Formulation, Optimization and Characterization of Fast Dissolving Tablet of Celecoxib

 

ABSTRACT:

The main objective in the present investigation to improve the dissolution of celecoxib through the formulation of solid dispersion using water soluble carriers like PVP-K30 and Pearlitol-200 SD by solvent evaporation methods and to convert the optimized solid dispersion in fast dissolving tablet formulation. Celecoxib is new non-steroidal anti-inflammatory drug acting by an inhibition of the synthesis of prostaglandin by inhibiting the activity of the enzyme, cyclooxygenase-2 (COX-2). It is more selective for COX –2 than COX-1. Celecoxib is preferred over conventional NSAIDs as they may lead to serious gastrointestinal complications such as ulcer, severe bleeding and perforation, resulting in hospitalization and even death. Celecoxib is practically insoluble in water and peak plasma levels of celecoxib occur approximately 3 hrs after an oral dose. It is practically insoluble in aqueous fluids. The rate and extent of dissolution of the drug from any solid dosage form determines the rate and extent of absorption of the drug. In the case of poorly water-soluble drugs, dissolution is the rate-limiting step in the process of drug absorption. Celecoxib may pose dissolution related absorption problem. In context of the above principles, a strong need is felt to developed a solid unit dosage form that deliver celecoxib in the GIT in a form that dissolve very rapidly to reduce its onset time to produce quick pharmacological effect.

 

 

INTRODUCTION:

A fast dissolving drug delivery system (FDDDS) can be defined as a dosage form for oral administration, which when placed in mouth, rapidly disintegrates or dissolves and can be swallowed in the form of liquid. Conventional dosage form is very popular in pharmaceutical industries because of its easy transportation and low manufacturing cost. However for pediatrics and geriatrics fast dissolving tablet is preferred due to its swallowing conveniences.  FDDTs disintegrate and/or dissolve rapidly in the saliva without the need for water. Some tablets are designed to dissolve in saliva remarkably fast, within a few seconds, and are true fast-dissolving tablets. Others contain agents to enhance the rate of tablet disintegration in the oral cavity, and are more appropriately termed fast-disintegrating tablets, as they may take up to a minute to completely disintegrate.

 

The target populations for these new fast-dissolving/disintegrating dosage forms have generally been pediatric, geriatric, and bedridden or developmentally disabled patients. Patients with persistent nausea, who are traveling, or who have little or no access to water are also good candidates for FDDTs.

 

MATERIALS AND METHODS:

Materials

Celecoxib was obtained as a gift sample. Pearlitol-200 SD and PVP-K30 from Colorcon Asia Ltd, Goa. Other solvents and reagents used were of analytical grade.

 

Preformulation Study

It is the first step in rational development of dosage forms of drug substance. Preformulation testing is defined as investigation of physical and chemical properties of a drug substance alone and when combined with excipients. The overall objective of preformulation testing is to generate information useful to the formulator in developing stable and bioavailability dosage forms that can be mass-produced.

 

 

Table 1: Formulation of tablets of celecoxib by solid dispersion

 

Formulation of Fast Dissolving Tablet of Celecoxib

Preparation of celecoxib tablets

The solid dispersion of batches H1 to H9 prepared by mixing solid dispersion of drug and PVP-K30 were mixed with a directly compressible Ac-di-sol (0-4%), Pearlitol-200SD, a glidant lubricant bland containing talc (2 %), magnesium stearates (1 %), and Lactose monohydrate as quantity sufficient for 3 min. This blend was compressed into tablets using 12 mm diameter flat face round tooling on a Rimek-I rotary tablets machine (Rimek minipress-I MT, Karnavati Engineering Ltd., Ahmadabad, India). The crushing strength of tablets was kept between 3 and 3.5 kg / cm². The prepared tablets were stored in tightly closed glass container and evaluated for various parameters.

 

A 3² full factorial design was adapted to optimize the variables⁶. Amount of Ac-Di-Sol (X1) and amount of Pearlitol-200SD (X2) were selected as independent variables. Cumulative % drug release was selected as dependent variables (response; Y). The preparation and evaluation method for tablets and amount of celecoxib were kept constant for all the trials. The composition of factorial batches H1 to H9 is shown in Table-1.

 

Evaluation of tablets for hardness and drug content

Compressed tablets were then evaluated for hardness¹, friability², and drug content. Monsanto type hardness tester measured hardness. For drug content analysis take two tablets were accurately weighed and finely powdered. Quantity of powder equivalent to 100 mg of celecoxib was taken into a 100 ml volumetric flask and dissolved in water containing 1% SLS. 5 ml of the filtrate was diluted to 100 ml with water containing 1% SLS and assayed for drug content at 254.0 nm using UV Spectrometer  (Shimadzu UV- 1700 UV/ Vis double beam Spectrophotometer, Kyoto, Japan).

 

Evaluation of tablets for wetting time

For determination of wetting time, a filter paper was kept in a petridish having diameter of 9.5 cm and containing 15 ml of purified water. A tablets having small amount of amaranth powder on the upper surface and tablet was placed on the filter paper. The time required to developed red color on the upper surface of the tablets was recorded as wetting time³.

 

Evaluation of tablets for disintegration time

One tablet was placed in each tube of disintegration apparatus (USP Disintegration test apparatus, model ED-2L, Electrolab, Mumbai, India). Disintegration test⁴ was carried out using distilled water as a disintegrating media at 24 ± 2⁰ C. The tablet should disintegrate within 3 min to pass the test.

 

In vitro dissolution study^{5, 6}

In vitro dissolution study of tablets were conducted using USP dissolution apparatus II (model TDT-06T, Electrolab) at 50 rpm, using distilled water containing 1% SLS as a dissolution media^{9, 10} maintaining at 37 ± 0.5⁰ C. Sample were withdrawn at various time intervals, filtered through a Whatman filter paper, diluted and assayed at 254 nm using UV/ Vis double beam spectrometer.

 

Optimization of formulation variables

Table 2: Composition of factorial batches

Batch	Variable level in coded form
	X1	X2
H1 H2 H3 H4 H5 H6 H7 H8 H9	-1 -1 -1 0 0 0 1 1 1	-1 0 1 -1 0 1 -1 0 1
Independent variable                            Real values                                              low(-1)          medium(0)            high(1) Ac-Di-Sol        (X1)            3 %              4 %                      5 % Pearlitol-200SD (X2)           6%               8 %                     10 %
All the batches contain 100 mg of celecoxib

 

Comparison of best batch with marketed tablets

The optimized tablet formulation (H6) was compared with conventional marketed tablets for in vitro drug release profile and Mean Dissolution Time. Percentage of drug dissolved in 10 min (Q₁₀) and Mean Dissolution Time were considered for comparison.

 

Accelerated stability study of best batch (H6)

In order to determine the change in in vitro release profile on storage, stability study of batch H6 was carried out at 40⁰ C in a humidity chamber having 75% RH. Sample were withdrawn after one-week interval and evaluated for change in invitro drug release pattern, hardness and disintegration time. The similarity factor (f₂) was applied to study the effect of storage on formulation H6

 

RESULTS AND DISCUSSION:

Results of hardness, friability and drug content and in vitro dissolution

Hardness of the prepared tablets was found to be 3.0 to3.5 kg /cm². Percentage friability of the tablets was observed in the range of 0.77 to 0.81 that was within the acceptable limit the % assay found was 101 ± 3 %, which was within the acceptable limit. 

 

Table 3: Cumulative percentage release of celecoxib from formulated tablets with factorial design

 

In vitro release profile of celecoxib from formulated tablet

 

Comparative cumulative % drug release Q₁₀ and mean dissolution time of celecoxib from formulation H6 and marketed product

 

Drug release profile of celecoxib before and after stability study of best batch H6

Result of comparison with marketed tablets

The batch H6 was compared with three-marketed tablet formulation for in vitro drug release profile (Q₁₀) and Mean Dissolution Time (MDT). The value of Q₁₀ for H6 was higher than marketed tablets indicating superiority of the formulation H6 and MDT was lower than the marketed tablets. Therefore formulation H6 was considered better formulation with higher and rapid in vitro dissolution.

 

Result of stability study of best batch (H6)

Sample withdrawn after three month showed no change in invitro drug release profile. The value of similarity factor was 90.81 indicating good similarity of dissolution profile before and after stability studies.

 

Comparison of formulation H6 with marketed celecoxib tablets

 

CONCLUSION:

In formulation lactose monohydrate was incorporated as a diluent to improve palatability. A 3² full factorial design was employed for preparation of tablets possessing optimized characteristics (batches H1 to H9). The amount of Ac-di-sol (X₁) and Pearlitol (X₂) were selected as independent variables. Cumulative % drug release selected as dependent variable (response; Y). Full and reduced models were derived for the prediction of the response variable, Y. Based on result of multiple linear regression analysis, it was concluded that higher dissolution of tablet could be obtained when X₁ is kept at optimum level and X₂ is kept at high level. Promising batch (H6) was compared with three marketed samples (CMT A, CMT B and CMT C) of celecoxib tablets for in vitro drug release after 20 min. Tablets of batch H6 exhibited better drug dissolution after 20 min than the marketed tablets. Stability study of batch H6 after three month showed no change in invitro drug release profile. It was concluded that by adopting a systematic formulation approach, an optimum point could be reached in the shortest time with minimum efforts.

 

REFERENCE:

1.     Maria Rosaria Lauro, Maria Luisa Torre, Lauretta Maggi, Francesco De Simone, Ubaldo Conte, Rita Patrizia Aquino Drug Development and Industrial Pharmacy Volume 28, Number 4 / 2002, 371-379

2.       Giovanni Filippo Palmieri, Franco Cantalamessa, Piera Di Martino, Cinzia Nasuti, Sante Martelli Drug Development and Industrial Pharmacy Volume 28, Number 10 / 2002, 1241-1250

3.       Han-Gon Choi, Dae-Duk Kim, H. Won Jun, Bong-Kyu Yoo, Chul-Soon Yong Drug Development and Industrial Pharmacy Volume 31, Number 7 / 2005, 697-707

4.       Evangelos Karavas, Georgios Ktistis, Aristotelis Xenakis, Emmanouel Georgarakis Drug Development and Industrial Pharmacy Volume 31, Number 6 / 2005, 473-490

5.       Chen Liu, Junhua Wu, Bin Shi, Yuanxing Zhang, Tiankun Gao, Yuanying Pei Drug Development and Industrial Pharmacy Volume 32, Number 1 / 2006, 115 – 123

6.       Mooter, G.V., Wuyts, M., Blaton, N., Busson, R., Grobrt, P., Augustijns, P and Kinget, R., Eur. J. Pharm. Sci., 2001, 12, 261

7.       Patel, D.M., Shah, R.R. and Jogani, P.D., Indian J. Pharm. Sci., 2004,66, 49

8.       Sandhya, K.G., Ganesan, V. and Remi, S.L., The Indian Pharmacist, 2004, May 59

9.       Devi, V.K., Vijayalaxmi, P. and Avinash, M., Indian J. Pharma. Sci., 2003, September-October, 542.

10.    Okonogi, S., Oguchi, Y., Yonemochi, E., Puttipipatkhachorn, S. and Yamamoto, K., Int. J. Pharm., 1997, 156, 175.

11.    H. Friedrich, A. Nada, Roland Bodmeier Drug Development and Industrial Pharmacy Volume 31, Number 8 / 2005, 719-728

12.    P. Mura, J. R. Moyano, M. L. González-Rodríguez, A. M. Rabasco-Alvaréz, M. Cirri, F. Maestrelli Drug Development and Industrial Pharmacy Volume 31, Number 4-5 / 2005, 417-424

13.    Hadi Valizadeh, Ali Nokhodchi, Nahid Qarakhani, Parvin Zakeri Milani, Shirzad Azarmi, Davood Hassanzadeh, Raimar Löbenberg Drug Development and Industrial Pharmacy Volume 30, Number 3 / 2004, 303-317

14.    Leticia S. Koester, Paulo Mayorga, Valquiria L. Bassani Drug Development and Industrial Pharmacy Volume 29, Number 2 / 2003, 139-144

15.    Lachman, L. and Lieberman, H.A., In; Pharmaceutical Dosage Forms, Tablets, Vol. 2, Marcel Dekker, Inc., New York.

16.    Indian Pharmacopoeia, 2^nd Edn. Controller of Publications, India, New Delhi, 1966,740

17.    Polli, J.E., Rekhi, G.S., Augsburger, L.L. and Shah, V.P., J. Pharm.Sci. 1997,86,690

18.    British Pharmacopoeia, 2005 Volume I, page no 40,41.

 

 

 

Received on 01.08.2012       Modified on 16.08.2012

Accepted on 21.08.2012      © RJPT All right reserved