Preparation, physicochemical characterization and ...

Asian Journal of Pharmaceutical Sciences 2012, 7 (4): 280-289

Preparation, physicochemical characterization and dissolution studies of etoricoxib-β-cyclodextrin complexes Sanchita Sharmin Chowdhurya, *, Md. Jahangir Alama, Md. Selim Rezab, Md. Manzur Rahman Farazic, Md. Habibur Rahmanb, Syed Shabbir Haiderb a

Department of Pharmacy, Jahangirnagar University, Savar, Dhaka 1342, Bangladesh Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Dhaka, Dhaka 1000, Bangladesh c Department of Statistics, Jahangirnagar University, Savar, Dhaka 1342, Bangladesh

b

Received 25 May 2011; Revised 12 July 2012; Accepted 28 November 2012

_____________________________________________________________________________________________________________

Abstract The aim of this work was to evaluate the role of β-cyclodextrin (β-CD), a cyclic oligosaccharide, in solubility and dissolution enhancement of poorly water-soluble etoricoxib (ETC), a specific cyclooxygenage II inhibitor by inclusion complex formation. The ETC-β-CD inclusion complexes were prepared by freeze drying (FD) and co-precipitation (CP) methods in 1:1 molar ratio while a physical mixture (PM) of same molar ratio was obtained by simple blending for comparison. To assess the feasibility of inclusion complex formation, the ETC-β-CD binding or association constant (Kc) was determined using the principle of Higuchi and Connors phase solubility method. Physicochemical characterization of the complexes was done by means of fourier transform infrared spectroscopy (FTIR), simultaneous differential thermal analysis-thermogravimetry-differential thermogravimetry (DTA/TG/DTG), powder X-ray diffractometry (PXRD) and scanning electron microscopy (SEM). Dissolution profiles of the complexes were studied in distilled water and pH 6.8 phosphate buffer medium. Kc value was 489.59 1/mol and it indicates suitability of ETC-β-CD complex formation in 1:1 molar ratio to enhance aqueous solubility of the drug. The characterization studies confirmed the formation of complexes of etoricoxib within the non-polar cavity of β-CD. Dissolution percentage (DP) and dissolution efficiency (DE) of the complexes increased greatly as compared to pure etoricoxib powder and the physical mixture. FD complex was superior in term of dissolution than CP. Poorly soluble etoricoxib can reveal better solubility and dissolution performance through complexation with β-CD by the specified methods. Keywords: Etoricoxib; β-cyclodextrin; Inclusion complex; Phase solubility study; Dissolution enhancement ____________________________________________________________________________________________________________

a promising one [5]. Cyclodextrins (CDs), some cyclic (α-1,4-linked) oligosaccharides of α-D-glucopyranose, possess interesting structural features of possessing hydrophobic central cavity and hydrophilic outer surface. Being less toxic and able to produce stable inclusion complexes, CDs have attracted formulators for being used as such complexing agents [6,7]. The present study was designed with the aim of preparation and characterization of ETC-β-CD complexes as well as to evaluate the complexes in terms of inclusion efficiency, solubility and dissolution. Among the three parent cyclodextrins (α-, β- and γ-CD) and their derivatives, β-CD (Fig. 1b) was taken under consideration as a complexing agent in this study because of its appropriate cavity size, superior drugcomplexation ability, ready availability in pure form and relatively low cost [8]. In addition, its bulky and hydrophobic structural feature prevents absorption of the complexes in an intact form. Although every CD is considered nontoxic for oral use due to lack of CD absorption through GIT, β-CD is the most costeffective compound. This compound, favourable for oral

1. Introduction Etoricoxib (ETC) [5-chloro-6’-methyl-3-{4(methylsulfonyl)phenyl}-2,3’-bipyridine] is a cyclooxygenase II (COX-2) selective inhibitor (Fig. 1A) and used for the treatment of various acute and chronic inflammatory diseases [1]. This is a class II drug (low solubility, high permeability) according to the biopharmaceutics classification system [2]. Thus, dissolution of this drug is the rate limiting step in its bioavailability which, in turn, is influenced by formulation type and release rate of the drug moiety from the drug product [3,4]. Formulation scientists have been using various techniques to improve dissolution and solubility pattern of class II drugs, among which, inclusion complex formation of the drug with suitable non-toxic agents is __________ *Corresponding author. Address: Department of Pharmacy, Jahangirnagar University, Savar, Dhaka-1342, Bangladesh. Tel: +4407983513530 E-mail: [email protected].

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2. Materials and methods

(A)

2.1. Materials Etoricoxib was kindly donated by Eskayef Bangladesh Ltd. β-Cyclodextrin was purchased from Nacalai Tesque, Kyoto, Japan. All other reagents and solvents used were of analytical grade. 2.2. Preparation of inclusion complexes Two different inclusion complex formulations of 1:1 molar ratio of each were prepared by co-precipitation and freeze drying methods. A physical mixture (PM) of ETC and β-CD using the same molar ratio was also prepared for comparison with the solid complexes. 2.2.1. Physical mixture (PM)

(B)

The PM of ETC and β-CD in 1:1 molar ratio was obtained by simple homogeneous blending of previously sieved (using 75 µm sieve) ETC & β-CD (3.58g and 11.35g respectively) in a mortar using a spatula [14]. 2.2.2. Co-precipitated complex (CP) To prepare the co-precipitated complex in a 1:1 molar ratio, etoricoxib (3.58 g) was dissolved in minimum quantity of methanol and was added drop wise to a stirred solution of β-CD (11.35 g) in minimum quantity of water warmed at 75°C. Stirring was maintained for 2 h at 75°C. Then the mixture was cooled gradually to room temperature with continued stirring [14]. The precipitate (CP) obtained was filtered, dried and stored in a desiccator until further study.

Fig. 1. Structures of (A) etoricoxib, (B) β-cyclodextrin.

2.2.3. Freeze dried complex (FD)

application, acts as a true carrier of orally administered poorly soluble drug by keeping the hydrophobic drug molecules stable in aqueous GI environment and delivering them to the surface of the biological membrane [9]. Solid dispersions of ETC with lipid carrier and hydrophilic swellable polymers have been reported for improving its dissolution [10, 11]. Patel et al reported the formation of inclusion complex of etoricoxib with β-CD by kneading method [12]. Besides, Manali S et al also reported on successful inclusion complexation of etoricoxib by some methods including lyophilization or freeze drying but used HPbetaCD for comlexation [13]. In the present study, two inclusion complexation methods, namely, co-precipitation (CP) and freeze-drying (FD) have been utilized to enhance the drug’s solubility as well as dissolution property using β-CD.

The required 1:1 stoichiometric quantity of ETC (1 mol) was added to the aqueous solution of β-CD (1mol) with continuous mixing using a magnetic stirrer. 5% 0.1M HCl was added to get a complete clear solution and lactose monohydrate was used as lyophilizant. After stirring for half an hour, the resultant solution was frozen at −70°C and was lyophilized in a freeze-dryer (Tofflon, China). It took around 98 hours time to complete the freeze drying operation [15,16]. 2.3. Phase solubility study One of the important parameters of inclusion complexes is the affinity of the guest molecule for the cyclodextrin cavity. The binding constant (Kc) or ETC-

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same sample [20, 21]. In this study TG, DTG and DTA curves were obtained simultaneously using a TG-DTA instrument (Thermal analyzer TG/DTA 6300, Japan) controlled with the software system EXSTAR 6000 station. About 5 mg of the samples each was weighed and taken in platinum crucible and first isothermally heated to 30°C for 2 min, and subsequently heated from 30 to 800°C under a flowing nitrogen atmosphere (air flow 5 l/h). The heating rate was 20°C 1/min. Highly sintered α-Al2O3 was used as a reference material [21].

β-CD association constant value is an indication of the affinity of the drug for β-CD [19]. In this study a phase solubility diagram was obtained using the principles of the phase-solubility method popularized by Higuchi and Connors [17]. An excess amount of ETC was added to purified water and β-CD aqueous solutions (2.5-15 mmol/l concentration range) in 25 ml volumetric flasks. The flask closures were sealed with parafilm and the mixtures were shaken at room temperature (25±3°C) on a flask shaker. After 48 hours of shaking to achieve equilibrium, 2 ml aliquots were withdrawn and filtered immediately using a 0.45 μm membrane filter. The filtered samples were diluted suitably and assayed for ETC by measuring absorbance at 232.5 nm (Simadzu UV-VIS spectrophotometer 1601, Japan). Shaking was continued until 3 consecutive estimations were equivalent. The solubility experiments were conducted in triplicate (coefficient of variation < 2%). The apparent association constant was calculated from the phase solubility diagrams (Fig. 2) using the following equation:

2.4.3. Powder X-ray diffractometry Powder X-ray diffraction (PXRD) patterns of all the samples were obtained using powder x-ray diffractometer (Philips PW 3040 X’Pert PRO XRD system with Cu-Kα radiation), operated at 40 kV and 30 mA, with angular range 200 ≤ 2θ ≤ 500. 2.4.4. Scanning electron microscopy (SEM)

slope Kc = S 0 (1 − slope)

The surface morphology of pure etoticoxib (ETC), β-CD, their PM, CP and FD binary systems were examined by scanning electron microscope (Hitachi S-3400N, Germany). The samples were fixed on an aluminium stub using double-sided tape. The pictures were then taken at an excitation voltage of 15 Kv.

Concnetration of etoricoxib (mmo l

The slope is obtained from the initial straight-line portion of the graph. S 0 is the intrinsic solubility of ETC in water and is obtained from the y intersect of the straight line. 2.500

2.5. Dissolution studies

2.000 1.500

In vitro dissolution studies of the pure ETC and the inclusion complexes were performed by adding the solid systems, equivalent to 60 mg of ETC to 900 ml of DI water maintained at 37±0.5°C and stirred at 50 r/min in a USP apparatus II (VEEGO VDA-6DR, India). At fixed time intervals, samples were withdrawn, filtered through syringe-filter (0.45 µm) and assayed spectrophotometrically ( SHIMADZU, UV-VIS 1601, Japan) for the drug content at λ = 232.5 nm after suitable dilution with water. A similar study of all the samples was done using another dissolution medium comprising of pH 6.8 phosphate buffer. The volume of the dissolution media was kept constant during the experiment and all the dissolution experiments were run in triplicate.

1.000 0.500 0.000 0

5

10

15

20

Concentration of beta-cyclodextrin (mmol/l)

Fig. 2. Phase-solubility plot of ETC-β-CD system in water.

2.4. Physiochemical characterization of the inclusion complexes 2.4.1. Infrared spectroscopy Infrared spectra of the PM, CP and FD samples were obtained using FTIR spectrophotometer (IR Prestige-21, Shimadzu, Japan) based on KBr disc method and compared with that of the pure ETC.

3. Results and discussion

2.4.2. Simultaneous thermal analysis

3.1. Phase solubility study

Simultaneous thermal analysis is combined DTA/ TG or DSC/TG system15 in which both thermal and mass change effects are measured concurrently on the

The phase-solubility diagram of ETC-β-CD was obtained by plotting the changes in guest (ETC) solubility (mmol/l) as a function of β-CD concentration

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T (%)

T (%)

T (%)

T (%)

T (%)

T (%)

(mmol/l) and is shown in Fig. 2. This plot shows that FD the aqueous solubility of the drug increases linearly as a function of β-CD concentration. The solubility diagram of ETC in various β-CD solutions can be classified as (A) (A) (A) AL type according to Higuchi and Connors [17]. The linear host-guest (β-CD-ETC) correlation with slope of less than 1(B) suggested the formation of a 1:1 ETC-β(B) (B) CD complex with respect to β-CD concentrations. The solubility of (A) the parent drug in distilled water at room (A) temperature was found experimentally to be only 0.01 (C) (C) CP (C) g /100 ml whereas solubility of β-CD in water has been (B) g /100 ml [9]. These values indicate (B) reported as 1.85 (D) (D) significant solubility enhancement scope of etoricoxib (D) when entrapped within β-CD cavity. The Kc, obtained (C) the linear portion of the phase solubility (C) the slope 4000 3500from 3000 2500 of2000 1500 1000 500 4000 3500 3000 4000 2500 3500 2000 3000 1500 25001000 20005001500 1000 500 diagram was 489.59-1 1/mol, is quite similar to the ) Wavenumber (cm ) Wavenumber (cm-1 Wavenumber (cm-1) Burnette and(D) Conors published mean binding constant (D) (A) for β-CD [32-34]. This value indicates adequate affinity between ETC and β-CD to enhance the amount of total 4000 3500dissolve 3000 drug 2500in GIT 2000 but1500 1000 the500 4000 3500 2500 2000 1500 1000 500 to permit dissociation of the 3000 PM -1 (B) Wavenumber (cm ) absorption of the drug [18, 19]. complex with subsequent Wavenumber (cm-1) 3.2. Infrared spectroscopy

(D) 4000 3500 β-CD

3000

2500

2000

1500

1000

500

Wavenumber (cm-1)

(A)

ETC

(B)

T (%)

IR spectroscopy partly reveals the evidence of complexation of a guest molecule with β-CD. Several authors have reported that the characteristic peaks of the guest molecule shift significantly to either a higher or lower frequency [20, 21]. Besides shifting, the peaks of the guest may disappear and broaden as an indication of interaction between the drug and β-CD molecules [22-23]. Fig. 3 represents FTIR spectra of pure drug (ETC), β-CD, their physical mixture (PM) and the inclusion complexes (CP and FD). The FTIR spectrum of pure etoricoxib showed characteristic peaks at 1598.99 & 1431.18 1/cm (C=C and C=N stretching in the ring); 1,143.79 1/cm, 1,083.99 1/cm (S=O stretching vibrations); 839.03 1/cm and 771.53 1/cm (C-Cl stretching vibration). Again, a characteristic broad absorption band at 3410.15 1/cm was observed in the β-CD spectrum (Fig. 3) may be due to –OH stretching including other characteristic peaks at 2926.01, 1157.29 and 1028.06 1/cm respectively. However, the spectrum of physical mixture (PM) exactly matched with both of spectra of β-CD and ETC. These spectral characteristics indicate that there was little interaction between ETC and β-CD in the physical mixture [12, 14, 26]. This was further confirmed by PXRD patterns of the physical mixture. In the case of CP, most of the characteristic peaks of ETC were significantly modified may be due to complex formation [30]. On the other hand, the spectrum of FD showed complete disappearance of all the

(C)

(C) (D) 4000

3500

3000

2500

2000

1500

1000

500

-1

Wavenumber (cm ) Fig. 3. FTIR spectra of ETC, β-CD and their binary systems: physical mixture (PM), co-precipitate (CP) & freeze-dried (FD) Complexes.

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characteristic ETC peaks, indicating strong drug–β-CD interaction in lyophilized stage and possible inclusion complexation of the drug with β-cyclodextrin as has been reported by Andreza et al and several other authors [27]. Although IR spectroscopy can be utilized as a supporting evidence for inclusion complex formation, but some other techniques like DTA or DSC and PXRD pattern study are also required to have satisfactory information regarding inclusion complexation [24-28] Therefore, we further performed simultaneous DTA/TG and PXRD studies for appropriate characterization of the complexes.

4D), indicating some drug-β-CD interaction [27]. Again, the absence of corresponding endothermic peaks in the thermogram of FD (Fig. 4E), as has been observed in the thermogram of ETC and β-CD or their physical mixture, is a sign of amorphous nature of the sample and indicating the formation of a true inclusion complex [27, 31]. 3.4. Powder X-ray diffractometry Powder X-ray diffraction (PXRD) patterns of pure ETC, β-CD, their physical mixture (PM) and the corresponding inclusion complexes (CP and FD) are presented in Fig. 5A to 5E. PXRD of ETC (Fig. 5A) showed a series of characteristic peaks at 17.21°, 18.78°, 23.41°, and 24.77°, which were indicative of their crystalline behaviour. β-CD also exhibited characteristic peaks (Fig. 5B) at 12.85°, 13.25°, 23.12° and 35.33° due to its crystalline nature. The diffractogram of the PM (Fig. 5C) showed distinguishing peaks at 13.18°, 17.09°, 18.61°, 23.27°, 24.65° and 35.28° indicating the existence of most of the characteristic peaks, both of the drug & β-CD with slight shifting and less height. Again, the disappearance of the peaks near 23.12° and 12.85° might result from the attenuation of the signals in mixture state. Overall, peak characteristics indicate, there was no interaction between ETC and β-CD in case of the physical mixture [26)] Disappearance of the distinguishing peaks of ETC and β-CD in CP (Fig. 5D) is a sign of complex formation and the sharp signals at 16.81°, 20.20°, 23.46°, 23.83°, 34.21° and 49.25° are the sign of formation of different crystals. In contrast, the diffraction pattern of freeze-dried complex (FD) is completely diffused (Fig. 5E) and the disappearance of important ETC crystalline peaks indicates the entirely amorphous nature of ETC in this product. These result may be attributed to the interaction between ETC and β-CD in the freeze-dried product, suggesting the presence of a new amorphous solid phase in the product, confirming the DTA/TG/DTG thermogravimetric observations.

3.3. Simultaneous thermal analysis The simultaneous DTA, TG and DTG curves of β-CD, ETC, their physical mixture (PM) and inclusion complexes (CP, FD) are shown in Fig. 4A to 4E. The top curves of each thermogram indicate % weigh remaining of the sample at different temperature (TG%), the curves in the middle of the thermograms indicate endothermic behaviour of the sample (DTA in µV) and the bottom counterparts depict weight change in mg per minute (DTG mg/min). Two endothermic peaks were observed in the thermal decomposition of β-CD as depicted in the Fig. 4B. The first peak at 95.3°C corresponds to the dehydration of β-CD [24]. The later broad endotherm is related to the degradation of the β-CD structure. Decomposition started at 290.3°C and the rapid weight loss continued up to 336.2°C, giving approx. 80% total weight loss. The melting of β-CD also occurred at this stage and thus the temperature range 290-311.9 (DTGmax) corresponds to the endothermic change of melting [25]. The thermogram of ETC (Fig. 4A) also shows two sharp endothermic peaks, one at 139.1°C and a slight broadened endothermic peak at 385.0°C indicating melting and decomposition of the drug respectively. Besides, the DTG curve shows that decomposition started at 287.5°C at a rate 0.027 mg/min and highest degradation rate was 2.461mg/min at 385.5°C. In the thermogram of ETC/β-CD physical mixture (Fig. 4C), two minor endothermic peaks were observed at 98.4°C and at 141.1°C. The first one indicates corresponding shifted peak of β-CD from 95.3°C and later is of shifted melting point with decomposition of the sample (as significant weight loss was accompanied by the enthotherm), indicating no true complexation through simple physical mixing [27]. At temperature 321.8°C half of the sample decomposed (58.2% samples remained) and highest decomposition was observed at 325.9°C at a rate 3.13mg/min. However, considering CP, there is a reduced, less intense endothermic peak corresponding the melting of the drug at a relatively lower temperature (Fig.

3.5. Scanning electron microscopy (SEM) Scanning electron microscopy (SEM), a qualitative method is typically used to study the microscopic aspects of pure compound (ie, CDs and drug substances) and the drug products obtained by different methods of preparation like kneading, co-precipitation and freeze drying method. Even if there is a clear difference in crystallization state of the raw materials and the products, this study is inadequate to affirm inclusion complexation, but nevertheless helps to assess the existence of a single component in the preparations obtained [27]. The ETC particles under SEM, as shown in Fig. 6a to 6b, were in

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(A)

(C)

(B)

(E)

(D)

Fig. 4. Simultaneous DTA / TG / DTG curves of (A) ETC (B) β-CD (C) PM (D) CP and (E) FD.

the form of small asymmetrical needle-shaped crystals with rough surfaces while that of β-CD (Fig. 6c to 6d) exhibited three-dimensional particles with relatively larger as well as thicker irregular parallelogram-shaped crystals. Again, the SEM appearance of the PM clearly depicts the crystalline structure of both ETC and β-CD (Fig. 6e-6f). On the other hand, the CP samples appears as a quite different shaped three dimensional asymmetric crystals with the adherence of some small particles onto the surface of the larger particles and the surfaces of each particles seemed smooth (Fig. 6g to 6h). In contrast, the freeze-dried complex (FD) showed amorphous and homogenous aggregates of relatively thin film-like particles than CP or FD (Fig. 6i to 6j). Under the high magnification, they appeared as irregular shaped particles with smooth surface. The distinctly different surface morphology of the freeze-dried complex than the others

was indicative of the presence of a new solid phase, which may be due to the molecular encapsulation of drug in the β-CD. 3.6. Dissolution studies Fig. 7 show dissolution profiles of the drug-β-CD inclusion complexes: co-precipitate (CP) and freeze dried (FD) complexes and their physical mixture (PM) in comparison to that of the pure drug (ETC) in distilled water and phosphate buffer pH 6.8 respectively. Table 1 represents dissolution percentage that is cumulative % drug dissolved (DP) and dissolution efficiency (DE) in percentage of PM, CP, FD with respect to ETC at two different time points (5 min and 75 min) in water and phosphate buffer pH 6.8. The reported values are the arithmetic mean of three replicate measurements.

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00


Table 1 Dissolution percentage (DP) and dissolution efficiency (DE) at 5 min and 75 min for pure drug, drug-β-cylodextrin physical mixture and the inclusion complexes in distilled water and in pH 6.8 phosphate buffer (mean ± SD). Medium

75 min

5 min

75 min

ETC

51.04±0.239

78.03±7.7E-05

25.52±0.001

72.21±0.001

PM

61.41±0.230

85.55±0.066

30.71±0.001

77.56±0.002

CP

61.85±0.232

97.70±0.232

30.93±0.001

88.99±0.001

FD

96.13±0.172

99.89±0.065

48.07±0008

95.99±0.0009

ETC

38.51±0.099

72.25±0.099

19.26±.0004

60.52±9.96E-05

PM

56.61

86.27±0.099

28.30

77.56±3.4E-05

CP

56.97±0.296

90.74±0.169

28.48±0.001

82.93±0.0003

FD

97.59±0.361

100.00±0.0001

48.79±0.001

96.28±0.0006

pH 6.8 phosphate buffer

(A)

T (%)

(B)

(B)(B)

(C)

(C)

(D) 3000

2500

One-way ANOVA (a statistical tool used to compare data for more than two groups) was used to test the statistical significance of differences between dissolution performance of pure drug and treated samples (physical mixture and inclusion complexes). Significance of differences in the means was further analyzed using post hoc tests (Dunnett t-test (2-sided) and Bonferroni test) at 95% confidence. As we can see, DP and DE values of all the complexes were higher than that of the pure drug in every case. Even the physical mixture of the drug and β-CD (PM) showed higher DP and DE values than that of the pure drug. In particular, FD complex exhibited almost 2 fold increased dissolution efficiency (Fig. 7) within just 5 minutes (DE5min) in water and that of PM and CP was even higher (1.2 time more) compared to ETC. Again, post hoc tests exhibited significantly higher dissolution of CP than PM (P < 0.001). Similar DE and DP performance (DE75min and DP75min) was observed at 75 min time point (Table 1). On the other hand, in phosphate buffer pH 6.8 (Table 1), both DE5min and DP5min value of PM and CP was about 1.5 fold and those of FD was 2.5 fold higher than that of the pure drug. Although at 75 minutes time point, DE75min and DP75min values of PM, CP and FD were significantly higher (P < 0.001) than that of the pure drug but not more than that observed at 5 minutes time point. Overall, the freeze-dried product showed much better dissolution performance (P < 0.001) than the co-precipitate complex, the physical mixture and the pure drug (the order of dissolution performance FD > CP>PM>ETC). This enhancement may be ascribed to the higher hydrophilic character of the systems due to drug-β-CD interaction, influencing dissolution kinetics and the total amount of poorly soluble drug in solution [8,19, 28,29].

(A)

(A)

2000

1000(D)500

1500 -1

Wavenumber (cm ) 4000

3500

3000

2500

DE(%)

5 min

Distilled water

3500

DP(%)

System

(C) 2000

1500

1000

500

-1

Wavenumber (cm )

(D)

(E)

2θ ( º ) Fig. 5. Powder X ray diffraction patterns of (A) β-CD (B) ETC (C) PM (D) CP and (E) FD.

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19 19 19

Fig. 6. SEM microphotographs of ETC (a -b), β-CD (c-d), PM (e-f), CP (g-h) and FD (i-j) at two different magnification (×2.50K and 19 19 ×5.00K) for each sample. 1 287 1


120 120

Labort ories Dhaka, Bangladesh for providing some instrumental support for this study. The other authors condole the sudden demise of Md. Habibur Rahman and gratefully acknowledge his contributions in the work.

(A)

Cumulative % drug releas

100 100 8080 6060

References

ETC PM

4040

CP FD

2020 00

517 517

00 120 120

55

10 10

15 15

30 30

45 45

60 60

75

(B)

Cumulative % drug releas

100 100 8080 6060 ETC

4040

PM CP

2020

FD

00 00

518 518 519 519

55

10 10

15 15

30 30

45 45

60 60

75

Time Time(min) (min)

520 520

Fig. 7. Dissolution profiles of etoricoxib-β-CD binary systems: physical mixture (PM), co-precipitate (CP), freeze-dried product (FD) as compared to that of the pure etoricoxib (ETC) in distilled water (A) and in pH 6.8 phosphate buffer (B).

521 521

4. Conclusion

522 522 523 523 524 524 525 525

The binding constant (k c value) of etoricoxib and β-CD, obtained from phase solubility study indicates the possibility of enhancement of drug’s dissolution if both Table Table 1 complexes at a 1:1 molar ratio. Basically, of them 1form the AL type solubility diagram ascertains the possibility of formation of inclusion complexes at 1:1 stoichiometric DP(%) DP(%) of ETCratio. Further physicochemical characterization Medium System Medium System β-CD binary systems by a variety 55min min as min of methods75such FTIR, DTA/TG/DTG, PXRD, SEM study revealed the 51.04r0.239 78.03r7.7E-05 ETC 51.04r0.239 78.03r7.7E-05 formation of trueETC complexes of ETC with β-CD. Again, the dissolution properties of ETC-β-CD binary systems PM 61.41r0.230 85.55r0.066 PM 61.41r0.230 85.55r0.066 Distilled water Distilled waterby co-precipitation (CP) and freeze drying (FD) prepared CP 61.85r0.232 97.70r0.232 CP 61.85r0.232 97.70r0.232 methods were superior to that of the pure drug. Overall, FD 99.89r0.065 FDsuperior96.13r0.172 96.13r0.172 99.89r0.065 FD system showed dissolution properties when compared to co-precipitate or physical mixture. ETC 38.51r0.099 72.25r0.099 ETC 38.51r0.099 72.25r0.099 pH pH6.8 6.8

PM

56.61 56.61

86.27r0.099 86.27r0.099

phosphate phosphatebuffer buffer

CP CP

56.97r0.296 56.97r0.296

90.74r0.169 90.74r0.169

PM Acknowledgement

526 526

The authors are thankful to Incepta Pharmaceutcials FD 97.59r0.361 100.00r0.0001 FD 97.59r0.361 100.00r0.0001 Ltd., Savar, Dhaka, Bangladesh; Techno Drugs Ltd., Norshingdi, Bangladesh and Bangladesh Atomic Energy Commission (BAEC), Dhaka, Bangladesh and BCSIR,

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[1] Leclercq P, Malaise MG. Etoricoxib (Arcoxia). Rev. Med. Liege. 2004, 59: 345-349. [2] Cochrane DJ, Jarvis B, Keating GM. Etoricoxib. Drugs. 2002, 62:2637-2651. [3] Kasim NA, Whitehouse M, Ramachandran C. et al. Molecular properties of WHO essential drugs and provisional biopharmaceutical classification. Mol. Pharm. 2004, 1:85-96. [4] Takano R, Sugano K, Higashida A, et al. Oral absorption of poorly water-soluble drugs: computer simulation of fraction absorbed in humans from a mini-scale dissolution test. Pharm. Res. 2006, 23:1144-1156. [5] Higuchi WI. Third international symposium on clathrate compounds. Tokyo: Hoshi University, 1984, 23-24. [6] Betteinetti GP, Gazzania A, Mura P, et al. The thermal behaviour and dissolution properties of naproxen in combinations with chemically modified β-cyclodextrins. Drug Dev. Ind. Pharm.1992,18: 39-53. [7] Blanco J, Vila-Jato JL, Otero FJ, et al. Influence of method of preparation on inclusion complexes of naproxen with different cyclodextrins. Drug Dev Ind Pharm.1991, 17:943-945. [8] Fucile MG, Mazzitell G, Ratti D, et al. Inclusion complex of isosorbide-5-mononitrate in β-cyclodextrin: comparison of preparation methods and assessment of analytical techniques. Eur J Pharm Biopharm. 1992, 38:140-144. [9] Challa R, Ahuja A, Ali J, et al. Cyclodextrins in drug delivery: an updated review. AAPS Pharm Sci Tech. 2005, 6:E329-357. [10] Chauhan B, Shimpi S, Paradkar A. Preparation and characterization of etoricoxib solid dispersions using lipid carriers by spray drying technique. AAPS PharmSciTech. 2005, 6: E405-412. DE(%) DE(%) [11] Suhagia BN, Patel HM, Shah SA, et al. Preparation, and dissolution of etoricoxibmin 75in-vitro min 5characterization min 75 min polyethylene glycol 4000-polyvinyl pyrrolidone K30 25.52r0.001 72.21r0.001 25.52r0.001 solid dispersions.72.21r0.001 Acta Pharm., 2006, 56: 285-298. [12] Patel HM, Suhagia BN, Shah SA, et al. Preparation and 30.71r0.001 77.56r0.002 30.71r0.001 77.56r0.002 characterization of etoricoxib-β-cyclodextrin complexes 30.93r0.001 88.99r0.001 30.93r0.001 prepared by the88.99r0.001 kneading method. Acta Pharm. 2007, 57:351-359. 48.07r0008 95.99r0.0009 48.07r0008 95.99r0.0009 [13] Manali S, Poonam K, Pankajkumar S, et al. Effect of 19.26r.0004 60.52r9.96E-05 19.26r.0004 60.52r9.96E-05 PVP K30 and/or L-Arginine on Stability constant of etoricoxib-HPβCD inclusion complex: preparation and 28.30 77.56r3.4E-05 28.30 77.56r3.4E-05 characterization of etoricoxib-HPβCD Binary System. 28.48r0.001 82.93r0.0003 28.48r0.001 82.93r0.0003 Drug Dev Ind Pharm. 2009, 35:118-129. [14] Moyano JR, Blanco MJA, Gines JM, et al. Solid state 48.79r0.001 96.28r0.0006 48.79r0.001 96.28r0.0006 characterization and dissolution characteristics of gliclazide beta-cyclodextrin inclusion complexes. Int. J. Pharm. 1997, 148:211-17.


[ 1 5 ] C a o F T, G u o J , P i n g Q . T h e p h y s i c o c h e m i c a l characteristics of freeze-dried scutellarin-cyclodextrin tetracomponent complexes. Drug Dev. Ind. Pharm. 2005, 31:747-56. [16] Tsinontides SC, Rajnaik P, Pham D, et al. Freeze dryingprinciples and practice for successful scale up to manufacturing. Int. J. Pharm. 2004, 28:1-16. [17] Higuchi T, and Connors KA. Phase solubility technique. Adv Anal Chem Instrum. 1965, 4:117-212. [18] Szejtli J. Medicinal applications of cyclodextrins. Med Res Rev. 1994, 14:353-386. [19] Miller LA, Carrier RL, Ahmed I. Practical considerations in development of solid dosage forms that contain cyclodextrin. J Pharm Sci. 2007, 96:1691-1707. [20] Mura P, Bettinetti GP, Manderioli A, et al. Interactions of ketoprofen and ibuprofen with β-cyclodextrin in solution and solid states. Int J Pharm. 1998, 166:189-203. [21] Ventura CA, Trendi S, Puglisi G, et al. Improvement of water solubility and dissolution rate of ursodeoxycholic acid and chenodeoxycholic acid by complexation with natural and modified beta-cyclodextrins. Int J Pharm. 1997, 149:1-13. [22] Guyot M, Fawaz F, Bildet J, et al. Physicochemical characterization and dissolution of norfloxacin/CD inclusion compounds and PEG solid dispersions. Int J Pharm.. 1995, 123:53-63. [23] Kurozumi M, Nambu N, Nagai T. Inclusion compounds of non-steroidal anti-inflammatory and other slightly water-soluble drugs with alpha and beta cyclodextrins in powdered form. Chem Pharm Bull. 1975, 23:3062-3068. [24] Shen Y, Yang S, Wu L, et al. Study on structure and characterization of inclusion complex of gossypol/beta cyclodextrin. Spectrochimica Acta. 2005, 61(Part A):1025-1028. [25] Yilmaz VT, Karadag A, Icbudak H. Thermal decomposition of β-cyclodextrin inclusion complexes of ferrocene

and their derivatives. Thermochimica Acta. 1995, 261: 107-118. [26] Sinha VR, Anitha R, Ghosh S, et al. Complexation of celecoxib with β-cyclodextrin: characterization of the interaction in solution and in solid state. J Pharm Sci. 2005, 94: 676-687. [27] Ribeiro A, Figueirus A, Santos D, et al. Preparation and solid state characterization of inclusion complexes formed between miconazole and methyl β-Cyclodextrin. AAPS Pharm Sci Tech. 2008, 9:1102-1109. [28] Carrier RL, Miller LA, and Ahmed I. The utility of cyclodextrins for enhancing oral bioavailability. J. Controlled Release. 2007, 123:78-99. [29] Baboota S, Dhaliwal M, Kohli K. Physicochemical characterization, in vitro dissolution behavior, and pharmacodynamic studies of rofecoxib–cyclodextrin inclusion compounds. Preparation and properties of rofecoxib hydroxypropyl betacyclodextrin inclusion complex: A technical note. AAPS PharmSciTech. 2005, 6: E83-90. [30] Patel VP and Patel NM. Evaluation of some methods for preparing glipizide-β-cyclodextrin inclusion complexes. IJPS. 2009, 5:191-198. [31] Singh R, Bharti N, Madan J, et al. Characterization of cyclodextrin inclusion complexes – a review. J Pharm Sci Tech. 2010, 2:171-183. [32] Burnette RR, Connors KA. Statistical properties of thermodynamic quantities for cyclodextrin complex formation. J Pharm Sci. 2000, 89:1389-1394. [33] Connors KA. Population characteristics of cyclodextrin complex stabilities in aqueous solution. J Pharm Sci. 1995, 84:843-848. [34] Rao VM, Stella VJ. When can cyclodextrins be considered for solubilization purposes? J Pharm Sci. 2003, 92:927-932.

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