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HardikRana*, BhargavVaghasiya, MansiDholakia
Department of Pharmaceutics,
Anand Pharmacy College, Anand, 388 001, Gujarat, India.

The objective of present study was to enhance the solubility of poorly soluble drug Ibuprofen using spherical crystallization technique.The potential agglomerates were prepared by addition of different concentrationof polymer selected on the basis of Phase solubility study. Spherical agglomerates were prepared using diethyl ether as bridging liquid by neutralizing technique, spherical agglomeration technique, Quasi emulsion solvent diffusion technique. Spherical agglomerates were evaluated for morphology, production yield, drug content, particle size and dissolution behaviour compared with pure drug.The result of phase solubility studies revealed that there is enhancement of solubility by PEG 4000. Rod shaped crystals of pure drug converted to spherical was confirmed by optical microscopy. The dissolution of agglomerates of optimum batch exhibited 88.24% release compare to 47.18% of pure drug within 60 minute. This study demonstrated that spherical crystallization technique can be consider as a suitable alteration of granulation. Ibuprofen spherical agglomerates can be prepared with PEG 4000. It exhibited excellent physicochemical, solubility, dissolution rate in comparison with pure drug. Among other spherical crystallization technique, QESD proved to be excellent techniquefor enhancement of solubility and dissolution.


PharmaTutor (ISSN: 2347 - 7881)

Volume 5, Issue 3

Received On: 20/08/2016; Accepted On: 23/11/2016; Published On: 01/03/2017

How to cite this article: Rana H, Vaghasiya B, Dholakia M;Solubility Enhancement of poorly Water Soluble Drug by Spherical Crystallization Technique; PharmaTutor; 2017; 5(3); 31-36


Aqueous solubility and dissolution are two of the crucial factors influencing drug absorption from the gastrointestinal tract (GIT). However, many newly discovered compounds exhibit low oral bioavailability. More than 40% of active substances during formulation development by the pharmaceutical industry are poorly water soluble.[1] Poor water solubility, which is associated with poor dissolution characteristics. As a result, much research has been conducted into methods of improving drug solubility and dissolution rates to increase the oral bioavailability of hydrophobic drugs. One way of improving dissolution involves the reduction of particle size and/or increasing saturation solubility. One of the most common approaches used to reduce particle size is milling, a mechanical micronization process. Milling is a well-established technique which is relatively cheap, fast and easy to scale-up. However, milling has several disadvantages, the main one being the limited opportunity to control important characteristics of the final particle such as size, shape, morphology, surface properties and electrostatic charge. In addition, milling is a high energy process which causes disruptions in the drug’s crystal lattice, resulting in the presence of disordered or amorphous regions in the final product.  These amorphous regions are thermodynamically unstable and are therefore susceptible to recrystallization upon storage, particularly in hot and humid conditions.[2]


The alteration of the surface properties also changes the milled product’s saturation solubility as well as blending and flow properties, which in turn, have an impact on the formulation process. Furthermore, milled particles often show aggregation and agglomeration which results in poor wettability and thus poor dissolution.[3]An alternative to milling involves growing the particle from a solution to the desired size range under controlled conditions, for example by spray drying, emulsion solvent-diffusion[4] and supercritical fluid technology.[5, 6] One of the advantages of these methods is the possibility of designing in certain beneficial characteristics such as enhancing dissolution rate by incorporating different polymers. The spherical crystallization technique has been successfully applied now days to improve the micromeritic properties of drug substances. [7] In the most common case, this technique is reputed to improve the wettability and dissolution rate of different drugs. [8, 9, 10, 11] Some drugs have also been recrystallized by the spherical agglomeration technique using polymeric materials to modify their release. [12, 13]

There are two main methods for spherical crystallization: spherical agglomeration (SA method) and emulsion solvent diffusion (ESD method). [14] In the SA method, a quasi-saturated solution of the drug, in a solvent in which it is very soluble, is poured into a poor solvent of the drug. Provided that the good and the poor solvents are freely miscible and interaction (binding force) between the solvents is stronger than drug interaction with the good solvent, crystals precipitate immediately. A suitable amount of a third solvent, which is not miscible with the poor solvent and which preferentially wets the precipitated crystals, is added to the system while stirring. This third solvent, which is called a ‘bridging liquid’, can collect the crystals suspended in the system by forming liquid bridges between the crystals due to capillary negative pressure and interfacial tension between the interface of solid and liquid. When interaction between the drug and the good solvent is stronger than that of the good and poor solvents, the good solvent drug solution is dispersed in the poor solvent, producing quasi emulsion droplets, even if the solvents are normally miscible. This is due to an increase in the interfacial tension between good and poor solvent. Then the good solvent diffuses gradually out of the emulsion droplet into the outer poor solvent phase. The counter diffusion of the poor solvent into the droplet induces the crystallization of the drug within the droplet due to the decreasing solubility of the drug in the droplet containing the poor solvent. This process is known as the emulsion solvent diffusion (ESD) process.[15]

Ibuprofen is a non-steroidal anti-inflammatory drug which is widely used as a pain killer. It has a low solubility in water and gastric fluids, which determines a low dissolution rate and hence inter individual variability on its bioavailability. [16]The aim of the present investigation is to enhance solubility hence dissolution rate by Spherical crystallization technique.

2.1.    Materials:
Ibuprofen was supplied as a gift sample by Baroque Pharmaceuticals Pvt. Ltd, Khambhat.  PEG 4000 was purchased from S.D. fine chemicals, Baroda. Deionized double-distilled water was used throughout the study.

2.2.Preparation of Ibuprofen agglomerates
The polymer according to specific concentration was dissolved along with 250 mg of drug (Ibuprofen) in the mixture of good solvent (ethanol= 3 ml) and bridging liquid (Dimethyl formamide= 1 ml) in the different drug: polymer mass ratio a shown in Table 1. The solution was poured into 100 ml distilled water (poor solvent) with an optimized stirring rate (800 rpm) using propeller type of agitator (Remi Motors Ltd., Mumbai, India) at room temperature. After agitating the system for 30 min, the prepared agglomerates were collected by filtration through Whatman filter paper no. 1.The spherical crystals were washed with distilled water and placed at room temperature for drying for 24 h and stored in desiccators.[17]

Table 1: Composition of Solid Dispersion





Ibuprofen (mg)




Ethanol (ml)




DMF (ml)




PEG 4000 (mg)




Water (ml)




Stirring Speed (rpm)




2.3.    Particle size determination
Particle size was determined using the optical microscopy. Optical microscopy was used to observe the crystal habit (size and shape) in this study. Optical microscopy was the simplest instrument to capture images of crystal habits, especially for wet samples or samples in solution. Optical microscopy (OM) can be divided into eye-piece, objective lens, object holder and stage.[18, 19]

2.4. Drug content
Drug content was determined by dissolving 100mg equivalent Ibuprofen powder in 100ml methanol and if necessary making further dilution using methanol. Amount of drug dissolved was analyzedspectrophotometrically (Shimadzu 1650PC) at wavelength of 221nmand drug content find out using calibration equation. All studies were carried out in triplicates.[20]

2.5.Saturation Solubility study
Excess amounts of Ibuprofen agglomerates and pure TBM drug powder was dispersed in 20mL distilled water. The dispersion was shaken at 100 rpm at 370C for 24 hrs. usingshaker thermostatic cabinet (Remi, RI’S-24BL, Mumbai).After 24 hours the dispersion was filtered through a whatman filter paper (grade 1, circles, 90 mm diameter), followed by dilution. The filtered sample solutions were analyzed using a UV–visible spectrophotometer (shimadzu 1650PC) at 221 nm. The mean results of triplicate measurements and the standard deviation were reported.[21]

The Gibbs-free energy of change (ΔG˚tr°) of tolbutamide occurred during formation of agglomerates from untreated TBM powder was calculated using equation (1).

Where S0/Ss, is the ratio of the molar solubility of Ibuprofen agglomerates in distilled water to that of the untreated TBM powder. R is gas constant, its value is 8.31 J K-1 mol-1 and T is temperature in Kelvin.

2.6. In vitro Dissolution study
The dissolution study was carried out by using a USP apparatus II (Electrolab, TDT-08L) using 900 ml of phosphate buffer pH 7.4 at a temperature of 37±10C at 75 rpm. At regular time intervals (5 min), suitable amount of sample was withdrawn and same amount replaced by fresh medium. Samples were suitably diluted and filtered through syringe filter (Axiva SFCA25X, 0.45µm). Drug amount released was obtained spectrophotometrically (shimadzu 1650PC) at wavelength of 221nm. All studies were carried out in triplicates.[21]


3.1. Selection of Solvents
The choice of the best solvent was done based on the available literature on solubility of tolbutamide and miscibility of the solvents.[22]Ethanol, N, N-Dimethyl formamide (DMF) and water were selected as a good solvent, bridging liquid and poor solvent, respectively. Selection of bridging liquid should be such that it should be immiscible with the poor solvent i.e. water and the drug should have slight solubility in it. [23] Agglomerates were formed by agitating the crystals in a liquid suspension and adding bridging liquid which preferentially wets the crystal surface to cause binding. The addition of bridging liquid (DMF) 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.

3.2. Effect of the Drug: Polymer Ratio
The agglomerated crystals prepared by incorporating water-soluble polymers can improve solubility and in vitro drug release. Addition of PEG water-soluble polymer increased the solubility of Ibuprofen in water as well as in the dissolution medium.

Table 2: Results of different Evaluation parameter


Drug: Polymer mass ratio

Stirring Speed in rpm

Mean particle size (µm) a

Percentage yield (%)

Drug content (%)

Appearance of the agglomerated crystals

PEG 4000

1: 0.03



88.6± 0.91

98.18± 0.45

Less agglomeration


1: 0.05



90.13± 0.42

98.64± 0.91

Large agglomerates


1: 0.08



94± 0.8

98.64± 0.91

Large and more number of agglomerates

Pure TBM





100.30± 0.26

Rod shaped crystals



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