PREPARATION AND CHARACTERIZATION OF NAPROXEN SODIUM AGGLOMERATES BY SPHERICAL CRYSTALLIZATION TECHNIQUE

About Authors:
Akash M Patel*, Jitul B Patel
*Faculty of Pharmacy, Dharmsinh Desai University,
Nadiad-387001, Gujarat
*aku.pharmacy@gmail.com

Abstract
The purpose of this research work to prepare agglomerate of naproxen sodium for enhanced dissolution and improved physicochemical properties. Spherical crystallization technique was used to prepare agglomerates of naproxen sodium. Solubility of naproxen sodium was determined in different solvents for find out good solvent and bad solvents. Agglomerates of naproxen sodium alone and with incorporation of different polymer were prepared and stirring rate was also optimized. Prepared agglomerates were characterized for particle size, in-vitro drug dissolution study, % compressibility and different tableting parameters. Prepared agglomerates were characterized by DSC, XRD, FT-IR, and SEM. Results of in-vitro dissolution study indicated that agglomerates prepared by spherical crystallization were having higher dissolution than the naproxen sodium alone. Incorporation of polymers like PEG 400 and PVP K30 was also improved tableting characteristics as well as in vitro dissolution than agglomerates without incorporation of polymers. In conclusion, agglomeration of poorly water soluble drugs like naproxen sodium by spherical crystallization technique was successfully implemented for dissolution enhancement.

REFERENCE ID: PHARMATUTOR-ART-1904

INTRODUCTION
Spherical crystallization is a particle design technique, by which crystallization and agglomeration can be carried out simultaneously in one step and which has been successfully utilized for improvement of flowability and compactability of crystalline drugs^1-5. Presently, particle design techniques are widely used in pharmaceutical industries to modify primary properties like particle shape, size, crystal habit, crystal form, density, porosity etc. as well a secondary properties like flow ability , compressibility, compact ability, reduction In air entrapment,etc Spherical crystallization is one of such particle design technique in which crystallization and agglomeration process are carried out simultaneously. Spherical Crystallization process transforms the fine crystal obtains during crystallization into spherical agglomerates. Agglomerates formed further improves the flowability and compressibility of pharmaceutical ingredient which enables direct tabletting of drug instead of further processing like mixing , granulation, seiving, drying etc. There are certain parameters which have to be optimized in order to obtain the maximum amount of spherical crystals^6-8.

Some advantages of the spherical crystallization technique are listed below:
1) Spherical crystallization technique has been successfully utilized for improving of flowability and compressibility of drug powder.
2) This technique could enable subsequent processes such as separation, filtration, drying etc to be carried out more efficiently.
3) By using this technique, physicochemical properties of pharmaceutical crystals are dramatically improved for pharmaceutical process i.e. milling, mixing and tabletting because of their excellent flowability and packability.
4) This technique may enable crystalline forms of a drug to be converted into different polymorphic form having better bioavailability.
5) For masking of the bitter taste of drug.

Spherical crystallization is a fast developing technique of particle design in which crystallization and agglomeration can be achieved simultaneously in one step. It has been successfully utilized for improvement of flow ability and compactability of crystalline drugs. The principle steps involved in the process of spherical crystallization are flocculation zone, zero growth zone, fast growth zone and constant size zone^9-15. General methods of spherical crystallization are emulsion solvent diffusion, spherical agglomeration, ammonia diffusion method and neutralization method. Factors controlling the process of agglomeration are solubility profile, mode and intensity of agitation, temperature of the system and residence time^{16, 17}. Characterization of spherical crystals can be carried out using Optical Microscopy, Scanning Electron Microscopy, X-ray Powder Diffraction, Fourier Transform Infrared spectroscopy, Differential Scanning Calorimetry and Thin layer Chromatography.

Naproxen sodium is a [(+)-(S)-2-(6-methoxynaphthalen-2-yl) propanoic acid], a non-steroidal anti-inflammatory drug (NSAID). It has been indicated for various painful indications and proved as effective as other NSAIDs with lower indications of gastro-intestinal adverse effects and thus, resulted in a greater compliance with treatment. Naproxen sodium is practically insoluble. Solubility of Naproxen Sodium is 0.00159 mg/ml. log P value of Naproxen Sodium is 3.29, which indicated lower solubility in water. For poorly soluble orally administered drugs, the rate of absorption is often controlled by the rate of dissolution.

Present investigation aims to enhance dissolution of Naproxen sodium. Naproxen sodium was poorly water soluble drug and has poor tableting properties. Agglomeration of Naproxen sodium with different polymers using spherical crystallization technique will provide agglomerates or spherical crystals have good aqueous solubility and tableting property. Agglomerates prepared using spherical agglomeration using PEG 400 and PVP K-30 showed higher drug dissolution and good flowability and compressibility.  

MATERIALS AND METHODS
Naproxen Sodium was procured from Sun Pharmaceuticals Advanced Research Center, Vadodara, India as a gift sample. PEG 400 and PVP K-30 was purchased from BASF Ltd, Mumbai, India. All the chemicals and solvents used in the preparation were of analytical grade. All materials were used as they were received.

EXPERIMENTAL

Development of Spherical Naproxen Sodium Crystals by Spherical Agglomeration Method
In order to produce spherical agglomerate of Naproxen sodium, 5 g of sample was dissolved in methanol (100 ml) at 60°C to make quasi-saturated solution. The resultant solution (5% w/v) was poured into mixture of water (840 ml) and PEG 400 (0.5 ml) thermally controlled at temperature 20 °C, with stirring at 400 rpm. The precipitated crystals were collected after 20 min by vacuum filtration. The obtained crystals were dried in an oven at 60°C for 3 h. The dried crystals were stored in desiccators at room temperature before use^18-20. The above process was repeated several times in order to obtain enough Naproxen sodium for flow and particle size analysis tests. Composition of different Batches of Spherical Agglomerates of Naproxen Sodium was depleted in Table 1.

Effect of polymer concentration
The polymer (PEG 400/PVP K-30) was dissolved along with poorly soluble drug in mixture of good solvent (methanol) and bridging liquid in the different polymer concentration. The solution was poured into specific volume of distilled water (poor solvent) with an optimized stirring rate (400rpm) using propeller type of agitator at room temperature^21,22. After agitating the system for 30min, the prepared agglomerates were collected by filtration through Whatman filter paper no.1. The spherical crystal were washed with distilled water and placed at room temperature for drying for 24 h.

Table 1: different Batches of Spherical Agglomerates of Naproxen Sodium

Evaluation of spherical agglomeration

Angle of repose
This is the common method used for determination of flow property. The angle of repose is the angle between the horizontal and the slop of the heap or cone of solid dropped from some elevation. Values for angle of repose ≤ 30 usually indicate free flowing material and angle ≥ 40 suggested a poor flowing material^23-25. The angle of repose can be obtained from equation

Where, h= height of the cone and d= diameter of the cone

% Compressibility
A simple indication of ease with which a material can be induced to flow is given by application of compressibility index^26-28

Where V = the volume occupied by a sample of powder after being subjected to a standardized tapping procedure and V_O = the volume before tapping. The value below 15% indicates good flow characteristics and value above 25% indicate poor flowability.

Particle size determination
Particle size determination was carried out using optical microscopy with a calibrated eye piece micrometer and stage micrometer by taking a small quantity of formulation on slide. About 100 spherical agglomerates size was measured individually, average was taken and their size range and mean diameter frequency was calculated^{29, 30}. Average Particle size is calculated by the formula,

                                         ∑nd
Average Particle size =     --------
                                          n

% Yield

It was determine by

 %yield    =     Practical yield * 100
                   ----------------------
                       Theoretical yield

Solubility study
Excess amounts of Naproxen Sodium agglomerates and pure Naproxen Sodium was dispersed in 20ml distilled water. The dispersion was shaken at 100rpm at 37°C for 24hrs using mechanical shaker. After 24hrs the dispersion was filtered through Whatman filter paper (grade1, circles, 90mm diameter), followed by dilution. The filtered sample solution was analyzed using a UV-visible spectrophotometer at 270nm. The mean results of triplicate measurements and the standard deviation were reported.

Drug content
Drug content was determined by dissolving 500 mg equivalent Naproxen Sodium in 100ml methanol and if necessary making further dilution using methanol^{31, 32}. Amount of drug dissolved was analyzed spectrophotometrically at λ_max of 270nm and drug content find out using calibration equation. All studies were carried out in triplicates.

In Vitro Dissolution Study
Accurately weighed SA of Naproxen sodium containing equivalent amount of Naproxen Sodium 500 mg was taken for in vitro dissolution study. In vitro dissolution study was carried out using USP dissolution apparatus type –II. 900 ml phosphate buffer pH 6.8 was taken as dissolution medium. Dissolution test was performed at 37ºC±5ºC. At regular time interval of 10 min 10 ml aliquots was withdrawn and fresh 10 ml dissolution medium was added to achieve sink condition. Sample withdrawn was analyzed at 270 nm using UV- spectrophotometer to calculate in vitro drug release (n=3).   

Physical Characterization of Spherical Agglomerates

Differential Scanning Calorimetry (DSC) Study
A differential scanning calorimeter was used to monitor thermal events during heating. Samples weighing 2 -3 mg were placed in an open aluminum pans and heated from 55 -250°c at a rate of 10°c per min. Nitrogen was used as a purge gas at a flux rate of 50ml/min. The onsets of melting points and enthalpies of fusion were recorded by software provided by supplier.

Fourier Transform infrared spectroscopy Study
The FTIR spectra of Naproxen Sodium agglomerates and untreated Naproxen Sodium drug powder were recorded on FTIR spectro photometer in the wavelength region of 4000-400cm^-1. Samples (about 1% w/w) were mixed with KBr powder and suitable amount of sample was placed in a sample holder.

X- ray Diffractometer Study
Powder X-ray diffraction (PXRD) patterns of Naproxen Sodium agglomerates and pure Naproxen Sodium were collected in transmission using an X-ray diffractometer with a rotating anode(Philips,  X-pert-MPD) with Cu Kα1 radiation (monochromator: graphite) generated at a 200mA and 40 kV. Powder was packed into the rotating sample holder between two films (PETP). Quantitative determination of crystallinity at same 2θ value suggests the degree crystallinity of drug in formulation relative to degree of crystallinity of pure drug.

RESULTS AND DISCUSSION

Selections of Solvents:
Spherical agglomerates of Naproxen Sodium were prepared by Spherical Agglomeration (SA) using a Methanol. It involves good solvent, poor solvent and a bridging liquid. The selection of these solvents depends on the miscibility of the solvents and the solubility of drug in individual solvent. Accordingly Methanol, dichloromethane, water were selected as a good solvent, bridging liquid, and poor solvent, respectively. Naproxen Sodium is highly soluble in methanol, but poorly soluble in water. Also it is soluble in dichloromethane which is immiscible in water. Hence, this solvent system was used in the present study. In Spherical Agglomeration (SA) method, when good solvent solution of drug plus bridging liquid were poured in the poor solvent under agitation. The counter-diffusion of the poor solvent into the droplets induces the crystallization of the drug within the droplet due to the decrease in solubility of the drug in the droplet containing the poor solvent. The bridging liquid wets the crystal surface to cause binding and promotes the formation of liquid bridges between the drug crystals to form spherical agglomerates. The spherically agglomerated crystals are formed by coalescence of these dispersed crystals. In the present study effect of different polymer on solubility and dissolution rate of spherical agglomerates of Naproxen Sodium were studied.

Effect of Drug: Polymer Ratio
The presence of polymers in spherical agglomerates influenced the particles size of resultant agglomerates. As the concentration of the polymers increased, the size of the agglomerates increased. The presence of polymers on the particle surface increases particle-particle interaction, causing faster squeezing out of DMF to the surface resulting in increased particle size. Table 2 represents the microscopic observation of pure Naproxen Sodium and prepared agglomerated crystals with polymers PVP K30, polyethylene glycol (PEG 400). The agglomerated crystals prepared by incorporating water-soluble polymers can improve solubility and in vitro drug release. Addition of PEG400 water soluble polymer increased the solubility of Naproxen Sodium in water as well as in the dissolution medium. In order to impart strength and sphericity besides increasing the solubility and drug release from agglomerates PVP K30 was selected. As the concentration of the PVP K30 increased, the size of the agglomerates increased.

Table 2: Results of Evaluation Parameters for Agglomerates of Naproxen Sodium