Optimization Of Propranolol Hydrochloride Controlled Release Matrix Tablet Using Factorial Design

Article ID: WMC00914 2046-1690 Optimization Of Propranolol Hydrochloride Controlled Release Matrix Tablet Using Factorial Design Corresponding Author: Dr. Ritesh Patel, Lecturer, Phrmaceutics and Pharmaceutical Technology, 382711 - India Submitting Author: Dr. Ritesh B Patel, Lecturer, Phrmaceutics and Pharmaceutical Technology, 382711 - India Article ID: WMC00914 Article Type: Research articles Submitted on:06-oct-2010, 08:12:05 AM GMT Article URL: http://www.webmedcentral.com/article_view/914 Subject Categories:PHARMACEUTICAL SCIENCES Published on: 06-Oct-2010, 07:29:58 PM GMT Keywords:Propranolol Hydrochloride, Hydroxypropylmethylcellulose K15M, Carbopol 934P, Controlled release, Matrix tablet How to cite the article:patel R, Patel H, Patel G. Optimization Of Propranolol Hydrochloride Controlled Release Matrix Tablet Using Factorial Design. WebmedCentral PHARMACEUTICAL SCIENCES 2010;1(10):WMC00914 Webmedcentral > Research articles Page 1 of 16

Optimization Of Propranolol Hydrochloride Controlled Release Matrix Tablet Using Factorial Design Author(s): Patel R, Patel H, Patel G Abstract Purpose: The objective of this study was to prepare Propranolol Hydrochloride controlled release matrix tablets and to investigate the effect of the polymer blends and the polymer concentration on drug release. Method: Propranolol Hydrochloride controlled release matrix tablets were prepared by direct compression technique. Hydroxypropylmethylcellulose K15M (HPMC K15M) and Carbopol 934P were used in formulating the matrix tablets. A 32 full factorial design were applied to carry out systematic studies. The blending ratio of HPMC K15M and Carbopol 934P (X1) and Polymer concentrations (X2) were selected as independent variables. The times required for 50% (t50) and 80% (t80) drug release were selected as dependent variables. The dissolution profile of all the batches was fitted to zero-order, first-order, Higuchi, and Korsemeyer and Peppas models to ascertain the kinetic modeling of drug release. Results: The results clearly indicate that the values of t50, t80, f2 and MDT are strongly dependent on the independent variables. In-vitro drug release profile of all possible batches of factorial design was compared with theoretical drug release profile. The results indicate that batch F7 showed the highest value among all the batches, and it also shows similarity in t50 and t80 values. The f2 value (74) of batch F7 indicates less than 5% difference in in-vitro drug release profile with theoretical release profile. Conclusions: It was observed that the blending ratio of HPMC K15M-Carbopol 934P and polymer concentration have distinct effect on in-vitro drug release profile. Release rate of Propranolol hydrochloride decreased proportionally with increased in concentration of Carbopol 934P and total polymer concentration. Introduction Propranolol hydrochloride is an b-adrenergic blocker and it has been widely use for the treatment of hypertension and angina. Propranolol hydrochloride is highly lipophilic and is almost completely absorbed after oral administration. Its oral bioavailability is about 26±10% and t½ is about 3.4±1.3 hour.1 The objective of present work was to optimize the formulation of Propranolol hydrochloride controlled release matrix tablet containing Hydroxypropyl-methylcellulose K15M and Carbopol 934P using 32 full factorial design. Use of a hydrophilic polymer matrix system is one of the most popular approaches in formulating a controlled release dosage form.2,3,4 There are few reports on the application of Carbopol with HPMC for controlled release matrix tablets.5,6,7,8,9 In the present work, it was intended to study the effect of polymer blend and polymer concentration on the in-vitro drug release rate from matrix tablets using full factorial design. The factorial design was used, selecting two independent variables X1 as blending ratio of HPMC K15M and Carbopol 934P and X2 aspolymer concentration. The time necessary for the in vitro release of 50% (t50) and 80% (t80) of the drug dose was selected as the response variables. Response surface and grid plot were performed from statistical mathematical models. Similarity factor (f2) and Mean dissolution time (MDT) values calculated from the data. The in vitro release data obtained were fitted in to various kinetic models (zero order, first order and Higuchi Equation). And to find out release mechanism the in vitro release data were applied in Korsmeyer Peppas equation. Methods Preparation of Propranolol Hydrochloride matrix tablet Propranolol Hydrochloride controlled release matrix tablets were prepared by direct compression technique, according to the formulation. For each formulation, the drug and polymer(s) were weighed and premixed for 5min. Filler and glidant were added and mixed for 10min. Magnesium stearate was added at the end and mixed for additional 2min. The formulations were compressed on an automated rotary press using 9.6mm round-concave punch to 300mg target tablet weight and 4-6kg/cm2 tablet hardness. Webmedcentral > Research articles Page 2 of 16

In-vitro drug release studies In-vitro drug release was tested according to USP 24 NF 19 modified release products in apparatus 1 at 50 rpm, using 750 ml of 0.1N HCl for the first two hours followed by 1000 ml of ph 6.8 buffer (adjusted by addition of 250 ml of 0.2 M trisodium phosphate).10 10 ml sample was withdrawn at appropriate time interval and replaced fresh dissolution medium. The samples were analyzed at 288 nm using reference blank dissolution medium on Systronic 2201 UV-VIS spectrophotometer. The drug release study was conducted in triplicate and mean values were plot. Water uptake studies Water uptake study was carried out by putting tablet into petridish containing 0.1N HCl for the 2 hour followed in ph 6.8 buffer solution up to 12 hour at 37±1oC. At predetermined time intervals (2, 4, 6, 9, and 12hour), tablets were removed from the medium and lightly blotted using tissue paper and weighed. The following equations were used to determine percent weight gain (water uptake).12 Full Factorial Design A 32 full factorial design was used in this study. In this design 2 factors were evaluated, each at 3 levels, and experimental trials were performed at all 9 possible combinations. The blending ratio of HPMC K15M and Carbopol 934P (X1) and Polymer concentrations (X2) were selected as independent variables. The times required for 50% (t50) and 80% (t80) drug dissolution were selected as dependent variables. Comparison of in-vitro release profile The in-vitro drug release profile of all batches with theoretical drug release profile was compared using similarity factor (f2), given by Scale Up and Pose Approval Changes (SUPAC) guidelines for modified release dosage form. 11 Mean dissolution time (MDT) of all batches were calculated using equation reported by Paulo Costa, 2001.11 Kinetic modeling and mechanism of drug release The dissolution profile of all the batches was fitted to zero-order, first-order, Higuchi, and Korsemeyer and Peppas models to ascertain the kinetic modeling of drug release according the method reported by Paulo Costa, 2001. 11 Results and Discussion An ideal controlled release tablet should release the required quantity of drug with predetermined kinetics in order to maintain effective drug plasma concentration. To achieve constant drug plasma concentration, tablet should be formulated in such a way that it can release the drug in a predetermined and reproducible manner. Optimization of tablet formulation using 32 full factorial design A 32 full factorial design was constructed to study the effect of the blending ratio of HPMC K15M and Carbopol 934P (X1) and the Polymer concentration (X2) on the drug release from controlled release matrix tablets. The time required for 50% and 80% drug release were selected as dependent variables. A statistical model incorporating interactive and polynomial terms was utilized to evaluate the response. where Y is the dependent variable, b0 is the arithmetic mean response of the 9 runs, and bi is the estimated coefficient for the factor Xi. The main effects (X1 and X2) represent the average result of changing one factor at a time from its low to high value. The interaction terms (X1 X2) show how the response changes when 2 factors are changed simultaneously. The polynomial terms (X12 and X22) are included to investigate nonlinearity. The full Equation (equation containing only statistically significant terms) is then used for drawing counter plots to visualize the impact of changing variables at a glance. The optimum point may be identified from the plot. The formulations and results of in-vitro drug release study of factorial batches (F1 to F9) are shown in Table 1. The statistical analysis of the factorial design batches was performed by multiple linear regression analysis carried out in Microsoft Excel. The t50, t80, f2 and MDT values for the 9 batches (F1 to F9) showed a wide variation; the results are shown in Table 1. The data clearly indicate that the values of t50, t80, f2 and MDT are strongly dependent on the independent variables. The fitted Equations relating the response t50, t80, f2 and MDT to the transformed factor are shown in following Equations (r2 = 0.9934) (r2 = 0.98724) The values of the correlation coefficient indicate a good fit. The polynomial Equation can be used to draw conclusions after considering the magnitude of coefficient and the mathematical sign it carries, (i.e. positive or negative). The response surface plot and counter plot were drawn using Sigma Plot Software 10.0 version. The data demonstrate that both X1 and X2 affect the in-vitro drug release (t50 and t80). The shaded area in the Figure 2 (±5% level from theoretical value) demonstrated the optimize area for both dependent Webmedcentral > Research articles Page 3 of 16

variable (t50 and t80). It may also conclude that the X1(blending ratio of HPMC K15M and Carbopol 934P) and X2 (polymer concentration) appear to favor the preparation of Propranolol hydrochloride controlled release tablets. It can conclude that the drug release profile may be changed by appropriate selection of the X1 and X2 levels. The shaded area (X1 and X2) in counter plot (Figure 2) will give nearly theoretical desired release profile of Propranolol hydrochloride controlled release matrix tablet. Comparison of in-vitro drug release profile The similarity factor (f2) given by SUPAC guidelines for modified release dosage form was used as a basis to compare dissolution profiles.13 The dissolution profiles are considered to be similar when f2 is between 50 and 100. In-vitro drug release profile of all possible batches of factorial design was compared with theoretical drug release profile. The results in Table 1 indicate that batches F1, F2, F3, F4, F5, F6 and F7 fulfill the above criteria. But batch F7 showed the highest value among all the batches, and this similarity is also in t50 and t80 values. The f2 value (74) of batch F7 indicates less than 5% difference in in-vitro drug release profile with theoretical release profile. The similarity between the theoretical release profile and the in-vitro drug release profile of F7 is clearly demonstrated in Figure 3. In-vitro release study of marketed formulation of Propranolol hydrochloride In-vitro drug release studies of Propranolol hydrochloride marketed formulations (M1- extended release, M2- time release, and M3- sustained release) were carried out using experimental condition as described above. Figure 4 shows the in-vitro drug release profile of marketed formulations and comparison with theoretical drug release profile. Further to evaluate complete similarity of optimize region in Figure 1, F10 batch was prepared with X1: + 0.75 (coded value) for blending ratio of HPMC K15M and Carbopol 934P and X2: -1 (coded value) for polymers concentration. In-vitro drug release was performed according to procedure. The results in Table 2 also indicated a similarity between F10 and Theoretical drug release profile. Water uptake studies Water uptake of Propranolol hydrochloride controlled release tablet was significantly greater in high concentration of HPMC K15M containing formulation (Figure 5). Marcos et al studies the potential of combining Carbopol 974P and HPMC K4M using Propranolol hydrochloride as a model drug and found that the amount of water imbibed in Carbopol was lower than that by HPMC alone or 1:1 mixture of two polymers. 5 So, as concentration of Carbopol 934P increases the water uptake of tablets was lower. Kinetic Modeling and Mechanism of drug release The in-vitro release data obtained were fitted in to various kinetic Equations. Correlations of individual batch with applied Equation are given in Table 3. The release rates were calculated from the slope of the appropriate plots. To find out release mechanism the in-vitro release data were fitted in Korsmeyer-Peppas equation where n is a factor, which indicates the mechanism of the drug release. For instance n: 0.5 for square root of time (pure diffusion controlled drug release) and n: 1 for zero order release. The values of n >1.0 indicates anomalous diffusion (swelling-controlled drug release or Case II transport) for all selected formulations. The release exponent n was determined and given in Table 3. All batches showed higher correlation with Highchi plot than zero order and first order. Batch F7 showed diffusion controlled release where as other batches shows anomalous effect (combined mechanism of diffusion and case II transport). Conclusion(s) It was observed that the blending ratio of HPMC K15M-Carbopol 934P and polymer concentration have distinct effect on in-vitro drug release profile. Use of Carbopol 934P and HPMC K15M (hydrophilic polymer) is an advantageous combination for formulating matrix tablets for direct compression. Release rate of Propranolol hydrochloride decreased proportionally with increased in concentration of Carbopol 934P and total polymer concentration. The results of full factorial design was indicated that the X 1 (the blending ratio of HPMC K15M and Carbopol 934P) and X 2 (polymer concentration) both have significant effect on in-vitro drug release profile. No significant difference was observed between desired release profile and batch F1, F2, F3, F4, F5, F7 and F8. Batch F7 showed highest f 2 (74) among all the batches. With marketed formulation M3 showed highest f 2 (83.55) among all batches. To evaluate optimize region in counter plot F10 batch was prepared. From in-vitro drug release profile of batch F10 showed f 2 (67), this indicate similarity with desired release profile. References 1. Goodman, Gillman. The pharmacological basis of therapeutics. The Mc Graw hill companies. Ed 9, 2002, pp 1776. Webmedcentral > Research articles Page 4 of 16

2. Alderman DA. A Review of Cellulose Ethers in Hydrophilic Matrices for Oral Controlled-Release Dosage Forms. Int J Pharm Tech Prod Manuf 1984; 5: 1-9. 3. Heller J. Use of Polymers in Controlled Release of Active Agents. In: Lee VHL, Robinson JR. Controlled Drug Delivery. Fundamentals and Applications. Marcel Dekker, New York, 1987, pp 179 212. 4. Longer MA, Robinson JR. Sustained-Release Drug Delivery Systems. In: Remington's Pharmaceutical Sciences. ed 18, 1990, pp 1676 1693. 5. Perez Marcos B, Ford JL, Armstrong DJ, Elliott PN, Hogan JE. Release of propranolol hydrochloride from matrix tablets containing hydroxypropyl-methylcellulose K4M and Carbopol 974. Int J Pharm 1994; 111: 251 259. 6. Draganoiu E, Stansbery A, Luo H, Wilber W, Guo JH. Effect of carbomer and HPMC combination on drug release from matrix tablets. Noveon Inc, Cleveland, OH, USA, 2000. 7. Mohammadi SS, Montaseri H, Kazemi A. The effect of polymer blends on release profiles of diclofenac sodium from matrices. Eur J Pharm and Biopharm 2003; 55: 351 355. 8. Sastry S, Reddy I, Khan M. Atenolol gastrointestinal therapeutic system: optimization of formulation variables using response surface methodology. J Control Release 1997; 45: 121-130. 9. Li S, Lin S, Daggy B, Mirchandani H, Chien YW. Effect of HPMC and Carbopol on the release and floating properties of Gastric Floating Drug Delivery System using factorial design. Int J Pharm 2003; 253: 13 22. 10. The United States Pharmacopeial Convention. XXVI. In: The United States Pharmacopeia. Rockville, MD: The United States Pharmacopeial Convention, Inc. 2003, pp 1947. 11. Costa P, Lobo JM. Modeling and comparison of dissolution profiles. Eur J Pharm and Biopharm 2001; 12: 123-133. 12. Colombo P, Bettini R, Peppas NA. Observation of swelling process and diffusion front position during swelling in Hydroxypropylmethylcellulose (HPMC) matrices containing a soluble drug. J Control Release 1999; 61: 83 91. 13. Guidance for Industry SUPAC-MR. Modified Release Solid Oral Dosage Forms Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls; In Vitro Dissolution Testing and In Vivo Bioequivalence Documentation. Available at: http://www.fda.gov/cder/guidance/index.htm. Webmedcentral > Research articles Page 5 of 16

Illustrations Illustration 1 Formulation and in-vitro drug release characteristics of batches in 32 Full Factorial Design Batch code Table 1: Formulation and in-vitro drug release characteristics of batches in 3 2 Full Factorial Design Variable level in coded form t 50 (min) t 80 (min) Similarity factor (f 2 ) MDT (min) X 1 X 2 F1-1 -1 184 461 53.52 230 F2-1 0 274 545 69.23 298 F3-1 +1 314 596 53.77 332 F4 0-1 205 489 62.85 249 F5 0 0 292 581 60.18 317 F6 0 +1 337 642 47.99 353 F7 +1-1 244 555 73.85 289 F8 +1 0 320 603 52.41 337 F9 +1 +1 393 701 39.35 392 Theoretical --- --- 236 526.5 --- 275.5 Coded Values -1 0 +1 Actual Values X 1 X 2 0.7:0.3 15% 0.5:0.5 20% 0.3:0.7 25% Webmedcentral > Research articles Page 6 of 16

Illustration 2 Comparison of check points between F10, Marketed formulations and theoretical drug release profile Table 2: Comparison of check points between F10, Marketed formulations and theoretical drug release profile. Check points Theoretical Profile Calculated F10 M1 M2 M3 valued from Equation t 50 (min) 236 229.5 224 513 771 239 t 80 (min) 526 531 518 913 1529 543 F 2 --- 69 67 28.56 23.6 83.55 MDT (min) 275.5 275 258 464.4 498.8 282.6 Webmedcentral > Research articles Page 7 of 16

Illustration 3 Correlation coefficient, in-vitro release rate and the release exponent of Propranolol hydrochloride Table 3: Correlation coefficient, in-vitro release rate and the release exponent of Propranolol hydrochloride from formulated tablets. Batch No. Zero-order First-order Higuchi Korsmeyer-Pep pas Release r 2 k o (h -1 ) r 2 K 1 (h -1 ) r 2 k H r 2 n value mechanism (h -1/2 ) F1 0.9099 7.49 0.9275 0.3422 0.9929 30.23 0.9905 0.538 Anomalous F2 0.9661 7.27 0.9273 0.2266 0.9888 28.43 0.9922 0.594 Anomalous F3 0.9683 6.95 0.9777 0.172 0.9864 27.1 0.998 0.657 Anomalous F4 0.9251 7.27 0.9083 0.287 0.9974 29.16 0.9962 0.527 Anomalous F5 0.9614 6.88 0.976 0.1801 0.9896 26.97 0.9877 0.58 Anomalous F6 0.969 6.46 0.9853 0.1453 0.9868 25.21 0.9929 0.604 Anomalous F7 0.9348 6.67 0.8949 0.2063 0.9961 26.60 0.9964 0.5 Diffusion controlled Webmedcentral > Research articles Page 8 of 16 F8 0.97 6.9 0.9817 0.167 0.9861 26.84 0.9988 0.658 Anomalous F9 0.9813 6.23 0.9828 0.1251 0.9871 23.93 0.9923 0.666 Anomalous

Illustration 4 Response surface plot of t50 Figure 1: Response surface plot of t 50 Webmedcentral > Research articles Page 9 of 16

Illustration 5 Overlapping Counter plots of the polymer viscosity (X1) and polymer concentration (X2) verses t50 an Webmedcentral > Research articles Page 10 of 16

Illustration 6 Comparison of F7 batch with Theoretical drug release profile Figure 3: Comparison of F7 batch with Theoretical drug release profile Webmedcentral > Research articles Page 11 of 16

Illustration 7 In-vitro drug release profile of marketed formulations Figure 4: In-vitro drug release profile of marketed formulations. Webmedcentral > Research articles Page 12 of 16

Illustration 8 Water uptake study of Propranolol hydrochloride controlled release matrix tablets (F1-F9 batches) Figure 5: Water uptake study of Propranolol hydrochloride controlled release matrix tablets (F1-F9 batches) Webmedcentral > Research articles Page 13 of 16

Disclaimer This article has been downloaded from WebmedCentral. With our unique author driven post publication peer review, contents posted on this web portal do not undergo any prepublication peer or editorial review. It is completely the responsibility of the authors to ensure not only scientific and ethical standards of the manuscript but also its grammatical accuracy. Authors must ensure that they obtain all the necessary permissions before submitting any information that requires obtaining a consent or approval from a third party. Authors should also ensure not to submit any information which they do not have the copyright of or of which they have transferred the copyrights to a third party. Contents on WebmedCentral are purely for biomedical researchers and scientists. They are not meant to cater to the needs of an individual patient. The web portal or any content(s) therein is neither designed to support, nor replace, the relationship that exists between a patient/site visitor and his/her physician. Your use of the WebmedCentral site and its contents is entirely at your own risk. We do not take any responsibility for any harm that you may suffer or inflict on a third person by following the contents of this website. Webmedcentral > Research articles Page 14 of 16

Reviews Review 1 Review Title: Optimization of propranolol HCl CR tablet Posted by Mr. Rikesh Patel on 11 Feb 2011 11:26:39 AM GMT 1 Is the subject of the article within the scope of the subject category? Yes 2 Are the interpretations / conclusions sound and justified by the data? Yes 3 Is this a new and original contribution? Yes 4 Does this paper exemplify an awareness of other research on the topic? Yes 5 Are structure and length satisfactory? Yes 6 Can you suggest brief additions or amendments or an introductory statement that will increase the value of this paper for an international audience? 7 Can you suggest any reductions in the paper, or deletions of parts? No 8 Is the quality of the diction satisfactory? Yes 9 Are the illustrations and tables necessary and acceptable? Yes 10 Are the references adequate and are they all necessary? Yes 11 Are the keywords and abstract or summary informative? Yes Rating: 5 Comment: This research article has enough strength to publish it. Competing interests: No Invited by the author to make a review on this article? : Yes Experience and credentials in the specific area of science: Presently I am working as a research associate in formulation and development department. Publications in the same or a related area of science: Yes How to cite: Patel R.Optimization of propranolol HCl CR tablet[review of the article 'Optimization Of Propranolol Hydrochloride Controlled Release Matrix Tablet Using Factorial Design ' by ].WebmedCentral 1970;2(2):REVIEW_REF_NUM456 No Webmedcentral > Research articles Page 15 of 16

Disclaimer This article has been downloaded from WebmedCentral. With our unique author driven post publication peer review, contents posted on this web portal do not undergo any prepublication peer or editorial review. It is completely the responsibility of the authors to ensure not only scientific and ethical standards of the manuscript but also its grammatical accuracy. Authors must ensure that they obtain all the necessary permissions before submitting any information that requires obtaining a consent or approval from a third party. Authors should also ensure not to submit any information which they do not have the copyright of or of which they have transferred the copyrights to a third party. Contents on WebmedCentral are purely for biomedical researchers and scientists. They are not meant to cater to the needs of an individual patient. The web portal or any content(s) therein is neither designed to support, nor replace, the relationship that exists between a patient/site visitor and his/her physician. Your use of the WebmedCentral site and its contents is entirely at your own risk. We do not take any responsibility for any harm that you may suffer or inflict on a third person by following the contents of this website. Webmedcentral > Research articles Page 16 of 16