INTRODUCTION:

Most of the new drugs come into category of poorly water soluble drugs, and it affects bioavailability of the drug. Spray drying is a technique observed in improving dissolution rate of several drugs with the use of hydrophilic polymers and organic solvent. Since the aqueous solubility of any drug substance plays an important role in pharmaceutical formulations, it is necessary to increase the aqueous solubility in order to further enhance dissolution characteristics of drug¹.Microspheres are multiparticulate drug delivery systems which are prepared to improve bioavailability, stability and to target the drug to specific site at a predetermined rate.

Microspheres are characteristically free flowing powders having particle size ranging from 1-1000 μm. Bicalutamide is most useful drug in prostate cancer treatment it is a non-steroidal antiandrogen. It acts by competitively inhibiting the action of androgens by binding to cytosol androgen receptors in the target tissue. It blocks the growth stimulating effect of androgens on prostate cancer. Spray drying has been used to prepare microspheres with polyesters, polymethacrylates, cellulose derivatives and biopolymers containing both hydrophilic and lipophilic drugs and macromolecules.

It has advantage over solvent evaporation techniques that it is one-step process, easiness to control and scale up, and possibility of being free of organic solvents. When used with organic solvents, the amount of residual solvent in particles is often lower than that reached with emulsification-solvent removal technique².

Bicalutamide microspheres were prepared by spray drying technique using different combinational ratios povidone K 30 with drug. Out of these concentrations, best ratio was selected based upon their efficiency to enhance the dissolution rate of the drug. Selected batch was carried further for the formation of the tablet.

MATERIALS AND METHODS:

The Bicalutamide was supplied as a gift sample by Khandelwal Laboratories, Thane, India. All other chemicals used were of analytical reagent grade.

METHODS:

Formulation of Microspheres using Spray Drying Technique:

a) Preparation of microspheres of Bicalutamide:

Microspheres of Bicalutamide with PVP-K30 as carrier were prepared by spray drying technique with different ratios.

b) Spray drying method:³

Drug-Polymer solution of PVP-K30 was prepared by dissolving respective ratios of drug-carrier in methanol. The solvent was evaporated by spray drying process, which was carried out using laboratory scale spray dryer conditions mentioned in table no.1 .The dried products were collected in the collection vessel and weighed.

Table No. 1: laboratory scale spray dryer conditions and Composition of Microspheres

Sr. No	Parameters	Values
1	Inlet Temperature	40
2	Outlet Temperature	30
3	Cool temperature	45
4	Inlet high	70
5	Outlet high	50
6	Aspiratory Speed	45
7	Feed pump flow	2 ml per min
8	D-Block on	1 sec
9	D-Block off	60 sec
10	Data log interval	225 n max

Sr. No	Batch Code	BICALUTAMIDE (g) and PVP
1	A	1:1
2	B	1:2
3	C	1:3
4	D	1:5

c) Preparation of tablet⁴:

Required quantities of Bicalutamide microsphere of optimized batch D having 1:4 ratios were taken, magnesium aluminum silicate, and lactose were accurately weighed and lubricated with persisted magnesium stearate through sieve no. 60 (250 microns) and mixed for 3 min. Lubricated microspheres were evaluated for flow characteristics and were compressed into tablets by using 8-stationcompression machine. Compressed tablets were allowed to equilibrate in desiccators for 24 h before evaluation.

Table No. 2: Formulation of tablet

INGREDIENTS	F1	F2	F3	F4
Bicalutamide Microspheres	50	50	50	50
Magnesium aluminum silicate	50	100	150	200
Avicel PH 200	41	38	35	31
Crospovidone	7.5	10	12.5	15.5
Magnesium stearate	1.5	2	2.5	3.5
Total Weight (mg)	150	200	250	300

CHARACTERIZATION:

1. Characterization of Microspheres:

a. Percentage yield:⁵

Microspheres were collected and weighed to determine practical yield (PY) from the following equation:

Practical Yield

Percentage Yield= ------------------- X 100

Theoretical Yield

b. Determination of % Drug Content:⁶

Microspheres equivalent to 10 mg of Bicalutamide were weighed accurately and dissolved in suitable quantity of solvent mixture methanol. The drug content was determined at 272 nm by UV spectrophotometer. Each sample analyzed in triplicate. The percent drug content was determined using the following equation:

Practical Drug Content

Drug Content = ---------------------------------------- X 100

Theoretical Drug Content

c. Fourier transform infrared spectroscopy (FTIR):⁴

FTIR has been used to assess the interaction between drug and carrier molecules in the solid state. Infrared spectra of microspheres powder were obtained using FTIR spectrometer (FTIR Jasco 4100). About 2-4 mg of moisture free microspheres sample was mixed with dry potassium bromide and FTIR spectra were obtained. The scanning range was 400-4000 cm-1.

d. In-vitro dissolution studies of Bicalutamide microspheres systems⁷:

In-vitro dissolution studies of pure drug and microspheres of spray dried Bicalutamide were carried out for 60 minutes using USP Dissolution test apparatus type II (Lab India DicS8000, eight stages) at 50 rpm. Microspheres equivalent to 50 mg of Bicalutamide was used for dissolution studies at 37±0.5°C in 900ml of pH 6.8 buffers as dissolution medium. Aliquots equal to 5 ml was withdrawn at regular time intervals, an equal volume of fresh dissolution medium was replaced to maintain the sink condition and aliquots were measured at 272 nm UV/Visible spectrophotometer. The dissolution studies were conducted in triplicate and the mean values were plotted versus time.

2. Characterization of tablet⁸:

a. Determination of tablet tensile strength (T)

The hardness of ten tablets was determined individually with the Monsanto hardness tester (Brook and Marshall, 1968). The mean values of the fracture loads were recorded.

b. Disintegration test:

The method described in the British Pharmacopoeia (2002) was followed using water maintained at 37°C as the disintegration fluid. Six tablets were used in each determination, which was carried out in triplicate and the mean results reported.

c. Friability test:

The friability test is to evaluate the ability of the tablet to withstand abrasion in packaging, handling and shipping. Ten (10) tablets were weighed initially (w1), placed in friabilitator (Roche) and were allowed to rotate at the speed of 25 rpm for 4 min. After four minutes of this treatment or 100 revolutions, the tablets are weighed and the weight (w2) compared with the initial weight. The loss due to abrasion is a measure of the tablet friability. The friability (%) was calculated by using Equation:

Friability (%) = (w1 - w2) × 100 / w1

d. Drug content:

From each batch, 10 tablets were randomly collected and powdered in a glass mortar. Accurately weighed drug equivalent of 50 mg of the powder was transferred into a 100 ml volumetric flask and dissolved in 20 ml of Bicalutamide. The drug-Bicalutamide solution was extracted with 1% sodium lauryl sulphate (SLS) solution with vigorous shaking on a mechanical shaker for 1 h and filtered into another 100 ml volumetric flask through 0.45 mm Millipore nylon filter disc and the filtrate was made up to the mark with 1% SLS solution to obtain 500 µg/ml. 0.5 ml of the above solution was further transferred into 50 ml volumetric flask and was diluted up to the mark with 1% SLS solution to get 5 µg/ml. Absorbance of the obtained solution was measured at 272 nm against blank (1% SLS solution) using a Ultraviolet and visible (UV/Vis) spectrophotometer (Elico SL 210) and the drug content was measured by using precalibrated curve equation

(Y = 0.0527X - 0.0438). All the above physicochemical properties were conducted on the existed marketed product ‘Tab’ for comparison.

e. In vitro dissolution studies:

In vitro studies were performed separately in 900 ml of 1% SLS maintained at 37 ± 0.5°C using USP XXII type II dissolution rate test apparatus at a stirring speed of 50 rpm which is official in Food and Drug Administration (FDA) dissolution methods. 5 ml aliquots were withdrawn at different time intervals up to one hour and replaced with same volume of drug free fresh dissolution medium so as to maintain sink conditions. The samples were filtered and estimated for the amount of Bicalutamide dissolved by measuring the absorbance at 272 nm in ultra violet (UV) spectrophotometer (Elico SL 210). The dissolution experiments were done in triplicate. Dissolution studies were carried out on existed marketed product ‘Tab’ in the similar way for comparison of drug release behavior.

RESULTS AND DISCUSSION:

1. Characterization of Microspheres:

a. Percentage Yield and Drug content:

Table No. 3: Percentage Yield and drug content of microspheres

Sr. No	Batch code	Percentage Yield (%)	% drug content
1	A	30	87.33
2	B	44	90.23
3	C	52	93.65
4	D	62	95.42

b. In vitro dissolution studies of Pure Drug and microspheres of Bicalutamide:

The prepared microspheres of batch B4 increase the dissolution rate up to 87.15%. It was evident that the pure drug exhibited a slow dissolution even after 60minutes where the percentage of drug dissolved after 60 minutes only reached about12.41±0.004% that could be related to the hydrophobicity, poor wettability and/or agglomeration of Bicalutamide particles resulting hindering its dissolution.

Table No. 4: Cumulative percentage drug release of Bicalutamide and Spray dried microspheres of Bicalutamide

Time (min)	Pure drug	% Cumulative drug release
Time (min)	Pure drug	A	B	C	D
0	0.00±0.00	0.00±0.00	0.00±0.00	0.00±0.00	0.00±0.00
5	1.10±0.08	30.37±0.04	32.33±0.03	34.30±0.02	37.13±0.04
10	2.22±0.04	38.42±0.03	39.41±0.08	39.10±0.06	46.40±0.02
15	4.21±0.03	44.62±0.05	48.24±0.02	49.22±0.02	58.17±0.06
20	6.28±0.02	57.13±0.08	59.14±0.04	60.21±0.04	65.13±0.02
25	9.32±0.08	69.24±0.02	70.22±0.02	74.10±0.03	78.11±0.03
30	12.41±0.04	75.30±0.04	81.33±0.06	82.11±0.02	87.15±0.02

*Values are of (n±SD), n=3

Fig No. 1: Percentage Drug release of pure drug and A, B, C, D Batches

Fig No. 2: FTIR Spectroscopy of Spray dried solid dispersion of Bicalutamide

2. Characterization of tablet:

Table No. 5 Tablet Strength, Disintegration, Friability and Drug Content Of tablet

Batches	Tablet strength	Disintegration Test	Friability Test	Drug Content
F1	75 0.14	3.2 0.21	0.38	99.05 0.5
F2	72 0.22	2.1 0.50	0.40	98.01 0.5
F3	73 0.42	3.8 0.11	0.44	99.02 0.4
F4	77 0.50	4.2 0.22	0.34	100.04 0.4
Marketed preparation	68 0.70	4.7 0.52	0.47	100.02 0.2

Table No. 6: Cumulative percentage drug release of Bicalutamide and Spray dried microspheres of Bicalutamide

BATCHES	15 MIN	30 MIN	45 MIN	60 MIN
F1	28.37±0.04	34.33±0.03	38.30±0.02	40.13±0.04
F2	37.42±0.03	38.41±0.08	45.10±0.06	54.40±0.02
F3	49.62±0.05	45.24±0.02	58.22±0.02	66.17±0.06
F4	67.13±0.08	68.14±0.04	85.21±0.04	88.13±0.02
MARKETED TABLET	55.24±0.02	67.22±0.02	71.10±0.03	78.11±0.03

*Values are of (n±SD), n=3

Fig No. 3: Percentage Drug release of Bicalutamide and Spray dried microspheres of Bicalutamide tablet

Among all the four batches of microspheres, batch D showed the better dissolution profile in which pvp was highest combination of hydrophilic polymers was used.

CONCLUSION:

From this research work we conclude that, Spray drying was used to produce microspheres of Bicalutamide. Dissolution studies showed that the spray dried particles with pvp in highest ratio had the highest dissolution rate. This indicated that the spray dying process contributed to enhanced dissolution rates. The improved particles wetting by presence of the hydrophilic surfactant seems to be the most important determinant.

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Received on 28.11.2017 Modified on 24.12.2017

Res. J. Pharm. Dosage Form. & Tech. 2017; 9(4): 168-172.

DOI: 10.5958/0975-4377.2017.00027.1