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`Frarx Group
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`Taylor
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`Drying
`lichnblogy
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`Drying Technology
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`ISSN 07373937 Print 15322300 Online Journal homepage httpwwwtandfonlinecomloildrt20
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`Preparation and Dissolution Profiles of the
`Amorphous Dihydrated Crystalline and
`Anhydrous Crystalline Forms of Paclitaxel
`
`SangHyun Pyo JinSuk Cho HoJoon Choi
`
`ByungHee Han
`
`To cite this article SangHyun Pyo JinSuk Cho HoJoon Choi
`ByungHee Han
`2007 Preparation and Dissolution Profiles of the Amorphous Dihydrated Crystalline and
`Anhydrous Crystalline Forms of Paclitaxel Drying Technology 2510 17591767 DOI
`10108007373930701593180
`
`To link to this article httpdxdoiorg10108007373930701593180
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`Published online 10 Dec 2007
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`

`

`0 Taylor
`
`Francis
`
`Taylor Francis Group
`
`Drying Technology 25 1759
`1767 2007
`Copyright © 2007 Taylor
`Francis Group LLC
`ISSN 07373937 print15322300 online
`DOT 1010SO07373930701593180
`
`Preparation and Dissolution Profiles of the Amorphous
`Dihydrated Crystalline and Anhydrous Crystalline Forms
`of Paclitaxel
`
`SangHyun Pyo12 JinSuk Cho1 HoJoon Choi1 and ByungHee Han2
`Bio Research Center YusungGu Daejeon South Korea
`1Samyang Genex Food
`2
`Department of Chemistry Chungnam National University YusungGu Daejeon South Korea
`
`The
`
`selection of pharmaceutical polymorphisms in the final
`in terms of product
`production step is very important
`recovery
`and storage The amorphous dihydrated crystalline
`properties
`and anhydrous
`crystalline forms of paclitaxel were prepared
`using
`spray drying and colloid formation methods These
`precipitation
`methods were found to be highly efficient and convenient giving
`time and good stability as com
`high recovery short processing
`pared with conventional methods such as freeze drying evaporation
`recrystallization and melting The polymorphic natures of
`the
`resulting paclitaxel samples were confirmed by XRPD IR TGA
`DSC and SEM The dissolution rates of the paclitaxel
`samples
`were studied in pharmaceutical solvents which included cotton seed
`tricaprylin and tributyrin For each solvent all of the
`oil corn oil
`amorphous paclitaxel samples showed much higher dissolution rates
`than the dihydrated crystalline anhydrous crystalline and commer
`forms and can be used for clinical applications that demand
`cial
`improvements in drug delivery
`
`Keywords
`
`Amorphous paclitaxel Anhydrous crystalline paclitaxel
`Dissolution
`rate
`Dihydrated
`Morphology
`
`crystalline paclitaxel
`
`INTRODUCTION
`Paclitaxel which is
`that was isolated
`a diterpenoid
`originally from the bark of Taxus brevifolia11 is one of
`agents this is due to its
`the most
`important anticancer
`unique cytotoxicity mechanism that involves the promotion
`of the assembly of tubulin and stabilization of the resulting
`microtubules241Paclitaxel
`is produced commercially by a
`iso
`semisynthetic method using 10deacetylbaccatin III
`lated from the leaves of yew trees and also by a plant cell
`culture method The selection in the final production step
`of polymorphic products such as the amorphous anhydrous
`crystalline and hydrated crystalline forms of paclitaxel
`very important with regard to product recovery properties
`
`is
`
`Correspondence Sang Hyun Pyo Department of Chemistry
`Chungnam National University 220 Gung Dong Yusung Gu
`Daejeon 305 764 South Korea E mail shpyocnuackr
`
`usage and storage and needs to be controlled with a view to
`the intended application Generally the amorphous form
`has the advantage of better solubility in pharmaceutical
`solvents while the crystalline form is more stable under
`storage conditions However
`little information is available
`on the optimal preparation methods Amorphous paclitaxel
`can be dissolved in pharmaceutical solvents
`to increase its
`clinical efficacy Paclitaxel which is a lipophilic anticancer
`drug has extremely low solubility in aqueous
`and most
`pharmaceutical solvents51 In previous attempts to increase
`solubility paclitaxel has been formulated in a vehicle com
`posed of a 5050 blend of Cremophor EL CrEL and absol
`ute ethanol and subsequently diluted with normal saline or
`
`dextrose solution 5 before administration61 However
`
`serious side effects such as hypersensitivity neurotoxicity
`nephrotoxicity and extraction of plasticizers from intra
`venous infusion line catheters have been noted for this for
`mulation781 Thus alternative
`delivery systems which
`and microspheres have
`involve liposomes cyclodextrins
`been examined to increase
`the solubility of
`lipophilic
`drugs9111 Particle formation methods in the final pro
`duction step are very important
`in determining the final
`product specifications and properties12131 On the other
`hand amorphous paclitaxel can be used to increase the
`solvents How
`solubility of paclitaxel
`in pharmaceutical
`there is little information available on the methods
`ever
`of preparation and the properties of amorphous paclitaxel
`In previous reports amorphous paclitaxel was prepared by
`heating it up to the melting temperature of 221°C followed
`involve evaporation
`by quench cooling5141 Protocols that
`and recrystallization
`low
`produce large size particles at
`yield151 In the patented invention of Janicki et al161
`amorphous paclitaxel possibly with crystalline additive
`was prepared by freeze drying at 50°C a system that
`requires a very low temperature and a long processing time
`The anhydrous crystalline and dihydrated crystalline
`forms of paclitaxel have better storage properties than the
`
`1759
`
`

`

`1760
`
`PYO ET AL
`
`amorphous form According to the US patent of Sharma
`et al171 hydrated paclitaxel and docetaxel which is
`a
`agent can be obtained with a
`paclitaxelderived anticancer
`yield of 84 by dissolving and stirring in acetonitrile at
`60°C followed by the addition of water and crystallization
`Unfortunately these methods use very harsh conditions
`that can result in product degradation in addition they are
`unsuitable for largescale production and they give low
`yields in the final purification step Therefore
`is
`largescale methods for the pro
`necessary to develop novel
`in the amorphous form as well as in
`duction of paclitaxel
`the dihydrate crystalline and anhydrous crystalline forms
`In the current study we describe
`various methods for
`obtaining paclitaxel of desired morphology and solubility
`These methods which involve spray drying precipitation
`and colloid formation are remarkably efficient and con
`as compared with the conventional methods
`venient
`described above We expect
`that
`improvements in dissol
`ution rates achieved using amorphous fine particles of
`as well as new methods for the production of
`paclitaxel
`the crystalline form of paclitaxel will
`facilitate largescale
`
`it
`
`production of this drug for clinical applications
`
`MATERIALS AND METHODS
`
`Materials
`
`Cells of Taxus chinensis were cultured in suspension
`Paclitaxel >995 purity was purified from the cultured
`cell using solvent extraction precipitation ODSHPLC
`and silicaHPLC as described previously Tributyrin
`tricaprylin corn oil and cotton seed oil were purchased
`from Sigma Chemical Co St Louis MO Highperformance
`liquid chromatography HPLCgrade solvents and water
`were used to prepare paclitaxel
`specimens with various
`morphologies for dilution and HPLC analysis
`
`Methods
`
`Chromatography Analysis
`Quantitative analyses of solubility were performed using
`a HPLC system HP1090 HewlettPackard Palo Alto
`CA together with a Curosil PFP column Phenomenex
`46 mm x 250 mm dp = 5 jam Elution was performed
`within 30 min with water and acetonitrile using a gradient
`from 6535 to 3565 flow rate = 10 mLmin The eluent
`at 227 nm with a photo diode array
`was monitored
`detector The content of residual solvent was analyzed in
`a GC system HP 5890 HewlettPackard using a Supelco
`fused silica capillary column 30 m x 053mm x 50 jam film
`thickness SigmaAldrich St Louis MO
`
`Spectrometry
`
`Xray powder diffraction XRPD was performed with a
`Model DMax3B diffractometer Rigaku Tokyo Japan in
`the 5 to 40° 20 range at a rate of 2° 20min using CuKa radi
`ation 45 kV 40 mA as the Xray source The appearance
`
`and size of the products were analyzed by scanning electron
`microscopy SEM JSM6635F Jeol Tokyo Japan
`Fourier transform infrared spectroscopy FTIR was per
`formed with a model FTS165
`spectrometer Digilab
`Division BioRad Cambridge MA using the potassium
`bromide KBr pellet technique
`
`Thermal Analysis
`Thermograms were generated with a differential
`scan
`ning calorimeter DSC DSC7 Perkin Elmer Wellesley
`MA which was calibrated with indium Approximately
`5 mg of each sample was placed on the aluminum pan
`The
`cell was purged with nitrogen at
`a flow rate of
`40 mLmin All measurements were carried out
`in the
`range of 25 300°C with a scan rate of 20°Cmin Thermo
`gravimetric analysis TGA was performed with the TGA7
`system Perkin Elmer Norwalk CT Approximately 5 mg
`and heated to 700°C at a rate
`of each sample was weighed
`of 20°Cmin under a nitrogen purge
`
`Preparation of the Amorphous Dihydrated Crystalline and
`Anhydrous Crystalline Forms of Paclitaxel
`The amorphous dihydrated crystalline and anhydrous
`crystalline forms of paclitaxel were prepared by evapor
`ation precipitation colloid formation or spray drying
`The first method was carried out using a rotary evaporator
`Rotavapor R124 Biichi Flawil Switzerland in a water
`bath at 35°C Paclitaxel was dissolved at a concentration
`
`acetone or ethyl acetate
`of 10°A in dichloromethane
`reduced
`pressure The
`under
`followed
`by evaporation
`that coated the surface of the evaporation flask
`
`paclitaxel
`
`was recovered and crushed Table 1 samples A J and K
`
`The second method of preparation used precipitation
`with two types of solvent Paclitaxel was dissolved at a con
`centration of 10°A in a solvent such as dichloromethane
`tetrahydrofuran THF or acetone and the solution was
`added slowly to a precipitation solvent such as nhexane
`n pentane or water at a 10 to 15 fold ratio to obtain
`the precipitate which was filtered Table 1 samples B C
`D E G H and L
`
`The
`third method of preparation
`involved
`colloid
`formation Paclitaxel was dissolved in acetone and evapo
`rated under reduced pressure to remove residual solvents
`The colloidal solution was formed by adding acetone at a
`ratio of 100 wv while rotating the evaporation bowl
`
`Paclitaxel was dispersed but not dissolved and the white
`using the same method Fine parti
`solution was evaporated
`cles were easily recovered from the evaporation bowl without
`the coating problem in the first method Table 1 sample I
`fourth method involved spray drying Table 1
`The
`sample F201 Paclitaxel was dissolved at a concentration
`of 10 in dichloromethane and loaded onto a mini spray
`dryer B191 Bfichi Flawil Switzerland which was
`temperature Table 1 sample F
`to 75°C inlet
`heated
`The spray drying was carried out at
`
`the liquid feed rate
`
`

`

`Sample
`A
`
`A
`DCM
`DCM
`DCM
`THF
`THF
`DCM
`
`Hexane
`
`Pentane
`
`Hexane
`
`Pentane
`
`THF
`
`Water
`
`Acetone
`
`Water
`
`Acetone
`
`Acetone
`
`EA
`
`Evaporation
`
`Precipitationb
`
`Precipitationb
`
`Precipitationb
`
`Precipitationb
`
`Spray dryd
`
`Precipitationb
`
`Precipitationb
`
`Colloid formation
`
`Evaporation
`
`Evaporation
`
`Amorphous
`Amorphous
`Amorphous
`Amorphous
`Amorphous
`Amorphous
`Dihydrate
`
`crystalline
`
`Dihydrate
`
`crystalline
`
`Anhydrous
`
`crystalline
`
`Anhydrous
`
`crystalline
`
`Anhydrous
`
`crystalline
`
`Anhydrous
`
`4109
`222
`345
`610
`112
`415
`
`4151
`
`116
`
`117
`
`3774
`
`24376
`
`1083
`
`145
`
`543
`570
`
`1317
`
`MORPHOLOGIES AND DISSOLUTION PROFILES OF PACLITAXEL
`
`1761
`
`Solvent condition
`
`TABLE 1
`Comparison of conditions for the preparation of the various morphologies of paclitaxel
`Residual solvent ppm
`Solvent A
`
`Bf
`
`Preparation method
`
`Morphology
`
`Solvent B
`
`Precipitationb
`
`Acetone
`Pentane
`After dissolving in solvent A the solution was evaporated
`bAfter dissolving in solvent A the solution was added to solvent B to obtain the precipitate which was filtered
`After formation of the colloid in solvent A the solution was evaporated
`dAfter dissolving in solvent A the solution was loaded onto a spray dryer
`Solvent A is the dissolving solvent DCM dichloromethane THF tetrahydrofuran EA ethylacetate
`Solvent B is the precipitation solvent
`
`crystalline
`
`<100
`
`of 10 mLmin drying aspiration flow rate of 25 m3h and
`nitrogen spray flow rate of 600 m3h To
`compressed
`remove residual solvents the paclitaxel samples obtained
`using the four different methods were dried in a vacuum
`dryer for 3 days at 40°C
`
`that
`
`described
`
`Determination of Dissolution Rates
`The method used for studying the dissolution rates of
`a modified version of
`paclitaxel was
`from each preparation
`samples
`previously1°1 Paclitaxel
`protocol were added to the selected pharmaceutical sol
`the solution for 2 mm
`vents followed by vortexing of
`solution was centrifuged at 10000 x g for 10 min
`The
`and diluted in meth
`and the supernatant was withdrawn
`for the HPLC analysis of paclitaxel
`anol or npropanol
`solubility The dissolution rate profile of paclitaxel
`in cot
`ton seed oil was obtained by analysis of samples that were
`shaken at 150 rpm for 48h at 20°C
`
`RESULTS AND DISCUSSION
`
`Preparation and Residual Solvent
`Paclitaxel of >995 purity which was obtained from
`and subjected
`cell cultures81
`to purification as
`
`plant
`
`described previously was used in all
`the experiments
`the different methods of paclitaxel
`The comparisons of
`preparation are summarized in Table 1 The properties of
`these samples were analyzed and confirmed by XRPD
`thermal analysis FTIR SEM and solubility testing Sam
`ples of the various paclitaxel morphologies were obtained
`by the application of various solvents and methods Under
`conditions that used the same solvent
`the physicochemical
`properties which include particle size appearance and
`amount of residual solvent differed In the case of dichlor
`omethane amorphous paclitaxel was obtained using every
`protocol The dihydrated crystalline form of paclitaxel was
`obtained by precipitation in water after dissolving in either
`acetone or THF followed by filtration Anhydrous crystal
`line paclitaxel was also obtained by these methods using
`other solvents such as acetone and ethylacetate
`The recovery of paclitaxel by evaporation under reduced
`pressure is much more difficult
`than recovery by the pre
`cipitation method due to sample coating of
`the surface
`of the flask However paclitaxel
`recovery in the precipi
`tation method was easily achieved by simple filtration In
`addition the anhydrous paclitaxel obtained by colloid for
`mation was of small particle size and had lower residual
`solvent content after vacuum drying Unlike the other
`
`

`

`1762
`
`PYO ET AL
`
`solvents the acetone formed colloidal
`solution of pacli
`taxel was evenly dispersed at a paclitaxel concentration of
`
`100 wv and the colloid form of highly concentrated
`paclitaxel >11 wv was evenly dispersed The resulting
`colloidal paclitaxel was easily recovered
`by evaporation
`reduced
`pressure without product coating of
`under
`the
`surface of the flask
`
`levels of
`
`The
`solvents were analyzed after
`vacuum drying for 3 days Table 1 Paclitaxel for clinical
`use should be dried to minimize the amount of residual
`
`residual
`
`solvent
`
`in accordance with the International Conference
`on Harmonization ICH guideline Q3C titled Impuri
`ties Residual Solvents Which Depend
`on Solvents
`Thus the effective
`removal of
`is an
`residual
`solvents
`
`be
`
`readily
`
`In samples A J and K
`factor
`important processing
`which were prepared by the conventional method there
`were high levels of residual solvents although these levels
`in the ICH
`than the recommended levels
`were lower
`guideline Samples B C D E G H and L which were
`obtained by the precipitation method tended to have low
`levels with the exception of sample G
`residual solvent
`Sample F which was
`by the
`spray drying
`obtained
`method and sample I which was obtained by colloid for
`mation showed low levels of residual solvents In general
`crystalline form contains 447 ± 072
`the dihydrated
`ww moisture which can
`removed by
`
`it
`
`the product
`
`simple vacuum drying
`Using the different preparation methods precipitation
`spray drying and
`colloid formation the amorphous
`anhydrous crystalline and dihydrated crystalline form of
`paclitaxel were obtained with high yields short processing
`times good reproducibility and high efficacy In previous
`studies5141 amorphous paclitaxel was prepared by heating
`to the melting temperature of 221°C followed by quench
`cooling as well as by freeze drying at 50°C Melting at
`221°C constitutes a harsh treatment
`that may lead to pro
`and freeze drying involves subjecting
`duct decomposition
`to 50°C for long periods of time
`and
`the crystalline forms of paclitaxel
`In general
`docetaxel have been prepared by dissolving at 40 60°C in
`a solvent such as methanol ethanol acetone or acetoni
`followed by recrystallization
`days
`for
`several
`at
`trile
`0 4°C172122 In these methods paclitaxel becomes oversa
`turated when subjected to high temperature and stirring for
`1 h ie the conditions necessary for high yields after crys
`tallization However
`is unstable especially in
`paclitaxel
`solutions of methanol ethanol and acetonitrile
`as well
`solutions91 Paclitaxel may be
`as in non neutral aqueous
`and epimerized under
`these conditions which
`degraded
`involve dissolving heating and stirring at 60°C for at least
`1 h In reality paclitaxel
`is rapidly degraded and epimerized
`and
`such as 10deacetylpaclitaxel
`to various compounds
`in methanol and acetonitrile solutions at
`7epipaclitaxel
`50°C data not shown Therefore these methods are not
`
`low yields
`suitable for
`production
`largescale
`give
`have poor
`longterm storage and can generate degraded
`paclitaxel due to the high temperatures used It
`to produce paclitaxel of >995 purity using
`difficult
`these methods which have been claimed as unique and
`useful technologies172122
`Thus the methods of spray drying precipitation and
`colloid formation are remarkably efficient and convenient
`when compared with conventional methods
`techniques
`such as evaporation recrystallization and melting
`
`is very
`
`in
`
`X Ray Powder Diffraction Thermal Analysis
`and FTIR Analysis
`All of the sample morphologies were confirmed by the
`XRPD technique
`are shown
`representative spectra
`Fig 1 The XRPD patterns of the amorphous and crystal
`line forms were significantly different The pattern of the
`amorphous form showed a broad line while many sharp
`peaks were noted for the dihydrate and anhydrous crystal
`line forms Taking into consideration the previous study51
`between
`and
`the
`differences
`in
`patterns
`dihydrate
`anhydrous paclitaxel can be easily confirmed by comparing
`the peak intensities eg 61 95 132 138° 20
`The DSC data for all of
`the samples were obtained
`between 25 and 250°C Fig 2 The DSC thermograms of
`the amorphous dihydrated crystalline and anhydrous crys
`talline forms were significantly different These results are in
`accordance with those of the previous study51 There was
`no significant single melting endotherm around 223°C as seen
`the anhydrous crystalline form and there were no
`for
`significant peaks at 70 140°C as noted for the dihydrate
`
`500
`
`1000
`
`2000
`
`020
`
`3000
`
`FIG 1 XRPD analysis of paclitaxel morphologies Representative
`spectra are shown for amorphous
`
`paclitaxel B dihydrated crystalline
`paclitaxel H anhydrous crystalline paclitaxel I and mixed crystalline
`paclitaxel N
`
`

`

`MORPHOLOGIES AND DISSOLUTION PROFILES OF PACLITAXEL
`
`1763
`
`3656 C
`are
`
`8878 C
`
`5144
`156408
`
`15550 C 00
`
`15E57 t
`
`15867
`
`151169 C
`
`789769V18810 C
`
`191150 C
`
`11405
`
`22330
`
`210137
`
`22028 t
`
`Temperabre t
`paclitaxel H anhydrous crystalline paclitaxel I and mixed crystalline paclitaxel N
`
`1bo
`
`163
`
`FIG 2 DSC analysis of paclitaxel morphologies Representative thermograms
`
`are shown for amorphous
`
`paclitaxel B dihydrated
`
`crystalline
`
`crystalline form Weight
`loss due to water evaporation was
`<10 for the amorphous and anhydrous crystalline forms
`according to the nonstructural water used in the TGA analy
`sis On the other hand weight loss for the dihydrated crystal
`line form was around 45 while the theoretical water
`is 405 Sample N which
`content of dihydrated paclitaxel
`a mixture of the dihydrated crystalline form and
`contained
`anhydrous crystalline form Figs 1 and 2 showed a weight
`loss of 24 These weight
`losses of samples were good
`agreement with theoretical water content
`respectively
`FTIR analysis was also used to distinguish the different
`morphologies Fig 3 In particular the peak pattern in the
`1700 cm 1
`range gave distinctive results for the different
`morphologies The peak patterns for the amorphous dihy
`drated crystalline anhydrous crystalline and commercial
`Sigma forms were broad singlet slightly doublet doublet
`and
`were
`confirmed
`whose morphologies
`doublet
`
`respectively
`
`Appearance and Size
`All of the samples were analyzed for shape appearance
`and size using SEM Figs 4 and 5 The particle sizes
`
`conventional method
`by
`samples
`of
`obtained
`the
`were >30 lam after crushing and these were hard particles
`
`4000
`
`3500
`
`3000
`
`2500
`
`2000
`
`1500
`
`1000
`
`500
`
`Wavenumber cm
`
`FIG 3 FT IR analysis of paclitaxel morphologies Representative spec
`
`tra are shown for amorphous paclitaxel B dihydrated crystalline pacli
`taxel H anhydrous crystalline paclitaxel I and anhydrous crystalline
`paclitaxel M
`
`

`

`1 764
`
`PYO ET AL
`
`SEI
`
`50W
`
`X800
`
`lflum WO 15 Omm
`
`after dissolving in dichloromethane A precipitation in
`FIG 4 Scanning electron micrographs of amorphous paclitaxel obtained by evaporation
`hexane after dissolving in dichloromethane B precipitation in pentane after dissolving in dichloromethane C precipitation
`ing in tetrahydrofuran D precipitation
`in pentane after dissolving in dichloromethane E spray drying after dissolving in dichloromethane F
`
`in hexane after dissolv
`
`Fig 4 A and Fig 5 J and K Clusters of fine amorphous
`particles were obtained by precipitation Fig 4 B C D
`and E Particles in the shape of broken empty spheres were
`obtained by spray drying Fig 4 F Meanwhile clusters of
`
`fine dihydrate or anhydrous
`
`crystalline particles were
`or colloid formation
`
`obtained either by precipitation
`
`Fig 5 G H I and L For example sample I obtained
`and sample L
`formation using acetone
`using acetone and npentane
`obtained by precipitation
`showed
`regular needle shapes and regular plate shapes
`
`by colloid
`
`respectively Fig 5 I and L
`
`Dissolution Rates of the Amorphous Dihydrated
`Crystalline and Anhydrous Crystalline Forms of Paclitaxel
`The dissolution
`rates in cotton seed oil corn oil
`tricprylin and tributyrin were compared under conditions
`of vortexing with the temperature set at 20°C for 2 min
`
`The dissolution rates of the amorphous dihydrated crystal
`line and anhydrous crystalline forms of paclitaxel prepared
`by the different methods are summarized in Table 2 All of
`samplesFalseTable 2 A F
`the amorphous paclitaxel
`showed higher dissolution rates than the dihydrated and
`anhydrous crystalline forms for all of the applied solvents
`the solubility of the
`For example in cotton seed oil
`amorphous sample F was 43 fold or 130 fold higher than
`that of the crystalline sample I or M respectively The
`dissolution rate of the amorphous sample A obtained by
`vacuum evaporation was lower than those of the amorph
`ous samples B F obtained by either precipitation or spray
`drying under all conditions This tendency which may
`be due to the large particle size and hardness of sample A
`Fig 4 A also held true for corn oil
`tricaprylin and
`tributyrin Meanwhile the dissolution rates of dihydrated
`crystalline samples 0 and H were lower
`than those of
`
`

`

`MORPHOLOGIES AND DISSOLUTION PROFILES OF PACLITAXEL
`
`1765
`
`precipitation
`
`Scanning electron micrographs of dihydrated crystalline paclitaxel obtained by precipitation in water after dissolving in tetrahydrofuran G
`FIG 5
`in water after dissolving in acetone H Scanning electron micrographs of anhydrous crystalline paclitaxel obtained by colloid formation
`after dissolving in ethylacetate K
`in acetone followed by simple evaporation I evaporation
`after dissolving in dichloromethane J evaporation
`in pentane after dissolving in actone L
`
`precipitation
`
`in tributyrin and were higher
`the amorphous forms except
`I and
`than those of the anhydrous crystalline samples
`L Anhydrous crystalline sample I with a regular needle
`shape and sample L with a regular plate shape showed
`J and K which
`lower dissolution
`rates
`than samples
`were obtained by evaporation under reduced pressure The
`crystalline form of paclitaxel which has a unique structure
`and appearance may cause the solubility to decrease As we
`the paclitaxel samples purchased from Sigma and
`expected
`Hauser which have large crystalline structures had the
`
`lowest dissolution rates Table 2 samples M and N
`
`Dissolution Profiles of the Amorphous Dihydrated
`Crystalline and Anhydrous Crystalline Forms of Paclitaxel
`The dissolution profiles of the amorphous dihydrated
`crystalline and anhydrous crystalline forms of paclitaxel
`in cotton seed oil are shown in Figs 6 and 7 The dissolution
`
`profiles of the amorphous samples were similar to each
`other However
`the dihydrated and anhydrous crystalline
`samples had very low dissolution rates with the exception
`of samples J and K which were prepared by evaporation
`Although samples J and K were crystalline forms of pacli
`they showed higher dissolution rates because they
`taxel
`resembled sample A with respect
`to surface properties
`and appearance which was also prepared by evaporation
`Figs 4 and 5 Since these samples had no regular crystal
`structures and a hard appearance the dissolution rates were
`expected to be similar The dissolution rates of sample F
`were the fastest while those of sample I and the commercial
`samples M and N were the lowest
`Crystalline structure is an important factor
`ution rate as well as for particle size Although paclitaxel
`that was formulated in a vehicle composed of a 5050 blend
`of Cremophor EL and ethanol showed promising clinical
`
`for dissol
`
`

`

`1766
`
`PYO ET AL
`
`TABLE 2
`Comparison of dissolution rates for the various forms of paclitaxel
`Solubility mgmL
`
`Solvent
`
`Morphology
`
`Preparation method
`
`Cotton seed oil
`
`Corn oil
`
`Tricaprylin
`
`Tributyrin
`
`Amorphous
`Amorphous
`Amorphous
`Amorphous
`Amorphous
`Amorphous
`Dihydrated
`
`Dihydrated
`
`Anhydrous
`
`Anhydrous
`
`Anhydrous
`
`Anhydrous
`
`Evaporation
`
`Precipitation
`
`Precipitation
`
`Precipitation
`
`117
`
`180
`
`190
`
`180
`
`Precipitation
`
`Spray dry
`
`Precipitation
`
`Precipitation
`Colloid formation
`
`Evaporation
`
`Evaporation
`
`Precipitation
`Commercial
`
`121
`205
`171
`
`187
`214
`367
`040
`049
`013
`139
`
`146
`033
`004
`
`318
`386
`371
`403
`382
`400
`220
`186
`17
`329
`337
`79
`030
`
`490
`613
`642
`651
`683
`634
`666
`686
`175
`507
`494
`313
`298
`
`Sample
`A
`B
`C
`D
`E
`F
`G
`H
`
`I
`
`J
`
`K
`L
`Nib
`Nb
`
`170
`260
`025
`051
`006
`126
`132
`031
`002
`004
`Commercial
`The morphologies of the amorphous dihydrated crystalline and anhydrous crystalline forms of paclitaxel were analyzed by
`XRPD
`bSamples M and N were purchased
`
`from Sigma and Hauser
`
`respectively
`
`effects Cremophor EL induced significant side effects such
`neurotoxicity nephrotoxicity and the
`as hypersensitivity
`extraction of plasticizers from the intravenous
`infusion
`catheter781 To overcome these obstacles numerous alter
`native pharmaceutical
`formulations such as
`liposomes
`and microspheres have been proposed9111
`cyclodextrins
`Solubility and dissolution rate are important
`factors for
`the development of drug delivery systems and these factors
`have been studied with regard to low solubility pharmaceu
`ticals in the presence of carriers cosolvents and surfac
`the solubility of valdecoxib was
`tants For example
`
`significantly by using PEG 4000 as the carrier
`enhanced
`ethanol as the cosolvent and sodium lauryl sulfate as the
`The
`surfactant231
`solubility of
`aqueous
`entacapone
`increased with increasing pH241 The dissolution rate of
`rofecoxib was enhanced by using solid dispersions SDs
`in urea as the carrier251 However
`these successes were
`achieved by changing the properties of the solution or by
`the inclusion of additives In this study the dissolution rate
`of paclitaxel was enhanced
`by the generation of
`the
`amorphous form
`
`12
`
`18
`
`G m H a 1
`
`30
`
`24
`Time hr
`K
`
`J
`
`42
`
`48
`
`M
`
`N
`
`E 6
`
`E 5
`
`LI
`
`4
`
`2 3
`
`min
`
`2 0 2
`
`Co
`
`FIG 7 Dissolution profiles of the dihydrated crystalline and anhydrous
`crystalline forms of paclitaxel
`in cotton seed oil
`
`2 min
`
`12
`
`18
`
`24
`
`30
`
`Time hr
`
`A
`
`B
`
`C
`
`42
`
`F
`
`FIG 6 Dissolution profiles of amorphous paclitaxel
`
`in cotton seed oil
`
`

`

`MORPHOLOGIES AND DISSOLUTION PROFILES OF PACLITAXEL
`
`1767
`
`CONCLUSIONS
`Most of the paclitaxel supplied commercially is in the
`anhydrous crystalline form which has a low dissolution
`rate and
`be
`used
`in formulation and
`can
`delivery
`studies26271 However
`there have been few reports on the
`controlled release of amorphous paclitaxel
`In the present
`study we conclude
`the dissolution rate of paclitaxel
`is one of the most
`in pharmaceutical
`important
`solvents
`factors in developing new delivery systems Paclitaxel with
`a high dissolution rate could be applied in various ways
`and at higher concentrations We expect
`that studies of
`delivery systems with controlled release of amorphous
`paclitaxel will overcome
`the clinical problems associated
`with the use of Cremophor EL and will
`facilitate the
`development of more effective
`formulation systems
`
`that
`
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