INTRODUCTION:

Ranitidine HCl as an H₂receptor antagonist is used for the therapy of upper digestive tract disease¹. Ranitidine HCl has a half-life of about 2-3 hours². In addition, ranitidine HCl is absorbed well only in the gastric and initial part of the small intestine, and also undergoes metabolism in the colon which causes low bioavailability³. To produce a longer release without increasing the dose of the drug, ranitidine HCl can be made into a slow-released preparation by modifying the formulation that can be retained in the gastric to maximize its absorption.

The long-held preparation in the gastric is also known as gastroretentive drug delivery system(GRDDS)⁴^,⁵. There are several types of gastroretentive drug delivery system (GRDDS), such as hydrodynamically balanced systems (HBS)/floating drug delivery system, swelling system, bioadhesive or mucoadhesive system and high density systems⁶. Floating system has a lower density compared to the gastric fluid thus it stays afloat in the gastric for a long period of time without being affected by the speed of gastric emptying. When the system floats in gastric fluid, the drug is released slowly as desired⁷^,⁸. The ability to float from a preparation is indicated by floating lag time, which is the time needed for tablet to appear on media surface and the floating total time, namely the duration of time to stay afloat. Floating lag time should be less than 15 minutes so that the preparation successfully floats before the gastric emptying time⁹ and the total floating time of more than 8 hours must be fulfilled to achieve a slow release effect¹⁰^,¹¹.

Floating preparation formulation usually uses expandable polymers such as Methocel, polysaccharide, and chitosan and effervescent agent, like sodium bicarbonate, is added to help the tablet floats¹² the wide range of recommended polymers, cellulose ether polymer is the most popular, especially hydroxypropyl methylcellulose (HPMC)¹³. HPMC is a hydrophilic matrix that can form gel and can control the release of drug ingredients¹⁴. From several available viscosities, HPMC K15M is one of the most used matrixs in a slow-released preparation using gastroretentive drug delivery method¹⁵.

Based on the description above, a study of the effect of the addition of ethyl cellulose 10 cps with various levels (0%, 5%, 10%, and 15%) on the floating characteristic and ranitidine HCl floating tablet release using the HPMC K15M matrix is carried out. This research is hoped to be able to produce ranitidine HCl floating table with floating characteristic and release that is in accordance with the requirement of slow-released preparation.

MATERIALS AND METHODS:

Data analysis performed included data on floating lag time test result, floating total time test, and release test. From the average result of floating lag time test tablet made with HPMC K15M matrix and ethyl cellulose 10 cps, the relationship of ethyl cellulose level to floating lag time of ranitidine HCl tablet was seen. From the average test result of floating time tablet made with HPMC K15M matrix and ethyl cellulose 10 cps, the relationship of ethyl cellulose level to floating time of ranitidine HCl tablet was seen. Furthermore, a statistical analysis was conducted to determine whether or not there were significant differences between formulas. After that, the release percentage of ranitidine HCl was calculated from the floating tablet according to the weight of the tablet.

The release kinetics was analyzed using kinetic equations of order, order one, and Higuchi equation. The analysis of the ranitidine HCl release mechanism from the matrix system was carried out using power law equation (diffusion/relaxation model) as in equation II.10. The value of n was sought by plotting the log value of the drug released from the time log. The value of n was indicated by the slope of the equation of the linear regression line formed¹³.

Prior to data analysis, processing was done statistically by ANOVA one-way variance analysis method, then the analysis was carried out with Honesty Significant Difference test. Statistical analysis performed included floating characteristics data (floating lag time and floating total time) and drug release rate with a confidence level of 0.95 (α = 0.05).

RESULT AND DISCUSSION:

Floating Characteristic Test:

The result of floating lag time and floating tablet total time of ranitidine HCl floating with HPMC K15M 20% matrix and ethyl cellulose 10cps at various contents.The four ranitidine HCl floating tablet formulas fulfilled the floating characteristic requirement with floating lag time <15 minutes¹⁶ and floating total time > 8 hours¹⁰.

Ranitidine HCl Release Test from Floating Tablet

The Determination of Maximum Wavelength of Ranitidine HCl:

The result of the observation of λ maximum of ranitidine HCl in phosphate buffer pH 7.4 of ranitidine HCl absorption at various wavelengths, the maximum wavelength of ranitidine HCl was obtained at 314.03nm.

Determine of Ranitidine HCl Raw Curve:

Relationship between levels of ranitidine HCl and absorption at λ maximum of 314.03nm in buffer pH 7.4. From the data, the value of linear correlation coefficient (r) 0.99992 was obtained where the value was greater than the r table value (r table = 0.602) so that it showed a linear correlation between absorption and ranitidine HCl solution.

The Examination of the Effect of Additional Materials on Absorption of Ranitidine HCl:

The results of the examination of the effect of additional materials on maximum λ ranitidine HCl From the results of the examination carried out on the supplementary constituent of the tablet, it was found that the additional materials used did not affect the absorption of ranitidine HCl.

Uniformity Test Results:

The results of the diversity of tablet weight sand the results of uniformity in the levels of ranitidine HCl. From the results of the preparation uniformity test, it was known that ranitidine HCl floating tablet fulfilled the requirements for uniformity of preparations with the requirements for active ingredient levels located between 90% -110% and relative standard deviation <6%¹⁷.

Ranitidine HCl Release Test:

The calculation results of the release profile of ranitidine HCl in dissolution media can be seen in figure 1.

Figure 1. Profile of release of ranitidine HCl from the ranitidine HCl floating tablet with HPMC K15M 20% matrix and ethyl cellulose 10 cps at various levels in 0.1N HCl

Results of Kinetics Analysis of the Ranitidine HCl Tablet Release:

Analysis of Order Zero Release Kinetics:

The analysis results of order zero release kinetics can be seen in figure 2.

Figure 2. Profile of ranitidine HCl release from floating tablet with HMPC K15M 20% matrix and ethyl cellulose 10 cps at various levels

Higuchi Release Analysis:

The analysis results of the Higuchi model release kinetics can be seen in Figure 3.

Figure 3. Profile release (Higuchi kinetics) of the ranitidine HCl from the floating tablet with HPMC K15M 20% matrix and ethyl cellulose 10 cps at various levels

Table 1. The analysis results of the kinetic release of ranitidine HCl from the tablet

Formula	Equation of order zero	Equation of order one	Higuchi Equation
F1 (0%)	y = 0.151x + 15.74	y = -0.001x + 1.934	y = 3.684x + 0.639
F1 (0%)	R² = 0.917	R² = 0.995	R² = 0.996
F2 (5%)	y = 0.136x + 14.71	y = -0.001x + 1.928	y = 3.327x + 1.180
F2 (5%)	R² = 0.912	R² = 0.990	R² = 0.996
F3 (10%)	y = 0.126x + 13.78	y =-0.000x + 1.931	y = 3.076x + 1.378
F3 (10%)	R² = 0.914	R ² = 0.988	R² = 0.996
F4 (15%)	y = 0.108x + 8.675	y = -0.000x + 1.961	y = 2.631x – 2.254
F4 (15%)	R² = 0.966	R² = 0.997	R² = 0.990

From the analysis results, it has to be noted that the release of formula 1, 2, 3 and 4 ranitidine HCl follows the Higuchi model and order one kinetics.

Analysis Results of the Ranitidine HCl Release Mechanism from Tablet:

The analysis results of the ranitidine HCl release mechanism can be seen in table 2 and figure 4.

Figure 4. Profile of release of ranitidine HCl mechanism with Power Law equation

Table 2. Regression equations, values n and category analysis of the mechanism for releasing ranitidine HCl from tablets floating with HPMC K15M 20% matrix and ethylcellulose 10 cps at various levels

Formula	Line equation	n (slope)	Release mechanism category
F1 (0%)	Y = 0.518x + 0.529	0.518	Non Fickian Diffusion
F2 (5%)	Y = 0.506x + 0.520	0.506	Non Fickian Diffusion
F3 (10%)	Y = 0.503x + 0.495	0.503	Non Fickian Diffusion
F4 (15%)	Y = 0.510x + 0.365	0.510	Non Fickian Diffusion

From the analysis results, it is known that the Ranitidine HCl release mechanism from the floating tablet of all four formulas follow non-fick diffusion.

Analysis Results of Ranitidine HCl Release Conformity from Tablet:

The analysis results of the ranitidine HCl release conformity with tablet slow release requirement according to Welling listed in table 3.

Table 3. Analysis results of the ranitidine HCl release conformity from ranitidine HCl floating tablet with HPMC K15M 20% matrix and ethyl cellulose 10 cps at various levels based on slow release requirements according to Welling

Time	Criteria	Ranitidine HCl released (%)
Time	Criteria	F1 (0%)	F2 (5%)	F3 (10%)	F4 (15%)
0.25 D (2 hours)	20-50%	43.08*	39.43 *	36,73 *	24.85 *
0.5 D (4 hours)	45-75%	58.58*	54,32 *	49.43 *	37.00
> 0.5-1 D (8 hours)	> 75%	79.94*	72,11	67.95	58.10

Notes: * meets the requirements

Of the four formulas, F1 meets the release requirements according to Welling for a D value of 8 hours.

Statistical analysis:

Statistical Analysis of Floating Lag Time:

Statistic analysis results of floating lag time with One-way ANOVA with α = 0.05 obtained F count of 1.065. This F count is smaller than F table which is 3.26 so there is no significant difference between formulas.

Statistical Analysis of Ranitidine HCl Release Rate:

Statistical analysis of the release rate is obtained by using slope from Higuchi equation which can be seen from table 4.

Table 4. Analysis results of ranitidine HCl release rate from floating tablet with HPMC K15M 20% matrix and ethyl cellulose 10 cps at various levels based on Higuchi's equation.

Formula	Replication I	Replication 2	Replication 3
F1	y = 3.683x + 1.371	y = 3.738x + 1.188	y = 3.634x – 0.657
(0%)	Slope = 3.683	Slope = 3,738	Slope = 3.634
F2 (5%)	y = 3.477x - 0.131	y = 3,340x + 0,867	y = 3.164x + 2.794
F2 (5%)	Slope = 3.477	Slope = 3,340	Slope = 3.164
F3 (10%)	y = 2.983x + 2.194	y = 3.313x - 0.640	y = 2.931x + 2.589
F3 (10%)	Slope = 2.983	Slope = 3,313	Slope = 2.931
F4 (15%)	y = 2.541x + 0.199	y = 2.671x - 5.839	y = 2.680x - 1.124
F4 (15%)	Slope = 2,541	Slope = 2,671	Slope = 2,680

The results of statistical analysis of one-way ANOVA release rate test obtain F count of 30.894. This F count is greater than F table which is 4.07 so that there is a significant difference between formulas. To find out which formula is significantly different, the HSD test is carried out. The results of statistical analysis of the ranitidine HCl release can be seen in table 5.

Table 5. HSD test results of HCl floating tablet release rate with HPMC K15M 20% matrix and ethyl cellulose 10 cps at various levels

Formula	F1 (0%)	F2 (5%)	F3 (10%)	F4 (15%)
F1 (0%)		-	+	+
F2 (5%)	-		-	+
F3 (10%)	+	-		+
F4 (15%)	+	+	+

Notes: (+) = significantly different

(-) = not significantly different

From the statistical analysis, the results show that the ranitidine HCl release rate from the floating tablet are between F1-F2 and F2-F3. There are no different meanings but F1-F3, F1-F4, F2-F4 and F3-F4 differ in meaning.

DISCUSSION:

Evaluation of floating characteristics is done by inserting the tablet into a dissolution test equipment using USP type II stirrer which contains 900ml of 0.1 N HCl solution at 37 ± 0.5^oC with stirring speed at 50rpm. The characteristics being evaluated are, floating lag time and floating total time. Floating lag time is determined by measuring the time it takes for the tablet to start floating on the surface of the dissolution media. For floating total time, it is determined by measuring the total time the tablet can float.

From the evaluation of floating lag time, results of the average floating lag time for formulas 1, 2, 3 and 4 are obtained that are 22.63±1.10 respectively; 23.03±2.12; 23.62±0.54 and 24.53±1.31 seconds. From the data known, all formulas show brief floating lag time that is in accordance with the provisions of the GDDS preparation where the preparation must be able to float in less than 15 minutes so that the preparation can float before the time of emptying the gastric⁹. These results also show that the greater the concentration of 10 cps ethyl cellulose in the formula, the greater its floating lag time. On the floating system, after contacting with the media, media penetration will occur into the matrix causing the matrix to expand and have a density of less than one, so it will float¹². The presence of ethyl cellulose 10 cps which is hydrophobic can inhibit water penetration into the matrix¹⁸. Thus, the time required for the preparation to float will be longer. Total floating time test is done for 8 hours and the results of the four formulas are still be able to float, which has fulfilled the minimum requirements for achieving a slow release effect.

Statistical analysis of floating lag time using one-way ANOVA with α = 0.05 gives the result of F count of 1.065 where the value is smaller than the table F value of 3.26. These results indicate that there is no significant difference between formulas. This is due to the influence of sodium bicarbonate which when in contact with the media will form CO2 gas which can be trapped in the gel and encourage the preparation to float on the surface of gastric fluid¹².

The determination of the maximum wavelength, the examination of the effect of additional materials, and the making of the raw curve of ranitidine HCl in 0.1N HCl gave a small absorption on the measurements using spectrophotometric methods. Ranitidine HCl provides good absorption on aquadest media or at an atmosphere of pH 7.4. Therefore ranitidine HCl solution is turned to base in 0.1 N HCl in advance. The culture process is carried out by adding 0.1 N NaOH with a certain volume. From the results of the optimization, the results obtain that 2.0ml of ranitidine HCl solution in 0.1 N HCl requires the addition of 0.1 N NaOH as much as 2.25ml to reach pH 7.4. To maintain pH stability, the solution is then added to a phosphate buffer 7.4 to a volume of 10.0 ml quantitatively on a 10.0ml volumetric flask.

The maximum wavelength obtained is 314.03nm. Furthermore, at the wavelength, a standard solution of ranitidine HCl is measured at a level of 0.5ppm to 40 ppm to obtain a standard curve of ranitidine HCl. From the results of the measurement, the linear regression equation ranitidine HCl is y = 0.04380x - 0.00813 with the value of the linear correlation coefficient (r) of 0.99992 (r table = 0.602). The calculated r value that is greater than r table shows that there is a linear correlation between absorption and levels of ranitidine HCl solution.

Ranitidine HCl release test from the floating tablet done in vitro is carried out with dissolution device for 8 hours in 0.1 N HCl media with an approach such as gastric fluid. The result of ranitidine HCl release test from floating tablet with HPMC K15M and ethyl cellulose 10 cps for formula I, II, III, and IV respectively 79.94± 0.86; 72.11±1.50; 67.95±2.14 and 58.10±2.30%. From these data it can be seen that release of ranitidine HCl F1> F2> F3> F4. Addition of ethyl cellulose 10 cps causes a decrease in ranitidine HCl release from the floating tablet. This is because the addition of hydrophobic polymers such as ethyl cellulose can increase the resistance of water entering the polymer so that it will inhibit the release of medicinal ingredients¹⁹. The greater the level of ethyl cellulose 10 cps added to F2, F3 and F4 causes the release of smaller ranitidine HCl.

To determine the model of ranitidine HCl release kinetics from each floating formula tablet, analysis of release kinetics using the zero order kinetics equation, order one and Higuchi equation is done. The release kinetics model is shown through equations with the highest linearity (R²: 0.98 to 0.99)²⁰ The results of the release kinetic analysis indicate that of all formulas, nothing follows the order zero kinetics. The release kinetics of F1, F2, F3, and F4 follow the Higuchi model and order one with the close value r²which are 0.996; 0.996; 0.998 and 0.990 for the Higuchi model and 0.995; 0.990; 0.991 and 0.997 for order one. Order one kinetics is influenced by the amount of residual drug in the matrix so that the rate of release of the drug can decrease over time. Whereas in Higuchi release kinetics besides being influenced by the content of the remaining drug ingredients in the matrix it is also influenced by the thickness of the matrix⁶.

The mechanism for releasing ranitidine HCl from the floating tablet analyzed from the slope obtained from the relationship between the log percent release to the time log. All formulas follow a non-Fickian diffusion mechanism with a slope value (n) each of them is 0.518; 0.506; 0.503, and 0.510. The non-Fickian diffusion release mechanism shows that the release of ranitidine HCl from the tablet is through the mechanisms of diffusion and erosion. Diffusion occurs because of the K15M HPMC that can expand. When the polymer is hydrated and expands, a high resistance gel will form because of the strong bonding polymer chain. It is the gel layer that controls the release of the drug in diffusion. However, after all the polymers expand, the gel layer becomes more hydrated and when enough water has accumulated, the polymer chain will be released causing erosion³. The mechanism of erosion is also caused by the presence of ethyl cellulose which is insoluble in water²¹.

In the conformity analysis ranitidine HCl release based on Welling requirements for 8 hours, data are obtained at 0.25D (2 hours) of the release of ranitidine HCl from F1, F2, F3 and, F4 are respectively 43.08%,; 39.43%; 36.73% and 24.85%. At 0.5D (4 hours) and 1D (8 hours), data obtained for F1, F2, F3 and F4 are respectively 58.58%; 54.32%; 49.43%; 37.99% and 79.94%; 72.11%; 67.95%; 58.10%. From these data it can be seen that only F1 meets the criteria with the criteria for 0.25D release of ranitidine HCl by 20-50%, at 0.5D 45-75% and at 1D> 75%. F2, F3, and F4 do not meet the requirements because the release is too low. F2 and F3 only meet the criteria in 0.25D and 0.5D while F4 only meets the criteria at 0.25D. The release test in this study is carried out for 8 hours because it is a minimum requirement for slow-release preparation and limited research time. The results of releasing ranitidine HCl obtained indicate the potential to release larger medicinal ingredients for a longer time. Therefore, it is necessary to do further release tests on ranitidine HCl floating tablet with HPMC K15M matrix and ethyl cellulose 10 cps with a longer total time (> 8 hours) to determine the conformity ranitidine HCl release according to Welling.

From the statistical analysis of ranitidine HCl release rate using one-way ANOVA with α = 0.05, obtained F count of 30.889 which is greater than F table which is 4.07 so there is a significant difference between formulas. To find out the different formula, HSD test is done. From the HSD test, the results show that the different formula pairs are F1 - F3, FI - F4, F2 - F4 and F3 - F4 where the ethyl cellulose 10 cps content is added at least 10%.

Based on the results above, it can be concluded that the addition of ethyl cellulose 10 cps at levels of 5%, 10% and 15% in ranitidine HCl floating tablet with HPMC K15M matrix produces tablets with floating lag time that is not different. Addition of ethyl cellulose 10 cps at 10% and 15% levels in ranitidine HCl floating tablet with HPMC K15M matrix decreases the ranitidine HCl release rate.

CONCLUSION:

Addition of ethyl cellulose 10 cps at the levels of 5%, 10%, and 15% in ranitidine HCl floating tablet with HPMC K15M matrix produces tablet with floating lag time that is not different. Addition of ethyl cellulose 10 cps at the levels of 10% and 15% in ranitidine HCl floating tablet with HPMC K15M matrix decreases the rate of release of ranitidine HCl. Ranitidine HCl floating tablet with HPMC K15M matrix without the addition of ethyl cellulose 10 cps results in a release that meets the release requirement of slow release according to Welling at D = 8 hours.

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Received on 12.12.2019 Modified on 08.02.2020

Research J. Pharm. and Tech. 2021; 14(2):735-740.

DOI: 10.5958/0974-360X.2021.00128.1