Journal of Crystal Growth 310(2008)110–115
Crystallization mechanisms of acicular crystals
Franc -ois Puel a ,Elodie Verdurand a ,Pascal Taulelle b ,Christine Bebon a ,Didier Colson a ,
Jean-Paul Klein a ,Ste
家长会内容phane Veesler b,Ãa
LAGEP,UMR CNRS 5007,Universite
´Lyon 1,CPE Lyon,Ba ˆt.308G,43Bd du 11novembre 1918,F-69622Villeurbanne Cedex,France b
Centre de Recherche en Matie
`re Conden ´e et Nanosciences (CRMCN)1—CNRS,Campus de Luminy,Ca 913,F-13288Marille Cedex 09,France Received 10September 2007;accepted 3October 2007
Communicated by K.Sato Available online 9October 2007
Abstract
In this contribution,we prent an experimental investigation of the growth of four different organic molecules produced at industrial scale with a view to understand the crystallization mechanism of acicular or needle-like crystals.For all organic crystals studied in this article,layer-by-layer growth of the lateral faces is very slow and clear,as soon as the supersaturation is high enough,there is competition between growth and surface-activated condary nucleation.This gives ri to pudo-twinned crystals compod of veral needle individuals aligned along a crystallographic axis;this is explained by regular over-and inter-growths as in the ca of twinning.And when supersaturation is even higher,nucleation is fast and random.
In an industrial continuous crystallization,the rapid growth of needle-like crystals is to be avoided as it leads to fragile crystals or needles,which can be partly broken or totally detached from the parent crystals especially along structural anisotropic axis corresponding to weaker chemical bonds,thus leading to slower growing faces.When an activated mechanism is involved such as a condary surface nucleation,it is no longer possible to obtain a steady state.Therefore,the crystal number,size
控烟令
and habit vary significantly with time,leading to troubles in the downstream processing operations and to modifications of the final solid-specific properties.
The results provide valuable information on the unique crystallization mechanisms of acicular crystals,and show that it is important to know the threshold and critical values when running a crystallizer in order to obtain easy-to-handle crystals.r 2007Elvier B.V.All rights rerved.
PACS:81.10.Aj;81.10.Dn;78.30.Jw
Keywords:A1.Crystal morphology;A2.Growth from solutions;B1.Organic compounds
1.Introduction卵黄膜
Many organic molecules exhibit anisotropic structural properties in their crystalline form,which gives ri to acicular or needle-like crystals.In the chemical and pharmaceutical industry,crystallization from solution is ud as a paration technique,and this crystal habit is usually not desirable,especially when the internal length-to-width ratio is high,as it will lead to problems in
downstream process (filtration,drying,storage,handling,etc.).
A better understanding of the mechanisms of nucleation and growth of the needle-like crystals will therefore lead to better control of crystallization process.In the literature,papers on molecular modeling of the needle-like crystals [1–3]suggest that in the ca of needle-like crystals,there is no slow-growing face in the needle direction.Practical aspects have been also studied for a few years now in our different rearch teams [4–6].
In this contribution,we prent an experimental investigation of the growth of four different organic molecules produced at industrial scale with a view to understand the crystallization mechanism of acicular
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0022-0248/$-e front matter r 2007Elvier B.V.All rights rerved.doi:10.1016/j.jcrysgro.2007.10.006
ÃCorresponding author.Tel.:+33662922866;fax:+33491418916.
E-mail address:veesler@crmcn.univ-mrs.fr (S.Veesler).
惊喜英文怎么写1
Laboratory associated to the Universities Aix-Marille II and III.
crystals from the molecular to the macroscopic scales.For all organic crystals studied in this article,layer-by-layer growth of the lateral faces is very slow and clearly,as soon as supersaturation is high enough,there is competition between growth and activated condary nucleation.The investigations show that crystals are agglomerated with the same crystallographic orientation for the individual con-stituents,as obrved by optical microscopy,scanning electron microscope(SEM)and atomic force microscopy (AFM);this is explained by regular over-and inter-growths as in the ca of twinning.And when supersaturation is even higher,nucleation is fast and random.The results provide valuable information on the unique crystallization mechanisms of acicular crystals,and show that it is important to know the threshold and critical values when running a crystallizer in order to obtain easy-to-handle crystals.
2.Materials and methods
2.1.Materials
The four organic molecules studied were:
(i)Irbesartan(C25H28N6O),an active pharmaceutical
ingredient crystallized in2-propanol and ud by Sanofi-Aventis in the treatment of hypertension; (ii)Product2(for the sake of confidentiality),an organic molecule exhibiting an alkyl cycle with one polar chemical group:this molecule crystallizes in its industrial solvent;
(iii)Hydroquinone(C6H6O2),which crystallizes in water in the prence of an additive ud at industrial scale to specifically reduce growth along the length axis of the needle;
(iv)Product4(for the sake of confidentiality)known to exhibit only needle-like habit whatever the solvent ud.
Structural data for thefirst three molecules are prented in Table1.2.2.Solid Characterization
Crystals were obrved under a(SEM;JEOL6320F). SEM photographs clearly show the needle-like crystal habit for the four systems studied(Fig.1).Crystals of Irbesartan pha A were also obrved by AFM using a Digital Nanoscope III atomic force microscope equipped with a12m m scanner.Images were collected in tapping mode using oxide-sharpened Si3N4cantilever tips(nano-probe TM).
2.3.Crystal preparation
Irbesartan and Product4crystals were grown in quiescent solutions(2mL)at known concentrations, under optical microscope(Nikon,Diaphot),at given temperatures,using the experimental tup previously described[7].
Product2and hydroquinone crystals were obtained from isothermal crystallization in2.5L stirred vesls in mi-batch and continuous operations,respectively.Experimental pro-cedures can be found in the following references[5,6,8]. The supersaturation is defined as b=C/C e,with C and C e are the concentration and solubility of the organic molecule.
3.Results and discussion
As shown in Fig.1,all the crystals prent a needle-like habit,which is due to a strong structural anisotropy along the z-axis for Irbesartan and hydroquinone,and x-axis for Product2(e Table1).This was confirmed by molecular modeling for Irbesartan[4]and Product2[9].Product4 structure has not yet been determined.
Table1 Structural data
Irbesartan pha A a Product2Hydroquinone
pha a a
a(A)37.09 4.92238.46
b(A)37.0915.71438.46
c(A)9.658.174 5.65
a(1)909090
b(1)90104.690
g(1)12090120
a Interestingly,Irbesartan pha A and hydroquinone pha a have the same space group
R-3.
Fig.1.Needle-like crystals obrved by SEM:(a)Irbesartan pha A,
(b)Product2,(c)hydroquinone pha a and(d)Product4.
F.Puel et al./Journal of Crystal Growth310(2008)110–115111
3.1.Crystallization of Irbesartan in stagnant conditions The experiments show that in all the temperature and supersaturation ranges,2–201C and 3–10,respectively,crystals obtained (Fig.2a,c and d )have a needle-like habit,compod by crystalline agglomerates.2Moreover,when supersaturation is too low,top faces do not grow.Supersaturation must exceed a threshold value in order for growth of the crystal in the needle direction (crystal-lographic z -axis)to be obrved.The width of this dead zone is a function of the temperature and increas when the temperature decreas.The growth rate of the needle increas with increasing supersaturation up to a critical supersaturation (a cond threshold)from which activated condary nucleation appears,leading to a random nucleation of needles (Fig.2b ).
In the growth zone,below the critical supersaturation (cond threshold),AFM obrvations clearly in
dicate that the agglomerate is compod of few needle-like crystals of different sizes but with the same crystallographic orienta-tion along the z -crystallographic axis (Fig.2c and d ).
3.2.Crystallization of Product 2and hydroquinone in isothermal stirred tank
Crystallizations in stirred crystallizers were studied for the two other systems,Product 2and hydroquinone.
3.2.1.Product 2
In the ca of Product 2,crystallizations were realized in mi-batch operations,supersaturation was incread by feeding the crystallizer with a hot,undersaturated and clear solution.Moreover,the crystallizer was initially eded with well-defined crystals in order to study activated condary nucleation and crystal growth.Supersaturation was measured during the experiment by HPLC measure-ment and resulted in the profile given in Fig.3.When feeding starts (at time 0),supersaturation begins to ri.Until supersaturation reaches 1.98,only growth of ed crystals is obrved,mainly for the lateral faces.Impurities from the industrial solvent slow down the growth of the terminal faces (Fig.4a ).It is noteworthy that as in the ca of Irbesartan (Fig.2),we do not obrve growth of a single crystal but a polycrystalline growth.Then,supersaturation in the crystallize
r reaches a maximum of 1.98,a threshold value (e supersaturation profile in Fig.3).At this value,activated surface condary nucleation starts creating fine needle crystals (condary nuclei)with a longer length-to-width ratio than ed crystals (Fig.4b ).Crystals are compod of a few needle-like crystals of different sizes but with the same crystallographic orientation along the x -crystallographic axis (Fig.4c ).
Moreover,in uneded mi-batch experiments,when greater supersaturations are reached up to 2.8,crystals showing random agglomeration are obrved due to fast primary nucleation (Fig.4d )as in the ca of Irbesartan pha A (Fig.2b ).
3.2.2.Hydroquinone
中国版图Preliminary batch-eded crystallization was performed.For continuous isothermal crystallization,first a hot undersaturated solution was fed in,then crystals were
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Fig.2.Crystals of Irbesartan pha A:(a,b)optical-microscopy images,(c)AFM image and (d)SEM image.
2
Usually the term agglomeration is ud for a two-step process:encounter and association between particles suspended in solution,while in this article,the term agglomerate is ud to qualify polycrystallinity with no assumption on the mechanism of formation.
F.Puel et al./Journal of Crystal Growth 310(2008)110–115
112
nucleated and developed after which the suspension was withdrawn automatically to maintain the level of the reactor and immediately filtered.The solute concentration was measured regularly by a potentiometry analysis.Thus,the supersaturation was calculated from the knowledge of the solubility.After washing the crystals in acetone and vacuum drying,the crystals were weighed and measured [10](image analysis)and obrved under SEM.
Fig.5illustrates the supersaturation profile during one typical run.For 20residence times,supersaturati
on did not reach a constant level,as normally expected.It showed two local maxima for the sixth and the venteenth residence times.By coupling the mass balance and the crystal size distribution measurements,it was possible to evaluate the total number of crystals.This number decread with an
increa in supersaturation,and suddenly ro after a supersaturation maximum.The significant bursts of nuclei were visible to the naked eye.Before and after each supersaturation maximum,the mean dimensions of the crystals,respectively,showed a significant ri and fall.The evolution of the length-to-width ratio around the first supersaturation maximum was monitored [8].Crystals nucleated and grown before this maximum were quite thick and exhibited a rod-like habit.Converly,most of the crystals which were nucleated and grown after this maximum had a 40%higher length-to-width ratio leading to a needle-like habit (e Fig.11in Ref.[8]).Moreover,it was very instructive to obrve how the appearance of the crystal surface evolved.During the first hours of the continuous operation,crystal surfaces were very smooth (e Fig.6a ).With the increa in supersaturation,crystals appeared to be more and more twinned.After the first maximum,the surfaces were rougher.On SEM
1.0
1.2
1.41.61.8
2.00
50
100150200
柠檬美容
250
Time (min)
β
Fig. 3.Supersaturation profile of eded mi-batch crystallization of Product
2.
Fig.4.SEM pictures of Product 2crystals withdrawn (a)before threshold value at the beginning of the experiment,(b,c)after threshold value—respectively fine and ed crystals and (d)at higher supersaturation.
1,050
1,100
5
10152025
Residence time (-)
S u p e r s a t u r a t i o n r a t i o β (-)
Fig.5.Supersaturation profile in suspension of continuous
crystallization of hydroquinone.
Fig.6.SEM pictures of hydroquinone withdrawn at different residence times during a continuous isothermal crystallization—(a)reduced time ¼5:before first burst of nuclei,(b)reduced time ¼7:after first burst of nuclei,(c)reduced time ¼13:before cond burst of nuclei and (d)reduced time ¼19:after cond burst of nuclei.
F.Puel et al./Journal of Crystal Growth 310(2008)110–115
113
obrvations,the crystals were compod of numerous needle-like crystals with the same crystallographic orienta-tion along the z -crystallographic axis (e Fig.6b ).Never-theless,progressively with time,the surface appeared smoother (e Fig.6c ).A cond increa in supersatura-tion followed by a cond burst of nuclei was obrved.Contrarily to the usual continuous operation,an unsteady state lasted throughout the run (20h)although a steady state was expected after only 4h.Lastly,whatever the operating conditions tested in terms of stirring rate and solid concentration,an irregular unsteady state was always obrved,including one or two local maxima of super-saturation corresponding to thresholds where surface-activated condary nucleati
on events started.Modifica-tions in crystal surface appearance were systematically obrved at different levels of supersaturation.3.3.Discussion
In the ca of Irbesartan,growth of the lateral faces was not obrved under the conditions,meaning that the threshold supersaturation (from which growth is obrva-ble)of the faces is higher than the critical supersaturation for condary nucleation.Thus,layer-by-layer growth of the lateral faces is more difficult than nucleation,meaning that surface-activated condary nucleation is easier than growth.However,from AFM experiments (Fig.2c ),it can be assumed that the thickness of the acicular crystals is the result of agglomeration of veral single needle-crystals.This agglomeration mechanism is not known but we can speak of regular over-and inter-growths,and as in the ca of twinned crystals,two mechanisms need to be considered:
Synosis :one individual nucleates,grows and deposits itlf by one of its natural face on a face of a cond already existing individual,in a proper crystallographic orientation according to the laws of regularity [11].
Faulted two-dimensional (2D)nucleation on the original composition plane :the island is put on a twin orientation on the face of the original composition plane and grows to give the twin.Twins appear,once a threshold supersaturation has been exceeded [12,13].
The obrvation of reentrant angles in Fig.7confirms the assumption of twinning;this effect is commonly
obrved for contact twins and named as the reentrant corner effect.
The crystallization of Irbesartan and Product 4were obrved for individual crystals,which are giving informa-tion on microscopic growth mechanisms.Experiments for Product 2and hydroquinone were performed in stirred vesls,providing macroscopic information for a popula-tion of crystals on the overall growth rate;similar experiments were carried-out on b -cyclodextrin [14].However,whether one looks at the results from the microscopic or macroscopic scale experiments,similar nucleation and growth mechanisms of acicular crystals are obrved.The crystallization mechanisms of Product 2crystals are probably the same as for Irbesartan form A crystals described previously.However,the growth dead zone at lower supersaturation is not obrved for Product 2,probably becau the mi-batch crystallizations per-formed here do not provide enough information.In the experiments,at lower supersaturation,overall growth of crystals is regular and smooth but polycrystalline (e SEM pictures in Fig.4a ).At higher supersaturation,the growth mechanism is different and 2D nuclei can form onto crystal surfaces.Once formed,the nuclei detach and either (i)dissolve or grow inside the solution depending on their size,or (ii)grow on the surface of the parent crystal (synosis mechanism).
Moreover,new nuclei can form on the still-growing surface needles giving an irregular appearance to ed crystals (faulted 2D nucleation).
四环素可的松眼膏The key parameter of the changes in behavior detected during the continuous crystallization of hydroquinone is the competition between growth and surface-activated condary nucleation mechanisms.When the crystals came from a eded batch operation,at low supersaturation levels,they exhibited a very smooth surface.The growth of the lateral surfaces was slow.The kinetics of attrition was poor and the total number of crystals decread with time;consumption of solute by growth was thus less and less able to compensate for solute feeding.Supersaturation incread until a threshold was reached,leading to a burst of nuclei by a surface-activated condary nucleation.On this emerging population,the lateral surfaces were striped along the needle direction and the condary nucleation was more inten.This rough surface appearance was also obrved on crystals produced during mi-batch experi-ments performed at higher level of supersaturation than continuous operations [10].The kinetic of the condary nucleation is then linked to the crystals surface appearance.For all organic crystals studied in this article,layer-by-layer growth of the lateral faces is very slow and clearly,as soon as the supersaturation is high enough,there is competition between growth and surface-activated cond-ary nucleation.Moreover,at high supersaturation level
s,surface-activated condary nucleation and 2D nucleation,or the ‘‘Birth and Spread’’growth mechanism,are cloly linked.This gives ri to pudo-twinned crystals compod of veral needle individuals aligned along a crystal-lographic axis.
Fig.7.Optical-microscopy image of needle-like crystal of Product 4.
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