Formulation development and optimization of fast orodispersible tablets of naratriptan hydrochloride by using factorial design

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1 ORIGINAL ARTICLE Formulation development and optimization of fast orodispersible tablets of naratriptan hydrochloride by using factorial design N.A. Oza 1*, A.R. Sahu 1, S.N. Tripathi 2, P.U. Patel 3, L.D. Patel 4, A. Ramkishan 5 1 Assistant Professor, 2 PG Student, 4 Director and Professor, C.U. Shah College of Pharmacy and Research, Wadhwancity, Surendranagar. 3 Professor and Head, S.K. Patel College of Pharmaceutical Education and Research, Kherva, Gujarat. 5 Depyuty Drug Controller, Central Drug Standard Control Organization, New Delhi. ABSTRACT BACKGROUND: The present research was to develop oral fast disintegrating tablets of naratriptan hydrochloride. MATERIALS AND METHODS: Tablets containing naratriptan hydrochloride, sodium starch glycolate (SSG), croscarmellose sodium (CCS) and kyron-t314 were prepared by direct compression technique. Among three super disintegrating agents, croscarmellose sodium was found to have better fast disintegrating properties and higher dissolution efficiency. A 3 2 full factorial design was employed to investigate the influence of two formulation variables: amount of croscarmellose sodium and kyron-t314. The tablets were evaluated for friability and disintegration time. RESULTS: The results of multiple linear regression analysis revealed that for obtaining a rapidly disintegrating dosage form, tablets should be prepared using an optimum ratio of croscarmellose sodium and kyron-t314. Contour plots were also presented to graphically represent the effect of the independent variables on the disintegration time and percent friability. CONCLUSION: A checkpoint batch was prepared to prove that validity of the evolved mathematical model. There was no difference observed in release profile and drug content after accelerated stability study for 1 month. Keywords: Contour plot, Croscarmellose sodium, Factorial design, Naratriptan Hydrochloride tablets, Orodispersible tablets INTRODUCTION Oral route of drug administration is the most appealing route for the drug delivery. Among the various dosage forms tablet is one of the most preferred dosage form because of its ease of manufacturing, convenience in administration, accurate dosing, stability compared with other forms etc. The bioavailability of a drug is dependent on disintegration, dissolution, and various physiological factors. In the recent yrs, scientists have focused their attention on the formulation of quickly disintegrating tablets and orodispersible tablets (ODTs). Food and Drug Administration of United States defined ODT as: A solid dosage form containing medicinal substance or active ingredient which disintegrates rapidly usually within a second when placed upon the tongue. The disintegration time for ODTs generally ranges from several seconds to about a minute 1,2. Orally disintegrating tablets are formulated by employing many processes, which differ in their methodology and the ODTs may vary in various properties such as, mechanical strength of tablets, taste and mouth feel, swallow ability, drug dissolution in saliva, bioavailability and stability. The task of developing rapidly disintegrating tablets is accomplished by using a suitable diluent and superdisintegrant. *Corresponding Author Mr. Nishant A. Oza (Assistant Professor) Department of Pharmaceutics, C.U. Shah College of Pharmacy and Research, Wadhwancity, Surendranagar (Gujarat-India) ozanishant@gmail.com Naratriptan hydrochloride is approved for acute oral migraine therapy. The drug is a selective agonist of 5-hydroxytryptamine 1 (5-HT 1 ) receptors, so it used in treatment of migraine attack and as well as in nausea, vomiting and headache. Naratriptan hydrochloride half life is 5 to 6 hrs. Hence, it is most suitable for manufacture of ODT because of its longer half life. In the Phase III trials of naratriptan hydrochloride compared with placebo, the relief at four hours was obtained in 60% and 68% of patients using the 2.5 mg dose, with recurrence of headache in 24 hours in 27% and 28% of patients 3,4,5. The aim of present study was to develop fast disintegrating tablet of naratriptan with possible advantages like, quick onset of action due to rapid dissolution and enhanced rapid absorption. Sodium starch glycolate (SSG), croscarmellose sodium (CCS) and kyron- T314 were screened in the present study, and the best one was used for further studies. Another approach used in developing ODT was to maximize the pore structure of the tablets. The direct compression technique was adopted for formulating the ODT of naratriptan hydrochloride. A 3 2 full factorial design was applied in optimization of the oral disintegrating tablets of naratriptan hydrochloride. The concentration of superdisintegrants CCS or kyron-t314 was taken as an independent variable. The dependent variables were friability and disintegration time to find out the 48 Int J Res Med. 2013; 2(4);48-53 e ISSN: p ISSN:

2 effect of independent variables on dependent variables 6,7. MATERIALS AND METHODS Materials: Naratriptan hydrochloride, sodium starch glycolate (SSG), croscarmellose sodium (CCS), polacrellin potassium (kyron-t314), talc, citric acid, mannitol, avicell ph 102, manitol megnesium stearet, sodium steryfumret were obtained as generous gift from West Coast Pharmaceuticals Ltd., Ahmedabad, Gujarat. (India). List of Equipments: Digital weighing balance (Contact Equipments Pvt. Ltd), UV Spectrophotometer {UV (USP) 1700, M/s Shimadzu}, Dissolution test apparatus (Electrolab- TDT-08L), FTIR apparatus (M/s Shimadzu), ph meter (Lab India), Tray Dryer (EIE-103, EIE Instrument Pvt. Ltd., Ahmedabad, India), Rotary Tablet Compression Machine LAB-Press 8 station; (Hardik Engineering Works, Ahmedabad, India.) Hardness Tester (Monsanto Hardness Tester), Bulk Density measuring apparatus (EIE-Instrument), Stability Chamber (Thermo Lab), Roche Friabilator (EIE- Instrument). Preparation of Orodispersible Tablets: Each ingredient was passed through #60 mesh sieve separately. The drug and the diluents were mixed in small portion and blended to get uniform mixture. The remaining ingredients were weighed and mixed in geometrical order. The tablets were prepared by direct compression technique 8,9. Optimization of Super Disintegrating Agent: Oral fast disintegrating tablets were prepared by direct compression. Croscamellose sodium, sodium starch glycolate and kyron-t314 were used in varying concentration as shown in Table-1. Batch (T1 to T4) contained 2, 3, 4 and 5% of sodium starch glycolate, respectively. Batch (T5 to T7) contained 2, 3 and 4% croscamellose sodium, respectively and batch (T8 to T11) contained 2,3,4, and 5% kyron-t314, respectively 10,11. Drug Excipient Compatibility Study: Drug- excipient interaction plays a vital role in the release of drug from formulation. Fourier transform infrared spectroscopy (FTIR) has been used to study the physical and chemical interactions between drug and the excipients used. Fourier transform infrared (FTIR) spectra of naratriptan hydrochloride, croscarmellose sodium, sodium starch glycolate, kyron-t 314, mannitol, and physical mixture of naratriptan hydrochloride were recorded using KBr mixing method on FTIR instrument 12. Spectrograph shown as in Figure 1 and 2. Drug expcipient compatibility data were presented in Table-2. Evaluation of Orodispersible Tablets: The tablets were evaluated for various parameters like weight variation, thickness, hardness, friability, wetting time, water absorption ratio, disintegration time ware measured as described by Gohel M et al 13, Swamy P A et al 14 and Malke S et al 15. In vitro Dissolution Test: In vitro dissolution test was performed using a dissolution test apparatus (USP TDT 06 PL, Electrolab, Mumbai) with a paddle rotation at 50 rpm. After placing a tablet containing 2.5 mg of naratriptan in 6.8 ph buffer solution, the 5 ml solution was withdrawn and filtered through a watmen filter of 0.2 mm pore size at different intervals of 1, 2, 3, 4, 6, 8, 10, 20, 30 min and diluted suitably using 6.8 ph buffer solution and analyzed at 224 nm for cumulative drug release using (UV-2450, Shimadzu Corp., Japan) spectro photometer 13. Accelerated Stability Study: Stability study of batch F5 was carried out at 40 0 C in a humidity chamber having 75% RH. Samples were withdrawn at regular intervals during the study of 60 days. Formulation is evaluated for change in in-vitro drug release, hardness and disintegration time 14,15,16. RESULTS Table 1: Formulation of batches T1 T11 for Optimizing Super disintegrating agent Ingredie nts (mg) 49 Int J Res Med. 2013; 2(4);48-53 e ISSN: p ISSN: Batch T1 T2 T3 T4 T5 T6 T7 T8 T9 T10 T11 Naratrip tan hydrchl oride SSG CCS Kyron Avicel PH Manitol SSF Talc D.M orange Citric acid Final weight Table 2: FTIR Drug-excipient compatibility data Drug / Excipiets Function al group Individua l Peak ( cm-1) Mixture Peak (cm-1) Inference Naratryptan 2⁰ Amine Hydrochloride R2-NH No Change Sodium starch Carboxyl glycolate Group No Change Ether No Change Croscarmrllose Methylene No Change sodium Ether No Change Methylene No Change Mannitol Hydroxyl 1⁰-OH No Change Kyron-T314 Carbonyl Group No Change MCC Ether No Change Full Factorial Design: A 3 2 randomized full factorial design was adopted to optimize the variables. In the design, 2 factors were evaluated, each at 3 levels, and experimental trials were performed at all 9 possible combinations. The amount of superdiintegrating agent (croscarmellose sodium, X 1 ) and (kyron-t314, X 2 ) were chosen as

3 Cumulative % drug release independent variables in a statistical model incorporating interactive and polygonal terms were used to evaluate the responses. The disintegration time (DT) and percent friability (%F) were selected as depende nt variables. Batches of factorial design were shown in Table-4. Table 3: Result and Evaluation of Batch T1- T11 Form ulatio n Weight varia tion (mg) Hard nes Kg/cm 2 Fria bilit y % Drug content % Weting Tim e (sec) Water Absorp tion ratio % Thic kn ess (mm) D.T (sec) T T T T T T T T T T T n=6 Table 4: Full Factorial Design Batches of Oral disintegrating Tablets Batch Code Variable Levels in Coded Form D.T %F X 1 X 2 B ± B ± B ± B ± B ± B ± B ± B ± B ± Check Point Coded Values X 1 (Croscarmelose sodium) Actual Values X 2 (Kyron-T314) Table 5: Result of Evaluation parameters of tablets of factorial batches B1 to B9 Fact orial Batc hes Hardness (kg/cm 2 ) Thickness (mm) Avg. Wt. (mg) Drug content (%) Wetting time B1 3.7± ± ± ±1.13 B2 3.2± ± ± ±1.19 B3 3.0± ± ± ±0.92 B4 2.88± ± ± ±1.2 B5 3.1± ± ±0.17 9±1.23 B6 2.7± ± ± ±0.98 B7 3.2± ± ± ±1.34 B8 3.24± ± ±0.3 18±1.21 B9 2.87± ± ±0.9 16±0.98 Figure 1: FTIR spectrum of Naratriptan Hydrochloride Figure 2: FTIR Spectrum of Physical mixture Figure 3: Cumulative % drug release of Batches T3, T7 and T CPR vs TIME Time %CPR T3 %CPR T7 Figure 4: Response surface plot for Disintegrating Time Figure 5: Response surface plot for % Friability 50 Int J Res Med. 2013; 2(4);48-53 e ISSN: p ISSN:

4 DISCUSSION For the preparation of ODTs of naratriptan hydrochloride, formulations were designed by selecting appropriate ingredients in appropriate concentrations and the concentrations of superdisintegrants were optimized thereafter. The batches T1-T11 were prepared to achieve an optimized concentration of superdisintegrant and the most efficacious one among the three superdisintegrants incorporated to prepare ODTs as shown by the Table-1. Among the formulations containing SSG (T1-T4), T3 exhibited the lowest wetting time, disintegration time and highest % cumulative drug release as shown in Table-3. This might be due to the reason that SSG swells in 3D. Up to 5% of SSG decreased disintegrating time and wetting time. Therefore, as the concentration of SSG increases from 2% to 4%, wetting time, disintegration time not extends beyond 1 minute and also the increased in drug release is seen. Among the formulations containing CCS (T5-T7), T7 exhibited lowest dispersion time, disintegration time and highest % cumulative drug release as revealed by Table-3. The formulations containing kyron-t314 (T8-T11), T11 depicted lowest wetting time disintegration time and highest % cumulative drug release as shown in Table-3. Thus the optimized concentrations of superdisintegrants were found to be 4% SSG, 4% CCS and 4% kyron-t314. So, we can conclude that among these three superdisintegrants, CCS came out to be the most efficacious superdisintegrant to prepare ODT of naratriptan hydrochloride as indicated by Figures 4, which exhibits the disentrigating time of optimized concentration of each superdisintegrant. Figures 1 exhibit dissolution profiles of formulations T3, T7, T11 respectively. For optimization of concentration of CCS and kyron-t314 to be used, A 3 2 factorial design was employed in the investigation. The amount of superdisntegrating agent (croscarmellose sodium, X1) and (kyron 314, X2) were chosen as independent variables in a 32 full factorial design. A statistical model incorporating interactive and polygonal terms was used to evaluate the responses. Y=b0+ b1x1+ b2x2+ b12x1x2+ b11x1x1+ b22x2x2. Where Y is the dependent variable, b 0 is the arithmetic mean response of the 9 runs, and b is the estimated coefficient for the factor Xi. The main effects (X 1 and X 2 ) represented the average result of changing 1 factor at a time from its low to high values. The interaction terms (X 1, X 2 ) showed how the response changes when two factors are simultaneously changed. The polynomial terms (X1 2 and X2 2 ) were included to investigate nonlinearity. Multiple linear regression analysis was performed using Sigma State 3.5 Demo version software to generate the statistical relationship between the independent variables and responses. For graphical representation of the influence of factors, the contour plots were generated for all dependent variables using Sigma Plot 12. The disintegrating time and % friability for the nine batches (B1 to B9) showed a wide variation (i.e., 16 to 41 sec and 0.43% to 1.02%, respectively time) in Table-3. The data clearly indicate that the disintegrating time and % friability values are strongly dependent on the selected independent variables. The fitted equations (full model) relating the responses disintegrating time and % friability to the transformed factors are shown in Table-6. The polynomial equations and response surface plot for % friability (Figure 3 and 4) can be used to draw conclusions after considering the magnitude of co-efficient 17. Table 7: Summary of results of Regression Analysis Coefficients D.T % F b b b b b b R In Table-7 the negative sign which gives synergistic effect and positive sign give antagonistic effect for disintegration time b 1 and b 2 posses negative sign which gives positive effect on disintegration time but b 1 have greater value than b 2 it means crosscarmellose sodium is more responsible for faster disintegration than kyron314 because porous structure was responsible for faster water uptake; hence it facilitates wicking action of kyron314 and for percent friability b 1 posses positive sign and b 2 posses negative sign i.e. croscarmellose sodium increase the friability because create porous structure in tablet but b 2 posses negative i.e. addition of kyron314 will helps to decrease in friability. For disintegrating time, as shown in figure 2 the surface plot reveled that a corresponding increase in the disintegrating time was observed with increase in concentration of croscarmellose sodium and kyron-t314. This may be due to powerful disintegrating properties. For percentage friability as shown in figure 3 the surface plot reveled that a corresponding increased in the percentage friability was observed with increase in concentration of croscarmellose sodium because of porous structure but the % Friability decreased when the concentration on kyron-t314 was increase. Check point batch (optimized batch) was prepared shown in table-4 at X 1 = 0.33 level and X 2 = The percentage friability of check point batch found to be 0.7% and the disintegration time found to be 21 sec. Table-7 indicates that the results are expected. Thus, 51 Int J Res Med. 2013; 2(4);48-53 e ISSN: p ISSN:

5 we can conclude that t he statistical model is mathematically valid Table 8: Physical Characteristics of oral fast disintegrating tablet of optimised Batch B9 at Temperature (40 C±2 C / 75% RH±5%) Parameters (Initial) (After 1 months at 40 C) Disintegrating Time 17± ±0.21 Wetting Time 13± ±0.19 Water absorption ratio 97.20±0.02% 95±0.04% Drug Content 98.20±1.01% 96.40±1.02% Table 9: Cumulative % drug release of Batch B9 at 40 C±2 C/75% RH±5% Time Cumulative % drug release (Initial) Cumulative % drug release (After 1 months at 40 C) CONCLUSION The use of superdisintegrating for preparation of fast disintegrating is highly effective and commercially feasible. The superdisintegrating accelerate disintegrating of tablets by virtue of their ability to absorb a large amount of water when exposed to an aqueous environment. The disintegrating is reported to have an effect on dissolution characteristics as well. Prepared fast disintegrating tablets dispersed in the mouth quickly and released the drug. Figure 3 shown the cumulative percentage of naratriptan hydrochloride released from formulated tablet with different concentration of sodium starch glycolate, croscarmellose sodium and kyron-t314. It is clear that the dissolution and disintegration of naratriptan hydrochloride improved considerably in batch T7 containing crosscarmellose sodium (4%) as compared to the rest of formulation coating sodium starch glycolate and kyron-t314. Batch T7 tablet showed good disintegrating efficiency (39 sec) and rapid dissolution in six minutes. The results of a 3 2 full factorial design revealed that the amount of croscarmellose sodium and kyron-t314 significantly affect the dependent variables, disintegration time, and percentage friability. The B9 batch shows good disintegrating properties (16sec) and high dissolution efficiency (in five minutes). It is thus concluded that by adopting a systematic formulation approach, an optimum point can be reached in the shortest time with minimum efforts. Direct compressible technique would be an effective alternative approach compared with the use of more expensive adjuvants in the formulation of ODT. There was no difference observed in release profile and drug content after accelerated Stability study for 1 month. REFERENCES 1. Chang R, Guo X, Burnside B and Couch R: A review of fast dissolving tablets. Phar m Tech North Am 2000; 12: Bi Y, Sunada H, Yonezawa Y, Danjo K and Iida K: Preparation and evaluation of compressed tablets rapidly disintegrating in the oral cavity. Chem Pharm Bull 1996; 44: Cady RK, Went JK and Kircher JR, Treatment of acute migraine with subceutanus sumatriptan. JAMA, 1991, 205, Tripathi KD: Essential of Medical Pharmacology, Jaypee Publisher Ltd, Sevent h Edition Kanthleen Parfitt: Martindale- The Complete Drug Reference, The Royal Pharmaceutical Society, Pharmaceutical Press, Thirty second Edition Sarasija, S., V. Pandit and H.P. Joshi, Mouth dissolving tablets of Salbutamol sulphate. Indian J. Pharm. Sci., 69: Indian Pharmacopoeia, the Controller of Publication Delhi, 1996, 2, Lachman L, Liberman H and Kanig J, The theory and practice of industrial pharmacy. Varghese Publishing Hous, 1987, Lachman, L., A. Lieberman and J.L. Kinig, The Theory and Practice of Industrial Pharmacy,Varghese Publishing House,pp: Khan S, Kataria P, Nakhat P and Yeole P, Taste masking of ondansetron hydrochloride by polymer carrier system and formulation of rapid-disintegrating tablets. AAPS Pharm.Sci.Tech, 2007, 8(2), Morita Y, Tsushima Y, Yasui M, Termoz R, Ajioka J and Takayama K, Evaluation of the disintegration time of rapidly disintegrating tablets via a novel method utilizing a CCD camera. Chem. Pharm, 2002,50(9), Ishikawa T, Kuizumi N, Mukai B, Utoguchi N, Fujii M, Matsumoto M, Endo H, Shirrotake S and Watanabe Y, Preparation of rapidly disintegrating tablet using new types of microcrystalline cellulose (PH-M series) and L- HPC by direct compression method. Chem. Pharm. Bull, 2001, 9, Gohel M, Patel M, Amin A, Agrawal R, Dave R and Bariya N, Formulation design andoptimization of mouth dissolve tablets of nimesulide using vacuum drying technique. AAPS PharmSciTech, 2004,5, Swamy, P.A., S.H. Areefulla, S.B. Shrisand, S. Gandra and B. Prashanth, Orodispersible tablets of meloxicam using superdisintegrant blends for improved efficiency. Ind. J. Pharm. Sci., 69(6): Int J Res Med. 2013; 2(4);48-53 e ISSN: p ISSN:

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