**1. Introduction**

640 Advances in Crystallization Processes

Talanin, V.I. & Talanin, I.E. (2006a). Formation of grown-in microdefects in dislocation-free

Talanin, V.I. & Talanin, I.E. (2007a). On the recombination of intrinsic point defects in

Talanin, V.I.; Talanin, I.E. & Voronin, A.A. (2007b). About formation of grown-in

Talanin, V.I.; Talanin, I.E. & Voronin A.A. (2008). Modeling of the defect structure in

Talanin, V.I. & Talanin, I.E. (2010a). Kinetic of high-temperature precipitation in dislocation-

Talanin, V.I. & Talanin, I.E. (2010b). Kinetics of formation of vacancy microvoids and

Talanin, V.I. & Talanin, I.E. (2010c). Modeling of defect formation processes in dislocation-

Talanin, V.I. & Talanin, I.E. (2011a). Kinetic model of growth and coalescence of oxygen and

Talanin, V.I.; Talanin, I.E. & Ustimenko N.Ph. (2011b). A new method for research of grown-

Yang, D.; Chen, J.; Ma, X. & Que, D. (2009). Impurity engineering of Czochralski silicon used

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Voronkov, V.V.; Dai B. & Kulkarni M.S. (2011). Fundamentals and engineering of the

Wang, Z. & Brown, R.A. (2001). Simulation of almost defect-free silicon crystal growth. *Journal Crystal Growth*, Vol. 231, No. 2, pp. 442-452, ISSN 0022-0248.

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Nova Science Publishers, Inc., ISBN 1-59454-920-6, New York, USA. Talanin, V.I. & Talanin, I.E. (2006b). On the formation of vacancy microdefects in

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*State*, Vol. 52, No. 9, pp. 1880-1886, ISSN 1063-7834.

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free silicon single crystals. *Physics of the Solid State*, Vol. 52, No. 10, pp. 2063-2069,

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carbon precipitates during cooling of as-grown silicon crystals*. Physics of the Solid* 

in microdefects in dislocation-free silicon single crystals. *Journal of Crystallization* 

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Czochralski growth of semiconductor silicon crystals. *Comprehensive Semiconductor* 

Solid dispersion is one of the most efficient techniques to improve the dissolution rate of poorly water-soluble drugs, leading to an improvement in the relative bioavailability of their formulations. At present, the solvent method and the melting method are widely used in the preparation of solid dispersions. In general, subsequent grinding, sieving, mixing and granulation are necessary to produce the different desired formulations.

The spherical agglomeration technique has been used as an efficient particle preparation technique developed by Kawashima in the 1980s (Kawashima et al., 1994). Initially, spherical agglomeration technique was used to improve powder flowability, packability, and compressibility (Usha et al. 2008; Yadav and Yadav, 2008; Bodmeier and Paeratakul et al., 1989). Then polymers were introduced in this system to modify their release (Di Martino et al., 1999). Currently, this technique is used more frequently for the solid dispersion preparation of water-insoluble drugs in order to improve their solubility, dissolution rate and simplify the manufacturing process (Cui et al.*,* 2003, Tapas et al. 2009, 2010). Spherical crystallization has been developed by Yoshiaki Kawashima and co-workers as a novel particulate design technique to improve processibility such as mixing, filling, tableting characteristics and dissolution rate of pharmaceuticals (Kawashima et al., 1974, 1976, 1981, 1982, 1983, 1984, 1985, 1989, 1991, 1994, 1995, 2002, 2003). The resultant crystals can be designated as spherical agglomerates (Kulkarni and Nagavi, 2002). Spherical crystallization is an effective alternative to improve dissolution rate of drugs (Sano et al., 1992). Now days functional drug devices such as microspheres, microcapsules, microballoons and biodegradable nanospheres were developed using the emulsion solvent diffusion techniques involving the introduction of a functional polymer into the system (Di Martino et al., 1999; Marshall and York, 1991; Garekani and Ford, 1999). This can be achieved by various methods such as


Preparation of Carvedilol Spherical Crystals Having Solid Dispersion Structure

solvent diffusion method has the second importance.

(polxamer F68 and poloxamer F127) as a hydrophilic polymer.

Fig. 2. Chemical structure of Carvedilol (CAR)

liberation of ammonia water.

agglomerates.

solvent.

by the Emulsion Solvent Diffusion Method and Evaluation of Its *in vitro* Characteristics 643

solvents when the drug solution was introduced into the poor solvent under certain temperature and stirring, the drug solution was dispersed immediately to form quasi o/w emulsion droplets, the emulsion droplets were gradually solidified, forming spherical agglomerates along with the diffusion of the good solvent from the droplets into the poor

Spherical agglomeration has got more importance than other methods because it is easy to operate and the selection of the solvents is easier than in the other methods. Quasi emulsion

An ammonia diffusion system is applicable to amphoteric drug substances. In this method, the mixture of three partially immiscible solvent i.e. acetone, ammonia water, dichloromethane was used as crystallization system. In this system ammonia water acted as bridging liquid as well as good solvent, acetone as the water miscible but poor solvent, thus drug precipitated by solvent change without forming ammonium salt. Water immiscible solvent such as hydrocarbon or halogenated hydrocarbons e.g. dichloromethane induced

In neutralization method sodium hydroxide acts as a good solvent and hydrochloric acid as a poor solvent or vice-versa. These solutions were added to each other in order to get neutralization. The bridging liquid was added drop wise under agitation to form spherical

In this study special attention was given to improving the solubility and dissolution rate of poorly water soluble drug carvedilol using quasi emulsion solvent diffusion method. Carvedilol (CAR) (fig. 2), (±)-1-(carbazol-4yloxy)-3-[[2-(o-methoxyphenoxy)ethyl]amino]-2 propanol is an α1, β1 and β2 adrenergic receptor antagonist (Sweetman, 2002). It is used to treat mild to moderate essential hypertension, mild to severe heart failure, and patients with systolic dysfunction after myocardial infraction. Carvedilol is practically insoluble in water and exhibits pH dependent solubility. Its solubility is <1µg/ml above pH 9.0, 23 µg/ml at pH 7, and about 100 µg/ml at pH 5 at room temperature. It's extremely low solubility at alkaline pH levels may prevent the drug from being available for absorption in the small intestine and colon, thus making it poor candidate for an extended release dosage form. In the present study, to overcome the problems related to solubility, dissolution rate, flowability, and compressibility, the microspheres having solid dispersions structure of Carvedilol were prepared by emulsion solvent diffusion method by using a poloxamer

Out of which first two are the most common methods in practice.

In the spherical crystallization process, crystal formation, growth and agglomeration occur simultaneously within the same system. In this method, a third solvent called the bridging liquid is added in a smaller amount to purposely induce and promote the formation of agglomerates. Crystals are agglomerated during the crystallization process and large spherical agglomerates are produced. A near saturated solution of the drug in a good solvent is poured into a poor solvent. The poor and good solvents are freely miscible and the "affinity" between the solvents is stronger than the affinity between drug and good solvent, leading to precipitation of crystals immediately. Under agitation, the bridging liquid (the wetting agent) is added, which is immiscible with the poor solvent and preferentially wet the precipitated crystals. As a result of interfacial tension effects and capillary forces, the bridging liquid acts to adhere the crystals to one another and facilitates them to agglomerate (Fig. 1).

Fig. 1. Two sample particles joined together by a liquid bridge

In spherical agglomeration method, when a drug solution (in good solvent) was poured into a poor solvent under agitation, the drug crystals were formed immediately and agglomerated with a bridging liquid dispersed in the poor solvent, because the bridging liquid has a preference for wetting the drug crystals.

Quasi emulsion solvent diffusion method is also known as transient emulsion method. Firstly the drug was dissolved in a mixed solvent of good solvent and bridging liquid. Because of the increased interfacial tension between the two solvents, the solution is dispersed into the poor solvent producing emulsion (quasi) droplets, even though the pure solvents are miscible. The good solvent diffuses gradually out of the emulsion droplets into the surrounding poor solvent phase, and the poor solvent diffuses into the droplets by which the drug crystallizes inside the droplets. The method is considered to be simpler than the SA method, but it can be difficult to find a suitable additive to keep the system emulsified and to improve the diffusion of the poor solute into the dispersed phase. Especially hydrophilic/hydrophobic additives are used to improve the diffusion remarkably. In this method the shape and the structure of the agglomerate depend strongly on the good solvent to poor solvent ratio and the temperature difference between the two

In the spherical crystallization process, crystal formation, growth and agglomeration occur simultaneously within the same system. In this method, a third solvent called the bridging liquid is added in a smaller amount to purposely induce and promote the formation of agglomerates. Crystals are agglomerated during the crystallization process and large spherical agglomerates are produced. A near saturated solution of the drug in a good solvent is poured into a poor solvent. The poor and good solvents are freely miscible and the "affinity" between the solvents is stronger than the affinity between drug and good solvent, leading to precipitation of crystals immediately. Under agitation, the bridging liquid (the wetting agent) is added, which is immiscible with the poor solvent and preferentially wet the precipitated crystals. As a result of interfacial tension effects and capillary forces, the bridging liquid acts to adhere the crystals to one another and facilitates

Out of which first two are the most common methods in practice.

Fig. 1. Two sample particles joined together by a liquid bridge

liquid has a preference for wetting the drug crystals.

In spherical agglomeration method, when a drug solution (in good solvent) was poured into a poor solvent under agitation, the drug crystals were formed immediately and agglomerated with a bridging liquid dispersed in the poor solvent, because the bridging

Quasi emulsion solvent diffusion method is also known as transient emulsion method. Firstly the drug was dissolved in a mixed solvent of good solvent and bridging liquid. Because of the increased interfacial tension between the two solvents, the solution is dispersed into the poor solvent producing emulsion (quasi) droplets, even though the pure solvents are miscible. The good solvent diffuses gradually out of the emulsion droplets into the surrounding poor solvent phase, and the poor solvent diffuses into the droplets by which the drug crystallizes inside the droplets. The method is considered to be simpler than the SA method, but it can be difficult to find a suitable additive to keep the system emulsified and to improve the diffusion of the poor solute into the dispersed phase. Especially hydrophilic/hydrophobic additives are used to improve the diffusion remarkably. In this method the shape and the structure of the agglomerate depend strongly on the good solvent to poor solvent ratio and the temperature difference between the two

them to agglomerate (Fig. 1).

solvents when the drug solution was introduced into the poor solvent under certain temperature and stirring, the drug solution was dispersed immediately to form quasi o/w emulsion droplets, the emulsion droplets were gradually solidified, forming spherical agglomerates along with the diffusion of the good solvent from the droplets into the poor solvent.

Spherical agglomeration has got more importance than other methods because it is easy to operate and the selection of the solvents is easier than in the other methods. Quasi emulsion solvent diffusion method has the second importance.

An ammonia diffusion system is applicable to amphoteric drug substances. In this method, the mixture of three partially immiscible solvent i.e. acetone, ammonia water, dichloromethane was used as crystallization system. In this system ammonia water acted as bridging liquid as well as good solvent, acetone as the water miscible but poor solvent, thus drug precipitated by solvent change without forming ammonium salt. Water immiscible solvent such as hydrocarbon or halogenated hydrocarbons e.g. dichloromethane induced liberation of ammonia water.

In neutralization method sodium hydroxide acts as a good solvent and hydrochloric acid as a poor solvent or vice-versa. These solutions were added to each other in order to get neutralization. The bridging liquid was added drop wise under agitation to form spherical agglomerates.

In this study special attention was given to improving the solubility and dissolution rate of poorly water soluble drug carvedilol using quasi emulsion solvent diffusion method. Carvedilol (CAR) (fig. 2), (±)-1-(carbazol-4yloxy)-3-[[2-(o-methoxyphenoxy)ethyl]amino]-2 propanol is an α1, β1 and β2 adrenergic receptor antagonist (Sweetman, 2002). It is used to treat mild to moderate essential hypertension, mild to severe heart failure, and patients with systolic dysfunction after myocardial infraction. Carvedilol is practically insoluble in water and exhibits pH dependent solubility. Its solubility is <1µg/ml above pH 9.0, 23 µg/ml at pH 7, and about 100 µg/ml at pH 5 at room temperature. It's extremely low solubility at alkaline pH levels may prevent the drug from being available for absorption in the small intestine and colon, thus making it poor candidate for an extended release dosage form. In the present study, to overcome the problems related to solubility, dissolution rate, flowability, and compressibility, the microspheres having solid dispersions structure of Carvedilol were prepared by emulsion solvent diffusion method by using a poloxamer (polxamer F68 and poloxamer F127) as a hydrophilic polymer.

Fig. 2. Chemical structure of Carvedilol (CAR)

Preparation of Carvedilol Spherical Crystals Having Solid Dispersion Structure

ml/min).

step time of 0.8 second.

**2.2.4 Powder X-ray diffraction studies** 

**2.2.5 Scanning electron microscopy** 

**2.2.6 Micromeritic properties** 

equation 1 and 2.

**2.2.7 Solubility studies** 

spectrophotometrically.

**2.2.8 Dissolution rate studies** 

splutter coated with gold before scanning.

by the Emulsion Solvent Diffusion Method and Evaluation of Its *in vitro* Characteristics 645

crucible and heated at the rate of 10 °C/min up to 300 °C under a nitrogen atmosphere (40

Powder X-ray diffraction patterns (XRD) of the CAR and its spherical agglomerates were monitored with an x-ray diffractometer (Philips Analytical XRD) using copper as x-ray target, a voltage of 40 KV, a current of 25 mA and with 2.28970 Å wavelength. The samples were analyzed over 2θ range of 10.01-99.990 with scanning step size of 0.020 (2θ) and scan

The surface morphology of the agglomerates was accessed by SEM. The crystals were

The size of agglomerates was determined by microscopic method using stage and eyepiece micrometers. The shape of the agglomerates was observed under an optical microscope (×60 magnification) attached to a computer. Flowability of untreated carvedilol and agglomerates was assessed by determination of angle of repose, Carr's index (CI) and Hausner's ratio (HR) (Wells, 2002). Angle of repose was determined by fixed funnel method (Martin et al., 2002). The mean of three determinations was reported. The CI and HR were calculated from the loose and tapped densities. Tapped density was determined by tapping the samples into a 10 ml measuring cylinder. The CI and HR were calculated according to the following

Tapped density – Bulk density C.I. = ×100

Tapped density H.R. = Bulk density

A quantity of crystals (about 100 mg) was shaken with 10 mL distilled water in stoppered conical flask at incubator shaker for 24 h at room temperature. The solution was then passed through a whatmann filter paper (No. 42) and amount of drug dissolved was analyzed

The dissolution rate studies of carvedilol alone and its spherical agglomerates were performed in triplicate in a dissolution apparatus (Electrolab, India) using the paddle method (USP Type II). Dissolution studies were carried out using 900 ml of 0.1N HCl (pH 1.2) at 37 ± 0.5 0C at 50 rpm as per US FDA guidelines (U.S. Food and drug administration [USFDA], 2010 and Bhutani et al., 2007.). 12.5 mg of carvedilol or its equivalent amount of

Tapped density (1)

(2)
