DESIGN AND EVALUATION OF MOUTH DISSOLVING FORMULATIONS OF CELECOXIB

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1 DESIGN AND EVALUATION OF MOUTH DISSOLVING FORMULATIONS OF CELECOXIB Daljit Masih* & Rajesh Gupta Shri Jagdish Prasad Jhabarmal Tibrewala University, Jhunjhunu, Rajasthan ABSTRACT The present investigation deals with design and development of mouth dissolving Celecoxib tablet by direct compression method. The Celecoxib tablet prepared using Sodium starch glycolate, Microcrystalline cellulose as binder. powder blend was evaluated for bulk density, tapped density, Angle of repose and Hausner's Ratio. The different tablet (C1-C8) were prepared by direct compression method and evaluated for Weight variation, Hardness, Thickness, Friability, Drug content, Wetting time, Water absorption ratio and In-vitro disintegration time. In vitro drug release profile of different batches (C1-C8) was done by using USP type II apparatus. The optimized batch C7 shows the better release (98.17%). The result indicates that C7 formulation exhibited excellent wetting time, water absorption ration and disintegration time as compared to other formulations. Moreover the C8 formulation exhibited lowest wetting time and disintegration time; and highest water absorption ratio. Keywords- Celecoxib, mouth dissolving tablet, Friability, Drug content, Pre formulation studies 1. Introduction Oral drug administration is perhaps the most appealing route for drug delivery (1). Of the various orally administered dosage forms, the tablet is one of the most preferred (2, 3). In recent years, the task of developing rapidly disintegrating tablets has been accomplished by using suitable diluents and super disintegrants. Celecoxib is a new non-steroidal, anti-inflammatory drug (NSAID) that acts by inhibiting the activity of the enzyme cyclooxygenase-2 (COX-2) (4 7). It is used mainly for osteoarthritis, rheumatoid arthritis, and dysmenorrhea (8 10). Celecoxib is practically insoluble in water (0.003 mg/ml), and peak blood levels are reached between 2 and 3 h after oral administration. Potential bioavailability problems are prevalent with extremely hydrophobic drugs (aqueous solubility less than 0.1 mg/ml at 37 C) due to erratic or incomplete absorption from the GIT (11). So in the present study attempt has been made to develop and evaluated mouth dissolving tablet of Celecoxib to overcome the above said problems. 2. Material and Methods Celecoxib and excipients used in study were obtained from Centaur Pharmaceuticals Pvt. Ltd Goa. Corresponding Author* Daljit Masih 1 P a g e

2 Drug excipients interaction study by FTIR To check the compatibility of drug and polymer in formulation the FTIR study was carried out. Formulation mixture (10 mg) and 400 mg of KBr were triturated in a mortar. A small amount of the triturated sample was seized and kept on to the sample holder and examined from 4000cm -1 to 400cm -1 in FTIR Spectrophotometer. The spectrum obtained was matched with that of the peaks obtained from the FTIR study of the pure drug sample and interpreted for the interaction of drug and excipients if any. 3. Formulation of Celecoxib tablets Eight formulations (C1-C8) were prepared by mixing various ingredients in a mortar and pestle as mentioned in Table-1.This powder blend was then allowed to dry for few minutes and then again mixed well and passed through sieve no 60. Then blend was used for further processing. Table -1 Formulation of mouth dissolving Celecoxib tablets Ingredients (mg) C1 C2 C3 C4 C5 C6 C7 C8 Celecoxib Crospovidone Sodium starch glycolate Microcrystalline cellulose Mannitol Mg. Stearate Talc Aspartame Theoretical Weight Evaluation of pre-compression characteristics of powder blend Bulk density The bulk density was measured using standard procedure. The following formula was used to determine the bulk density: Bulk Density = W / V W= Weight of the powder V= Volume of the powder Tapped density Tapped density was determined; the mixtures were filled in a measuring cylinder. After that the measuring cylinder was tapped 100 times. Measure the weight of the total powders. The tapped density was calculated by applying following formula: Tapped Density = W / V tapped W = weight of the powder V tapped =Tapped Volume of the powder Angle of repose In this process the fennel was placed above graph paper at 2 P a g e

3 distance of 6 cm. The powder kept on fennel and slowly removed the fennel. The scale was used to measure the height of the heap. The angle of repose was calculated by applying following formula: θ= tan -1 h / r Where, h = height of heap of granular bed, r = radius of heap of granular bed. Hausner s ratio Hausner s ratio was calculated by using following formula and it was expressed in percentage H=D t /D b Where D t denoted the tapped density of the powder D b denoted the bulk density of the powder 5. Compression of powders into tablets Tablets of powder blend were prepared by direct compression method, using 10mm diameter, flat faced punches. Before compression of powder into tablets, the Lubricant (talc) and glidant (magnesium stearate) were mixed to smooth ejection of tablets from machine. 6. Evaluation of compression characteristics of tablets The thickness, friability, hardness, weight variation and dissolution test were evaluated for prepared tablets using standard procedures. Weight variation test In this process the 20 tablets were weighed separately. The average weight of one tablet was calculated by taking average mean. On I.P. it has mentioned that not more than 2 tablets produce distinctive weight. As per I.P note more than 2 of the distinctive weights from the mean weight, and none should be aberrant by longer than twice that percentage given in the monographs. Thickness test By the help venirer caliper, we measure the thickness of the tablets in terms of micrometer. The averages of three readings were noted and the results of mean were recorded (n = 3) Hardness test The Monsanto hardness tester was used to determine the hardness of formulated tablets. The hardness was calculated in respect to kg/cm 2. Thrice readings were measured and average was noted. Friability test The Roche friabilator was used to measure the abrasion rate of formulated tablets. Measure the weight of 20 tablets and kept in the friabilator chamber. The friabilator was rotted at speed of 25 rpm for 4 min. After completion of rotation of friabilator tablets were weighted and by the help of formula the percentage weight loss was calculated. Drug content The drug content was calculated by triturating the three tablets in a mortar with pestle to get fine powder. Taken powder equivalent weight of one tablet and was dissolved in ph 6.8 phosphate. Measure the absorbance of diluted sample of Celecoxib at 252 nm, 3 P a g e

4 using UV-Visible Spectrophotometer. The drug content was calculated by using standard calibration curve. Wetting time The wetting time was calculated by placing the tablets in Petridish. The Petridish was consisting of 6 ml of purified water along with tissue paper folded two times. The time required for complete wetting of tablets was measured. Water absorption ratio The procedure used in wetting time was applied for the determination of water absorption ratio. Water absorption ratio R was calculated using equation. In-vitro disintegration time The disintegration test apparatus was used to determine the disintegration of mouth dissolving tablets. Each tube of basket of disintegration apparatus containing formulated tablet. The ph 6.8 (simulated saliva fluid) used for the determination of disintegration of tablets at temperature 37±2 C. The total time required to complete breakdown of the tablets was observed and noted. In-vitro drug release study The in vitro release of mouth dissolving tablets was determined by using tablet dissolution test apparatus USP XXIII, apparatus I. The media used in dissolution apparatus was phosphate buffer ph6.8 (900 ml) and maintained it at 37 ± 1 C. The sample of 10 ml was withdrawn at different interval and volume of media was maintained by putting fresh media in chamber. The aliquots were evaluated spectrophotometrically at 252 nm for Celecoxib. Kinetic model of drug release The different kinetics model of drug release was calculated for all the formulations: Zero order kinetics was calculated by plotting graph between cumulative percent drug released vs. time First order kinetics was calculated by plotting graph between log cumulative percent drug retained vs. time Higuchi s equation was calculated by plotting graph between log cumulative percent drug released vs. square root of time Peppas equation was calculated by plotting graph between log of cumulative percentage release Vs log time 7. Results and Discussion Drug polymer compatibility studies FTIR of the best formulation (C7) of Celecoxib mouth dissolving tablet shows that the peaks obtained between the ranges of main principle peaks and were found to be very near to the FTIR of pure drug Celecoxib. No major deviation in peaks were obtained in IR spectra, hence this indicates that drug was compatible with other tablet ingredients (Fig 1 & Fig 2). 4 P a g e

5 Fig 1: FTIR spectra of Celecoxib Fig 2: FTIR spectra of Celecoxib excipient mixture 5 P a g e

6 Characterization of mouth dissolving tablets Evaluation of pre-compression characteristics of Celecoxib powder blend The Pre-compression evaluations of prepared powders were shown below. The powders were estimated for bulk density, tapped density, Hausner s ratio and angle of repose and consistency in data obtained as indicated by their standard deviation values shown in table 2. Pre-compression characteristics were investigated for all 8 formulations of both drugs and the study showed following results. Bulk density and tapped density of different formulations were computed. The result of bulk density range from to and tapped density from to Hausner s ratio was found to be in between 1.12 to 1.19; and Compressibility Index from to Angle of repose displayed good to excellent flow properties of the powdered blend (Table 2). Table 2: pre-compression characteristics of Celecoxib powder blend Parameters C1 C2 C3 C4 C5 C6 C7 C8 Angle of repose* ± S.D ± ± ± ± ± ± ± ± 0.05 Apparent bulk density* (g/cm 3 ± 0.01 ± 0.06 ± 0.03 ± 0.05 ± 0.02 ±0.09 ±0.03 ±0.07 ) ± S.D Tapped bulk density* (g/cm 3 ) ± S.D. Compressibility Index* (%) Hausner s Ratio* ± ± ± ± ± ± ± ± ± ± ± ± 0.06 *Value shown in tables is mean of three determinations 1.19 ± ± ± ± 0.01 Evaluation of mouth dissolving tablet of Celecoxib The physicochemical character of mouth dissolving tablet of Celecoxib was evaluated, and results in below table-3. Thickness of all formulations was found to be between 2.25 to From table -3 it has been observed that tablet weights of all bathes were found with in recommended USP limits, between 218 ± 1 mg. The tablets of all batches exhibited the hardness between 3.14 to 3.72 (Kg/cm 2 ). The result of friability, inferred that all formulation can have ability to withstand shocks, because the percentage friability were less than 1%. The data of uniformity of content which was performed by UV spectroscopy and 6 P a g e

7 all the formulation exhibited drug content between to %. The wetting time and water absorption ratio were found to be to seconds (Table 4 and Fig 3) and to seconds (Table 5 and Fig 4), respectively. The disintegration time of mouth dissolving tablets ranges from to 31.84seconds (Table 6 and Fig 5). From above result it has been observed that C7 formulation exhibited excellent wetting time, water absorption ration and disintegration time as compared to other formulations. Moreover the C8 formulation exhibited lowest wetting time and disintegration time; and highest water absorption ratio. This parameter enhances due to gelling and its subsequent viscosity producing effects. Table 3: Evaluation of Celecoxib mouth dissolving tablets Parameters C1 C2 C3 C4 C5 C6 C7 C Uniformity of ± ± ± ± ± ± ± ± weight (mg)* Thickness (mm)* 2.25 ± ± ± ± ± ± ± ± 0.01 Friability (%)* 0.18 ± ± 0.05 Tablet 3.43 ± 3.59 ± Hardness (Kp)* Assay (%) ± ± *Average of three times measure 0.21 ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 0.37 Table 4: Evaluation of wetting time of Celecoxib mouth dissolving tablets Formulation Wetting time (Sec) C ±0.18 C ±0.21 C ±0.02 C ±0.08 C ±0.12 C ±0.06 C ±0.05 C ± ± ± ± P a g e

8 Water Absorption ratio Wetting time (Sec) INTERNATIONAL JOURNAL OF C1 C2 C3 C4 C5 C6 C7 C8 Formulations Fig 3: Wetting time of Celecoxib mouth dissolving tablets Table 5: Evaluation of water absorption ratio of Celecoxib mouth dissolving tablets Formulation Water absorption ratio C ±1.35 C ±1.17 C ±1.24 C ±1.56 C ±1.09 C ±1.42 C ±1.26 C ± C1 C2 C3 C4 C5 C6 C7 C8 Formulations Fig 4: Water absorption ratio of Celecoxib mouth dissolving tablets 8 P a g e

9 Disintegration time (Sec) INTERNATIONAL JOURNAL OF Table 6: Evaluation of in-vitro disintegration time of Celecoxib mouth dissolving tablets Formulation In vitro disintegration time (sec) C ±0.14 C ±0.08 C ±0.19 C ±0.03 C ±0.07 C ±0.11 C ±0.08 C ± C1 C2 C3 C4 C5 C6 C7 C8 Formulations Fig 5: Disintegration time of Celecoxib mouth dissolving tablets In vitro drug release studies Celecoxib mouth dissolving tablets From table -7 of in-vitro dissolution studies revealed that 76 to 100% of drug release from various formulations. The 50% of the drug was released from the C7 and C8 within 4 minutes. The rapid drug dissolution might be due to easy breakdown of particle by superdisintegrant action. From in vitro dissolution data, it was observed that 98.89% of Celecoxib released in 14 minutes indicates that the tablet complies as per IP specifications, that is, 85% 110%. Table -8 and table -9 represents the log cumulative percent drug release and log cumulative percent drug remain in Celecoxib mouth dissolving tablets, respectively. The dissolution rate was found to increase linearly with increase in the concentration of superdisintegrant. Mechanism it followed was wicking and swelling with minimum gelling. 9 P a g e

10 It was observed that C8 formulation released 98.73% drug in 12 minutes. This formulation has large amount of superdisintegrant that may cause tablets fragile. So that C7 was selected for further studies. Table -7 In-vitro dissolution study of Celecoxib mouth dissolving tablets Sq. Cumulative percent drug release Time rt. Log in of Time C1 C2 C3 C4 C5 C6 C7 C8 mins Time Table -8 Log cumulative percent drug release from Celecoxib mouth dissolving tablets Sq. Log cumulative percent drug release Time rt. Log in of Time C1 C2 C3 C4 C5 C6 C7 C8 min. Time Table-9 Log cumulative percent drug remain in Celecoxib mouth dissolving tablets Sq. Cumulative percent drug remain Time rt. Log in of Time C1 C2 C3 C4 C5 C6 C7 C8 mins Time P a g e

11 %Log Drug Remain %Cumulative Drug Release INTERNATIONAL JOURNAL OF C1 C C3 C4 C5 20 C6 C C8 Time (min) Fig 6: In-vitro drug release profile of Celecoxib mouth dissolving tablets according to zero order release C1 C2 C3 C4 C5 C6 C7 C8 Time (min) Fig -7 In-vitro drug release profile of Celecoxib mouth dissolving tablets according to first order release 11 P a g e

12 %Log Drug Release %Cumulative Drug Release INTERNATIONAL JOURNAL OF Fig -8 In-vitro drug release profile of Celec Sq. Root of Time C1 C2 C3 C4 C5 C6 C7 C8 oxib mouth dissolving tablets according to higuchi s model Log Time C1 C2 C3 C4 C5 C6 C7 C8 Fig 9 In-vitro drug release profile of Celecoxib mouth dissolving tablets according to korsmeyer and peppas model 12 P a g e

13 Kinetics of in vitro drug release of Celecoxib mouth dissolving tablets The formulations of Celecoxib tablets were subjected to four model fitting analysis namely zero order (Fig 6), first order (Fig 7), Higuchi (Fig 8) and Korsmeyer-peppas model (Fig 9). Table - 10 indicate that all the formulations follow the first order kinetics as the co-efficient of regression (R 2 ) was more near to unity as compared to the regression value of zero order and Higuchi model. Among all the formulations it was observed that R 2 value of formulation C7 was more near to one than formulations. On the basis of this parameter, C7 was selected for further study. Table-10 Kinetics of in vitro drug release profile of Celecoxib mouth dissolving tablets Korsmeyer and Formulation Zero order First order Higuchi Peppas Model code R 2 R 2 R 2 n R 2 C C C C C C C C Model fitting analysis of formulations of Celecoxib The values of n in Korsmeyer- peppas model suggested that all formulations of Celecoxib tablets follow Non Fickian- Anamolous (Table-11) Table -11 Model fitting analysis of all the formulation of Tolperisone Formulation code Value of n R 2 Value Mode of transport C Non Fickian Anamolous C Non Fickian Anamolous C Non Fickian Anamolous C Non Fickian Anamolous C Non Fickian Anamolous C Non Fickian Anamolous C Non Fickian Anamolous C Non Fickian Anamolous 13 P a g e

14 Summary The result of FTIR study indicates that there is no major deviation in peaks of IR spectra, hence this manifests that there is no fundamental interaction between drug and other tablet ingredients. Powder blend prepared were investigated for diverse rheological properties like bulk density, tapped density, Hausner s ratio, angle of repose by using standard procedures. The result of bulk density of Celecoxib range from to and tapped density from to Hausner s ratio was found to be in between 1.12 to 1.19; and Compressibility Index from to Angle of repose showed good to excellent flow properties of the powdered blend The thickness of all formulations of Celecoxib was noted to be between 2.25 to The tablet weights of all bathes of were found within recommended USP limits, between 218 ± 1 mg. The hardness and friability of tablets of all batches of Celecoxib were in acceptable limits. The uniformity content of active ingredients in tablets was under USP limit. The wetting time of Celecoxib tablets was to seconds. The water absorption ratio of was to seconds. The disintegration time of was to seconds. From results it has been observed that C7 formulation exhibited excellent wetting time, water absorption ration and disintegration time as compared to other formulations. Results of in vitro drug release of Celecoxib from mouth dissolving tablets revealed that 76 to 100% of drug release from various formulations. The formulation C7 exhibited 98.89% of Celecoxib released in 14 minutes from tablets. The dissolution rate was found to increase linearly with increase in the concentration of superdisintegrant. Mechanism it followed was wicking and swelling with minimum gelling. Hence C7 was selected for further studies. Results exhibited that all the formulations follow the first order kinetics as the coefficient of regression (R 2 ) was more near to unity as compared to the regression value of zero order and Higuchi model. Among all the formulations it was observed that R 2 value of formulation C7 was more near to one than formulations. On the basis of this parameter, C7 was selected for further study. The values of n in Korsmeyer- peppas model suggested that all formulations of Celecoxib tablets follow Non Fickian Anamolous. References 1. Martin, A. Drug Product Design. In Physical Pharmacy, 4th ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 1993; pp Banker, G. S.; Anderson, N. R. Tablets. In The Theoryand Practice of Industrial Pharmacy, 3rd ed.; Lachman, L., Lieberman, H. A., Kanig, J. L., Eds.; Lea & Febiger: Philadelphia, PA, 1986; pp Gohel, M. C.; Jogani, P. D. A review of co-processed directly compressible excipients. J. Pharm. Pharm. Sci. 2005, 8 (1), Modi, A.; Tayade, P. Enhancement of Dissolution Profile by Solid Dispersion (Kneading) Technique. 14 P a g e

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