Research Paper. Development and Evaluation of Guaifenesin Bilayer Tablet

Transcription

1 1122 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 3 Issue 3 October-December 2010 International Journal of Pharmaceutical Sciences and Nanotechnology Research Paper Volume 3 Issue 3 October - December 2010 Development and Evaluation of Guaifenesin Bilayer Tablet B. Vijaya Kumar *, G. Prasad, B. Ganesh, C. Swathi, A. Rashmi, G. Amarender Reddy Janagoan institute of pharmaceutical sciences, Jangoan, India ABSTRACT: The objective of the present research was to develop a Bilayer tablet of guaifenesin (GBT) using superdisintegrant MCC and sodium starch glycolate for the fast release layer and metalose 90 SH and carbopol 934 for the sustaining layer. The guaifenesin SR granules of different formulation were evaluated for bulk density, tapped density, angle of repose, Carr s index and Hausners ratio and results were found to be ± 0.12 to ± 0.03 gm/cm 3, ±0.03 to ±0.04 gm/cm 3, 19 ±0.01 to 26 ± 0.23, ± 0.03 to ± 0.04 & to 1.196, respectively. The prepared bilayer tablets were evaluated for weight variation, hardness, friability, drug content and in vitro drug release. In vitro dissolution studies were carried out in a USP 24 apparatus I. The formulations gave an initial burst effect to provide the loading dose of the drug followed by sustained release for 12 h from the sustaining layer of matrix embedded tablets. In vitro dissolution kinetics followed the Higuchi model via a non-fickian diffusion controlled release mechanism after the initial burst release. Stability studies conducted for optimized formulation did not show any change in physical appearance, drug content, matrix integrity and in vitro drug release. The results of the present study clearly indicated that GBT was a stable dosage form and a promising potential of the guaifenesin bilayer system as an alternative to the conventional dosage forms. KEYWORDS: GBT, Guaifenesin, Bilayer, immediate release, control release Introduction In the last few years controlled release dosage forms have made significant progress in terms of clinical efficacy and patient compliance. The objective of designing a controlled release system is to deliver drug at a rate necessary to achieve and maintain a constant drug blood level (Makhija et al., 2002; Acevez et al., 2000). The multilayered tablet concept has been long utilized to develop sustained release formulations. Such a tablet has a fast releasing layer and may contain bi- or triple layers to sustain the drug release. The pharmacokinetic advantage relies on the fact that drug release from fast releasing granules leads to a sudden rise in the blood concentration. However, the blood level is maintained at steady state as the drug is released from the sustaining granules (Abraham et al., 1997; Makhija et al., 2002; Rahman et al., 2006; Uzdemir et al 2000). Guaifenesin is an expectorant, a drug which increases respiratory tract fluid secretions and helps to loosen phlegm and bronchial secretions. Guaifenesin is readily absorbed from the intestinal tract and is rapidly metabolized and excreted in urine but has a short plasma * For correspondence: B. Vijaya Kumar, Tel: , vijaypharmacy2000@yahoo.com half-life of one hour. Because of the rapid metabolization and excretion of guaifenesin, typical immediate release dosage tablets of guaifenesin provide only short window of therapeutic effectiveness for patients and require multiple dosing for maintaining therapeutic effect throughout day; hence there is a potential need for sustained dosage form. In comparison with the single sustain layer tablet, a double layer containing one immediate release compartment and one sustain release layer offers advantages (Thummel et al 2006; Check et al 1982; Bennett et al 2004). The objective of present study was to develop guaifenesin Bilayer tablet by wet granulation technique and also evaluated their precompression and post compression properties Materials and Methods Materials All the materials used were of pharmaceutical grade of purity. Guaifenesin was obtained as a gift sample from Ajantha Pharma. Ltd., Bombay. Microcrystalline cellulose ph 102, Metalose 90 SH and Carbopol 934 was procured as a gift sample from Dr. Reddy s Laboratories, Hyderabad, polyvinayl pyrrolidine K30 (PVP K30), starch, sodium starch glycolate, magnesium stearate, talc, 1122

2 B. Vijaya Kumar, et.al. : Development and Evaluation of Guaifenesin Bilayer Tablet 1123 aerosol was purchased from M/s S.D. fine chemicals Mumbai. All other solvents and reagents were of analytical grade. Methods Preparation Bilayer tablets The Bilayer tablets of guaifenesin were prepared by wet granulation technique composition of each table is shown in Table 1, it consists of three step process. Step 1 formulation of immediate release granules: Guaifenesin was passed through # 40 and all the other components (as per the formulae given in table 1) were passed through no. 60 sieve, then thoroughly mix and then granulated with 10% w/w starch paste. The wet mass was passed through #10 and the granules were dried at 45 o C for a period of 2 hr in hot air oven. The dried granules were passed through # 20 and lubricated with magnesium stearate by further blending for 3mins and finally talc was added to the blend. Table 1 Formulae of Guaifenesin immediate release layer. Composition Weight Per Tablet (mg) Guaifenesin 100 MCC ph Sodium starch glycolate 10 Starch 5 Purified water QS * Magnesium stearate, Talc and Aerosil were used as glidents and lubricants at 1% Step 2 formulation of sustain release granules: Guaifenesin was passed through # 40 and all the other components (as per the formulae given in table 2) were passed through no. 60 sieve, then thoroughly mix and then granulated with 20% w/w PVP K 30 paste. The wet mass was passed through #10 and the granules were dried at 45 o C for a period of 1 hr in hot air oven. The dried granules were passed through # 20 and lubricated with magnesium stearate by further blending for 3 mins and finally talc was added to the blend. Step 3 compression of Bilayer tablet: Accurately weighted quantity of immediately release and sustain release granules were compressed on 10 station Rimek tablet compression machine (M/s Karnawati Engg. Ltd. Ahemadabad) using 12 mm punches (Abraham et al., 1997; Makhija et al., 2002). Evaluation of SR granules Prior to the compression into tablets SR granules were evaluated for properties like Bulk density, tapped density, powder flow properties i.e., angle of repose, carr s index and hausner ratio. Bulk density and tapped density were measured by using bulk density apparatus. Flow properties of powders was measured by (Staniforth J 2002; Rawlins EA 1996; Martin et al 2002; Ansel et al 2002; Guyot et al 1998) (i) Angle of repose: It was measured by using funnel method and calculated by using formula Ө = tan -1 (h/r) Where Ө = angle of repose h = height in cm of pile r = radius (ii) Carr s index was calculated by using formulae Dt Db I = 100 D Where D t = Tapped density D b = Bulk density (iii) Hausner ratio was calculated by Dt H = D b t Table 2 Formulae of Guaifenesin sustain release layer. Ingredients (mg/tablet) Formulations F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 Guaifenesin Metalose 90SH Carbopol MCC ph PVP K Magnesium stearate Talc Purified water QS QS QS QS QS QS QS QS QS QS

3 1124 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 3 Issue 3 October-December 2010 Evaluation of Bilayer Tablets Post compression parameters The prepared tablets were evaluated for weight variation, hardness, thickness, friability and drug content uniformity In weight variation, 20 tablets were randomly selected from each batch and weighed individually; thereafter average weight and standard deviation of 20 tablets were calculated. Hardness was measured by using Pfizer hardness tester. Thickness of tablets was measured by using digital vernier caliper. Friability was measured by taking randomly 20 tablets which was weighed and placed in the friabilator and rotated at 25 rpm for a period of 4 min. After revolution the tablets were dusted and weighed. Finally drug content uniformity was calculated. Guaifenesin Absorbency was measured at 256nm, using double beam UV visible spectrophotometer (elico) (Ansel et al 2002; Merchant et al 2006; Bourne DW 2002). In vitro Drug Releases Studies In vitro dissolution studies were performed by using USP XXIV dissolution apparatus type II at 100 rpm. Dissolution test was carried out using 900ml of 0.1N HCl, at 37 ± 0.5 o C. A 5ml sample of solution was withdrawn from the dissolution apparatus hourly and the samples were replaced by fresh dissolution medium then the samples were filtered and absorbancy were measured at 274nm using UV/Visible spectrophotometer (Costa et al 2001; Wagner 1969; Cobby et al 1974; Pather et al 1998; Merchant et al 2006; Guyot et al 1998). Kinetic analysis of dissolution data The rate and mechanism of release of guaifenesin from the prepared bilayer tablets were analyzed by fitting the dissolution data into the zero-order equation Q = k0t Where Q is the amount of drug released at time t, and k0 is the release rate constant, fitted to the first order equation ln (100 Q) = ln 100 k1t Where k1 is the release rate constant. The dissolution data was fitted to the Higuchi s equation (Higuchi et al 1988; Higuchi T 1963, Higuchi T 1961) Q = k2 t1/2 Where k2 is the diffusion rate constant. The dissolution data was also fitted to the well known equation (Korsmeyer equation), which is often used to describe the drug release behavior from polymeric systems (Korsmeyer et al 1983; Peppas NA 1985; Harland et al 1988) log (Mt/M ) = log k + n log t Where Mt is the amount of drug released at time t, M is the amount of drug release after infinite time, k is a release rate constant incorporating structural and geometric characteristics of the tablet and n is the diffusional exponent indicative of the mechanism of drug release (Thummel et al 2006; Merchant et al 2006; Bourne DW 2002; Guyot et al 1998; Brabander et al 2002). Stability studies Stability studies were performed according to ICH and WHO guidelines. Optimized GBT formulations were strip packed in laboratory in aluminum foil with polyethylene lamination and various replicates were kept in the humidity chamber maintained at 45 o C and 75% RH and 37 o C for 3 months. At the end of studies, samples were analyzed for the drug content, in vitro dissolution, floating behavior and dimensional stability (Mathews BR 1999; Sharma et al 2005; Brabander et al 2002). Results and Discussions The guaifenesin SR granules of different formulation from F 1 to F 10 were evaluavted for bulk density, tapped density, angle of repose, carr s index and hausners ratio (as shown in Table 3). The results of bulk density and tapped density ranges from ± 0.12 to ± 0.03 gm/cm 3 & ±0.03 to ±0.04 gm/cm 3 and angle of repose, carr s index and hausners ratio were found to be 19 ±0.01 to 26 ± 0.23, ± 0.03 to ± 0.04 & to respectively. The prepared bilayer tablets were evaluated for various physical properties. All the batches were produced under similar conditions to avoid processing variables. These were evaluated for physical parameters such as weight variation, hardness, friability and drug content as shown in Table 4. Hardness of tablets were ranged from 6.5 ± 0.50 to 8.0 ± 0.5 kg/cm 2, thickness of the tablets ranged from 5.8 ± 0.21mm to 6.2 ± 0.65mm. The percentage friability of all formulation was between ± 0.02 to ± 0.04%. The drug content uniformity was within the range from 95.4 ± 0.12% to 99.4 ± 0.67%. All the different formulations of prepared tablets of good quality with regard to hardness, thickness, friability and drug content. All the tablets complied with pharmacopeial specification for weight variation and friability.

4 B. Vijaya Kumar, et.al. : Development and Evaluation of Guaifenesin Bilayer Tablet 1125 Formulation Code Table 3 Precompression properties of guaifenesin SR granules. Bulk density (gm/cm 3 ) Tapped density (gm/cm 3 ) Angle of repose (Ө) Carr s index Hausner ratio F ± ± ± ± F ± ± ± ± F ± ± ± ± F ± ± ± ± F ± ± ± ± F ± ± ± ± F ± ± ± ± F ± ± ± ± F ± ± ± ± F ± ± ± ± Mean ± SD n=6 Table 4 Post compression properties of GBT. Formulation Code Weight variation (mg) Hardness (kg/cm 2 ) Thickness (mm) Friability Drug content F ± ± ± ± ± 0.32 F ± ± ± ± ± 0.12 F ± ± ± ± ± 0.08 F ± ± ± ± ± 0.23 F ± ± ± ± ± 0.32 F ± ± ± ± ± 0.45 F ± ± ± ± ± 0.65 F ± ± ± ± ± 0.67 F ± ± ± ± ± 0.45 F ± ± ± ± ± 0.25 Mean ± SD n=6 Dissolution studies In vitro dissolution studies are valuable tools to judge stability and quality of sustain release dosage forms and often used to predict the in vivo performance. The release of guaifenesin from prepared formulations was analyzed by plotting the cumulative percent drug release vs. time as shown in fig. 1. From the graph its shows an initial burst release i.e., over 20% of guaifenesin was released within first half an hour of dissolution study. This initial high amount of guaifenesin release can be attributed to release of drug from the immediate release layer of the formulation. The initial release of guaifenesin was due to MCC and SSG. The initial release of GBT with low concentration of metalose 90SH in F 1 to F 3 was very high compared to other formulation. This high percent release can be ascribed to release of drug from the immediate release layer and also release of drug from the surface of sustained release layer of the tablet. The release rate was found to be decreasing as the concentration of metalose 90SH increase in F 4 to F 8. This is due to swelling is less because of higher concentrations of polymer. In F 8 cumulative percent drug release was about 99% in 12hr; further release rate was found to be very less as increase in the concentration of metalose 90SH from F 9 to F10. Drug release kinetic from the F 8 exhibit best correlation by Higuchi equation proving that the release is by diffusion mechanism as shown in Table 5, Koresmeyer and Peppas equation revealed that F 8 formulation have n value indicates that they follow Non-fickian diffusion. Stability studies were carried out at 45 C and 75% RH for three months (climatic zone IV condition for accelerated testing) to assess their long-term (2 years)

5 1126 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 3 Issue 3 October-December 2010 stability of CBT formulation. The protocols of stability studies were in compliance with the guidelines in the WHO document for stability testing of products intended for the global market. After storage, the formulation was subjected to a drug assay, floating behavior and in vitro dissolution studies. The statistical analysis of the parameter of dissolution data (F 2 = 80.23), floating behavior and drug content after storage at 45 C and 75% RH for three months in the Table 6 showed no significant change cumulative % Drug release Time in hours F 1 F 2 F 3 F 4 F 5 F 6 F 7 F 8 F 9 F 10 Fig. 1 Dissolution profile of different formulations of GBT. Table 5 Diffusion Kinetics and Model Fitting Data of GBT. Formulation Drug rlease kinetics, correlation coefficient r Release exponentional in Korsmeyer Korsmeyer & Peppas (n) Zero order First order Higuchi and peppas F F F F F F F F F F

6 B. Vijaya Kumar, et.al. : Development and Evaluation of Guaifenesin Bilayer Tablet 1127 Table 6 Comparison characteristics of GBT before and after storage. Parameters Before storage a,b After storage a,b Drug content 99.4 ± ± 2.36 Hardness ( kg/cm 2 ) 8.0 ± ± Matrix integrity Very good Very good Similarity factor(f 2) a Storage at 45 C/75% RH for three months. b Mean ± SD, n = 6 Conclusion In this study the GBT was prepared by using fast releasing components for immediate release, Metalose 90SH and Carbopol polymers were used for sustain release. GBT showed biphasic release in the first phase, the first fraction of the dose (immediate dose) was released as a burst effect in less than 60 minutes, because of fast releasing components of loading layer then second phase was released from matrix layer as a controlled non fickian diffusion release fashion. Thus, results of the current study clearly indicate, GBT was a stable dosage form and a promising potential of the bilayer system as an alternative to the conventional dosage form. However, further clinical studies are needed to assess the utility of GBT. Reference Abraham AM and Shirwaikar A. Formulation of multilayered sustained release tablets using insoluble matrix system. Indian J. Pharm. Sci. 59: (1997) Acevez JM, Cruz R and Hernandes E. Preparation and characterization of furosemide-eudragit controlled release system. Int. J. Pharm. 195: (2000) Ansel HC, Allen LV and Popovich NG, Capsules and Tablets, in Pharmaceutical Dosage Formsand Drug Delivery Systems, 7th ed., Lippincott Williams &Wilkins, Philadelphia 2002 Bennett S, Hoffman N and Monga M. "Ephedrine- and guaifenesin-induced nephrolithiasis". J Altern Complement Med 10: (2004) Bourne DW, Pharmacokinetics, Modern Pharmaceutics, Marcel Dekker, New York Brabander CD, Vervaet C and Remon JP. Development and Evaluation of sustained release matrix tablet. J.Controlled Release. 77: (2002). Check JH, Adelson HG and Wu CH. Improvement of cervical factor with guaifenesin. Fertil. Steril. 37: (1982) Cobby J, Mayersohn M, and Walker GC. Influence of shape factors on kinetics of drug release from matrix tablets. II. Experimental. J. Pharm. Sci. 63: (1974) Costa P and Labo JSMS. Modelling and comparison of dissolution profiles. Eur. J. Pharm. Sci. 13: (2001) Guyot M and Fawaz F. Nifedipine loaded polymeric microspheres: preparation and physical characteristics, Int. J. Pharm. 175: (1998) Harland RS, Gazzaniga A., Sangalli ME, Colombo P, and Peppas NA. Drug/polymer matrix swelling and dissolution. Pharm. Res. 5: (1988). Higuchi F, Seta Y, Otsuka T, Nishimura K, Okada R and Koike H. Preparation and pharmacological evaluation of captopril sustained release dosage forms using oily semisolid matrix. Int. J. Pharm. 41: (1988) Higuchi T. Mechanism of sustained action medication, J. Pharm. Sci. 52: (1963) Higuchi T. Rate of release of medicaments from ointment bases containing drugs in suspension. J. Pharm. Sci. 50: (1961) Korsmeyer RW, Gurny R, Doelker E, Buri P and Peppas NA. Mechanism of solute release from hydrophilic polymers, Int. J. Pharm. 15: (1983) Makhija SN and Vavia PR. Once daily sustained release tablets of venlafaxine, a novel antidepressant. Eur. J. Pharm. Biopharm. 54: 9 15 (2002) Martin A, Bustamante P and Chun A. Micromeritics, Physical Pharmacy-Physical Chemical Principles in the Pharmaceutical Sciences, Lippincott Williams and Wilkins, Baltimore Mathews BR. Regulatory aspects of stability testing in Europe, Drug Dev. Ind. Pharm. 25: (1999) Merchant HA, Shoaib HM, Tazeen J and Yousuf RI. Once-daily tablet formulation and in vitro release evaluation of cefpodoxime using hydroxypropyl methylcellulose: A technical note. AAPS Pharm. Sci. Tech. 7: (2006)

7 1128 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 3 Issue 3 October-December 2010 Pather I, Russell I, Syce JA and Neau SH. Sustained release theophylline tablets by direct compression, Part 1: formulation and in vitro testing. Int. J. Pharm. 164: 1 10 (1998) Peppas NA. Analysis of Fickian and non Fickian drug release from polymers, Pharm. Acta Helv. 60: (1985) Rahman Z, Ali M and Khar RK.Design and evaluation of bilayer floating tablets of captopril. Acta Pharm. 56: (2006) Rawlins EA. Formulation, in Bentley s Text Book of Pharmaceutics, Bailliere Tindall, London 1996 Sharma S, Praveen S, Shraddha B, and Pawar AP. Adsorption of Meloxicam on Porous Calcium Silicate: Characterization and tablet formulation. AAPS PharmSciTech. 6: (2005). Staniforth J. Powder Flow, in Pharmaceutics the Science of Dosage Form Design, Churchill Livingstone, London Thummel KE, Shen DD, Isoherranen N and Smith HE, Design and Optimization of Dosage Regimens; Pharmacokinetic Data, Goodman and Gilman s The Pharmacological Basis of Therapeutics, McGraw-Hill Medical Publishing Division, London USP 24/NF 19, USP Convention, Rockville Uzdemir N, Ordu S and Ozkan Y. Studies of floating dosage forms of furosemide: in vitro and in vivo evaluation of bilayer tablet formulations, Drug Dev. Ind. Pharm. 26: (2000) Wagner JG. Interpretation of percent dissolved-time plots derived from in vitro testing of conventional tablets and capsules, J. Pharm. Sci. 58: (1969).