Response Surface Optimization of Diltiazem HCl Gastric Floating Matrix Tablets

Asian Journal of Pharmaceutic s • Jul-Sep 2020 • 14 (3) | 422 Response Surface Optimization of Diltiazem HCl Gastric Floating Matrix Tablets Srinivasa Venkata Subramanyam Garudaiahgari 1 , Nyamathulla Shaik 1,2 , Surya Prakasarao Kovvasu 1,3 , Siva Naga Koteswara Rao Gudhanti 1,4 , Venkata Ramana Murthy Kolapalli 1 1 Department of Pharmaceutical Technology, A. U. College of Pharmaceutical Sciences, Andhra University, Visakhapatnam, Andhra Pradesh, India, 2 Department of Pharmaceutical Technology, University of Malaya, University of Malaya, 50603 Kuala Lumpur, Malaysia, 3 Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona - 91766, California, USA, 4 Department of Pharmaceutics, K L College of Pharmacy, Koneru Lakshmaiah Education Foundation, Vaddeswaram, Guntur, Andhra Pradesh, India Abstract Objective: The objective of the present research work was to formulate and optimize the hydroxyethyl cellulose (HEC) based gastric floating matrix tablets (GFMT) of diltiazem HCl by employing a three factor, three levels statistical design, namely, Box-Behnken design. Materials and Methods: Optimization studies were carried out using Box-Behnken statistical design with three factors, three levels, and 15 runs. Selected independent variables include HEC quantity (X 1), %w/w of sodium bicarbonate (X 2), and %w/w of Pharmatose (lactose monohydrate) (X 3). Cumulative percent drug released at 12 h was selected as dependent variable (Y). Tablets were evaluated for in vitro buoyancy characteristics, in vitro drug release and other tablet characteristics. Results and Discussion: The GFMT’s of diltiazem HCl prepared with HEC fulfilled all the requirements of tablets. Floating lag times for all the prepared formulations were found to be in the range of 156–2040 s. The obtained optimum values of the independent test variables are; 93.50 mg quantity of HEC (X 1), 11.47% w/w of sodium bicarbonate (X 2), and 10.40% w/w of Pharmatose (lactose monohydrate) (X 3). The model predicts that the formulation with 100% drug release in 12±1 h can be obtained using the above optimum concentrations. Optimized formulation DNAso showed a floating lag time of 405 s. Drug release from DNAs (optimized formulation) and Dilzem SR (commercial sustained release formulation) followed zero-order release kinetics with diffusion mechanism. Conclusion: Results demonstrated that significance of Box-Behnken statistical design in the optimization of critical variables of gastric floating matrix tablets of diltiazem HCl for achieving desired in vitro buoyancy characteristics and in vitro drug release characteristics Keywords: Box-Behnken design, diltiazem HCl, gastric floating matrix tablets, hydroxyethyl cellulose Address for correspondence: Srinivasa Venkata Subramanyam Garudaiahgari, A. U. College of Pharmaceutical Sciences, Andhra University, Visakhapatnam - 530 003, Andhra Pradesh, India. Phone: +91-8639148896. E-mail: drgsvs 74@gmail.com Received: 16-05-2019 Revised: 11-01-2020 Accepted: 26-05-2020 INTRODUCTION O ptimization process involving onevariable-at-a-time method is an expensive method and it requires much time. In conventional optimization method, only one factor is varied and all other factors are kept fixed at a specific set of conditions. This method of optimization requires the higher number of experiments and also may lead to unreliable results. In addition, it is inferior to the statistical methods of optimization since it neglects the interaction between the variables and it does not guarantee attaining the optimal point. Statistical experimental designs are useful in minimizing the error in determining the effect of parameters and allow simultaneous, systematic, and efficient variation of all the selected critical variables. These statistical experimental designs can be adopted at various stages such as for the ORIGINAL AR TICLE

Garudaiahgari, et al .: GFMT of diltiazem Hcl by response surface optimization Asian Journal of Pharmaceutic s • Jul-Sep 2020 • 14 (3) | 423 selection of critical variables by screening experiments, or for the optimization of selected variables, i.e., finding their optimal conditions [1-8] Response surface methodology (RSM) is one of the most commonly used method to find the optimal conditions, which is an efficient statistical technique for optimization of the selected multiple critical variables with minimum number of experiments and for prediction of the interactions between different components of a formulation The following problems are associated in the design of sustained/controlled release products for the drug substances having a narrow absorption window with site specific absorption and other characteristics such as low solubility in alkaline pH, local action required at stomach, or upper parts of small intestine, since there is a possibility for wide variations in the desired plasma drug concentration when administered orally in the form of conventional/sustained and controlled release dosage forms. Hence, to avoid the above indicated problems, design of drug delivery systems with retention characteristic in the stomach is required, which are called as gastric retentive drug delivery systems (GRDDS) [9-27] Diltiazem HCl is a calcium ion influx inhibitor and used in the treatment of cardiovascular disorders such as angina, arrhythmias, and hypertension. The maximum dosage is listed as up to 540 mg/day when given orally. Its mean elimination half-life is 3–4.5 h. It is available as immediate release tablet which shall be administered from 3 to 4 times daily and also as sustained release tablet which is suitable for twice daily dosage regimens. Diltiazem HCl is absorbed more predominantly in the upper parts of the gastro intestinal tract [28,29] Hence, design of GRDDS is a suitable option for improving its oral bioavailability The GRDDS of the present investigation are designed to make it retained in the stomach for longer periods of time and deliver the diltiazem HCl effectively. The system provides increased absorption of the diltiazem HCl at a rate such that effective plasma drug levels can be achieved and maintained for a prolonged duration. Based on the results achieved in the preliminary experiments during the development of prototype formulation, HEC polymer quantity, concentrations of sodium bicarbonate and Pharmatose (lactose monohydrate) were identified as critical variables. Selected variables were studied to find the optimized conditions for achieving a formulation which can release the total drug content in 12±1 h with good floating properties using Box-Behnken design, a RSM approach MATERIALS AND METHODS Materials Diltiazem HCl was gift sample from Sun Pharma Ltd., Baroda, India. Hydroxyethyl cellulose (HEC) was gift sample from Wockhardt Ltd., Aurangabad, India. All other remaining chemicals used in the experiment were of analytical grade Box-Behnken experimental design Box-Behnken statistical design [30] with three factors, three levels, and 15 runs was selected for the optimization of selected variables in the present research study. The experimental design consists of a set of points lying at the midpoint of each edge and the replicated center point of the multidimensional cube which defines the region of interest. The higher order terms show the quadratic nature of the relationships The independent and dependent variables of the present research study are listed in Table 1. The polynomial equation generated using Statistica Release 6, Statsoft Inc. is as follows: Y i = b 0 +b 1 X 1 +b 2 X 2 +b 3 X 3 +b 12 X 1 X 2 +b 13 X 1 X 3 +b 23 X 2 X 3 +b 11 X 1 2 + b 22 X 2 2 +b 33 X 3 2 Where, Y i is dependent variable; b 0 is intercept; b 1 to b 33 are the regression coefficients; and X 1 , X 2 , and X 3 are independent variables that were selected from the initial experiments. Redundancy of the model can be known from the ratio of number of experimental runs to the maximum number of experimental runs. Box-Behnken design requires less number of runs than the full factorial design along with less redundancy. These runs along with the response variable are mentioned in Table 2 . Selection of levels of the independent variables was done based on the observations made in the preliminary experimental trials Preparation of tablets All the ingredients were passed through the sieve No. 40 (Diltiazem HCl, HEC, Pharmatose and sodium bicarbonate) and sieve No. 60 (Talc and magnesium stearate). Drug was geometrically mixed with polymer. Polyvinylpyrrolidone (PVP K 30) in 70% v/v isopropyl alcohol was used as binder solution for preparing the granules. Prepared wet granulate Table 1: Variables and their levels in Box-Behnken design Experimental range and levels of the independent variables Range and levels −1 0 +1 Quantity of polymer (in mg); X 1 70 90 110 % w/w sodium bicarbonate; X 2 (% w/w to drug and polymer weight) 10 15 20 % w/w lactose monohydrate; X 3 (% w/w to drug and polymer weight) 5 10 15 Dependent variable: Cumulative % drug released at 12 h; Y

Garudaiahgari, et al .: GFMT of diltiazem Hcl by response surface optimization Asian Journal of Pharmaceutic s • Jul-Sep 2020 • 14 (3) | 424 was passed through sieve No. 10 and dried at 50±5°C. The dried granules were passed through sieve No. 24 and mixed with the sodium bicarbonate (effervescent agent), Pharmatose (channeling agent) wherever necessary, talc, and magnesium stearate. The granules and the extra-granular excipients were mixed thoroughly using low-density polyethylene bag. Final blend was then compressed into tablets containing diltiazem HCl equivalent to a dose of 90 mg using rotary tabletpunching machine (M/s. Cadmach Machinery Co. Pvt. Ltd., India) fitted with 9 mm round plain punches at a hardness range of about 4–6 kg/cm² Evaluation of tablets The floating properties of the prepared gastric floating matrix tablets (GFMT) were assessed by in vitro buoyancy test. The prepared GFMT were also evaluated for their physical properties such as hardness (Monsanto Hardness Tester), friability (Labindia Analytical Instruments Private Limited), uniformity of weight and chemical properties such as drug content uniformity and in vitro drug release. The results of the physical and chemical evaluation of prepared GFMT formulations are mentioned in Table 3 Estimation of drug content Ten tablets from each batch were weighed and transferred to mortar. Tablets were crushed and powder equivalent to 50 mg of diltiazem HCl was transferred to 50 ml volumetric flask. Diltiazem HCl was extracted with 25 ml of 0.1 N hydrochloric acid (HCl) with vigorous shaking using a mechanical shaker for 1 h. The samples were filtered into a 50 ml volumetric flask through nylon filter disk (0.45 µ m, Millipore) and volume made up to 50 ml with 0.1 N HCl. Absorbance’s were measured at 237 nm with appropriate dilutions against blank (0.1 N HCl) using Systronics-117 UV visible spectrophotometer In vitro buoyancy determination Floating characteristics are essential for the gastric floating drug delivery systems, since they influence the in vivo behavior of the drug delivery system. All the prepared GFMT formulations of diltiazem HCl were evaluated by the in vitro buoyancy test. 900 mL of 0.1 N HCl in 1 L glass beaker was Table 2: Box-Behnken experimental design with measured responses Formulae X 1 X 2 X 3 Y DNAB 1 70 10 10 100.00 DNAB 2 110 10 10 99.99 DNAB 3 70 20 10 100.00 DNAB 4 110 20 10 94.99 DNAB 5 70 15 5 100.00 DNAB 6 110 15 5 97.88 DNAB 7 70 15 15 100.00 DNAB 8 110 15 15 99.99 DNAB 9 90 10 5 100.00 DNAB 10 90 20 5 94.05 DNAB 11 90 10 15 100.00 DNAB 12 90 20 15 100.00 DNAB 13 90 15 10 99.99 DNAB 14 90 15 10 99.62 DNAB 15 90 15 10 100.00 Table 3: Physical and chemical characteristics of hydroxyethyl cellulose based gastric floating matrix tablets of diltiazem HCl prepared by using Box-Behnken design Formulation Weight (mg) Drug content (%) Hardness (kg/cm 2 ) Friability (%) Floating lag time (sec) DNAB 1 200.13±0.21 100.11±0.79 4–6 0.55 1659 DNAB 2 248.10±0.30 100.33±0.70 4–6 0.36 256 DNAB 3 216.13±0.25 99.89±0.56 4–6 0.35 1003 DNAB 4 268.07±0.15 100.00±0.17 4–6 0.58 156 DNAB 5 200.20±0.17 99.67±0.17 4–6 0.61 2040 DNAB 6 248.07±0.15 100.33±0.20 4–6 0.23 315 DNAB 7 216.03±0.21 100.00±0.26 4–6 0.81 1532 DNAB 8 268.07±0.15 100.00±0.36 4–6 0.26 215 DNAB 9 214.93±0.15 99.89±0.17 4–6 0.38 1359 DNAB 10 232.90±0.26 99.78±0.87 4–6 0.71 303 DNAB 11 233.20±0.17 100.11±1.01 4–6 0.11 820 DNAB 12 250.80±0.87 100.00±0.70 4–6 0.25 494 DNAB 13 232.87±0.21 100.00±0.26 4–6 0.32 451 DNAB 14 233.27±0.15 100.22±0.80 4–6 0.27 431 DNAB 15 232.93±0.15 100.11±1.11 4–6 0.31 481

Garudaiahgari, et al .: GFMT of diltiazem Hcl by response surface optimization Asian Journal of Pharmaceutic s • Jul-Sep 2020 • 14 (3) | 425 used to determine the buoyancy lag time. The time interval between the introduction of the tablet into the medium and its buoyancy to the top of medium was taken as buoyancy lag time. Floating characteristics are shown in Figure 1 Drug-polymer interaction studies Fourier transform infrared spectrophotometry (FTIR) using Perkin Elmer (Model Spectrum One), differential scanning calorimetry (DSC) using Mettler Toledo Star e SW 8.10 (Model no: DSC 822 e ) and X-ray diffractometry (XRD) studies was carried out using RIGAKU Diffractometer (D/MAX-B) and CU - K α radiation, for checking the interactions if any between drug and polymer, as shown in Figures 2-4 In vitro drug release studies In vitro dissolution of diltiazem HCl from the prepared GFMT formulations was studied using USP XXIV dissolution rate test Apparatus II (Model: DISSO 2000, M/s. Lab India). 900 ml of 0.1 N hydrochloric acid maintained at a temperature of 37±0.5°C was used as dissolution medium and the paddle speed was set at 100 rpm. At each and every time interval, 5 ml of samples were withdrawn by means of a syringe fitted with a pre-filter and immediately replaced with 5 ml of fresh dissolution medium maintained at 37±0.5°C. After suitable dilution with the medium, the samples absorbance was measured at 237 nm using Systronics-117 UV-Visible Spectrophotometer. For comparison, commercially available diltiazem HCl sustained release formulation (Dilzem SR) was also subjected to dissolution studies and the results are shown in Figures 5-8. Dissolution data were fitted to zero-order, first-order, Higuchi, and erosion equations to establish the release kinetics of the drug and its mechanism RESULTS AND DISCUSSION Evaluation of tablets All the formulations complied with compendia standard for uniformity of weight. A hardness range of 4–6 kg/cm 2 was found for the all the tablet formulations. The percentage weight loss in the friability test was found to be <1% for all the batches. Thus, the GFMT’s of diltiazem prepared with HEC fulfilled all the requirements of tablets. These results clearly indicate that the HEC can be used in the design of GFMTs Estimation of drug content The estimated drug content was found to be within the specified limits, i.e., <±10% variation of the stated quantity of diltiazem HCl In vitro buoyancy determination GFMT each comprising 90 mg of diltiazem HCl were prepared using the HEC. NaHCO 3 was used as effervescent agent. Carbon dioxide which was liberated on contact with gastric fluid got entrapped in the jellified hydrocolloid. This resulted in an upward motion of the dosage form and maintained its buoyancy to float on the gastric fluids. Floating lag times for the all the prepared formulations were found to be in the range of 156–2040 s Drug – polymer interaction studies FTIR spectrophotometry The FTIR spectrum of diltiazem HCl exhibited characteristic stretches as followed. Characteristic stretches of Enolic-OH group at 3440 cm −1 , tertiary amine –N-CH 3 group at 2390 cm −1 , -C=O group at 1742 cm −1 , -C=CH 2 at 1679 cm −1 , asymmetric stretch of-C-O-C at 1247 cm −1 , and symmetric stretch of-C-O-C at 1054 cm −1 . The FTIR spectrum of HEC exhibited the characteristic stretches of alcoholic -OH group at 3438 cm −1 , symmetric stretch of-C-O-C at 1024 cm −1 , and -C=CH 2 at 1646 cm −1 . Optimized formulation DNAso exhibited all the characteristic peaks of diltiazem HCl with negligible shifts. This spectrum showed stretches related to tertiary amine -N-CH 3 group at 2379 cm −1 , -C=O group at 1743 cm −1 , enolic-OH group at 3388 cm −1 , -C=CH 2 stretch at 1679 cm −1 , asymmetric stretch of -C-O-C at 1249 cm −1 , and Figure 1: Photographs showing the in vitro floating characteristics of gastric floating matrix tablets of the diltiazem HCl (DNAso). (a) Photograph taken immediately after placing the tablet in to beaker; (b) and (c) are the photographs taken during the intermediate stages of tablet floating; (d) Photograph taken immediately after the tablet floated onto the surface a b c d

Garudaiahgari, et al .: GFMT of diltiazem Hcl by response surface optimization Asian Journal of Pharmaceutic s • Jul-Sep 2020 • 14 (3) | 426 symmetric stretch of-C-O-C at 1058 cm −1 . FTIR spectrum of optimized formulation showed characteristic peaks of pure drug, diltiazem HCl, and HEC indicating compatibility between the drug and polymer, as shown in Figure 2 DSC DSC thermogram of diltiazem HCl pure drug substance showed sharp melting peak at 212.94°C, similarly pure polymer HEC at 137.36°C. There is a minor shift in the melting peak of diltiazem HCl in the optimized formulation, i.e., 185.73°C, as shown in Figure 3. This observed minor shift in the melting peak of diltiazem HCl in the test formulation may be due to physical interaction between the drug and polymer leading to partial conversion of its crystalline form to amorphous form during the manufacturing of tablets, which is indicated by the conversion of sharp melting peak of pure drug diltiazem HCl to broadened peak in the formulation. In addition, HEC is hydrophilic in nature with melting point less than that of pure drug diltiazem HCl. The pure polymer which melts before the drug may influence in the shift of melting point of diltiazem HCl in the test formulation. Further, it can be confirmed that the observed minor shift in melting peak of the diltiazem HCl in the test formulation can be only due to partial conversion of its crystalline form to amorphous form and not due to chemical interaction or complexation between the drug and the polymer, by the unaltered characteristic peaks of diltiazem HCl in FTIR spectra of test formulation Figure 2: Fourier-transform infrared spectra of (a) diltiazem HCl, (b) hydroxyethyl cellulose (HEC) and (c) formulation DNAso a b c

Garudaiahgari, et al .: GFMT of diltiazem Hcl by response surface optimization Asian Journal of Pharmaceutic s • Jul-Sep 2020 • 14 (3) | 427 XRD The XRD of diltiazem HCl showed sharp peaks due to crystalline nature of the drug substance. However, pure polymer HEC did not show any peaks indicating its amorphous nature. Formulation DNAso showed characteristic peaks of pure drug substance with less intensity, minor shifts in the peaks, disappearance of some peaks, and appearance of new peaks, as shown in Figure 4. The reason for these changes in the XRD pattern, i.e., reduced crystallinity of drug substance in the prepared GFMT’s might be due to the fine dispersion of the drug in the polymer during mixing and due to the compression force applied during the preparation of the tablets. Reduce crystallinity of the drug substance in the formulation can also be confirmed by the broadened melting peak observed in the DSC thermogram of formulation to that of sharp melting peak observed in the DSC thermogram of pure drug substance diltiazem HCl Figure 3: Differential scanning calorimetry thermo grams of (a) Diltiazem HCl (b) hydroxyethyl cellulose and (c) formulation DNAso a b c

Garudaiahgari, et al .: GFMT of diltiazem Hcl by response surface optimization Asian Journal of Pharmaceutic s • Jul-Sep 2020 • 14 (3) | 428 Figure 4: X-ray diffract to grams of (a) diltiazem HCl, (b) hydroxyethyl cellulose and (c) formulation DNAso a b c Figure 5: Dissolution profiles of hydroxyethyl cellulose based gastric floating matrix tablet formulations DNAB 1 to DNAB 5 Figure 6: Dissolution profiles of hydroxyethyl cellulose based gastric floating matrix tablet formulations DNAB 6 to DNAB 10

Garudaiahgari, et al .: GFMT of diltiazem Hcl by response surface optimization Asian Journal of Pharmaceutic s • Jul-Sep 2020 • 14 (3) | 429 In vitro drug release studies The results of in vitro drug release studies of all the prepared diltiazem HCl GFMT formulations indicated slow and extended release of diltiazem HCl for a prolonged period of time, i.e., up to 14 h Release kinetics of the drug from HEC based formulations resulted from Box-Behnken design such as DNAB 2, DNAB 3, DNAB 4, DNAB 6, DNAB 8, DNAB 10, DNAB 12, DNAB 13, and DNAB 14 followed zero-order release kinetics whereas DNAB 1, DNAB 5, DNAB 7, DNAB 9, DNAB 11, and DNAB 15 followed first-order release kinetics. Mechanism of the drug release from formulations, DNAB 2, DNAB 3, DNAB 4, DNAB 5, DNAB 6, DNAB 7, DNAB 8, DNAB 10, DNAB 12, DNAB 13, DNAB 14, and DNAB 15 followed diffusion mechanism while from formulations DNAB 1, DNAB 9, and DNAB 11 followed erosion mechanism Statistical application By subjecting the cumulative percent drug released at 12 h of the formulations generated by Box-Behnken design for the analysis using STASTSTICA ® 6.0 software gave the optimal values of selected independent variables for obtaining a formulation which can release the total drug content at 12 h. It provides the information about optimal values for attaining the anticipated response and also the potential interaction effects of selected independent variables on the response, i.e., dependent variable Analysis of variance (ANOVA) results for second-order response surface model fitting are given in Table 4 with very low probability values ( P = 0.01) demonstrate a very high significance for the regression model [31-35] The goodness of fit of the model was evaluated by the determination coefficient (R 2 ). The values of the determination coefficient were found to be (R 2 = 0.9414) indicating only 5.86% of the total variations were not explained by the studied statistical design. The values of the adjusted determination coefficient (Adj. R 2 : 0.8359) are also very high and support the high significance of the selected statistical design [32-35] An excellent correlation between the independent variables [36] was confirmed by higher correlation coefficient (R 0.9703) values The application of RSM [36,37] yielded the following regression equation which is an empirical relationship between the logarithmic values of cumulative % drug released at 12 h and test variables in coded unit: Y DNAB =98.9-0.8933*X 1 -1.3684*X 2 +1.0071*X 3 - 1.2494*X 1 *X 2 +1.4875*X 2 *X 3 Where Y is the response, that is, the cumulative % drug released at 12 h in logarithmic and X 1 , X 2 , and X 3 are the coded values of the test variables polymer quantity, %w/w of sodium bicarbonate and %w/w of Pharmatose (lactose monohydrate) to the weight of drug and polymer, respectively Student’s t -test and “ P ” values were used to determine the significance of each coefficient and are listed in Table 5. The larger the magnitude of the “ t ” value and smaller the “ P ” value, the more significant is the corresponding coefficient [34,35] The first-order main effects of all the selected independent variables such as polymer quantity, %w/w of sodium bicarbonate, and %w/w of Pharmatose (lactose monohydrate) Figure 7: Dissolution profiles of hydroxyethyl cellulose based gastric floating matrix tablet formulations DNAB 11 to DNAB 15 Figure 8: Comparative dissolution profiles of optimized gastric floating matrix tablets formulation (DNAso) with commercial sustained release formulation (Dilzem SR)

Garudaiahgari, et al .: GFMT of diltiazem Hcl by response surface optimization Asian Journal of Pharmaceutic s • Jul-Sep 2020 • 14 (3) | 430 are highly significant which is evident from their respective P -values, i.e., 0.0238 (for HEC); 0.0044 (for % w/w of sodium bicarbonate); and 0.0153 (for % w/w of Pharmatose) The combinatorial effect of polymer concentration and sodium bicarbonate as well as sodium bicarbonate and Pharmatose (lactose monohydrate) was also found to be significant based on their “ P ” values, i.e., 0.0248 (for HEC and %w/w of sodium bicarbonate); and 0.0130 (for %w/w of sodium bicarbonate and %w/w of Pharmatose (lactose monohydrate). However, combined effect of polymer concentration and Pharmatose (lactose monohydrate) is less significant indicated by its “ P ” = 0.2389 The first-order main effects of all the selected independent variables such as polymer quantity, %w/w of sodium bicarbonate, and %w/w of Pharmatose (lactose monohydrate) are highly significant which is evident from their respective “ P ” values. The combinatorial effect of polymer concentration and sodium bicarbonate as well as sodium bicarbonate and Pharmatose (lactose monohydrate) was also significant based on their “ P ” values. These suggest that the amount of the polymer and concentrations of sodium bicarbonate, Pharmatose (lactose monohydrate), combined effect of polymer concentration and sodium bicarbonate and also sodium bicarbonate and Pharmatose (lactose monohydrate) have got a direct relationship for achieving a formulation which releases the total drug content in 12±1 h. However, combined effect of polymer concentration and Pharmatose (lactose monohydrate) is less significant indicated by its “ P ” values Table 4: Analysis of variance (ANOVA) for the quadratic model Source of variations Sum of squares Degrees of freedom Mean square F-value Prob. (P) Regression 49.900 9 5.544 8.928 0.013 Residual 3.105 5 0.621 Total 53.005 Regression summary for dependent variable: Y R=0.9703; R²=0.9414; Adjusted R²=0.83597 Response surface plots are more useful for understanding both the main and the interaction effects of any two selected factors and keeping all other factors at fixed levels (zero, for instance). These plots can be easily obtained by calculating from the model, the values taken by one factor where the second varies (from −1 to +1, step 5 for instance in case of sodium bicarbonate and Pharmatose [lactose monohydrate] concentrations and 20 in case of polymer quantity). Response Figure 9: Response surface plot showing the effect of polymer (hydroxyethyl cellulose) and sodium bicarbonate on cumulative % drug released at 12 h Table 5: Model coefficients estimated by multiples linear regression (significance of regression coefficients) Factor Coefficient Computed t -value P -value Intercept 98.9086 434.7803 0.0000 Hydroxyethyl cellulose −0.8934 −3.2064 0.0238* Sodium bicarbonate −1.3685 −4.9117 0.0044* Pharmatose 1.0071 3.6147 0.0153* Hydroxyethyl cellulose × Hydroxyethyl cellulose 0.0424 0.2068 0.8444 Sodium bicarbonate × Sodium bicarbonate 0.5207 2.5395 0.0519 Pharmatose × Pharmatose 0.1582 0.7714 0.4753 Hydroxyethyl cellulose × Sodium bicarbonate −1.2495 −3.1711 0.0248* Hydroxyethyl cellulose × Pharmatose 0.5268 1.3369 0.2389 Sodium bicarbonate × Pharmatose 1.4875 3.7751 0.0130*

Garudaiahgari, et al .: GFMT of diltiazem Hcl by response surface optimization Asian Journal of Pharmaceutic s • Jul-Sep 2020 • 14 (3) | 431 plots drawn in between polymer quantity and %w/w of sodium bicarbonate, polymer quantity, and %w/w of Pharmatose (lactose monohydrate) and %w/w of Pharmatose (lactose monohydrate) and %w/w of sodium bicarbonate are shown in Figures 9-11 Figure 9 shows that the release of the drug was prolonged with increase in concentration of polymer along with concentration of sodium bicarbonate which may be due to increased intensity of carbon dioxide gas pockets surrounding the sticky surface of the tablet. Increase in the concentration of sodium bicarbonate at a low polymer concentration initially enhanced the release of the drug due to initial channeling effect associated with low intensity of carbon dioxide gas pockets, followed by retardation in release of the drug by the controlling effect associated with increased intensity of carbon dioxide gas pockets The response surface plot [ Figure 10] shows that increase in the concentration of Pharmatose greatly enhanced the release of the drug due to its channeling effect despite increased the concentration of the polymer. Similarly, the response surface plot [ Figure 11] shows that increase in the concentration of Pharmatose greatly enhanced the release of the drug due to its channeling effect despite the increased intensity of carbon dioxide gas pockets associated with increased concentration of sodium bicarbonate Verification of optimized formulations The obtained optimum values of the independent test variables are as follows; 93.50 mg quantity of HEC (X 1), 11.47 % w/w of sodium bicarbonate (X 2), i.e., 21 mg and 10.40% w/w of Pharmatose (lactose monohydrate) (X 3), i.e., 19.1 mg, as shown in Table 6. The model predicts that the formulation Figure 10: Response surface plot showing the effect of polymer (hydroxyethyl cellulose) and Pharmatose (lactose monohydrate) on cumulative % drug released at 12 h Figure 11: Response surface plot showing the effect of sodium bicarbonate and Pharmatose (lactose monohydrate) on cumulative % drug released at 12 h Table 6: Formula composition of optimized formulation DNAso Ingredient mg/tablet Diltiazem HCl 90.0 Hydroxyethyl cellulose 93.5 Polyvinylpyrrolidone 3.0 Sodium bicarbonate 21.0 Pharmatose 19.1 Magnesium stearate 3.0 Talc 2.0 Tablet weight (in mg) 231.6 Table 7: Observed responses and predicated values Formulae Actual value Predicated value Residual DNAB 1 100.00 99.76 0.24 DNAB 2 99.99 100.47 −0.48 DNAB 3 100.00 99.52 0.48 DNAB 4 94.99 95.23 −0.24 DNAB 5 100.00 99.88 0.12 DNAB 6 97.88 97.04 0.84 DNAB 7 100.00 100.84 −0.84 DNAB 8 99.99 100.11 −0.12 DNAB 9 100.00 100.36 −0.36 DNAB 10 94.05 94.65 −0.60 DNAB 11 100.00 99.40 0.60 DNAB 12 100.00 99.64 0.36 DNAB 13 99.99 99.87 0.12 DNAB 14 99.62 99.87 −0.25 DNAB 15 100.00 99.87 0.13

Garudaiahgari, et al .: GFMT of diltiazem Hcl by response surface optimization Asian Journal of Pharmaceutic s • Jul-Sep 2020 • 14 (3) | 432 with 100% drug release in 12±1 h can be obtained using the above optimum concentrations. Verification of the optimized conditions was done by carrying out in vitro dissolution experiments, which showed a desired dissolution profile. These experimental findings are in close agreement with the model predictions and are shown in Table 7. The results of physical and chemical evaluation of optimized GFMT formulation DNAso were observed to be satisfactory, as shown in Table 8. Floating lag time of optimized formulation DNAs is 405 s. Release of the drug substance from DNAso (optimized formulation) and Dilzem SR (commercial sustained release formulation) followed zero-order release kinetics with diffusion mechanism CONCLUSION Statistical optimization of GFMT of diltiazem HCl resulted in predicting the optimum concentrations of polymer, gas generating agent, and channeling agent for obtaining the desired prolongation of drug release along with the required floating characteristics ACKNOWLEDGMENT The author Srinivasa Venkata Subramanyam Garudaiahgari is thankful to UGC (University Grants Commission, India) for granting and awarding the research fellowship for carrying out this research work REFERENCES 1. Bhalekar MR, Madgulkar AR, Sheladiya DD, Kshirsagar SJ, Wable ND, Desale SS. Statistical optimization of sustained release venlafaxine HCI wax matrix tablet. Indian J Pharm Sci 2008;70:472-6 2. Ghosh A, Bose A, Bhaumik U, Mandal U, Gowda KV, Pal TK. Application of response surface methodology in the formulation of sustained release matrix tablets of metformin hydrochloride. Asian J Chem 2008;20:5541-56 3. Mandal U, Gowda V, Ghosh A, SelvanS, Solomon S, Pal TK. Formulation and optimization of sustained release matrix tablet of metformin HCL 500 mg using response surface methodology. Yakugaku Zasshi 2007;127:1281-90 4. Singh B, Ahuja N. Book review on pharmaceutical experimental design. Int J Pharm 2000;195:247-8 5. Strobel R, Sullivan G. Experimental design for improvement of fermentations. In: Demain AL, Davies JE, editors. Manual of Industrial Microbiology and Biotechnology. Washington, DC: ASM Press; 1999. p. 80-93 6. Gawande BN, Patkar AY. Application of factorial designs for optimization of cyclodextrin glycosyltransferase production from Klebsiella pneumoniae Pneumoniae AS-22. Biotechnol Bioeng 1999;64:168-73 7. Ooijkaa LP, Wilkinson EC, Tramper J, Buitelaar RM. Medium optimization for spore production of Coniothyrium minitans using statisticallybased experimental designs. Biotechnol Bioeng 1999;64:92-100 8. Pham PL, Taillandier P, Delmas M, Strehaiano P. Optimization of a culture medium for xylanase production by Bacillus sp. Using statistical experimental designs. World J Microbiol Biotechnol 1998;14:185-90 9. Deshpande AA, Shah NH, Rhodes CT, Malick W. Development of a novel controlled-release system for gastric retention. Pharm Res 1997;14:815-9 10. Urquhart A, Theeuwes F. Drug Delivery System Comprising a Reservoir Containing a Plurality of Tiny Pills. US Patent No. 4, 434, 153; 1984 11. Mamajek RC, Moyer ES. Drug-Dispensing Device and Method. US Patent No. 4, 207, 890; 1980 12. Lehr CM. Bioadhesion technologies for the delivery of peptide and protein drugs to the gastrointestinal tract. Crit Rev Ther Drug Carrier Syst 1994;11:119-60 13. Ponchel G, Irache JM. Specific and non-specific bioadhesive particulate systems for oral delivery to the gastrointestinal tract. Adv Drug Deliv Rev 1998;34:191-219 14. Caldwell LJ, Gardner CR, Cargill RC. Drug Delivery Device Which can be Retained in the Stomach for a Controlled Period of Time. US Patent No. 4, 735, 804; 1988 15. Caldwell LJ, Gardner CR, Cargill RC, Higuchi T. Drug Delivery Device Which Can be Retained in the Stomach for a Controlled Period of Time. US Patent No. 4, 758, 436; 1988 16. Caldwell LJ, Gardner CR, Cargill RC. Drug Delivery Device Which Can be Retained in the Stomach for a Controlled Period of Time. US Patent No. 4, 767, 627; 1988 17. Kedzierewicz F, Thouvenot P, Lemut J, Etienne A, Hoffman M, Maincent P. Evaluation of peroral silicone dosage forms in humans by gamma-scintigraphy. J Control Release 1999;58:195-205 18. Rednick AB, Tucker SJ. Sustained Release Bolus for Animal Husbandry. US Patent No. 3, 507, 952; 1970 19. Bechgaard H, Ladefoged K. Distribution of pellets in the gastrointestinal tract: The influence on transit time Table 8: Physical and chemical characteristics of optimized formulation DNAso Formulation Weight (mg) Drug content (%) Hardness (kg/cm 2 ) Friability (%) Floating lag time (sec) DNAso 231.4±0.32 100.4±0.57 4–6 0.22 405

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