Comparative Study of Etoricoxib Loaded Solid Dispersion and Beta-cyclodextrin Complexes for improvement of Dissolution Profile
Jigar Vyas, Hemant Parmar, Himan Patel
Sigma Institute of Pharmacy, Ajwa-Nimeta Road, Vadodara, Gujarat, 390019, India.
*Corresponding Author E-mail: drjigarvyas@gmail.com
ABSTRACT:
Solid dispersions of Etoricoxib were prepared using polyethyleneglycols in different proportions by fusion and solvent evaporation method. Physical mixtures were also prepared in same proportions by simple kneading. Batch F6 containing drug: PEG4000 1:4, having greater saturation solubility, was selected and formulated in tablet (batch TF6) and evaluated for in-vitro drug dissolution and sixmonth stability. The results were compared with that of tablet containing physical mixture of drug: PEG4000 in the same ratio (batch TP6) and conventional tablet containing plain Etoricoxib (batch CT). Tablet TF6 has shown significant improvement of dissolution profile of Etoricoxib when compared with that of tablet TP6 and CT. Present study conclusively suggested that PEG4000 enhanced water solubility of Etoricoxib by amorphisation, which was confirmed by XRPD, FTIR, SEM and DSC. The study also demonstrated that solid dispersions can be successfully stabilized by non ionic surfactants.
KEYWORDS: Etoricoxib, solubility enhancement solid dispersion, polyethyleneglycols.
INTRODUCTION:
Etoricoxib, a non-steroidal anti-inflammatory drug (NSAID), is a potent and highly selective cyclooxygenase-2 (cox-2) inhibitor. The poor aqueous solubility of drug (201 mcg/ml) results in variable dissolution rate and hence poor bioavailability.(1) Consequently, numerous attempts have been made to modify the dissolution characteristics of this drug in an effort to attain more rapid and more complete absorption. Among the techniques to increase aqueous solubility/dissolution rate, the formulation of solid dispersions is one of the most popular techniques, although only few marketed products rely on this concept. The interest in amorphous drug–polymer solid dispersions has grown due to the potential of improving bioavailability, particularly for poorly water soluble.
This immense interest is due to the fact that rate of dissolution would be increased in hundreds to thousands fold, even for the most insoluble active pharmaceutical ingredients.(2) Solid dispersion represents a useful pharmaceutical technique for increasing the dissolution, absorption, and therapeutic efficacy of drugs in dosage forms.(3-4) The properties, performance, and practical applications of solid dispersions depend on factors such as the method of preparation, composition, selection of a suitable carrier, and physicochemical properties of the drug.(5-6) The dissolution of etoricoxib notably increases when prepared as complex with beta cyclodxtrin.(7)
In the present study, we prepared solid dispersions of Etoricoxib using hydrophilic carriers (PEGs) by two methods (fusion and solvent evaporation method) and using beta-cycloextrins by kneading techniques to enhance dissolution rate by improving its water solubility.
MATERIALS:
Etoricoxib was obtained as a gift sample from Zydus Pharmaceuticals Ltd. (Ahmedabad, India); PEG4000, PEG8000, PVP K30, talc, crosspovidone XL10, and flowlac-100 were purchased from S.D. Fine Chemicals Ltd. (Mumbai, India); β-CD and HP β-CD were purchased from CDH (Mumbai, India) hydrochloric acid, acetone and chloroform were purchased from Loba Chem (Ahmedabad, India). All the chemicals and reagents used were of AR grade and used without further purifications.
EXPERIMENTALS:
Methods:
Preparation of solid dispersions, physical mixtures and inclusion complexes:
In melting method, solid dispersions were prepared by melting the carriers in porcelain dish at around 10°C above the melting point of carriers on sand bath, dispersing the drug onto the molten carrier and cooling immediately on freezing mixture of ice and sodium chloride. In solvent evaporation method, solid dispersions were prepared by dissolving drug and carriers in a solvent mixture of acetone and chloroform (1:1) and evaporating the solvent at 40°C on a water bath with continuous stirring. Physical mixtures and inclusion complexes were prepared by kneading drug and carriers (PEGs and CDs) for 30 minutes and then grounding in mortar with pestle.
The resulting residues were dried under vacuum for 3 hours and stored in desiccators overnight. The dry mass was ground in a mortar, passed through sieve #40 (420 µm) and stored in desiccator until further use.
Characterization of solid dispersions, physical mixtures and inclusion complexes:
Saturation solubility of Etoricoxib was determined in mgmL-1 using UV-1700 (Shimadzu, Japan) measuring maximum absorption (λmax) at 222nm after filtration and necessary dilutions. Melting point was determined using precision melting point apparatus (Remi, India).
Phase solubility study - An excess of Etoricoxib was added to aqueous solutions of increasing concentrations (0-30 mM) of cyclodextrin in 25 ml stoppered conical flasks and stirred at room temperature (25-27ºC) on a magnetic stirrer.(8) Aliquots were withdrawn, filtered (0.45 μm Millipore) and measured at 222 nm for drug content. The apparent stability constant (Kc) of the drug-cyclodextrin complex was calculated according to equation.(9)
Kc = (slope/S0) × (1 - slope)
Where, Kc is the apparent stability constant (L mol-1), slope is obtained from the linear portion of the phase solubility diagram, and S0 is the aqueous solubility of Etoricoxib. Each experiment was carried out in triplicate (RSD < 3%).
FTIR spectra of moisture free powdered samples were obtained using a FTIR-8400S with IR solution software (Shimadzu, Japan) in potassium bromide. The scanning range was kept between 400 and 4000cm-1 and the resolution was kept constant at 1cm-1.
DSC scan of powdered samples were recorded using DSC- 822e (Mettler Toledo, Japan). All the samples were weighed (4-5mg) and heated for total time of 40 min at a scanning rate of 5°C min-1 under dry air (N2) flow (50 mL min-1) at pressure of 25 Pa between 50 and 250°C (furnace temperature). Aluminium pans and lids (40μL capacity) were used for the study.
X-ray powder diffraction (XRPD) patterns were recorded on Phillip PW 1130/00 diffractometer (X”Perts, Philips, the Natherlands), employing Ni filtered CuKα radiation source operating at 30 mA and 40 kV. Samples were scanned from 6 to 40° 2θ at a scanning rate of 0.02° 2θ s-1.
The surface of powdered drug, carrier and their binary system, was examined by means of scanning electron microscope (JSM-6400 Jeol, Japan). The samples were previously fixed on a brass stub using double-sided adhesive tape and were then made electrically conductive by coating with a thin layer of gold and palladium alloy (180-200 Å) using a fine coat ion sputter (JFC-1100 Jeol, Japan). The pictures were then taken at an excitation voltage of 20 kV with magnification in the range of 118 to 245X.
Preparation and evaluation of tablets containing Etoricoxib:
Tablets containing solid dispersions, physical mixture and pure drug, equivalent to 100mg of Etoricoxib, were prepared by direct compression method after mixing with required amount of different ingredients.
All the prepared tablets were subjected to content uniformity test and then evaluated for in-vitro dissolution.
In-vitro dissolution study of Etoricoxib was performed on 8 vessel USP XXVIII type II dissolution test apparatus (Electrolab, India) in 0.1N hydrochloric acid with constant temperature of 37 + 0.5°C and speed at 50 rpm. Aliquots were withdrawn at predetermined time intervals, filtered (0.45µm Whatman filter paper) and measured at 233nm after necessary dilutions. The cumulative percentage release of drug was recorded.(10)
RESULTS AND DISCUSSION:
Solid dispersions of Etoricoxib with PEG4000 and PEG8000 were prepared successfully by melting method and complex of Etoricoxib with beta-cyclodextrin and HP beta-cyclodextrin were prepared successfully by solvent evaporation method. All the prepared formulations were evaluated for saturation solubility and melting point (Table I).
Table I. Composition and evaluations of Etoricoxib loaded solid dispersions and complexes
|
Batch |
Drug: carrier |
PEG8000 |
PEG4000 |
||||
|
Batch |
SS (mg mL-1) |
MP (°C) |
Batch |
SS (mg mL-1) |
MP (°C) |
||
|
Fusion method |
1:1 |
F1 |
1.25 |
115 |
F4 |
2.28 |
124 |
|
1:2 |
F2 |
1.40 |
113 |
F5 |
2.51 |
122 |
|
|
1:4 |
F3 |
1.75 |
110 |
F6 |
3.15 |
119 |
|
|
Solvent evaporation method |
1:1 |
S1 |
1.13 |
123 |
S4 |
2.04 |
138 |
|
1:2 |
S2 |
1.25 |
120 |
S5 |
2.27 |
136 |
|
|
1:4 |
S3 |
1.57 |
118 |
S6 |
2.83 |
132 |
|
|
Physical mixtures |
1:1 |
P1 |
0.43 |
163 |
P4 |
0.54 |
165 |
|
1:2 |
P2 |
0.47 |
161 |
P5 |
0.61 |
164 |
|
|
1:4 |
P3 |
0.59 |
160 |
P6 |
0.76 |
162 |
|
|
Co-grinding Complex |
|
β-Cyclodextrin |
HP β-Cyclodextrin |
||||
|
1:1 |
C1 |
1.05 |
141 |
C4 |
1.60 |
133 |
|
|
1:2 |
C2 |
1.41 |
139 |
C5 |
2.10 |
129 |
|
|
1:4 |
C3 |
1.95 |
135 |
C6 |
2.85 |
126 |
|
SS=saturation solubility, melting point values are mid points of the melting temperature range and corrected to nearest integer, Values of saturation solubility and melting point (MP) are average of three determinations
It was observed in the present study that the solubility of Etoricoxib was increased with increased proportion of PEGs. This might be due to the improved wetting of surface of drug particles by hydrophilic carrier due to which the particle surface became hydrophilic. Higher solubility enhancement was observed with PEG4000 than PEG8000 which might be due to the similar melting behavior and crystalline properties of PEG4000 and Etoricoxib which led to perfect solution of drug into carrier.
Batch F6 (fusion method) and S6 in (solvent evaporation method) has shown highest improvement in solubility of Etoricoxib. However batch F6 was selected for further study because the saturation solubility of Etoricoxib was greater in batch F6 (3.15mg mL-1) as compared to S6 (2.83mg mL-1).
Batch F6 was characterized by FTIR (Fig. I), DSC (Fig. II), XRPD (Fig. III) and SEM (Fig. VI) to understand possible mechanism of solubility enhancement. Physical mixture batch P6 was also characterized and compared with batch F6 to understand the mechanism of solubility enhancement of Etoricoxib.
Fig. I. FTIR spectra of a) Etoricoxib, b) PEG 4000, c) SD batch F6 and d) PM batch P6
FTIR spectra (Fig. I) showing characteristic peaks of Etoricoxib at 3307 and 3167cm-1 for Aliphatic -NH stretching hydrogen bond; 3069 and 3027cm-1 for aromatic –CH stretching; 2976 and 2926cm-1 for aliphatic –CH stretching; 1685cm-1 for -C=O of amide and 1080cm-1 for -S=O groups. PEG 4000 showed characteristic peaks at 3436cm-1 for -OH stretching and at 2890cm-1 for -CH stretching of CH2 groups. In spectra of batch F6, peaks at 3307 and 3167cm-1 are absent, or rather split into 3337 and 2888cm-1 due to breaking of hydrogen bond between -NH and -CH stretching to form the bond between -NH group of Etoricoxib with -OH group of PEG 4000. Also the intensity of peak at 1686 cm-1 was decreased and a peak at 1080cm-1 in pure drug was shifted to 1060 cm-1 in solid dispersion indicating absence of free drug in solid dispersion.
Fig. II. DSC thermogram of a) Etoricoxib, b) PEG 4000, c) SD batch F6 and d) PM batch P6
DSC thermogram (Fig. II) of pure drug has shown very sharp melting endotherm at 167°C - 171°C and an exotherm at 174°C – 190°C due to its decomposition. DSC thermogram of PEG 4000 has given a sharp endotherm at 59°C – 62°C for melting. Solid dispersions batch F6 (drug: PEG 4000 1:4, melting method) has given a sharp endotherm at 59°C – 63°C that suggested that melting peak of Etoricoxib was absent and melting point of the formulation was near to that of PEG 4000. Hence the DSC study also suggested alteration in the state of Etoricoxib which supported the amorphisation of drug that led to increase in solubility.
Fig. III. X-ray powder diffraction spectra of a) Etoricoxib, b) PEG 4000, c) SD batch F6 and d) PM batch P6
It was observed in XRPD diffractogram (Fig. III) that Etoricoxib is crystalline in nature showing at least three intense peaks along with several small to intermediate peaks in diffractogram and PEG 4000 is semi-crystalline showing two intense peaks in diffractogram. Solid dispersions showed no intense peaks but only few peaks of lesser intensity when compared to pure drug and carrier. This study confirmed that Etoricoxib was converted in amorphous state in solid dispersion F6 which led to solubility enhancement. In diffractogram of physical mixture (batch P6), reduction of number of peaks as well as intensity of peaks was observed confirming only partial conversion of crystalline to amorphous form.
Fig. IV shows SEM images of the pure components, solid dispersion and physical mixture. PEG 4000 (Fig.IV5a) existed in a crystalline mixture of smooth-surfaced particles (100-300μm) with few smaller particles (20-40μm), while Etoricoxib (Fig. IVb) existed as small irregular particles (10-20μm). On the contrary, physical mixture batch P6 (Fig. IVc) consisted of more spherical particles of rather irregular surface. In the case of solid dispersion batch F6 (Fig. IVd), the particles had a surface morphology similar to that of pure PEG 4000 which demonstrates the homogeneity of solid dispersion. The novel arrangements between particles of Etoricoxib and PEG 4000 might be responsible for the enhanced solubility of Etoricoxib in solid dispersion.
Batch F6 was formulated as tablet and extensively evaluated for in-vitro dissolution and stability study. Tablet containing batch P6 was prepared to understand the effect of simple mixing and tablet containing pure drug was prepared to understand magnitude of improvement in dissolution rate.
Table II. Composition of tablet containing pure drug, solid dispersion and physical mixture
|
Tablet ingredients |
Batch TF6 |
Batch TP6 |
Batch CT |
|
Drug (100 mg) + carrier (400 mg) |
500 |
500 |
100 |
|
PVP K30 |
37.5 |
37.5 |
37.5 |
|
FlowLac-100 |
150 |
150 |
150 |
|
Cross povidone XL10 |
37.5 |
37.5 |
37.5 |
|
Talc |
25 |
25 |
25 |
|
Total |
750 |
750 |
350 |
|
Content uniformity |
98.55 |
99.61 |
97.95 |
Batch TF6, TP6 and CT are coded for tablet of batch F6, batch P6 and conventional tablet respectively.
All the three tablet batches were characterised for in-vitro drug dissolution and six months stability (Table III). The solid dispersion F6 and physical mixture P6 were also studied for six months stability by taking melting point and saturation solubility as evaluation parameters (Table III).
Fig. IV. Scanning electron microscopy images of a) PEG 4000, b) Etoricoxib, c) PM batch P6 and d) SD batch F6
Table III. Stability data for six months
|
Batches |
Melting point (°C) |
Saturation solubility (mg mL-1) |
Cumulative percentage drug release after 1 hour |
|||
|
0m |
6m |
0m |
6m |
0m |
6m |
|
|
F6/TF6a, b |
119 |
135 |
2.58 |
1.86 |
92.79 |
67.04 |
|
P6/TP6 a, b |
162 |
168 |
0.62 |
0.60 |
57.93 |
51.24 |
|
drug/CT a, b |
178 |
179 |
0.067 |
0.066 |
46.34 |
45.55 |
|
Study on stabilised Formulationsc |
||||||
|
SF6/TSF6 |
118 |
124 |
2.60 |
2.36 |
95.29 |
84.46 |
|
SP6/TSP6 |
161 |
165 |
0.63 |
0.64 |
56.76 |
55.82 |
n=3, values sown above are average of three determinations
a melting point and saturation solubility data is that of batch F6, P6& pure drug
b Cumulative percentage drug release after 1hour data is of batch TF6, TP6 and CT.
c Batch F6 and P6 were prepared again with 1 % Tween80 as stabilizer and subjected to similar study.
It was observed that, melting point of solid dispersion (batch F6) was increased by 9.2% as compared to 1.2% and 0.6% in physical mixture (batch P6) and conventional tablet (batch CT) respectively, suggested stability problem in solid dispersion. Saturation solubility was decreased by 27.9% in batch F6 as compared to 3.2% and 3.0% in batch P6 and batch CT respectively. Similarly cumulative percent drug release was decreased by 27.8% in batch F6 as compared to 11.7 % and 6.0% in batch P6 and batch CT respectively. This data strongly suggested poor stability of solid dispersion or the amorphous form. Hence stabilization of solid dispersion was needed to make this formulation strategy successful.
CONCLUSIONS:
Solid dispersions of Etoricoxib prepared with different polyethyleneglycols (PEG 4000 and PEG 8000) by melting and solvent evaporation method resulted in increased saturation solubility of Etoricoxib. As demonstrated by characterization of solid dispersion by FTIR, DSC, XRPD and SEM study, a decreased crystallinity of Etoricoxib as well as modification in surface morphology of Etoricoxib due to coating of hydrophilic carrier (PEG) can explain the enhanced solubility and improved dissolution rate. This study conclusively demonstrated that solid dispersion can be utilized successfully to improve dissolution profile of poorly water soluble drug after stabilizing the solid dispersions with suitable method.
ACKNOWLEDGEMENTS:
The authors acknowledge from Zydus Pharmaceuticals Ltd. (Ahmedabad, India) for providing Etoricoxib as a gift sample.
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Received on 19.03.2020 Modified on 06.04.2020
Accepted on 20.04.2020 ©AandV Publications All right reserved
Res. J. Pharma. Dosage Forms and Tech.2020; 12(2): 63-67.
DOI: 10.5958/0975-4377.2020.00011.7