The aim of the present study was to improve solubility and dissolution of the poorly aqueous soluble drug, etoricoxib by solvent evaporation technique using various sugar carriers, such as lactose, sucrose, and mannitol. Etoricoxib solid dispersions and their respective physical mixtures using lactose, sucrose, and mannitol were prepared in different ratios by solvent evaporation technique. The percent yield, drug content, saturation solubility, and in vitro dissolution of etoricoxib solid dispersions and physical mixtures were analyzed. Etoricoxib solid dispersions were characterized by FTIR spectroscopy, XRD, and DSC analysis. The FTIR spectroscopic analysis revealed the possibility of intermolecular hydrogen bonding in various solid dispersions. The XRD and DSC studies indicated the transformation of crystalline etoricoxib (in pure drug) to amorphous etoricoxib (in solid dispersions) by the solid dispersion technology. Both the aqueous solubility and dissolution of etoricoxib were observed in all etoricoxib solid dispersions as compared with pure etoricoxib and their physical mixtures. The in vitro dissolution studies exhibited improved dissolution in case of solid dispersion using lactose than the solid dispersions using both sucrose and mannitol. The in vitro dissolution of etoricoxib from these solid dispersions followed Hixson-Crowell model.
Poorly aqueous soluble drugs are usually characterized by a low bioavailability due to less absorption, which is a major concern of pharmaceutical industries worldwide. Attempts to improve the solubility of these drug candidates have been performed by various approaches [
Etoricoxib, 5-chloro-6′-methyl-3 [4-(methyl sulfonyl) phenyl]-2, 3′–bypyridine, is a highly selective second generation cyclooxygenage-2 (COX-2) inhibitor administered orally as an analgesic and nonsteroidal anti-inflammatory drug (NSAID) (Figure
Chemical structure of etoricoxib.
Etoricoxib was obtained as a gift sample from Cadila Healthcare Ltd., Moraiya, India. Lactose, sucrose, mannitol, potassium dihydrogen phosphate, and sodium hydroxide were purchased from S.D. Fine Chemicals Ltd., Mumbai, India. Ethanol (Bengal Chemicals and Pharmaceuticals Ltd., Kolkata, India) was used. All reagents were of A.R. graded. Double distilled water was used throughout the experiment.
Physical mixtures of etoricoxib were prepared by mixing etoricoxib with lactose, sucrose, and mannitol in 1 : 1 and 1 : 5 ratios in a glass mortar by mixing for 10 minutes.
Solid dispersions of etoricoxib were prepared by solvent evaporation technique using various sugars like lactose, sucrose, and mannitol as carriers in 1 : 1 and 1 : 5 ratios. Etoricoxib was dissolved in ethanol to get clear solution. Lactose, sucrose, and mannitol were dispersed as fine particles and the solvent was removed by evaporation on a water bath at 60°C. The dried mass was stored in desiccator until constant mass was obtained, crushed, and passed through sieve no. 22.
The percent yield of etoricoxib solid dispersions was determined by using the following formula:
Solid dispersions of etoricoxib (25 mg) were placed in 25 mL volumetric flask. Ethanol (10 mL) was added, mixed thoroughly using a rotating shaker for 1 hour. The volume was made up to the mark with ethanol. The solution was suitably diluted with ethanol and spectrophotometrically assayed for drug content at 233.5 nm using the following formula:
To evaluate the increase in solubility of etoricoxib from solid dispersions, saturation solubility measurements were conducted and compared these data with that of pure etoricoxib and physical mixtures of respective ratios. The known excess samples (etoricoxib solid dispersions, physical mixtures, and pure etoricoxib) containing 10 mg equivalent weight of etoricoxib were added to 10 mL of phosphate buffer, pH = 7.4, and these samples were rotated at 20 rpm in a water bath (
Physicochemical characterization was performed using Fourier transform-infrared (FTIR) spectroscopy. For this purpose, samples were reduced to powder and analyzed as KBr pellets by using a FTIR spectrometer (Shimadzu Corporation, Japan).
XRD patterns were recorded on an X diffractometer (Phillip PW 1130/00 diffractometer, The Netherlands), employing CuK
The samples were analyzed by differential scanning calorimeter (Model DT-60, Shimadzu) at a constant scanning speed of 10°C min−1 from 0–300°C. The 5–7 mg samples were accurately weighed into solid aluminium pans without seals.
In vitro dissolution studies were performed in phosphate buffer (pH 7.4, 900 mL) at
Various etoricoxib solid dispersions using sugars like lactose, sucrose, and mannitol at different ratios (1 : 1 and 1 : 5) were prepared by solvent evaporation technique to increase the solubility and/or dissolution of poorly aqueous soluble drug, etoricoxib. The percent yield of various etoricoxib solid dispersions was within the range of
Percent yield and percent drug content of etoricoxib solid dispersions.
Solid dispersion type | Ratio | Percent yield (%)$ | Percent drug content (%)$ |
Etoricoxib : lactose | 1 : 1 | 88.13 ± 7.53 | 96.68 ± 1.99 |
1 : 5 | 91.18 ± 3.19 | 98.39 ± 2.42 | |
Etoricoxib : sucrose | 1 : 1 | 85.43 ± 2.43 | 97.94 ± 2.50 |
1 : 5 | 89.63 ± 3.62 | 98.60 ± 2.13 | |
Etoricoxib : mannitol | 1 : 1 | 83.09 ± 2.13 | 95.75 ± 2.91 |
1 : 5 | 86.51 ± 2.15 | 97.32 ± 0.85 |
$Mean ± SD,
The saturation solubility of pure etoricoxib, various newly prepared etoricoxib solid dispersions using sugars (lactose, sucrose, and mannitol), and their respective physical mixtures in phosphate buffer, pH 7.4 were measured. As etoricoxib has pH-dependent solubility [
Saturation solubility of different etoricoxib solid dispersions along with pure etoricoxib and physical mixtures using same carriers (Mean ± SD,
Type | Ratio | Saturation solubility ( | |
Physical mixtures | Solid dispersions | ||
1 : 1 | 91.65 ± 4.95 | 124.28 ± 1.93 | |
Etoricoxib : lactose | 1 : 5 | 98.27 ± 5.04 | 142.26 ± 2.01 |
1 : 1 | 84.91 ± 1.44 | 107.88 ± 2.87 | |
Etoricoxib : sucrose | 1 : 5 | 89.80 ± 4.12 | 120.42 ± 2.55 |
1 : 1 | 90.50 ± 5.20 | 118.82 ± 2.01 | |
Etoricoxib : mannitol | 1 : 5 | 95.76 ± 6.67 | 131.98 ± 3.48 |
Pure etoricoxib | — | Saturation solubility ( | |
78.48 ± 1.47 |
$Mean ± Standard deviation,
FTIR spectroscopy analysis was done to analyze physicochemical interactions between etoricoxib and sugar carriers in form of solid dispersions. FT-IR spectra of pure etoricoxib and various etoricoxib solid dispersions are shown in Figures
Fourier transform-infra red (FTIR) spectra of pure etoricoxib (a) and drug to carrier ratio, 1 : 5 etoricoxib solid dispersions using lactose (b), sucrose (c), and mannitol (d).
The XRD patterns of pure etoricoxib and various newly prepared etoricoxib solid dispersions using sugars are presented in Figures
XRD pattern of pure etoricoxib (a) and drug to carrier ratio, 1 : 5 etoricoxib solid dispersions using lactose (b), sucrose (c), and mannitol (d).
DSC analysis was done for pure etoricoxib and solid dispersions of etoricoxib using lactose, the sugar carrier which showed higher saturation solubility than other sugars examined in this investigation. DSC pattern of etoricoxib solid dispersion using lactose, pure etoricoxib along with that of lactose are shown in Figure
DSC thermogram of lactose (a), pure etoricoxib (b), and etoricoxib solid dispersions (c) using lactose (1 : 5).
The in vitro dissolution profiles of the drug (etoricoxib), various solid dispersions using sugars, and their respective physical mixtures in phosphate buffer (pH = 7.4) for 120 minutes are shown in Figures
(a) Comparative in vitro dissolution profiles of etoricoxib solid dispersions using lactose [SD-L (1 : 1), SD-L (1 : 5)], etoricoxib-lactose physical mixtures [PM-L (1 : 1), PM-L (1 : 5)], and pure etoricoxib [ET] (Mean ± SD,
In order to predict and correlate the mechanism and kinetics of etoricoxib release from etoricoxib solid dispersions using sugars, it is necessary to fit into a suitable mathematical model. The in vitro drug release data of these newly prepared solid dispersions were evaluated kinetically using various mathematical models like zero order, first order, Higuchi, Hixson-Crowell, and Korsmeyer-Peppas model [
Zero-order model:
First-order model:
Higuchi model:
Hixson-Crowell model:
Korsmeyer-Peppas model:
The results of the curve fitting into these above-mentioned mathematical models indicate the release behaviour of etoricoxib from these newly prepared solid dispersions (Table
Correlation coefficient (
Mathematical models | Formulation codes* | |||||
SD-L (1 : 1) | SD-L (1 : 5) | SD-S (1 : 1) | SD-S (1 : 5) | SD-M (1 : 1) | SD-M (1 : 5) | |
Zero-order model | 0.9462 | 0.9681 | 0.9276 | 0.9389 | 0.9276 | 0.9502 |
First-order model | 0.9846 | 0.9871 | 0.9599 | 0.9689 | 0.9718 | 0.9807 |
Higuchi model | 0.9892 | 0.9852 | 0.9756 | 0.9782 | 0.9714 | 0.9824 |
Hixson-Crowell model | 0.9943 | 0.9958 | 0.9886 | 0.9882 | 0.9837 | 0.9897 |
Korsmeyer-Peppas model | 0.9870 | 0.9807 | 0.9754 | 0.9718 | 0.9728 | 0.9739 |
SD-L (1 : 1), and SD-L (1 : 5): etoricoxib solid dispersions using lactose
SD-S (1 : 1), and SD-S (1 : 5): etoricoxib solid dispersions using sucrose
SD-M (1 : 1), and SD-M (1 : 5): etoricoxib solid dispersions using mannitol.
Hixson-Crowell’s dissolution plots of etoricoxib solid dispersions using sugars SD-L (1 : 1), and SD-L (1 : 5): etoricoxib solid dispersions using lactose; SD-S (1 : 1), and SD-S (1 : 5): etoricoxib solid dispersions using sucrose; SD-M (1 : 1), and SD-M (1 : 5): etoricoxib solid dispersions using mannitol.
Etoricoxib solid dispersions using various sugars like lactose, sucrose, and mannitol were successfully prepared by solvent evaporation technique. FTIR spectroscopy revealed the possibility of intermolecular hydrogen bonding in various solid dispersions. XRD and DSC observations indicated that the transformation of crystalline etoricoxib (in pure drug) to amorphous etoricoxib (in solid dispersions) by solid dispersion technology. The saturation solubility and in vitro dissolution studies showed a remarkable increase in both the solubility and dissolution of etoricoxib solid dispersions using sugars as compared with pure etoricoxib and their physical mixtures. The in vitro dissolution studies of all these newly prepared solid dispersions showed that the improved solubility and dissolution in case of solid dispersion using lactose than the solid dispersions using both sucrose and mannitol. The in vitro dissolution of etoricoxib from these solid dispersions was found to follow Hixson-Crowell model. Therefore, the solubility and dissolution of poorly aqueous soluble etoricoxib can be enhanced by the preparation of solid dispersions using sugars as hydrophilic carriers.
The authors are grateful to Cadila Healthcare Ltd., Moraiya, India for providing etoricoxib as a gift sample. They are also thankful to Dr. Subrata Mallick, Professor, SOA University, Bhubaneswar, Orissa for FTIR facility. The authors thank the Principal and Management of Seemanta Institute of Pharmaceutical Sciences, Jharpokharia, India for proving research facilities.