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Particle Engineering by Spherical Crystallization:Mechanisms and Influence of Process Conditions
KTH, School of Chemical Science and Engineering (CHE), Chemical Engineering and Technology, Transport Phenomena.
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Spherical agglomerates of benzoic acid crystals have been successfully prepared by drowning-out crystallization in three solvent partial miscible mixtures. Benzoic acid is dissolved in ethanol, bridging liquid is added and this mixture is fed to the agitated crystallizer containing water as the anti-solvent. Small crystals are produced by crystallization of the substance, and the crystals are agglomerated through the action of the bridging liquid. Different solvents: chloroform, toluene, heptane, pentane, cyclohexane, ethyl acetate and diethyl ether are chosen as bridging liquids, all being low soluble in water and showing good wettability for benzoic acid crystals. The influence of process conditions such as concentration of solute, agitation rate, feeding rate, amount of bridging liquid and temperature on the properties of benzoic acid spherical agglomerates, are investigated. Different sets of experiments were accomplished to track how the properties of the particles gradually change during the normal spherical crystallization experiment. Other sets of experiments were performed to examine the influence of agitation and process time for agglomeration. The product properties such as particle size distribution, morphology and mechanical strength have been evaluated. The mechanical strength of single agglomerates has been determined by compression in a materials testing machine, using a 10 N load cell. Compression characteristics for single agglomerates are compared with the data on bed compression.

The present study shows that the bridging liquid has significant influence on the product properties, using diethyl ether and ethyl acetate no agglomerates are formed. Using any of the other five solvents (chloroform, toluene, heptane, pentane, and cyclohexane) spherical agglomerates are formed, as long as a sufficient amount of the bridging liquid is used. Using cyclohexane as bridging liquid at 5°C and toluene at 20°C the particles are larger compared to particles formed at other conditions. The highest particle fracture stress is obtained by using toluene as the bridging liquid at 5 and 20°C. Particle morphology depends on the bridging liquid used and the particles are completely spherical when toluene and pentane are used as bridging liquids.

Different process parameters are found to have a significant influence on the physico-mechanical properties of the product. The range of operation for spherical agglomeration is relatively narrow and only at certain conditions spherical agglomerates are produced. With increasing amount of bridging liquid the particle size and strength increase and the morphology improves. Particle size decreases and the fracture force increases with increasing feeding rate, but the morphology remains unchanged. For all the solvents, the particle size and the fracture stress increase with decreasing temperature. For four of the solvents the morphology improves with decreasing temperature. For cyclohexane the result is the opposite, in that the particles are spherical at 20°C and irregular at 5°C. Spherical agglomerates of benzoic acid, both as single particles as well as in the form of a bed, have a high compressibility and low elastic recovery, properties that are favorable for direct tabletting.

As the feed solution is supplied to the crystallizer the amount of benzoic acid that can crystallize actually does crystallize fairly rapidly. Hydrodynamics are responsible for bringing particles together for the agglomeration. Experiments reveal that during the gradual addition of the feed to the agitated aqueous solution, both particle size and particle number increases. It is clear from the experiments that not only further addition of feed solution leads to larger product particles but also continued agitation. Along the course of the process the properties of the particles change gradually but substantially. By continued agitation, the particle porosity decreases, density, strength gradually increases and also the spherical shape develops gradually. 

 

 

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology , 2011. , ix, 76 p.
Series
Trita-CHE-Report, ISSN 1654-1081 ; 2011:30
Keyword [en]
Spherical agglomeration; Benzoic acid; Solubility; Phase diagram; Physico- mechanical properties (size distribution, particle morphology and crushing strength, elastic recovery, compressibility)
National Category
Chemical Engineering
Identifiers
URN: urn:nbn:se:kth:diva-32519ISBN: 978-91-7415-953-0OAI: oai:DiVA.org:kth-32519DiVA: diva2:410938
Public defence
2011-05-09, E1, Lindstedtsvägen 3, Stockholm, 10:00 (English)
Opponent
Supervisors
Note
QC 20110419Available from: 2011-04-19 Created: 2011-04-15 Last updated: 2011-04-19Bibliographically approved
List of papers
1. Spherical Crystallization of benzoic acid
Open this publication in new window or tab >>Spherical Crystallization of benzoic acid
2008 (English)In: Internation Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 348, no 1-2, 61-69 p.Article in journal (Refereed) Published
Abstract [en]

This paper deals with the development of a method for spherical crystallization of benzoic acid. Benzoic acid is dissolved in ethanol, water is used as anti-solvent and chloroform is used as bridging liquid. After an introductory screening of different methods, the influence of the amount of the bridging liquid, the solute concentration and the stirring rate is investigated. The product particle characterization includes the particle size distribution, morphology and strength. The mechanical strength of single agglomerates has been determined by compression in a materials testing machine, using a 10 N load cell. It is found that favourable properties are obtained if the bridging liquid is added during the crystallization. Larger and stronger well-shaped agglomerates are formed. The stress-strain curves are J-shaped with no clear fracturing of the particles, and are well correlated by an exponential-polynomial equation.

Keyword
crystallization, spherical agglomeration, benzoic acid, physico-mechanical properties (size distribution, particle morphology, compression strength)
National Category
Chemical Engineering
Identifiers
urn:nbn:se:kth:diva-7885 (URN)10.1016/j.ijpharm.2007.07.006 (DOI)000253036600009 ()2-s2.0-37249086046 (ScopusID)
Note
Uppdaterad från accepted till published(20101119) QC 20101119Available from: 2008-01-10 Created: 2008-01-10 Last updated: 2011-04-19Bibliographically approved
2. On the mechanisms of formation of spherical agglomerates
Open this publication in new window or tab >>On the mechanisms of formation of spherical agglomerates
2011 (English)In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 42, no 4, 365-379 p.Article in journal (Refereed) Published
Abstract [en]

Spherical agglomerates of benzoic acid have been successfully prepared by semi-batch, agitated vessel, drowning-out crystallization in water-ethanol-toluene mixtures. Benzoic acid is dissolved in ethanol, toluene is added and this mixture is fed at constant rate to the agitated crystallizer containing water. The influence of the amount of bridging liquid and the feeding rate on the product particle size distribution, morphology, and mechanical compression characteristics have been investigated. Compression characteristics for single agglomerates are compared with data on bed compression. With increasing amount of bridging liquid the particle size and strength increases and morphology improves. Particle size decreases and the fracture force increases with increasing feeding rate but the morphology remains unchanged. Using toluene as opposed to chloroform as the bridging liquid leads to improved product properties. Experiments have also been performed to reveal the mechanisms of the formation of the agglomerates. The results show that along the course of the process the properties of the particles change gradually but substantially. Particle size and number increases along with increasing feed. The spherical shape does not appear immediately but develops gradually, and is shown to be very much the result of the agitation of the slurry.

Keyword
Spherical agglomeration, Benzoic acid, Solubility phase diagram, Physico mechanical properties, Size distribution, Particle morphology and crushing strength
National Category
Chemical Engineering
Identifiers
urn:nbn:se:kth:diva-32630 (URN)10.1016/j.ejps.2011.01.001 (DOI)000289027100007 ()2-s2.0-79952281300 (ScopusID)
Note
QC 20110419Available from: 2011-04-19 Created: 2011-04-18 Last updated: 2011-04-19Bibliographically approved
3. Particle engineering by spherical agglomeration of benzoic acid
Open this publication in new window or tab >>Particle engineering by spherical agglomeration of benzoic acid
(English)Manuscript (preprint) (Other academic)
Identifiers
urn:nbn:se:kth:diva-32766 (URN)
Note
QC 20110418Available from: 2011-04-19 Created: 2011-04-19 Last updated: 2011-04-19Bibliographically approved
4. Solubility of Benzoic Acid in Pure Solvents and Binary Mixtures
Open this publication in new window or tab >>Solubility of Benzoic Acid in Pure Solvents and Binary Mixtures
2010 (English)In: Journal of Chemical and Engineering Data, ISSN 0021-9568, E-ISSN 1520-5134, Vol. 55, no 11, 5124-5127 p.Article in journal (Refereed) Published
Abstract [en]

The solubility of benzoic acid has been determined in ethanol, toluene, heptane, cyclohexane, pentane, and chloroform and in binary mixtures of ethanol + heptane and ethanol toluene, in the temperature range of (278.15 to 323.15) K. The solubility is high in ethanol, reasonably high in chloroform, lower in toluene, and quite low in the remaining three pure solvents. In the binary mixtures the solubility of benzoic acid increases with increasing concentration of ethanol. The solubility of benzoic acid increases with increasing temperature.

National Category
Chemical Engineering
Identifiers
urn:nbn:se:kth:diva-27368 (URN)10.1021/je100675r (DOI)000284017600088 ()2-s2.0-78449271910 (ScopusID)
Note
QC 20101213Available from: 2010-12-13 Created: 2010-12-13 Last updated: 2011-04-19Bibliographically approved

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