Formulation Development and Evaluation of Floating Beads of Propranolol Hydrochloride

Madhuri Pardeshi, Shashikant Barhate, Manoj Bari, Shaikh Samir

Shri Sureshdada Jain Institute of Pharmaceutical Education and Research,

Jamner Dist. Jalgaon, Maharashtra, India.

*Corresponding Author E-mail: madhuripardeshi3209@gmail.com

ABSTRACT:

Purpose: The purpose of present research work was to prepare sodium alginate and pectin antihypertensive floating beads of propranolol hydrochloride. Methods: Floating beads were prepared by using Ionotropic gelation technique using various natural and synthetic polymers in different proportion like sodium alginate, pectin, hydroxy propyl methyl cellulose k4m and calcium carbonate. Result: The floating beads were formulated and evaluated to physiochemical studies, Entrapment efficiency, swelling index, Invitro drug release, drug content, buoyancy studies (Floating time, floating lag time, total floating time) on the basis of evaluation of all floating beads were show good results. Conclusion: It Concluded that floating drug delivery system are float immediately upon contact with gastric fluid for increasing the bioavailability of drug and patient compliance.

KEYWORDS: Propranolol Hydrochloride, Ionotropic Gelation Technique, Floating Time, Patient Compliance.

INTRODUCTION:

Oral route is the most preferable route for the drug administration. Floating drug delivery system are low-density based systems with sufficient buoyancy to float over the gastric contents.^1,2 Floating drug delivery system promises to be a potential approach for gastric retention. Floating drug delivery system (FDDS) is hydrodynamically balanced system have bulk density lower than gastric fluid and thus remains in the body for prolonged period of time.^3,17,19 Propranolol Hydrochloride is Beta adrenergic receptor antagonist used to treat hypertension it has a long duration of action it is given once or twice daily.

It is BCS class I drug i.e., High Solubility High Permiability. Propranolol hydrochloride is a nonselective beta- adrenergic blocking agent. It inhibits response to adrenergic stimuli by competitively blocking, beta- adrenergic receptors within the myocardium and within bronchial and vascular smooth muscle. Propranolol hydrochloride has no intrinsic sympathomimetic activity.^4,13 Beads are distinct spherical microcapsule that works as the solid substrate on which the drug is coated or encapsulated in the core of beads. Floating beads is useful for several categories of drugs which act locally in stomach, poorly soluble in alkaline pH, having narrow absorption window, unstable in intestine or colonic environment and primarily absorbed in stomach^30,15. Floating beads are formulated for various drugs which are available for treatment of diseases like gastric ulcer, duodenal ulcer, Zollinger – Ellison syndrome and hypertension. It is expected that floating beads may enhance the pharmacotherapy of drugs.^5,6,7,18

Table No 1: Composition of Floating Beads:

Sr. No.	Ingredient mg	Batches
		B1	B2	B3	B4	B5	B6	B7	B8	B9
1	Propranolol Hydrochloride	500	500	500	500	500	500	500	500	500
2	Sodium Alginate	2000	2000	2000	2000	2000	2000	2000	2000	2000
3	Pectin	1000	396	500	750	1000	750	1100	750	500
4	Calcium Carbonate	1000	1250	1500	1600	1500	890	1250	1250	1000
5	Hydroxy Propyl Methyl Cellulose (K4M)	100	100	100	100	100	100	100	100	100
6	Calcium Chloride	2000	2000	2000	2000	2000	2000	2000	2000	2000

EXPERIMENTAL:

Material:

Propranolol Hydrochloride is obtained Medley Pharmaceuticals Pvt. Ltd., Andheri, Sodium Alginate, Pectin, Calcium Carbonate, Hydroxy Propyl Methyl Cellulose K₄M, Medley Pharmaceuticals Pvt. Ltd.

Method: Ionotropic Gelation Method

Preparation of Floating Propranolol Hydrochloride Beads: Firstly, weigh all ingredients properly. Sodium alginate and Pectin was dissolved in distilled water (100 RPM on magnetic stirrer for 1 hr). Add HPMC K4M (hydroxy propyl methyl cellulose) in pectin and sodium alginate solution, then stirred it properly. Add calcium carbonate into above solution. (Stirred the solution for 30 min until solution become clear). Then Add Propranolol hydrochloride into above solution (stirred the solution until become dissolve). Fill the solution into syringe. Calcium chloride (cross linking agent) dissolved in distilled water (stirred for 10 min). Drug and Polymer solution dropped via syringe into calcium chloride solution to obtain beads. The solution containing beads was stirred slowly by magnetic stirrer for about 10 min. The beads were further allowed to remain in the same solution for 20 min to improve mechanical strength. The formed beads were filtered (by using filter paper), washed with distilled water, overnight air-dried at room temperature on another day dried in oven (at 50 ̊C) and stored^7,8,16,20.

Micromeritic Properties^21,22,29:

1) Angle of Repose:

Angle of repose helps to evaluate beads flowability by assessing interparticulate friction. If, the higher is the angle of repose poor is the flowability of powder. The angle of repose of each powder blend was determined by glass funnel method, by using following equation,

tan θ = h/r  

θ = tan-1 (h/r)

 Where, θ = Angle of repose,

 h = Height of the pile,

r = Radius of the cone made by powder blend

2) Bulk Density:

It is ratio of mass to bulk volume. Bulk density may influence dissolution and other properties and depends on the particle size, shape and tendency of particles to adhere together. Bulk was determined by taking a known mass of beads in a 5 ml graduated measuring cylinder. The cylinder was dropped three times from a height of one inch at an interval of two seconds. The bulk density was calculated by following equation,^12,14

ρ_b = M / V_b

 Where, ρ_b = Bulk density,

 M = Weight of the beads,

V_b = Bulk volume.

4) Carr’s Compressibility Index:

This is an important property in maintaining uniform weight. It is calculated using following equation,

Carr’s Index = (Tapped density – Bulk density) × 100

                                           Tapped density

5) Hausner’s Ratio:

Hausner’s ratio less than 1.25 indicates good flow and greater than 1.5 indicates poor flow whereas between 1.25 and 1.5 indicates glidant normally improves flow. Hausner’s ratio can be calculated by formula,

Hausner’s Ratio = Tapped Density / Bulk Density

6) Drug Content:

Drug content of prepared drug floating beads estimated in UV spectrophotometry. An accurately weight quantity of floating beads was taken and dissolved in 100 ml of 0.1 N HCL, from the solution 1ml of solution was diluted to 10 ml and estimated the drug Content by using UV at 228 nm.^10,23

%Drug content = (Test Absorbance / Standard Absorbance) × 100

7) Determination of Percentage Yield:

The Prepared beads were collected and weighed. The measured weight was divided by the total amount of all non-volatile components, which were used for the preparation of the beads^9,30.

8) Drug Entrapment Efficiency:

Beads equivalent to 100mg of the drug were taken for evaluation. The amount of drug entrapped was estimated by rushing the beads and extracting with aliquots of 0.1N HCL repeatedly. The extract was transferred to a 100ml of volumetric flask and volume was made up using 0.1 N HCL. The solution was filtered and the absorbance was measured at suitable wavelength against appropriate blank. The amount of drug entrapped in the beads was calculated by the following formula^9,10.

EE (%) = Actual Drug Content/Theoretical Drug Content × 100

9) In Vitro Buoyancy:

The floating properties of beads were evaluated in a dissolution vessel (USP Type II dissolution tester) containing 900 ml of 0.1 N HCl, pH 1.2. Few beads were placed in testing medium. Paddle rotation speed of dissolution tester was 50 revolution per minute as 37 ± 0.5 ̊C. The buoyancy of floating beads was seen by visual observation. Percentage buoyancy was calculated for each formulation batch.^5,24

%Buoyancy = [Number of beads/Total number of beads] × 100

i) Floating Lag Time / (Buoyancy Lag Time):

Floating lag time was determined by weighing few mg of beads into dissolution vessel containing 900ml of 0.1 N HCl, pH 1.20 at 37±0.5 ̊C. Time taken by the experimentally designed beads formulation to emerge on surface of dissolution medium was noted and referred as floating (or buoyancy) lag time.^5,28

ii) Total Floating Duration: The time taken by the floating beads to float constantly on the surface of the simulated gastric fluid at pH 1.20, temperature 37± 0.5 ̊C, paddle rotation at 50rpm was measured using stopwatch.^5,27

10) Swelling Index: Beads were studies for swelling characterization. All the prepared formulations were taken and weighed and placed in a beaker containing 100 ml of 0.1 N HCl (pH 1.2) maintained at 37 ̊C. The beads were periodically removed at predetermined intervals for 120 min. and excess moisture is removed using a blotting paper and the immediately weighed. The swelling ratio was calculated as per the following formula.^10,25

 Swelling ratio = Wt/Wo × 100

Wt = weight of beads at time ‘t’

 Wo = initial weight

11) In-vitro Drug Release Study:

The drug release study from beads is performed using USP dissolution apparatus type- 1 (Basket Type) in 900 ml of 0.1 N HCl dissolution media (pH-1.2) at 100rpm and 37 ̊C±0.5 ̊C. 5ml sample was withdrawn at 1 hr. time interval for 12 hr. and same volume of fresh medium was replaced to maintained sink condition. Withdrawn samples were assayed spectrophotometrically at suitable wavelength. The drug release was analyzed by UV spectrophotometer^11,26.

Formula for Calculation of % Drug Release,

                 Test Abs.       Std. dilution          Purity

% DR = ----------------- X -------------- X ---------------

               Std. Abs.           Test dilution     Label claim

RESULT AND DISCUSSION:

Micromeritic Properties:

Micromeritic properties of floating beads of optimized formulation PHCL1 to PHCL9 were carried out as shown in table no 2. The Angle of repose was found to be in the range of 26. 56 to 29.24 which shows good flowability of beads. The bulk density, tapped density, Carr’s index and the Hausner’s ratio was found to be in the good range.

Melting Point:

The melting point of propranolol hydrochloride was found to be in the range of 162 – 163 ̊C by capillary tube method.

Determination of UV Spectrum and Calibration Curve of Propranolol Hydrochloride:

UV spectrum of Propranolol Hydrochloride was presented in fig. 1 and the calibration curve shows the straight-line equation given in fig. 2.

 Table No 2: Micromeritic Properties

Parameter	Batches
	PHCL1	PHCL2	PHCL3	PHCL4	PHCL5	PHCL6	PHCL7	PHCL8	PHCL9
Bulk Density (gm/ml)	0.53	0.59	0.63	0.52	0.49	0.55	0.61	0.56	0.50
Tapped Density (gm/ml)	0.61	0.67	0.70	0.60	0.57	064	0.69	0.60	0.58
Compressibility Index (%)	13.11	11.94	10	13.33	14.03	14.06	11.59	6.66	13.79
Hausner’s Ratio	1.15	1.13	1.11	1.15	1.16	1.16	1.13	1.07	1.16
Angle of Repose (θ)	26.56	30.96	36.86	33.42	32.21	28.36	28.81	33.02	29.24

Fig. No. 1: Wavelength Maxima of PHCL Fig. No. 2: Calibration Curve of PHCL in Buffer pH 1.2+

3. Fourier Transform Infrared Spectroscopy (FTIR):-

Fig.No.3 FTIR Spectra of API Fig. No. 4: FTIR Spectra of API and Pectin

Fig. No. 5: FTIR Spectra of API and SA Figure No. 6: FTIR Spectra of Overlay

4. Differential Scanning Calorimetry (DSC): -

Fig.No.7: DSC Thermogram of API Fig No. 8: DSC Thermogram of Overlay

Optimization and Data Analysis of Optimized Floating Beads of Propranolol Hydrochloride:

Using the CCD method 9 batches of floating beads were prepared by taking a different concentration of dependent factors produced by DoE software and evaluated using various parameters like % Drug release, Floating time.

Table No. 3: Central Composite Design with Dependent Variables

Batches	Variable Level in Coded Form		Dependent Variable (Y)
	X1	X2	% Drug Release (%)	Floating Time (Hrs.)
PHCL1	+1	-1	80.11	8
PHCL2	-α	0	86.94	9
PHCL3	-1	+1	84.02	10
PHCL4	0	+α	80.46	11
PHCL5	+1	+1	81.15	10
PHCL6	0	-α	80.13	8
PHCL7	+α	0	81.46	9
PHCL8	0	0	88.42	9
PHCL9	-1	-1	84.47	8

1) Effect of Independent Variables on % Drug Release:

All nine formulation of prepared sustained release floating beads of Propranolol Hydrochloride were subjected to in-vitro drug release studies. These studies were carried out using dissolution medium (Buffer pH 1.2), by using USP–I (Basket type) dissolution apparatus. The Result were evaluated for 8 hrs. Among of the 9 batches PHCL-8 showed uniformity of the drug release up to 8 hrs and was considered as ideal formulation of sustained release floating beads. The evaluation result of in-vitro drug release was shown in fig no. 9.

Fig.No. 9: In-Vitro Drug Release study of Optimized Batches of Floating Beads (PHCL1-PHCL9)

On applying CCD, it produces an equation in terms of coded form for % drug release,

% Drug Release (Y1)

= +88.42-1.80A+0.1321B+0.3725AB-1.99A²-4.04B²

Concerning dissolution, the results of multiple linear regression analysis showed that the coefficients A bear a positive sign and B bear a negative sign. It revealed that % drug release increases with increase in pectin and while % drug release minor increases with increase in calcium carbonate. Less amount of pectin was expected to increase the % drug release of floating beads. ANOVA was used to identify the significant effect. The result was found to be significant at that level of probability (P< 0.0001).

Fig. no.10 Response surface contour Graph Fig. no.11 3D Surface Graph

2) Effect of Independent Variables on Floating Time:

Floating Time (Y2) = +9.11+0.0000A+1.03B.

Concerning dissolution, the results of multiple linear regression analysis showed that the coefficients A bear a positive sign and B bear a positive sign. It revealed that floating time increases with increase in calcium carbonate and while floating time minor increases with increase in pectin. ANOVA was used to identify the significant effect. The result was found to be significant at that level of probability (P< 0.0001)

Fig.no.12 Response Surface Counter Graph Fig.no.13 3D Surface Graph

Table No 4: Evaluation of Post- Compression Parameters of Optimized Batches of Floating Beads

Parameter	Batches
	PHCL1	PHCL2	PHCL3	PHCL4	PHCL5	PHCL6	PHCL7	PHCL8	PHCL9
Drug Content (%)	67.65	74.04	79.57	81.27	85.53	76.59	77.87	87.23	85.10
Percentage Yield (%)	95.42	93.94	91.94	92.71	85.71	63.62	82.68	69.77	75.28
Entrapment Efficiency (%)	62.09	76.08	77.04	82.032	80.06	65.2	71.46	83.3	78.06
Swelling Index (%)	85.64	78.39	81.23	69.50	83.38	76.81	74.34	89.67	80.04

Table No 5: Buoyancy Studies: -

Parameter	Batches
	PHCL1	PHCL2	PHCL3	PHCL4	PHCL5	PHCL6	PHCL7	PHCL8	PHCL9
Floating (Buoyancy) Lag Time (Sec.)	27	19	13	9	11	21	17	14	24
Total Floating Time (Hrs.)	8	9	10	11	10	8	9	9	8
% Buoyancy	53.34	72.64	81.66	86.66	78.33	61.23	70	73.33	63.33

CONCLUSION:

The Propranolol hydrochloride was characterized for colour, odour, taste and it matches with the standard as per certificate of analysis. The melting point of Propranolol hydrochloride was also confirmed by DSC at 162 to 164⁰C was found within the range, the wavelength of Propranolol Hydrochloride was found 228 nm by using UV-Visible Spectrophotometer.

The optimization was done by applying two factor three level central composite design by design expert software. The generated batches were prepared and evaluated. The PHCL 8 was given as the best batch by the design expert software.

The invitro drug release study and the buoyancy study were performed. The optimized batch PHL8 shows the 88.42 % drug release in 8 hours, The % buoyancy 73.33 % and floating time 9 hours.

On the basis of present work, particularly the results obtained from in vitro release rate studies, it can be concluded that Pectin, Sodium alginate and calcium carbonate utilized as a base for sustained release of drug. The formulated Floating beads will show better yield with minimum loss, better bioavailability characteristic while comparing with commercial conventional drugs.

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Received on 26.11.2023         Modified on 30.01.2024

Accepted on 09.03.2024   ©AandV Publications All Right Reserved

Res.  J. Pharma. Dosage Forms and Tech.2024; 16(2):137-143.

DOI: 10.52711/0975-4377.2024.00022