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RESEARCH PAPER
Crystal Habit Modifications ofIbuprofen and Their Physicomechanical
Characteristics
H A Garekani1 F Sadeghi1 A Badiee1
S A Mostafa2 and A R Rajabi-Siahboomi2
1School of Pharmacy Mashhad University of Medical SciencesMashhad Iran2School of Pharmacy and Chemistry Liverpool John MooresUniversity Liverpool UK
ABSTRACT
Ibuprofen was crystallized from methanol ethanol isopropanol and hexane atsimilar conditions Marked differences in crystal habit of the samples obtainedfrom these solvents were observed The samples crystallized from methanol andethanol had a polyhedral crystal habit while those from hexane were needlelikeThose from isopropanol were elongated crystals X-ray powder diffraction(XPD) and differential scanning calorimetry (DSC) studies confirmed thatthese samples were structurally similar therefore polymorphic modificationswere ruled out The results showed that crystal habit modification had a greatinfluence on the mechanical properties (compressibility flow rate and bulk den-sity) of ibuprofen crystals Samples obtained from methanol and ethanol exhib-ited the highest bulk density and the best flow rate while those from hexaneshowed the lowest bulk density and the worst flow rate The samples obtainedfrom ethanol exhibited the best compression forcehardness profiles and thoseobtained from hexane produced the softest tablets
Corresponding author Current address Dr Ali R Rajabi-Siahboomi Technical Director Colorcon Limited FlagshipHouse Victory Way Crossways Dartford Kent DA2 6QD UK Fax thorn44 (0) 1322 627200 E-mail asiahboomicolorconcouk
Drug Development and Industrial Pharmacy 27(8) 803ndash809 (2001)
803
Copyright 2001 by Marcel Dekker Inc wwwdekkercom
ORDER REPRINTS
Key Words Bulk density Compression Crystal habit Crystallization Flowrate Ibuprofen
INTRODUCTION
Crystallization from a solution is widely used forthe purification of drugs during their final stagesof manufacture The crystallization technique canchange such crystal properties as habit polymor-phism and crystal size The extent of these changesdepends on the crystallization conditions such asthe presence of impurities type of solvent and cool-ing rate (1)
The crystal habit of a drug is an important vari-able in pharmaceutical manufacturing Differentcrystal forms of a particular drug possess differentplanes and thus differ not only in their specific sur-face but also in their free surface energy Thereforethey may exhibit different physicomechanical prop-erties (2) Properties such as dissolution ratepowder flow and compressibility which are ofpharmaceutical interest can differ for differenthabits of the same drug (3ndash5) Attempts to changethe morphology and the workability of drugsusing alternative crystallization procedures includemodification of the crystal habits of drugs suchas paracetamol (5) hexamethylmelamine (6) andnitrofurantoin (47)
The aim of this study was to investigate the influ-ence of controlled crystallization of ibuprofen fromdifferent solvents on crystal habit and the physico-mechanical properties of the different crystal habits
EXPERIMENTAL
Ibuprofen powder was obtained from BootsLimited (UK) Analytical grades of absolute ethanolBP methanol isopropanol and hexane wereobtained from Merck Limited (Germany)
Crystallization Procedures
Different quantities of ibuprofen powder 100 g80 g 70 g or 17 g were added to 50ml of methanolethanol isopropanol or hexane respectively in a200-ml round-bottom flask The flasks were placedin a water bath at 45C 1C and stirred until aclear solution was produced then the temperature
of the water bath was reduced to 40C When the
flasks were cooled to 40C 100mg of ibuprofen
powder (lt60 mm particle size) were added to all
flasks to act as nuclei (seeds) Then the flasks were
placed in a water bath at 25C and the temperature
was gradually reduced to 0C over 200min (Fig 1)
while stirring For maximum crystal recovery the
samples were allowed to stand at 0C for 2 h
The cooling rates for all flasks were the same The
crystals were then collected by filtration using a sin-
tered glass No 3 funnel under vacuum and dried at
40C for 24 h The dried crystals were stored in a
desiccator at room temperature before use
Figure 1 Cooling curve of crystallization medium over200min
804 Garekani et al
ORDER REPRINTS
Crystal Shape and Size
The particle shape and size of the crystals werestudied using an optical microscope (Olympusmodel BX60 Japan) and a scanning electron micro-scope (Jeol model JSM T200 Tokyo Japan) Thespecimens were mounted on a metal stub withdouble-sided adhesive tape and coated undervacuum with gold in an argon atmosphere prior toobservation For all crystals the length and thewidth of a minimum of 100 crystals were deter-mined and their distributions were reported
Differential Scanning Calorimetry
A differential scanning calorimeter (DSC) modelDSC7 (Perkin Elmer Baconsfield UK) controlledby a Perkin Elmer TAC7 was used The equipmentwas calibrated using indium and zinc Samples
of ibuprofen crystals (4ndash6mg) were heated at10C min1 in crimped aluminum pans under nitro-gen atmosphere The melting point onsets the melt-ing point peaks and the enthalpies of fusion of thesamples were determined
X-ray Powder Diffraction
For X-ray powder diffraction (XPD) X-ray dif-fraction spectra of ibuprofen samples were obtainedusing an X-ray diffractometer (Siemens Germany)The cavity of the metal sample holder was filledwith the ground sample powder and then smoothedwith a spatula The spectra of samples wereobtained using a scanning rate of 1 2y min1 overthe range 10 to 42 2y
Measurement of Powder Flow
The flow rate of ibuprofen crystals was deter-mined using a flow meter (Flowdex Erweka GDT
(c) (d)
Figure 2 Photomicrographs of ibuprofen crystallized from (a) methanol (b) ethanol (c) isopropanol and (d) hexane(magnification 140)
(a) (b)
Crystal Habit Modifications of Ibuprofen 805
ORDER REPRINTS
Germany) For each sample 10 g were pouredthrough the funnel of the flow meter the timerequired for all the sample to pass from the funnelwas automatically measured by the instrument Theresults are reported as grams per second
In addition the bulk densities of the crystalswere determined by gently placing equal weights ofeach crystal in a volumetric cylinder and theirvolumes were measured Their bulk densities werecalculated by dividing the weights by their volume
Compression
Compression of the crystals was carried out usingan instrumented single-punch tableting machine(Korsch EK-72 Germany) fitted with 10-mm flat-faced punches The die wall was prelubricated with4ww magnesium stearate in acetone before eachcompression Sieved fractions (gt250 mm) of ibupro-fen samples were hand filled into the die Fourtablets (400mg) were produced at compressionforces of 5 10 15 20 25 30 or 35 kN
The crushing strength of the tablets was mea-sured using an Erweka tablet hardness tester(Erweka GDT)
RESULTS AND DISCUSSION
Figure 2 shows the micrographs of ibuprofencrystals obtained from different solvents The mor-phology of the crystals obtained may be describedas follows From methanol or ethanol polyhedralor grainlike crystals were obtained from isopro-panol we obtained elongated crystals and fromhexane needlelike crystals were the result
Marshal and York (7) and Garti and Tibika (8)reported that nitrofurantoin particles crystallizedfrom formic acid were tabular while those crystal-lized from a mixture of formic acid and water wereneedlelike Davey et al (9) demonstrated that crys-tallization of succinic acid from water or isopro-panol produced platelike and needlelike habitsrespectively Garekani et al (5) reported that para-cetamol crystallized from water or ethanol producedprismatic polyhedral crystals while those obtainedfrom a mixture of water and ethanol were thin andplatelike In this study the influence of crystalliza-tion solvent and crystallization method on habitmodification of ibuprofen crystals was clearlyshown
The solvent influences crystal growth from dis-solved drug molecules through various mechanismsSolvent properties such as its polarity molecularweight and interaction with the dissolved drug arefactors that may influence the direction in whichcrystals grow on the nuclei The formation of differ-ent habits of ibuprofen crystals therefore may beattributed to interactions of ibuprofen and thesecrystallization solvents
Figure 3 shows the particle size distributions ofibuprofen crystals obtained from different solventsThere is a large difference between the size distribu-tion of these samples This indicates strong inhibi-tion of crystal growth at some crystal faces andinducement to more growth at other faces for theneedlelike (from hexane) crystals compared to thepolyhedral or grainlike crystals (from ethanol ormethanol)
The DSC results (Table 1) indicate that there isno significant difference (Tuckyrsquos test Plt05)
Figure 3 Size distributions of ibuprofen crystallized fromdifferent solvents (a) length of particles and (b) width of
particles
806 Garekani et al
ORDER REPRINTS
between the mean values of the melting point onsetsand melting points of the ibuprofen samples crystal-lized from different solvents indicating that nopolymorphic modification occurred during the crys-tallization in these particlesThe X-ray powder diffraction spectra of samples
are presented in Fig 4 X-ray powder diffractionhas been a useful method for determining the pres-ence of polymorphs or crystal habit modificationsin drug crystals In general for two forms of crys-tals when the patterns (ie peak positions) areidentical they have the same internal structures
Figure 4 The X-ray powder diffraction spectra of ibuprofen crystallized from (a) methanol (b) ethanol (c) hexane and (d)isopropanol
Table 1
Melting Point Onset Melting Peak Temperatures andEnthalpy of Fusion Hf for Ibuprofen Crystallized from
Different Solvents
Crystallized Melting Point Melting Hffrom Onset (C) Peak (C) (Jg)
Methanol 757 774 1356Ethanol 758 778 1259
Isopropanol 759 778 1208Hexane 757 771 1137
Crystal Habit Modifications of Ibuprofen 807
ORDER REPRINTS
whereas if the patterns are different then the crys-tals have different internal structures and are poly-morphs (10) Here all the samples exhibited spectrawith similar peak positions (2y values) (Fig 4)Therefore the presence of different polymorphs ofibuprofen in these samples was ruled out Howeverthe relative intensities of their XPD peaks weremodified This was attributed to the markedly dif-ferent crystal habits of the samples Therefore therelative abundance of the planes exposed to theX-ray source would have been altered producingthe variations in the relative intensities of the peaks(57) or this may be due to differences in the crystalsizes (11)
Table 2 shows the values of bulk densities of ibu-profen samples crystallized from different solventsThe samples crystallized from ethanol and methanolhad the highest bulk densities followed by the sam-ples obtained from isopropanol and those obtainedfrom hexane These differences may be related totheir markedly different crystal habits leading todifferent contact points and frictional and cohesiveforces between the crystals These factors affect thesliding of the particles against each other leading todifferent packing geometry and thus different bulkdensities Table 2 also shows that crystals obtainedfrom ethanol and methanol exhibited the bestflow rate while those from hexane had the leastflow These results are in agreement with the mor-phology and bulk density data that polyhedral crys-tals with higher bulk densities exhibited a betterflow rate
The effect of compression force on the crushingstrength of tablets made from ibuprofen crystals isillustrated in Fig 5 Two-way analysis of varianceshowed that there were significant differencesbetween the crushing strength of tablets made from
different samples of ibuprofen (Plt05) The sam-
ples obtained from ethanol exhibited the best com-pression properties and at each compression forcethe tablets had higher crushing strength than tabletsmade from other samples
Figure 5 also indicates that with increasing com-pression force beyond 10 kN the crushing strengthfor all the samples decreased except for the samplesobtained from ethanol This may indicate that ibu-
profen crystallized from ethanol underwent moreplastic and less elastic deformation during compres-sion than other samples
It has been reported that poor compressibility of
drug crystals can be attributed to the presence ofcrystal faces that give poor adhesion to other crys-tals and the absence of the faces that are requiredfor optimal adhesion (12) Here for the needlelikeand grainlike ibuprofen crystals (Fig 2) the
relative abundance of the different faces within thecrystals was modified This can affect the inter-particulate bonding between these crystals resulting
Figure 5 The effect of compression force on the crushingstrengths of tablets made from ibuprofen crystallized fromdifferent solvents
Table 2
Bulk Densities and Flow Rates for Ibuprofen Crystallizedfrom Different Solvents
Crystallized Bulk Flowfrom Density SD (gml) Rate SD (gS)
Methanol 045 003 44 05Ethanol 045 001 52 07Isopropanol 042 003 36 06
Hexane 029 005 0 0
808 Garekani et al
ORDER REPRINTS
in different compression properties In a similarstudy Garekani et al (5) reported that thin plate-like crystals of paracetamol underwent more elasticdeformation during compaction than polyhedralcrystals
CONCLUSIONS
Crystallization of ibuprofen from ethanol metha-nol isopropanol and hexane caused marked modi-fications to its crystal habit The samples obtainedfrom ethanol and methanol were polyhedral orgrainlike and those obtained from isopropanol andhexane were elongated and needlelike respectivelyIt was shown that these samples were structurallysimilar and polymorphic modifications wereruled outCrystal habit had a great influence on the
mechanical properties of ibuprofen Samplesobtained from ethanol and methanol exhibited thebest flow rate The samples obtained from ethanolalso exhibited better compression properties withhigher crushing strength than other samples Thesamples obtained from hexane showed the worstflow and compression properties
ACKNOWLEDGMENT
The financial support for this study was obtainedfrom the Vice Chancellor of Research of MashhadUniversity of Medical Sciences Iran
REFERENCES
1 Mullin JW In Crystallisation 3rd Ed Butterworths
Oxford UK 19932 Huttenrauch R Modification of Starting Materials
to Improve Tableting Properties Pharm Ind 1983 4
435ndash440
3 York P Solid-State Properties of Powders in theFormulation and Processing of Solid Dosage FormsInt J Pharm 1983 14 1ndash28
4 Marshall PV York P The Compaction Propertiesof Nitrofurantoin Samples Crystallised from DifferentSolvents Int J Pharm 1991 67 59ndash65
5 Garekani HA Ford JL Rubinstein MH
Rajabi-Siahboomi AR Formation and CompressionProperties of Prismatic Polyhedral and Thin Plate-likeCrystals of Paracetamol Int J Pharm 1999 187
77ndash89
6 Gonda I Abd-El Khalik AF Britten AZ SolidForms of Hexamethylmelamine J Pharm Pharma-col 1985 37 117P
7 Marshall PV York P Crystallisation SolventInduced Solid-State and Particulate Modifications ofNitrofurantoin Int J Pharm 1989 55 257ndash263
8 Garti N Tibika F Habit Modifications of
Nitrofurantoin Crystallised from Formic AcidMixtures Drug Dev Ind Pharm 1980 6 379ndash398
9 Davey RJ Mullin JW Whiting MJL Habit
Modification of Succinic Acid Crystals Grownfrom Different Solvents J Cryst Growth 1982 58304ndash312
10 Byrn SR In Solid-State Chemistry of Drugs
Academic Press New York 1982 29ndash59
11 El-Said Y Effect of Co-solvents on Water Contentand Physical Properties of AcetaminophenCrystallised from Aqueous Solutions STP Pharma
Sci 1995 5 232ndash237
12 Milosovitch G Direct Compression of Tablets DrugCosm Ind 1963 5 557ndash669
13 Marshall K Compression and Consolidation of
Powder Solids In Theory and Practice of IndustrialPharmacy 3rd Ed Lachman L Liberman HAKanig JL Eds Lea and Febiger Philadelphia
1986 66ndash89
14 York P Particle Slippage and Rearrangement DuringCompression of Pharmaceutical Powders J PharmPharmacol 1978 30 6ndash10
Crystal Habit Modifications of Ibuprofen 809
Order now
Reprints of this article can also be ordered at
httpwwwdekkercomservletproductDOI101081DDC100107243
Request Permission or Order Reprints Instantly
Interested in copying and sharing this article In most cases US Copyright Law requires that you get permission from the articlersquos rightsholder before using copyrighted content
All information and materials found in this article including but not limited to text trademarks patents logos graphics and images (the Materials) are the copyrighted works and other forms of intellectual property of Marcel Dekker Inc or its licensors All rights not expressly granted are reserved
Get permission to lawfully reproduce and distribute the Materials or order reprints quickly and painlessly Simply click on the Request PermissionReprints Here link below and follow the instructions Visit the US Copyright Office for information on Fair Use limitations of US copyright law Please refer to The Association of American Publishersrsquo (AAP) website for guidelines on Fair Use in the Classroom
The Materials are for your personal use only and cannot be reformatted reposted resold or distributed by electronic means or otherwise without permission from Marcel Dekker Inc Marcel Dekker Inc grants you the limited right to display the Materials only on your personal computer or personal wireless device and to copy and download single copies of such Materials provided that any copyright trademark or other notice appearing on such Materials is also retained by displayed copied or downloaded as part of the Materials and is not removed or obscured and provided you do not edit modify alter or enhance the Materials Please refer to our Website User Agreement for more details
ORDER REPRINTS
Key Words Bulk density Compression Crystal habit Crystallization Flowrate Ibuprofen
INTRODUCTION
Crystallization from a solution is widely used forthe purification of drugs during their final stagesof manufacture The crystallization technique canchange such crystal properties as habit polymor-phism and crystal size The extent of these changesdepends on the crystallization conditions such asthe presence of impurities type of solvent and cool-ing rate (1)
The crystal habit of a drug is an important vari-able in pharmaceutical manufacturing Differentcrystal forms of a particular drug possess differentplanes and thus differ not only in their specific sur-face but also in their free surface energy Thereforethey may exhibit different physicomechanical prop-erties (2) Properties such as dissolution ratepowder flow and compressibility which are ofpharmaceutical interest can differ for differenthabits of the same drug (3ndash5) Attempts to changethe morphology and the workability of drugsusing alternative crystallization procedures includemodification of the crystal habits of drugs suchas paracetamol (5) hexamethylmelamine (6) andnitrofurantoin (47)
The aim of this study was to investigate the influ-ence of controlled crystallization of ibuprofen fromdifferent solvents on crystal habit and the physico-mechanical properties of the different crystal habits
EXPERIMENTAL
Ibuprofen powder was obtained from BootsLimited (UK) Analytical grades of absolute ethanolBP methanol isopropanol and hexane wereobtained from Merck Limited (Germany)
Crystallization Procedures
Different quantities of ibuprofen powder 100 g80 g 70 g or 17 g were added to 50ml of methanolethanol isopropanol or hexane respectively in a200-ml round-bottom flask The flasks were placedin a water bath at 45C 1C and stirred until aclear solution was produced then the temperature
of the water bath was reduced to 40C When the
flasks were cooled to 40C 100mg of ibuprofen
powder (lt60 mm particle size) were added to all
flasks to act as nuclei (seeds) Then the flasks were
placed in a water bath at 25C and the temperature
was gradually reduced to 0C over 200min (Fig 1)
while stirring For maximum crystal recovery the
samples were allowed to stand at 0C for 2 h
The cooling rates for all flasks were the same The
crystals were then collected by filtration using a sin-
tered glass No 3 funnel under vacuum and dried at
40C for 24 h The dried crystals were stored in a
desiccator at room temperature before use
Figure 1 Cooling curve of crystallization medium over200min
804 Garekani et al
ORDER REPRINTS
Crystal Shape and Size
The particle shape and size of the crystals werestudied using an optical microscope (Olympusmodel BX60 Japan) and a scanning electron micro-scope (Jeol model JSM T200 Tokyo Japan) Thespecimens were mounted on a metal stub withdouble-sided adhesive tape and coated undervacuum with gold in an argon atmosphere prior toobservation For all crystals the length and thewidth of a minimum of 100 crystals were deter-mined and their distributions were reported
Differential Scanning Calorimetry
A differential scanning calorimeter (DSC) modelDSC7 (Perkin Elmer Baconsfield UK) controlledby a Perkin Elmer TAC7 was used The equipmentwas calibrated using indium and zinc Samples
of ibuprofen crystals (4ndash6mg) were heated at10C min1 in crimped aluminum pans under nitro-gen atmosphere The melting point onsets the melt-ing point peaks and the enthalpies of fusion of thesamples were determined
X-ray Powder Diffraction
For X-ray powder diffraction (XPD) X-ray dif-fraction spectra of ibuprofen samples were obtainedusing an X-ray diffractometer (Siemens Germany)The cavity of the metal sample holder was filledwith the ground sample powder and then smoothedwith a spatula The spectra of samples wereobtained using a scanning rate of 1 2y min1 overthe range 10 to 42 2y
Measurement of Powder Flow
The flow rate of ibuprofen crystals was deter-mined using a flow meter (Flowdex Erweka GDT
(c) (d)
Figure 2 Photomicrographs of ibuprofen crystallized from (a) methanol (b) ethanol (c) isopropanol and (d) hexane(magnification 140)
(a) (b)
Crystal Habit Modifications of Ibuprofen 805
ORDER REPRINTS
Germany) For each sample 10 g were pouredthrough the funnel of the flow meter the timerequired for all the sample to pass from the funnelwas automatically measured by the instrument Theresults are reported as grams per second
In addition the bulk densities of the crystalswere determined by gently placing equal weights ofeach crystal in a volumetric cylinder and theirvolumes were measured Their bulk densities werecalculated by dividing the weights by their volume
Compression
Compression of the crystals was carried out usingan instrumented single-punch tableting machine(Korsch EK-72 Germany) fitted with 10-mm flat-faced punches The die wall was prelubricated with4ww magnesium stearate in acetone before eachcompression Sieved fractions (gt250 mm) of ibupro-fen samples were hand filled into the die Fourtablets (400mg) were produced at compressionforces of 5 10 15 20 25 30 or 35 kN
The crushing strength of the tablets was mea-sured using an Erweka tablet hardness tester(Erweka GDT)
RESULTS AND DISCUSSION
Figure 2 shows the micrographs of ibuprofencrystals obtained from different solvents The mor-phology of the crystals obtained may be describedas follows From methanol or ethanol polyhedralor grainlike crystals were obtained from isopro-panol we obtained elongated crystals and fromhexane needlelike crystals were the result
Marshal and York (7) and Garti and Tibika (8)reported that nitrofurantoin particles crystallizedfrom formic acid were tabular while those crystal-lized from a mixture of formic acid and water wereneedlelike Davey et al (9) demonstrated that crys-tallization of succinic acid from water or isopro-panol produced platelike and needlelike habitsrespectively Garekani et al (5) reported that para-cetamol crystallized from water or ethanol producedprismatic polyhedral crystals while those obtainedfrom a mixture of water and ethanol were thin andplatelike In this study the influence of crystalliza-tion solvent and crystallization method on habitmodification of ibuprofen crystals was clearlyshown
The solvent influences crystal growth from dis-solved drug molecules through various mechanismsSolvent properties such as its polarity molecularweight and interaction with the dissolved drug arefactors that may influence the direction in whichcrystals grow on the nuclei The formation of differ-ent habits of ibuprofen crystals therefore may beattributed to interactions of ibuprofen and thesecrystallization solvents
Figure 3 shows the particle size distributions ofibuprofen crystals obtained from different solventsThere is a large difference between the size distribu-tion of these samples This indicates strong inhibi-tion of crystal growth at some crystal faces andinducement to more growth at other faces for theneedlelike (from hexane) crystals compared to thepolyhedral or grainlike crystals (from ethanol ormethanol)
The DSC results (Table 1) indicate that there isno significant difference (Tuckyrsquos test Plt05)
Figure 3 Size distributions of ibuprofen crystallized fromdifferent solvents (a) length of particles and (b) width of
particles
806 Garekani et al
ORDER REPRINTS
between the mean values of the melting point onsetsand melting points of the ibuprofen samples crystal-lized from different solvents indicating that nopolymorphic modification occurred during the crys-tallization in these particlesThe X-ray powder diffraction spectra of samples
are presented in Fig 4 X-ray powder diffractionhas been a useful method for determining the pres-ence of polymorphs or crystal habit modificationsin drug crystals In general for two forms of crys-tals when the patterns (ie peak positions) areidentical they have the same internal structures
Figure 4 The X-ray powder diffraction spectra of ibuprofen crystallized from (a) methanol (b) ethanol (c) hexane and (d)isopropanol
Table 1
Melting Point Onset Melting Peak Temperatures andEnthalpy of Fusion Hf for Ibuprofen Crystallized from
Different Solvents
Crystallized Melting Point Melting Hffrom Onset (C) Peak (C) (Jg)
Methanol 757 774 1356Ethanol 758 778 1259
Isopropanol 759 778 1208Hexane 757 771 1137
Crystal Habit Modifications of Ibuprofen 807
ORDER REPRINTS
whereas if the patterns are different then the crys-tals have different internal structures and are poly-morphs (10) Here all the samples exhibited spectrawith similar peak positions (2y values) (Fig 4)Therefore the presence of different polymorphs ofibuprofen in these samples was ruled out Howeverthe relative intensities of their XPD peaks weremodified This was attributed to the markedly dif-ferent crystal habits of the samples Therefore therelative abundance of the planes exposed to theX-ray source would have been altered producingthe variations in the relative intensities of the peaks(57) or this may be due to differences in the crystalsizes (11)
Table 2 shows the values of bulk densities of ibu-profen samples crystallized from different solventsThe samples crystallized from ethanol and methanolhad the highest bulk densities followed by the sam-ples obtained from isopropanol and those obtainedfrom hexane These differences may be related totheir markedly different crystal habits leading todifferent contact points and frictional and cohesiveforces between the crystals These factors affect thesliding of the particles against each other leading todifferent packing geometry and thus different bulkdensities Table 2 also shows that crystals obtainedfrom ethanol and methanol exhibited the bestflow rate while those from hexane had the leastflow These results are in agreement with the mor-phology and bulk density data that polyhedral crys-tals with higher bulk densities exhibited a betterflow rate
The effect of compression force on the crushingstrength of tablets made from ibuprofen crystals isillustrated in Fig 5 Two-way analysis of varianceshowed that there were significant differencesbetween the crushing strength of tablets made from
different samples of ibuprofen (Plt05) The sam-
ples obtained from ethanol exhibited the best com-pression properties and at each compression forcethe tablets had higher crushing strength than tabletsmade from other samples
Figure 5 also indicates that with increasing com-pression force beyond 10 kN the crushing strengthfor all the samples decreased except for the samplesobtained from ethanol This may indicate that ibu-
profen crystallized from ethanol underwent moreplastic and less elastic deformation during compres-sion than other samples
It has been reported that poor compressibility of
drug crystals can be attributed to the presence ofcrystal faces that give poor adhesion to other crys-tals and the absence of the faces that are requiredfor optimal adhesion (12) Here for the needlelikeand grainlike ibuprofen crystals (Fig 2) the
relative abundance of the different faces within thecrystals was modified This can affect the inter-particulate bonding between these crystals resulting
Figure 5 The effect of compression force on the crushingstrengths of tablets made from ibuprofen crystallized fromdifferent solvents
Table 2
Bulk Densities and Flow Rates for Ibuprofen Crystallizedfrom Different Solvents
Crystallized Bulk Flowfrom Density SD (gml) Rate SD (gS)
Methanol 045 003 44 05Ethanol 045 001 52 07Isopropanol 042 003 36 06
Hexane 029 005 0 0
808 Garekani et al
ORDER REPRINTS
in different compression properties In a similarstudy Garekani et al (5) reported that thin plate-like crystals of paracetamol underwent more elasticdeformation during compaction than polyhedralcrystals
CONCLUSIONS
Crystallization of ibuprofen from ethanol metha-nol isopropanol and hexane caused marked modi-fications to its crystal habit The samples obtainedfrom ethanol and methanol were polyhedral orgrainlike and those obtained from isopropanol andhexane were elongated and needlelike respectivelyIt was shown that these samples were structurallysimilar and polymorphic modifications wereruled outCrystal habit had a great influence on the
mechanical properties of ibuprofen Samplesobtained from ethanol and methanol exhibited thebest flow rate The samples obtained from ethanolalso exhibited better compression properties withhigher crushing strength than other samples Thesamples obtained from hexane showed the worstflow and compression properties
ACKNOWLEDGMENT
The financial support for this study was obtainedfrom the Vice Chancellor of Research of MashhadUniversity of Medical Sciences Iran
REFERENCES
1 Mullin JW In Crystallisation 3rd Ed Butterworths
Oxford UK 19932 Huttenrauch R Modification of Starting Materials
to Improve Tableting Properties Pharm Ind 1983 4
435ndash440
3 York P Solid-State Properties of Powders in theFormulation and Processing of Solid Dosage FormsInt J Pharm 1983 14 1ndash28
4 Marshall PV York P The Compaction Propertiesof Nitrofurantoin Samples Crystallised from DifferentSolvents Int J Pharm 1991 67 59ndash65
5 Garekani HA Ford JL Rubinstein MH
Rajabi-Siahboomi AR Formation and CompressionProperties of Prismatic Polyhedral and Thin Plate-likeCrystals of Paracetamol Int J Pharm 1999 187
77ndash89
6 Gonda I Abd-El Khalik AF Britten AZ SolidForms of Hexamethylmelamine J Pharm Pharma-col 1985 37 117P
7 Marshall PV York P Crystallisation SolventInduced Solid-State and Particulate Modifications ofNitrofurantoin Int J Pharm 1989 55 257ndash263
8 Garti N Tibika F Habit Modifications of
Nitrofurantoin Crystallised from Formic AcidMixtures Drug Dev Ind Pharm 1980 6 379ndash398
9 Davey RJ Mullin JW Whiting MJL Habit
Modification of Succinic Acid Crystals Grownfrom Different Solvents J Cryst Growth 1982 58304ndash312
10 Byrn SR In Solid-State Chemistry of Drugs
Academic Press New York 1982 29ndash59
11 El-Said Y Effect of Co-solvents on Water Contentand Physical Properties of AcetaminophenCrystallised from Aqueous Solutions STP Pharma
Sci 1995 5 232ndash237
12 Milosovitch G Direct Compression of Tablets DrugCosm Ind 1963 5 557ndash669
13 Marshall K Compression and Consolidation of
Powder Solids In Theory and Practice of IndustrialPharmacy 3rd Ed Lachman L Liberman HAKanig JL Eds Lea and Febiger Philadelphia
1986 66ndash89
14 York P Particle Slippage and Rearrangement DuringCompression of Pharmaceutical Powders J PharmPharmacol 1978 30 6ndash10
Crystal Habit Modifications of Ibuprofen 809
Order now
Reprints of this article can also be ordered at
httpwwwdekkercomservletproductDOI101081DDC100107243
Request Permission or Order Reprints Instantly
Interested in copying and sharing this article In most cases US Copyright Law requires that you get permission from the articlersquos rightsholder before using copyrighted content
All information and materials found in this article including but not limited to text trademarks patents logos graphics and images (the Materials) are the copyrighted works and other forms of intellectual property of Marcel Dekker Inc or its licensors All rights not expressly granted are reserved
Get permission to lawfully reproduce and distribute the Materials or order reprints quickly and painlessly Simply click on the Request PermissionReprints Here link below and follow the instructions Visit the US Copyright Office for information on Fair Use limitations of US copyright law Please refer to The Association of American Publishersrsquo (AAP) website for guidelines on Fair Use in the Classroom
The Materials are for your personal use only and cannot be reformatted reposted resold or distributed by electronic means or otherwise without permission from Marcel Dekker Inc Marcel Dekker Inc grants you the limited right to display the Materials only on your personal computer or personal wireless device and to copy and download single copies of such Materials provided that any copyright trademark or other notice appearing on such Materials is also retained by displayed copied or downloaded as part of the Materials and is not removed or obscured and provided you do not edit modify alter or enhance the Materials Please refer to our Website User Agreement for more details
ORDER REPRINTS
Crystal Shape and Size
The particle shape and size of the crystals werestudied using an optical microscope (Olympusmodel BX60 Japan) and a scanning electron micro-scope (Jeol model JSM T200 Tokyo Japan) Thespecimens were mounted on a metal stub withdouble-sided adhesive tape and coated undervacuum with gold in an argon atmosphere prior toobservation For all crystals the length and thewidth of a minimum of 100 crystals were deter-mined and their distributions were reported
Differential Scanning Calorimetry
A differential scanning calorimeter (DSC) modelDSC7 (Perkin Elmer Baconsfield UK) controlledby a Perkin Elmer TAC7 was used The equipmentwas calibrated using indium and zinc Samples
of ibuprofen crystals (4ndash6mg) were heated at10C min1 in crimped aluminum pans under nitro-gen atmosphere The melting point onsets the melt-ing point peaks and the enthalpies of fusion of thesamples were determined
X-ray Powder Diffraction
For X-ray powder diffraction (XPD) X-ray dif-fraction spectra of ibuprofen samples were obtainedusing an X-ray diffractometer (Siemens Germany)The cavity of the metal sample holder was filledwith the ground sample powder and then smoothedwith a spatula The spectra of samples wereobtained using a scanning rate of 1 2y min1 overthe range 10 to 42 2y
Measurement of Powder Flow
The flow rate of ibuprofen crystals was deter-mined using a flow meter (Flowdex Erweka GDT
(c) (d)
Figure 2 Photomicrographs of ibuprofen crystallized from (a) methanol (b) ethanol (c) isopropanol and (d) hexane(magnification 140)
(a) (b)
Crystal Habit Modifications of Ibuprofen 805
ORDER REPRINTS
Germany) For each sample 10 g were pouredthrough the funnel of the flow meter the timerequired for all the sample to pass from the funnelwas automatically measured by the instrument Theresults are reported as grams per second
In addition the bulk densities of the crystalswere determined by gently placing equal weights ofeach crystal in a volumetric cylinder and theirvolumes were measured Their bulk densities werecalculated by dividing the weights by their volume
Compression
Compression of the crystals was carried out usingan instrumented single-punch tableting machine(Korsch EK-72 Germany) fitted with 10-mm flat-faced punches The die wall was prelubricated with4ww magnesium stearate in acetone before eachcompression Sieved fractions (gt250 mm) of ibupro-fen samples were hand filled into the die Fourtablets (400mg) were produced at compressionforces of 5 10 15 20 25 30 or 35 kN
The crushing strength of the tablets was mea-sured using an Erweka tablet hardness tester(Erweka GDT)
RESULTS AND DISCUSSION
Figure 2 shows the micrographs of ibuprofencrystals obtained from different solvents The mor-phology of the crystals obtained may be describedas follows From methanol or ethanol polyhedralor grainlike crystals were obtained from isopro-panol we obtained elongated crystals and fromhexane needlelike crystals were the result
Marshal and York (7) and Garti and Tibika (8)reported that nitrofurantoin particles crystallizedfrom formic acid were tabular while those crystal-lized from a mixture of formic acid and water wereneedlelike Davey et al (9) demonstrated that crys-tallization of succinic acid from water or isopro-panol produced platelike and needlelike habitsrespectively Garekani et al (5) reported that para-cetamol crystallized from water or ethanol producedprismatic polyhedral crystals while those obtainedfrom a mixture of water and ethanol were thin andplatelike In this study the influence of crystalliza-tion solvent and crystallization method on habitmodification of ibuprofen crystals was clearlyshown
The solvent influences crystal growth from dis-solved drug molecules through various mechanismsSolvent properties such as its polarity molecularweight and interaction with the dissolved drug arefactors that may influence the direction in whichcrystals grow on the nuclei The formation of differ-ent habits of ibuprofen crystals therefore may beattributed to interactions of ibuprofen and thesecrystallization solvents
Figure 3 shows the particle size distributions ofibuprofen crystals obtained from different solventsThere is a large difference between the size distribu-tion of these samples This indicates strong inhibi-tion of crystal growth at some crystal faces andinducement to more growth at other faces for theneedlelike (from hexane) crystals compared to thepolyhedral or grainlike crystals (from ethanol ormethanol)
The DSC results (Table 1) indicate that there isno significant difference (Tuckyrsquos test Plt05)
Figure 3 Size distributions of ibuprofen crystallized fromdifferent solvents (a) length of particles and (b) width of
particles
806 Garekani et al
ORDER REPRINTS
between the mean values of the melting point onsetsand melting points of the ibuprofen samples crystal-lized from different solvents indicating that nopolymorphic modification occurred during the crys-tallization in these particlesThe X-ray powder diffraction spectra of samples
are presented in Fig 4 X-ray powder diffractionhas been a useful method for determining the pres-ence of polymorphs or crystal habit modificationsin drug crystals In general for two forms of crys-tals when the patterns (ie peak positions) areidentical they have the same internal structures
Figure 4 The X-ray powder diffraction spectra of ibuprofen crystallized from (a) methanol (b) ethanol (c) hexane and (d)isopropanol
Table 1
Melting Point Onset Melting Peak Temperatures andEnthalpy of Fusion Hf for Ibuprofen Crystallized from
Different Solvents
Crystallized Melting Point Melting Hffrom Onset (C) Peak (C) (Jg)
Methanol 757 774 1356Ethanol 758 778 1259
Isopropanol 759 778 1208Hexane 757 771 1137
Crystal Habit Modifications of Ibuprofen 807
ORDER REPRINTS
whereas if the patterns are different then the crys-tals have different internal structures and are poly-morphs (10) Here all the samples exhibited spectrawith similar peak positions (2y values) (Fig 4)Therefore the presence of different polymorphs ofibuprofen in these samples was ruled out Howeverthe relative intensities of their XPD peaks weremodified This was attributed to the markedly dif-ferent crystal habits of the samples Therefore therelative abundance of the planes exposed to theX-ray source would have been altered producingthe variations in the relative intensities of the peaks(57) or this may be due to differences in the crystalsizes (11)
Table 2 shows the values of bulk densities of ibu-profen samples crystallized from different solventsThe samples crystallized from ethanol and methanolhad the highest bulk densities followed by the sam-ples obtained from isopropanol and those obtainedfrom hexane These differences may be related totheir markedly different crystal habits leading todifferent contact points and frictional and cohesiveforces between the crystals These factors affect thesliding of the particles against each other leading todifferent packing geometry and thus different bulkdensities Table 2 also shows that crystals obtainedfrom ethanol and methanol exhibited the bestflow rate while those from hexane had the leastflow These results are in agreement with the mor-phology and bulk density data that polyhedral crys-tals with higher bulk densities exhibited a betterflow rate
The effect of compression force on the crushingstrength of tablets made from ibuprofen crystals isillustrated in Fig 5 Two-way analysis of varianceshowed that there were significant differencesbetween the crushing strength of tablets made from
different samples of ibuprofen (Plt05) The sam-
ples obtained from ethanol exhibited the best com-pression properties and at each compression forcethe tablets had higher crushing strength than tabletsmade from other samples
Figure 5 also indicates that with increasing com-pression force beyond 10 kN the crushing strengthfor all the samples decreased except for the samplesobtained from ethanol This may indicate that ibu-
profen crystallized from ethanol underwent moreplastic and less elastic deformation during compres-sion than other samples
It has been reported that poor compressibility of
drug crystals can be attributed to the presence ofcrystal faces that give poor adhesion to other crys-tals and the absence of the faces that are requiredfor optimal adhesion (12) Here for the needlelikeand grainlike ibuprofen crystals (Fig 2) the
relative abundance of the different faces within thecrystals was modified This can affect the inter-particulate bonding between these crystals resulting
Figure 5 The effect of compression force on the crushingstrengths of tablets made from ibuprofen crystallized fromdifferent solvents
Table 2
Bulk Densities and Flow Rates for Ibuprofen Crystallizedfrom Different Solvents
Crystallized Bulk Flowfrom Density SD (gml) Rate SD (gS)
Methanol 045 003 44 05Ethanol 045 001 52 07Isopropanol 042 003 36 06
Hexane 029 005 0 0
808 Garekani et al
ORDER REPRINTS
in different compression properties In a similarstudy Garekani et al (5) reported that thin plate-like crystals of paracetamol underwent more elasticdeformation during compaction than polyhedralcrystals
CONCLUSIONS
Crystallization of ibuprofen from ethanol metha-nol isopropanol and hexane caused marked modi-fications to its crystal habit The samples obtainedfrom ethanol and methanol were polyhedral orgrainlike and those obtained from isopropanol andhexane were elongated and needlelike respectivelyIt was shown that these samples were structurallysimilar and polymorphic modifications wereruled outCrystal habit had a great influence on the
mechanical properties of ibuprofen Samplesobtained from ethanol and methanol exhibited thebest flow rate The samples obtained from ethanolalso exhibited better compression properties withhigher crushing strength than other samples Thesamples obtained from hexane showed the worstflow and compression properties
ACKNOWLEDGMENT
The financial support for this study was obtainedfrom the Vice Chancellor of Research of MashhadUniversity of Medical Sciences Iran
REFERENCES
1 Mullin JW In Crystallisation 3rd Ed Butterworths
Oxford UK 19932 Huttenrauch R Modification of Starting Materials
to Improve Tableting Properties Pharm Ind 1983 4
435ndash440
3 York P Solid-State Properties of Powders in theFormulation and Processing of Solid Dosage FormsInt J Pharm 1983 14 1ndash28
4 Marshall PV York P The Compaction Propertiesof Nitrofurantoin Samples Crystallised from DifferentSolvents Int J Pharm 1991 67 59ndash65
5 Garekani HA Ford JL Rubinstein MH
Rajabi-Siahboomi AR Formation and CompressionProperties of Prismatic Polyhedral and Thin Plate-likeCrystals of Paracetamol Int J Pharm 1999 187
77ndash89
6 Gonda I Abd-El Khalik AF Britten AZ SolidForms of Hexamethylmelamine J Pharm Pharma-col 1985 37 117P
7 Marshall PV York P Crystallisation SolventInduced Solid-State and Particulate Modifications ofNitrofurantoin Int J Pharm 1989 55 257ndash263
8 Garti N Tibika F Habit Modifications of
Nitrofurantoin Crystallised from Formic AcidMixtures Drug Dev Ind Pharm 1980 6 379ndash398
9 Davey RJ Mullin JW Whiting MJL Habit
Modification of Succinic Acid Crystals Grownfrom Different Solvents J Cryst Growth 1982 58304ndash312
10 Byrn SR In Solid-State Chemistry of Drugs
Academic Press New York 1982 29ndash59
11 El-Said Y Effect of Co-solvents on Water Contentand Physical Properties of AcetaminophenCrystallised from Aqueous Solutions STP Pharma
Sci 1995 5 232ndash237
12 Milosovitch G Direct Compression of Tablets DrugCosm Ind 1963 5 557ndash669
13 Marshall K Compression and Consolidation of
Powder Solids In Theory and Practice of IndustrialPharmacy 3rd Ed Lachman L Liberman HAKanig JL Eds Lea and Febiger Philadelphia
1986 66ndash89
14 York P Particle Slippage and Rearrangement DuringCompression of Pharmaceutical Powders J PharmPharmacol 1978 30 6ndash10
Crystal Habit Modifications of Ibuprofen 809
Order now
Reprints of this article can also be ordered at
httpwwwdekkercomservletproductDOI101081DDC100107243
Request Permission or Order Reprints Instantly
Interested in copying and sharing this article In most cases US Copyright Law requires that you get permission from the articlersquos rightsholder before using copyrighted content
All information and materials found in this article including but not limited to text trademarks patents logos graphics and images (the Materials) are the copyrighted works and other forms of intellectual property of Marcel Dekker Inc or its licensors All rights not expressly granted are reserved
Get permission to lawfully reproduce and distribute the Materials or order reprints quickly and painlessly Simply click on the Request PermissionReprints Here link below and follow the instructions Visit the US Copyright Office for information on Fair Use limitations of US copyright law Please refer to The Association of American Publishersrsquo (AAP) website for guidelines on Fair Use in the Classroom
The Materials are for your personal use only and cannot be reformatted reposted resold or distributed by electronic means or otherwise without permission from Marcel Dekker Inc Marcel Dekker Inc grants you the limited right to display the Materials only on your personal computer or personal wireless device and to copy and download single copies of such Materials provided that any copyright trademark or other notice appearing on such Materials is also retained by displayed copied or downloaded as part of the Materials and is not removed or obscured and provided you do not edit modify alter or enhance the Materials Please refer to our Website User Agreement for more details
ORDER REPRINTS
Germany) For each sample 10 g were pouredthrough the funnel of the flow meter the timerequired for all the sample to pass from the funnelwas automatically measured by the instrument Theresults are reported as grams per second
In addition the bulk densities of the crystalswere determined by gently placing equal weights ofeach crystal in a volumetric cylinder and theirvolumes were measured Their bulk densities werecalculated by dividing the weights by their volume
Compression
Compression of the crystals was carried out usingan instrumented single-punch tableting machine(Korsch EK-72 Germany) fitted with 10-mm flat-faced punches The die wall was prelubricated with4ww magnesium stearate in acetone before eachcompression Sieved fractions (gt250 mm) of ibupro-fen samples were hand filled into the die Fourtablets (400mg) were produced at compressionforces of 5 10 15 20 25 30 or 35 kN
The crushing strength of the tablets was mea-sured using an Erweka tablet hardness tester(Erweka GDT)
RESULTS AND DISCUSSION
Figure 2 shows the micrographs of ibuprofencrystals obtained from different solvents The mor-phology of the crystals obtained may be describedas follows From methanol or ethanol polyhedralor grainlike crystals were obtained from isopro-panol we obtained elongated crystals and fromhexane needlelike crystals were the result
Marshal and York (7) and Garti and Tibika (8)reported that nitrofurantoin particles crystallizedfrom formic acid were tabular while those crystal-lized from a mixture of formic acid and water wereneedlelike Davey et al (9) demonstrated that crys-tallization of succinic acid from water or isopro-panol produced platelike and needlelike habitsrespectively Garekani et al (5) reported that para-cetamol crystallized from water or ethanol producedprismatic polyhedral crystals while those obtainedfrom a mixture of water and ethanol were thin andplatelike In this study the influence of crystalliza-tion solvent and crystallization method on habitmodification of ibuprofen crystals was clearlyshown
The solvent influences crystal growth from dis-solved drug molecules through various mechanismsSolvent properties such as its polarity molecularweight and interaction with the dissolved drug arefactors that may influence the direction in whichcrystals grow on the nuclei The formation of differ-ent habits of ibuprofen crystals therefore may beattributed to interactions of ibuprofen and thesecrystallization solvents
Figure 3 shows the particle size distributions ofibuprofen crystals obtained from different solventsThere is a large difference between the size distribu-tion of these samples This indicates strong inhibi-tion of crystal growth at some crystal faces andinducement to more growth at other faces for theneedlelike (from hexane) crystals compared to thepolyhedral or grainlike crystals (from ethanol ormethanol)
The DSC results (Table 1) indicate that there isno significant difference (Tuckyrsquos test Plt05)
Figure 3 Size distributions of ibuprofen crystallized fromdifferent solvents (a) length of particles and (b) width of
particles
806 Garekani et al
ORDER REPRINTS
between the mean values of the melting point onsetsand melting points of the ibuprofen samples crystal-lized from different solvents indicating that nopolymorphic modification occurred during the crys-tallization in these particlesThe X-ray powder diffraction spectra of samples
are presented in Fig 4 X-ray powder diffractionhas been a useful method for determining the pres-ence of polymorphs or crystal habit modificationsin drug crystals In general for two forms of crys-tals when the patterns (ie peak positions) areidentical they have the same internal structures
Figure 4 The X-ray powder diffraction spectra of ibuprofen crystallized from (a) methanol (b) ethanol (c) hexane and (d)isopropanol
Table 1
Melting Point Onset Melting Peak Temperatures andEnthalpy of Fusion Hf for Ibuprofen Crystallized from
Different Solvents
Crystallized Melting Point Melting Hffrom Onset (C) Peak (C) (Jg)
Methanol 757 774 1356Ethanol 758 778 1259
Isopropanol 759 778 1208Hexane 757 771 1137
Crystal Habit Modifications of Ibuprofen 807
ORDER REPRINTS
whereas if the patterns are different then the crys-tals have different internal structures and are poly-morphs (10) Here all the samples exhibited spectrawith similar peak positions (2y values) (Fig 4)Therefore the presence of different polymorphs ofibuprofen in these samples was ruled out Howeverthe relative intensities of their XPD peaks weremodified This was attributed to the markedly dif-ferent crystal habits of the samples Therefore therelative abundance of the planes exposed to theX-ray source would have been altered producingthe variations in the relative intensities of the peaks(57) or this may be due to differences in the crystalsizes (11)
Table 2 shows the values of bulk densities of ibu-profen samples crystallized from different solventsThe samples crystallized from ethanol and methanolhad the highest bulk densities followed by the sam-ples obtained from isopropanol and those obtainedfrom hexane These differences may be related totheir markedly different crystal habits leading todifferent contact points and frictional and cohesiveforces between the crystals These factors affect thesliding of the particles against each other leading todifferent packing geometry and thus different bulkdensities Table 2 also shows that crystals obtainedfrom ethanol and methanol exhibited the bestflow rate while those from hexane had the leastflow These results are in agreement with the mor-phology and bulk density data that polyhedral crys-tals with higher bulk densities exhibited a betterflow rate
The effect of compression force on the crushingstrength of tablets made from ibuprofen crystals isillustrated in Fig 5 Two-way analysis of varianceshowed that there were significant differencesbetween the crushing strength of tablets made from
different samples of ibuprofen (Plt05) The sam-
ples obtained from ethanol exhibited the best com-pression properties and at each compression forcethe tablets had higher crushing strength than tabletsmade from other samples
Figure 5 also indicates that with increasing com-pression force beyond 10 kN the crushing strengthfor all the samples decreased except for the samplesobtained from ethanol This may indicate that ibu-
profen crystallized from ethanol underwent moreplastic and less elastic deformation during compres-sion than other samples
It has been reported that poor compressibility of
drug crystals can be attributed to the presence ofcrystal faces that give poor adhesion to other crys-tals and the absence of the faces that are requiredfor optimal adhesion (12) Here for the needlelikeand grainlike ibuprofen crystals (Fig 2) the
relative abundance of the different faces within thecrystals was modified This can affect the inter-particulate bonding between these crystals resulting
Figure 5 The effect of compression force on the crushingstrengths of tablets made from ibuprofen crystallized fromdifferent solvents
Table 2
Bulk Densities and Flow Rates for Ibuprofen Crystallizedfrom Different Solvents
Crystallized Bulk Flowfrom Density SD (gml) Rate SD (gS)
Methanol 045 003 44 05Ethanol 045 001 52 07Isopropanol 042 003 36 06
Hexane 029 005 0 0
808 Garekani et al
ORDER REPRINTS
in different compression properties In a similarstudy Garekani et al (5) reported that thin plate-like crystals of paracetamol underwent more elasticdeformation during compaction than polyhedralcrystals
CONCLUSIONS
Crystallization of ibuprofen from ethanol metha-nol isopropanol and hexane caused marked modi-fications to its crystal habit The samples obtainedfrom ethanol and methanol were polyhedral orgrainlike and those obtained from isopropanol andhexane were elongated and needlelike respectivelyIt was shown that these samples were structurallysimilar and polymorphic modifications wereruled outCrystal habit had a great influence on the
mechanical properties of ibuprofen Samplesobtained from ethanol and methanol exhibited thebest flow rate The samples obtained from ethanolalso exhibited better compression properties withhigher crushing strength than other samples Thesamples obtained from hexane showed the worstflow and compression properties
ACKNOWLEDGMENT
The financial support for this study was obtainedfrom the Vice Chancellor of Research of MashhadUniversity of Medical Sciences Iran
REFERENCES
1 Mullin JW In Crystallisation 3rd Ed Butterworths
Oxford UK 19932 Huttenrauch R Modification of Starting Materials
to Improve Tableting Properties Pharm Ind 1983 4
435ndash440
3 York P Solid-State Properties of Powders in theFormulation and Processing of Solid Dosage FormsInt J Pharm 1983 14 1ndash28
4 Marshall PV York P The Compaction Propertiesof Nitrofurantoin Samples Crystallised from DifferentSolvents Int J Pharm 1991 67 59ndash65
5 Garekani HA Ford JL Rubinstein MH
Rajabi-Siahboomi AR Formation and CompressionProperties of Prismatic Polyhedral and Thin Plate-likeCrystals of Paracetamol Int J Pharm 1999 187
77ndash89
6 Gonda I Abd-El Khalik AF Britten AZ SolidForms of Hexamethylmelamine J Pharm Pharma-col 1985 37 117P
7 Marshall PV York P Crystallisation SolventInduced Solid-State and Particulate Modifications ofNitrofurantoin Int J Pharm 1989 55 257ndash263
8 Garti N Tibika F Habit Modifications of
Nitrofurantoin Crystallised from Formic AcidMixtures Drug Dev Ind Pharm 1980 6 379ndash398
9 Davey RJ Mullin JW Whiting MJL Habit
Modification of Succinic Acid Crystals Grownfrom Different Solvents J Cryst Growth 1982 58304ndash312
10 Byrn SR In Solid-State Chemistry of Drugs
Academic Press New York 1982 29ndash59
11 El-Said Y Effect of Co-solvents on Water Contentand Physical Properties of AcetaminophenCrystallised from Aqueous Solutions STP Pharma
Sci 1995 5 232ndash237
12 Milosovitch G Direct Compression of Tablets DrugCosm Ind 1963 5 557ndash669
13 Marshall K Compression and Consolidation of
Powder Solids In Theory and Practice of IndustrialPharmacy 3rd Ed Lachman L Liberman HAKanig JL Eds Lea and Febiger Philadelphia
1986 66ndash89
14 York P Particle Slippage and Rearrangement DuringCompression of Pharmaceutical Powders J PharmPharmacol 1978 30 6ndash10
Crystal Habit Modifications of Ibuprofen 809
Order now
Reprints of this article can also be ordered at
httpwwwdekkercomservletproductDOI101081DDC100107243
Request Permission or Order Reprints Instantly
Interested in copying and sharing this article In most cases US Copyright Law requires that you get permission from the articlersquos rightsholder before using copyrighted content
All information and materials found in this article including but not limited to text trademarks patents logos graphics and images (the Materials) are the copyrighted works and other forms of intellectual property of Marcel Dekker Inc or its licensors All rights not expressly granted are reserved
Get permission to lawfully reproduce and distribute the Materials or order reprints quickly and painlessly Simply click on the Request PermissionReprints Here link below and follow the instructions Visit the US Copyright Office for information on Fair Use limitations of US copyright law Please refer to The Association of American Publishersrsquo (AAP) website for guidelines on Fair Use in the Classroom
The Materials are for your personal use only and cannot be reformatted reposted resold or distributed by electronic means or otherwise without permission from Marcel Dekker Inc Marcel Dekker Inc grants you the limited right to display the Materials only on your personal computer or personal wireless device and to copy and download single copies of such Materials provided that any copyright trademark or other notice appearing on such Materials is also retained by displayed copied or downloaded as part of the Materials and is not removed or obscured and provided you do not edit modify alter or enhance the Materials Please refer to our Website User Agreement for more details
ORDER REPRINTS
between the mean values of the melting point onsetsand melting points of the ibuprofen samples crystal-lized from different solvents indicating that nopolymorphic modification occurred during the crys-tallization in these particlesThe X-ray powder diffraction spectra of samples
are presented in Fig 4 X-ray powder diffractionhas been a useful method for determining the pres-ence of polymorphs or crystal habit modificationsin drug crystals In general for two forms of crys-tals when the patterns (ie peak positions) areidentical they have the same internal structures
Figure 4 The X-ray powder diffraction spectra of ibuprofen crystallized from (a) methanol (b) ethanol (c) hexane and (d)isopropanol
Table 1
Melting Point Onset Melting Peak Temperatures andEnthalpy of Fusion Hf for Ibuprofen Crystallized from
Different Solvents
Crystallized Melting Point Melting Hffrom Onset (C) Peak (C) (Jg)
Methanol 757 774 1356Ethanol 758 778 1259
Isopropanol 759 778 1208Hexane 757 771 1137
Crystal Habit Modifications of Ibuprofen 807
ORDER REPRINTS
whereas if the patterns are different then the crys-tals have different internal structures and are poly-morphs (10) Here all the samples exhibited spectrawith similar peak positions (2y values) (Fig 4)Therefore the presence of different polymorphs ofibuprofen in these samples was ruled out Howeverthe relative intensities of their XPD peaks weremodified This was attributed to the markedly dif-ferent crystal habits of the samples Therefore therelative abundance of the planes exposed to theX-ray source would have been altered producingthe variations in the relative intensities of the peaks(57) or this may be due to differences in the crystalsizes (11)
Table 2 shows the values of bulk densities of ibu-profen samples crystallized from different solventsThe samples crystallized from ethanol and methanolhad the highest bulk densities followed by the sam-ples obtained from isopropanol and those obtainedfrom hexane These differences may be related totheir markedly different crystal habits leading todifferent contact points and frictional and cohesiveforces between the crystals These factors affect thesliding of the particles against each other leading todifferent packing geometry and thus different bulkdensities Table 2 also shows that crystals obtainedfrom ethanol and methanol exhibited the bestflow rate while those from hexane had the leastflow These results are in agreement with the mor-phology and bulk density data that polyhedral crys-tals with higher bulk densities exhibited a betterflow rate
The effect of compression force on the crushingstrength of tablets made from ibuprofen crystals isillustrated in Fig 5 Two-way analysis of varianceshowed that there were significant differencesbetween the crushing strength of tablets made from
different samples of ibuprofen (Plt05) The sam-
ples obtained from ethanol exhibited the best com-pression properties and at each compression forcethe tablets had higher crushing strength than tabletsmade from other samples
Figure 5 also indicates that with increasing com-pression force beyond 10 kN the crushing strengthfor all the samples decreased except for the samplesobtained from ethanol This may indicate that ibu-
profen crystallized from ethanol underwent moreplastic and less elastic deformation during compres-sion than other samples
It has been reported that poor compressibility of
drug crystals can be attributed to the presence ofcrystal faces that give poor adhesion to other crys-tals and the absence of the faces that are requiredfor optimal adhesion (12) Here for the needlelikeand grainlike ibuprofen crystals (Fig 2) the
relative abundance of the different faces within thecrystals was modified This can affect the inter-particulate bonding between these crystals resulting
Figure 5 The effect of compression force on the crushingstrengths of tablets made from ibuprofen crystallized fromdifferent solvents
Table 2
Bulk Densities and Flow Rates for Ibuprofen Crystallizedfrom Different Solvents
Crystallized Bulk Flowfrom Density SD (gml) Rate SD (gS)
Methanol 045 003 44 05Ethanol 045 001 52 07Isopropanol 042 003 36 06
Hexane 029 005 0 0
808 Garekani et al
ORDER REPRINTS
in different compression properties In a similarstudy Garekani et al (5) reported that thin plate-like crystals of paracetamol underwent more elasticdeformation during compaction than polyhedralcrystals
CONCLUSIONS
Crystallization of ibuprofen from ethanol metha-nol isopropanol and hexane caused marked modi-fications to its crystal habit The samples obtainedfrom ethanol and methanol were polyhedral orgrainlike and those obtained from isopropanol andhexane were elongated and needlelike respectivelyIt was shown that these samples were structurallysimilar and polymorphic modifications wereruled outCrystal habit had a great influence on the
mechanical properties of ibuprofen Samplesobtained from ethanol and methanol exhibited thebest flow rate The samples obtained from ethanolalso exhibited better compression properties withhigher crushing strength than other samples Thesamples obtained from hexane showed the worstflow and compression properties
ACKNOWLEDGMENT
The financial support for this study was obtainedfrom the Vice Chancellor of Research of MashhadUniversity of Medical Sciences Iran
REFERENCES
1 Mullin JW In Crystallisation 3rd Ed Butterworths
Oxford UK 19932 Huttenrauch R Modification of Starting Materials
to Improve Tableting Properties Pharm Ind 1983 4
435ndash440
3 York P Solid-State Properties of Powders in theFormulation and Processing of Solid Dosage FormsInt J Pharm 1983 14 1ndash28
4 Marshall PV York P The Compaction Propertiesof Nitrofurantoin Samples Crystallised from DifferentSolvents Int J Pharm 1991 67 59ndash65
5 Garekani HA Ford JL Rubinstein MH
Rajabi-Siahboomi AR Formation and CompressionProperties of Prismatic Polyhedral and Thin Plate-likeCrystals of Paracetamol Int J Pharm 1999 187
77ndash89
6 Gonda I Abd-El Khalik AF Britten AZ SolidForms of Hexamethylmelamine J Pharm Pharma-col 1985 37 117P
7 Marshall PV York P Crystallisation SolventInduced Solid-State and Particulate Modifications ofNitrofurantoin Int J Pharm 1989 55 257ndash263
8 Garti N Tibika F Habit Modifications of
Nitrofurantoin Crystallised from Formic AcidMixtures Drug Dev Ind Pharm 1980 6 379ndash398
9 Davey RJ Mullin JW Whiting MJL Habit
Modification of Succinic Acid Crystals Grownfrom Different Solvents J Cryst Growth 1982 58304ndash312
10 Byrn SR In Solid-State Chemistry of Drugs
Academic Press New York 1982 29ndash59
11 El-Said Y Effect of Co-solvents on Water Contentand Physical Properties of AcetaminophenCrystallised from Aqueous Solutions STP Pharma
Sci 1995 5 232ndash237
12 Milosovitch G Direct Compression of Tablets DrugCosm Ind 1963 5 557ndash669
13 Marshall K Compression and Consolidation of
Powder Solids In Theory and Practice of IndustrialPharmacy 3rd Ed Lachman L Liberman HAKanig JL Eds Lea and Febiger Philadelphia
1986 66ndash89
14 York P Particle Slippage and Rearrangement DuringCompression of Pharmaceutical Powders J PharmPharmacol 1978 30 6ndash10
Crystal Habit Modifications of Ibuprofen 809
Order now
Reprints of this article can also be ordered at
httpwwwdekkercomservletproductDOI101081DDC100107243
Request Permission or Order Reprints Instantly
Interested in copying and sharing this article In most cases US Copyright Law requires that you get permission from the articlersquos rightsholder before using copyrighted content
All information and materials found in this article including but not limited to text trademarks patents logos graphics and images (the Materials) are the copyrighted works and other forms of intellectual property of Marcel Dekker Inc or its licensors All rights not expressly granted are reserved
Get permission to lawfully reproduce and distribute the Materials or order reprints quickly and painlessly Simply click on the Request PermissionReprints Here link below and follow the instructions Visit the US Copyright Office for information on Fair Use limitations of US copyright law Please refer to The Association of American Publishersrsquo (AAP) website for guidelines on Fair Use in the Classroom
The Materials are for your personal use only and cannot be reformatted reposted resold or distributed by electronic means or otherwise without permission from Marcel Dekker Inc Marcel Dekker Inc grants you the limited right to display the Materials only on your personal computer or personal wireless device and to copy and download single copies of such Materials provided that any copyright trademark or other notice appearing on such Materials is also retained by displayed copied or downloaded as part of the Materials and is not removed or obscured and provided you do not edit modify alter or enhance the Materials Please refer to our Website User Agreement for more details
ORDER REPRINTS
whereas if the patterns are different then the crys-tals have different internal structures and are poly-morphs (10) Here all the samples exhibited spectrawith similar peak positions (2y values) (Fig 4)Therefore the presence of different polymorphs ofibuprofen in these samples was ruled out Howeverthe relative intensities of their XPD peaks weremodified This was attributed to the markedly dif-ferent crystal habits of the samples Therefore therelative abundance of the planes exposed to theX-ray source would have been altered producingthe variations in the relative intensities of the peaks(57) or this may be due to differences in the crystalsizes (11)
Table 2 shows the values of bulk densities of ibu-profen samples crystallized from different solventsThe samples crystallized from ethanol and methanolhad the highest bulk densities followed by the sam-ples obtained from isopropanol and those obtainedfrom hexane These differences may be related totheir markedly different crystal habits leading todifferent contact points and frictional and cohesiveforces between the crystals These factors affect thesliding of the particles against each other leading todifferent packing geometry and thus different bulkdensities Table 2 also shows that crystals obtainedfrom ethanol and methanol exhibited the bestflow rate while those from hexane had the leastflow These results are in agreement with the mor-phology and bulk density data that polyhedral crys-tals with higher bulk densities exhibited a betterflow rate
The effect of compression force on the crushingstrength of tablets made from ibuprofen crystals isillustrated in Fig 5 Two-way analysis of varianceshowed that there were significant differencesbetween the crushing strength of tablets made from
different samples of ibuprofen (Plt05) The sam-
ples obtained from ethanol exhibited the best com-pression properties and at each compression forcethe tablets had higher crushing strength than tabletsmade from other samples
Figure 5 also indicates that with increasing com-pression force beyond 10 kN the crushing strengthfor all the samples decreased except for the samplesobtained from ethanol This may indicate that ibu-
profen crystallized from ethanol underwent moreplastic and less elastic deformation during compres-sion than other samples
It has been reported that poor compressibility of
drug crystals can be attributed to the presence ofcrystal faces that give poor adhesion to other crys-tals and the absence of the faces that are requiredfor optimal adhesion (12) Here for the needlelikeand grainlike ibuprofen crystals (Fig 2) the
relative abundance of the different faces within thecrystals was modified This can affect the inter-particulate bonding between these crystals resulting
Figure 5 The effect of compression force on the crushingstrengths of tablets made from ibuprofen crystallized fromdifferent solvents
Table 2
Bulk Densities and Flow Rates for Ibuprofen Crystallizedfrom Different Solvents
Crystallized Bulk Flowfrom Density SD (gml) Rate SD (gS)
Methanol 045 003 44 05Ethanol 045 001 52 07Isopropanol 042 003 36 06
Hexane 029 005 0 0
808 Garekani et al
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in different compression properties In a similarstudy Garekani et al (5) reported that thin plate-like crystals of paracetamol underwent more elasticdeformation during compaction than polyhedralcrystals
CONCLUSIONS
Crystallization of ibuprofen from ethanol metha-nol isopropanol and hexane caused marked modi-fications to its crystal habit The samples obtainedfrom ethanol and methanol were polyhedral orgrainlike and those obtained from isopropanol andhexane were elongated and needlelike respectivelyIt was shown that these samples were structurallysimilar and polymorphic modifications wereruled outCrystal habit had a great influence on the
mechanical properties of ibuprofen Samplesobtained from ethanol and methanol exhibited thebest flow rate The samples obtained from ethanolalso exhibited better compression properties withhigher crushing strength than other samples Thesamples obtained from hexane showed the worstflow and compression properties
ACKNOWLEDGMENT
The financial support for this study was obtainedfrom the Vice Chancellor of Research of MashhadUniversity of Medical Sciences Iran
REFERENCES
1 Mullin JW In Crystallisation 3rd Ed Butterworths
Oxford UK 19932 Huttenrauch R Modification of Starting Materials
to Improve Tableting Properties Pharm Ind 1983 4
435ndash440
3 York P Solid-State Properties of Powders in theFormulation and Processing of Solid Dosage FormsInt J Pharm 1983 14 1ndash28
4 Marshall PV York P The Compaction Propertiesof Nitrofurantoin Samples Crystallised from DifferentSolvents Int J Pharm 1991 67 59ndash65
5 Garekani HA Ford JL Rubinstein MH
Rajabi-Siahboomi AR Formation and CompressionProperties of Prismatic Polyhedral and Thin Plate-likeCrystals of Paracetamol Int J Pharm 1999 187
77ndash89
6 Gonda I Abd-El Khalik AF Britten AZ SolidForms of Hexamethylmelamine J Pharm Pharma-col 1985 37 117P
7 Marshall PV York P Crystallisation SolventInduced Solid-State and Particulate Modifications ofNitrofurantoin Int J Pharm 1989 55 257ndash263
8 Garti N Tibika F Habit Modifications of
Nitrofurantoin Crystallised from Formic AcidMixtures Drug Dev Ind Pharm 1980 6 379ndash398
9 Davey RJ Mullin JW Whiting MJL Habit
Modification of Succinic Acid Crystals Grownfrom Different Solvents J Cryst Growth 1982 58304ndash312
10 Byrn SR In Solid-State Chemistry of Drugs
Academic Press New York 1982 29ndash59
11 El-Said Y Effect of Co-solvents on Water Contentand Physical Properties of AcetaminophenCrystallised from Aqueous Solutions STP Pharma
Sci 1995 5 232ndash237
12 Milosovitch G Direct Compression of Tablets DrugCosm Ind 1963 5 557ndash669
13 Marshall K Compression and Consolidation of
Powder Solids In Theory and Practice of IndustrialPharmacy 3rd Ed Lachman L Liberman HAKanig JL Eds Lea and Febiger Philadelphia
1986 66ndash89
14 York P Particle Slippage and Rearrangement DuringCompression of Pharmaceutical Powders J PharmPharmacol 1978 30 6ndash10
Crystal Habit Modifications of Ibuprofen 809
Order now
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httpwwwdekkercomservletproductDOI101081DDC100107243
Request Permission or Order Reprints Instantly
Interested in copying and sharing this article In most cases US Copyright Law requires that you get permission from the articlersquos rightsholder before using copyrighted content
All information and materials found in this article including but not limited to text trademarks patents logos graphics and images (the Materials) are the copyrighted works and other forms of intellectual property of Marcel Dekker Inc or its licensors All rights not expressly granted are reserved
Get permission to lawfully reproduce and distribute the Materials or order reprints quickly and painlessly Simply click on the Request PermissionReprints Here link below and follow the instructions Visit the US Copyright Office for information on Fair Use limitations of US copyright law Please refer to The Association of American Publishersrsquo (AAP) website for guidelines on Fair Use in the Classroom
The Materials are for your personal use only and cannot be reformatted reposted resold or distributed by electronic means or otherwise without permission from Marcel Dekker Inc Marcel Dekker Inc grants you the limited right to display the Materials only on your personal computer or personal wireless device and to copy and download single copies of such Materials provided that any copyright trademark or other notice appearing on such Materials is also retained by displayed copied or downloaded as part of the Materials and is not removed or obscured and provided you do not edit modify alter or enhance the Materials Please refer to our Website User Agreement for more details
ORDER REPRINTS
in different compression properties In a similarstudy Garekani et al (5) reported that thin plate-like crystals of paracetamol underwent more elasticdeformation during compaction than polyhedralcrystals
CONCLUSIONS
Crystallization of ibuprofen from ethanol metha-nol isopropanol and hexane caused marked modi-fications to its crystal habit The samples obtainedfrom ethanol and methanol were polyhedral orgrainlike and those obtained from isopropanol andhexane were elongated and needlelike respectivelyIt was shown that these samples were structurallysimilar and polymorphic modifications wereruled outCrystal habit had a great influence on the
mechanical properties of ibuprofen Samplesobtained from ethanol and methanol exhibited thebest flow rate The samples obtained from ethanolalso exhibited better compression properties withhigher crushing strength than other samples Thesamples obtained from hexane showed the worstflow and compression properties
ACKNOWLEDGMENT
The financial support for this study was obtainedfrom the Vice Chancellor of Research of MashhadUniversity of Medical Sciences Iran
REFERENCES
1 Mullin JW In Crystallisation 3rd Ed Butterworths
Oxford UK 19932 Huttenrauch R Modification of Starting Materials
to Improve Tableting Properties Pharm Ind 1983 4
435ndash440
3 York P Solid-State Properties of Powders in theFormulation and Processing of Solid Dosage FormsInt J Pharm 1983 14 1ndash28
4 Marshall PV York P The Compaction Propertiesof Nitrofurantoin Samples Crystallised from DifferentSolvents Int J Pharm 1991 67 59ndash65
5 Garekani HA Ford JL Rubinstein MH
Rajabi-Siahboomi AR Formation and CompressionProperties of Prismatic Polyhedral and Thin Plate-likeCrystals of Paracetamol Int J Pharm 1999 187
77ndash89
6 Gonda I Abd-El Khalik AF Britten AZ SolidForms of Hexamethylmelamine J Pharm Pharma-col 1985 37 117P
7 Marshall PV York P Crystallisation SolventInduced Solid-State and Particulate Modifications ofNitrofurantoin Int J Pharm 1989 55 257ndash263
8 Garti N Tibika F Habit Modifications of
Nitrofurantoin Crystallised from Formic AcidMixtures Drug Dev Ind Pharm 1980 6 379ndash398
9 Davey RJ Mullin JW Whiting MJL Habit
Modification of Succinic Acid Crystals Grownfrom Different Solvents J Cryst Growth 1982 58304ndash312
10 Byrn SR In Solid-State Chemistry of Drugs
Academic Press New York 1982 29ndash59
11 El-Said Y Effect of Co-solvents on Water Contentand Physical Properties of AcetaminophenCrystallised from Aqueous Solutions STP Pharma
Sci 1995 5 232ndash237
12 Milosovitch G Direct Compression of Tablets DrugCosm Ind 1963 5 557ndash669
13 Marshall K Compression and Consolidation of
Powder Solids In Theory and Practice of IndustrialPharmacy 3rd Ed Lachman L Liberman HAKanig JL Eds Lea and Febiger Philadelphia
1986 66ndash89
14 York P Particle Slippage and Rearrangement DuringCompression of Pharmaceutical Powders J PharmPharmacol 1978 30 6ndash10
Crystal Habit Modifications of Ibuprofen 809
Order now
Reprints of this article can also be ordered at
httpwwwdekkercomservletproductDOI101081DDC100107243
Request Permission or Order Reprints Instantly
Interested in copying and sharing this article In most cases US Copyright Law requires that you get permission from the articlersquos rightsholder before using copyrighted content
All information and materials found in this article including but not limited to text trademarks patents logos graphics and images (the Materials) are the copyrighted works and other forms of intellectual property of Marcel Dekker Inc or its licensors All rights not expressly granted are reserved
Get permission to lawfully reproduce and distribute the Materials or order reprints quickly and painlessly Simply click on the Request PermissionReprints Here link below and follow the instructions Visit the US Copyright Office for information on Fair Use limitations of US copyright law Please refer to The Association of American Publishersrsquo (AAP) website for guidelines on Fair Use in the Classroom
The Materials are for your personal use only and cannot be reformatted reposted resold or distributed by electronic means or otherwise without permission from Marcel Dekker Inc Marcel Dekker Inc grants you the limited right to display the Materials only on your personal computer or personal wireless device and to copy and download single copies of such Materials provided that any copyright trademark or other notice appearing on such Materials is also retained by displayed copied or downloaded as part of the Materials and is not removed or obscured and provided you do not edit modify alter or enhance the Materials Please refer to our Website User Agreement for more details
Order now
Reprints of this article can also be ordered at
httpwwwdekkercomservletproductDOI101081DDC100107243
Request Permission or Order Reprints Instantly
Interested in copying and sharing this article In most cases US Copyright Law requires that you get permission from the articlersquos rightsholder before using copyrighted content
All information and materials found in this article including but not limited to text trademarks patents logos graphics and images (the Materials) are the copyrighted works and other forms of intellectual property of Marcel Dekker Inc or its licensors All rights not expressly granted are reserved
Get permission to lawfully reproduce and distribute the Materials or order reprints quickly and painlessly Simply click on the Request PermissionReprints Here link below and follow the instructions Visit the US Copyright Office for information on Fair Use limitations of US copyright law Please refer to The Association of American Publishersrsquo (AAP) website for guidelines on Fair Use in the Classroom
The Materials are for your personal use only and cannot be reformatted reposted resold or distributed by electronic means or otherwise without permission from Marcel Dekker Inc Marcel Dekker Inc grants you the limited right to display the Materials only on your personal computer or personal wireless device and to copy and download single copies of such Materials provided that any copyright trademark or other notice appearing on such Materials is also retained by displayed copied or downloaded as part of the Materials and is not removed or obscured and provided you do not edit modify alter or enhance the Materials Please refer to our Website User Agreement for more details