INTRODUCTION:

Multiparticulate drug delivery is a new system for oral dosage form developed so as to get a sustained and extended release consisting of a multiplicity of small discrete units where drug is divided into small units of spherical shape which can then be either encapsulated or compressed into a tablet.^[1] They are discrete particles which exhibit multiple unit system having advantages like small size, single unit dosing, drugs combination can be achieved, different release rate, minimum dose dumping, and no local irritation, less gastric transit time between subjects, and gastric emptying time independent of food state.^[2-6] Release of drug from this system is not the same in comparison to enteric coated or film coated tablet as here each subunit has its own release characteristic so a damage in coating damages release of that subunit and not the whole system which is the case with enteric or film coated tablet which leads to ulcer, reduced efficacy and also leads to dose dumping.^[7]Nowadays more emphases is being given to develop multiparticulate system instead of single dose as they have unique characters like increased bioavailability, reduced risk of systemic toxicity, reduced risk of local irritation and predictable gastric emptying.

In multiparticulate system the drug /dose is being administered in subunits having active ingredients and the dose is the sum of the subunits involved individually.^[8] Multiparticulate system can be prepared by pelletization, granulation, spray drying, and spray congealing in which drug can be either entrapped in the system or layered around them so as to obtain desired release profile. Release profile like sustained release (SR), targeted release, delayed release, and pulsatile release mainly depends on the coating materials used which can be achieved either by air suspension, compression coating, solvent evaporation, coacervation, and interfacial complexation, spray drying and spray congealing.

The rationale behind the formulation of multiparticulate system of propanolol hydrochloride is for extended release in therapy of cardiovascular disease where optimal peak blood level of a medicament must be maintained at the steady state level to achieve the desired therapeutic effect.

Half life of Propranolol hydrochloride is 3 to 4 hrs so frequent dosing is essential to obtain long term therapeutic levels of drug. Furthermore, Propranolol usually dissolves readily in the digestive juices and the total dosage is immediately fed into the blood stream. After high initial peak concentrations, the level of drug in the blood stream constantly decreases because of the biological elimination, so there is little or no therapeutic effect at the end of the period between doses. As a result, the therapeutic effect fluctuates between doses corresponding to the peaks and valleys in the level of drug in the blood^[9].Extended release can be achieved by formulating a tablet which can be reservoir or matrix system. Reservoir system is successful for the highly soluble drug which creates enough osmotic pressure and hydrostatic pressure to release drug from release controlling membrane (ethylcellulose and hydroxypropylmethylcellulose combination), where internal pressure is required to release the drug whereas tablet based matrix formulations have variations in gastric emptying rates and overall transit times leading to intra-and inter-subject variability of plasma profiles, poor water solubility, and difficulty to combine two chemically incompatible active ingredients or substances in a single unit^[10]. Pelletization is another way to make multiparticulate formulations with extended release formulation which offers flexibility in dosage form design and also reduce variations in gastric emptying rates and overall transit times.^11-17 So there is a need to develop a drug delivery system for Propranolol in form of extended release multiparticulates, which can deliver, preferably for 24 hour, by a dose sufficient to exceed the liver’s metabolic capacity and to maintain therapeutic levels.

2. EXPERIMENTAL:

2.1. Materials:

The following chemicals were obtained from commercial suppliers as gift samples Propranolol Hydrochloride from IPCA Laboratories (Mumbai). Propranolol hydrochloride extended release tablets label claim 160mg were purchased from local market. Other excipients and solvent were purchased from different manufacturer like Isopropyl alcohol, Dichloromethane, Petroleum ether, from RFCC, Ltd., New Delhi, Microcrystalline Cellulose (Avicel PH) 101 from FMC Biopolymers, Hydroxypropyl methylcellulose E-5 (LVP) from Dow Chemicals, Ethylcellulose N-50 from Herculus, Triethyl citrate from Morflex Inc. All other chemicals used were of analytical grade.

2.2. Equipments:

The following equipments were used for the experiment as Dissolution apparatus (Electrolab, Mumbai), pH meter (HI8 4240, Microcom.PH meter, Italy), Rapid dryer and Sieve shaker (Retsch Gmbh and Co. Ltd., Germany), Extruder and Spheronizer (Fauji Paudal Co. Ltd., Japan), Fluidized Bed Processor (Anish Pharma, Nashik).

2.3 Solubility of drug in different solution:

Solubility of propranolol hydrochloride was determined by placing excess amount of drug in contact with the dissolution media at 25^oC in mechanical shaker for 24 hrs like Distilled water, 1.2 pH buffer, pH 6.8 Phosphate buffer, pH 7.5 Phosphate buffer to attain equilibrium. These suspensions were then filtered and quantified by U.V Spectroscopy.

Propranolol HCl and different types of excipients (Microcrystalline Cellulose, Hydroxypropylmethylcellulose E-5, Ethylcellulose N-50 and others) were taken in 1:1 ratio passed through a 40 mesh and mixed together, transferred to a 60 cc HDPE bottles and kept at 5^o C ,40^o /75% RH, and 60^oC for one month and visually inspected.

2.4 Methods:

2.4.1 Preparation of core pellets:

Propranolol Hydrochloride and Avicel 101 were mixed in a planetary mixer and granulated using water and binder to plastic mass and passed through a extruder (Fauji Paudal Co. Ltd., Japan) screen size (1.0 mm and 1.2 mm) to get cylindrical extrudes and then were rotated in a spheronizer (Fauji Paudal Co. Ltd., Japan) to get spherical pellets. Pellets were dried in rapid fluidized drier (Retsch Gmbh and Co. Ltd., Germany) and passed through various mesh sizes to obtain uniform pellets.

Coating of pellets were carried out using various coating solutions and concentrations like IPA and DCM in 1:1 ratio in which pellets having optimum size in ratio of 4:1 (0.85 mm and 0.63 mm) were coated with fluidized bed processor. Similarly pellets of size greater than 0.85mm were coated with fluidized bed processor.

2.4.2 Optimization of core pellets:

2.4.2.1 Drug Excipient ratio:

In the preparation of Propranolol hydrochloride pellets different concentrations of drug: excipient (table 1) were tried so as to find out which batch meets the best efficacy needed in terms of extended release with good release profile and stability. The process controlling parameters are shown in table 2.

Table 1: Different drug polymer ratio

Ingredients	Trail (Quantity per capsule, mg)
Ingredients	I	II	III	IV	V
Propranolol HCl	160.40	160.40	160.40	160.40	160.40
Avicel 101	89.60	77.1	82.10	83.35	84.60
HPMC-E5 (5%w/w)	-	12.5		-	-
HPMC-E5 (3%w/w)	_	_	7.5	_	_
HPMC-E5 (2.5 %w/w)	_	_	_	6.25	_
HPMC-E5 (2.0 %w/w)	_	_	-	_	5.0
Water	qs.	qs.	qs.	qs.	qs.

Table 2: Controlling parameters for operating conditions in pellets formation

S.N.	Controlling Parameters	Values
1.	Water quantity	120 ml
2.	Time for addition of water	2.0 min
3.	Kneading	1.0 min
4.	Extruder speed	63 rpm
5.	Extruder screen	1.0 mm
6.	Spheronizer speed	950 rpm
7.	Spheronization time	4.0 min

2.4.2.2 Optimization of Fluidized Bed Processor (FBP)

Optimization of FBP was done on the basis of dissolution study of coated pellet in USP Drug Release Test apparatus I. Trails were conducted by keeping one parameter as variable while others parameters were kept constant and then dissolution of coated pellets was carried out in dissolution media for 24 hrs and the parameters which release drug for 24 hrs were stable and the ones which release drug rapidly were considered unsuitable. The parameters which where optimized include load, fluidization, total polymer content, atomization pressure, and spray rate as shown in table 3.

Table 3: Optimized operating conditions in FBP coating

S.N.	Parameter	Result
1	Load	400 g
2	Fluidization	22 Hz
3	Coating solution (Total polymer content)	3 % w/w
4	Inlet air temp.	45⁰C
5	Bed temp,	31-34⁰C
6	Heater	55⁰C
7	Atomization pressure	1-1.2 kg/cm²
8	Needle operating pressure	2 kg/cm²
9	Spray rate	25 g/min

2.4.2.3 Coating of Optimized batch:

For coating of optimized batches appropriate quantity of IPA and DCM were taken in 1:1 ratio. In second step, appropriate quantity of EC N50 and HPMC E5 were taken, mixed together and dissolved in solvent mixture by mechanical stirrer to make 3% w/w coating solution. Appropriate quantity of TEC was added as plasticizer in coating solution obtained from second step. For coating 400 gm of pellets having optimum size in ratio of 4:1 (0.85 mm i.e. retained on mesh 20 and 0.63 mm i.e. retained on mesh 30) obtained from optimized batches were taken to fluid bed processor and process controlling parameters were set for coating.

3. RESULT AND DISCUSSION:

A significant difference in solubility of Propranolol HCl in different dissolution medias was observed when excess amount of drug was solubilized at 25^oC as 146 mg/ml in 6.8 pH citrate buffer, 7.5 pH phosphate buffer and in water; and 80 mg/ml in 1.2 pH buffer. The responses were linear in working UV range in concentration range 20-100 µg/ml.

Compatibility studies of Propranolol HCL with different excipients was done at different temperatures and relative humidities with drug: excipient 1:1 ratio and passed through 40 mesh transferred to a 60 cc HDPE bottles and kept at 5°C, 40^o /75% RH, and 60°C for one month and visually inspected. Drug was showing sticking property with MGS and TEC at 60°C temperature. It was observed that compatibility studies at different temperature and relative humidity showed that drug itself was stable at higher temperature and relative humidity as well as compatible with all above used excipients.

The core pellets were optimized for different drug: polymer ration and amount of water as shown in table 1. The controlling parameters for the optimization of trial I are given in table 2. In this trial strength of extrudate was not good and shape of pellets was not spherical due to lack of binder. Thus in subsequent trials hydroxypropyl methylcellulose E5 was used as a binder. In trail II and III dumbbell shaped pellets were obtained due to excessive quantity of binder, therefore in next trail (trial IV), less quantity of binder relative to previous trials, was used. In trial IV Spherical pellets were obtained. For further improvement in pellet shape trial V was planned to use 2% w/w of binder but it resulted in excess of fines during spheronization and moreover size distribution of pellets was not good. Thus, trial IV was considered satisfactory for further optimization process.

Fluidized Bed Processor (FBP) was optimized on the basis of following parameters as load, fluidization, total polymer content, atomization pressure, spray rate, bed temperature, inlet air temperature as shown in table 3.Load was optimized by taking 200gm, 400, and 500 gm of pellet in FBP and fluidization was started, in which batch size of 400gm pellets showed uniform fluidization. Fluidization was optimized visually by checking height of fluidization, which should be enough for efficient drying of pellets during coating. Total polymer content was optimized by taking various concentrations of polymer content like 3%, 5% and checking its spray pattern, the polymer causing chocking of the nozzle is discarded. Atomization Pressure was optimized by taking various pressures as 1, 1.2 and 1.6 Kg/cm2 while other parameters were set constant and release profile was observed by USP drug release test apparatus I as shown in figure 1. Spray rate was optimized by using various spray rates as 5, 15, 25, 40-gm/ minute and other parameter was kept constant and spray pattern and its action were noted and spray pattern selected on the basis of dissolution in USP Test apparatus 1 as shown in figure 2.

Fig 1: Dissolution profile pellet coated at different atomization pressure

For coating, EC N50: HPMC in ratio of 70:30 and Triethyl citrate (10% of EC) as plasticizer was taken. Coated pellets showed significant higher release than marketed formulation (MF). Further studies were conducted with increasing build up of coating and the effect of pellet size on drug release profile was studied (figure3).Based on these studies it was concluded that to decrease release of drug in water, the size of coated pellet should be increased. Therefore amount of water was decreased serially to get best shape and coating of core pellets as shown in table 4.

Table 4: Comparison of trials taken with 1.2 mm Extruder screen

Parameters	Trials
Parameters	IVa	IVb	IVc	IVd
Water qty (%)	38	38.6	39.33	40
HPMC (%W/W)	2.25	2.25	2.25	2.25
Propranolol HCL	64	64	64	64
Avicel (%W/W)	33.75	33.75	33.75	33.75
(20 retained: 30 retained) in %age	88:12	90:10	96:4	-
Bulk Density (gm/ml)	0.57	0.58	0.58	-
Tapped density (gm/ml)	0.621	0.618	0.615	-
% CI	8.23	6.14	5.69	-
Drug Content (%)	101	101.6	104.5	-
Spheronizer speed (RPM)	950	950	1100	1100

Fig 2: Dissolution profile in USP Test 1 of Trials coated at different Spray rate

Fig. 3: Dissolution profile in USP Test 1 (Trial IV, IVc) Vs. MF

Among all the trials core pellets obtained from trial IVc were found to be spherical with maximum yield. So the formulation of trial IVc was optimized for 1.2 mm extruder screen, with 750 gm load and 295 ml of water was considered optimum for getting spherical shape pellet at extruder speed of 63 rpm and at spheronization speed of 1100 rpm.

On studying dissolution of pellets in different media, we could conclude that pellets coated with 10% build up were found to match MF release profile. Moreover, similar release profile of optimized formulation with MF was confirmed by calculation of two factors i.e. differential factor (F2) and similarity factor (F1). F1 and F2 were found to be; 9.15 and 71.85 as shown in figure 4.

Fig. 4: Comparison of Dissolution Profile of MF and Optimized Formulation in USP Drug Release Test 1 Dissolution media

CONCLUSION:

Extrusion spheronisation was done to prepare core pellets containing drug. MCC was selected as a spheronizing agent and HPMC used as binder. For extended release coating, ethyl cellulose polymer was selected as release controlling material along with hydroxypropyl methylcellulose which acts as pore forming agent in coating. Triethyl citrate was used as a plasticizer. Coating was done in FBP on core pellets having different size. Coating was done with different ratios of EC to HPMC with different buildup. Dissolution study was carried out in USP drug release test 1 and test 2, pH 7.5 Phosphate buffer and water and compared with marketed preparation. Resulting dissolution profile was similar to marketed formulation that was confirmed by F1 and F2 calculation.

ACKNOWLEDGEMENT:

We are thankful to Managing Director, RKDFIST for providing funds for this project. We are also thankful to IPCA Labs (Mumbai) for providing gift sample of Propranolol hydrochloride.

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Received on 15.02.2010 Modified on 03.03.2010

Research J. Pharm. and Tech.3 (3): July-Sept. 2010; Page 835-839