DESIGN, DEVELOPMENT AND EVALUATION OF LABETALOL HCl GRF TABLETS

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The main aim of present research study is to formulate the floating tablets of Labetalol HCl using 32 factorial design. Labetalol HCl, non selective α, -β- adreno receptor antagonist, Indicated for treatment of Hypertension/moderate Heart Failure. The Floating tablets of Labetalol HCl were prepared employing different concentrations of HPMCK4M and sodium bicarbonate in different combinations by Direct Compression technique. The concentration of HPMCK4M and sodium bicarbonate required to achieve desired drug release was selected as independent variables, X1 and X2 respectively whereas, time required for 10% of drug dissolution (t10%), 50% (t50%), 75% (t75%) and 90% (t90%) were selected as dependent variables. 9 formulations were designed and are evaluated for hardness, friability, thickness, % drug content, Floating Lag time, In-vitro drug release. From the Results concluded that all the formulation were found to be within the Pharmacopoeial limits and the In-vitro dissolution profiles of all formulations were fitted in to different Kinetic models, the statistical parameters like a,b,r were calculated. Polynomial equations were developed for t10%, t50%, t75%, t90%. Validity of developed polynomial equations were verified by designing 2 check point formulations.The selected formulation (F8) follows Higuchi’s kinetics, and the mechanism of drug release was found to be NonFickian Diffusion (n= 1.033, Super Case-II transport).

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Raghavendra Kumar et al. Int. J. Adv. Pharm. Biotech. 2018 42: 13-24 www.ijapbjournal.com IJAPB 13 I J A P B International Journal of Advances in Pharmacy and Biotechnology Vol.4 Issue-2 2018 13-24 ISSN: 2454-8375 Research Article Open Access DESIGN DEVELOPMENT AND EVALUATION OF LABETALOL HCl GASTRO RETENTIVE FLOATING TABLETS Raghavendra Kumar Gunda 1 Prasada Rao Manchineni 1 MV Kiran Kumar 2 GSN Koteswara Rao 3 1 M.A.M College of Pharmacy Kesanupalli Narasaraopet Guntur Dt A.P. India-522601. 2 CMR College of Pharmacy Hyderabad Medchal Road Telangana India-501401. 3 K L College of Pharmacy KLEF Deemed to be University Guntur A.P. India-522502. Corresponding author e-mail: raghav.gundagmail.com Received: 10 August 2018 Revised: 20 August 2018 Accepted: 25 August 2018 ABSTRACT: The main aim of present research study is to formulate the floating tablets of Labetalol HCl using 3 2 factorial design. Labetalol HCl non selective α - β- adreno receptor antagonist Indicated for treatment of Hypertension/moderate Heart Failure. The Floating tablets of Labetalol HCl were prepared employing different concentrations of HPMCK4M and sodium bicarbonate in different combinations by Direct Compression technique. The concentration of HPMCK4M and sodium bicarbonate required to achieve desired drug release was selected as independent variables X1 and X2 respectively whereas time required for 10 of drug dissolution t10 50 t50 75 t75 and 90 t90 were selected as dependent variables. 9 formulations were designed and are evaluated for hardness friability thickness drug content Floating Lag time In-vitro drug release. From the Results concluded that all the formulation were found to be within the Pharmacopoeial limits and the In-vitro dissolution profiles of all formulations were fitted in to different Kinetic models the statistical parameters like intercept slope regression coefficient were calculated. Polynomial equations were developed for t10 t50 t75 t90. Validity of developed polynomial equations were verified by designing 2 check point formulations. According to SUPAC guidelines the formulation F8 containing combination of 20 HPMCK4M and 3.75 sodium bicarbonate is the most identical formulation which meets the objective of work. The selected formulation F8 follows Higuchi’s kinetics and the mechanism of drug release was found to be Non- Fickian Diffusion n 1.033 Super Case-II transport. Keywords: Labetalol HCl 3 2 Factorial Design Gastro retentive Floating Tablet HPMCK4M sodium bicarbonate Floating Lag Time. 1. INTRODUCTION Enteral route is the most comfortable extensively used route of administration for both prompt delivery systems and new drug delivery systems. Tablets are the most famous solid formulations available in the market and are preferred by patients and physicians alike. In case of treatment of chronic disease conditions conventional release formulations are required to be administered in frequent manner and therefore shows patient non-adherence to prescription. 1 However ingestion of majority of drugs shows first pass effect and/or first pass hepatic metabolism presystemic elimination by gastrointestinal degradation as a result of which low systemic bioavailability and shorter duration of action

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Raghavendra Kumar et al. Int. J. Adv. Pharm. Biotech. 2018 42: 13-24 www.ijapbjournal.com IJAPB 14 and development of non-active or toxic transformed products. 2 Rapid gastrointestinal transit can result in incomplete drug release from a Dosage form above the absorption zone leading to diminished efficacy of the administered dose. Therefore different approaches have been postulated to reside the formulation in the gasric environment reduces the wastage of drug and improves systemic availability of drug. These include bioadhesive systems swelling altered density systems and expanding systems. Large single-unit dosage forms undergo significant swelling after oral administration and the swollen matrix inhibits gastric emptying even when the pyloric sphincter is in an uncontracted state. 3 The utilization of macromolecules like polymers in modulating the rate of drug release has turn to an essential tool in the product development of pharmaceutical formulations. Numerous reports over many years reveals that they play key role in the release of drugs from dosage form for various drugs. 4 Oral sustained release dosage form by direct compression technique is a simple approach of drug delivery systems that proved to be rational in the pharmaceutical arena for its ease compliance faster production avoid hydrolytic or oxidative reactions occurred during processing of dosage forms .5-6 In the present research work a Gastro retentive floating dosage form of Labetalol HCl has been developed that makes less frequent administering of drug also to improve Bioavailability. Labetalol hydrochloride 2-Hydroxy-5-1- hydroxy-2-1-methyl-3-phenylpropyl- amino ethyl-benzamide a non-selective α β-adrenoceptor antagonist which is used in the treatment of hypertension. It is appreciably soluble in lower and higher pH solutions with minimum solubility between pH 6 to 10. The drug shows variable bioavailability ranging from 10-80 which may be attributed to its instability in alkaline pH and poor absorption due to precipitation. It is administered in doses ranging from 50- 200 mg twice a day due to its shorter half life of 3-6 hrs suggesting the need for sustained release formulation. The major objective of the present investigation was to develop a gastro retentive drug delivery system containing Labetalol Hydrochloride using 3 2 Factorial design as an optimization technique. The present study involved the design of Labetalol Hydrochloride gastric floating matrix tablets by combining HPMCK4M Sodium bicarbonate and investigation of the combined effect of these Formulation variables on the floating behavior and in vitro release pattern of the drug. 7-13 Hence an attempt is made in the current research study to formulate Floating Tablets of Labetalol HCl using HPMCK4M and sodium bicarbonate. Instead of heuristic method a standard statistical tool design of experiments is employed to study the effect

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Raghavendra Kumar et al. Int. J. Adv. Pharm. Biotech. 2018 42: 13-24 www.ijapbjournal.com IJAPB 15 of formulation variables on the release properties. Large scale production needs more simplicity in the formulation with economic and cheapest dosage form. The Floating tablets formulation by direct compression method is most acceptable in large scale production. A 3 2 full factorial design was employed to systematically study the drug release profile. A 3 2 full factorial design was employed to investigate the effect of two independent variables factors i.e the amounts of HPMCK4M and Sodium bicarbonate on the dependent variables i.e. t 10 t 50 t 75 t 90 Time taken to release 1050 7590 respectively 2. MATERIALS AND METHODS Materials used in this study were obtained from the different sources. Labetalol HCl was a gift sample from Aurobindo Pharma Pvt Ltd Hyderabad India. HPMCK4M from colorcon sodium bicarbonate Micro crystalline cellulose were procured from Loba Chemie Pvt. Ltd Mumbai. Other excipients such as stearic acid citric acid Aerosil and talc were procured from S.D. Fine Chem. Ltd. Mumbai. Formulation Development of Labetalol HCl Gastroretentive Tablets: The factorial design is a technique that allows identification of factors involved in a process and assesses their relative importance. In addition any interaction between factors chosen can be identified. Construction of a factorial design involves the selection of parameters and the choice of responses . 14-16 A selected three level two factor experimental design 3 2 factorial design describe the proportion in which the independent variables HPMCK4M and sodium bicarbonate were used in formulation of Labetalol HCl Floating Tablets. The time required for 10 t 10 50 t 50 75 t 75 and 90 t 90 drug dissolution were selected as dependent variables. Significance terms were chosen at 95 confidence interval p0.05 for Final Equations. Polynomial equations were developed for t 10 t 50 t 75 t 90 step-wise backward Linear Regression Analysis. The three levels of factor X 1 HPMCK4M at a concentration of 10 15 20. Three levels of factor X 2 sodium bicarbonate at a concentration of 3.75 7.5 11.25 with respect to total Tablet weight was taken as the rationale for the design of the Labetalol HCl floating tablet formulation. Nine Labetalol HCl floating tablet formulations were prepared employing selected combinations of the two factors i.e X 1 X 2 as per 3 2 Factorial and evaluated to find out the significance of combined effects of X 1 X 2 to select the best combination and the concentration required to achieve the desired prolonged release of drug by providing gastro retentivity from the dosage form. Preparation of Labetalol HCl Floating Tablets: All the ingredients were accurately weighed and passed through mesh 60. In order to mix the ingredients thoroughly drug and HPMCK4M were blended geometrically in a mortar and pestle for 15 minutes then

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Raghavendra Kumar et al. Int. J. Adv. Pharm. Biotech. 2018 42: 13-24 www.ijapbjournal.com IJAPB 16 sodium bicarbonate talc and aerosil were mixed one by one. After mixing these ingredients the powder blend was passed through 44 mesh. Powder blend was subjected to compression by using rotary tablet punching machine RIMEK Ahmedabad. Compressed tablets were examined as per official standards and unofficial tests. Tablets were packaged in well closed light resistance and moisture proof containers. Experimental Design: Experimental design utilized in present investigation for the optimization of excipients quantities such as amount of HPMCK4M was taken as X 1 and amount of Sodium bicarbonate was taken as X 2. Experimental design was given in the Table 1. Three levels for the Concentration of HPMCK4M were selected and coded as -1 10 015 +120. Three levels for the Concentration of Sodium bicarbonate were selected and coded as -1 3.75 07.5 +111.25. Formulae for all the experimental batches were given in Table 2. EVALUATION OF LABETALOL HCl SUSTAINED RELEASE TABLETS: Hardness The hardness of the tablets was tested by diametric compression using a Monsanto Hardness Tester. A tablet hardness of about 2-4 kg/cm 2 is considered adequate for mechanical stability. Friability The friability of the tablets was measured in a Roche friabilator Camp-bell Electronics Mumbai. Tablets of a known weight W 0 or a sample of 20 tablets are dedusted in a drum for a fixed time 100 revolutions and weighed W again. Percentage friability was calculated from the loss in weight as given in equation as below. The weight loss should not be more than 1 .18 Friability Initial weight- Final weight / Initial weight x 100 Content Uniformity In this test 20 tablets were randomly selected and the percent drug content was determined the tablets contained not less than 85 or more than 115 of the labelled drug content can be considered as the test was passed. Assay The drug content in each formulation was determined by triturating 20 tablets and powder equivalent to average weight was dissolved in 100ml of 0.1N Hydrochloric acid by sonication for 30 min. The solution was filtered through a 0.45μ membrane filter diluted suitably and the absorbance of resultant solution was measured spectrophotometrically at 302 nm using 0.1 N Hydrochloric acid as blank. 712 Thickness Thickness of the all tablet formulations were measured using vernier calipers by placing tablet between two arms of the vernier calipers.

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Raghavendra Kumar et al. Int. J. Adv. Pharm. Biotech. 2018 42: 13-24 www.ijapbjournal.com IJAPB 17 In-Vitro Buoyancy Studies The tablets were placed in a 100-mL beaker containing 0.1N HCl. The time required for the tablet to rise to the surface and float was determined as floating lag time. 15 In-Vitro Dissolution Study The In-vitro dissolution study for the Labetalol HCl Floating tablets were carried out in USP XXXIX type-II dissolution test apparatus Paddle type using 900 ml of 0.1 N HCl as dissolution medium at 50 rpm and temperature 37±0.5°C. At predetermined time intervals 5 ml of the samples were withdrawn by means of a syringe fitted with a pre-filter the volume withdrawn at each interval was replaced with same quantity of fresh dissolution medium. The resultant samples were analyzed for the presence of the drug release by measuring the absorbance at 302 nm using UV Visible spectrophotometer after suitable dilutions. The determinations were performed in triplicate n3. 12 Kinetic modeling of drug release The dissolution profile of all the formulations was fitted in to zero-order first-order Higuchi and Korsmeyer-peppas models to ascertain the kinetic modeling of drug release. 17-19 3. RESULTS AND DISCUSSION: Gastro Retentive Floating tablets of Labetalol HCl were prepared and optimized by 3 2 factorial design in order to select the best combination of different release rate modifiers HPMCK4M sodium bicarbonate and also to obtain the desired retention drug at gastric environment. The 2 factorial parameters involved in the development of formulations are amount of HPMCK4M sodium bicarbonate as independent variables X 1 X 2 and In vitro dissolution parameters such as t 10 t 50 t 75 t 90 as dependent variables . Nine formulations were prepared using 3 levels of 2 factors and all the formulations containing 200 mg of Labetalol HCl were prepared as a floating tablet dosage form by Direct Compression technique as per the formulae given in Table 2. All the final trails were evaluated for various pharmacopoeial tests such as drug content mean hardness friability mean thickness mean diameter Floating lag time and results are summarised in Table 3. The hardness of tablets was in the range of 4.41-4.68 Kg/cm 2 . Weight loss in the friability test was not more than 0.67. Drug content of prepared tablets was within acceptance range only. Results for all Post-compression parameters were tabulated or shown in Table 3. In-vitro Dissolution studies were performed for prepared tablets using 0.1 N HCl as a dissolution media at 50 rpm and temperature 37±0.5°C. The In-vitro dissolution profiles of tablets are shown in Fig.1 and the dissolution parameters are given in Table 4. Cumulative Drug release of Factorial Design Formulations F 1-F 9 at 10 Hr were found to be in the range of 72.98- 100.05 . From the result it reveals that as the quantity of HPMCK4M increases the drug release rate decreases and as the concentration of gas generating agent NaHCO 3 increases the drug release

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Raghavendra Kumar et al. Int. J. Adv. Pharm. Biotech. 2018 42: 13-24 www.ijapbjournal.com IJAPB 18 increases and at the same time floating lag time decreases. Therefore required release of drug can be obtained by manipulating the composition of HPMCK4M and sodium bicarbonate. Much variation was observed in the t 10 t 50 t 75 and t 90 due to formulation variables. Formulation F 8 containing 40 mg of HPMCK4M 30 mg of sodium bicarbonate showed promising dissolution parameter t 10 0.415 h t 50 2.749 h t 75 5.495 h t 90 9.125 h which meets the objective of work by providing more gastric retentivity and maximum drug release. The difference in burst effect of the initial time is a result of the difference in the viscosity of the polymeric mixtures. Dortunc and Gunal have reported that increased viscosity resulted in a corresponding decrease in the drug release which might be due to the result of thicker gel layer formulation. 20 The In-Vitro dissolution data of Labetalol HCl Floating formulations was subjected to goodness of fit test by linear regression analysis according to zero order and first order kinetic equations Higuchi’s and Korsmeyer-Peppas models to assess the mechanism of drug release. The results of linear regression analysis including regression coefficients are summarized in Table 4 and plots shown in fig.1234. It was observed from the above that dissolution of all the tablets followed first order kinetics with co-efficient of determination R 2 values in the range of 0.872-0.998. The values of r of factorial formulations for Higuchi’s equation was found to be in the range of 0.931-0.997 which shows that the data fitted well to Higuchi’s square root of time equation confirming the release followed diffusion mechanism. Kinetic data also treated for Peppas equation the slope n values ranges from 0.901- 1.301 that shows Non-Fickian diffusion mechanism Super Case-II Transport. Polynomial equations were derived for t 10 t 50 t 75 and t 90 values by backward stepwise linear regression analysis. The dissolution data Kinetic parameters of factorial formulations F 1 to F 9 are shown in Table 5. Polynomial equation for 3² full factorial designs is given in Equation Y b 0+b 1 X 1+b 2 X 2+b 12 X 1X 2+b 11 X 1²+b 22 X 2 ²… Where Y is dependent variable b 0 arithmetic mean response of nine batches and b 1 estimated co-efficient for factor X 1. The main effects X 1 and X 2 represent the average result of changing one factor at a time from its low to high value. The interaction term X 1X 2 shows how the response changes when two factors are simultaneously changed. The polynomial terms X 1² and X 2² are included to investigate non-linearity. Validity of derived equations was verified by preparing Two Check point Formulations of Intermediate concentration C 1 C 2. The equations for t 10 t 50 t 75 and t 90 developed as follows Y 1 0.580+0.169X 1-0.079X 2+0.003X 1X 2- 0.0911 X 1 2 -0.053X 2 2 for t 10 Y 2 3.822+1.111X 1-0.551X 2+0.017X 1X 2-0.601 X 1 2 -0.340X 2 2 for t 50

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Raghavendra Kumar et al. Int. J. Adv. Pharm. Biotech. 2018 42: 13-24 www.ijapbjournal.com IJAPB 19 Y 3 7.631+2.224X 1-1.12X 2+0.027X 1X 2-1.200 X 1 2 -0.682X 2 2 for t 75 Y 4 12.682+3.701X 1-1.820X 2+0.04X 1X 2-1.984 X 1 2 -1.135X 2 2 for t 90 The positive sign for co-efficient of X 1 in Y 1 Y 2 Y 3 and Y 4 equations indicates that as the concentration of HPMCK4M increases t 10 t 50 t 75 and t 90 value increases. In other words the data demonstrate that both X 1 quantity of HPMCK4M and X 2 quantity of sodium bicarbonate affect the time required for drug release t 10 t 50 t 75 and t 90. From the results it can be concluded that as the amount of HPMCK4M in the tablet formulation increases the drug release rate decreases and as the concentration of gas generating agent NaHCO 3 increases the drug release increases drug release pattern may be changed by appropriate selection of the X 1 and X 2 levels. The Dissolution parameters for predicted from the polynomial equations derived and those actual observed from experimental results are summarized in Table 6. The closeness of predicted and observed values for t 10 t 50 t 75 and t 90 indicates validity of derived equations for dependent variables. From the results the formulation F 8 is considered as best formulations which meets the primary objectives of research work. 4. CONCLUSION The present research study envisages the applicability of drug release rate modifier and Gas generating agent such as HPMCK4M and sodium bicarbonate respectively in the design and development of Gastro Retentive Floating tablet formulations of Labetalol HCl utilizing the 3 2 factorial design. From the results it was clearly understand that as the amount of polymer in the tablet formulation increases the drug release rate decreases and as the concentration of gas generating agent NaHCO 3 increases the drug release increases and both of these polymers can be used in combination since do not interact with the drug which may be more helpful in achieving the desired floating delivery of the drug for longer periods. The optimized formulation followed Higuchi’s kinetics while the drug release mechanism was found to be Non-Fickian Diffusion Super Case-II Transport First order release type controlled by diffusion through the swollen matrix. On the basis of evaluation parameters the optimized formulation F 8 may be used once a day administration in the management of Hypertension Angina Pectoris and moderate Heart Failure. 5. ACKNOWLEDGEMENT: The author would like to thank Management Principal Teaching Non-teaching Staff of M.A.M. College of Pharmacy KesanupallV Narasaraopet Guntur D.t A.P. India for providing support for successful completion of research work. 6. REFERENCES 1. Swati Jain Neelesh Kumar Mehra Akhlesh Kumar Singhai and Gaurav Kant Saraogi. Development and evaluation of sustained release matrix tablet of lamivudine. Int J Pharm Sci Research 2011 Vol. 21: 454-461. 2. R. Ruben Singh. Design Formulation and In Vitro Evaluation of Lamivudine Hcl Sustained Release Tablets. Int J of Res in

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Raghavendra Kumar et al. Int. J. Adv. Pharm. Biotech. 2018 42: 13-24 www.ijapbjournal.com IJAPB 20 Pharm and Nano Sciences 2014 32: 113 – 121. 3. Dasharath M. Patel Natavarlal M. Patel Viral F. Patel and Darshini A. Bhatt. Floating Granules of Ranitidine Hydrochloride-Gelucire 43/01: Formulation Optimization Using Factorial Design. AAPS PharmSciTech 2007 8 2 Article 30. 4. Raghavendra Kumar Gunda J. N. Suresh Kumar Chandan Kumar Brahma V. Satyanarayana K. Naga Prashant. Design Formulation and Evaluation of Atenolol Gastro Retentive Floating Tablets. Asian J of Pharm. 2015 9 4: S34-S42. 5. Prakash P Porwal M Saxena A. Role of natural polymers in sustained release drug delivery system: application and recent approaches. Int Res J of Pharmacy 201129:6-11. 6. Rhodes C.T Robinson J.R. Sustained and controlled drug delivery system. In Banker GS editor. Modern Pharmaceutics 4th ed. USA: Marcel Dekker 2003. P. 503-505. 7. Ravi K. Barde optimization of Gastroretentive drug delivery system of Labetalol HCl using simplex centriod design. Int J Pharm Sci Res. 2011 29: 2439-2445. 8. Hitesh Jain Anmol eldose. Formulation and evaluation of floating tablet of Labetalol hydrochloride. Mint J Pharm Med Sci.201654:16-19. 9. Saurabh Kumar A. Rahaman. Floating Drug delivery System: A Novel approach for Gastroretentive Drug Delivery. Research J. Pharm. and Tech. 201147:1027-1032. 10. Subhash Kumar V Saranya Nair P. Formulation and Evaluation of floating tablets of Labetalol hydrochloride. J Pharm Sci Bioscientific Res. 2016 64:509-515. 11. Amit Porwal1 Harinath Dwivedi. Decades of research in drug targeting using Gastroretentive drug delivery systems for Antihypertensive therapy. Braz. J. Pharm. Sci. 2017533: e00173. 12. H. Garse M. Vij M. Yamgar V. Kadam and R. Hirlekar. Formulation and Evaluation of a gastroretentive dosage form of Labetalol hydrochloride. Arc Pharm Res .2010333: 405–410. 13. Prajapati S. T. Gastric floating matrix tablets: Design and optimization using combination of polymers. Acta Pharm. 2008 583:221–229. 14. A. A. Kharia S. N. Hiremath A. K. Singhai l. K. Omray and s. K. Jain. Design and Optimization of Floating Drug Delivery System of Acyclovir Indian J Pharm Sci. 2010 72 5: 599-606. 15. Raghavendra Kumar Gunda J. N. Suresh Kumar. Formulation Development and Evaluation of Carvedilol Phosphate Gastro Retentive Floating Tablets. Int Res J of Pharmacy 2016 71: 44-51. 16. Raghavendra Kumar Gunda. Formulation Development and Evaluation of Rosiglitazone Maleate Sustained Release Tablets Using 3 2 Factorial Design Int J Pharm Tech Res 2015 Vol. 84: 713- 724. 17. Notari RE. Biopharmaceutics and clinical pharmacokinetics. 4th ed. New York: Marcel Dekker Inc 1987. p. 6-21. 18. Higuchi T. Mechanism of sustained- action medication. Theoretical analysis of rate of release of solid drugs dispersed in solid matrices. J Pharm Sci 1963 51:1145-9.

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Raghavendra Kumar et al. Int. J. Adv. Pharm. Biotech. 2018 42: 13-24 www.ijapbjournal.com IJAPB 21 19. Peppas NA. Analysis of Fickian and non- Fickian drug release from polymers. Pharm Acta Helv 1985 60:110-1. 20. Dortunc B Gunal N. Release of acetazolamide from swellable HPMC matrix tablets. Drug Dev Ind Pharm 1997 23:1245-9. Table 1: Experimental design layout Table 2: Formulae for Labetalol HCl floating tablets Formulation Code X 1 X 2 F 1 1 1 F 2 1 0 F 3 1 -1 F 4 0 1 F 5 0 0 F 6 0 -1 F 7 -1 1 F 8 -1 0 F 9 -1 -1 C 1 -0.5 -0.5 C 2 0.5 0.5 Name of Ingredients Quantity of Ingredients per each Tablet mg F 1 F 2 F 3 F 4 F 5 F 6 F 7 F 8 F 9 Labetalol HCl 200 200 200 200 200 200 200 200 200 HPMCK4M 80 80 80 60 60 60 40 40 40 Sodium bicarbonate 45 30 15 45 30 15 45 30 15 Micro crystalline cellulose 17 32 47 37 52 67 57 72 87 Stearic acid 40 40 40 40 40 40 40 40 40 Citric acid 10 10 10 10 10 10 10 10 10 Aerosil 4 4 4 4 4 4 4 4 4 Talc 4 4 4 4 4 4 4 4 4 Total Weight 400 400 400 400 400 400 400 400 400

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Raghavendra Kumar et al. Int. J. Adv. Pharm. Biotech. 2018 42: 13-24 www.ijapbjournal.com IJAPB 22 Table 3: Post-compression parameters for the formulations S.No. Formulation Code Hardness kg/cm 2 Floating lag time min Diameter mm Thickness mm Friability Weight Variation Drug Content 1 F 1 4.63 1.11 9.98 4.66 0.61 400.07 95.65 2 F 2 4.68 3.52 9.95 4.67 0.62 400.32 95.77 3 F 3 4.66 4.34 9.99 4.68 0.55 400.05 95.58 4 F 4 4.51 0.91 9.99 4.51 0.67 400.60 93.07 5 F 5 4.60 3.22 9.98 4.59 0.66 400.45 95.60 6 F 6 4.65 4.15 10.02 4.62 0.55 400.90 97.35 7 F 7 4.41 0.31 10.00 4.42 0.67 400.23 94.66 8 F 8 4.51 2.92 10.01 4.49 0.63 400.66 97.09 9 F 9 4.53 3.85 10.00 4.54 0.57 400.03 96.88 Table 4: Regression analysis data of 3 2 factorial design formulations F 1 to F 9 are factorial formulations r-correlation coefficient a-Intercept b-Slope and MP-Marketed Product. Table 5: Dissolution parameters for factorial design batches S. No Formu lation Code Kinetic Parameters Zero Order First Order Higuchi Korsmeyer-Peppas A b r a b r a b r A b r 1 F 1 12.137 7.732 0.969 1.993 0.071 0.996 5.282 27.408 0.991 0.959 1.056 0.938 2 F 2 10.575 7.335 0.975 1.990 0.063 0.998 5.717 25.920 0.992 0.938 1.050 0.941 3 F 3 9.408 7.169 0.978 1.993 0.058 0.998 6.303 25.234 0.991 0.911 1.059 0.949 4 F 4 14.528 8.269 0.961 2.005 0.090 0.994 4.642 29.625 0.991 0.999 1.062 0.919 5 F 5 12.929 7.410 0.959 1.977 0.066 0.994 4.2999 26.553 0.990 0.965 1.043 0.914 6 F 6 10.522 7.487 0.965 1.997 0.064 0.994 6.387 26.596 0.986 0.901 1.104 0.924 7 F 7 42.212 6.712 0.808 1.959 0.159 0.872 20.917 26.853 0.931 1.301 0.809 0.822 8 F 8 18.613 8.403 0.952 2.027 0.110 0.984 1.685 30.512 0.995 1.033 1.032 0.890 9 F 9 16.337 8.467 0.964 2.025 0.105 0.986 3.463 30.413 0.997 1.032 1.044 0.910 S.No Formulation Code Kinetic Parameters t 10 h t 50 h t 75 h t 90 h 1 F 1 0.642 4.217 8.432 14.002 2 F 2 0.732 4.815 9.624 15.988 3 F 3 0.787 5.158 10.315 17.135 4 F 4 0.510 3.363 6.723 11.166 5 F 5 0.696 4.568 9.135 15.178 6 F 6 0.718 4.712 9.419 15.652 7 F 7 0.288 1.887 3.776 6.258 8 F 8 0.415 2.749 5.495 9.125 9 F 9 0.439 2.877 5.752 9.554

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Raghavendra Kumar et al. Int. J. Adv. Pharm. Biotech. 2018 42: 13-24 www.ijapbjournal.com IJAPB 23 Table 6: Dissolution parameters for predicted and observed values for check point formulations Formulation Code Predicted Value Actual Observed Value t 10 h t 50 h t 75 h t 90 h t 10 h t 50 h t 75 h t 90 h C 1 0.505 3.3079 6.615 10.974 0.503 3.3068 6.611 10.977 C 2 0.583 3.875 7.733 12.855 0.585 3.872 7.731 12.852 Fig. 1 Comparative Zero order plots Fig. 2 Comparative First order plots

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Raghavendra Kumar et al. Int. J. Adv. Pharm. Biotech. 2018 42: 13-24 www.ijapbjournal.com IJAPB 24 Fig. 3 Comparative Higuchi plots Fig. 4 Comparative Korsmeyer Peppas plots How to cite this article: Raghavendra Kumar et al. Design development and evaluation of labetalol HCl gastro retentive floating tablets. Int. J. Adv. Pharm. Biotech. 2018 42: 13-24.

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