International Journal of Drug Development and Research

Keywords

Aceclofenac; Inclusion complex; Phase solubility study; In-Vitro Dissolution.

Introduction

Aceclofenac (2-[(2, 6-diclorophenyl) amine] phenylacetoxyacetic acid) is a non-steroidal antiinflammatory drug (NSAID) of phenyl acetic acid group, which possesses remarkable antiinflammatory, analgesic and anti-pyretic properties1, 2. Aceclofenac appears to be well tolerated among NSAIDs with a lower incident of gastro intestinal adverse effects3. Unfortunately Aceclofenac suffers from low aqueous solubility (0.058 μg/ml), leading to poor dissolution and insufficient oral bioavailability. The biopharmaceutical classification system (BCS) divides all drug candidates into four different groups, according to their solubility and permeability4. Aceclofenac is an example of BCS class II compound (Highly Permeable & Low Soluble); its oral bioavailability is determined by dissolution rate in the gastro intestinal tract5, 6. Therefore the improvement of Aceclofenac dissolution is an important issue for enhancing its bioavailability and therapeutic efficacy.

Several techniques are commonly used to improve dissolution and bioavailability of poorly water soluble drugs, such as size reduction, use of surfactants, salt formation, pH adjustment, complexation, prodrug, and nanomization, preparation of liposome and formation of solid dispersions (SD) 7-9.Solid dispersion refers to a group of solid products consisting of at least two different components, generally a hydrophilic matrix and a hydrophobic drug. The matrix can be either crystalline or amorphous. The drug can be dispersed molecularly, in amorphous particles (clusters) or in crystalline particles10, 11. Transformation of crystalline drug to amorphous drug upon solid dispersion formulation increases the dissolution rate12. Solid dispersion techniques have been extensively used to increase the solubility of a poorly water soluble drug13. Solid dispersion is a viable and economic method to enhance bioavailability of poorly water soluble drug and also it overcomes the limititations of previous approaches14.

The present study is aimed at improving the dissolution rate of poorly water soluble drug Aceclofenac using β-CD.

Materials and Methods: Aceclofenac from Dishman Pharmaceuticals, Ahmedabad and β- Cyclodextrin from Cadila Pharmaceuticals, Ahmedabad. All other ingredients were of analytical or pharmaceutical grade. Double UV – Vis Spectrophotometer (Shimadzu UV-1800, japan), USP Dissolution Apparatus model (ELECTROLAB Dissolution tester TDT-08L), FTIR Instrument (Shimadzu FTIR 8400S spectrometer), Differential Scanning Calorimeter (Shimadzu DSC 60, Japan).

Methods

SOLUBILITY STUDY

Solubility of Aceclofenac was determined in different media including distilled water, 0.1 N HCL and Phosphate buffer pH 6.8. Excess amount of Aceclofenac was added into three different conical flask containing 100 ml of distilled water, 0 .1 N HCL and phosphate buffer pH 6.8. These solutions were shaken for 48 h at room temp on a magnetic stirrer. After equilibrium, the suspensions were filtered through 0.45 μm Millipore membrane filters. The filtrate was appropriately diluted and the concentration of the Aceclofenac in the filtrate was determined by UV spectrophotometer Shimadzu- 1800, Japan at 276 nm (Table No-1).

PHASE SOLUBILITY STUDY

Phase solubility study for ACE was performed as described by Higuchi and Connors15. Excess amount of ACE was added into 100 ml pH 6.8 phosphate buffer containing β-CD and shaken for 48 hr at room temp on a magnetic stirrer (Table no-2).

FORMULATION OF ACECLOFENAC INCLUSION COMPLEX WITH 9- CYCLODEXTRIN (9-CD)

Preparation of Physical mixture

Weigh the required quantity of Aceclofenac and β-CD as per the ratio shown in the Table No-3. Both were mixed properly by spatula and pass it through # 80.

Preparation of Co-grinding mixture

Weigh the required quantity of Aceclofenac and β-CD as per Table No-3 and pass it through 80 #. The drug and carrier were mixed in mortar for 5 minutes and stored in glass jar.

Preparation of inclusion complex by kneading method

The required quantity of β-CD was weighed and water added to get dough like consistency. To the paste weighed quantity of Aceclofenac was added. The mixer was kneaded in glass mortar for 30 min16 and then completely dried in oven at 600 C. The dry product was sieved through # 80 to obtain powder and stored in glass jar (Table No-3 & 4).

SOLID STATE CHARACTERIZATION:

DIFFERENTIAL CALORIMETRY STUDIES (DSC)

The possibility of any interaction between the drug and the carriers during preparation of Physical mixture, Co-grinded mixture and Kneading method were assessed by carrying out thermal analysis of drug and polymer alone as well as physical mixture, Co-grinded mixture and Kneading method using DSC. DSC was performed by Perkin-Elmer 7 series thermal analysis system for the drug (Aceclofenac) and solid dispersion of drug with β-CD. Samples were scanned at 200C to 3000C at a rate of 100C/minute in a N2–(Nitrogen) environment. Interaction between drug and polymer, if any was indicated either by shift in the peak or presence of additional peak of temperature other than those correspondence to the drug and polymer.

FOURIER TRANSFORMS INFRARED SPECTROSCOPY (FTIR):

FTIR spectral studies were carried out for the pure drug and the solid dispersion to check the compatibility between drug and carrier using SHIMANDZU FTIR-8400 S. The spectrum was recorded in the range of 4000- 400 cm-1.Interaction between the components, if any, was indicated by either producing additional peaks or absence of characteristic peak corresponding to drug and carrier.

IN-VITRO DISSOLUTION STUDIES

In-vitro Dissolution studies were performed in phosphate buffer (pH 6.8) at 37+0.5oC using USP II rotating paddle apparatus (ELECTROLAB Dissolution tester TDT-08L) at 100 RPM. Pure drug/solid dispersion/inclusion complex (equivalent to 100 mg of Aceclofenac) was subjected to dissolution. 5ml of the samples were withdrawn at time intervals of 10, 20, 30, 40, 60, 90 and 120 minutes. The sample was filtered through Whatman paper (0.7 μ size). The volume of the dissolution fluid was adjusted by replacing 5ml of dissolution medium after each sampling. The absorbance of the solution was measured at 276 nm using dissolution medium as reference standard. The concentration of Aceclofenac was calculated by using standard curve equation.

RESULTS AND DISCUSSION

Phase Solubility Study:

Figure No-1 shows the solubility profiles of Aceclofenac in pH 6.8 phosphate buffer influenced by carrier material concentration at room temperature. Solubility of Aceclofenac increases with β- Cyclodextrin inclusion complex and this increase in solubility having a linear correlation with conc. of carrier. β-Cyclodextrin show r2 value more than 0.95 having AL type of curve.

IN-VITRO DRUG RELEASE OF SOLID DISPERSION

Aceclofenac: 9-Cyclodextrin inclusion complex

The dissolution profile of pure drug is shown in Table No-5 & Fig No-2. The dissolution rate of pure drug is very poor and during 120 minutes a maximum of about 6.1 % of drug was dissolved.

Fig. No-6 shows the dissolution profile of 1:1 ACE: β- CD inclusion complex prepared by physical mixing, co-grinding and kneading method. From this data it was clearly evident that kneading method gives highest dissolution among the three methods of prepared inclusion complex (Table No-6).

Fig.No-3 to 6 shows the dissolution profile of 1:0.5, 1:1, 1:1.5 and 1:2 molar ratio of ACE: β-CD inclusion complex prepared by kneading method. Fig.No-7 & Table No-7shows the comparative dissolution profile of all the four batches. From Fig No-7, it is observed that as we increase the proportion of β-CD from half molar to two molar the dissolution of drug at 120 minutes increases from 40.97 % to 68.13 %.

SOLUBILITY STUDY

Solubility of Aceclofenac in distilled water, 0.1 N HCL and Phosphate buffer pH 6.8 are shown in Table No- 1. Solubility of Aceclofenac in water, 0.1 N HCL and Phosphate buffer pH 7.5 were found to be 88.6, 33.6 and 1058.9 μg/ml17

FTIR (FOURIER TRANSFORM INFRA RED SPECTROSCOPY)

The FTIR spectrum of pure Aceclofenac and dispersion are shown in figure No-8. The spectrum of Aceclofenac are shown characteristic bands at 3319.3 cm-1 (N-H stretching), 2970.2and 2035.5 cm-1 (O-H stretching), 1716.5 cm-1 (C-O stretching), 1589.2 cm- 1(skeleton vibration of aromatic C-C stretching for NH) 1380 cm-1 (O-H in plane bending), 1280.6 cm-1 (CN aromatic amine), 944 cm-1(O-H out plane bending) and 746 cm-1 (out plane bending for N-H).The characteristic bands of β-Cyclodextrin (3305, 1420, 1460 and 1083 cm-1) were also observed. The absence of any significant change in the IR spectrum pattern in the formulation containing the drug and carrier indicate the absence of interaction between the drug and carrier employed for solubility enhancement.

DSC (DIFFERNTIAL SCANNING CALORIMETRY)

The DSC curve obtained for pure Aceclofenac and β- Cyclodextrin in solid dispersion were displayed in the fig No-9 & 10. Pure Aceclofenac exhibit an endothermic peak at 156.110C which represent the melting point of Aceclofenac. DSC curve of β- Cyclodextrin showed a slightly sharp endothermic peak at 107.540C corresponding to the melting point of β-Cyclodextrin.DSC further support that Aceclofenac was compatible with the polymer. There was a noticeable reduction in endothermic peak height and heat of fusion, in physical mixture and in solid dispersion as compared to pure Aceclofenac. These suggest that the physical state of Aceclofenac changed from crystalline to amorphous. It has been that transforming the drug to amorphous or partially amorphous state leads to a high energy state and high disorder, resulting in enhanced solubility and faster dissolution.

SUMMARY AND CONCLUSION

The present study was performed to enhance the dissolution rate and aqueous solubility of Aceclofenac, a poorly soluble drug using β- Cyclodextrin as carrier. Nature and amount of carrier used to play an important role in the enhancement of dissolution rate

Solid dispersion of drug and β- Cyclodextrin were prepared at various ratios (1:0.5, 1:1, 1:1.5, 1:2). Dissolution studies were performed for pure drug, physical mixture, co-grinded mixture, and Kneading method in phosphate buffer at pH 6.8 using USP dissolution apparatus type-II. From the dissolution data it was shown that, all the solid dispersion (molecular inclusion complex) gave faster dissolution when compared to pure and physical mixture. The enhancement in the dissolution of Aceclofenac from the solid dispersion system may be due to several factors like lack of crystallization, particle size reduction in interfacial tension between hydrophobic drug and dissolution medium increased wettability and effective surface adsorption of drug on hydrophilic carrier.

Result from FTIR spectroscopy concluded that there is no well-defined interaction between Aceclofenac and carrier employed in the preparation of solid dispersion.DSC thermo gram of physical mixture and solid dispersion indicated complete miscibility of the drug in the melted carrier. In conclusion, β- Cyclodextrin could be used as potential carriers in the dissolution rate enhancement of Aceclofenac.

Kneading method > Co-grinding> Physical mixture

Conflict of Interest

NIL

Source of Support

NONE

Tables at a glance

Table 1 Table 2 Table 3 Table 4 Table 5 Table 6 Table 7

Figures at a glance

Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10

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