, about 200 mg each of pure drug, melt granulation, solid dispersion, and physical mixture were weighed into glass vials. The samples were monitored for three months at 30 °C and 60% relative humidity (RH). Samples were removed periodically and characterized by dissolution-rate measurement and the presence of crystallinity.

Preparation and characterization of tablets. Melt granules equivalent to 15 mg of meloxicam with 5% Ac-Di-Sol (FMC BioPolymer, Philadelphia, PA) were geometrically mixed and lubricated with 1% w/w magnesium stearate, which was manufactured according to Indian Pharmacopoeia standards. Formulations were passed through a #30 mesh sieve and directly compressed with a 12-station tablet machine (Minipress II MT, Karnawati Rimek, Ahmedabad, India) with an 8-mm punch diameter and circular punches with flat faces. The machine setting was adjusted to produce 160-mg tablets with a hardness of 3.5 6 0.25 kg/cm2 .

The tablets' friability (n = 10) was determined with a friabilator (Roche, Veego Scientific, Mumbai, India). A hardness tester (Monsanto, LabHosp, Mumbai, India) determined the hardness of tablet samples (n = 10). The disintegration of tablets (n = 6) was determined using a disintegration-test apparatus (Veego Scientific) in distilled water at 37 ± 0.5 °C (see Table I).

Table I: Studies of various tablet parameters.


Tablet-dissolution studies were performed in triplicate. Dissolution was achieved in a 900-mL phosphate butter (pH 7.4) using a USP 24 Type II dissolution apparatus (Veego Scientific). The dissolution medium was stirred at 100 rpm and maintained at 37 ± 0.5 °C. Drug release was determined using an ultraviolet spectrophotometer (UV-1700, Shimadzu) at 363.5 nm. For comparison, a commercial tablet (Metflam, Unichem Laboratories, Mumbai, India) was also studied. Data obtained from the dissolution studies were analyzed using PCP Disso software (PCP, Pune, India).

Results and discussion

Drug-content estimation. The granules and solid dispersion showed less variation in percentage drug content. The percentage drug content was between 96.82 ± 0.75% and 101.39 ± 1.18%. These values indicate a uniform distribution of drug in the granules and solid dispersion obtained using myrj-52.

Saturation solubility. All of the test samples showed an increase in drug solubility (see Figure 1). The physical mixture, solid dispersion, and granules prepared by melt granulation showed higher saturation solubility compared with pure meloxicam. This result might arise from an improvement in the wetting of drug particles and localized solubilization by myrj-52.

Figure 1: Saturation solubility of melt granulation (MG), physical mixture (PM), and solid dispersion (SD) of meloxicam with myrj-52 in an aqueous solution at room temperature.

An increase in a drug's saturation solubility can explain the improved dissolution of melt granulation, physical mixture, and solid dispersions, according to the Noyes–Whitney equation, because the saturation solubility of a compound depends on particle size. Thus, one can improve meloxicam's saturation solubility by reducing its particle size through various approaches. The saturation solubility of pure meloxicam was 23 μg/mL. Melt granulation, physical mixture, and solid dispersion exhibited improved solubility.

The saturation solubility of solid dispersion prepared with myrj-52 increased to 1.2 mg/mL. Solubility is increased almost 52.17 times with myrj-52.

Solubilization effect of myrj-52. The results from the current study showed that myrj-52 has a significant solubilizing effect on meloxicam. Figure 2 shows the phase-solubility curve of meloxicam in the presence of myrj-52. Meloxicam's solubility increased when the concentration of myrj-52 in the water increased. The solubility enhancement may result from the improved dissolution of meloxicam particles in the water by myrj-52.

Figure 2: Solubility of meloxicam in an aqueous solution of myrj-52.

The process of the transfer of meloxicam from the pure water to the aqueous solution of myrj-52 was obtained using the values of Gibb's free-energy change. The Gibb's free energy of transfer (Gtr) of meloxicam from the pure water to aqueous solution of myrj-52 was calculated using the following equation:

in which So/Ss is the ratio of molar solubility of meloxicam in aqueous solutions of myrj-52 to that of pure water, R is the gas constant, and T is the temperature in Kelvin. Table II presents the obtained values of Gibb's free energy.

Table II: Thermodynamic parameters of the solubility process of meloxicam in myrj-52 and aqueous solution at 25 °C.

The data provide information regarding the increased solubility of meloxicam in the presence of myrj-52. The Gibb's free-energy values show whether the reaction conditions are favorable or unfavorable for drug solubilization in the aqueous carrier solutions. Negative Gibb's free energy indicates favorable conditions. Gtr values were negative for myrj-52 at various concentrations, indicating the spontaneous nature of meloxicam solubilization. The values decreased as myrj-52 concentration increased, demonstrating that the reaction become more favorable as the concentration of myrj-52 increased.

Infrared. IR studies were performed to determine the interaction and structural changes of drug and excipients. The IR spectrum of pure meloxicam showed characteristic peaks at 1620 cm–1 (amide carbonyl), 3290 cm–1 (–N–H stretching of secondary amine), and prominent bands such as 848–570 cm–1 (–CH aromatic ring bending and heteroaromatic), 1043 cm–1 (S=O stretching), and 1456 cm–1 (C=C stretching), as shown in Figure 3. The IR spectrum of myrj-52 showed characteristics peaks at 3600 cm–1 (–OH stretching), 1737 cm–1 (–C=O of ester), and 2893 cm–1 (–C–H stretching).

Figure 3: Fourier transform infrared spectra of pure meloxicam, myrj-52, StarLac, melt granulation (MG) of meloxicam in myrj-52, physical mixture (PM) of meloxicam in myrj-52, and solid dispersion (SD) of meloxicam in myrj-52.

Characteristic peaks of the drug were also present in the IR spectra of PM, melt granules (MG), and SD with broadening and reducing intensity. Yet the peak at 3290 cm–1 was significantly suppressed for PM, SD, and MG, compared with pure meloxicam. This result indicates hydrogen bonding between meloxicam and the excipients.

Differential scanning calorimetry. The thermal properties of the drug, myrj-52, PM, SD, and granules prepared by melt granulation were studied using DSC (see Figure 4). Meloxicam shows a sharp melting endothem at 258.1 °C. The exothermic peak after the melting peak may be part of the decomposition peaks also observed by Cantera et al. in tenoxicam (13). Thin-layer chromatography of meloxicam melted at 265 °C on an oil bath showed two different bands, which indicate the decomposition of the drug in melt form. The color of drug after melting at 265 °C also changed from yellow to reddish brown. Slow, controlled heating of the drug in DSC did not yield two separate peaks for melting and decomposition. DSC of pure myrj-52 showed an endothermic peak at 51 °C. The thermogram of pure StarLac showed endothermic peaks at 150 and 215 °C for starch and lactose, respectively. The thermogram of physical mixture with myrj-52 showed endothermic peaks at 49.9, 103.9, 216, and 231 °C, corresponding to myrj-52, starch, lactose, and meloxicam, respectively. Normalized enthalpics of PM, SD, and MG samples were lower (i.e., 63.8, 77.0, and 61.2 J/g, respectively) compared with pure meloxicam (338.1 J/g).

Figure 4: Differential scanning calorimetry curves of pure meloxicam, myrj-52, StarLac, melt granulation (MG) of meloxicam in myrj-52, physical mixture (PM) of meloxicam in myrj-52, and solid dispersion (SD) of meloxicam in myrj-52.

The shift and breadth of the endothermic peak probably results from the partial reduction in crystallinity, which may be confirmed in PXRD studies.

Powder X-ray diffractometry. The authors performed PXRD analysis to confirm the crystalline nature of meloxicam in the granules. The numerous sharp and intense peaks in the diffractrogram of untreated meloxicam shows that the drug is crystalline.

PXRD of meloxicam showed characteristic peaks at 13°, 14.5°, 18.5°, and 26°. Peaks at 26° were used to compare the PXRD pattern of the drug with those of PM, MG, and SD (see Figure 5). A significant reduction in peak intensities was observed in the PXRD patterns of PM, MG, and SD compared with that of the pure drug. The PXRD pattern of myrj-52 showed two typical peaks in the region of 19.5° and 24°. The PXRD patterns of PM, MG, and SD showed all of meloxicam's peaks except for the peak at 26°. The disappearance of the peak at 26° in the patterns of PM, SD, and MG might result from an attenuation of the signal in the presence of excipients or preferential orientation.

Figure 5: X-ray diffraction pattern of pure meloxicam, myrj-52, StarLac, melt granulation (MG) of meloxicam in myrj-52, physical mixture (PM) of meloxicam in myrj-52, and solid dispersion (SD) of meloxicam in myrj-52.

The traces of PM, MG, and SD are similar to each other. The characteristic peaks of the drug are always present, indicating that meloxicam is crystalline in PM, MG, and SD samples. Therefore, X-ray data confirm that the enhanced dissolution rate of the drug does not result from the transformation of the crystalline form into the amorphous state.

Scanning electron microscopy. Figure 6 shows SEM images of pure meloxicam and the melt granulation with myrj-52. Both photographs of melt granules clearly show granules with rough surfaces.

Figure 6: Scanning electron microscope images of (a) pure meloxicam at 2×, (b) melt granules of myrj-52 at 4×, and (c) melt granules of myrj-52 at 20×.

Production and characterization of granules. Several publications show that process variables such as mixing time, temperature, and amount of binder greatly affect the characteristics of the granules obtained by melt granulation (4, 5). Therefore, the authors performed preliminary tests to select the binder concentration and the process parameters using a placebo formulation containing only StarLac and myrj-52. When good conditions were achieved, 10% (w/w) of StarLac was replaced with meloxicam. Drug-loaded granules were obtained using the parameters described in the "Methods" section above. Figure 7 shows the granules' size distribution. The amount of fine powder (< 75 μm) and the amount of big lumps (size > 1400 μm) are less than 1% and 5 %, respectively. This finding confirms that the parameters were correct. The main fraction was 200–500 μm, and more than 70% of the granules had a size in the range of 200–750 μm.

Figure 7: Size distribution of meloxicam granules obtained by melt granulation using myrj-52 as a meltable binder.

Table III shows the meloxicam content in each granule fraction. The larger the granule size was, the higher the drug loading was. In many cases, the drug content is slightly higher (10%) than the theoretical drug content. One explanation could be that the material lost during granulation was mainly the binder, which was present in the molten form after heating the mixture and could partially stick to the vessel.

Table III: Content of meloxicam in each granule fraction using myrj-52 as a meltable binder.

In vitro dissolution studies. To assess whether the authors had improved the dissolution rate of melt granules containing meloxicam, in vitro dissolution profiles of MG, PM, and SD were compared with those of the pure drug (see Figure 8).

Figure 8: Dissolution profiles of pure meloxicam, melt granulation (MG), physical mixture (PM), and solid dispersion (SD) of meloxicam in myrj-52.

Pure meloxicam has a low dissolution profile. The percentage of drug dissolved in 50 min is 38.5%. Formation of PM improves this value. On the other hand, the profiles of MG and SD show a great increase in drug dissolution compared with the profiles of pure meloxicam. Reults showed that 80.2% and 90.40% of drug dissolved during the first 15 min in MG and SD prepared with myrj-52, respectively.

The dissolution enhancement can be attributed to the solubilization effect of myrj-52 and improved wettability and dispersibility of the drug from MG as well as SD (14).

The sample mixture of the components also improves the release of meloxicam, thus suggesting that melt granulation using myrj-52 could be a useful method to improve the dissolution rate of meloxicam.

Figure 9: Dissolution profile of melt granules (MG) prepared with myrj-52 after storage at 30 °C and 60% relative humidity for 3 months.

Stability studies. To evaluate the stability of the granules, in vitro dissolution tests and X-ray analysis were performed on the samples after three months at 30 °C and 60% RH (see Figure 9). The dissolution profiles of the melt granules stored for three months were similar to those of freshly prepared ones. In addition, the authors found no difference in the X-ray graph. These results suggest the physical stability of the samples, at least for the examined time.

Figure 10: Permeation profile of meloxicam through hairless mouse skin from saturated solution of pure meloxicam and melt granules (MG) in myrj-52.

Permeation study. Figure 10 shows the total amount of drug permeated (μg/cm2 ) through the hairless mice skin during 360 min. The permeation profiles for individual data were linear, and R ranged from 0.970 to 0.999. The results indicated that the hairless mouse skin was permeable to meloxicam and that the percutaneous absorption might be described by zero-order kinetics during the time of the study. The permeation rate of the drug from its saturated solution, in phosphate buffer (pH 7.4), across the membrane was calculated from the slope of the graph as μ–2 h–1 (see Table IV).

Table IV: Permeation rate and permeation coefficient of meloxicam through hairless mouse skin.

The higher permeation rate could be attributed to the increased solubility of meloxicam. Thus, the increased drug availability at the surface of the mice skin formed a concentration gradient.

Characterization of tablets. Tests for parameters such as hardness, friability, uniformity of content, disintegration time, weight variation, and dissolution were carried out for marketed tablets and tablets containing myrj-52 granules. Tablets containing myrj-52 granules exhibited better release than preparations available on the market (see Figure 11).

Figure 11: Dissolution profile of tablets containing meloxicam: MCAM (Unichem Laboratories, Mumbai, India) marketed 15 mg, tablet containing myrj-52 granules.


This study suggests that myrj-52 can be used as a binder in melt granulation. Solid dispersion achieves greater solubility enhancement, but because of its complex preparation method and cost ineffectiveness at the industrial level, melt granulation would be an easier and faster method to improve meloxicam's dissolution rate. The granules show an increased dissolution rate of meloxicam compared with those of pure drug and physical mixture. Characterization of the samples by differential scanning calorimetry and powder X-ray diffraction indicates that this effect could be correlated to the improved wettability and dispersibility of drug granules, which results from the solubilizing effects of the binder.


The authors would like to thank Glenmark Pharmaceuticals, Signet Chemicals, and Merck Ltd. for providing drugs and excipients.

Pramodkumar Sharma is a professor and department head at the Institute of Pharmacy, Bundelkhand University Jhansi, U.P., India. Praveen Chaudhari* is an assistant professor, and Hiren Bhagat is a student at the Padm. Dr. D.Y. Patil Institute of Pharmaceutical Sciences and Research, Pune University, India, tel. +91 9850179873, fax +91 22 27421097, pdchaudhari_21@yahoo.comNishant Varia is a trainee research associate at Sun Pharmaceuticals Industries, Vadodara, India.

*To whom all correspondence should be addressed.

Submitted: Apr. 17, 2007. Accepted: May 29, 2007.


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