针状晶体生长机理

ARTICLE IN PRESSEI.SBVTERAvailable online at www.sciencedir6ct.conrJCHJRhWL OF CRYSTALGROWTHX* ScienceDirectJournal of Crystal Growth 310 (2008) 110 - 115Crystallizationmechanisms of acicular crystalsFranGois Puela, Elodie Verdurand a, Pascal Taulelleb, Christine Bebona, Didier Colsona,Jean-Paul Klein a, Stephane Veeslerb, ?aLAGEP, UMR CNRS 5007, Un iversite Lyon 1, CPE Lyo n, Ba?t. 308G, 43 Bd du 11 novembre 1918, F-69622 Villeurba nne Cedex, Fra neebCentre de Recherche en Matiere Condense et Nanosciences (CRMCN) Corresponding author. Tel.: +33 6 6292 2866; fax: +33 4 9141 8916. E-mail address: veeslercrmcn.univ-mrs.fr (S. Veesler). Laboratory associated to the Universities Aix-Marseille II and III.0022-0248/$ - see front matter r 2007 Elsevier B.V. All rights reserved. doi: 10.1016/j.jcrysgro.2007.10.006 CNRS, Campus de Luminy. Case 913, F-13288 Marseille Cedex 09, FranceReceived 10 September 2007; accepted 3 October 2007Communicated by K. SatoAvailable online 9 October 2007AbstractIn this contribution, we present 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 facesis very slow and clear, as soon as the supersaturation is high enough, there is competition between growth and surface-activated secondary nucleation. This gives rise to pseudo-twinned crystals composed of several needle individuals aligned along a crystallographic axis; this is explained by regular over- and inter-growths as in the case 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 secondary surface nucleation, it is no longer possible to obtain a steady state. Therefore, the crystal number, size and habit vary signi?cantly with time, leading to troubles in the downstream processing operations and to modi?cations of the ?nal solid-speci?c properties.These results provide valuable information on the unique crystallization mechanisms of acicular crystals, and show that it is important to know these threshold and critical values when running a crystallizer in order to obtain easy-to-handle crystals.r 2007 Elsevier B.V. All rights reserved.PACS: 81.10.Aj; 81.10.D n; 78.30.JwKeywords: A1. Crystal morphology; A2. Growth from solutions; B1. Organic compoundsARTICLE IN PRESSARTICLE IN PRESS1. IntroductionMany organic molecules exhibit anisotropic structural properties in their crystalline form, which gives rise to acicular or needle-like crystals. In the chemical and pharmaceuticalindustry,crystallizationfrom solution isused as a separation 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 processes (?ltration, drying, storage, handling, etc.).A better understanding of the mechanisms of nucleation and growth of these needle-like crystals will therefore lead to better control of crystallization processes. In the literature, papers on molecular modeling of these needlelike crystals 1 - 3$uggest that in the case of needle-like crystals, there is no slow-growing face in the needle directi on. Practical aspects have bee n also studied for a few years now in our different research teams 4 - 6In this con tributi on,we prese nt an experime ntalinvestigation of the growth of four different organic molecules produced at in dustrial scale with a view to un dersta nd the crystallizatio n mecha nism of acicularARTICLE IN PRESSF. Puel et al. / Journal of CrystalGrowth 310 (2008)110 - 115111crystals 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 supersaturati on is high eno ugh, there is competiti on betwee n growth and activated sec on dary n ucleati on. These investigations show that crystals are agglomerated with the same crystallographicorie ntati onfor the in dividual constituents, as observed by optical microscopy, scanning electron microscope (SEM) and atomic force microscopy (AFM); this is explained by regular over- and inter-growths as in the case of twinning. And when supersaturation is even higher, nucleation is fast and random. These results provide valuable information on the unique crystallization mechanisms of acicular crystals, and show that it is importantto know these threshold and critical valueswhen running a crystallizer in order to obtain easy-to- handle crystals.2. Materials and methods2.1. MaterialsThe four organic molecules studied were:(i) Irbesartan (C25H28N6O), an active pharmaceuticalingredientcrystallized in 2-propanol and used bySano?-Aventis in the treatment of hypertension;(ii) Product 2 (for the sake of con?dentiality),an organicmolecule exhibiting an alkyl cycle with one polar chemical group: this molecule crystallizes in its in dustrial solve nt;(iii) Hydroquinone (C6H 6O2), which crystallizes in water in the prese nce of an additive used at in dustrial scale to speci?cally reduce growth along the length axis of the n eedle;(iv) Product 4 (for the sake of con?dentiality)known toexhibit only n eedle-like habit whatever the solve nt used.Structural data for the ?rst three molecules are presented in Table 1.Table 1Structural data2.2. Solid CharacterizationCrystals were observed under a (SEM; JEOL 6320F). SEM photographs clearly show the needle-like crystal habit for the four systems studied (Fig. 1). Crystals of Irbesartan phase A were also observed by AFM using a Digital Nano scope III atomic force microscope equipped with a 12 mm scanner. Images were collected in tapping mode using oxide-sharpe ned Si3N 4 can tilever tips (nanoprobe ).2.3. Crystal preparationIrbesarta nand Product 4 crystals were grow n inquiesce nt soluti ons (2 mL) at known concen trati ons, under optical microscope (Nikon, Diaphot), at given temperatures, using the experimentalsetup previouslydescribed 7.Product 2 and hydroquinone crystals were obtained from isothermal crystallizatio n in 2.5 L stirred vessels in semi-batch and continuous operations, respectively. Experimental procedures can be found in the following references 5,6,8. The supersaturation is de?ned as b= C/Ce, with C and Ce are the concentration and solubility of the organic molecule.3. Results and discussionAs shown in Fig. 1, all the crystals present a needle-like habit, which is due to a strong structural anisotropy along the z-axis for Irbesartan and hydroquinone, and x-axis forstructureIrbesartan phase A aProduct 2Hydroquinone phase aaa (A)37.094.92238.46b (A)37.0915.71438.46c(A)9.658.1745.65a (1)909090b (1)90104.690g(1)12090120aInterestingly,Irbesartan phase Aand hydroquinonephase a have thesame space group R-3.Fig. 1. Needle-like crystals observed by SEM: (a) Irbesartan phase A, (b) Product 2, (c) hydroquinone phase a and (d) Product 4.Product 2 (see Table 1). This was con?rmed by molecular modeling for Irbesartan 4 and Product 2 9. Product 4 has not yet been determined.ARTICLE IN PRESS112F. Puel et al. / Journal of Crystal Growth 310 (2008) 110 - 115Fig. 2. Crystals of Irbesartan phase A: (a, b) optical-microscopy images, (c) AFM image and (d) SEM image.3.1. Crystallizationof Irbesartanin stagnant conditionsThe experiments show that in all the temperature and supersaturation ranges, 2 - 20IC and 3 - 10, respectively, crystals obtained (Fig. 2a, cand d) have a needle-like habit,2composed by crystalline agglomerates. Moreover, 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 n eedle directi on (crystallographic z-axis) to be observed. The width of this dead zone is a fun cti on of the temperature and in creases whe n the temperature decreases. The growth rate of the needle in creases with in creas ing supersaturati on up to a critical supersaturation (a second threshold) from which activated sec on dary n ucleati on appears, leadi ng to a ran dom nucleation of needles (Fig. 2b).In the growth zone, below the critical supersaturation (second threshold), AFM observations clearly indicate that the agglomerate is composed of few needle-like crystals of different sizes but with the same crystallographic orientation along the z-crystallographic axis (Fig. 2c and d).3.2. Crystallizationof Product 2 and hydroquinone inisothermal stirred tankCrystallizations in stirred crystallizers were studied for the two other systems, Product 2 and hydroquinone.2Usually the term agglomeration is used for a two-step process: encounter and association between particles suspended in solution, while in this article, the term agglomerate is used to qualify polycrystallinity with no assumption on the mechanism of formation.3.2.1. Product 2In the case of Product 2, crystallizations were realized in semi-batch operati ons, supersaturati on was in creased by feeding the crystallizer with a hot, undersaturated and clear solution. Moreover, the crystallizer was initially seeded with well-de?ned crystals in order to study activated sec on dary n ucleati on and crystal growth. Supersaturati on was measured during the experiment by HPLC measurement and resulted in the pro?le given in Fig. 3. When feeding starts (at time 0), supersaturation begins to rise. Un til supersaturati onreaches 1.98, only growth of seedcrystals is observed, mainly for the lateral faces. Impurities from the in dustrial solve nt slow dow n the growth of the terminal faces (Fig. 4a). It is noteworthy that as in the case of Irbesartan (Fig. 2), we do not observe growth of a single crystal but a polycrystalline growth. Then, supersaturation in the crystallizer reaches a maximum of 1.98, a threshold value (see supersaturationpro?le in Fig. 3). At this value,activated surface sec on dary n ucleati on starts creat ing ?ne needle crystals (secondary nuclei) with a longer length-to- width ratio than seed crystals (Fig. 4b). Crystals are composed of a few needle-like crystals of different sizes but with the same crystallographicorientationalong thex-crystallographic axis (Fig. 4c).Moreover, in unseeded semi-batch experiments, when greater supersaturations are reached up to 2.8, crystals showing random agglomeration are observed due to fast primary nucleation (Fig. 4d) as in the case of Irbesartan phase A (Fig. 2b).3.2.2. HydroquinonePreliminary batch-seeded crystallization was performed. For continuous isothermal crystallization, ?rst a hot undersaturated solution was fed in, then crystals wereARTICLE IN PRESSF. Puel et al. / Journal of CrystalGrowth 310 (2008)110 - 115113Fig. 3. Supersaturation pro?le of seeded semi-batch crystallization of Product 2.Fig. 4. SEM pictures of Product 2 crystals withdrawnvalue at the beginning of the experiment,(a) before threshold(b, c) after threshold value respectively?ne and seed crystals and (d)at higher supersaturation.nucleated and developed after which the suspension was withdrawn automatically to main tain the level of the reactor and immediately ?ltered. The solute concentration was measured regularly by a potentiometry analysis. Thus, the supersaturation was calculated from the knowledge of the solubility. After wash ing the crystals in acet one and vacuum drying, the crystals were weighed and measured 10 (image analysis) and observed under SEM.Fig. 5 illustrates the supersaturation pro?le during one typical run. For 20 reside nee times, supersaturati on did not reach aeon sta nt level, as no rmally expected. It showed two local maxima for the sixth and the seve ntee nth reside nee times. By coupling the mass balanee and the crystal size distribution measurements, it was possible to evaluate the total number of crystals. This number decreased with an1,0501Loeal maxima*Local maxima* + +* *A*辛1,100051015Residence time (-)2025Fig. 5. Supersaturation pro?le in suspension of continuous crystallization of hydroquinone.Fig. 6. SEM pictures of hydroquinone withdrawn at different residence times during a continuous isothermal crystallization (a)sduced time ? 5: before ?rst burst of nuclei, (b) reduced time ? 7: after ?rst burst of nuclei, (c) reduced time ? 13: before second burst of nuclei and (d) reduced time ? 19: after second burst of nuclei.din crease in supersaturati on,and sudde nly rose after asupersaturation maximum. These signi?cant bursts of nuclei were visible to the naked eye. Before and after each supersaturation maximum, the mean dimensions of the crystals, respectively, showed a signi?cant rise and fall. The evolutionof the length-to-widthratio around the ?rstsupersaturation maximum was monitored8. Crystalsnucleated and grown before this maximum were quite thick and exhibited a rod-like habit. Conversely, most of the crystals which were nucleated and grown after this maximum had a 40% higher length-to-widthratio leadingto aneedle-like habit (seeFig. 11 in Ref. 8). Moreover, it was very instructiveto observe how the appearanee ofthe crystal surface evolved. Duringthe ?rst hours ofthe continuousoperation,crystal surfaces were verysmooth (see Fig. 6a). With the in crease in supersaturati on, crystals appeared to be more and more twinned. After the ?rst maximum, the surfaces were rougher. On SEMARTICLE IN PRESS114F. Puel et al. / Journal of CrystalGrowth 310 (2008)110 115observations, the crystals were composed of numerous needle-like crystals with the same crystallographic orientation along the z-crystallographic axis (see Fig. 6b). Nevertheless, progressively with time, the surface appeared smoother (see Fig. 6c). A sec ond in crease in supersaturation followed by a second burst of nuclei was observed. Contrarily to the usual continuous operation, an unsteady state lasted throughout the run (20 h) although a steady state was expected after only 4 h. Lastly, whatever the operating conditions tested in terms of stirring rate and solid concentration, an irregular unsteady state was always observed, includingone or two local maxima of supersaturation corresponding to thresholds where surface- activated sec on dary n ucleati on eve nts started. Modi?ca- tions in crystal surface appearanee were systematically observed at different levels of supersaturation.3.3. DiscussionIn the case of Irbesartan, growth of the lateral faces was not observed under these conditions,meaning that thethreshold supersaturation (from which growth is observable) of these faces is higher than the critical supersaturation for sec on dary n ucleati on. Thus, layer-by-layer growth of the lateral faces is more dif?cult than nucleation, meaning that surface-activated sec on dary n ucleati on is easier tha n growth. However, from AFM experiments (Fig. 2c), it can be assumed that the thickness of the acicular crystals is the result of agglomeration of several single needle-crystals. This agglomeration mechanism is not known but we can speak of regular over- and inter-growths, and as in the case of twinned crystals, two mechanisms need to be considered:Syno sis: one in dividual n ucleates, grows and deposits itself by one of its natural face on a face of a second already exist ing in dividual, 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 observation of reentrant angles in Fig. 7 con?rms the assumption of twinning; this effect is commonlyFig. 7. Optical-microscopy image of needle-like crystal of Product 4.observed for con tact twi ns and n amed as the reentrant corner effect.The crystallization of Irbesartan and Product 4 were observed for in dividual crystals, which are givi ng in formation on microscopic growth mechanisms. Experiments for Product 2 and hydroquinone were performed in stirred vessels, providing macroscopic information for a population of crystals on the overall growth rate; similar experime nts were carried-out on b-cyclodextri n 14. However, whether one looks at the results from the microscopic or macroscopic scale experiments, similar nucleation and growth mechanisms of acicular crystals are observed. The crystallization mechanisms of Product 2 crystals are probably the same as for Irbesartan form A crystals described previously. However, the growth dead zone at lower supersaturation is not observed for Product 2, probably because the semi-batch crystallizations performed here do not provide enough information. In these experiments, at lower supersaturation, overall growth of crystals is regular and smooth but polycrystalline (see SEM pictures in Fig. 4a). At higher supersaturation, the growth mechanism is different and 2D nuclei can form onto crystal surfaces. Once formed, these nuclei detach and either (i) dissolve or grow in side the soluti on depe nding on their size, or (ii) grow on the surface of the pare nt crystal (synosis mechanism). Moreover, new nuclei can form on these still-growing surface needles giving an irregular appearanee to seed crystals (faulted 2D nucleation).The key parameter of these changes in behavior detected during the continuous crystallization of hydroquinone is the competitionbetween growth and surface-activatedsec on dary n ucleati on mecha ni sms. When the crystals came from a seeded 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 decreased with time; consumption of solute by growth was thus less and less able to compensate for solute feeding. Supersaturation in creased un til a threshold was reached, lead ing to a burst of n uclei by a surface-activated sec on dary n ucleati on. On this emerging population, the lateral surfaces were striped along the n eedle directi on and the sec on dary n ucleati on was more intense. This rough surface appearanee was also observed on crystals produced during semi-batch experiments performed at higher level of supersaturation than con ti nuous operati ons 10. The kin etic of the sec on dary nucleation is then linked to the crystals surface appearanee.For all organic crystals studied in this article, layer-bylayer growth of the lateral faces is very slow and clearly, as soon as the supersaturati onis high eno ugh, there iscompetition between growth and surface-activated secondary nucleation. Moreover, at high supersaturation levels, surface-activated sec on dary n ucleati on and 2D n ucleati on, or the Birtiind Spread growth mechanism, are closely linked. This gives rise to pseudo-twinned crystals composed of several needle individuals aligned along a crystallographic axis.ARTICLE IN PRESSF. Puel et al. / Journal of Cr