Development and Evaluation of Floating Matrix Tablets of Propranolol HCl

Kasani Harikrishna Gouda*, V. Sai Kishore and N. Balaji

Department of Pharmaceutics, Bapatla College of Pharmacy, Bapatla, Guntur (Dt), Andhra Pradesh-522101, India.

ABSTRACT:

In the present investigation, an attempt was made to formulate floating matrix tablets of Propranolol HCl using tamarind gum (Tamarind Kernel Powder) with HPMC 50, HPMC K100M as release modifier. Twelve batches of floating matrix tablets of Propranolol HCl were prepared by using different drug : polymer (Propranolol HCl : HPMC 50+Tamarind gum) ratios viz. F₁ (1:1), F₂ (1:2), F₃ (1:4), F₄ (1:6), F₅ (1:8), F₆ (1:10) and drug : polymer (Propranolol HCl : HPMC K100M+Tamarind gum) ratios viz.F₇ (1:1), F₈ (1:2), F₉ (1:4), F₁₀ (1:6), F₁₁(1:8), F₁₂(1:10). The compressed tablets were evaluated for hardness, uniformity of weight, friability, drug content, buoyancy lag time and duration of buoyancy. All the readings are within the prescribed limits. There was no interaction between the drug, polymer and excipients it was found out by IR studies. Swelling index studies were also carried out. The in vitro release data were fitted to different order of reactions such as zero order, first order, Higuchi’s reaction and Korsmeyer-Peppas reaction. It was found that, the drug release follows Korsmeyer-Peppas reaction.

KEYWORDS: Tamarind Kernel Powder (tamarind gum), Gastric residence time, Propranolol hydrochloride, Floating drug delivery, Hydroxypropyl methyl cellulose.

INTRODUCTION:

The oral route is considered as the most promising route of drug delivery. Effective oral drug delivery may depend upon the factors such as gastric emptying process, GI transit time, drug release from the dosage form and site of absorption. Gastric emptying of dosage forms is an extremely variable process, due to unpredictable gastric emptying rate and short gastric residence time. Gastric retention provides, longer residence time in the stomach that improves bioavailability for drugs that are readily absorbed upon release in the GI tract¹. These drugs can be delivered ideally by slow release from the stomach. Floating drug delivery, this system basically floats in the gastric fluid because of its lower density, than the gastric medium. Propranolol, a non-selective beta adrenergic blocking agent, has been widely used in the treatment of angina pectoris, hypertension, and many other cardiovascular disorders. It undergoes high first-pass metabolism by the liver, and on average, only about 25% of propranolol reaches the systemic circulation after oral administration. The t_1/2 of propranolol is 3-4 hrs². Thus, propranolol has relatively short half-life. It also shows p^H dependent solubility; solubility at p^H 1.2 is 225 mg/ml, while at p^H 6.8 it is 130 mg/ml. The objective of the present work was to develop floating matrix tablets using tamarind gum with HPMC 50, HPMC K100M as release modifier in different ratios.

MATERIALS AND METHODS:

Materials:

Propranolol HCl was obtained as gift sample from NATCO Pharma. Ltd., Hyderabad and Tamarind Kernel Powder (tamarind gum), HPMC 50, HPMC K100M, sodium bicarbonate, microcrystalline cellulose, magnesium stearate, talc were obtained from commercial sources.

Methods:

Isolation of gum from Tamarind Seed:

The crushed seeds of Tamarindus indica were soaked in water for 24 hrs, boiled for 1 hr, and kept aside for 2 hrs for the release of gum into water. The soaked seeds were taken and squeezed in a muslin bag to remove marc from the filtrate. Then, to the filtrate, equal quantity of absolute ethyl alcohol was added to precipitate the gum. The gum was separated by filtration. The marc was not discarded but it was sent for multiple extractions with decreasing quantity of extracting solvent, i.e. water with the increase of number of extractions. The isolation was continued until the material was free of gum. The separated gum was dried in hot air oven at temperature 40°C. The dried gum was powdered and stored in airtight containers at room temperature³.

Preparation of Propranolol HCl floating matrix tablets:

Twelve formulations of floating matrix tablets of Propranolol HCl were prepared by using different drug : polymer (Propranolol HCl : HPMC 50+Tamarind gum) ratios viz. F₁ (1:1), F₂ (1:2), F₃ (1:4), F₄ (1:6), F₅ (1:8), F₆ (1:10) and drug : polymer (Propranolol Hcl : HPMC K100M+Tamarind gum) ratios viz. F₇ (1:1), F₈ (1:2), F₉ (1:4), F₁₀ (1:6), F₁₁(1:8), F₁₂(1:10). All the tablets were directly compressed in 16 station rotary tablet press. All the formulations contained 40 mg of Propranolol Hcl, sodium bicarbonate (15%) as gas generating agent, microcrystalline cellulose as diluent, magnesium stearate (2%) as lubricant and talc (2%) added as glidant. The details of composition of each formulation are given in Table 1.

Evaluation of Floating Tablets:

1. Evaluation of powder blend:

The powder blend was evaluated for flow properties⁴. Different tests that were carried out are angle of repose, bulk density, tapped density, compressibility index, and Hausner ratio was calculated.

2. Physical evaluation of floating matrix tablets:

The prepared floating matrix tablets were evaluated for thickness and diameter of 10 tablets, uniformity of weight using 20 tablets, hardness (Monsanto tester), friability using 10 tablets (Roche type friabilator)⁵.

3. In vitro buoyancy studies:

In vitro buoyancy was determined by buoyancy lag time, floating duration, matrix integrity. Buoyancy lag time test was performed to check the floating behavior. The tablets were dropped in the dissolution medium, i.e. 0.1N Hcl and the time taken by them to come to the surface of the dissolution medium, i.e. time taken for floating on surface and float was taken as floating lag time (FLT). The duration of time the dosage form constantly remained on the surface of medium was determined as the total floating time (TFT) ⁶. Matrix integrity: The swollen mass of the tablets remained intact or not was checked. Matrix integrity² was observed throughout in vitro dissolution studies.

4. Drug content:

In drug content¹ determination, ten tablets will be weighed and powdered, 400 mg from it will be transferred to a 100 ml volumetric flask, 5 ml of dilute Hcl will be added, and it will be allowed to stand and swirled occasionally. About 70 ml of methanol will be added, shaken well and the volume will be made up. It will be mixed and a small portion of the solution will be centrifuged. A suitable volume of this will be diluted with methanol to obtain a solution containing 40μg of Propranolol Hcl per ml and the resulting solution will be measured at 290 nm using methanol as the blank solution.

5. Swelling Index:

Formulated tablets will be weighed individually (W₀) and placed separately in petridish containing 50 ml of 0.1N HCl. The petridishes will be placed in an incubator maintained at 37±0.5^oC. At regular 1 hr time intervals until 4 hrs, the tablets will be removed from the petridish, reweighed (W_t), and the % swelling index⁷ is calculated using the following formula.

% W_U = (W_t-W_o/W_o) × 100

W_U – Water uptake

W_t – Weight of tablet at time t

W_o – Weight of tablet before immersion.

6. In vitro dissolution test:

The release of Propranolol HCl from the tablet will be studied using dissolution apparatus USP -Type II paddle apparatus. Drug release profile will be carried out in 900 ml of 0.1N HCl maintained at 37±0.5°C temperature at 100 rpm. 5 ml of samples will be withdrawn at regular time intervals. The samples will be replaced by its equivalent volume of dissolution medium and will be filtered through 0.45 µm whatman filter paper and analyzed at 290 nm by UV spectrophotometer⁸.

7. IR Spectral Analysis:

IR Spectral analysis is used to study the interactions between the drug, polymer and the excipients⁹. The drug and excipients must be compatible with one another to produce a product stable, efficacious and safe.

Table 1: Composition of Propranolol Hcl floating matrix tablets

Ingredients	F1	F2	F3	F4	F5	F6	F7	F8	F9	F10	F11	F12
Propranolol HCl	40	40	40	40	40	40	40	40	40	40	40	40
HPMC 50 Cps	20	20	20	20	20	20	--	--	--	--	--	--
HPMC K100M	--	--	--	--	--	--	20	20	20	20	20	20
Tamarind gum	20	60	140	220	300	380	20	60	140	220	300	380
Sodium bicarbonate (15%)	90	90	90	90	90	90	90	90	90	90	90	90
Microcrystalline cellulose	406	366	286	206	126	46	406	366	286	206	126	46
Magnesium stearate (2%)	12	12	12	12	12	12	12	12	12	12	12	12
Talc (2%)	12	12	12	12	12	12	12	12	12	12	12	12

*Total weight of tablet 600mg. All weights in milligrams. HPMC Hydroxypropyl methyl cellulose.

Table 2: Results of post compression properties of Propranolol HCl floating matrix tablets

Formulation code	Thickness (mm)	Diameter (mm)	Hardness (kg/cm^2)	Friability (%)	Drug content (%)	Weight variation (mg)
F1	4.06±0.05	12.08	3.5	0.61	100.21	599.54±0.55
F2	4.05±0.08	12.12	3.67	0.42	99.64	599.34±0.60
F3	4.11±0.1	12.06	3.83	0.54	100.04	599.38±0.59
F4	4.12±0.1	12.06	4.0	0.39	99.9	599.06±0.54
F5	4.03±0.05	12.06	4.2	0.48	100.01	599.13±0.92
F6	4.11±0.02	12.12	4.5	0.45	99.78	599.26±0.33
F7	4.01±0.1	12.06	3.5	0.55	99.56	599.36±0.59
F8	4.11±0.02	12.12	3.82	0.43	100.01	599.31±0.34
F9	4.07±0.05	12.08	3.6	0.63	99.78	599.54±0.55
F10	4.13±0.1	12.06	4.5	0.38	99.67	599.06±0.55
F11	4.04±0.05	12.06	4.2	0.48	99.56	599.24±0.93
F12	4.06±0.08	12.12	4.5	0.42	100.23	599.32±0.61

RESULTS AND DISCUSSION:

Propranolol is a non-selective beta adrenergic blocking agent, used in the treatment of hypertension, angina pectoris, and in other cardiovascular disorders. Prolonged gastric retention improves solubility for drugs that are less soluble in high p^H environment .Propranolol shows p^H dependent solubility, at p^H 1.2 is 225 mg/ml, while at p^H 6.8 it is 130 mg/ml. Also the effervescence production decreases several local gastrointestinal tract side effects, such as gastric irritation, nausea and gastritis⁶. Floating matrix tablets of Propranolol HCl were developed to increase the gastric residence time of the drug, so that they can be retained in stomach for longer time and help in controlled release of drug up to 12 hrs. The tablets were made, using tamarind gum with HPMC 50, HPMC K100M as release modifier, along with effervescing agent sodium bicarbonate. All the formulations were prepared by direct compression method. Talc and magnesium stearate were employed for their glidant and lubricant property. The prepared tablets of all the formulations were evaluated for pre compression parameters like angle of repose, bulk and tapped density and compressibility index and physical characters like tablet hardness, friability, weight variation, buoyancy lag time, total floating time, in-vitro drug release. The main aim was to optimize the formulation for 12 hrs in-vitro release and total floating time to more than 12 hrs.

Evaluation of powder blend:

Values of angle of repose were found to be between 27.89⁰ and 31.80^0. The powder blend with Hausner ratio of 1.25 has good flow properties and the values were found to be between 1.17 and 1.28. So, these values showed that the powder blend had acceptable flow properties. The % Compressibility was in the range of 13-19, the values between 12-20 have good compressibility which indicates that the powder blend is an acceptable range.

Evaluation of floating matrix tablets:

Floating matrix tablets were evaluated for thickness, diameter, hardness and friability. The drug content estimations showed values in the range of 99.56 to 100.23%, which reflects good uniformity in drug content among different formulations. All the tablets passed weight variation test as the % weight variation was within the Pharmacopoeial limits of ±5% of the weight. All the formulations showed values within the prescribed limits for tests like hardness, friability and weight variation which indicate that the prepared tablets are of standard quality. The results are given in Table 2.

In vitro buoyancy studies:

All tablets were prepared by effervescent approach. Sodium bicarbonate was added as a gas generating agent. Sodium bicarbonate induced carbon dioxide generation in presence of dissolution medium (0.1N Hcl acid). It was observed that the gas generated is trapped within the gel, formed by hydration of polymers (Tamarind gum and HPMC), thus decreasing the density of the tablet (< 1), and the tablet becomes buoyant. The tablet swelled radially and axially during in vitro buoyancy studies. The Propranolol Hcl floating matrix formulations F₁, F₂, F₃, F₇, F₈ and F₉ failed to float and the formulations F₄, F₅, F₆, F₁₀, F₁₁ and F₁₂ remained intact throughout the dissolution studies. The formulations with low viscosity grade HPMC 50 with tamarind gum showed short floating lag time and floated for longer duration as compared with the formulations containing high viscosity grade HPMC K100M. This indicated that the molecular weight distribution or viscosity of the gel forming polymers influenced the in vitro buoyancy. The buoyancy studies results showed that the formulations containing HPMC 50 with tamarind gum, showed good floating lag time (FLT) and total floating time (TFT) when compared to formulations containing tamarind gum with HPMC K100M as release modifier. Thus the formulations F₅, F₆ were found to achieve floatability for more than 21 hrs. The results of in vitro buoyancy studies are tabulated in Table 3.

Table 3: Results of In vitro Buoyancy study of Propranolol HCl floating matrix tablets

Formulation code	Matrix Integrity	Buoyancy Lag Time (Sec)	Total Floating Time (hrs)
F1	-	-	-
F2	-	-	-
F3	-	-	-
F4	+	200	> 20
F5	+	125	> 21
F6	+	75	> 21
F7	-	-	-
F8	-	-	-
F9	-	-	-
F10	+	245	< 20
F11	+	200	< 20
F12	+	180	< 18

Swelling Index studies:

Tablets composed of polymeric matrices build a gel layer around the tablet core, when they come in contact with water. This gel layer governs the drug release. Kinetics of swelling is important because the gel barrier is formed with water penetration. Swelling Index studies are conducted for the formulations F₄, F₅, F₆, F₁₀, F₁₁ and F₁₂ which passed the matrix integrity test. The formulations containing tamarind gum with HPMC 50 resulted in higher swelling index than compared with formulations containing HPMC K100M with tamarind gum, due to HPMC grade also affects the swelling and hydration, with considerably higher swelling index for HPMC 50 than HPMC K100M apart from swelling and hydration of tamarind gum. The reason for this appeared to be its high viscosity and high water retention property of HPMC K100M. The results are shown in Figure 1 and 2.

Figure 1: Results of Swelling Index Studies of formulations F₄-F₆

Figure 2: Results of Swelling Index Studies of formulations F₁₀-F₁₂

In vitro dissolution studies:

In vitro dissolution studies of all the formulations of floating matrix tablets of Propranolol Hcl were carried out in 0.1N Hcl. The study was performed for 12 hrs and the cumulative drug release was calculated. Formulations F₁, F₂, F₃, F₇, F₈ and F₉ failed to float and the formulations F₄, F₅, F₆, F₁₀, F₁₁ and F₁₂ remained floating and intact throughout the dissolution studies. All the formulations contained equal amount of gas generating agent (sodium bicarbonate). A significantly higher rate and extent of drug release was observed from the formulations containing tamarind gum with HPMC 50. Drug release from the formulations containing HPMC K100M was lesser owing to its high viscosity and also due to less permeability of water, as the drug release rate was dependent on the viscosity grade and the concentration of the polymers used.

Release kinetics for formulations of floating matrix tablets:

To know mechanism of drug release from these formulations, the data were treated with various models such as zero-order, first-order, matrix (Higuchi) and Korsmeyer-Peppas. The data were processed for regression analysis using MS EXCEL statistical function. The results are given in Table 5 and graphs from Figure 3 to 7. The limits for drug release from extended release Propranolol Hcl capsule are stated in Table 4. Formulations F_5, F₁₀ and F₁₁ showed drug release within the limits stated in Table 4, where F₁₀ showed drug release up to 11 hrs and F₅ and F₁₁ shown drug release for more than 12 hrs and more sustained drug release was resulted from formulation F_11. This controlled release of drug from F₁₁ could be attributed to the formation of a thick gel structure that delays drug release from the tablet matrix. So formulation F₁₁ was considered to be as the final optimized formulation. In the present study, in vitro release profiles could be best expressed by Korsmeyer-Peppas equation, as optimized formulation (F₁₁) showed good linearity (R²: 0.985). Different results that were obtained and the model which best fits the drug release for optimized formulation are shown in Table 5.

Figure 3: Zero order release kinetics of optimized formulation (F₁₁)

Figure 4: Comparison of in vitro dissolution profiles of F₄-F₆ and F₁₀-F₁₂

Figure 5: Korsmeyer and Peppas release kinetics of optimized formulation (F₁₁)

Table 4: Limits for Percent Drug Released from Extended Release Propranolol Hydrochloride Capsules

Time (hrs)	% Release (USP standard)	Observed release for F11 (%)
0.5	NMT 30	12.02
4	35-60	37.30
8	55-80	55.03
14	70-95	--
24	81-110	--

USP US Pharmacopeia, NMT not more than, F formulation

Table 5: Kinetic Release Data of Different Model for Optimized Formulation (F₁₁)

Model	Slope	R^2
Zero order	7.086	0.923
First order	-0.051	0.918
Higuchi (matrix)	0.048	0.931
Korsmeyer-Peppas	1.562	0.985

Figure 6: Higuchi matrix release kinetics of optimized formulation (F₁₁)

Figure 7: First order release kinetics of optimized formulation (F₁₁)

IR spectral studies:

Based on the IR data, it was found that, there is no significant interaction between the drug and polymer as evidenced by the presence of bands due to the corresponding reactive functional groups. IR spectral analysis for drug and optimized formulation are shown in Figure 8 and 9 respectively.

Figure 8: Infrared spectrum of Propranolol HCl.

Figure 9: Infrared spectrum of physical mixture of optimized formulation (F₁₁).

CONCLUSION:

Natural polymers when used as release retardant exhibits uniform release over longer period of time. Hence it can be concluded that, the tamarind gum which is a natural polymer can be used as a promising drug release retardant. And further the drug release can be modified by using different HPMC grades in combination with tamarind gum.

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Received on 02.04.2011

Accepted on 14.04.2011

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Research Journal of Pharmaceutical Dosage Forms and Technology. 3(2): March-April 2011, 67-72