Int J App Pharm, Vol 15, Issue 6, 2023, 125-131Original Article

EFFECT OF VARIOUS SUSTAINED RELEASE POLYMERS ON FLOATING TABLETS OF CARVEDILOL PHOSPHATE-A COMPARATIVE STUDY

K. RAVI SHANKAR1, SHAIK AMINABEE2*, KNV CHENCHU LAKSHMI1, G. RAMANA REDDY1, REEHANA SHAIK1, VINEETHA TIYAGURA1, SHAIK ALMAAS SULTANA1, SHAIK BASHA1, KANDEPU MOKESH SAI1, JALADI BHAGAVAN1, CHELLI DINESH KUMAR1

1KVSR Siddhartha College of Pharmaceutical Sciences, Vijayawada, Krishna, Andhra Pradesh, India. 2*V. V. Institute of Pharmaceutical Sciences, Gudlavalleru-521356, Krishna, Andhra Pradesh, India
*Corresponding author: Shaik Aminabee; *Email: aminaammi786@gmail.com

Received: 19 Aug 2023, Revised and Accepted: 04 Oct 2023

ABSTRAC

Objective: This study aimed to develop floating tablets of Carvedilol phosphate containing various excipients such as HPMC K100M, Carbopol, Polyox WSR, HPMC K4M, and sodium bicarbonate to generate gas. Additionally, the impact of DCP, spray dried lactose, and HPβCD on drug release was investigated.

Methods: A total of eighteen formulations were prepared using the direct compression method and evaluated for hardness, drug content, friability, floating lag time, floatation time and drug release properties.

Results: FTIR analysis confirmed that there were no chemical interactions between Carvedilol phosphate and the excipients used in the formulation of the floating tablets. Most of the Carvedilol phosphate floating tablets, except for F9 and F10, did not disintegrate in water, alkaline fluids (pH 7.4), or acidic aqueous solutions (pH 1.2). These tablets exhibited satisfactory quality attributes in terms of hardness, drug content, and friability, making them suitable for sustained release. The floating lag time of the tablets ranged from 25 seconds to 34 min, while the floating duration varied from 2 to 24 h. The drug release from the tablets was gradual and sustained over 12 h, depending on the composition of the tablets. Polyox WSR (F9 and F10) resulted in a rapid drug release, whereas an increase in the polymer concentration led to a decrease in the rate of drug release across all formulations.

Conclusion: The study reveals that the use of hydrophilic polymers enhanced the drug release, whereas hydrophobic polymers decreased the drug release. As such, formulations, F11, F15, and F16, which gave 100% drug release within 12 h are finalized as the optimized formulations of Carvedilol phosphate floating tablet.

Keywords: Carvedilol phosphate, Floating, Polymers, Sustained release

© 2023 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/)
DOI: https://dx.doi.org/10.22159/ijap.2023v15i6.49170. Journal homepage: https://innovareacademics.in/journals/index.php/ijap

INTRODUCTION

The drug administration through oral route is the most reliable drug delivery system because of its comfort and easy way of consumption. A solid drug dosage is more robust stable and also exhibits additional advantages such as easy to handle and popular way of medicine consumption. Hence, better subject compliance and drug treatment can be observed with oral route of medications than with any other administration routes of dosage forms. Carvedilol is chemically named as “(±)-1-(Carbazol-4-yloxy)-3-[[2-(o-methoxyphenoxy)ethyl]amino]-2-propanol”. Carvedilol is preferred in the management of hypertension, decreases rate of heart myocardial contractility rate and also reduces systolic pressure when diastolic pause increases. It is a third-generation lipophilic molecule, which is highly nonselective β1 adrenergic receptor blocking agent selectively blocks the β1adrenoceptor with α1-blocking activity coordinated vascular dilatory action and significant action on the function of vascular endothelial cells [1, 2]. Blocking receptors have effects like decreases in stroke and cardiac output capacity, heart muscle oxygen consumption, plasma renin activity, and inhibition of norepinephrine release [3].

Carvedilolcomes under Class II of BCS Classification which distinguish by low dissolution rate (due to its less aqueous solubility) and has a less plasma half-life of about 6 h with an elimination half-life of 2 h. Due to its poor solubility in alkaline pH environments, the bioavailability of Carvedilol Phosphate is negatively affected, limiting its absorption at the intended site [4]. Therefore, Carvedilol Phosphate is a suitable candidate for the formulation of gastroretentive floating tablets, as it can enhance its bioavailability by prolonging gastric residence time and achieving sustained release for twice-daily administration over 12 h [3]. This study aims to develop and assess floating tablets of Carvedilol Phosphate using various matrix-forming polymers such as HPMC K100 M, Carbopol, Polyox WSR, and HPMC K4M. The tablets will be evaluated for hardness, drug content, friability, disintegration time, floating time, floating lag time, as well as drug release kinetics and mechanisms.

MATERIALS AND METHODS

Chemical/reagents

Carvedilol phosphate and was a gift sample from M/s Aizant Drug Research Solutions Pvt. Ltd., Hyderabad. HPMC K100 and K4M, Carbopol, Polyox WSR, sodium bicarbonate, dicalcium phosphate (DCP), lactose were procured from commercial sources. All other materials used were of Pharmacopoeial grade.

Formulation of carvedilol phosphate floating tablets

The preparation of Carvedilol phosphate tablets involved utilizing HPMC K100M, Carbopol, Polyox WSR, and HPMC K4M as matrix-forming polymers, while sodium bicarbonate was employed as a gas-generating agent. Lactose and dicalcium phosphate were used as fillers. A total of twenty different formulations of Carvedilol phosphate floating tablets were developed using various combinations of matrix-forming agents and fillers through the direct compression method [5].

Methods of preparation of floating tablets of carvedilol phosphate

To prepare the Carvedilol phosphate floating tablets, the predetermined quantities of Carvedilol phosphate, matrix-forming polymer, sodium bicarbonate, fillers, talc, and magnesium stearate were thoroughly mixed inside a closed polyethylene bag. The mixing process ensured the homogeneity of the powder blend. Subsequently, a multi-station tablet compression machine was employed, along with an 8 mm round flat punch. The powder mixture was directly compressed using 9 mm flat punches, applying sufficient force to achieve a hardness ranging between 4-6 kg/cm2. This compression step ensured the formation of tablets with the desired physical properties.

FT-IR

The FT-IR spectra of carvedilol and optimized solid dispersion were recorded by (Make: Bruker Optics, Model: Alpha). For this, KBR disc technique was used. The sample was combined with potassium bromide dry powder and was compacted into a transparent disc which placed in IR spectrophotometer using specialised dies at high pressure. The spectrum read in a frequency range 4000-400 cm-1 to evaluate polymer-drug interaction studies [6].

Characterization of tablet

The formulated Carvedilol phosphate floating tablets underwent several evaluations to assess their quality and performance. The following tests were conducted tablet Weight variation test, tablet hardness, drug content, tablet friability, in vitro dissolution and Buoyancy/floating test.

Weight variation

In the quality control process, twenty tablets from each batch were selected, and their individual weights were measured in grams. The average weight of the tablets was calculated by summing the weights of all the tablets and dividing by twenty. The standard deviation, which indicates the variation in tablet weights within the batch, was also determined. After obtaining the average weight and standard deviation, the results were compared against the established limitations or specifications. Compliance or non-compliance with the weight requirements was determined based on whether the average weight fell within the specified range and if the standard deviation was within acceptable limits [7].

Tablet hardness

The hardness of the tablets was determined using a hardness testing apparatus. The tablet was placed longitudinally between the two plungers of the apparatus, and the force required to break the tablet was measured. The hardness value was expressed in kilograms per square centimeter (kg/sq. cm). By measuring the tablet hardness, it was possible to assess its mechanical strength and integrity [8].

Drug content

To assess the drug content of the prepared floating Carvedilol tablets, ten tablets were selected for analysis. These tablets were powdered, and an amount equivalent to the weight of one tablet was transferred into a 100 ml volumetric flask. The powder was then dissolved in methanol and diluted with 0.1N HCL buffer solution up to the mark on the flask. The resulting solution was subjected to sonication for 10 min to ensure complete dissolution. Next, the drug concentration in the solution was determined spectrophotometrically using a UV-visible spectrophotometer (specifically, the UV 1800 Shimadzu spectrophotometer) at a wavelength of 240 nm. The solution was filtered prior to the spectrophotometric analysis. By measuring the drug concentration, the drug content in the floating Carvedilol tablets could be quantified, providing information on the amount of active pharmaceutical ingredient present in each tablet [9].

Friability test

The forces that break tablets are friction and shock. The friability test estimates a tablet's ability to resist abrasion while being handled, packaged, and transported, which is related to tablet hardness. Typically, it is assessed with a Roche friabilator. Tablets were weighted and subjected to abrasion as they fell 6 inches every time the device turned. The weight of the pills was measured after 100 spins and contrasted with the starting weight. Weight loss serves as a proxy for tablet friability, which is reported as a percentage [10]. The common consensus is that a loss of weight is not more than 1% of total weight is acceptable.

In vitro dissolution

This test was executed by Type II USP as a dissolution test apparatus. The formulations thus prepared were placed into the dissolution medium holder, which holds 0.1N HCL Buffer of 900 ml at 37 °C±0.5 °C and fix at 50rpm (n=3). Aliquots of 5 ml sample collected through 0.45μm microfilter periodically at predetermined intervals of time and refill with 5 ml of new dissolution medium. The Nebivolol concentration was evaluated spectrophotometrically by UV spectrophotometer (UV 1800 shimandzu spectrophotometer) at λ max 240 nm. All drug release experiments were conducted in triplicate (n=3).

Floating time and floating lag time determination

The floating lag time and flotation time are parameters used to measure the time intervals during which the tablet enters the dissolution medium and rises to the upper third of the dissolution vessel, and the duration for which the dosage form remains afloat, respectively. These measurements were performed using a USP Type II dissolution unit, with 900 ml of 0.1 N HCl serving as the dissolution buffer. The experiments were conducted at a temperature of 37 °C. By observing and recording the floating lag time and flotation time, valuable information regarding the buoyancy and floating behaviour of the tablets in the specific dissolution conditions was obtained [11].

RESULTS AND DISCUSSION

The objective of utilizing floating tablets is to achieve an extended residence time in the stomach and upper gastrointestinal (GI) tract, leading to improved bioavailability and sustained release of the drug. In this study, the focus was on preparing floating tablets of Carvedilol phosphate.

To quantify the concentration of Carvedilol phosphate, an UV-visible spectrophotometer was employed, measuring absorbance at 240 nm in 0.1 N hydrochloric acid buffer. A calibration curve was constructed to verify the method's precision, linearity, and potential interference. The concentrations ranged from 0 to 10 µg/ml, adhering to Beer's rule. The method exhibited excellent reproducibility, with low relative standard deviation (RSD) values (<1.92%).

Fig. 1: FTIR spectra of carvedilol phosphate

Fig. 1-5 depict the FT-IR spectra of pure Carvedilol phosphate and physical mixtures. The IR peaks observed in the spectra of Carvedilol indicate that there are no significant interactions between Carvedilol and the excipients employed in this study. This confirms the compatibility of Carvedilol with the selected excipients, supporting their use in the formulation [10].

Fig. 2: FTIR spectra of carvedilol phosphate and HPCK100M

Fig. 3: FTIR spectra of carvedilol phosphate and carbopol

Fig. 4: FTIR spectra of carvedilol phosphate and HPMCK4M

Fig. 5: Overlay of FTIR spectra of carvedilol phosphate with HPMCK100M, carbopol and HPMCK4M

Carvedilol phosphate floating tablets

Carvedilol phosphate floating tablets were developed using the concept of gas generation. Each tablet contained 20 mg of Carvedilol phosphate and was formulated using HPMC K100M, Carbopol, Polyox WSR, and HPMC K4M as matrix-forming polymers. Sodium bicarbonate was incorporated as the gas-generating agent. The impact of DCP, spray dried lactose, and HPβCD on drug release was also investigated. A total of eighteen Carvedilol phosphate floating tablets were prepared using the direct compression technique, following the specific compositions outlined in table 1-2. The formulated tablets underwent comprehensive characterization to evaluate their quality and performance. Tests conducted included hardness assessment, determination of drug content, evaluation of friability, measurement of disintegration time, determination of floating time, observation of floating lag time, and analysis of drug release characteristics. By conducting these extensive evaluations, valuable insights were obtained regarding the tablet's physical properties, drug content uniformity, mechanical strength, floating behaviour, and drug release profile [12]. These evaluations were crucial in assessing the overall performance and suitability of the Carvedilol phosphate floating tablets for their intended use (table 3).

Table 1: Composition of carvedilol phosphate floating tablets (F1-F8)

Ingredient (mg/tab) F1 F2 F3 F4 F5 F6 F7 F8
Carvedilol phosphate 20 20 20 20 20 20 20 20
HPMC K100 M 100 50 - - 100 50 - -
Carbopol 934 - - 100 50 - - 100 50
HPβCD - - - - 30 30 30 30
Sodium bicarbonate 40 40 40 40 40 40 40 40
Dicalcium phosphate 32 82 32 82 12 52 12 52
Talc 4 4 4 4 4 4 4 4
Magnesium stearate 4 4 4 4 4 4 4 4
Total weight (mg) 200 200 200 200 200 200 200 200

Table 2: Formulae of carvedilol phosphate floating tablets (F9-F18)

Ingredient (mg/tab) F9 F10 F11 F12 F13 F14 F15 F16 F17 F18
Carvedilol phosphate 20 20 20 20 20 20 20 20 20 20
HPMC K100 M - - - - - - - -
Carbopol 934 - - 100 50 - - - 75
HPMC K4M - - - - 100 50 75 - 100 50
Polyox WSR 100 50 - - - - - -
Sodium bicarbonate 40 40 40 40 40 40 40 40 40 40
Spray dried lactose 32 82 32 82 32 82 57 27 - -
HPβCD - - - - - - - 30 - -
DCP - - - - - - - 32 82
Talc 4 4 4 4 4 4 4 4 4 4
Magnesium stearate 4 4 4 4 4 4 4 4 4 4
Total weight (mg) 200 200 200 200 200 200 200 200 200 200

The hardness of the tablets fell within the range of 4.0-5.0 kg/cm2, meeting the desired specifications. The tablets also exhibited excellent resistance to abrasion during the friability test, with a weight loss of less than 0.85% in each case. Furthermore, the Carvedilol phosphate drug content in all tablet formulations met the specified limit of 100±3%.

With the exception of formulations F9 and F10, all the floating tablets produced did not disintegrate in water, aqueous acidic (pH 1.2), and alkaline (pH 7.4) fluids. This indicates that the tablets had strong structural integrity and were capable of maintaining their shape under different conditions. Consequently, based on the satisfactory results obtained from the characterization tests, the manufactured floating tablets were deemed of high quality and suitable for sustained release purposes.

During the in vitro buoyancy evaluation, the floating lag time of multiple tablets adhered to the specified range of 25 seconds to 34 min. Additionally, the floating time varied across different floating tablets, ranging from 2 to 24 h. These results indicate that the tablets exhibited satisfactory floating behaviour and could remain buoyant for an extended period.

Table 3: Physical parameters of carvedilol phosphate floating tablets

Formulation

Hardness*1

(Kg/cm2) mean±sd

Friability*2

(% wt. loss) mean±sd

Drug *3 content

(%) mean±sd

Floating lag time*4

(seconds) mean±sd

Floating time*5

(h)
F 1 4±0.05 0.82±0.015 99.6±1.98 30±0.5 >24
F 2 5±0.03 0.75±0.010 98.2±1.25 15±0.5 >24
F 3 5.5±0.06 0.65±0.012 100.3±1.50 22±0.4 >24
F 4 4±0.06 0.87±0.015 99.5±1.65 13±0.2 >24
F 5 5±0.03 0.77±0.013 97.3±1.50 90±1.5 >24
F 6 6±0.05 0.55±0.001 99.8±2.00 60±1.5 >24
F 7 5.5±0.06 0.60±0.012 98.7±1.90 28±0.4 >24
F 8 6±0.06 0.45±0.010 99.6±1.45 18±0.2 >24
F 9 6±0.05 0.34±0.006 101.2±1.50 10±0.2 Up to 4 h
F 10 5±0.05 0.6±0.012 100.8±1.85 14±0.2 Up to 3 h
F 11 5±0.05 0.74±0.010 99.5±1.56 5±0.1 Up to 10 h
F 12 4±0.04 0.47±0.010 98.5±1.50 5±0.1 >24
F 13 5±0.04 0.65±0.011 99.3±1.75 48±0.3 >24
F 14 6±0.04 0.52±0.010 99.5±1.50 22±0.3 >24
F 15 6±0.04 0.45±0.009 98.7±1.60 14±0.2 >24
F 16 6±0.04 0.38±0.006 98.4±175 25±0.2 >24
F 17 5±0.04 0.56±0.010 99.6±1.35 30±0.15 >24
F 18 5.5±0.05 0.29±0.005 101.5±2.00 14±0.15 >24

*1= n=10 tablets, *2= weight equal to 6.5 g., *3 = n= 10 tablets, *4= n= 10 tablets, *5= n= 10 tablets

In order to examine the release profile of carvedilol phosphate from the floating tablets, the tablets were subjected to in vitro dissolution testing using 0.1N HCl buffer. The drug release pattern was visually represented in fig. 6-7, while the specific drug release characteristics were summarized in table 4. The release of the drug from the tablets followed a gradual and sustained pattern over duration of 12 h. The release kinetics was influenced by the composition of the tablets, highlighting the importance of the tablet formulation in controlling the drug release behaviour [13, 14].

Table 4: Release parameters of carvedilol phosphate floating tablets

Formulation Rate of release Release exponent (n) mean±sd*
K0 (mg/h) mean±sd* K1(h-1) mean±sd*
F1 0.76±0.01 0.0510±0.001 0.800±0.01
F2 0.80±0.01 0.0539±0.001 0.765±0.01
F3 0.91±0.01 0.0713±0.001 0.589±0.01
F4 2.40±0.04 0.4075±0.008 0.688±0.01
F5 0.89±0.01 0.0671±0.001 0.694±0.01
F6 1.12±0.02 0.0901±0.001 0.926±0.01
F7 1.35±0.02 0.1263±0.002 0.992±0.01
F8 4.82±0.06 0.3152±0.006 0.657±0.01
F9 9.87±0.15 1.868±0.036 0.169±0.003
F10 8.56±0.15 1.601±0.02 0.696±0.01
F11 1.57±0.03 0.240±0.006 0.656±0.01
F12 2.89±0.03 0.580±0.01 0.733±0.015
F13 1.03±0.01 0.083±0.002 0.733±0.01
F14 2.65±0.05 0.486±0.01 0.896±0.01
F15 1.50±0.02 0.143±0.002 0.709±0.01
F16 1.66±0.01 0.332±0.006 0.701±0.01
F17 0.95±0.01 0.067±0.001 0.945±0.01
F18 2.23±0.02 0.168±0.003 0.964±0.01

*n=3 (All drug release experiments were conducted in triplicate (n=3))

Fig. 6: Dissolution profiles of carvedilol phosphate floating tablets (F1-F8)

Fig. 7: Dissolution profiles of carvedilol phosphate floating tablets (F9-F18)

A notable finding from the study was that a decrease in the polymer concentration resulted in an increase in the release of the drug across the mentioned formulations. The incorporation of the hydrophilic excipients HPβCD and lactose led to an enhancement in the rate of drug release. A rapid release of the drug was observed with these formulations, which were formulated with Polyox WSR. Hence Polyox WSR was not suitable in formulation of Carvedilol floating tablets. A decrease in drug rate release was observed with dicalcium phosphate and HPMC K 100 M. Formulations F11, F15, and F16 gave 100% drug release within 12 h.

To analyse the release date, various kinetic models, including zero order, first order, Higuchi, and Korsemeyer-Peppas models were utilized [15-19]. The coefficients of determination (R2 values), which indicate the goodness of fit, were determined for each model and presented in table 5. First-order kinetics was followed by all formulations except in case of F2, F7, F11, F15, and F18. A zero-order release was observed with formulations F2, F7, F11, F15, and F18.

Table 5: Coefficient of determination (R2) Values in the evaluation of carvedilol phosphate drug release as per different kinetic models

Formulation

 Zero-order First order Higuchi Korsemeyer-Peppas
F1 0.981 0.995 0.974 0.998
F2 0.993 0.986 0.919 0.933
F3 0.939 0.986 0.919 0.995
F4 0.895 0.993 0.979 0.968
F5 0.895 0.965 0.914 0.983
F6 0.961 0.981 0.953 0.978
F7 0.999 0.990 0.953 0.994
F8 0.981 0.984 0.849 0.995
F9 0.968 0.936 0.988 0.882
F10 0.657 0.807 0.999 0.769
F11 0.945 0.913 0.955 0.990
F12 0.733 0.881 0.913 0.882
F13 0.970 0.993 0.981 0.956
F14 0.917 0.974 0.955 0.953
F15 0.979 0.926 0.950 0.979
F16 0.959 0.965 0.969 0.976
F17 0.976 0.982 0.953 0.981
F18 0.963 0.864 0.842 0.964

All the formulated tablets were shown diffusion-controlled drug release as it obtained by Higuchi plots.

When the drug release pattern analysed through Korsemeyer-Peppas gives 0.692-0.800, 0.657, 0.65-0.733, 0.709 and 0.701 as release exponent (n) for formulations F1-F5, F9, F11-F13, F15 and F16 respectively proving the release mechanism as ‘non-Fickian diffusion’. For Formulations F6-F8, F14, F17 and F18, the obtained release exponent ‘n’ are 0.916-0.992, 0.896, 0.945 and 0.965, respectively, showing drug release mechanism as Super case II transport.

Formulations F9, F10, which show fast release, exhibited drug release mechanism asfickian diffusion [17].

As such, formulations F11, F15 (HPMCK4M 32.5% and lactose) and F16 (Carbopol 32.5% and HPβCD a) gave 100% drug release within 12 hand 0.696, 0.709 and 0.701 as release exponent ‘n’ respectively. F11, F15 and F16 formulations indicating ‘non-Fickian release. A zero-order release was observed with formulations F11 and F15 and a first-order release was observed in case of formulation F16 [20-22].

As such, formulations F11 (Carbopol 50% and spray-dried lactose), F15 (HPMCK4M 32.5% and lactose) and F16 (Carbopol 32.5% and HPβCD), which gave 100% drug release within 12 h are finalized as the optimized floating formulations of Carvedilol phosphate recommended for bid administration.

CONCLUSION

The present work is to formulate floating tablets of Carvedilol phosphate. The FTIR spectra analysis revealed no evidence of chemical interactions between Carvedilol phosphate and the excipients used in the formulation of the floating tablets. With the exception of formulations F9 and F10, the Carvedilol phosphate floating tablets exhibited good quality characteristics, including hardness, drug content, and friability. The floating lag time of multiple tablets fell within the specified range of 25 seconds to 34 min, while the floating duration varied from 2 to 24 h across different tablet formulations. The drug release from the manufactured tablets followed a gradual and sustained pattern over a 12-hour period, with the release kinetics dependent on the composition of the tablets. Based on these observations, formulations F11 (Carbopol 50% and spray-dried lactose), F15 (HPMCK4M 32.5% and lactose), and F16 (Carbopol 32.5% and HPβCD) were identified as optimized formulations for Carvedilol phosphate floating tablets and are recommended for twice-daily administration.

ACKNOWLEDGEMENT

The authors would like to acknowledge and express their gratitude to the management of KVSR Siddhartha College of Pharmaceutical Sciences, Vijayawada, and V. V. Institute of Pharmaceutical Sciences, Gudlavalleru, Krishna District, Andhra Pradesh for their support and provision of research facilities that were instrumental in the successful completion of this study.

FUNDING

Nil

AUTHORS CONTRIBUTIONS

All authors were responsible for every part of this work and contributed to data analysis, drafting, and revision of the manuscript.

CONFLICT OF INTERESTS

The authors confirm that there are no conflicts of interest regarding the publication of this article.

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