Microspheres by Spray Drying: An Approach to Enhance Solubility of Bicalutamide

 

Rutuja S. Shah, Rutuja R. Shah, Manoj M. Nitalikar, Chandrakant S. Magdum

Department of Pharmaceutics, Rajarambapu College of Pharmacy,

 

ABSTRACT:

A major challenge in the drug development and delivery process is improving aqueous solubility and rate of dissolution of drugs, which ultimately improves absorption of the drug. Bicalutamide is most useful drug in prostate cancer treatment it is a non-steroidal antiandrogen. It comes under class of poorly water-soluble drug. Poor water-solubility of drugs leads to slow drug absorption, and low bioavailability, for which its solubility is to be enhanced to improve the oral bioavailability of the. One of the possible way to overcome this outcome is to use formulate solid dispersion by using spray drying technique. Spray-drying is a unit operation by which a liquid product is atomized in a hot gas current to instantaneously obtain a powder. The purpose of this research was to improve the solubility profile of Bicalutamide by spray drying technique using Methanol and Polyvinyl pyrolidone-K30. Prepared solid dispersions were evaluated for drug release profile. The compatibility was studied by Fourier Transforms Infrared spectroscopy (FTIR). Prepared Microspheres were subjected to various physicochemical evaluations and in-vitro dissolution profile. The effects of different concentrations of polymer on Solubility enhancement were studied.

 

 

 

 

1. INTRODUCTION:

Approximately 40% of the new drugs fall into category of poorly water-soluble drugs, poor solubility in turn affects bioavailability of the drug. Spray drying is a technique used to enhance drug solubility and dissolution rate. It is observed that dissolution rate of several drugs has been improved by spray drying with the aid of hydrophilic polymers. 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 and absorption characteristics.¹

 

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. They are made from polymeric natural, semi synthetic and synthetic polymers. Microspheres are characteristically free flowing powders having particle size ranging from 1-1000μm. The range of techniques for the preparation of microspheres provides multiple options to control as drug administration aspects and to enhance the therapeutic efficacy of a given the drug. Bicalutamide, Cabazitaxel, Casodex, Degarelix, Docetaxel, Enzalutamide, Flutamide, like various drugs are used in treatment of prostate cancer. Among which Bicalutamide is most useful drug in prostate cancer treatment it is a non-steroidal antiandrogen. It comes under class of poorly water-soluble drug. Poor water-solubility of drugs leads to slow drug absorption, and low bioavailability, for which its solubility is to be enhanced to improve the oral bioavailability of the Bicalutamide. 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 technique.²

 

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.

 

The composition of microspheres is shown in table no.1.

 

Table No. 1: Composition of Microspheres.

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

 

b. Preparation of Physical mixtures:

Physical mixtures of Bicalutamide with different ratios were prepared by systematically mixing Bicalutamide with PVP K-30 in a glass mortar by triturating for 15 minutes.

 

Fig No. 1: Spray Dryer Labultima LU222 Advanced.

C. 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.2.The dried products were collected in the collection vessel and weighed.

 

Table No. 2: laboratory scale spray dryer conditions

 

Characterization of Microspheres:

a. Percentage practical yield:

Percentage practical yields were calculated to know about percent yield or efficiency of the method, thus it helps in selection of appropriate method of production. Microspheres were collected and weighed to determine practical yield (PY) from the following equation:

 

b. Determination of % Drug Content:

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:

 

c. Determination of saturation solubility of prepared microspheres:

The saturation solubility studies were carried out to determine the solubility of microspheres. Excess amount of different microspheres formulations of Bicalutamide were added to 10ml of water and phosphate buffer pH 6.8 separately in 10 ml volumetric flasks. Samples were shaken using mechanical shaker for 48 hours. Samples were then filtered, diluted suitably and analyzed spectrophotometrically at272 nm.

 

d. Fourier transform infrared spectroscopy (FTIR)^4,5:

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.

 

e. Scanning Electron Microscopy (SEM):

SEM of microspheres was carried out using JSM 6360, JEOL India Pvt. Ltd.To study the morphological characteristics of the optimized batch of microspheres.

 

f. X-ray diffraction analysis (XRD):

X-Ray powder diffraction patterns were obtained at room temperature using a Philips X’ Pert MPD diffractometer, with Cu as anode material and graphite monochromator, operated at a voltage of 40 mA, 45 kV. The process parameters used were set as scan step size of 0.0170 (2).

 

g. In-vitro dissolution studies of Biclutamide microspheres systems⁶:

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 (10, 20, 30, 40, 50, 60 mins), an equal volume of fresh dissolution medium was replaced to maintain the sink condition and aliquots were measured at 315 nm UV/Visible spectrophotometer. The dissolution studies were conducted in triplicate and the mean values were plotted versus time.

 

h. Determination of the physical stability⁷:

To determine the physical stability of optimized microspheres, a stability study of prepared microspheres was carried out at 25°C and 60% relative humidity for 3 months according to the ICH guidelines. The spherical agglomerates were packed in high density polyethylene (HDPE) container and placed in stability chamber. The samples were withdrawn at the interval of 0, 1and 3 months and evaluated for appearance, and compared with initial results.⁵⁰

 

RESULTS AND DISCUSSION:

Characterization of Microspheres:

a. Percentage Practical Yield:

Percentage practical yield were calculated to know about percent yield or efficiency of any method, thus it helps in selection of appropriate method of production. The results of percent practical yield studies are shown in Table No. 7.4. The % Practical yield of the prepared microspheres by spray dryer method was found to be in the range of 30 ‐62 %. The maximum yield was found 62. % in D batch.

 

Table No. 3: Percentage Practical Yield of microspheres by Spray drying method.

 

b. Saturation solubility of microspheres in various solvents:

The solubility of spray dried microspheres of Bicalutamide in distilled water and in phosphate buffer (pH 6.8) was determined so as to select an appropriate batch of microspheres for further formulation of tablets. The increase in solubility was linear with respect to the weight fraction of the carrier. The increase in solubility in the presence of PVP-K30 can probably be explained by increased wettability of Bicalutamide. The results of solubility study of solid dispersion of Bicalutamide are tabulated in Table No. 4.

 

Table No.4: Solubility studies of prepared solid dispersion.

Sr. No	Batch Code	Polymer used	Drug: Polymer ratio	Solubility in Distilled water* (mg/ml)	Increase in Solubility In Distilled Water (no. of folds)	Phosphate Buffer (pH 6. 8)*	Increase in Solubility in Phosphate buffer (no. of folds)
1	A	PVP	1:1	0.0031	1.040	0.0215	1.72
2	B	PVP	1:2	0.0038	1.275	0.0290	2.75
3	C	PVP	1:3	0.0052	1.744	0.0315	2.52
4	D	PVP	1:5	0.0065	2.181	0.0440	3.52

*Values are of (n±SD), n=3.

 

The solubility of Bicalutamide was markely enhanced by PVP-K30. Among all the solid dispersions batches of Bicalutamide, batch B4 exhibited greater enhancement of aqueous solubility (2.181 fold). The enhancement of drug solubility could be explained by solubilization effect of carriers, their improving influence on drug wettability and through the formation of soluble complexes between hydrophobic drug and hydrophilic carrier.

 

c. Drug content of Bicalutamide in prepared Microspheres:

The spray dried compositions had drug content of 87.33 to 95.42% of Bicalutamide, suggesting that the spray drying process was successful in achieving good encapsulation of the drug. Percent drug content of Bicalutamide in spray dried solid dispersions was found to be increased with increase in the concentration hydrophilic polymers. The percent drug content values of Bicalutamide in different drug content of batches are shown in Table No.5.

 

Table No. 5: Percent Drug content of BICALUTAMIDE in microspheres batches

 

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

The dissolution profiles were calculated and are shown in (Table No. 6).

Compared with the pure powdered drug, the presence of PVP-K30 increase the dissolution of Bicalutamide from the microspheres, which increases the dissolution rate. 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. As general observations, the dissolution rate of Bicalutamide from microspheres particles was higher than that of the pure drug. All microspheres showed enhanced dissolution rate compared to pure Bicalutamide that might be due to the effect of hydrophilic carriers on drug wettability and dispersibility.

 

 

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

*Values are of (n±SD), n=3

 

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. The Drug and PVP-K30 in ratio of 1:4 has better dissolution profile. These results could be attributed to the general phenomenon of particle size reduction of Bicalutamide particle during the spray drying operation. Other explanations were related to the solubilization, molecular/colloidal dispersion of drug in the mixture and reduction in the drug crystallinity (i.e. polymorphic transformation of drug crystals) that were obtained via the formulation of microspheres by the spray dryer.

 

Fig No. 2: Percentage Drug release of Pure drug and A, B, C, D Batches

 

Fig No.3. FTIR spectra of Bicalutamide:

e. FTIR Spectroscopy of optimized microspheres batch (D):

In FTIR spectra of Bicalutamide (Fig No.3.), all the important peaks were found to be present, which confirmed the purity of sample.

 

FTIR spectra of neat BCL which is characterized by sulphate (1, 517 cm-1), hydroxyl group (3, 581 cm-1), carbonyl (1, 689 cm-1), amide (3, 338 cm-1) and nitrile (2, 230 cm- 1). Characteristic peak of Bicalutamide at 3115.14, 3580 and 1504.3 cm.-1 due to stretching of O-H, C-H stretch and C-H asymmetric stretch were observed.

 

 

Fig. No.4 The IR spectra of PVP-K30

 

The IR spectra of PVP-K30:

Shows 2360.44 cm–1 (C-H stretching vibrations), 1630.52cm–1 (C = O Carbonyl stretching), and 1384.64 cm –1 (C-N stretching vibrations). If the drug and polymers would interact, then the functional groups in the FTIR spectra would show band shifts and broadening compared to the spectra of pure drug and polymer.

 

FTIR spectra obtained from microspheres of optimized batch (Fig No.5) showed peaks which were summation of characteristics peaks of Bicalutamide as well as polymer. This showed that there were no chemical interactions drug and polymer. FTIR of optimized solid dispersion batch showed reduction of sharpness of peak that is due to reduction of crystallinity of drug.

 

Fig No. 5: FTIR Spectroscopy of Spray dried solid dispersion of Bicalutamide

 

g. Scanning Electron Microscopy of Batch D:

Scanning electron microscope (SEM) photomicrograph of the prepared Bicalutamide microspheres is shown in Fig 3. All spray-dried particles of Bicalutamide - polymers were spherical products (Fig 3-A, B, C and D). SEM showed smooth surface of Bicalutamide microspheres particles indicated the complete coating of Bicalutamide with polymer particles. Microspheres particles looked like an irregular shaped matrix which suggest that particle shape and surface topography is changed during formation of microspheres. These findings demonstrate that reduction in particle size, increased surface area and close contact between drug and carrier may be responsible for the enhanced solubility of drug.

 

   

                                                                A                                                                              B

 

     

                                                                C                                                                              D

 

h. Determination of the physical stability

The results of the stability study of prepared microspheres (1:3 w/w) of Bicalutamide stored at 25⁰C and 60% relative humidity for 3month is presented in table 4. The influence of physical stability on the prepared crystals was investigated. Prepared microspheres of Bicalutamide were stable and complied with all the properties when compared to initial results of prepared microspheres of bicalutamide.

 

Table No 7 Stability study

 

CONCLUSION:

I 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.

 

ACKNOWLEDGEMENTS:

The authors are thankful to Dr. C. S. Magdum; Principal and Dr. S. K. Mohite; Vice- Principal for providing research facilities necessary for the research work.

 

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Received on 26.05.2017          Accepted on 16.08.2017        

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