Formulation and Evaluation of Nifedipine Bilayer Floating Tablets

Haridwar Lodh*, Sheeba FR

Department of Pharmaceutics, Mallige College of Pharmacy, Bangalore - 560090, Karnataka, India.

*Corresponding Author E-mail: haridwar462@gmail.com

ABSTRACT:

In the present investigation concern, the formulation and evaluation of bilayer floating tablet of Nifedipine which after an oral administration increase gastric residence time, to increase the bioavailability. Nifedipine is the Calcium channel blocker of the dihydropyridine type which used in angina pectoris and hypertension. It has a half-life of 2-4hours and bioavailability of 45-56%. It is advantageous to formulate bilayer floating tablet of Nifedipine helps to increase bioavailability, reduce dosing frequency, and reach maximum plasma concentration rapidly. Bilayer floating tablets comprised of two layers, immediate and sustain release layers. The immediate release layer is comprised of super disintegrating agent Karaya gum, and sustain release layer comprised of low density release retardant polymers like HPMC K4M and Guar gum; and sodium bicarbonate and citric acid gas generating agents. The prepared powder mixtures were subjected to FT-IR for all interaction. The tablets were prepared by direct compression. First, the powder blends of sustained release layer was pre-compressed and then powder blends of immediate release layer was added. Hardness, friability, drug content, floating lag time, total floating time, swelling index and in-vitro drug release were evaluated. In the present study, it was found that formulation F4 containing HPMC K4M and Guar gum in the ratio of 2:1 showed maximum drug release. The release data were adjusted to various mathematical models such as Higuchi, 1st order and zero order to evaluate the kinetics and mechanisms of the drug release and it was best suited for the Higuchi model. There were no notable changes in stability studies.

KEYWORDS: Floating drug delivery system; Nifedipine; Direct compression technique; Bilayered Floating Tablet; Buoyancy lag time; In-vitro study.

INTRODUCTION:

The drug delivery system is the pure raw form of drugs in solid, liquid or semi-solid form, which should be therapeutic effective, safe and sufficiently stable to deliver a required quantity of the drug to the specified site in the body to reach instantaneously, to achieve the correct concentration and subsequently maintain the appropriate concentration. Many marketed drug delivery systems are orally administered drugs systems¹.

Because of the low cost of treatment, it is best to increase patient compliance and facilitate oral drug delivery. Despite multiple benefits, the frequency of administration of a medication should be increased as it is easily emptied from the stomach².

To overcome these obstacles, the administration of drugs should allow the gastric residence time to be extended. Gastroretention contributes to increased bioavailability, improved duration of drug release, minimises drug waste and improves drug solubility which is less soluble at a high environmental pH³. Many drugs released into the stomach have the greatest therapeutic effect because they are continually delayed and controlled in release. This type of drug delivery method would have comparatively less side effects and would eliminate the need for repeated doses⁴. In the pharmaceutical dosage, the formulation of drugs in multilayer/bi-layer tablets is an innovative approach to supply the loading dose and maintenance dose in a tablet. This design allows the preparation of an extended release with an immediate quantity of one-layer medication and an extended release proportion in the second, thus maintaining an extended blood level. The immediate release portion disintegrates shortly after absorption, providing an initial dose of drug for immediate effect. The matrix layer remains intact most of the time as it passes through the intestine, gradually dissolving from the exposed phase along the way and helping to maintain the blood levels initially reached⁵.

Hypertension According to WHO, systolic blood pressure is 150mm Hg or higher and diastolic blood pressure is 95mm Hg or higher. Nifedipine reduces arterial smooth muscle contractility and subsequent vasoconstriction by blocking the influx of calcium ions through L-type calcium channels. Nifedipine reduces peripheral arterial resistance and relieves coronary artery spasm⁶.

Therefore, it has antihypertensive and anti-angina characteristics. The vasodilatory effect of nifedipine leads to an overall decrease in blood pressure. The main goal in the development of this system is to prepare a sustained release composition that releases nifedipine over a long period of time⁷.

MATERIAL AND METHOD:

Nifedipine was purchased from Yarrow Chem Products Pvt. Ltd, Mumbai. Sterculia gum was purchased from Morning Star Enterprises (India). HPMC K4M was purchased from Nirmay Pharmaceuticals Ltd. (Nashik). Guar gum and Avicel pH 302 were purchased from Indian Fine Chemicals, Mumbai. Carbopol 934P was purchased from Loba Chemie Pvt. Ltd. Sodium bicarbonate, Citric acid, Magnesium stearate and Talc were purchased from SD Fine Chem. Limited (Mumbai). Ferric oxide red was purchased from Molychem, Mumbai.

Preformulation study:⁸

Determination of organoleptic properties:

The physical aspects of the drug was observed and compared with the pharmacopoeial specifications.

Determination of melting point:

Nifedipine's melting point was determined using a capillary method.

Solubility:

A small amount of nifedipine was added to 10mL of solvent (distilled water, acetone, ethanol, diethyl ether, acetic acid) in a 25mL standard stoppered flask with vigorous shaking. The solution was visually observed if the solution was clear and no undissolved particles were observed, if it was insoluble again another increment of particular solvent was added and the procedure was continued until undissolved Nifedipine was found.

Fourier transforms Infrared spectroscopy (FTIR):

Standard curve of Nifedipine pH 1.2:

10mg of nifedipine was accurately weighed and transferred to a 100mL volumetric flask and dissolved with little amount of ethanol and then the volume was made up by adding the phosphate buffer solution pH 6.8 in 100ml volumetric flasks. Then 10ml from above solution was taken into another 100ml volumetric flask and volume was made up with stock solution. 2ml, 4ml, 6 ml, 8 ml and 10ml volumes were taken from the prepared solution in a 10ml volumetric flask and diluted to the mark at pH 6.8 phosphate buffers. The absorbance of the above solution was scanned in the UV region and nifedipine was detected to have absorbance at 235nm. The calibration curve was prepared by plotting the concentration against the absorbance.

Formulation of Bilayer Floating Tablets:⁹

First, a pre-weighed amount of delayed release floating layer was introduced into the die cavity as the second layer and compressed very lightly to obtain a uniform layer, then weighed amount of immediate release layer mixture was introduced into the die cavity as the first layer and finally compressed to obtain bilayer tablet. In this method, the immediate release layer is compressed once, providing rapid disintegration and avoiding double compression. Details of the composition of the floating Bilayer tablets are shown in the table below.

Dose calculation for bilayer tablet:⁹

Dose Calculation:

For sustained drug release up to 12hr, the immediate dose of drug was calculated from total dose of Nifedipine sustained release tablet, which is 50 mg.

Dt = Dose (1 + 0.693 × t/t 1/2)

Where,

Dt = Total dose;

Dose = Immediate release dose;

t = Total duration for which an extended release is required.

t1/2 = Half-life of the drug (Nifedipine) 2hr

For example, Nifedipine (50mg) = Dose [1+ (0.693 ×12)/2]

Dose = 9.69mg Nifedipine.

According to dose calculation, IR dose of drug is 9.69mg for the preparation of bilayer tablets. The maintenance dose is 40.31mg.

Table No. 1: Formulation for Bilayer floating tablets of Nifedipine

Ingredients(mg)	F1	F2	F3	F4	F5	F6	F7
*Immediate Release Layer*	*IR₁*	*IR₂*	*IR₃*	*IR₄*	*IR₅*	*IR₆*	*IR₇*
Nifedipine	9.69	9.69	9.69	9.69	9.69	9.69	9.69
Stercula/karaya gum	6	6	6	6	6	6	6
Magnesium Stearate	0.53	0.53	0.53	0.53	0.53	0.53	0.53
Avicel pH 102	78.8	78.8	78.8	78.8	78.8	78.8	78.8
*Sustain Release Layer*	*SR₁*	*SR₂*	*SR₃*	*SR₄*	*SR₅*	*SR₆*	*SR₇*
Nifedipine	40.3	40.3	40.3	40.3	40.3	40.3	40.3
HMPC K4M	120	_	100	80	60	40	20
Guar gum	_	120	20	40	60	80	100
Carbopol 934P	10	10	10	10	10	10	10
Sodium bicarbonate	30	30	30	30	30	30	30
Citric acid	15	15	15	15	15	15	15
Magnesium Stearate	6	6	6	6	6	6	6
Talc	2.5	2.5	2.5	2.5	2.5	2.5	2.5
Avicel pH 102	30.4	30.4	30.4	30.4	30.4	30.4	30.4
Ferric oxide red	0.8	0.8	0.8	0.8	0.8	0.8	0.8
Total(mg)	350	350	350	350	350	350	350

*All quantities in ‘mg”; *Total Weight of Bilayer Floating tablet: 350mg; *HPMC: Hydroxy Propyl Methyl Cellulose.

EVALUATION:

Pre-compression Studies^10-13,15

Bulk Density and Tapped Density:

Bulk Density = W / V₀

Tapped Density = W / V_f

Where,

V₀ = Initial volume

V_f = Final Volume

Compressibility Index and Hausner’s Ratio:

The compressibility and Hausner’s ratio were calculated from the bulk density (ρ bulk) and tap density (ρ tap) measurements as follows: TBD- LBD

Compressibility index (%) = ------------------- X 100%

TBD

Hausner’s ratio = ----------

LBD

Where,

TBD = Tapped bulk density

LBD = Loose bulk density

Angle of Repose:

= tan^-1 (h/r)

where,

θ = Angle of repose

h = height of the pile

r = radius of the base of pile

Post-compression studies^14-17

Shape and Appearance:

The prepared tablets were visually observed for shape and color.

Uniformity of thickness:

Thickness and diameter of the tablets were measured using a Vernier Caliper.

Weight Variation Test:

The weight variation test was carried out in order to verify the uniformity of the weight of tablets in each formulation.

Thickness of Tablets:

The thickness of the tablets was determined using a Vernier Caliper.

Friability of Tablets:

F = (W₁-W₂)/W₁ x 100

Where,

W₁ = Weight of tablets before testing.

W₂ = Weight of tablets after the test.

The percentage of friability of tablets < 1% is considered acceptable.

Hardness of the Tablets: The crushing strength of prepared tablets of Nifedipine was determined using Monsanto tablet hardness tester.

Swelling Index:

SI = (M_t – M_o / M_o) X 100

Where,

SI = swelling index,

M_t = weight of tablet at time‘t’,

M_o = weight of tablet at time t=0.

Disintegration Time:

Six tablets were taken randomly from each batch for the disintegration test. Disintegration test was performed in simulated gastric fluid using disintegration tester. Immediate release layer was subjected to measure disintegration time (DT).

In-vitro buoyancy test:

The duration for which the formulation floats in the dissolution medium in the upper one-third of dissolution vessel (USP apparatus II, paddle type), was visually observed periodically following figure shows the disintegration of immediate release layer, effervescence produced on tablet surface and floating of sustain release layer as it is placed in dissolution medium. The time between introducing of the dosage form and its buoyancy on the 0.1 N HCl (lag time) and the time during that the dosage form maintained buoyancy (total buoyancy time) were visually determined. Three replicates of each formulations were performed.

In-vitro Drug Release Study:

In-vitro dissolution studies of floating tablets of Nifedipine were carried out in USP dissolution test apparatus-II, employing a paddle type apparatus at 50 rpm using 900ml of 0.1N HCl as dissolution medium at 37±0.5ºC. One tablet was applied to each test. At predetermined time intervals 5ml of the samples were withdrawn with the help of a syringe. The volume withdrawn at each interval was replaced with same quantity of fresh dissolution medium maintained at 37±0.5ºC. A 0.45μm membrane filter was used to filter the collected sample and analyzed by using UV spectrophotometer at λmax 235nm.

RESULT AND DISCUSSION:

Nifedipine is a yellow odorless crystalline powder. The melting point of pure drug was found to be 173°C. As per the Pharmacopoeia, the melting point of Nifedipine was reported to be 173°C, thus indicating purity of sample. Nifedipine is soluble in organic solvents such as ethanol, DMSO and dimethyl formamide at room temperature i.e. 22 – 25°C whereas it is sparingly soluble in aqueous buffers.

Table No. 4: Result of Pre-compression parameter of immediate release and floating sustained release blend of Nifedipine.

Sl. No.	Formulation Code	Loose Bulk Density (g/ml)	Tapped Bulk Density (g/ml)	Compressibility Index (%)	Hausner’s Ratio	Angle of Repose (θ)
01.	IR	0.56 ± 0.12	0.658 ±0.22	13.98 ±0.33	1.16 ±0.08	24.29 ± 0.16°
02.	SR1	0.489 ±0.08	0.547 ±0.18	10.69 ±0.37	1.12 ±0.06	27.27 ±0.05°
03.	SR2	0.646 ±0.09	0.753 ±0.15	14.21 ±0.41	1.16 ±0.05	29.13 ±0.04°
04.	SR3	0.519 ±0.11	0.562 ±0.09	7.65 ±0.35	1.08±0.17	27.14 ±0.32°
05.	SR4	0.612 ±0.08	0.706 ±0.11	13.62±0.09	1.15 ±0.001	27.04 ±0.05°
06.	SR5	0.614 ±0.07	0.698 ±0.20	12.09 ±0.028	1.13 ±0.04	26.38 ±0.98°
07.	SR6	0.598 ±0.04	0.701±0.07	14.69±0.032	1.004±0.03	27.54 ±1.03°
08.	SR7	0.598±0.06	0.678±0.07	11.79 ±0.33	1.13 ±0.08	26.12 ±0.94°

Note: All the values are mean of three readings ± SD

Hence all the formulations studied exhibited good compressibility index.

Table No.5: Result of post-compression parameters of Bilayer Floating tablet of Nifedipine

Formulation Code	Thickness (mm)	Hardness (Kg/cm²)	Friability (%w/w)	Weight Variation (mg)	Drug Content (%)
F1	3.7 ±0.05	6.3±0.42	0.152±0.33	350.54 ±1.28	98.25 ±0.75
F2	3.5 ±0.09	6.1±0.37	0.205±0.13	348.05 ±1.12	98.45 ±1.2
F3	3.5 ±0.08	6.4±0.34	0.244±0.21	349.87 ±1.10	100.07 ±0.31
F4	3.6 ±0.03	6.2±0.65	0.197±0.25	349.59 ±1.29	99.01 ±0.42
F5	3.6 ±0.10	5.9±0.33	0.278±0.18	349.98 ±1.47	98.94 ±0.82
F6	3.7 ± 0.09	6.2±0.54	0.240±0.15	350.35 ±1.05	101.47 ±1.0
F7	3.5 ±0.08	6.1±0.51	0.217±0.17	349.75 ±1.37	100.81 ±0.7

Note: All the values are mean of three readings ± SD

All the physical parameters of the manually compressed tablets were within pharmacopoeial limit.

Table No.6: Result of post-compression parameters of Bilayer Floating tablet of Nifedipine

Formulation Code	Disintegrating Time (Sec)	Swelling Index	Floating Lag Time (sec)	Total Floating Time (hrs)
F1	49±0.82	25.04±0.31	68±0.4	>12
F2	44±0.23	33.84±0.18	56±0.1	>12
F3	45±0.27	45.27±0.33	58±0.1	>12
F4	41±0.75	53.51±0.23	52±0.3	>12
F5	47±0.37	23.81±0.41	65±1.5	>12
F6	44±0.47	31.66±0.26	54±0.5	>12
F7	48±0.1	42.19±0.29	62±0.2	>12

Note: All the values are mean of three readings ± SD

Figure 2: In-vitro buoyancy test after 1 minute of prepared bilayer floating tablet.

Table No. 7: Cumulative % Drug Release of Bilayer Floating tablet of Nifedipine

Time (hr)	F1	F2	F3	F4	F5	F6	F7
0	0	0	0	0	0	0	0
1	31.32	26.28	25.38	25.38	24.48	26.28	23.94
2	34.74	30.20	31.06	31.06	30.18	31.46	30.56
3	40.14	36.32	36.78	36.78	35.76	37.76	34.86
4	45.40	41.56	42.50	42.50	40.28	43.54	41.54
5	52.50	50.96	50.16	50.16	46.44	48.82	47.88
6	57.82	56.46	55.94	56.88	53.00	54.50	54.08
7	64.26	62.34	63.18	64.58	61.74	58.58	61.76
8	70.56	67.72	68.60	71.38	69.46	63.94	67.86

Figure 3: In-vitro drug release curve for batch 1-7

CONCLUSION:

Bilayer Floating tablets of Nifedipine were successfully prepared by direct compression technique using different concentration of polymers. Sodium bicarbonate and tartaric acid was used as gas forming reagent to float the tablets in the stomach.

An attempt to develop bilayer floating tablets of Nifedipine using sodium bicarbonate as gas generating agent and HPMC as hydrophilic polymer by direct compression technique. The formulated tablets showed compliance with various physico-chemical parameters; tablet dimensions, hardness, friability, total floating time, tablet density and swelling index. In simulated gastric fluid, dissolution studies were performed. F4 showed maximum drug release as compared to the other formulations.

The present work can be investigated further to assess the long term stability study of Nifedipine bilayer floating tablets, determination of gastric residence time using Gamma scintigraphy, in-vivo evaluation of Nifedipine bilayer tablets and establishment of in-vitro and in-vivo co-relation.

AKNOWLEDGEMENT:

The authors would like to thank Dr. Shivakumar Swamy, Principal and Director of Mallige College of Pharmacy, Bangalore for providing the facilities to carry out the research work; guide and friends for their continuous support and guidance.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

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Received on 31.08.2022 Modified on 13.02.2023

Asian J. Pharm. Res. 2023; 13(4):244-248.

DOI: 10.52711/2231-5691.2023.00045