Issn No: 0976-3090

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RESEARCH ARTICLE

FORMULATION OF CELECOXIB IN TO IMMEDIATE RELEASE TABLETS

BHARATH KUMAR DADE1* and ARUNA KANTH CHAVALA2 1. Hindu College of pharmacy, Guntur, (A.P), India.

2. Governor State University, Illinois, United States of America.

ABSTRACT Studies were carried out on enhancement of solubility and dissolution rate of Celecoxib, a poorly soluble drug by solid dispersion technology.In the solvent evaporation and physical mixtures techniques, the polymers Croscarmellosesodium, Crospovidone, cd were evaluated as carriers in solid dispersions for enhancing the solubility and dissolution rate of Celecoxib. Solid dispersions of Celecoxib with polymers were prepared at different ratios of drug and carrier and the dispersions were evaluated for drug content uniformity, dissolution rate and efficiency in comparison to Celecoxib as such. The feasibility of formulating the solid dispersions into compressed tablets was also investigated. The solid dispersions of Celecoxib with polymers could be prepared by solvent evaporation method employing methanol as solvent for Celecoxib.Solid dispersions in the polymer fraction gave rapid and higher dissolution of Celecoxib The increasing order of dissolution profiles given by polymers is CCS>CP>cd.Among the polymer ratios the increasing order of dissolution is given as 1:3 < 1:2 < 1:1.Formulation of solid dispersions (co-evaporates) into compressed tablets resulted in increase in the dissolution rate of Celecoxib. The enhanced dissolution rate and efficiency of solid dispersions were retained. The work resulted in the development of new technology of enhancing the solubility and dissolution rate of insoluble drugs (such as Celecoxib) by solid dispersion technology (physical mixtures and co-evaporates). The solid dispersions with high solubility and dissolution rate could be employed in the formulation of immediate release tablets.

KEYWORDS: Celecoxib, Physical Mixtures, Co-evapourates, Cyclodextrins

INTRODUCTION The areas of current interest which have a significant impact on clinical therapy are enhancement of dissolution rate and bioavailability of insoluble (1) and poorly soluble drugs. In general this drug comes under the category of the poorly soluble drugs. Poorly soluble drugs are the ones which do not readily dissolve in the gastric environment and hence they are not available at the desired therapeutic effect for producing the desired action. These drugs generally exhibit the characters of low solubility, variable bioavailability and variable drug absorption in their pure form. They also pose problems in the design of the controlled release products due to their insoluble characters. In order to improve the efficiency of the drug at the desired site, they should be readily dissolved in the specific environment.

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Dissolution and absorption of drugs from solid dosage forms:

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Scheme-l indicates the processes involved in the absorption of drugs after oral administration in the form of a tablet or capsule. Dissolution of the drug occurs not only from the particles of drug ultimately produced but also to a small degree from intact dosage form before its disintegration and from fragments and agglomerates produced after disintegration. In vivo process 4 (scheme-I) involves the absorption of the drugs. The drug dissolved in the gastrointestinal contents must diffuse in the aqueous fluids to the gastro-intestinal barrier and then be transported through the barrier to the circulation. When the dissolution(2) process is very much lower than the other processes, then the dissolution essentially and completely controls absorption rate. Thus dissolution rate of a poorly soluble drug can be increased by increasing either solubility or surface area or both. These two variables can be altered by the following techniques: 1. Controlling the solubility of weak acid or base by buffering either the entire dissolution medium or the microenvironment i.e. the In the present study Solid Dispersion Technology is used to enhance the solubility and dissolution of the poorly soluble drug Etoricoxib. SOLID DISPERSION TECHNOLOGY (3) Solid Dispersion is defined as the dispersion of one or more active ingredients in an inert carrier or matrix at solid state prepared by the melting, solvent or melting solvent method. This solid dispersion can be broadened to include certain nanoparticles, microcapsules and other dispersions of drug in polymers prepared by using any one of the processes. Most of the solid dispersion systems initially focused on producing increased dissolution rates and diffusion layer surrounding a particle through the use of buffers and salts. 2. Controlling the solubility of the drug through the choice of physical state such as crystal form, its hydrates its amorphous form and so on. 3. Controlling the surface area of the drug through control of particle size.

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sustained release of drugs with improved solubility and stability. Solid dispersions have been classified mainly into six major categories as: 1. Simple Eutectic mixtures 2. Solid solutions 3. Glass solutions of suspension 4. Compound or complex formations 5. Amorphous precipitates 6. Any combinations of these groups. METHODS OF PREPARATION(4): In general the various methods of preparing solid dispersions are: 1. Fusion Process 2. Solvent Process 3. Fusion Solvent method. CHARACTERIZATION OF SOLID DISPERSIONS5: A number of methods have been used to characterize solid dispersions they are: 1. Thermal methods of analysis Differential thermal & thermomicroscopial methods 2. Powder X ray diffraction 3. Microscopial studies 4. Spectroscopic studies i.e. IR 5. Dissolution rate determination 6. Thermodynamic investigation 7. Dynamic dialysis. The most important and frequently used methods among these are thermo analytical, powder X-RD and dissolution rate. EXPERIMENTAL INVESTIGATIONS Material used: 1. 2. 3. 4. Celecoxib (A gift sample from Hetero drugs Ltd, Hyderabad, A.P). Croscarmellosesodium (A gift sample from Hetero drugs Ltd, Hyderabad, A.P). Crospovidone (A gift sample from Hetero drugs Ltd, Hyderabad, A.P) Lactose (Loba Chemie, Mumbai) 5. Methanol.

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6. 0.1N Hcl (35-38%) (Finar Chemicals, Ahmedabad) 7. magnesium stearate (s.d fine chem., Mumbai) 8. microcrystalline cellulose (Kemphasol, Bombay) 12. Starch (Hi-Pure Fine Chem Industries) 13. Sodiumlaurylsulphate (s.d fine chem., Mumbai) UV SPECTROPHOTOMETRIC METHOD FOR THE ESTIMATION OF CELECOXIB: A spectrophotometric method based on the measurement of absorbance of Celecoxib at 235nm in various solvents was employed in the present study. preparation of the Standard Solution: 100mg of Celecoxib was dissolved in methanol in a 100ml volumetric flask and the solution was made up to the volume with methanol. PREPARATION CELECOXIB Preparation of Physical Mixtures of Celecoxib: Physical mixtures of the drug (CEL) with the excipients in the desired ratios were prepared by mixing thoroughly for 5min in a mortar until a homogeneous mixture was obtained. This was passed through mesh no.#100 desiccated environment.. Preparation of Co-evaporates of Celecoxib: The Co-evaporates were prepared by using the Solvent Evaporation Method(6). Etoricoxib was dissolved in a solvent blend of methanol and dichloromethane (1:1) to get a clear solution in a 100ml round bottom flask. The excipients was then added and dispersed. The solvent in the mixture was removed by evaporation at 50oC under pressure while mixing the contents. INCLUSION COMPLEXES ARE PREPARED BY TWO METHODS and stored in OF SOLID DISPERSIONS OF

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1) KNEADING METHOD(7): The drug (CEL) and the cyclodextrin (cd) were triturated in a mortar with a small volume of a solvent blend of water methanol (3:2). The thick slurry was kneaded for 45 mins and then dried at 550C until dry. The dried mass was pulverized and sieved through mesh No.100. 2) CO-EVAPORATION METHOD(8): Celecoxib was dissolved in a solvent blend of methanol and dichloromethane (1:1) to get a clear solution in a 100ml round bottom flask. The excipients was then added and dispersed. The solvent in the mixture was removed by evaporation at 50oC under pressure while mixing the contents. The mass obtained was pulverized, mixed and passed through mesh no. #100. In each case, solid dispersion systems as well as physical mixtures were prepared employing various ratios of Drug: Excipients such as 1:1, 1:2, and 1:3. All the Solid dispersions and Physical mixtures prepared were evaluated for 1. Drug Content estimation 2. Dissolution Rate studies 3. Physical Studies. FORMULATION OF THE SOLID DISPERSIONS INTO TABLET DOSAGE FORMS Formulation of Celecoxib Tablets Tablets each containing 90 mg of Celecoxib were formulated employing Celecoxib Co-evaporates

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of Croscarmellosesodium, Crospovidone and solid dispersions of -cd by kneading process (1:3&1:1) along with the usual tablet excipients. The formula of the Celecoxib tablets prepared is given in Formulation table 4.46. Preparation of Tablets Celecoxib tablets were prepared by conventional direct compression method as per Formula given in table 03. solid dispersion, Celecoxib or its microcrystalline

cellulose , Croscarmellose sodium, talc, magnesium stearate were taken in a mortar and triturated then it is weighed and compressed in to tablets Evaluation of Tablets (9) The tablets prepared were evaluated for drug content, hardness, friability, disintegration time and dissolution rate. Dissolution rate studies on Etoricoxib Formulations Dissolution rate of Etoricoxib as such from formulations was studied using lab India DISSO 2000, an 8 stage dissolution rate testing apparatus, with a paddle stirrer. The dissolution fluid was 900ml of 1% SLS. The formulation of Celecoxib were placed in the dissolution medium, a speed of 75 rpm and a temperature of 370.5oC were used in each test. Samples of dissolution medium (5ml) were withdrawn at different time intervals, suitably diluted and assayed for Etoricoxib by measuring absorbance at corresponding absorption maximum. The dissolution experiments were conducted in triplicate.

Fig. 1 :Calibration Curve for the Estimation of CEL in Methanol

1
absorbance (nm)

0.5

0
0 concentration 5 10) (mcg/ml 15

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Fig. 2: DISSOLUTION DATA OF CELECOXIB AS SUCH AND FROM ETO--CD INCLUSION COMPLEXES BY KNEADING METHOD

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Fig. 3 :DISSOLUTION DATA OF CELECOXIB AS SUCH AND FROM ETO--CD INCLUESION COMPLEXES BY SOLVENT EVAPORATION METHOD

100 90 80
%dossolved(mg)

90 80 70
%dissolved(mg)

70 60 50 40 30 20 10 0 0 20 40 Time(min) 60 80

PURE DRUG 1:1by kneading 1:3by kneading 1:5 by kneading

60 50 40 30 20 10 0 0 20 40 Time(min) 60 80

PURE DRUG 1:1bycoevaporation 1:3bycoevaporation 1:5bycoevaporation

Fig. 4: DISSOLUTION DATA OF CELECOXIB AS SUCH AND FROM ETO-CCS PHYSICAL MIXTURE

Fig . 5 DISSOLUTION PROFILES OF CEL AS SUCH AND FROM ETO-CP SOLVENT EVAPORATION METHOD

90 80
%dissolved(mg)

80 70 60
%dissolved(mg)

70 60 50 40 30 20 10 0 0 20 40 Time(min) 60 80 PURE DRUG 1:1CCS PM 1:2 CCS PM 1:3 CCS PM

50 40 30 20 10 0 0 20 40 Tim e(m in) 60 80

PURE DRUG 1:1CP PM 1:2 CP PM 1:3 CP PM

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TABLE: 01Dissolution parameters of CELECOXIB solid dispersions by physical mixtures: INCLUSION COMPLEX/SOLID DISPERSION Pure Drug CEL :cd(1:1) CEL :cd(1:3) CEL :cd(1:5) CEL :CCS(1:1) CEL:CCS(1:2) CEL:CCS(1:3) CEL:CP(1:1) CEL:CP(1:2) CEL:CP(1:3) T10 8 5 3 3 6 4 3 6 4 3 T50 >60 32 18 16 43 30 28 47 39 28 T90 >60 >60 60 57 >60 >60 >60 >60 >60 >60 %DISSOLVED IN 10min 5.08 20.76 31.01 29.37 14.18 18.48 23.54 13.42 15.57 19.75 D.E30 % 14.26 24.03 38.33 39.33 22.5 28.33 30.33 16.66 21.66 28.33 K1 0.0105 0.0216 0.0382 0.0389 0.0163 0.0218 0.029 0.0145 0.0172 0.0232 r' VALUE 0.9757 0.9983 0.9978 0.9879 0.9975 0.995 0.9987 0.9977 0.9976 0.997

TABLE: 02 Dissolution parameters of CELECOXIB solid dispersions by co-evaporation: INCLUSION COMPLEX/SOLID DISPERSION pure drug CEL : cd(1:1) CEL :cd(1:3) CEL :cd(1:5) CEL:CCS(1:1) CEL:CCS(1:2) CEL:CCS(1:3) CEL:CP(1:1) CEL:CP(1:2) CEL:CP(1:3)

T10 8 7 3 3 3 2 2 4 3 2

T50 >60 52 27 25 19 15 10 27 22 17

T90 >60 >60 >60 >60 >60 48 40 >60 >60 60

%DISSOLVED IN 10min 5.08 13.04 23.67 22.15 29.75 36.2 46.33 22.91 26.33 30.63

D.E30 % 14.26 18.33 30 30.66 39.16 45.33 56.66 28.33 33.33 40

K1 0.0105 0.0135 0.0232 0.26 0.0366 0.0465 0.0628 0.0257 0.0308 0.0391

r' VALUE 0.9757 0.997 0.994 0.997 0.999 0.995 0.995 0.998 0.998 0.998

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TABLE: 03 FORMULATION OF THE TABLETS: (FOR ONE TABLET)

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S.NO 1 2 3 4 5 6 7 8 9 10 11

Ingredients(mg/tab) Celicoxib CEL : cd(1:1) CEL : cd(1:3) CEL :CCS(1:1) CEL :CCS(1:3) CEL :CP(1:1) CEL :CP(1:3) MCC CCS Talc Magnesium Stearate Total weight of tablet(mg)

F1 90 _ _ _ _ _ _ 390 10 5 5 500

F2(1:1) _ 180 _ _ _ _ _ 300 10 5 5 500

F3(1:3) _ _ 360 _ _ _ _ 120 10 5 5 500

F4(1:1) _ _ _ 180 _ 180 _ 300 10 5 5 500

F5(1:3) _ _ _ _ 360 _ 360 120 10 5 5 500

F6(1:1) _ _ _ 180 _ 180 _ 300 10 5 5 500

F7(1:3) _ _ _ _ 360 _ 360 120 10 5 5 500

FIG . 06 DISSOLUTION PROFILES OF FORMULATIONS OF CEL AS SUCH, CEL-CD TABLETS AND MARKETED SAMPLES

FIG 07: DISSOLUTION PROFILES OF FORMULATIONS OF CEL AS SUCH, CEL-CCS TABLETS AND MARKETED SAMPLES

100 90 80 70 60 50 40 30 20 10 0 0 20 40 Time(min) 60 80

120
PURE ETO FM
%dissolved(mg)

100 80 60 40

PURE ETO FM ETO marketed sample ETO:CCS 1:1FM ETO:CCS 1:3FM

%dissolved(mg)

ETO marketed sample ETO: CD 1:1FM ETO: CD 1:3FM

20 0 0 20 40 Time(min) 60 80

EVALUATION OF TABLETS: TABLE: 04 DRUG CONTENT ESTIMATION FOR FORMULATIONS OF CEL Vol.1 (2) Nov-Dec-2010

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TYPE OF FORMULATION F1 F2 F3 F4 F5 F6 F7 PERCENT DRUG CONTENT 99.35 0.033 99.85 0.120 99.82 0.043 99.71 0.086 99.50 0.068 98.320.122 99.020.213

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TABLE: 05 DISINTEGRATION, HARDNESS, FRIABILITY AND WEIGHT VARIATION TESTS S. No 1. 2. 3. 4. 5. 6. FORMULATION 1:1 CEL- CD 1:3 CEL - CD 1:1 CEL -CCS 1:3 CEL -CCS 1:1 CEL -CP 1:3 CEL -CP DISINTEGRATION TIME (min) 4 5 3 2 4 3 HARDNESS (kg/cm2) 3.5 3.7 4.0 4.3 4.5 4 FRIABILITY (%) 0.344 0.722 0.992 0.692 0.762 0.956 WEIGHT VARIATION ( %) 2.5 1.8 2.1 1.2 2.6 1.9

RESULTS AND DISCUSSION

t

The polymers Croscarmellosesodium, Crospovidone, -CD were evaluated as carriers in physical mixtures and co-evaporates for enhancing the dissolution rate of Celicoxib, a poorly soluble drug. Celicoxib Polymer mixtures and co-evaporates were prepared at three different ratios of drug: carrier namely 1:1, 1:2, and 1:3. PHYSICAL MIXTURES: Physical mixtures gave improved and higher TABLETS

y.dt 100

y100t

Celicoxib in the form of solid dispersions (1:1), (1:3) for CCS, CP and CD were formulated into compressed tablets with the usual tablet excipients. The tablets were prepared by direct compression method. All the tablets were of good quality with regard to drug content, hardness and friability. They fulfilled the official requirements with regard to the above. The two formulations exhibited much difference in disintegration and dissolution characteristics. Tablet formulation (1:3), prepared gave relatively rapid and higher dissolution than formulation (1:1) prepared in both polymers. The dissolution profiles of 1:3 and 1:1 for CCS, CP and CD are shown in Figures 2,3,4 325

dissolution of Celicoxib when compared to pure drug. Etoricoxib dissolution followed first order kinetics. T50 (Time for 50% dissolution), T10(Time for 10% dissolution) and Dissolution Efficiency (DE30) values for physical mixtures were calculated from the dissolution data and profiles and are given in Tables 2 Dissolution efficiency DE30 values were calculated as per KhanR using the formula. Dissolution Efficiency (DE) = Vol.1 (2) Nov-Dec-2010

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The dissolution profile for Etoricoxib formulations followed first order kinetics. The first order dissolution plots for CCS, CP and CD formulations are shown in figures 5,6,7 SUMMARY AND CONCLUSIONS The following conclusions drawn from the results of investigation: Studies were carried out on enhancement of solubility and dissolution rate of Celicoxib, a poorly soluble drug by solid dispersion technology. (i) (ii) Physical mixtures technique. Solvent evaporation technique.

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dispersion technology (physical mixtures and coevaporates). The solid dispersions with high solubility and dissolution rate could be employed in the formulation of immediate release tablets. BIBLIOGRAPHY 1. Noyes, A. A. and Whitney, W.R., J. Am.

Chem. Soc., 1897, 19, 930. 2. Leonards, J. R., Clin. Pharmacol. Ther. 4, 1963 476. 3. Truitt, E. B. and Morgan, A.M., J. Pharm. Sci., 1964, 53, 129. 4. Javid, K. a. and Eadwallachr, D. E., J. Pharm. Sci., 1964, 53, 129. 5. Neloson, E., J. Pharm. Sci., 1958, 47, 30. 6. Chowdary, K. P. R. and Ravi Kumar, T., Indian J. Pharm. Sci., 1983, 45, 228. 7. Chowdary, K. P. R. and Srirama Murthy, A., Indian Drugs, 1985, 22, 538. 8. Wan, S. H., Pentikainnen, P. L. and Azarnoff, D. L., J.Pharm. Sci., 1974, 63, 708. 9. Nelson, E., Knoechel, E.L., Hamlin, W. E., and Wagner, J. G., J. Pharm. Sci., 1962, 51, 509. 10. Nelson, E., J. Amer. Pharm. Assoc. Sci. Ed., 1959, 48, 96.

In the solvent evaporation and physical mixtures techniques, the polymers Croscarmellosesodium, Crospovidone, cd were evaluated as carriers in solid dispersions for enhancing the solubility and dissolution rate of Celicoxib. Solid dispersions of Celicoxib with polymers were prepared at different ratios of drug and carrier and the dispersions were evaluated for drug content uniformity, dissolution rate and efficiency in comparison to Celicoxib as such. The feasibility of formulating the solid dispersions investigated. The solid dispersions of Celicoxib with polymers could be prepared by solvent evaporation method employing methanol as solvent for Celicoxib.Drug content was uniform in a batch of physical mixture and co-evaporates prepared.Solid dispersions in the polymer fraction gave rapid and higher dissolution of Celicoxib. The increasing order of dissolution profiles the given by polymers ratios is the CCS>CP>cd.Among 1:1. The work resulted in the development of new technology of enhancing the solubility and dissolution rate of insoluble drugs (such as Celicoxib) by solid polymer into compressed tablets was also

ADDRESS FOR CORRESPONDENCE

bharathdade@gmail.com

increasing order of dissolution is given as 1:3 < 1:2 <

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