C Taylor Francis
`
`row Group
`
`Taylor
`
`AUG DEVELOPMENT
`AND INDUSTPt Ai
`44AFIMACY
`
`Drug Development and Industrial Pharmacy
`
`ISSN 03639045 Print 15205762 Online Journal homepage httowwwtandfonlinecomloiiddi20
`
`Conteol of Crystal Growth in Drug Suspensions
`1 Design of a Conteol Unit and Application to
`Acetaminophen Suspensions
`
`K H Ziller
`
`H Rupprecht
`
`To cite this article K H Ziller H Rupprecht 1988 Conteol of Crystal Growth in Drug
`Suspensions 1 Design of a Conteol Unit and Application to Acetaminophen Suspensions Drug
`Development and Industrial Pharmacy 141517 23412370 DOI 10310903639048809152019
`
`To link to this article httpdxdoiorg10310903639048809152019
`
`I
`
`I
`
`MOODIl
`
`Published online 20 Oct 2008
`
`aSubmit your article to this journal 0
`
`1111 Article views 77
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`51 View related articles 0
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`ft Citing articles 10 View citing articles 0
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`Full Terms Conditions of access and use can be found at
`
`httpwwwtandfonlinecomactionjournalInformationjournalCode=iddi20
`
`Download by American Red Cross Tom Poison
`
`Date 11 May 2017 At 1 1
`
`1 5
`
`Abraxis EX2050
`Actavis LLC v Abraxis Bioscience LLC
`1PR201701101 1PR201701103 1PR201701104
`
`
`
`row Group
`
`Taylor
`
`AUG DEVELOPMENT
`AND INDUSTPt Ai
`44AFIMACY
`
`Drug Development and Industrial Pharmacy
`
`ISSN 03639045 Print 15205762 Online Journal homepage httowwwtandfonlinecomloiiddi20
`
`Conteol of Crystal Growth in Drug Suspensions
`1 Design of a Conteol Unit and Application to
`Acetaminophen Suspensions
`
`K H Ziller
`
`H Rupprecht
`
`To cite this article K H Ziller H Rupprecht 1988 Conteol of Crystal Growth in Drug
`Suspensions 1 Design of a Conteol Unit and Application to Acetaminophen Suspensions Drug
`Development and Industrial Pharmacy 141517 23412370 DOI 10310903639048809152019
`
`To link to this article httpdxdoiorg10310903639048809152019
`
`I
`
`I
`
`MOODIl
`
`Published online 20 Oct 2008
`
`aSubmit your article to this journal 0
`
`1111 Article views 77
`
`51 View related articles 0
`
`ft Citing articles 10 View citing articles 0
`
`Full Terms Conditions of access and use can be found at
`
`httpwwwtandfonlinecomactionjournalInformationjournalCode=iddi20
`
`Download by American Red Cross Tom Poison
`
`Date 11 May 2017 At 1 1
`
`1 5
`
`Abraxis EX2050
`Actavis LLC v Abraxis Bioscience LLC
`1PR201701101 1PR201701103 1PR201701104
`
`
`
`DRUG DEVELOPMENT
`
`AND INDUSTRIAL
`
`PHARMACY 141517 23412370 1988
`
`CONTROL OF CRYSTAL GROWTH
`IN DRUG SUSPENSIONS
`
`1 DESIGN OF A CONTROL UNIT AND APPLICATION TO
`
`ACETAMINOPHEN SUSPENSIONS
`
`KH Ziller and H Rupprecht
`
`Department of Pharmaceutical
`
`Technology
`
`University of Regensburg
`
`Universitatsstr
`
`31
`
`D8400 Regensburg FRG
`
`ABSTRACTS
`
`A monitor system is described for the control of particle
`
`growth by crystallization in real pharmaceutical
`
`Dedicated to ProfDr E Nurnberg on the occassion
`
`of his 60th birthday
`
`2341
`
`Copyright © 1988 by Marcel Dekker Inc
`
`
`
`2342
`
`ZILLER AND RUPPRECHT
`
`suspensions based on the measurement of drug concentration
`
`in the liquid phase in contact with the drug crystals The
`
`control unit consists of a thermostated vessel containing
`
`the drug suspension and a monitoring circuit
`including a
`dedector ie refractive index UV absorption The
`is recorded in
`concentration of
`the liquid supernatant
`
`parallel with the actual
`
`temperature Typical concentration
`
`time curves indicate any dissolution or crystallization if
`temperature cycling AT 1 10K is applied on the
`
`suspensions
`
`It
`
`is demonstrated by acetaminophen
`
`crystals that after
`
`decreasing the temperature the crystal growth appears
`significantly impeded even by very small amounts of PVP 3
`ppm mol mass 180000 The polymer did not
`
`influence the
`
`rate of dissolution of
`
`the crystals at higher
`
`temperature
`
`Surfactants reduce the protective
`
`action of PVP on crystal
`
`growth in particular anionic surfactant which neutralize
`
`the protective action totally
`
`Crystal growth can be successfully inhibited by substances
`
`which are irreversibely adsorbed
`
`to the crystal surface by
`
`specific interactions with their functional groups and a
`
`polymer structure of high molecular mass
`
`INTRODUCTION
`
`Particle growth by crystallization is one of
`
`the most
`
`destabilizing physical processes in drug suspensions
`
`
`
`CONTROL OF CRYSTAL
`
`GROWTH
`
`IN DRUG SUSPENSIONS
`
`I
`
`2343
`
`It
`
`is promoted by temperature changes during storage
`
`especially if
`
`the solubility of
`
`the drug is strongly
`
`dependent
`
`on temperature In this case the crystallised
`
`drug may dissolve with increasing temperature
`
`followed
`
`by particle growth when the temperature decreases
`
`again Supersaturated
`
`drug solutions are then formed
`
`which stimulate crystallization Crystal growth
`
`however
`
`favours rapid sedimentation and may finally
`
`lead to non redispersable sediments or caking 1
`
`Several approaches
`
`are described in the literature both
`
`to monitor
`
`these processes and to impede
`
`crystallization from supersaturated solutions by the
`
`addition of polymers surfactants
`
`and dyes 27 We
`
`describe here a control unit designed to monitor
`
`crystal growth and dissolution even
`
`in highly
`
`concentrated
`
`suspensions
`
`The
`
`influence of additives on
`
`crystallization processes can also be evaluated
`
`CONTROL OF SUSPENSION STABILITY
`
`1 Measurement of particle size
`
`In a suspension the total volume of the solid phase is
`
`the sum of the individual volumes of the single
`particles ie crystals
`Any dissolution or crystallization process will
`
`change
`
`this solid phase volume On cooling a drug suspension
`
`
`
`2344
`
`ZILLER AND RUPPRECHT
`
`particle growth from supersaturated solution may be the
`
`preferred process with the suspended crystals acting
`
`as nuclei Consequently the particle size of
`crystals increases This can be evaluated from mea
`
`the
`
`surements of the particle size distribution in the
`suspension 28910
`
`Different
`
`techniques
`
`have been described for example
`
`the Andreasen pipette 9 the Coulter Counter 2810
`determination from microscopic images 4 However
`
`or the semi or full automatic particle size
`
`the
`
`analysis of representative samples from pharmaceutical
`
`concentrated suspensions is more or less an arbitrary
`
`procedure
`
`Any pretreatment of
`
`the suspensions such as
`
`shaking redispersion etc as well as the sampling
`
`location in the suspension are not standardized
`
`An alternative approach is the study of crystal growth
`
`on single crystals mounted under
`
`the microscope
`
`Although this method is an elegant principle it maybe
`
`restricted to fundamental aspects such as the
`
`individual growth of different crystal
`
`faces
`
`changes
`
`in crystal habit etc It does not account
`
`for the
`
`mutual
`
`influence of solid particles in real
`
`suspensions In addition experimental difficulties
`
`arise from the need for proper mounting of the crystals
`
`
`
`CONTROL OF CRYSTAL
`
`GROWTH
`
`IN DRUG SUSPENSIONS
`
`I
`
`2345
`
`and from necessity of a constant and equal flow of the
`feeding solution around the crystal 41112
`
`2 Control of solute concentration in the liquid phase
`
`Sekikawa 12 proposed control of crystallization in
`suspensions by monitoring the concentration of the drug
`
`in the liquid phase In a closed suspension system
`
`dissolution and crystallization must change
`
`the
`
`concentration of
`
`the solute in the liquid phase In
`
`this way coprecipitation and particle growth from
`
`ethanolic acetaminophen solutions have been controlled
`
`by intermittant measurement of
`
`the drug concentration
`
`in the supernatant
`
`liquid
`
`This method can however
`
`be improved by continously
`
`controlling the drug concentration in the liquid phase
`
`of a suspension both under
`
`isothermal and temperature
`
`cycling conditions thereby simulating the stress on
`
`storage at varying temperatures
`
`According to Varney 14 the rate of crystal growth is
`on a variety of parameters such as the
`dependent
`solubility of the drug ie the saturation
`concentration and their temperature dependence
`
`the
`
`
`
`2346
`
`ZILLER AND RUPPRECHT
`
`degree of supersaturation the temperature difference
`
`on storage and the frequence of
`
`temperature cycling
`
`Any mechanical stress such as stirring must also be
`
`considered Particles smaller than 1 Am may
`
`additionally exhibit Ostwald ripening
`
`3 Description of
`
`the Suspension Control Unit
`
`The control unit was designed to measure drug
`
`concentration in the liquid phase and simultaneously
`
`the temperature in the suspension Depending on the
`
`applied monitor system the concentration of additives
`
`influencing the crystallization can also be determined
`
`The main elements and their function are shown in
`
`Fig 1 A graduated Erlenmayer flask with a ground glass
`
`stopper containing connecting passages
`
`is used as a
`
`liquid phase to which the solid drug is added
`
`The
`
`the
`
`stirrer vessel 1 This contains 50100 ml of
`suspension is then stirred by a magnetic stirrer 2 at
`ca 300 RPM driven by a magnetic water turbine 4
`Feddeler Essen FRG Sliding bearings can adjust
`
`stirrer
`
`shank in the stopper
`
`The Erlenmeyer flask is
`
`contained in a thermostat
`temperature adjustment
`than t 011 and is equipped with heat
`
`better
`
`the
`
`
`
`FIGURE 1
`System for monitoring the drug concentration in the liquid
`
`phase of suspensions during temperature cycling
`
`1 stirrer vessel
`
`2 stirrer with bearing
`
`axis magnetic pin
`
`8
`
`9
`
`peristaltic pump
`
`septum for sample
`
`injection and
`
`sampling an
`
`bubble removement
`
`3 heat exchanger
`
`TM
`
`temperature
`
`heating and cooling
`
`control
`
`4 turbine for the magnetic
`
`Therm thermostat
`
`for
`
`stirrer drive
`
`5
`
`temperature sensor
`
`6 frit
`
`temperature
`
`control of
`
`the
`
`suspension
`
`7 membrane
`
`filter
`
`Th
`
`thermostat
`
`for the
`
`monitor system
`
`NO
`
`monitor for drug
`
`concentration
`
`Rec
`
`twin channel
`
`recorder
`
`
`
`2348
`
`ZILLER AND RUPPRECHT
`
`exchangers
`
`Braun Frigomix 1496Thermomix
`
`1480 BKV unit
`
`for heating and cooling 3 supplied by a
`= Therm
`A Pt 100 sensor 5 connected
`to a Knauer control unit
`TM controlls the temperature in the suspension
`
`A circuit
`
`is then established to control drug andor
`
`additive concentrations
`
`The
`
`liquid phase is
`
`transported through Teflon and Isoversinic tubes by
`
`means of a peristaltic pump Gilson Miniplus 8 The
`G3 or G4 6 to trap
`
`circuit starts with a glass frit
`
`course solid particles
`
`The liquid then passes
`
`through
`
`a membrane filter
`
`dpore 8 Am cellulose nitrate
`Sartorius 7 and a HPLCseptum injector Perkin
`Elmer 9 so as to remove fine particles and bubbles
`
`before passing the monitor The monitors applied were
`
`selected from HPLC equipment
`
`a differential
`
`refractometer Knauer
`
`single beam UV
`
`spectrophotometer Gilson spectrochrome U Shimadzu UV
`
`102 and UV 10002 and double beam spectrophotometer
`UV 210A Shimadzu were used
`
`The
`
`flow through cells in the monitor are maintained at
`
`temperatures
`
`10K higher
`
`than the upper limiting
`
`temperature of any cycle thermostatsIn this way
`
`is avoided
`For UV
`crystallization in the cuvettes
`measurements quartz cells 110 mm are used Hellma
`
`
`
`CONTROL OF CRYSTAL
`
`GROWTH
`
`IN DRUG SUSPENSIONS
`
`I
`
`2349
`
`The
`
`following parameters have to be considered when
`
`selecting an appropriate monitor
`
`linearity between the
`
`signal and the drug concentration controlled by
`
`calibration the sensitivity the signaltonoise
`
`ratio and the thermic drift
`
`compensation
`
`Due
`
`to the
`
`high concentrations in saturated drug solutions it
`
`is
`
`better
`
`to measure concentration at a wave length apart
`
`from the absorption maximum In this case the validity
`
`of
`
`the Lambert Beer law has to be carefully evaluated
`
`Temperature and concentration signals are recorded in
`
`parallel versus time as is demonstrated in Fig 2
`
`The following criteria are prerequisites for an
`
`adequate control of a suspension system
`
`a dissolution and crystallisation can be directly
`
`controlled by drug concentration without dilution
`
`steps
`b the rates of dissolution and crystallization are
`
`relatively high
`c polymorphism and pseudo polymorphism are excluded
`d interaction between drug crystals and excipients
`
`are well defined or can be independently
`
`determined
`e influences on crystal growth can be independently
`measured by other methods 471113
`
`
`
`HYMIZ
`
`GMV
`
`1HDU1ddflU
`
`MIN
`
`tom
`
`110
`
`2101
`
`3104
`
`06
`
`5110
`
`30
`
`61
`
`715
`
`0
`
`CONC
`
`CYC1
`
`followingfigures
`
`the
`
`hatchedareaalsoi
`
`n
`
`the
`
`curveover
`
`Temperature
`
`ml
`
`5mg100
`
`mg100m
`
`l
`
`10
`
`04
`
`02
`
`K17
`
`K30
`
`PVP
`
`PVP
`
`bAdditive
`
`aAdditive
`
`3
`
`ml
`
`100
`
`naqueousacetaminophensuspensions
`
`Temperaturecyclingi
`
`FIGURE2
`
`TIME
`
`50
`
`40
`
`30
`
`20
`
`01
`
`0
`
`MIN
`
`TIME
`
`40
`
`30
`
`20
`
`01
`
`0
`
`3
`
`6r
`
`rf
`
`CYCj
`
`11 11
`
`ZOO
`
`110
`21O
`
`A
`
`1I iI01
`
`51T
`
`O
`
`40
`
`100
`
`II
`
`71
`
`Normomu
`
`PVP
`
`OF
`
`CONC
`
`ONT
`
`MIJ
`
`G100
`
`CvC
`
`CONC
`H
`
`ACETAMINOPHEN
`
`21H
`
`1261
`
`22uj
`
`11q30
`
`a
`
`136
`
`133
`
`C
`
`git
`
`25
`
`24
`
`23
`
`11
`
`b
`
`a
`
`
`
`CONTROL OF CRYSTAL
`
`GROWTH
`
`IN DRUG SUSPENSIONS
`
`I
`
`2351
`
`4 Design of Temperature Cycling
`
`14g of drug particle size 10
`
`50 Am are necessary
`
`for one experiment suspended in 50100 ml
`
`liquid
`
`phaseThe experiments are carried out at
`
`room
`
`temperature
`
`AT ± 10K
`
`according to the temperature
`
`conditions during distribution and storage of drug
`
`preparation 60 min proved to be a reasonable compromise
`
`for one temperature cycle Considering heating and
`
`cooling rates the length of
`
`temperature plateau phases
`
`at
`
`the upper
`
`limiting temperature to attain
`
`equilibrium and a cooling period limited to 30 min
`
`5The Control of Crystal Growth of Acetaminophen
`
`in the
`
`Presence of PVP
`
`The
`
`function and sensitivity of the control unit was
`
`evaluated by means of model suspensions as to evaluate
`
`and predict suspension stability Acetaminophen was
`selected as a drug model and polyvinylpyrrolidone PVP
`
`as an effective additive to inhibit crystal growth
`41215
`
`In Fig 2a2b dissolution and crystallization of
`
`acetaminophen
`
`in aqueous
`
`suspensions during temperature
`
`cycling are demonstrated PVPs of different molecular
`
`
`
`2352
`
`ZILLER AND RUPPRECHT
`
`mass were added
`
`to the suspensions
`
`In the diagrams the
`
`temperature
`
`curve over
`
`the hatched area and the
`
`concentration of
`
`the drug in the liquid phase versus
`
`the time are given Locating marks indicate the points
`
`of
`
`temperature reversal
`
`The number of temperature
`
`cycles are listed in the column cyc and the
`the added PVP in the column cone
`
`concentration of
`
`During the cooling periods the rate of crystallization
`
`obviously decreases with increasing amounts of PVP in
`
`the suspensions Significant
`
`influences both on
`
`dissolution and crystallization are exhibited by PVP
`
`m 43000 and PVP K90 mol mass m
`K30 mol mass
`180000Fig 38 The PVP K17 with its lower molecular
`
`mass of m 9000 has only a minor influence on these
`
`processes
`
`The number of temperatur cycles also influences the
`
`effectiveness
`
`of PVP Starting with the 4th cycle
`
`supersaturated solutions are obtained during the
`
`dissolution period related to the solubility at
`
`the
`
`upper limiting temperature The concentration passes
`through a maximum after 810 min then declines to the
`
`saturation concentration Simultaneously the inhibiting
`
`action on crystallization at the lower limiting
`
`temperature appears more pronounced
`
`and
`
`supersaturated suspensions are stabilized over several
`
`
`
`K9
`
`0
`
`PVP
`
`f5m
`
`g
`
`bSingularadditiono
`
`CONTROL OF CRYSTAL
`
`GROWTH
`
`IN DRUG SUSPENSIONS
`
`UI
`
`5 55 5
`
`CONC
`
`mg100m
`
`l
`
`15
`
`02
`
`K90
`
`PVP
`
`aAdditive
`
`naqueousacetaminophen
`
`Temperaturecyclingi
`
`3
`
`ml
`
`100
`
`suspensions
`
`TIMEM
`
`IN
`
`ZO50
`
`3I0
`
`20
`
`10
`
`0
`
`MIN
`
`TIME
`
`50
`
`i
`
`LO
`
`30
`
`20
`
`T
`
`T
`
`10
`
`0
`
`FIGURE3
`
`126
`
`130H
`
`cc
`
`cc a
`
`133
`
`0
`
`1361
`
`3 0 0
`
`1401
`
`261
`
`251
`
`241
`
`231
`
`221
`
`211
`
`b
`
`a
`
`
`
`2354
`
`ZILLER AND RUPPRECHT
`
`hours This is also demonstrated by temperature cycling
`
`at constant concentrations of PVP after the second
`cycle 5 mg100 ml PVP K90 Fig 313 Only a small
`
`decrease
`
`in concentration is observed during repeated
`
`cooling periods
`
`In Fig 4 acetaminophen
`
`concentrations are shown
`
`obtained during the cooling periods of temperature
`
`cycling after 10 and 25 min respectively
`
`They are
`
`contrasted with the increasing amounts of PVP K17 and
`
`PVP K90 semilogarithmic plot added to the system An
`
`effective inhibition of crystallization is indicated by
`
`high drug concentrations in the supernatant at
`
`low PVP
`
`concentrations and by a small difference between the
`
`concentration curves at 10 min and 25 min It
`
`is thus
`
`confirmed that PVP K 90 is a potent crystallization
`
`inhibitor With increasing frequency of temperature
`
`cycling the inhibiting action of PVP K90 is reduced
`
`to
`
`a fairly constant
`
`level
`
`even after a further increase
`
`of polymer concentration identical values were
`
`obtained by PVP K 30 not shown in this diagram
`
`is concluded
`From these experiments it
`that
`approximately 3mg PVP = 30 ppm K30 or K90 is the most
`effective amount of polymer to inhibite the
`
`crystallization of acetaminophen
`
`in suspensions
`
`
`
`CONTROL OF CRYSTAL
`
`GROWTH
`
`IN DRUG SUSPENSIONS
`
`I
`
`2355
`
`c
`
`AT 253 °C
`UPPER TEMPERATURE
`
`LIMIT
`
`br
`
`A
`
`I
`
`0
`
`oI
`
`4
`
`1
`
`02
`
`1
`05
`
`PVP K17
`
`0
`64
`6o AFTER 10 MIN
`lir AFTER 25 MIN
`AFTER 10 MIN COOLING
`
`PVP K90
`
`05 AT
`207 °C
`LOWER TEMPERATURE
`
`LIMIT
`
`10
`
`5
`
`10
`
`POLYMERE
`
`CONC MG10 0 ML
`
`FIGURE 4
`
`140 J
`
`135
`
`130
`
`71
`
`D9
`
`CONC
`
`ACETAMINOPHEN
`
`Temperature cycling in aqueous acetaminophen
`
`suspensions Drug concentration in the supernatant
`
`liquid phase in the presence of
`
`o
`
`A
`
`o
`
`A
`
`PVP K17 10 min
`
`PVP K90 10 min
`
`0
`
`A
`
`0
`
`A
`
`PVP K17 25min
`
`PVP K90 25 min
`
`
`
`2356
`
`ZILLER AND RUPPRECHT
`
`4nitroacetanilide was introduced for comparsion as a
`
`drug model The stucture of this molecule differs in
`the paraposition to the acetamino groups ie the OH
`group is replaced by a nitro group In this way the
`
`influence of single functional groups on drug
`
`crystallization in the presence of PVP can be evaluated
`Fig 5 The
`crystallization of 4nitroacetanilide appears
`
`inhibitory effect of PVP K50 on the
`
`to be
`
`smaller compared with acetaminophen However
`
`BSA a
`
`polymer of the proteintype is also effective in crystal
`
`growth inhibition of 4nitroacetanilide at
`concentration of 20 mg100 ml = 200 ppm This may be
`due to the inability of the nitro group to form
`
`hydrogen bonds as a donor
`
`leading to weaker
`
`interactions with PVP
`
`7 Influence of
`
`low molecular pyrrolidones bovine serum
`
`albumin and surfactants
`
`on acetaminophen crystallisation
`
`71 Addition of 1methylpyrrolidone and piracetam
`
`The crystallization of acetaminophen during the cooling
`
`period in temperature cycling is not significantly
`
`influence by either 1methylpyrrolidone or piracetam
`Fig 6 Both substances
`
`are compounds of similar
`
`
`
`CONTROL OF CRYSTAL
`
`GROWTH
`
`IN DRUG SUSPENSIONS
`
`I
`
`2357
`
`0N
`
`0
`
`NC CH3
`
`CYCI
`
`40MG100ML
`BSA
`
`200MG100ML
`PVP K 30
`
`WITHOUT
`ADDITIVE
`
`2
`
`2
`
`1
`
`2 7
`
`5
`
`ACETAMINOPHENCONC
`
`190
`
`20
`
`18
`
`0
`
`<105
`w
`
`16
`
`141
`
`12
`
`0
`
`15
`
`30
`
`45 TIME MIN
`
`FIGURE 5
`
`Temperature cycling in aqueous 4nitroacetanilide
`
`suspensions 100 ml 3 Additives PVP K30 and BSA
`
`structure as the pyrrolidone monomers Even relatively
`
`high concentrations of
`
`these additives compared with
`
`PVP are ineffective During the third cycle PVP K30
`
`was added and was fully effective even in the presence
`
`of both additives These experiments confirm the
`results obtained by Metha 11 He reported that
`
`
`
`2358
`
`ZILLER AND RUPPRECHT
`
`I
`
`I
`
`I
`
`I
`
`I
`
`CH21
`Jn
`
`0
`
`` CYC
`PVP K 30 s
`20 MG 100ML
`
`3
`
`0
`
`H2C CNH2
`
`N
`
`0
`
`CH3
`
`MRACETAM1METHYL
`PYRROLIDON200MGMOOML
`
`WITHOUT
`
`ADDITIVE
`
`CONCG100ML1
`
`ACETAMINOPHEN
`
`125 I
`
`120 1
`
`1151
`
`20
`
`18
`
`Ui
`
`CC
`
`16
`
`10sLU
`CC
`
`X
`
`LU
`
`16
`
`1001
`
`0
`
`15
`
`30
`
`45 TIME MIN
`
`FIGURE 6
`
`Temperature cycling in aqueous acetaminophen
`
`suspensions 50 ml 3
`
`piracetam and 1methylpyrrolidone respectively added
`
`in the second cycle
`
`
`
`CONTROL OF CRYSTAL
`
`GROWTH
`
`IN DRUG SUSPENSIONS
`
`I
`
`2359
`
`vinylpyrrolidone does not
`
`influence the crystallization
`
`of sulfathiazole which is also a low molecular mass
`
`compound of similar structure A specific influence of
`
`the pyrrolidone ring system on the protective action of
`
`PVP can therefore be ruled out
`
`72 Addition of BSA
`
`Bovine
`
`serum albumin BSA was selected as an example
`
`of a polymer which shows strong interactions with a
`great number of drugs in aqueous solution 1519 In
`Fig 7 the influence of BSA on acetaminophen
`
`concentration in the liquid bulk phase during
`
`temperature cycling of
`
`the suspension is given This
`
`polymer
`
`inhibits the crystallization of acetaminophen
`
`to the same extent as PVP
`73 Combinations of PVP and surfactants
`
`Surfactants are reported to influence crystallization
`
`by adsorption and solubilization effects
`29102122 They are also widely used in suspension
`and preservatives 25
`formulations as wetting agents
`We studied their possible interference with both the
`inhibiting polymer 24 and the crystal surfaces during
`
`
`
`2360
`
`ZILLER AND RUPPRECHT
`
`FIGURE 7
`
`Temperature cycling in aqueous acetaminophen
`
`suspensions in the presence of BSA 50 ml 3
`
`temperature cycling experiments with acetaminophen
`
`suspensionsThe
`
`crystallization of acetaminophen is not
`
`influenced by the nonionic polyoxyethylene
`
`polypropylene copolymer Pluronic F68
`
`
`
`CONTROL OF CRYSTAL
`
`GROWTH
`
`IN DRUG SUSPENSIONS
`
`I
`
`2361
`
`In combination with PVP K17 the rate of crystallization is
`
`only slightly increased by the presence of
`
`Fig 8
`
`the surfactant
`
`The nonionic PEG10oleylether and hexadecylpyridinium
`
`cations both reduce the inhibiting effect of PVP on
`crystallization Fig 9a and b These surfactants are
`reported to exhibit no significant
`interactions with
`PVP in solution 2526 although they may be adsorbed
`the drug In this way they
`to the crystal surfaces of
`
`can disturb the structure of
`
`the protective polymer at
`
`the crystal surface
`
`Hexadecylsulfate
`
`however neutralizes the protective
`
`action of PVP on acetaminophen crystallization almost
`completely Fig 9b This anionic surfactant
`aggregates with PVP in the aqueous phase 27 thus
`preventing the PVP from establishing protective layers
`
`on the drug crystals
`
`DISCUSSION
`
`Specific and strong interactions between functional
`
`groups of the drug and a polymer are obviously a
`
`necessary but not a sufficient prerequisite to
`
`inhibit
`
`the crystallization from supersaturated
`
`solutions in drug suspensions
`
`This is demonstrated by
`
`
`
`2362
`
`ZILLER AND RUPPRECHT
`
`CYC 10 MG100 ML
`P V P K17
`
`0 1
`
`0 2
`
`0 MG100 ML
`PLURONIC
`F68
`
`WITHOUT
`ADDITIVE
`
`125
`
`120
`
`115H
`
`110H
`20 105
`
`73
`
`18
`
`100
`
`095
`
`160
`
`TEMPERATURE
`
`14
`
`12
`
`o
`
`1s
`
`30
`
`TIME MIN
`
`FIGURE 8
`
`Temperature cycling in aqueous acetaminophen suspension
`
`50 ml 3 in the presence of PVP K17 and pluronic F68
`
`the low molecular pyrrolidone compounds which are more
`
`or less ineffective in influencing crystallization The
`
`second essential property of a protective substance
`
`seems to be the formation of an polymer adsorbate on
`
`the surface of
`
`the drug crystals This impedes
`
`the
`
`
`
`CONTROL OF CRYSTAL
`
`GROWTH
`
`IN DRUG SUSPENSIONS
`
`I
`
`2363
`
`C
`
`b
`
`CYC
`
`PVP IC 30
`
`10OLEYL
`ETHER
`
`1 WITHOUT
`ADDITIVE
`
`ICY C
`2 PVP X 30
`
`1 HEXA
`
`DECYLPYRIDINION
`CHLORIDE
`134NA HEXA
`plcrksuLFATE
`
`jJ WITHOUT
`ADOITIVE
`
`00
`
`0
`
`0
`
`120i
`
`1101
`
`100
`
`°C
`
`TEMPERATURE
`
`20
`
`18
`
`16
`
`141
`
`12
`
`0
`
`15
`
`30 TIME MIN
`
`0
`
`15
`
`30
`
`TIME MIN
`
`FIGURE 9
`
`Temperature cycling in aqueous acetaminophen
`
`suspensions 50 ml 3 in the presence of mixtures of
`PVP K30 20 mg100 ml with
`
`a PEG10oleylether
`b hexadecylpyridinium chloride and sodium
`
`hexadecylsulfate
`
`respectively
`
`
`
`2364
`
`ZILLER AND RUPPRECHT
`
`FROM
`DETERMINED
`SUPERNATANT
`rt 11
`
`LJ
`
`0
`
`o
`
`0
`
`o
`
`FROM
`DETERMINED
`mrsnn nyr rI171ACITIMAI
`HLAJWID41C Urnrvoi
`two
`
`301
`
`1
`
`20
`
`1010
`
`Z 7
`
`ADSORBEDAMOUNT
`
`20
`
`60
`10
`EQUILIBRIUM CONC MG100ML
`
`BO
`
`FIGURE 10
`
`Adsorption of PVP 14CK1 9K17 150 onto
`
`acetaminophene
`
`crystals
`
`approach of drug molecules from solution onto free
`
`spaces of
`
`the crystal
`
`lattice
`
`In the series of pyrrolidone compounds applied to
`
`acetaminophen
`
`suspensions only the high molecular mass
`
`polymers PVP K50
`
`PVP K90 show a pronounced
`
`protective action The adsorption of PVP K17 on
`
`acetaminophen crystals is shown in Fig 10 The
`
`
`
`CONTROL OF CRYSTAL
`
`GROWTH
`
`IN DRUG SUSPENSIONS
`
`I
`
`2365
`
`Langmuirian nature of
`
`the isotherm indicates that
`
`the
`
`adsorption is reversible in contrast
`
`to the high
`
`molecular mass polymers It can be imagined that
`
`the structures of PVP and BSA adsorbates formed on
`from the good solvent water 28 are
`responsible for the crystallization inhibiting effect
`
`acetaminophen
`
`The polymer is hydrated to a great extent
`
`in the
`
`adsorbate and attached to the crystal surface by some
`so called trains Fig 11 Water molecules
`
`segments
`
`remain therefore in permanent contact with the
`
`crystal surface On raising the temperature the
`
`dissolution process can start
`
`immediately and drug
`
`molecules dissolved from the crystal can diffuse
`
`through the adsorbate into the bulk liquid phase
`
`The
`
`inhibiting action of PVP on crystallisation is
`
`presumably a kinetic effect
`
`PVP inhibits the
`
`introduction of drug molecules from solution into the
`
`crystal
`
`lattice by occupying the adsorption sites which
`
`are also free lattice sites The adsorption of polymers
`
`onto solids is known to become progressively more
`irreversible with increasing chain length 28 This is
`also the case if only weak or medium adsorption forces
`
`are present on a single adsorption site For the
`
`desorption of a polymer molecule the activation energy
`
`of desorption must
`
`be simultaneously achieved for every
`
`
`
`2366
`
`ZILLER AND RUPPRECHT
`
`Dissolution and Crystallization
`
`in the Presence of an Adsorbed Polymer
`
`polymer
`
`hydration shell
`
`drug solution
`
`crystal
`
`temperature
`
`increase
`
`decrease
`
`+ +
`
`drug solubility
`
`polymer adsorption
`
`polymer solvation
`
`Consequences
`
`dissolution by water
`
`crystal growth inhibited
`
`molecules in contact
`
`adsorbed polymer must
`
`between adsorbed poly
`
`be replaced from active
`
`mer molecules
`
`crystal sites
`
`FIGURE 11
`
`Schematic sketch of the polymer adsorbate on a drug
`
`crystal and the influence of
`
`temperature cycling on the
`
`adsorbate
`
`
`
`CONTROL OF CRYSTAL
`
`GROWTH
`
`IN DRUG SUSPENSIONS
`
`I
`
`2367
`
`single contact point
`
`In acetaminophen suspension only
`
`a gradual
`
`replacement of polymer contact sites on the
`
`crystals by drug molecules is envisaged
`
`The adsorbed
`
`polymer may form a mechanical barrier against
`
`crystallization which has increasing protective action
`
`by increasing the polymer chain length and
`
`consequently
`
`the irreversible nature of adsorption
`
`When applying this method to suspensions of drugs which
`
`form polymorphs or pseudopolymorphs
`
`it must be
`
`considered that the more stable crystal form may be
`
`formed as well as different crystal habits This could
`
`influence the results of
`
`the temperature cycling
`
`experiments
`
`The method we presented in this paper may be a useful
`
`tool
`
`to detect and characterize the influence of
`
`additives on drug crystallization in suspensions Even
`
`very small amounts
`
`in the ppm range
`
`show their
`
`protective action It may succesfully be applied in the
`
`optimization of suspension stability and in the control
`
`of
`
`these dosage forms
`
`REFERENCES
`
`1 Florence AT and D Attwood in
`Physicochemical Principles of Pharmacy Macmillan
`
`Houndmills Basingstoke London 1981
`
`
`
`2368
`
`ZILLER AND RUPPRECHT
`
`2 Carless JE and AA Forster JPharmPharmacol
`18 1966 697708
`IA AR Ebian SA Khalil and MM
`3 Moustafa
`Motawi JPharmSci 64 1975 14851489
`4 Simonelli AP SC Mehta and WI Higuchi
`JPharmSci 59 1970 633637
`5 Nath BS and RV Gaitonde IndJPharm 37
`1975 7780
`6 Badawi AA AA ElSayed and I Haroun
`PharmInternational 56 1977 16
`7 Nuernberg E and P Kohl PharmazZtg 124 1979
`523529
`8 Carless JE MA Moustafa and HDC Rapson
`20 1968 630638 639645
`JPharmPharmacol
`9 Hasegawa J and T Nagai ChemPharmBull
`1958 129137
`10 Higuchi WI
`and PK Lau JPharmSci
`1962 10811084
`11 Mehta SC PD Bernardo WI Higuchi
`and AP
`59 1970 638644
`Simonelli JPharmSci
`12 Mehta SC PHDThesis Univ Michigan 1969
`13 Sekikawa H M Nakano and T Arita
`Chem Pharm Bull 26 1978 118126
`14 Varney G JPharmPharmacol 19 Suppl 1967
`19s 23s
`15 Motawi AM SA Morbuda F El Khawas and KL
`28 1982 211215
`El Khodery Acta PharmTechnol
`
`51
`
`6
`
`
`
`CONTROL OF CRYSTAL
`
`GROWTH
`
`IN DRUG SUSPENSIONS
`
`I
`
`2369
`
`16 Davison C and PK Smith
`J Pharmacol Exptl Therap 133 1961 161170
`17 Eichman ML DE Guttman Q van Winkle and
`EP Guth JPharmSci
`51 1962 6671
`18 Keen PM BritJPharmacol 26 1966 704712
`19 Lindenbaum A and J Schubert
`jPhysChem 60
`1956 16631665
`20 Patel NB P C Sheen and LE Taylor
`JPharmSci 57 1968 13701374
`21 Michaels AS and AR Colville JPhysChem 64
`1960 1319
`22 Michaels AS and FW Tausch
`1961 17301734
`23 Higuchi WI Swarbrick J Norman FH Simonelli
`AP and A Martin Particle Phenomena
`Dispersions in Remingtons Pharmaceutical
`Sciences 17th ed Geunaro AR Mack
`Publishing comp Easton Pa 1985 pp 301
`24 Saito S Polymer Surfactant
`Interactions in
`Nonionic Surfactants MJ Schick ed Marcel
`
`jPhysChem 65
`
`and Coarse
`
`Dekker
`
`Inc
`
`New York Basel 1987 pp 881
`
`25 Saito S KollZuZPolymere 249 1971 1096
`
`1100
`
`26 Saito S and K Kitamura JCollIntSci
`1971 346353
`
`35
`
`
`
`2370
`
`ZILLER AND RUPPRECHT
`
`27 Saito S T Taniguchi and K Kitamura
`JCollIntSci
`154164
`28 Tadros TF in Polymer Colloids Buscall R
`Corner T and Stageman JF ed Elsevier Applied
`SciPubl
`New York 1985 pp 105
`London
`
`37 1971
`
`
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