KTH Chemical Engineering and Technology

Spherical Crystallization of Benzoic acid

Jyothi Thati

Licentiate Thesis

.

Royal Institute of Technology

School of Chemical Science and Engineering Department of Chemical Engineering and Technology

Division of Transport Phenomena

Stockholm 2007

Chemical Engineering and Technology Royal Institute of Technology, KTH SE-100 44 Stockholm Sweden

AKADEMISK AVHANDLING Som med tillstånd av Kungliga Tekniska Högskolan i Stockholm framlägges till offentlig granskning för avläggande av teknologie licentiatexamen den 18 januari 2008, kl. 10:00 i D41 at Lindstedtsvägen 17, KTH, Stockholm. Avhandlingen försvaras på engelska. TRITA-CHE-REPORT 2007:87 ISSN 1654-1081 ISBN 978-91-7178-843-6 © Jyothi Thati Stockholm 2007 Tryck: Universitetsservice US-AB, Stockholm 2007

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LIST OF PAPERS This thesis is based on the following papers i. Katta, J., Rasmuson, Å. C., 2007. Spherical Crystallization of benzoic acid. Int. J. Pharmaceut. doi:10.1016/j.ijpharm.2007.07.006, accepted paper. ii. Thati, J., Rasmuson, Å. C., 2007. Spherical Crystallization of Benzoic Acid in Ethanol - Water - Toluene to be submitted to International journal of pharmaceutics. iii. Thati, J., Rasmuson, Å. C., Evaluation of bridging liquid on spherical crystallization of benzoic acid (Manuscript) Additional Conference Contributions 1V. Katta, J., Rasmuson, Å. C., 2006. Spherical Crystallization of benzoic acid, The 7th International Workshop on the Crystal Growth of Organic Materials, CGOM-7, University of Rouen, France. V. Thati, J., Rasmuson, Å. C., Evaluation of bridging liquid on spherical crystallization of benzoic acid, to be submitted to the Proceedings of the 17th International Symposium on Industrial Crystallization, ISIC-17 and CGOM-8, Maastricht, The Netherlands.

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NOTATIONS BSR Volume of bridging liquid

Volume of solid

Cs Concentration of solid [g/ml]

N Stirring speed [rpm]

F Force [N]

d Diameter [mm]

l Displacement [mm]

H Height of the bed [µm]

M Mass [g]

He Recovered size [µm]

Hc Minimum size [µm]

Hi Initial size [µm]

ER Elastic recovery ratio [ %]

P1, P2, P3, P4 Parameters -

V Volume [mm3]

d0 Initial particle size [mm]

hr Current particle vertical linear dimension [mm]

h Segment height [mm]

a Segment radius [mm]

ρ Density [kg/m3]

σ Stress [MPa]

ε Strain -

S Segment

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TABLE OF CONTENTS 1. INTRODUCTION ……………………………………………………………………1 2. LITERATURE REVIEW …………………………………………………………. 3 3. EXPERIMENTAL WORK ……………………………………………………….... 9 3.1 Materials …….…………………………………………………………………….... 9 3.1.1 Benzoic acid ……………...…………………………………………………. ...9 3.1.2 Solvents ………………….…..………………………………………………... 9 3.2 Determination of phase diagram ………………………………………………....10 3.3 Spherical crystallization …………………………………………..……………... 10 3.3.1 Apparatus ….……………….…..……………………………………………...10 3.3.2 Process A ….………….…………………………………………………….....10 3.3.3 Process B ….……….………………………………………………………….11 3.4 Methods of characterization ……………...……..……………………………..... 11 3.4.1 Sieving …..…………..…………………………….…………………………..11 3.4.2 Particle morphology …….………………………….………………………. 12 3.4.3 Strength analysis ….……….……...………………….……………………… 12 3.4.4 Yield ……………………….………………………….……………………… 14 4. RESULTS & DISCUSSION ……...…….…………………………………………. 15 4.1 Phase diagram …………………………………………………………………….. 15 4.2 Influence of operating parameters on particle size ……………………………... 15 4.2.1 Stirring rate ……………………...………………...……………………….… 15 4.2.2 Initial concentration…………...…………………….………………………... 16 4.2.3 Amount of bridging liquid ………………………..………………….……… 17 4.2.4 Feeding rate ……………………...…………………………………….………19

4.2.5 Temperature ………………………………...…………………...….................19 4.2.6 Bridging liquid …………………………...……………………………………20 4.2.7 Operating procedures .………………………………………...……………….22 4.3 Influence of operating parameters on particle morphology …………………… 22 4.3.1 Operating procedures…………………………………………………………. 22 4.3.2 Amount of bridging liquid..……………...…………………………………… 24

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4.3.3 Bridging liquid ……………………………………………………………….. 26 4.4 Influence of operating parameters on particle mechanical strength ......……… 28 4.4.1 Compression behavior ……………………………………………………….. 28 4.4.2 Agglomerate strength ………………………………………………………… 30 4.4.3 Average stress-strain curves………………………………..………………… 33 4.4.4 Elastic recovery and compressibility…………………………………………..35 4.4.5 Calculation schematic over changing particle shape ………………………… 37 4.5 Influence of temperature on yield ……………………………………………….. 40 5. INDUSTRIAL OUT LOOK ……………………………………………………….. 41 6. CONCLUSIONS …………………………………………………………………… 43 REFERENCES ……………………………………………………………………....... 45 ACKNOWLEDGMENTS…………………………………………………………….. 51

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1. INTRODUCTION Crystallization is the most used purification process in the broad range of industries such as pharmaceuticals, food products, chemicals, catalysts, cosmetics etc. In the manufacturing of the active pharmaceutical ingredient particles smaller than 10µm are often produced by crystallization and precipitation in order to increase the dissolution rate, and reach sufficient bioavailability. However processing of these fine particles is very difficult, as the flow properties are poor and the dosage control is difficult. Desired physical properties of the crystals such as filtering, drying, handling and packing etc. can be obtained by size enlargement. The well known phenomenon in particle technology is the agglomeration where the small crystals adhere to form bigger particles. Today the tablet is the most popular dosage form of pharmaceuticals. The most economical solution to prepare the tablet is the direct compression method especially for large volume products. For the direct compression method less equipment and space, lower labor costs, less processing time and lower energy consumption are required. One of the most recent developments in agglomeration is the invention of spherical crystallization in which spherical agglomerates are produced in situ by the agglomeration of the small crystals during crystallization. These particles gain favorable downstream processing characteristics combined with desirable bioavailability properties. In pharmaceutical production improved flowability and compaction reduces the number of formulation components and processing operations. Among the advantages of spherical agglomerates are good physico-chemical properties like compressibility, uniform and predictable dissolution, suitability for microencapsulation, flowability, packability that improve mixing, filling and tabletting (Chow and Leung 1996, Lasagabaster et al., 1994). Solvents and solvent composition, amount of bridging liquid, the agitation rate, initial particle size, feeding rate, stirring rate, temperature and concentration of the solid etc are the important parameters which influence the spherical crystallization. These parameters influence not only the productivity but also particle size distribution, morphology and strength of the product. The influence of above parameters has been explored earlier by using different materials as model compounds. Benzoic acid normally crystallizes as needles or flakes that can be difficult to handle in downstream processing and are unsuitable for direct compression into tablets. So in the present work benzoic acid has been chosen as a model compound. The aim of the present research is to advance the engineering of pharmaceutical agglomerates, for the purpose of tailoring the properties by modulation of processing conditions like solvent composition, hydrodynamics, and the generation of supersaturation. The study also includes evaluation of different experimental procedures and to elucidate the effect of amount of bridging liquid, the concentration of solid, agitation rate, feeding rate and the temperature effect on the physico – mechanical properties of the product particles like size, shape and mechanical strength.

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2. LITERATURE REVIEW Farnand et al., 1961; Sutherland 1962, discovered that adding barium sulfate in a mixture of benzene and small amounts of water would cause barium sulfate to form spherical clusters. A more deep study of spherical agglomeration was done in the 1960’s and 1970’s at the Canadian National Research Counsil (Farnand et al., 1961; Sutherland, 1962; Sirianni et al., 1969; Kawashima and Capes., 1974 and 1976). Their main interest of study was selective agglomeration of coal, but they also studied several other compounds (silica sand, glass and calcium carbonate etc). They studied the mechanisms, kinetics of spherical agglomeration, and the effect of process variables on the agglomerates. Kawashima et al., (1982) gave a second boost to spherical crystallization by introducing this technique into pharmaceutical manufacturing in the early 1980’s. It also inspired research in other fields. The technique also exploited in the preparation of food colorants (Lasagabaster et al., 1994), and new studies on selective recovery of fine mineral particles were conducted by Sadowski, (1995). Bausch and Leuenberger, (1994) have used it to protein crystallization as well. Spherical agglomeration provided a significant improvement to the production of pharmaceuticals with bioactive proteins. They agglomerated hydrophilic proteins from organic solvents using water as bridging liquid which wets the particles and causes them to agglomerate spherically. Spherical agglomeration use has been extended to the agglomeration of several other pharmaceutical drugs. For example, Goczo et al., (2000), acetylsalicylic acid, Martino et al., (1999), fenbufen, Kawashima et al., (1982), aminophylline. Spherical crystallization can be achieved by different methods. 1. Spherical Agglomeration (SA) 2. Quasi Emulsion Solvent Diffusion (QESD) 3. Ammonia diffusion system (ADS) 4. Neutralization

In the SA method a third solvent called the bridging liquid is added in a smaller amount to promote the formation of agglomerates (Kawashima et al., 1994). 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 become larger size agglomerates (Kawashima et al., 1984).

Chow et al., (1996) showed that agglomeration takes place as the wetted particles collide and the bridging liquid hold the particles together by forming liquid bridges between

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them. Many authors (Subero et al., 2006, Farnand et al., 1961, Kazuhiko et al., 2002, Kawashima et al., 1995 and 2002) have discussed the mechanism of spherical agglomeration. Farnand et al., 1961 suggested that when two immiscible solvents are present and one of the solvents preferentially wets the solid surface, a collision between two wetted particles forms a liquid bridge between the particles. This liquid bridge holds the particles together and further collisions cause formation of larger spherical agglomerates. This behaviour is similar to liquid bridge formation in granulation, except the continuous medium is liquid but not gas. Subero et al., (2005), developed a phenomenological model based on the experimental observations with the system (salicylic acid – water – chloroform) and on analogy with the granulation process; it is assumed that the agglomeration mechanisms during the growth period are governed by the agglomerate deformability. After a brief period of wetting of the particles by the bridging liquid, the agglomerates grow by coalescence like process until they reach a maximum size and then agglomerates get compacted. Kawashima et al., (2003) found that depending on the solvent combination for crystallization, the primary crystals were agglomerated by two different mechanisms, i.e. emulsion solvent diffusion (ESD) and spherical agglomeration (SA) mechanisms. Kawashima et al., (1995) described the spherical crystallization behaviour in the miscible region of the three-solvent system in terms of the solubility phase diagram. The most important parameters in spherical agglomeration are the selection and amount of the bridging liquid, the agitation rate, concentration of the solid, temperature, initial particle size and feeding rate. Many studies have been done to optimize the amount of bridging liquid to be added into the system (Bausch and Leuenberger 1994; Blandin et al., 2005) and found that less than the optimum amount of bridging liquid added, produces plenty of fine particles and more than optimum amount produces secondary agglomerates. The choice of the bridging liquid has an influence on the rate of agglomeration and the strength of the agglomerates. The viscosity of the continuous phase effects the size distribution of the agglomerates. In general, increasing amount of the bridging liquid leads to increased agglomerate size. Depending upon the amount of bridging liquid the particles can either form loose flocs or compact pellets. Subero et al., (2006) developed the visualization cell to enable the observation of solids capturing by individual droplet. These experiments in the cell were also used to compare the saturation of the binder droplets with the amount of bridging liquid used in agglomeration process. This could also be used as a first step in the design of the agglomeration process to select the binder and test different BSR values. The agitation speed of the system is one of the main parameter determining the average diameter of agglomerated crystals. With increasing agitation speed of the system, the shear force applied to the droplets increases, leading to more dispersed and consolidated droplets. This results in a reduction of the particle size of the product. An increasing stirring speed makes the agglomeration process less efficient (Bos and Zuiderweg 1987; Tambo and Watanabe 1979). Blandin et al., (2003) found that at higher stirring rate the final agglomerates tend to be less porous and more resistant.

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Capes and Sutherland (1967) showed that the final agglomerate size varied directly with the ratio of the interfacial tension to the initial solid particle size. It also varied directly with the weight of solids being agglomerated and inversely with stirrer speed. Kawashima and Capes (1976) found that the initial solid particle size had a strong influence on the agglomeration process. Very fine particles required less amount of bridging liquid but the agglomerate size distribution was wider than when using larger initial particles. Kawashima et al., (1981) found the agglomerate size increased with decreasing size in the case of lactose. Kawashima et al., (1984), studied the temperature effect for spherical agglomeration of salicylic acid in water - ethanol - chloroform system. With increasing temperature the recovery of the crystals decreased compared with the increased solubility of chloroform. At high temperatures, if the amount of available bridging liquid for agglomeration of the crystals increased it leads to large agglomerates. At low temperatures the recovery of the crystals increased, where as the constituent crystal size and the solubility of chloroform in the solvent mixture decreased. Amount of available bridging liquid was enough for agglomeration of fine particles resulting in the large agglomerates. The bulk density of the agglomerates decreased with increasing crystallization temperature. The large agglomerates produced at higher temperatures were bulky, less spherical and loosely compacted in a container leading to low bulk density. Temperature also affects the crystallization steps such as initial crystal nucleation, crystallization accompanied by agglomeration at early stage and agglomeration of crystals at the later stage. In the kinetic studies Kawashima and Capes (1976) confirmed that spherical agglomeration follows first order kinetics. Spherical agglomeration has more importance than the other methods because it is easy to operate and selection of the solvents is easier than the other methods. In other methods quasi emulsion method got the 2nd importance and below all the methods are explained briefly. Quasi - emulsion solvent diffusion is also known as transient emulsion method. In this method only two solvents are required (Kawashima et al., 1994), a solvent that readily dissolves the compound to be crystallized (good solvent), and a solvent that act as an antisolvent generating the required supersaturation (poor solvent). In the ESD method (Sano et al., 1992) the “affinity” between the drug and the good solvent is stronger than that of good solvent and poor solvent. Because of the poor miscibility and 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 (Ribardiere et al., 1996). In this method the shape and the structure of the agglomerate

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depended strongly on the good solvent to poor solvent ratio and temperature difference between the two solvents (Espitailer et al., 1993). Kawashima et al., 1989, directly agglomerated the fine crystals of antibacterial drug crystals during the crystallization process without using any binder by using quasi emulsion solvent diffusion model. Poorly compressible crystals of acebutolol hydrochloride were agglomerated by the spherical crystallization technique (ESD) with a two-solvent system to improve the compressibility for direct tabletting (Kawashima et al., 1994 and 1995). Ueda et al., 1990 modified the spherical crystallization technique and developed a new agglomeration system i.e. ammonia diffusion system (ADS) which is applicable to amphoteric drug substances like enoxacin. In this method ammonia water act as bridging liquid and collects the fine crystals and transforms into spherical agglomerates. Puechagut et al., 1998, Gohel et al., 2003 has prepared agglomerated crystals of norfloxacin and ampicillin trihydrate by a spherical crystallization technique using the NH3 diffusion system (ADS). Sano et al., 1990, reported spherical crystallization of anti diabetic drug tolbutamide by neutralization method. The drug was dissolved in a sodium hydroxide solution and hydroxy propyl ethyl cellulose aqueous solution. Hydrochloric acid was added to neutralize the sodium hydroxide solution of tolbutamide and crystallize out the same. The bridging liquid was added drop wise followed by agglomeration of the tolbutamide crystals. The compressibility and tablettability of the spherical agglomerates were improved due to their increased plastic property and reduced adhesive property compared to the original crystals. The micromeritic properties of agglomerated crystals, such as flowability, packability and compactability were dramatically improved, resulting in successful tabletting. Most articles do not address the reasoning behind their solvent selection; Chow and Leung, 1996 have found some general rules to use as a starting point. There are few guidelines to select solvents and proceed further using different methods.

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Table 1: Suggested solvents and agglomeration methods for spherical agglomeration of various types of solids (Chow and Leung, 1996). SA= Spherical agglomeration, QESD = Quasi-emulsion solvent diffusion. Solid Continuous phase Bridging liquid Method Soluble in water Water-immiscible

Organic solvent 20% calcium chloride solution

SA

Soluble in organic solvents

Water Water-immiscible Organic solvent

SA

Soluble in water- miscible organic solvents

Saturated aqueous solution

Organic solvent mixture

QESD

In Soluble in water or any organic solvent

Water-immiscible Organic solvent

20% calcium chloride Solution+ binding agent

SA

7

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3. EXPERIMENTAL WORK 3.1 Materials 3.1.1 Benzoic acid Benzoic acid also called benzene carboxylic acid and phenyl carboxylic acid has the molecular formula C6H5COOH. It is a colorless crystalline solid. It has a molar mass of 122.123kg/k-mol, a crystal density 1266kg/m3, a melting point of 122.40C and a boiling point of 249.20C. The solubility of benzoic acid in pure water is 0.0034g of benzoic acid /g of solution and in ethanol 0.584g of benzoic acid /g solution at 250C (Othmer, 1993). Benzoic acid and its salts are used mainly as food preservative against yeast and mould. It is used to make a large number of chemicals such as phenol, benzoate plasticizers etc. Benzoic acid is also used as bacteriostatic and bactericidal agent and acts as antiseptic stimulant and also an ingredient in Whitfield’s ointment in treatment of ringworm. It is also used in cosmetics, resin preparation and plasticizers etc. Benzoic acid has been chosen for this study as a test substance because it gives needle like crystals which are difficult to handle and have poor tabletting properties. The solubility of benzoic acid in different solvents, crystal growth and habit, solvent effect and also influence of process conditions has explored in previous studies (Davey, 1978, Mersmann, 2001, Åslund and Rasmuson, 1992, Holmbäck and Rasmuson, 2002). In this study attempt was made to improve the mechanical properties of the benzoic acid by using spherical agglomeration method.

C

O

OH

Figure1. Benzoic acid, C6H5COOH. 3.1.2 Solvents Solvents used in this work were chosen based on the principle of spherical crystallization. As for simple spherical agglomeration the first solvent (ethanol) should have a good solubility with benzoic acid, the 2nd solvent (water) is a anti solvent which is used to crystallize the benzoic acid from the feed solution and the 3rd solvent (chloroform, toluene, heptane, cyclo hexane, pentane etc) will be immiscible with the 2nd solvent. This liquid can collect the small crystals and hold them together by forming liquid bridges between them.

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Many solvents were considered to use as bridging liquids based on the immiscibility with water. Those included are carbon tetrachloride, chloroform, cyclohexane, 1, 2-dichloroethane, diethyl ether, dimethyl formamide, dichloromethane, ethyl acetate, heptane, hexane, methyl-tert-butyl ether, pentane, toluene, methylene chloride and 2, 2, 4-trimethylpentane. Except chloroform, the most suitable solvents for industrial use were selected for spherical agglomeration. Table 1: Solvents used as bridging liquids (Murov, 1997) Solvents Boiling point (0C) Solubility in water

g/100gm of water at 200C

Chloroform 61.2 0.8 Toluene 110.6 0.05 Heptane 98.4 0.01 Cyclo hexane 80.7 <0.1 Pentane 36 0.04 Di ethyl ether 34.6 6.9 Ethyl acetate 77.1 8.3 3.2 Determination of the phase diagram The phase diagram of the three solvents (water – ethanol – toluene) at the temperature of 200C has investigated. Different ratios of poor solvent (water) and good solvent (ethanol) were mixed in conical flasks and a small quantity of iodine was added to enable observation of the phase separation point. Toluene was added carefully with a syringe and the mixture was shaken vigorously by hand. When phase separation occurred, a small violet droplet was clearly observed. Only the system water – ethanol – toluene has been investigated. 3.3 Spherical Crystallization 3.3.1 Apparatus A 250ml (6 cm in diameter) jacketed crystallizer, was used for spherical agglomeration, equipped with a three-blade marine propeller (2.5 cm in diameter), feeding pump (Yale Apparatus, syringe pump YA-12), and heat & refrigerated circulation unit (Julabo, FP50-HP). 3.3.2 Process A Benzoic acid is dissolved in ethanol at 400C to create a saturated solution and is fed to the syringe pump. This solution (at 200C) is pumped at the rate of 2.4ml/min onto the liquid surface of the poor solvent in the jacketed vessel which is at 200C. Then the solution is allowed to mature for 30 min. Agglomeration is initiated by introducing bridging liquid (chloroform) quickly by means of a syringe and the agitation is started. The solution is

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stirred for a certain time at the required speed. At the end of the experiment, the agglomerates are filtered and dried in an oven. This procedure follows that originally outlined by Kawashima et al., 1984, except for that the solution is gradually added to the poor solvent. By following this procedure, smaller agglomerates were formed when baffles were used (1-3 mm) than without baffles. 3.3.3 Process B Benzoic acid is dissolved in ethanol to create a solution at 400C. This solution can be kept at room temperature for a sufficient time without crystallizing. To this solution at room temperature is added the required amount of bridging liquid. By using the syringe pump the mixture is then fed onto the surface of the agitated aqueous phase in the crystallizer. The agitation is kept at 600 rpm for one hour, after which the agglomerates are filtered, washed with water and dried at room temperature. Chloroform, toluene, heptane, cyclo hexane, pentane, di ethyl ether, ethyl acetate were used as bridging liquids in this work. The operating parameters like stirring rate, initial concentration of solid are studied with the process A, chloroform as a bridging liquid. All other operating parameters like amount of bridging liquid, feeding rate, (toluene as bridging liquid), temperature (heptane as bridging liquid) and effect of different bridging liquids are studied by process B. The initial concentration of benzoic acid in the ethanol (Cs) 0.275, 0.325, 0.375 and 0.425; (g/ml). The stirring speed (N) 200, 400, 500, 600, 700, 800 and 900; (rpm). BSR 0.47, 0.58, 0.7, 0.8, 0.93, 1.05, 1.16, 1.28; (volume of bridging liquid / volume of solid). Feeding rate 1.7, 2.7, 3.9, 4.7 and 9.7; (ml/min). Temperature 5, 10, 20 and 30; (0C). The volume of solid is determined as the weight of solid originally dissolved divided by the density of Benzoic acid (1316kg/m3, Kirk –Othmer 1992). 3.4 Methods of characterization The influence of the processing parameters on size distribution, shape, compression strength and yield has been evaluated. 3.4.1 Sieving For determination of the particle size distribution the dried spherical agglomerates were sieved with woven wire test sieves of DIN 4188 standard. The sieve stack was shaken for

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10 min after which the fractions were weighed. The sieving was carried out in 10 min intervals until the weight of the different fractions remained constant. The particle size distribution is obtained from measuring the weight of the sieve fractions and are presented as cumulative over size mass distributions. 3.4.2 Particle morphology The structure of the agglomerates from each sieve fraction was examined by optical microscopy (Olympus SZX12). Agglomerates were also crushed for microscopic examination. 3.4.3 Strength analysis The mechanical strength of single agglomerates was determined by compression in materials – testing machine (Zwick Z2.5/TSIS), using a 10N load cell. As shown in figure 2 the agglomerate was placed and a gradually increasing load was applied to the agglomerate by a constant movement of the upper plane towards the lower plane with a speed of 0.5mm/min. About 100 to 150mg of agglomerates were poured into a cylindrical steel cup (8.2mm in diameter) and the powder bed was compressed.

Figure 2. Compression of the spherical agglomerates. The measured force (F) - displacement (l) curve (Figure 3) is recalculated into a stress (σ) - strain (ε) curve by Equations 1 and 2, using the diameter d measured for each particle.

⎟⎟⎠

⎞⎜⎜⎝

⎛=

4

2dFπ

σ (1)

dl

=ε (2)

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Figure 3. Force vs Displacement curves of sieve fraction 1000-1250µm: bridging liquid =toluene Benzoic acid conc. =0.375 g/ml, N= 600rpm, BSR =0.8, Feeding rate= 1.7ml/min. Here the normalization is done based on the initial cross sectional area. From each experiment and each sample 30 particles were compressed in the materials testing machine. For these particles average fracture force and fracture stress were found. Fracture force is defined as the force required for the first breakage. To find the average curves the data has been exported to Excel (Microsoft Office Excel 2003) and then to Origin (Origin 6.1) for processing. An average of the 30 stress-strain curves of each experimental sample was determined. The stress - strain curve for a single particle contains roughly 3000 values and for each sample an average curve is determined based on the data over the 30 particles. For each strain value an average stress value is calculated from the 30 curves by using the Origin module: “Averaging multiple curves, version 6”. When required the program interpolates or extrapolates data while calculating the average Y value. These data of the average curve were fitted to an exponential – non linear equation: σ = P1* EXP (P2+P3* ε +P4* ε 2) (3) by using Origin’s nonlinear least squares curve fitter which is very flexible for non linear fitting. P1, P2, P3, P4 are parameters to be determined in the fitting procedure. Repeated compression was done for the single agglomerates and bed of the particles to find the elasticity. Initial size (Hi) and the minimum size (Hc) of the agglomerate at maximum compression was determined, as well as the size of the particle after releasing the load (He) to determine the elastic recovery ratio (ER). The elastic recovery for each compression was calculated by equation 4.

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Elastic Recovery ratio = ⎥⎦⎤

⎢⎣⎡

−−

HcHiHcHe (4)

A compressibility index is defined to evaluate the compressibility of the bed of the particles.

Compressibility Index = p

p

ρρρ 0−

(5)

where pρ is the compressed density at the maximum load and 0ρ bulk density.

Here ρ = VM

V = Volume of cylinder = (6) Hr 24π 3.4.4 Yield Yield is defined as a ratio of the amount of final product obtained to the initial amount of benzoic acid into the system. Yield = Amount of final solid (7) Amount dissolved in the feed

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4. RESULTS AND DISCUSSION 4.1 Phase diagram The solubility of toluene in water - ethanol mixture at 200C was investigated and the results of the phase diagram are shown in figure 4. Since the spherical agglomeration depends on the amount of bridging liquid in the system it is useful to know the phase diagram. The experimental points defining the phase separation line shows the boundary between the two phase region (to the left of the line) and the one phase region (to the right of the line). The agglomeration experiments are performed at conditions where the final solvent composition in the crystallizer corresponds to the shaded area, just inside the two-phase region.

Figure 4. Solvent phase diagram for Ethanol, Water, Toluene. 4.2 Influence of operating parameters on particle size Physico-mechanical properties like particle size, morphology and strength were explored. Some of the results are discussed and shown here and further more could be found in papers listed in appendix. The operating parameters like stirring rate, initial concentration of solid are studied with the process A, chloroform as a bridging liquid. All other operating parameters like amount of bridging liquid, feeding rate, (toluene as bridging liquid), temperature (heptane as bridging liquid) and effect of different bridging liquids are studied by process B. 4.2.1 Stirring rate Stirring rate was studied for water–ethanol–chloroform system by process A. At 200 rpm single crystals, at 400 rpm irregular agglomerates and at 900 rpm a paste were formed. The spherical agglomerates were obtained only in the range of 500 – 800 rpm. With

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increasing stirring rate the size of the agglomerates increases up to about 600 rpm as shown in figure 5. A lower stirring rate reduces the rate of particle collision and a higher stirring rate increases agglomerate disruption.

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r Siz

e (%

)

500600700800

Figure 5. Change in particle size distribution with stirring rate (rpm): (Benzoic acid conc. =0.375 g/ml, BSR =0.93). 4.2.2 Initial concentration The initial concentration of solid was evaluated with process A using chloroform as bridging liquid. The agglomerate size increases with increasing initial solute concentration as shown in figure 6. With low initial solute concentration, more fines were found. This is in agreement with Blandin et al., 2003, reported that the final size of the agglomerates at first increases with increasing initial solute concentration and then reaches a plateau.

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e(%

)0.2750.3250.3750.425

Figure 6. Change in particle size distribution with dissolved amount of benzoic acid (g/ml) (N=600 rpm, BSR=0.93). 4.2.3. Amount of bridging liquid The amount of bridging liquid is the most important parameter and there is a critical range of BSR outside of which spherical agglomerates are not formed. For the system (water- ethanol- toluene) the critical range of BSR was found to be 0.47 - 1.16. The maximum measurable size of agglomerates was found at BSR=1.16. However, the mean size of the particles from the experiments with BSR equal to 1.05 and 1.16, are in the range of 2 to 5 mm, which are too large to be properly characterized by the sieving set used. Above BSR=1.16 the material remained as a paste and particles are heterogeneous in size. Below BSR=0.47 the agglomerates are very small in size and irregular in shape. Blandin et al., 2003, suggested for the salicylic acid, using chloroform as bridging liquid, BSR should be in the range of 0.35 to 0.5, in order to produce spherical agglomerates. Using toluene as bridging liquid the size of the agglomerates was increased with increasing BSR as shown in figure 7. According to Kawashima et al., 1982, with increasing BSR the probability of cohesion of particles increases which leads to larger agglomerates. Subero et al., 2006, showed the agglomerate mean size to increase with BSR squared, and this dependence can also correlate the data shown in figure 8.

17

0

0.2

0.4

0.6

0.8

1

0 500 1000 1500 2000

Particle Size (µm)

Cum

ulat

ive

over

siz

e 0.470.580.70.80.93

Figure 7. Influence of BSR on product particle size distribution, Benzoic acid conc. = 0.375 g/ml, N= 600rpm, feeding rate=1.7ml/min.

0

500

1000

1500

2000

0.35 0.55 0.75 0.95 1.15

BSR

Agg

lom

erat

e m

ean

size

(µm

)

Figure 8. Influence of BSR on product particle mean size, Benzoic acid conc. = 0.375 g/ml, N= 600rpm, feeding rate=1.7ml/min.

18

4.2.4 Feeding rate Using process B and toluene as bridging liquid spherical agglomeration of benzoic acid was carried out at different feeding rates and the size distribution of the product particles is shown in figure 9. At high feeding rate the product particle size becomes lower. Feed flow rate influences the rate of generation of super saturation and hence also the level of super saturation. An increased flow rate shortens total processing time and hence reduces time for agglomeration and breakage. This result is in agreement with the results of Sang et al., 2006, and Kawashima et al., 1982.

0

0.2

0.4

0.6

0.8

1

0-450

450-6

30

630-8

00

800-1

000

1000

-1250

1250

-1400

1400

-1600

1600

-2000

2000

Sieve size (µm)

Cum

ulat

ive

over

siz

e

1.72.73.74.79.7

Figure 9. Influence of feeding rate (ml/min) on product particle size distribution, Benzoic acid conc. = 0.375 g/ml, BSR= 0.93, N= 600rpm. 4.2.5 Temperature With heptane as bridging liquid and using process B, the size of the particles decreases with increasing temperature (figure 10). At low (50C) temperature the particles are much bigger than at higher temperature (300C). At low temperatures the solubility of benzoic acid and of bridging liquid is low so the available bridging liquid is more hence the particles have an opportunity to grow bigger size agglomerates.

19

0

0.2

0.4

0.6

0.8

1

0-250

250-4

50

450-6

30

630-8

00

800-1

000

1000

-1250

1250

-1400

1400

-1600

1600

-2000

2000

Sieve Size (µm)

Cum

ulat

ive

unde

r siz

e

5102030

Figure 10. Influence of temperature on product particle size distribution: Benzoic acid conc. = 0.375 g/ml, N= 600rpm, feeding rate=1.7ml/min, at 50C: BSR = 0 .97 & at 10, 20, 300C: BSR = 0.86. 4.2.6 Bridging liquid Size distribution of the particles with different bridging liquids at 200C and 50C are given in figures 11 and 12 respectively. As shown in figures there is a difference in size distribution of the particles based on the bridging liquid used. When Toluene is used as bridging liquid, particles are larger compared to other solvents used as bridging liquid. As a result of interfacial tension effects and capillary forces, the bridging liquid adhere the crystals to one another (Kawashima et al., 1984). As good wettability (small angle of contact) is precondition for agglomeration with capillary forces (Alderborn and Nyström 1996), difference in wettability of different bridging liquids to benzoic acid crystals may be a cause of different properties of the particles.

20

0

0.2

0.4

0.6

0.8

1

0-280

280-4

50

450-6

30

630-8

00

800-1

000

1000

-1250

1250

-1400

1400

-1600

1600

-2000

2000

Sieve Size (µm)

Cum

ulat

ive

unde

r siz

e

CyclohexaneHeptaneChloroformToluene

Figure 11. Influence of bridging liquid on product particle size distribution at 200C: Benzoic acid conc. = 0.375 g/ml, N= 600rpm, feeding rate=1.7ml/min, BSR= (cyclo hexane 1.06, chloroform, toluene and heptane 0.93).

0

0.2

0.4

0.6

0.8

1

1.2

0-280

280-4

50

450-6

30

630-8

00

800-1

000

1000

-1250

1250

-1400

1400

-1600

1600

-2000

2000

Sieve size (µm)

Cum

ulat

ive

unde

r siz

e

Cyclo hexanePentaneHeptane

Figure 12. Influence of bridging liquid on product particle size distribution at 50C: Benzoic acid conc. = 0.375 g/ml, N= 600rpm, feeding rate=1.7ml/min BSR= (cyclo hexane 1.14, pentane 1.22, heptane 0.97).

21

4.2.7. Operating procedures Spherical agglomeration by using chloroform as bridging liquid was done for both processes A and B. At comparable conditions, 85% of the product could be agglomerated by process B while only 60% could be done by process A (figure 13). Particles prepared from the process B seem to be more favorable for production of spherical agglomerates than process A.

0

10

20

30

40

50

60

70

80

90

100

0-280

280-4

50

450-6

30

630-8

00

800-1

000

1000

-1250

1250

-1400

1400

-1600

1600

Sieve size (µm)

Cum

ulat

ive

over

siz

e (%

)

Figure 13. Product particle size distributions ■ process A, ▲ process B (Benzoic acid conc. =0.375 g/ml, BSR =0.93, Stirring rate= 600rpm. 4.3. Influence of operating parameters on particle morphology 4.3.1 Operating procedures Observations by optical microscopy show that the agglomerates are formed by elementary particles tightly piled up as shown in figure 14a. When observed, the crushed agglomerates (figure 14b) show that they are made up of smaller crystals grown together.

22

Figure 14. Particle morphology of a) spherical agglomerate b) crushed spherical agglomerate size 800-1000 µm (50x). Benzoic acid conc. = 0.375 g/ml, N=600 rpm, BSR = 0.93. As shown in figure 15 and 16 the particle characteristics vary depending on sieve fraction, using chloroform as bridging liquid with process A and process B respectively. The two smallest sieve fractions (0-450 µm in size, 15a and 15b) are dominated by irregularly shaped agglomerates, consisting of thin and needle like crystals. Particles in sieve fraction 450-630 µm (15c) are still irregular in shape, but these agglomerates appear to be denser.

a b

c d e

Figure 15. Particle morphology of different sieve fractions from process A: a) 0-280 µm (32x), b) 280-450 µm (32x), c) 450-630 µm (20x), d)630-800 µm (25x), e) 800-1000 µm (12.5x). Benzoic acid conc. = 0.375 g/ml, N=600 rpm, BSR = 0.93.

23

Above particle size 630 µm, the dense agglomerates start to be spherical. This is illustrated in figure 15e showing particles from sieve fraction 800-1000 µm. In reality some of the spherical agglomerates are some-what tabular and not completely spherical. All the particles prepared by process A have same morphology for the operating parameters (stirring rate, concentration of solid) studied. The sphericity of the larger particles by process B is quite good they are looking completely spherical (figure 16e). All examined samples exhibit a similar visual change from thin and irregularly shaped agglomerates to more dense and spherical agglomerates with increasing particle size. Only particles >630 µm are spherical agglomerates. The smaller particles are either thin, irregularly shaped agglomerates or fragments from larger agglomerates. From this one can observe that particles prepared by process B shows improved particle morphology compared to process A.

a b

c d e

Figure 16. Particle morphology of different sieve fractions from process B: a) 0-280 µm (32x), b) 0280-450 µm (25x), c) 450-630 µm (25x), d)630-800 µm (25x), e) 800-1000 µm (20x). Benzoic acid conc. = 0.375 g/ml, N=600 rpm, BSR = 0.93. 4.3.2 Amount of bridging liquid The characteristics of the particles prepared with process B, using toluene as bridging liquid varies according to BSR. As shown in figure 17 at low BSR particles from small sieve fraction are irregular in shape and needle like crystals.

24

a b Figure 17. Particle morphology of different sieve fractions: a. 0-125µm.50x, b. 800-1000µm.25x; Benzoic acid conc. = 0.375 g/ml, N=600 rpm, BSR = 0.47, feeding rate =1.7ml/min. Larger sieve fraction particles are denser but still irregular in shape and are like cauliflower. As the BSR increases the particles tend to be more spherical in shape and at higher BSR (0.93), the particles are completely spherical (figure 18).

a b

c d Figure 18. Influence of BSR on particle morphology of dominating sieve fraction: a. BSR = 0.58, 800-1000µm, b. BSR = 0.7, 1000-1250µm, c. BSR = 0.8, 1000-1250µm; 20x, d. BSR= 0.93, 1400-1600µm.20x, Benzoic acid conc. = 0.375 g/ml, N=600 rpm, feeding rate =1.7ml/min

25

4.3.3. Bridging liquid The morphology of the particles prepared with different bridging liquids and from process B are given and compared. As shown in figure 19 the particles prepared from cyclo-hexane as bridging liquid at 200C, are denser but only higher sieve fraction particles are spherical, at 50C the particles are denser but not spherical at low sieve fraction (figure 20). Using heptane as bridging liquid at 200C, low sieve fraction (0-280µm) particles are single needle like crystals and 280-630µm the particles are denser and only upper fraction of the particles are spherical (figure 21) where as the particles prepared at 50C are completely spherical (figure 22). At 50C pentane as bridging liquid there is no single or irregular particles all are denser and spherical (figure 23). The particles from the experiment where toluene used as bridging liquid are completely spherical agglomerates (figure 18). Chloroform as bridging liquid only the particles >630 µm are spherical agglomerates (figure 16). From this observation one can say that bridging liquid has significant effect on particle morphology.

a) 280-450µm.32x b) 1400-1600µm.16x Figure 19. Particle morphology of different sieve fractions at 200C: Benzoic acid conc. = 0.375 g/ml, N=600 rpm, BSR (cyclo hexane) = 0.94, feeding rate =1.7ml/min

a) 250-800µm.20x b) 2000µm.12.5x Figure 20. Particle morphology of different sieve fractions at 50C: Benzoic acid conc. = 0.375 g/ml, N=600 rpm, BSR (cyclo hexane) = 1.14, feeding rate =1.7ml/min

26

a) 0-280µm.40x b) 1250-1400µm.20x Figure 21. Particle morphology of different sieve fractions at 200C: Benzoic acid conc. = 0.375 g/ml, N=600 rpm, BSR (heptane) = 0.93, feeding rate =1.7ml/min

a) 250-630µm.32x b) 1250-1400µm.20x Figure 22. Particle morphology of different sieve fractions at 50C: Benzoic acid conc. = 0.375 g/ml, N=600 rpm, BSR (Heptane) = 0.97, feeding rate =1.7ml/min

a) 800-1000µm.25x b) 2000µm.12.5x Figure 23. Particle morphology of different sieve fractions at 50C: Benzoic acid conc. = 0.375 g/ml, N=600 rpm, BSR (pentane) = 1.22, feeding rate =1.7ml/min

27

4.4. Influence of operating parameters on particle mechanical strength 4.4.1. Compression behavior Particles prepared by process A and chloroform are compressed without any obvious breakages as shown in figure 24. The stress–strain curves are J shaped (Mai and Atkins, 1989), and there is a spread among the particles from the same sample. However, this is expected, partly because the surface area was taken as the cross sectional area of a spherical particles having the diameter as the initial height of the particle when the compression starts. In addition Ålander et al., 2003, experienced a significant distribution in the different properties of the agglomerated particles from an experiment. The spherical agglomerates of benzoic acid are easily deformed to a strain of at least 50% without any particle fracture. From process B, using toluene as bridging liquid the compression curves are given in figures 25 and 26. At low BSR = 0.58 the particles deformed with no major breakages same as the particles from chloroform as bridging liquid (figure 25). The small peaks represent the rearrangement of crystallites and possibly fracture of individual crystalline bridges. At low BSR =0.47 the dominating size fraction is 180-250µm which unfortunately is too small for a proper strength analysis.

Figure 24. Stress – Strain curve of sieve fraction 800-1000µm: Benzoic acid conc. =0.375 g/ml, N= 600rpm, BSR=0.93, Feeding rate= 1.7ml/min

28

Figure 25. Stress – Strain curve of sieve fraction 450-630µm: Benzoic acid conc. =0.375 g/ml, N= 600rpm, BSR=0.58, Feeding rate= 1.7ml/min

0.0 0.2 0.4 0.6 0.80.00

0.25

0.50

Stre

ss (M

Pa)

Strain

Figure 26. Stress vs. strain curves for individual particles from sieve fraction 1600-2000 µm: Benzoic acid conc. = 0.375 g/ml, N=600 rpm, BSR = 0.93, Feeding rate=1.7ml/min At higher BSR the compression curve exposes a more clear fracture peak, as illustrated by figure 26 showing the behavior of particles from the upper sieve fraction for BSR=0.93. This also reveals that there is a considerable spread among the particles from same sample. The force increases until a major breakdown of the agglomerate occurs showing the first peak and a sudden drop in the force, then force again increases until further breakage as the compression continued. The curves further show that there is an initial “linear” relation between stress and strain from which we can estimate an elastic

29

modulus, and then a plateau region with a nearly constant flow stress to a large strain. After the plateau region the flow stress increased rapidly because of densification. Same trend is seen for open cellular alloys (Yamada et al., 1999). 4.4.2 Agglomerate strength Average fracture force and fracture stress of the 30 particles from process B, toluene as bridging liquid, different experiments and different sieve fractions are shown in Table 2. The fracture stress is increased with increasing BSR. As expected, among the particles from the same experiment the fracture force increases with increasing particle size, and this goes hand in hand with the findings of Antonyuk et al., 2005. However, the corresponding fracture stress decreases with increasing product particle size (figure 27). The average fracture force of the particles increases with increasing feeding rate, while the fracture stress is unchanged until the feeding rate is so high that the mean size decreases. As the feeding rate increases the agglomerates on the average tend to become smaller and stronger. Table 2: Average fracture force and fracture stress values for different sieve fraction and at different feeding rates and BSR (Benzoic acid conc. =0.375 g/ml, Stirring rate 600rpm,)

Feeding rate (ml/min)

BSR Sieve size (µm)

Fracture Force (N)

Fracture stress (MPa)

1.7 0.58 450-630 0.05 0.218 1.7 0.7 800-1000 0.1138 0.239 1.7 0.8 1000-1250 0.179 0.289 1.7 0.93 800-1000 0.2024 0.3768 1.7 0.93 1000-1250 0.2625 0.2954 1.7 0.93 1400-1600 0.3470 0.2318 1.7 0.93 1600-2000 0.4842 0.2012 4.7 0.93 1000-1250 0.3114 0.29 4.7 0.93 1400-1600 0.3873 0.2583 9.7 0.93 1000-1250 0.3354 0.3779

30

0.15

0.2

0.25

0.3

0.35

0.4

800-1000 1000-1250 1400-1600 1600-2000

Sieve Size (µm)

Frac

ture

Str

ess

(MPa

)

Figure 27: Fracture stress for different sieve fractions: Benzoic acid conc. =0.375 g/ml, N= 600rpm, BSR=0.93, Feeding rate= 1.7ml/min As shown in figure 28, fracture stress differs with bridging liquid at 200C. Among all the bridging liquids used, the particles show high fracture stress when toluene is used as bridging liquid and have low value of fracture stress when heptane is used as bridging liquid. In figure 29, at 50C, the effect of bridging liquid was shown and higher fracture stress for cyclo-hexane was observed. Different bridging liquids have the different wetting properties with the benzoic acid and therefore give different properties to the particles. Pentane has very low boiling point so the experiments were conducted only at 50C for this bridging liquid. Effect of temperature on fracture stress was studied for heptane as bridging liquid (figure 30). The temperature has significant effect on the strength of the particles. Fracture stress is increasing with decreasing temperature. At low temperatures the particles are much stronger than at high temperatures, it may be because of the low solubility of benzoic acid and bridging liquid with decreasing temperature.

31

0

0.05

0.1

0.15

0.2

0.25

0.3

1 2 3 4

Bridging liquid

Frac

ture

Str

ess

(MPa

)

Figure 28. Fracture stress for different bridging liquids at 200C: Benzoic acid conc. =0.375 g/ml, N= 600rpm, Feeding rate= 1.7ml/min: 1. Chloroform (BSR = 0.93); 2. Toluene (BSR=0.93); 3. Heptane (BSR=0.93); 4. Cyclo hexane (BSR= 0.94).

0

0.1

0.2

0.3

0.4

0.5

0.6

1 2 3

Bridging liquid

Frac

ture

Str

ess

(MPa

)

Figure 29. Fracture stress for different bridging liquids at 50C: Benzoic acid conc. =0.375 g/ml, N= 600rpm, feeding rate= 1.7ml/min: 1. Pentane (BSR=1.22); 2. Cyclo hexane (BSR= 1.14); 3. Heptane (BSR=0.97).

32

0

0.05

0.1

0.15

0.2

0.25

0.3

1 2 3

Frac

ture

Str

ess

(MPa

)

Figure 30. Fracture stress at different temperatures: Benzoic acid conc. =0.375 g/ml, N= 600rpm, feeding rate= 1.7ml/min: 1) at 50C (BSR= 0.97); 2) 100C (BSR=0.86); 3) 200C (BSR=0.86). 4.4.3. Average stress-strain curves Parameters of non linear equation for the average stress –strain curves (figure 31) at different agitation rates and chloroform as bridging liquid, with process A are given in Table 3. Chi2 has very low value and R2 is close to 1, which shows that equation 3 is a very good model to represent the data of stress vs. strain for benzoic acid. Since this is a non linear fit and the data for 30 curves exhibit a significant variation, we are not able to estimate the confidence interval of the parameter values. Table 3: Parameters of nonlinear equation for different stirring speeds (Benzoic acid conc.=0.375g/ml, BSR =0.93) Stirring speed(rpm)

P1 P2 P3 P4 R^2 Chi^2 (χ2)

500 0.02319 -1.57261 8.19706 -0.84194 0.995 0.00042

600 0.06799 -0.34116 3.53567 2.63484 0.998 0.00186

700 0.08862 -0.08739 -1.93621 7.54353 0.997 0.00043

800 0.13354 0.37768 -3.65623 8.14615 0.994 0.00307

33

0.0 0.2 0.4 0.6 0.8 1.00

1

2

3

4

5St

ress

(MPa

)

Strain

500rpm 600rpm 700rpm 800rpm

Figure 31. Average Stress – Strain for different stirring rates from process A (Benzoic acid conc. =0.375 g/ml, BSR =0.93) With process B using toluene as bridging liquid, the influence of the feeding rate on the average stress – strain curves are shown in figure 32. This size fraction (1000-1250µm) is the dominating fraction in the experiment of 9.7 ml/min, while it is the second most dominating in the other two experiments.

0

0.4

0.8

1.2

1.6

0 0.2 0.4 0.6 0.8 1

Strain

Stre

ss (M

Pa) 1.7

4.79.7

Figure 32. Influence of feeding rate (ml/min) on average stress – strain curve for 1000-1250µm sieve fraction: Benzoic acid conc. =0.375 g/ml, N= 600rpm, BSR=0.93

34

4.4.4. Elastic Recovery and Compressibility In figure 33, 34 and 35 the compression characteristics of single agglomerates and beds of agglomerates are presented and compared. The data is normalized against the initial height before compression (figure 33). For single particle compression the maximum force used 0.5N, which corresponds to a maximum stress of 0.43MPa based on the particle cross sectional area. For a bed of the particles the maximum force used is 10N, corresponds to a maximum stress of 0.19 MPa based on total bed cross sectional area. In the first compression-release cycle, the single agglomerate using toluene as the bridging liquid only recover 41 µm out of the 1012 µm total compression, i.e. only 4 % and elastic recovery for chloroform is 3%, cyclo hexane is 2%, heptane is 2% and for pentane is 4% (Table 4). The particles are clearly plastic in their compression. In comparison, the elastic recovery of a bed of particles from an experiment using toluene as bridging liquid is 28 %, and the corresponding values for chloroform is 21 %, cyclo hexane 16%, heptane 27%, pentane 32%. In the second compression-release cycle the elastic recovery in all cases is much higher (figure 34 & 35). Several single particles and beds of particles from different sieve fractions have been studied, and overall the result is that for single particles the initial elastic recovery is below 4% and for beds it is 15 - 30%. It is generally believed that to create strong compacts (Sandell et al 1993), either a plastic deformation or an extensive fragmentation of the particles must occur.

0

0.2

0.4

0.6

0.8

1

1 2 3 4 5 6 7 8 9 10

Sample

Nor

mal

ized

siz

e

Figure 33. First Compression of the agglomerates from sieve fraction 1000-1250µm: Chloroform: 1) single agglomerate 2) bed of the particles; Toluene: 3) single agglomerate 4) bed of particles, Cyclohexane: 5) single agglomerate 6) bed of particles, Heptane: 7) single agglomerate 8) bed of particles, Pentane: 9) single agglomerate 10) bed of particles Benzoic acid conc. = 0.375 g/ml, N=600 rpm, BSR = 0.93 Hi/Hi; Hc/Hi; He/Hi As shown in table 4 the compressibility for bed of particles is in the range of 30-50%. When chloroform is used as bridging liquid, the particles show high compressibility. A weak and easily compressed bed is signified by a high value of the compressibility index.

35

Even though the load used for bed compression is very low the particles have shown a significant compressibility. Table 4. Compression of the agglomerates from process B and different bridging liquids

Sample Hi = Initial Size (µm)

Hc= Final Size (µm)

He=Recovered Size (µm)

Elastic Recovery ratio (%)

Compre ssibility (%)

Single 1244 276 308 3 Chloroform

Bed 4842 2583.5 3066 21 46.6

Single 1216 349.5 391 4 Toluene Bed 4856 3230.5 3690 28 33.5

Single 1089 412 425 2 Cyclo hexane Bed 6787 4185 4608 16 38.4

Single 1081 260.5 280 2.4 Heptane Bed 7204 4076 4928 27 43.4

Single 1314 486.5 522 4.2 Pentane

Bed 5914 3965.5 4594 32 32.9

0

20

40

60

80

100

120

1 2 3 4

Compression run

Elas

tic R

ecov

ery

(%)

ChloroformTolueneCyclohexaneHeptanePentane

Figure 34. Repeated compression of the single agglomerates from sieve fraction 1000-1250µm: Benzoic acid conc. = 0.375 g/ml, N=600 rpm, BSR = 0.93

36

0

20

40

60

80

100

120

1 2 3 4 5

Compression run

Elas

tic R

ecov

ery

(%)

ChloroformTolueneCyclohexaneHeptanePentane

Figure 35. Repeated compression of the particle bed from sieve fraction 1000-1250µm: Benzoic acid conc. = 0.375 g/ml, N=600 rpm, BSR = 0.93 4.4.5. Calculation schematic over changing particle shape The strongly J-shaped curves that are obtained in the present work deserve to be analyzed more properly to distinguish at least approximately the influence of the changing cross-sectional area from the actual behavior of the compact itself. According to the definition, stress is the force per unit area: σ = F/A, The simplest approach is to define A as the initial cross-sectional area prior to the application of the load. This is called engineering stress or nominal stress and is used quite often. However, for samples that undergo a substantial change in cross-sectional area during the compression, this does not describe the properties of the material – the true stress. For small degrees of deformation, the change in cross-sectional area is small and the difference between nominal and true stress is insignificant. However, for the large deformation of the particles of the present work this is not the case. For an initially spherical particle this problem is even more complex since early during the compression the load is unlikely to be evenly distributed across the particle cross-section area. In the first approximate approach below we assume the volume of the particle to be constant, even though we realize that this is not necessarily true. We then treat the particle as a cylindrical body that increases its diameter as the compression increases:

Volume of the sphere: V = 6

3dπ (8)

Cross sectional area: rh

V = rh

d6

30π

(9)

37

Here d0 is initial particle size and hr is the current particle vertical linear dimension, i.e. the distance between the upper and the lower punch. This approximation is expected to have its greatest validity towards the end of the compression. However, according to equation. 9, the cross sectional area is quite large also in the beginning, which is probably less realistic. Hence, in the second approach we assumed the particle to be compressed as is illustrated in Fig. 36. We assume the cross sectional area for calculation of the stress to increase from zero at the initial contact between the upper punch and the particle. When the particle is compressed the cross sectional area is visualized as the surface remaining after removal of a segment (S). The area is determined by assuming that the volume of imaginary particle equals two times the volume of the segment plus the volume of the initial particle: Volume of the particle = 2 (Volume of segment) + Volume of initial particle

623

32

6

30

23 dhdhd πππ

+⎥⎦

⎤⎢⎣

⎡⎟⎠⎞

⎜⎝⎛ −= (10)

Where d = 2r, 2h equals the linear compression of the particle and d0 is the original diameter of the real particle.

Since

rhhd += 2 (11) We may derive at:

066

30

322 =−++

dhhhhh rrr (12)

Figure 36. Calculation schematic over changing particle shape upon compression

38

Since d0 is known from the first moment of the compression and is obtained from the experiment at each moment, can be calculated from equation. 12, and d from equation 11.

)(thr

)(th

Calculate the segment radius (a) from figure 36

21

22 aar +=

hra −=1

21

2 ara −= (13) then the segment cross sectional area ( ) and the stress by equation (1). In this way for all the points the stress was calculated and stress vs. strain was drawn. In figure 37 the 1st curve represents the normalized curve based on initial cross sectional area, 2nd is when the volume of the particle is assumed as constant and initial area is replaced with current area , 3rd one based on the gradual change of the particle shape. Obviously the true stress is much lower than the engineering stress towards the end of the compression.

2aπ

Figure 37. Single particle stress strain curves: 1) based on initial cross sectional area; 2) based on gradually changing area assuming constant particle volume according to equation 8; 3) gradually changing area based on shape changing according to equation 12.

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4.5 Influence of temperature on yield With decreasing temperature the amount of the product obtained increased as shown in table 5. At all the temperatures, even though the drowning ratio (water/ethanol) used is same but the crystallized amount is higher at low temperatures. Because of the low solubility of benzoic acid in water and the available bridging liquid was enough for agglomeration of the particles, lead to more yield. The agglomerated amount of benzoic acid is also changed with the solvent used as bridging liquid. Obtained product is higher with the cyclo hexane as bridging liquid. Table 5: Influence of temperature on the yield: Benzoic acid conc. = 0.375 g/ml, N= 600rpm, feeding rate=1.7ml/min Bridging liquid

Temperature (0C) Yield (%)

Heptane 5 84

Heptane 10 81

Heptane 20 78

Heptane 30 73

Cyclo hexane 5 87

Cyclo hexane 20 71

Pentane 5 78

Toluene 20 84

Chloroform 20 85

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5. INDUSTRIAL OUT LOOK Many of the compounds gives irregular, thin and needle like crystals having a high surface area to volume ratio, but are quite difficult to handle. Downstream handling of such particles will be difficult, tedious and expensive. In pharmaceutical industries tablets are the most popular and convenient dosage form of drugs. As an intermediate step in making tablets out of the powder often granulation is used, by which the powder is converted into a material with improved handling properties. However, the granulation step is time consuming, and adds additional costs to the manufacturing, that could be avoided if the micro crystals are agglomerated directly in the crystallization step using spherical crystallization method. Spherical agglomeration can reduce the number of unit operations; it combines several processes into one step, including synthesis, crystallization, separation and agglomeration. Spherical agglomerates gain favorable downstream processing characteristics (filtering, drying and handling etc) combined with desirable bioavailability properties. These agglomerates can be directly compressed into a tablet form without intermediate processing steps. With the direct compression the processing of these particles will be easier, which means less equipment and space, lower labour costs, less processing time, and lower energy consumption. In order to scale up a process for spherical agglomeration the first step is to choose the solvents, method and then design of the experiments to know the effect of operating conditions. For the spherical agglomeration in most of the cases, the solvent system can be easily selected, but there is no clear principle to choose the solvents. Until and unless the solvents are tried it is hard to say if the solvents work well or not to get the good product. Some times it is like trial and error method and the chances are more to waste the solvents. As mentioned in this work the spherical agglomeration can be done with different solvents, one can always go for the environment friendly and cheaper solvents. By this method, for many of the compounds mostly water being one of the solvents, it is possible to reduce the production cost. Next step would be to select the optimal process for the production of spherical agglomerates and then validate the process for reproducibility. The spherical agglomerates were produced in different methods and one valid method was selected to manufacture the spherical agglomerates. But still there is a uncertainty about adding the bridging liquid. In this work some problems are still unsolved like the difference in behavior of the particles with different bridging liquids used. The solubility of benzoic acid in the solvent mixture of different systems is not known. The range of operation for spherical agglomeration is very narrow, it depends mostly on the amount of bridging liquid, but vessel design, mixing, solid loading and characteristics of the solid which include particle size, size distribution and wetting properties are also important. So when operating in large scale one should be very careful to control all the operating parameters to avoid the unwanted properties of the particles. Effect of the operating conditions like amount of bridging liquid, agitation rate, feeding rate,

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temperature and concentration of solid etc on spherical agglomeration are studied and reported in the literature. In this method the final solution is always a mixture of 2 or 3 solvents which will be complicated for the industries to handle with. For the benzoic acid agglomeration the final solution is mixture of water, ethanol and some traces of bridging liquid can be separated by using for example distillation. The yield (solid recovery from the initial amount of solid fed into the system) is found to be up to 87%, but the productivity is found to be very less (about 5 to 10%). So far the productivity is low which is considered as a main problem in this work. Mechanism behind the spherical agglomeration is also not completely known even though the literature is available and more work has to be done to know the mechanism properly. In this area so far no literature is found about the scaling up of the process. Still this is a method that seems to have great potential, but much more work is required before the mechanisms are fully understood and process can be efficiently and safely designed. The spherical agglomerates prepared using this method possesses good physico mechanical properties like compressibility, packability and flowability that improve mixing, filling and tabletting. This method can be applied not only to the pharmaceuticals but also for the preparation of food colorants and selective recovery of fine mineral and in protein crystallization.

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6. CONCLUSIONS Spherical agglomerates of benzoic acid have been successfully prepared by drowning out crystallization in ethanol-water, using different solvents as the bridging liquid (chloroform, toluene, cyclo hexane, pentane, heptane, ethyl acetate and diethyl ether). The selection of solvent as bridging liquid seems to have an influence on the characteristics of the crystalline product. With ethyl acetate and diethyl ether no spherical agglomerates are formed. Spherical agglomerates tend to appear mainly in the larger size fractions, and within each sieve size fraction the properties of the agglomerates vary significantly. The agglomerate size increases with increasing initial solute concentration and increasing agitation rate up to a certain level. It was found that particle size significantly decreased with increasing feeding rate and temperature. The results show that the amount of bridging liquid is critical for the formation of agglomerates. Particle morphology improved with increasing amount of bridging liquid and no change has been found with change in feeding rate. Particles are looking completely spherical from toluene as bridging liquid when higher amount of bridging liquid used. The choice of the bridging liquid, amount of bridging liquid, feeding rate and the temperature change has significant influence on the mechanical strength of the particles. When toluene is used as bridging liquid the particles start to have fracturing behavior with increasing amount of bridging liquid. Fracture stress was increasing with increasing amount of bridging liquid and feeding rate. For the same conditions applied, the fracture force of the particles is increased with increase in the particle size. At 50C cyclo hexane as bridging liquid and at 200C toluene as bridging liquid the particle shows higher fracture stress than the particles when other solvents are used as bridging liquid. Low elastic recovery and high compressibility of the single particles and of a bed of particles reveals that the spherical agglomerates prepared in this work are expected to be favorable for direct tabletting. Stress was calculated by taking into consideration of change in cross sectional area during compression prior to change in particle shape. The stress - strain curves are J-shaped and are well correlated by an exponential – polynomial equation. Over all the particles prepared when the bridging liquid is initially mixed to the solution and fed under agitation have improved physico mechanical properties than, when being added to the agitated solution afterwards.

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ACKNOWLEDGMENTS This work has been carried out at the division of Transport Phenomena, Institution of Chemical Engineering and Technology, School of Chemical Science and Engineering, Royal Institute of Technology (KTH), Stockholm, Sweden. IKF is greatly acknowledged for the financial support. I am thankful to: I would like to express my sincere gratitude to my supervisor, Professor Åke Rasmuson, for his commitment, great patience, support, encouragement and guidance through out this work. Andreas Fischer (Department of Chemistry, Inorganic Chemistry) for the great help with the X-ray diffraction analysis. Jan Appelqvist for the kind help during my work at the department. Past and present colleagues at the institution for their knowledge experience and help. Special thanks to Dr. Eva Ålander for the suggestions and help during the work. My parents, brother, sisters and friends for giving me strength and love. Finally my husband Kranthi Kumar Thati for his support, care, love and encouragement.

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