Table No 1 Full factorial Experimental Design

Code	Coded Values			Actual values in mg			Dependent Variables
	X1	X2	X3	X1	X2	X3	Y1	Y2	Y3	Y4
FC-1	-1	-1	-1	20	20	10	32	30.7	68.22	97.8
FC-2	+1	-1	-1	40	20	10	35	35.63	50.46	86.83
FC-3	-1	+1	-1	20	40	10	37	32.35	57.32	89.16
FC-4	+1	+1	-1	40	40	10	40	32.36	58.37	83.47
FC-5	-1	-1	+1	20	20	20	28	37.93	57.47	85.67
FC-6	+1	-1	+1	40	20	20	34	17.53	40.75	65.89
FC-7	-1	+1	+1	20	40	20	35	6.82	24.44	62.02
FC-8	+1	+1	+1	40	40	20	36	15.87	28.67	48.6
FC-9	0	0	0	30	30	15	34	9.09	38.89	67.69

X1: Concentration of METHOCEL DC2 K4M (mg), X2: Concentration of METHOCEL DC2 K100M (mg) X3: Concentration of KHCO3 (mg), Y1: Floating lag time (s), Y2: Drug release at end of 2 hour (h), Y3: Drug release at end of 8 hours (h), Y4: Drug release at end of 15 hours (h)

Table No 2. Composition of the Domperidone Floating Tablet

Ingredient (mg)/ Formulation Code	FC-1	FC-2	FC-3	FC-4	FC-5	FC-6	FC-7	FC-8	FC-9
Domperidone Maleate	30	30	30	30	30	30	30	30	30
Methocel DC2 K4M	20	40	20	40	20	40	20	40	30
MethocelDC2 100M	20	20	40	40	20	20	40	40	30
Potassium bicarbonate	10	10	10	10	20	20	20	20	15
SLS	7	7	7	7	7	7	7	7	7
DCP	90	70	70	50	80	60	60	40	65
Talc	1	1	1	1	1	1	1	1	1
Magnesium stearate	2	2	2	2	2	2	2	2	2
Total Weight	180	180	180	180	180	180	180	180	180

The independent variable selected were numeric factors, X1-concentration of Methocel DC2 K4M, X2-concentration of Methocel DC2 K100M andX3- concentration of floating agent potassium bi carbonate (Table No 1).The responses studied for statistical optimisation were Y1- floating lag time in seconds, Y2 - drug release in percent at 2hours Y3 - drug release in percent at 8hours, Y4 -drug release in percent at 15 hours. All the ingredients were passed through sieve no:20 weighed and blended thoroughly and then the prepared powder blends were evaluated for precompression parameters like bulk density, tapped density, angle of repose, and Carr’s compressibility index. The tablets of weight 180mg were prepared using Rimek Mini Press II MT single station tablet compression machine (Karnavati Engineering Private Ltd.)

Drug-Excipients Compatibility:

The drug-excipients compatibility study was carried out by comparing the Infra-red spectra of pure drug and formulation using Shimadzu IR Affinity-I, Japan. Infra-Red spectra were observed for any shift or appearance of unusual peaks.⁸

Evaluation of Floating Drug Delivery System:

The tablets were weighed using sartorious electronic balance and the dimensions of the tablets were measured using vernier caliper .⁹ Hardness was tested using Monsanto hardness tester. The Friability test was carried out for tablets using Roche friabilator.¹⁰The tablets were further evaluated for drug content, invitro buoyancy test, and invitro drug release.¹¹

In-vitro buoyancy studies:

The test was carried out by placing a tablet in a beaker, containing100ml of 0.1NHCl.The time taken by the tablet to rise and float on top of the beaker was recordedas the lag time for floating. The total time for which the tablet floated was also recorded.^9,12

Drug content:

A total of 20 tablets were weighed and powdered. Powder equivalent to dose of 30 mg of the drug was weighed accurately and dissolved in 20ml of 0.1N HCl and made up to 100ml in volumetric flask. The contents in flask were sonicated, filtered and necessary dilutions were done using 0.1N HCL. The drug content was analysed at 283nm using Shimazu UV 1800 Spectrophotometer.

Study of drug release:

The study of drug releasein vitro, for floating domperidone maleate tablets were carried out using USP type II dissolution apparatus, for which 900ml of 0.1N HCl was used as dissolution media at 37ºC± 2ºC and paddle set at 50 rpm. Samples of 5ml were withdrawn at a regular interval of 60 mins up to 24hrs and replaced with fresh media. The sample withdrawn was analysed for drug content at 283 nm using UV Spectrophotometer (UV 1800Shimadzu).^13,14,15

Release Kinetics:

Drug release mechanism was studied by analysing the dissolution data using Higuchi, Korsmeyer peppas and Hixson Crowell cube root equation and plot.¹⁶

Statistical Analysis:

Design expert software version 13.0 of stat ease was used for statistical analysis. Statistical analysis helps to determine the effects of independent variables on the responses. Analysis of variance(ANOVA) and response surface plots were used to study the contribution of each factor on the responses.¹⁷

RESULTS AND DISCUSSIONS:

The results of the precompression characteristics of formulation blends are given in Table no 3. The bulk and the tapped density of the formulation blends indicated good packing properties. The Carr’s index was below 15% and angle of repose was between 13-20% indicating excellent flow properties of the powder blends.

Drug-Excipients Compatibility:

The IR spectra of pure drug domperidone maleate and the drug in combination of excipients were compared (Fig 1). The characteristic peaks representing specific functional group in pure drug were identified and were found in IR spectra of drug in combination with excipients. There was no shift or appearance of extra peak in the IR spectra of drug with excipients indicating that there is no chemical interaction between drug and the excipients.

Evaluation of tablets:

All the tablets were round in shape with convex bevel edges and white in colour. These tablets were further tested for all the post compression parameters such as thickness, diameter, hardness, floating lag time, assay and total floating lag time the results of which are recorded below in the Table No 4. The dissolution studies for all the formulation were carried out and graph was plotted of percent drug release verse time. (Fig 2). Weight variation test was also performed on the formulation batches which found to be on the compliance range that is from 178.65mg – 181.35 mg. (±7.5% variation). Also, friability was less than 1% for all the formulation batches.

Table No 3: Pre-compression characteristics of formulation blends

Formulation	Angle of Repose (θ)	Bulk Density (g/ml)	Tapped Density (g/ml)	Carr’ s Index
FC-1	15.50 ± 0.05	0.546 ± 0.01	0.594 ± 0.01	14.53 ±0.03
FC-2	13.49 ± 0.03	0.545 ± 0.01	0.635 ± 0.02	13.45±0.09
FC-3	16.59 ± 0.05	0.456 ± 0.01	0.434 ± 0.02	10.40 ±0.10
FC-4	13.34 ± 0.22	0.334 ±0.01	0.425 ± 0.02	12.36 ±0.18
FC-5	19.56 ± 0.09	0.345 ±0.01	0.345 ± 0.01	9.67 ±0.16
FC-6	15.83 ± 0.11	0.574 ±0.02	0.672 ± 0.02	10.22 ±0.17
FC-7	15.49 ± 0.05	0.323 ± 0.04	0.356 ± 0.01	12.66 ±0.08
FC-8	15.72 ± 0.12	0.556± 0.01	0.634 ±0.02	13.62±0.10
FC-9	15.68 ± 0.01	0.56± 0.12	0.667 ± 0.02	13.62 ± 0.15

(a) (b)

Fig 1 FTIR Spectra of Pure drug Domperidone Maleate(a) and Drug with excipients (b)

Table No 4 Physicochemical characterizations of Domperidone maleate tablets

Formulation	Thickness (mm)	Diameter (mm)	Hardness (kg/cm²)	Floating lag time (secs)	Assay (%)	Floating Total Time (hrs)
FC-1	4.64±0.005	8.57±0.205	5.67±0.47	32±0.71	97.3±0.12	16
FC-2	4.74±0.008	8.48±0.047	5.33±0.47	35±0.71	98.41±0.04	17
FC-3	4.57±0.051	8.51±0.057	5.67±0.47	37±0.71	98.26±0.55	18
FC-4	4.40±0.104	8.47±0.123	6.33±0.94	40±0.71	98.24±0.49	20
FC-5	4.58±0.050	8.55±0.144	6.67±0.47	28±0.71	99.73±0.11	20
FC-6	4.56±0.094	8.52±0.50	5.67±0.47	34±0.71	97.66±0.07	24
FC-7	4.52±0.054	8.55±0.151	5.67±0.47	35±0.71	98.59±0.15	24
FC-8	4.59±0.045	8.62±1.129	6.67±0.47	36±0.71	98.99±0.42	24
FC-9	4.52±0.006	8.69±0.125	6.33±0.471	34±0.71	98.36±0.30	20

n=6 The data is presented as mean ± SD

Fig. 2: In vitro drug release profile of Domperidone Maleate gastroretentive tablet

Table No 5 Drug Release Kinetics of Formulation

Statistical analytical criteria	FC-1	FC-2	FC-3	FC-4	FC-5	FC-6	FC-7	FC-8	FC-9
Zero order	0.9844	0.9482	0.9958	0.9926	0.9930	0.9875	0.9844	0.9927	0.9897
First order	0.7699	0.5016	0.7042	0.3748	0.1810	0.7114	0.9394	0.7982	0.8340
Higuchi	0.6936	0.5389	0.6254	0.6823	0.6885	0.7222	0.5818	0.6737	0.6676
Kors-peppas	0.9617	0.8536	0.9262	0.9527	0.9542	0.9870	0.9867	0.9712	0.9916
Hixson crowell	0.8263	0.5477	0.7341	0.4680	0.3291	0.7256	0.9530	0.8025	0.9264

Drug release kinetics

The data from the dissolution study was fitted in zero order, first order, Higuchi, Korsmeyer peppas and Hixson Crowell cube root equation and are indicated in Table No 5. It was found that all the of matrix floating tablets of domperidone maleate formulations best fitted in the zero order kinetics

Statistical analysis:

The best suited model was determined using design expert software 13.0 trial version for independent and dependent variables. ANOVA was implemented at 5% level of significance. The model is found to be significant when the value of p<0.05.¹⁷ Table No 6 summarizes the data obtained from ANOVA.

Table No 6 Summary of regression analysis

Response	P Value	R²	SD	CV %
Y1	0.01	0.9260	1.27	3.68
Y2	0.0056	0.9999	0.0778	0.3166
Y3	0.0331	0.9997	0.5374	1.17
Y4	0.0085	0.9317	4.45	6.23

Effect of formulation variables on floating lag time:

The data from ANOVA for response Y1 i.e., floating time lag depicted linear model as best fit model and wasfound to be significant as the p value was less than 0.05. The terms A, B and C i.e., concentration of Methocel DC2 K100M, Methocel DC2 K4M and potassium bicarbonate were found to be significant model terms with the p value of 0.0226,0.0062, and 0.0380 respectively that had effect on floating lag time. The polynomial equation generated by Design Expert software for response Y1 is given below:

Y1= 34.63 + 1.62A + 2.37B – 1.38C

It was observed from the equation that factors A and B had agonist effect on the floating lag time while C has antagonist effect on the floating lag time which is also depicted from response surface plot Fig 3, wherein increase in concentration of Methocel DC2 K4M and K100M caused increase in the floating lag time.

Fig 3 Effect of concentration of polymers on floating lag time

Effect of variables on Drug release at 2 hours:

The data for response Y2 i.e., Drug release at 2 hours showed a linear model as a best fit. The model F-value was 18903.70p value was found to be 0.0056 which is < 0.05 hence the model was found to be significant. The predicted R² and Adjusted R² were 0.9994 and 0.9999 respectively, the difference between this two was found to be less than 0.2 and hence were found to be in reasonable agreement. The adequate precision which measures signal to noise ratio was 377.3624, which indicated adequate model discrimination. The polynomial equation forresponse Y2i.e. drug release at 2 hours is given below:

Y2= 24.58 −1.12A −2.23B −6.80C+AB−4.20BC +2.73ABC

The effect of independent variables A,B, was seen from the response surface plots where in factors A and B had antagonistic effect on drug release and the same is also depicted from the negative coefficient values of terms A, B,and C.

Fig 4 Effect of concentration of polymers on drug release at 2hours

Effect of variables on Drug release at 8 hours:

The ANOVA study showed a linear model as a best fit for response Y3 i.e., Drug release at 8 hours. The p value was found to be 0.0331 which is < 0.05 hence the model was found to be significant. The predicted R² and Adjusted R² were 0.9801 and 0.9978 respectively, the difference between this two was found to be less than 0.2 and were found to be in reasonable agreement. The adequate precision was 56.7345 and was greater than4 which indicated adequate model discrimination. The polynomial equation for response Y3 is given below

Y3= 45.78 – 3.30 A – 1.14C +5.51AB +7.62AC –0.996BC+ 3.80ABC

From the polynomial equation it was seen that concentration of Methocel DC2 K100M(A) has a negative effect on drug release while concentration of potassium bicarbonate (C) has antagonist effect on the drug release while it is seen that interaction between AB and AC has a agonistic effect on drug release. Concentration of Methocel K4M DC2 was found to have greater sustaining effect than concentration of methocel K100DC as seen from the response surface plot (Fig 5)

Fig 5. Effect of concentration of polymers on drug release at 8hours

Effect of variables on Drug release at 15 hours:

The data of ANOVA study showed a linear model as a best fit for response Y4 i.e., Drug release at 15 hours. The model F-value was 18.19 and p value was found to be 0.0085 which is < 0.05 hence the model was found to be significant. The predicted R² and Adjusted R² were found to be in reasonable agreement with the difference less than 0.2 and the adequate precision was 12.4658. The polynomial equation generated for response Y4 is given below

Y4= 71.36 – 6.23A + 8.52AC +4.86ABC

From the polynomial equation it was observed that the variable A has an antagonist effect on the drug release at 15 hours while interaction between AC has agonist effect and interaction between all the three independent variables ABC also has agonist effect on the drug release

Fig 6 Effect of concentration of polymers on drug release at 15hours

Statistical Optimisation:

Domperidone maleate gastroretentive tablet was optimised by setting the desired goalsusing design expert software 13.0 trial version. The goals set for optimisation in this study was to have minimum floating lag time and 80 percent drug release at 15hours. The design expert software provided 44 solutionsamong which one of the various solutions, was among the formulation batch i.e., FC-5. This formulation was selected as best optimised batch having desirability of 0.896.

CONCLUSION:

Design expert software was useful tool for statistical designing and optimisation of the gastroretentive floating domperidone maleate matrix tablet. Formulation FC-5 was selected as the optimised formulation by the software for which the floating lag time was found to be 28 secs with drug release at 8 hours, and 15 hours was,57.47%, and 85.67% respectively. The polymers Methocel DC2 Grades K4M and K100M were found to provide good compression characteristics for cost effective manufacturing and effective in sustaining the release of the drug up to22hours.

ACKNOWLEDGEMENT:

Authors are grateful to Geno Pharmaceuticals Goa for providing gift sample of domperidone maleate and,also would like to thank Dr S. N. Mamle Desai, Principal of P. E. S’s Rajaram and Tarabai Bandekar College of Pharmacy for providing research facility and for his support whenever required.

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Received on 25.02.2024 Modified on 13.05.2024

Research J. Pharm. and Tech 2024; 17(11):5525-5530.

DOI: 10.52711/0974-360X.2024.00844