INTRODUCTION:

For absorption to be possible from the gastrointestinal tract, achieving a solution of drug in the GI fluid is a critical requirement for poorly water soluble drug. Many approaches such as salt formation, solubilization and particle size reduction have commonly been used to increase the dissolution rate and thereby oral absorption and bioavailability of such drugs Of which solid dispersion have tremendous potential for improving drug solubility due to the following factors: a reduction of drug’s particle size to nearly a molecular level, a solubilising or a co solvent effect on the drug by the carrier material, and the formation of amorphous form of drug and carrier.

Etoricoxib, 5-chloro-6'-methyl-3-[4-(methylsulfonyl) phenyl]-2,3'-bipyridine a novel COX-2 inhibitor, is a potent non-steroidal anti-inflammatory drug that is indicated for treatment of rheumatoid arthritis, psoriatic arthritis, osteoarthritis, ankylosing spondylitis, chronic low back pain, acute pain and gout. Although it has excellent oral bioavailability (100 %), its poor aqueous solubility (10 μg /mL, 25°C) makes its absorption dissolution rate limited and thus delays onset of action. There are however various techniques to improve the solubility of water insoluble drugs.

For example, traditional methods for the production of particles for the production of particles to enhance the solubility include the pulverization of large drug particles using a ball mill or jet mill, salt formation, solubilization. Of which the solid dispersion method by which a drug is dispersed in a carrier in the molecular state, is a useful pharmaceutical approach most commonly employed to improve the dissolution property and oral bioavailability of poorly water soluble drugs.

The present work aims to prepare and characterize solid dispersion of poorly water soluble drug etoricoxib using lipid carriers by different technique and attempts to see the possible mechanism of improved dissolution rate.

Lipid carriers such as polyglycolized glycerides (Gelucire44/14) have been used for the preparation of solid dispersion by Co-evaporation and direct filling in the hard gelatin capsule method. The solid dispersion obtained was sticky and therefore Sterotex KNF (hydrogenated cottonseed oil) was used as lubricant.

The chemical structure is shown below

Code No.	Gelucire 44/14	PEG 4000	Etoricoxib	Surfactant
F1	60	-	60	130
F2	180	-	60	10
F3	190	-	60	-
F4	-	60	60	130
F5	-	180	60	10
F6	-	190	60	-

The solid dispersion prepared were characterized by drug content, scanning electron microscopy (SEM) hot stage microscopy (HSM), differential scanning calorimetry (DSC), radiograph powder diffraction (XRPD), Total moisture determination and in –vitro release in comparison with pure drug and corresponding physical mixtures.

MATERIALS AND METHODS:

Etoricoxib was obtained as a gift sample from Sun Pharmaceuticals Limited (India). Gelucire 44/14 (Laourly Macrogoglycerides , HLB 14) and sterotex-KNF (hydrogenated cottonseed oil, free flowing white solid powder, m.P = 58 to 62ºC, HLB = 1.5) were generous gifts from Gattefosse (St Priest, Cedex, France). All of the other chemicals were of analytical grade.

Preparation of the physical mixtures:

Etoricoxib, Gelucire44/14 and the Sterotex KNF were taken in the ratio of 1:1:0.5 and mixed well by using pestle mortar.

In the same way Etoricoxib, Gelucire44/14, and Aerosil (1:1:0.5) were mixed using pestle mortar and stored above two preparation in desiccators

Preparation of Solid dispersions:

Solid dispersion containing Etoricoxib and Gelucire44/14 were prepared by Co-evaporation and direct filling method and stored in desiccators until use.

Co-evaporation Method:

Weighed quantity of Etoricoxib was dissolved in dichloromethane to get a clear solution. Gelucire44/14 was then dissolved followed by Sterotex KNF/ Aerosil and solvent was removed by evaporation on a water bath at 75 ˚C. The dried mass was stored in desiccators until constant mass was obtained, pulverized and passed through

Direct filling into hard gelatin capsules:

Necessary amounts of the excipients in each formulation shown in the Table .1.were weighed in a silica dish to and heated to about 10˚C above the M.P. of Gelucire44/14 on the water bath. The calculated amount of drug for total mass was added to the molten vehicle with continuous stirring. Then mixture was poured into a plastic injector and filled into hard gelatin capsules at the temp. Close to the solidification point of the material to prevent the precipitation of the solid drug in the molten vehicle.

Phase -solubility study:

15mg of drug was weighed in conical flask.10ml of phosphate buffer (pH 7.4±0.2) alone and as mixed with Gelucires44/14 to give different concentration (0.1, 0.25, 0.5, 0.75, 1%w/v) were added to the conical flask.

Similarly 30 mg of solid dispersion and physical mixtures prepared by different method were weighed in conical flask.10ml of phosphate buffer (pH 7.4 ±0.2) were added to the conical flask.

Table.1.Composition:

All capped conical flask were shaken in a water bath at 37˚C and at temperature corresponding to the M.P. of the Gelucire 44/14 for 48hrs.After this time period. The resulting suspensions were filtered and assayed spectrophotometrically at the wavelength 284nm.

Moisture determination:

To calculate the total amount in solid dispersion prepared by co-evaporation method Karl Fischer titration was performed

Dissolution rate studies:

Dissolution of pure etoricoxib powder as such and from its physical mixture or solid dispersion equivalent to 60mg of etoricoxib was carried out with the USP23 Dissolution Test apparatus (paddle) at 37 ±0.5˚C and 100 rpm using 900ml phosphate buffer (pH 7.4 ±0.2) with 0.5% sodium laurly sulphate (SLS) as dissolution medium (n=3). Sample of solution were withdrawn at predetermined time interval (2ml) and an equal amount of fresh dissolution medium was added .Test samples were filtered suitably diluted and assayed for etoricoxib at 284nm using a blank solution as reference with UV-Visible double beam spectrophotometer .The percentage released of etoricoxib at predetermined time interval was calculate

Thermoscopy (Hot stage microscopy):

HSM of pure drug, solid dispersion and physical mixture were conducted using Mettler Toledo hot stage assembled on a Leica DMLP polarizing microscopy equipped with Leica DC300 (Germany) 0f 200 magnification using IM50 software. A small amount (2-4mg) 0f sample was placed on a glass slide with a cover glass and heated at 3˚C/min. Changes in sample morphology were noted as a function of temperature

RESULTS:

Phase solubility study indicated the drug solubility increased linearly with increase in polymer concentrationas shown in figure.1

Figure.1 Phase solubility diagram of etoricoxib with increasing concentration of Gelucire 44/14 in phosphate buffer (pH 7.4±0.2) at λ max 284 nm

The total moisture content in solid dispersion of etoricoxib with Gelucire 44/14 and Sterotex-KNF, and solid dispersion of etoricoxib with Gelucire 44/14 and Aerosil were found to be 1.42% and 1.9%w/w, respectively

The dissolution of etoricoxib requires phosphate buffer (pH 7.4±0.2) with 0.5% sodium laurly sulphate as dissolution medium. Due to this dissolution was improved up to 99.95% in 120mins (co-evaporation method) and 99.84% in 90min (direct filling method) [shown in figure.2.]a)

Figure.2 Comparative profile of cumulative % drug released of different formulation in phosphate buffer (pH 7.4±0.2) with 0.5% SLS at λ max 284 nm prepared by (a) Direct filling method (b) Co-evaporation method

The HSM examination of the solid dispersion prepared by co evaporation method showed that complete melting of the carrier occur at 75˚C without birefringence (figure 3). In the SD, we observed the birefringence of drug in the molten lipid carriers. After heating up to 75˚C etoricoxib was easily recognized as tiny particles dispersed throughout the molten carrier. Physical mixture showed more birefringence as compared with respective solid dispersion. The birefringence was completely absent at122.40˚C. The SD prepared by direct filling method showed the melting of lipid carrier at 45 ˚C and birefringence in SD was completely absent at 45.2˚C.

Etoricoxib 25ºC Etoricoxib65ºC

Etoricoxib 129ºC Gelucire 44/14 25 ºC

Gelucire 44/14 75ºC Aerosil 25ºC

Aerosil 45ºC Aerosil 81.20ºC

F3 25 ºC F3 75 ºC

F3 75ºC

Figure.3 Hot stage microscopy of (a)etoricoxib (b) Gelucire44/14 (c) Aerosil (e)SD F3

The X ray diffraction of etoricoxib, Gelucire 44/14, physical mixture of formulation F3 and its solid dispersion were shown in Figure 4. The XRD pattern of pure etoricoxib showed numerous distinctive peaks in the region of 10 to 26°(2θ)(11,16.5,23°(2θ) .Solid dispersion showed all the peaks shown by the drug however intensity of the peaks found was markedly reduced and d-spacing increases(8.13554,5.28692,3.87345). It was also observed that some peaks shown by pure etoricoxib are absent. In case of pure Gelucire 44/14, the predominant peaks were observed at 19.2° and 23.3°.

The amorphous drug formulated in the form of solid dispersion tends to recrystallize on storage at high temperature and humidity. Based on the results of initial characterization and model independent parameters the solid dispersion F3 was thought to be superior formulation and hence subjected to accelerated stability studies as per ICH guidelines shown in figure.5 .

Figure.5 Comparative graph showing the ageing effect on% dissolved for F3

DISCUSSION:

From the result of phase solubility studies it was concluded that the solubility of etoricoxib increased linearly with the increase in Gelucire 44/14 concentration. This was due to improvement of wetting characteristics and micellar solubilisation of the drug.

In case of dissolution the use of surfactant is more meaningful due to the presence of natural surfactant like bile salt in the gastrointestinal tract. When the drug was immersed in surfactant solution wetting of the drug could be observed clearly since it rapidly leave the surface and was dispersed in the bulk of the solution , unlike in the pure phosphate buffer. The result was attributed to wetting, micellar solubilization and/or deflocculation.

HSM have demonstrated the ability of melted Gelucire44/14 to dissolve the crystal of etoricoxib at increasing temperatures

The XRD pattern of pure etoricoxib indicated the crystalline nature of etoricoxib. In case of pure Gelucire 44/14 the two predominant peaks confirmed that Gelucire44/14 is made up of mixture of glycerides and fatty acid esters of polyethylene glycol as they had approximately the same parameters as those in PEG6000.The result indicated that the drug in solid dispersion is amorphous as compared to the pure drug. Hence, increased dissolution of the drug was observed because an amorphous or metastable form will dissolve at the fastest rate because of its higher internal energy thermodynamic properties relative to crystalline materials.

From the data of stability studies it was concluded that after 1, 2 and 3 month at 25 ºC and 30 ºC no change in physical appearance was observed. Drug content and dissolution of etoricoxib was almost similar to that at time zero during the whole period of investigation. The improved stability of solid dispersion could be due to the hydrogen bonding in between the drug and the polyglycolized glycerides carriers and the adsorption on the surface of amorphous silicon dioxide .But the result also showed that solid dispersion was unstable at higher temperature and higher relative humidity (40 ºC /75%RH). The visual observation from our study showed that the solid dispersion was sticky due to water uptake and finally it liquefies after 3 month. Dissolution of etoricoxib after 3 month from solid dispersion decreased as a function of storage time. This is due to the change of physical state of the polymer and not that of the drug that is responsible for decreased dissolution properties. Another reason for the reduced dissolution rate has been attributed to possible cross linking of the gelatin shell after storage at stress condition. This is due to the peak melting temperature of the vehicle which is about 44ºC.

CONCLUSIONS:

Solid dispersion prepared from co-evaporation and direct filling method using amphiphillic excipients were effective in improving drug dissolution. The dispersion containing Gelucire 44/14 and Aerosil (F3) prepared from co-evaporation method shows acceptable dissolution compared to pure drug and dispersion prepared from other method. The study revealed that optimum levels of amphiphillic excipients ensure prompt and complete dissolution that are used in oral pharmaceutical formulations.

ACKNOWLEDGEMENTS:

Authors are thankful to NIPER (Mohali) and AIIMS (Delhi) for carrying out the characterization studies

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Received on 10.12.2009 Modified on 23.02.2010

Research J. Pharm. and Tech. 3(2): April- June 2010; Page 578-582