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Impact of Gas Composition in the Mother Liquor on the Formation of Macroscopic Inclusions and Crystal Growth Rates. Case Study with Ciclopirox Crystals Published as part of a virtual special issue of selected papers presented at the 9th International Workshop on the Crystal Growth of Organic Materials (CGOM9). Audrey Waldschmidt,‡,§ Nicolas Couvrat,‡ Benjamin Berton,§ Valerie Dupray,§ Sandrine Morin,§ Samuel Petit,*,‡ and Gerard Coquerel‡ ‡
Laboratoire Sciences et Methodes Separatives, UPRES EA 3233, Universite de ROUEN, 1, rue Lucien Tesniere, F-76821 Mont-Saint-Aignan cedex, France § Laboratoire Sciences et Methodes Separatives, UPRES EA 3233, Centre Universitaire d'Evreux, Universite de ROUEN, 1, rue du 7eme chasseurs, BP 281, F-27002 Evreux cedex, France ABSTRACT: A homemade setup was designed in order to investigate the influence of gas bubbling on the crystal growth of the active pharmaceutical ingredient ciclopirox. It appears from these experiments performed in stagnant and isothermal conditions that gases containing oxygen atoms (air, dioxygen, nitrous oxide, and carbon dioxide) lead to high crystal growth rates and promote the formation of liquid inclusions whereas gases free from oxygen (nitrogen, helium, argon, dihydrogen), as well as degassing treatments, cause a dramatic decrease in growth rates and give rise to crystals deprived of liquid inclusions. It could also be demonstrated by hot-stage optical microscopy that, beside the evolution of fluid inclusions upon heating and/or maturation toward negative crystals, all liquid inclusions contain, at the temperature of crystal growth, gas bubbles in equilibrium with a saturated solution. Furthermore, an AFM study revealed that liquid inclusions are produced specifically during the growth of rough faces presenting a high potential for physical adhesion/ adsorption and possibly gas bubble nucleation. An original explanation based on a local growth inhibition is therefore proposed, and the large contribution of microbubbles in the formation of macroscopic fluid inclusions, but also in the global growth kinetics suggests that the role of gaseous matter in crystal growth mechanisms of organic materials has probably been, up to now, underestimated.
1. INTRODUCTION Ciclopirox (6-cyclohexyl-1-hydroxy-4-methylpyridin-2-one, Figure 1) is an active pharmaceutical ingredient (API) used for its antifungal activity. Purification of crude ciclopirox can be achieved by cooling crystallization but has been shown to be limited by the occurrence of macroscopic defects inside crystalline particles, consisting mainly of enclosed vacuoles filled with gas or saturated solution.1 Because of the fundamental importance of chemical purity in pharmaceutical industrial processes, the understanding of the formation mechanism(s) of such defects has been attempted by means of a systematic crystal growth study in various solvents and under several operating conditions.2 Surprisingly, these investigations have shown that the formation of liquid inclusions inside ciclopirox single crystals cannot be understood by using the established theories dealing with the adsorption of solvent or impurity molecules on specific growing surfaces.35 Furthermore, it was shown that kinetic factors play a role opposite to that usually described. In previous studies, the amount of trapped solution was demonstrated to increase with global growth rates,6 cooling rates and relative supersaturation, whereas the initial r 2011 American Chemical Society
temperature can induce antagonist effects.7,8 In the case of ciclopirox, macroscopic inclusions can be observed only if the relative supersaturation is below a threshold, and the disappearance of liquid inclusions by increasing the supersaturation is concomitant with a morphological transition from a hexagonal shape to an elongated habit, without any change of the obtained crystalline phase. However, it could also be demonstrated that liquid inclusions are initiated by the crystal growth inhibition of specific faces, namely {(111)} and {(111)}. Hence, because neither the solvent nor the presence of impurities are responsible for the formation of macroscopic inclusions, and owing to the presence of gaseous macrobubbles in numerous liquid inclusions (in particular for crystals grown in ethyl acetate), it was decided to focus our attention on the influence of gas in the growth medium. Although the incidence of gaseous macro- or microbubbles on crystal growth has been poorly investigated,9,10 the bubble Received: February 23, 2011 Revised: March 31, 2011 Published: April 04, 2011 2463
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Figure 1. Molecular formula of the API ciclopirox.
Figure 2. Schematic representation of the homemade setup designed for the saturation in gas of the growth medium (solvent: ethanol or ethyl acetate).
nucleation in solution is well understood and has been reviewed by Jones et al.11 It was concluded by these authors that, beyond the permanent existence of metastable microbubbles in the solution bulk, the heterogeneous nucleation of gaseous bubbles can occur at low relative supersaturation from pre-existing gas cavities (often consisting of roughness of the vessel surface which contain a small amount of gas trapped inside and becoming a preferential site for bubble nucleation) of suitable dimensions. One can therefore assume that different crystal surfaces may exhibit distinct abilities for bubble nucleation but also distinct adhesion forces. In this context, the aims of this work were (i) to investigate the incidence of the nature of the gas on the crystal growth behavior of ciclopirox (ii) to monitor the evolution of vacuoles (shape evolution of liquid inclusions and appearance/disappearance of gaseous macrobubbles) as a function of temperature and (iii) to evaluate the roughness of crystal surfaces and to assess the relative strength of adhesion forces on specific crystal faces by means of atomic force microscopy (AFM) observations and measurements.
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represented in Figure 2. These gases were used directly from tanks without purification. This setup allows the control of: (i) the temperature, (ii) the supersaturation of the solute, and (iii) the saturation of the solution in a single gas. Compared to the previously described crystallization protocol, three supplementary steps were added for gas addition: bubbling in the solvent prior to the preparation of the undersaturated solution at high temperature (50 °C in order to ensure a complete dissolution), control of the atmosphere during the dissolution of the solute, and bubbling in the supersaturated solution prior to seeding at the growth temperature of 20 °C. 2.2. Optical Microscopy. The occurrence of macroscopic liquid inclusions within crystals was observed by optical microscopy using a Nikon Eclipse LV100 which enables a magnification up to 1000. The evolution of liquid inclusions possibly containing a gas macrobubble as a function of temperature was monitored using an Olympus BX41 microscope (maximum magnification 1000), with a CCD camera coupled to the microscope and connected to a computer. The cooling or heating rates were controlled with a THMS 600 hot-stage setup (Linkham). 2.3. Atomic Force Microscopy. The identification of the studied crystal faces was made possible by the indexation of the two experimental morphologies. Miller indices of the most developed faces were deduced from the orientation of a representative single crystal with reference to crystallographic axes, using a SMART APEX (Bruker) diffractometer, and confirmed by morphological predictions.2 Well-faceted crystals were collected for AFM analyses and mounted on a glass rod. Each face of interest was set parallel to the coverslip. AFM experiments were performed several times on different regions of a same face to ensure the representativity of our results, using a Molecular Imaging PICOSPM AFM apparatus equipped with silicon nitride cantilevers having a spring constant of 0.32 N/m. AFM imaging were performed at room temperature in constant force contact mode for each sample, using a permanent minimum contact force in order to avoid damage on the crystal face. Deflection and topographic mode images were scanned simultaneously with a scan size of 5 μm 5 μm at a fixed scan rate of about 1 line/s with a resolution of 512 512 pixels. Three dimensional images were constructed using measurement of the z-piezo movements. Forcedistance data were collected using the same AFM device. These data correspond to approach-retract curves and provide quantitative information about forces between the tip and the sample as a function of the tipsample distance.
3. RESULTS AND DISCUSSION 2. EXPERIMENTAL SECTION 2.1. Crystallization Protocol. Crude ciclopirox was supplied by PCAS company (Limay, France), and recrystallized in ethyl acetate prior to experiments with a 70% yield (HPLC purity >99%). Solvents were purchased from Acros (minimum purity 99% or HPLC grade) and were used without further purification. After solubility measurements by gravimetric method, crystallization experiments were carried out under controlled temperature and initial supersaturation (β = 1.1), giving concomitantly the two morphologies reported earlier2 (relative supersaturation β is defined as C/Cs where C stands for the actual concentration and Cs for the solubility at the same temperature), in a closed vial and using either ethyl acetate or ethanol as solvent. In stagnant and isothermal conditions, supersaturated solutions were seeded at the growth temperature, in accordance with a wellestablished protocol.2 Crystal growth experiments with solutions saturated in various gases (hydrogen, helium, argon, nitrogen, oxygen, air, nitrous oxide, and carbon dioxide) were performed by using a homemade setup
3.1. Incidence of Gas in Solution. It has been shown in a previous study that, in the absence of gas bubbling prior to seeding, crystals grown from ethanol at an initial supersaturation of 1.1 contain liquid inclusions usually deprived of detectable macrobubble (prior to thermal treatment), whereas most liquid inclusions within crystals grown at the same supersaturation from ethyl acetate contain a gas macrobubble.2 In order to identify the incidence of specific gases on the formation of liquid inclusions with or without gas macrobubble, crystal growth experiments including a bubbling step were performed using the homemade setup and the protocol presented in section 2.1. Depending on the nature of the gas, these “bubbling experiments” revealed two different behaviors during crystal growth. Actually, a classification into two categories can be proposed: gases containing oxygen atoms (G1) and gases free from oxygen atom (G2). 2464
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Figure 3. Photographs of crystals grown from ethanol: (a) without gas bubbling, (b) with air bubbling, (c) with carbon dioxide bubbling, (d) with dioxygen bubbling, (e) with nitrous oxide bubbling.
Figure 4. Photographs of crystals grown from an ethanolic solution: (a) without bubbling, (b) after nitrogen bubbling, (c) after hydrogen bubbling, (d) after helium bubbling, (e) after argon bubbling.
3.1.1. Case of Dioxygen, Air, Nitrous Oxide, and Carbon Dioxide (G1). Crystals grown in ethanol without bubbling or after a bubbling step with a gas of the G1 group are shown in Figure 3. In all experiments, large liquid inclusions can be observed inside numerous crystals. Interestingly, these experiments also indicate that all liquid inclusions obtained after a bubbling step contain a large gaseous macrobubble, whereas no gas bubble is detected in the absence of bubbling. It can therefore be deduced that the bubbling step, inducing a saturation of the growth medium in the selected gas, has a significant incidence during the formation of macroscopic defects. Furthermore, the nature of the solvent itself is not a decisive parameter for the occurrence of bubbles inside liquid inclusions because both ethyl acetate (with or without bubbling) and ethanol (with bubbling) allow the formation of gaseous vacuoles.
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3.1.2. Case of Nitrogen, Helium, Hydrogen, and Argon (G2). When bubbling experiments were performed with gases of the G2 group (i.e., deprived of oxygen atom), a different but reproducible crystal growth behavior was observed, mainly characterized by a dramatic decrease of growth rates. Indeed, about 4 days were required to reach complete crystallization after bubbling with a G2 gas, whereas the absence of bubbling allows an almost complete growth about thirty minutes after seeding in similar conditions (it was checked that the solubility is not affected by bubbling). Furthermore, by contrast with the mixture of morphologies usually obtained under these conditions (hexagonal and elongated, both containing liquid inclusions), the particles collected after a bubbling step with a gas of the G2 group only exhibit a hexagonal shape and unexpectedly, are free from macroscopic liquid inclusions (and therefore of gas macrobubbles), as illustrated in Figure 4. It can be deduced from these observations that the nature of the gas in solution plays a decisive role on crystal growth rates and on the formation of liquid inclusions. Surprisingly, saturation of the solution with a gas deprived of oxygen atom reduces the growth rates to such an extent that the morphological transition does not occur, which may indicate a change of growth mechanism. Two hypotheses could actually be proposed to explain this kinetic slow down in the presence of gases free from oxygen atom in solution: on the one hand, it could be assumed that the presence of oxygen, nitrous oxide, or carbon dioxide is actually responsible for the high growth rates of ciclopirox crystals, therefore acting simultaneously as catalysts of the crystal development and as promoters of the formation of macroscopic liquid inclusions. On the other hand, one may envisage that because of their specific properties and behaviors, gases of the G2 group are able to hinder the crystal growth or even to change the growth mechanism.12 Although previous investigations had shown that liquid inclusions are formed only below a threshold of supersaturation, the magnitude of growth inhibition with G2 gases appears to be so large that the growth occurs in close-toequilibrium conditions, resulting in a high crystal purity.13 It is therefore difficult, from these observations, to determine whether the absence of liquid inclusions is due to the specific nature and properties of G2 gases or is a result of a secondary effect of the very low growth rates. 3.1.3. Case of Degassed Solutions. In view of the previous results, complementary experiments were designed with the aim of decreasing as far as possible the amount of gas in the growing medium. Three strategies were applied as degassing treatment: boiling of solvent, submitting of solvent to reduced pressure, and using a gas-filtrating membrane (commonly applied for HPLC). Whatever the applied degassing protocol, a dramatic decrease of growth rates was observed. As in the case of G2 gases, the crystal growth is slowed down to such an extent that ca. 3 days are required to ensure complete crystallization. The major part of the crystals exhibit a hexagonal morphology with the usual crystal size and morphological index. Most of them appeared to be deprived of detectable liquid inclusions (Figure 5). Hence, it can be deduced from these experiments with bubbling or degassing treatments that the formation of macroscopic liquid inclusions is actually determined by the presence in solution of dioxygen, nitrous oxide or carbon dioxide. Specific interactions or effects of these gases on {(111)} or {111)} surfaces are probably responsible for the formation of macroscopic liquid inclusions. Surprisingly, gases containing an oxygen atom also induce high growth rates in an almost isotropic way, 2465
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Figure 5. Photographs of crystals grown in a: (a) non-degassed solution, (b, c) degassed solution.
Figure 6. Evolution of a liquid inclusion initially containing a gas macrobubble versus temperature: (a) at 20 °C, (b) after a heating treatment up to 50 °C, (c) after a cooling treatment to 20 °C.
from which it can be supposed that dissolved gas molecules may accelerate the crystal growth either through specific interactions (i.e., hydrogen bonds) with ciclopirox molecules at crystal-solution interfaces or by facilitating the desolvation of solute molecules, thus permitting a faster adsorption on growing surfaces. 3.2. Evolution of Liquid Inclusions versus Time and Temperature. Most of the liquid inclusions observed in ciclopirox crystals present a rounded or irregular shape (e.g., see Figure 3 above and photographs in refs 1 and 2). However, it has been reported in the literature that liquid inclusions may evolve with time or upon heating toward negative crystals, which occurs when liquid inclusions come to a shape similar to that of the crystal.1417 A systematic study of the evolution of liquid inclusions (and when relevant, of the enclosed gas macrobubbles) versus time and temperature was therefore undertaken. These experiments can be reported according to three distinct situations: thermal behavior in the presence (case 1) or in the absence (case 2) of a mobile gas macrobubble in a liquid inclusion, and aging of an inclusion initially free from detectable gas macrobubble (case 3). 3.2.1. Case of a Liquid Inclusion Containing Initially a Gas Macrobubble. Hexagonal-shaped crystals grown in ethyl acetate usually exhibit several liquid inclusions, each of them containing a mobile gas macrobubble. Such crystals were selected in order to study the thermal evolution of liquid inclusions and revealed that heating crystals from 20 to 50 °C at 1 K/min results, on the one hand, in the disappearance (or significant reduction) of gas bubbles and, on the other hand, in the reshaping of the liquid inclusions toward negative crystals (Figure 6). The latter phenomenon is actually associated to a dissolution process, and the occurrence of negative crystals is probably related to the minimization of interfacial energies. The simultaneous disappearance of gas macrobubbles can be explained by the combination of several concomitant phenomena: increase of temperature, dissolution of ciclopirox, probable increase in the internal pressure in the liquid inclusion, and increase in the inclusion volume. It is noteworthy that the effects of heating are reversible. Indeed, upon cooling from 50 to 20 °C at 1 K/min, the liquid inclusions return gradually to their quasi-spherical shape (comparable to a
Figure 7. Evolution of a liquid inclusion initially free from gas macrobubble during thermal treatments at a 1 K/min heating and cooling rate (double images are due to an optical phenomenon caused by the orientation of this liquid inclusion inside the crystal).
roughening transition12) and gaseous macrobubbles reappear “instantaneously” at ca. 34 °C, almost simultaneously in all liquid inclusions. It should also be noticed that applying this thermal treatment several times to a same crystal leads to reproducible observations. However, the shape of negative crystals becomes persistent at 20 °C, after ten to thirteen cycles, which can be assimilated to a virtual aging of ciclopirox crystals. The behavior of the gas bubble remains unchanged after more than twenty cycles. 3.2.2. Case of Liquid Inclusions Initially Free from Gas Macrobubble. Hexagonal-shaped crystals grown from ethanol (i.e., without detectable gas bubble inside inclusions) were selected for a second set of experiments, consisting of cooling 2466
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Figure 8. Evolution of a liquid inclusion without detectable gas macrobubble maturated during 4 months prior to thermal treatment at: (a) 20, (b) 50, and (c) 20 °C.
and heating treatments at a rate of 1 K/min. As illustrated in Figure 7, a continuous slow cooling induced, at ca. 120 °C, the appearance of gaseous macrobubbles, again almost simultaneously in all liquid inclusions (inclusions remain liquid at this temperature). Unexpectedly, these gas bubbles were persistent on return to room temperature, but disappeared upon heating up to 50 °C, concomitantly with an evolution toward a shape of negative crystals. A third step consisting of a cooling down to the initial temperature of 20 °C produced similar observations as that described in section 3.2.1, i.e., the spontaneous reappearance in all liquid inclusions of a gas macrobubble before reaching the temperature of 20 °C. Therefore, the existence of gas bubbles at room temperature constitutes a stable state because they are still persistent several months after these experiments. It can be deduced from these experiments that the presence of gaseous bubbles enclosed in liquid vacuoles do not constitute a fortuitous observation and, as shown from bubbling experiments (see section 3.1.1.), do not depend on the use of a specific solvent. Indeed, applying a deep enough cooling initiates the formation of a macroscopic gas bubble in every liquid inclusion that subsequently persists after return to room temperature. Despite the absence of observable gas macrobubble in some liquid inclusions, our results indicate that these vacuoles do, however, contain gas in a supersaturated state in the solution. A suitable thermal treatment can promote the appearance of a gas macrobubble by means of an agglomeration process or by its nucleation.11 3.2.3. Aging and Thermal Treatment of a Liquid Inclusion Free from Gas Macrobubble. Assuming that both the shape and the thermal behavior of liquid inclusions could slowly evolve over time, hexagonal-shaped crystals grown from ethanol (i.e., free from detectable gas bubble in liquid inclusions) were therefore stored for four months under ambient conditions, and then heated up to 50 °C at 1 K/min. As expected, the reversible evolution of liquid inclusions toward negative crystal was observed, but the cooling step down to room temperature revealed a distinct and interesting observation, consisting of the appearance at ca. 30 °C of a gas macrobubble, simultaneously with the partial recrystallization of the entrapped solution (Figure 8). Such spontaneous formation of gas bubbles was not observed when freshly produced crystals were submitted to an identical thermal treatment. It can therefore be stated from these observations that aging (or maturation) of crystals promotes the formation of gaseous macrobubbles within liquid inclusions, thus confirming that all liquid inclusions contain (possibly non visible) gaseous matter. 3.3. Study of Crystal Surface Roughness by Atomic Force Microscopy (AFM). During our previous crystal growth study, the formation of liquid inclusions was observed in situ, and revealed that the formation of liquid inclusions inside ciclopirox
Figure 9. AFM imaging on the surface of specific crystal faces of the hexagonal morphology: {(111)} upper, {(200)} middle, and {(110)} lower, represented at the same scale (units: μm).
crystals is initiated specifically on {(111)} or {111)} faces.2 An AFM study was therefore carried out with the assumption that {(111)} or {(111)} faces may exhibit specific topological features. This hypothesis is reinforced by the occurrence of these faces in the hexagonal morphology and their absence among elongated crystals.2 To evaluate the relative adhesion strength on specific crystal surfaces, AFM observations and measurements were applied to different representative crystals of the two morphologies (grown without bubbling at different supersaturations). 3.3.1. Case of Hexagonal Crystals Containing Liquid Inclusions. The characterization by AFM of the crystal surface roughness for the hexagonal morphology is depicted in Figure 9. It can be seen that the roughness of {(111)} faces is significantly higher than that of {(200)} and {(110)} faces, suggesting a direct correlation with the formation of liquid inclusions. The high roughness of these faces may actually indicate that gaseous microbubbles of oxygen, nitrous oxide or carbon dioxide can adsorb more easily on {(111)} and {(111)} faces than on {(200)} and {(110)} faces, and that gas cavities promoting the formation of such bubbles may appear more easily on these 2467
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Figure 10. Forcedistance displacement data for crystal faces of the hexagonal morphology (curves are shifted for clarity).
rough surfaces, in good consistency with bubble nucleation theories.11 To quantify the roughness variations from one face to another, the peak-to-valley heights Rz, corresponding to the difference between the highest and the deepest points of a surface area, were measured. The obtained values (average values) show that the roughness of {(111)} faces (320 ( 50 nm) is more than twelve times larger than that of {(200)} faces (25 ( 10 nm) and about three times higher than the roughness of {(110)} faces (95 ( 30 nm). The specific adhesion forces between the tip and specific surfaces were also considered in order to assess the strength of physical adhesion phenomena. The forcedistance displacement curves, presented in Figure 10, show that the interaction between the tip and the crystal is by far much stronger for {(111)} faces, corresponding to an adhesion strength about ten times larger than, for instance, on {(200)} surfaces. It appears from these data that {(111)} surfaces present a higher ability for physical adhesion, associated to a larger roughness of crystal faces. Assuming that gaseous microbubbles are involved in the formation of liquid inclusions, two different hypotheses can be formulated: (i) gas microbubbles existing in solution may adhere more strongly on growing surfaces exhibiting the higher roughness and the larger adhesion forces, or (ii) the presence of “pre-existing gas cavities” (well-defined by Jones et al.11) on {(111)} and {(111)} surfaces may induce, in stagnant conditions, the nucleation of gas bubbles on these sites, thus affecting the growth of these specific faces and initiating the formation of liquid inclusions. However, this second hypothesis is poorly consistent with the continuous development of faces during crystal growth. It may also be postulated that the high roughness of {(111)} and {(111)} surfaces may be a consequence of bubble adhesion and of an induced irregular growth mechanism. 3.3.2. Case of a Needlelike Crystal. The characterization of the crystal surface roughness for the elongated morphology by AFM is depicted in Figure 11. It can be seen that the roughness of the most developed surfaces is low and that {(202)} faces are particularly flat. As previously mentioned, elongated crystals do not usually exhibit liquid inclusions, confirming the correlation between the formation of liquid inclusions and the surface roughness. Measurement of peak-to-valley heights gave values of the same magnitude (20 ( 10 nm for {(200)} and 40 ( 15 nm for {(202)}) as that of the smooth faces of the hexagonal morphology, so the existence of “productive” gas cavities is
Figure 11. AFM imaging on specific crystal surfaces of the elongated morphology: {(202)} upper and {(200)} lower (unit: μm).
rather unlikely on these surfaces. Therefore, the absence of macroscopic inclusion inside crystals with an elongated habit appears consistent with the absence of suitable adhesion and/or nucleation sites on the corresponding smooth crystal surfaces. For complete comparison, the specific adhesion forces between the tip and relevant surfaces were measured, leading to lower values (less than 0.64 nN) than that determined for the smoothest faces of the hexagonal morphology (data not shown). Hence, this AFM study has provided decisive data concerning the relative roughness and adhesion forces of various crystal faces. It clearly appears that {(111)} and {(111)} faces of the hexagonal morphology present specific topological features most probably involved in the nucleation and/or in the adhesion of gas bubbles, which may initiate the formation of liquid inclusions in hexagonal crystals. 3.4. General Discussion. The combination of data collected in the present study with that obtained during our previous investigations devoted to the crystal growth behavior of ciclopirox2 provides sufficient information to propose a global mechanism consistent with all available experimental results. Decisive data for the elucidation of this mechanism can be summarized as follows: (1) Neither the presence of chemical impurities nor the nature of the solvent is responsible for the formation of liquid inclusions in ciclopirox crystals formed at moderated supersaturation. (2) The starting step consists of a local crystal growth inhibition for specific faces, namely {(111)} and {(111)}. (3) In single crystals containing liquid inclusions, these faces present a high roughness as well as a strong ability for bubble nucleation and/or physical adhesion. (4) A degassing treatment or a saturation of the solution with a gas deprived of oxygen atom, prior to crystal growth, impedes the appearance of liquid inclusions and dramatically reduces the global growth kinetics (Table 1). (5) By contrast, the saturation of the solution with dioxygen, air, nitrous oxide or carbon dioxide increases crystal growth rates and promotes the formation of large liquid inclusions. (6) All these liquid inclusions exhibit, at the growth temperature, a macroscopic gas bubble, indicating a significant excess of gaseous molecules within inclusions with reference to the gas solubility. 2468
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Table 1. Summary of Growth Kinetics of Ciclopirox Crystals As a Function of Bubbling Pretreatment bubbling
gas
growth duration
yes
O2
10 min
yes no
air, CO2, N2O (air)
2025 min 3035 min
no
(degassing)
34 days
yes
N2, Ar, H2, He
45 days
Figure 12. Schematic representation of the crystal growth behavior in solution of ciclopirox.
As a consequence, it can be assumed that the key step for the formation of liquid inclusions consists of the strong physical adhesion on {(111)} and {(111)} faces of dioxygen, nitrous oxide or carbon dioxide microbubbles existing in solution, possibly combined with the nucleation of bubbles from gas cavities formed on these rough surfaces, as illustrated in Figure 12. Because of the high roughness of {(111)} and {(111)} faces, the presence of oxygenated microbubbles results in high growth rates that favor the formation of defects specifically from these faces. Indeed, fast crystal growth may induce the agglomeration of a large number of these microbubbles, leading to a crystal growth inhibition on a limited part of a {(111)} and/or {(111)}
surfaces. The continuous development of surrounding less affected regions of {(111)} or {(111)} surface and of other faces leads progressively to the closure of a macroscopic defect containing a saturated solution and a significant amount of dissolved gas or gas microbubbles. If the latter are able to merge together, this will result in a macroscopic gas bubble easily detectable by optical microscopy. However, gaseous microbubbles may also persist for a long time in a metastable state, in particular if their adhesion strength is high. In this case, a detectable gas bubble appears only after sufficient aging17 or upon a sufficient cooling, as illustrated in section 3.2.2. Although the hypothetical mechanism presented in Figure 12 appears consistent with all experimental data related to the formation of liquid inclusions and their evolution with time or temperature, it fails to account for some of our observations. In particular, the dramatic decrease of crystal growth rates after degassing treatments or bubbling with inert gases cannot be elucidated from the above interpretations, and deserves further investigations, since the existence of rough {(111)} and {(111)} faces appears as a necessary but insufficient condition for the formation of macroscopic liquid inclusions. From the present state of the art, it can only be speculated that, when the growth solution contains dissolved molecules with oxygen atoms (dioxygen, carbon dioxide, nitrous oxide, and air), the latter may contribute through a catalytic effect in one or more step(s) of crystal growth. For instance, these dissolved gas molecules could facilitate the desolvation of solute molecules prior to their docking at crystal-solution interfaces, thus inducing a much faster global crystal growth. Gas molecules containing oxygen atoms may also be involved in solvation effects of crystal surfaces through hydrogen bonds, in complement with the adsorption or the adhesion of gas microbubbles depicted above. Future work will therefore focus on the possible contribution(s) of gases in terms of crystal growth behaviors and kinetic effects.
4. CONCLUSION The unusual crystal growth behavior of ciclopirox, mainly characterized by the frequent occurrence of large fluid inclusions inside single crystals has prompted us to develop a specific strategy for the elucidation of such phenomena, known to be detrimental in terms of chemical and crystalline purity. From the combination of various experimental methods, it could be demonstrated that the adhesion of gas microbubbles on specific surfaces during crystal growth in stagnant conditions could have dramatic consequences, not only in terms of formation of liquid inclusions but also, more unexpectedly, in terms of global growth kinetics. Assuming that these poorly recognized phenomena occurring at crystalsolution interfaces may be of general relevance, it can be suggested that the incidence of gaseous matter (including air) should be taken into account for the complete rationalization of any crystallization. In this context, the combination of bubbling experiments with in situ optical microscopy observations and AFM studies constitutes a powerful strategy toward the elucidation of the formation mechanism of macroscopic defects in organic (or inorganic) crystals. ’ AUTHOR INFORMATION Corresponding Author
*Tel.: þ33-2-35-52-24-28. Fax: þ33-2-35-52-29-59. E-mail:
[email protected]. 2469
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’ ACKNOWLEDGMENT Region Haute-Normandie (F) is acknowledged for its financial support to the Ph.D thesis of A. Waldschmidt. Thanks are also due to PCAS (Limay, France) for supplying high grade ciclopirox. ’ REFERENCES (1) Couvrat, N.; Blier, A. S.; Berton, B.; Cartigny, Y.; Dupray, V.; Coquerel, G. Cryst. Growth Des. 2009, 9, 2719–2724. (2) Waldschmidt, A.; Dupray, V.; Berton, B.; Couvrat, N.; Petit, S.; Coquerel, G. J. Cryst. Growth, 2011, in press (doi:10.1016/j.jcrysgro. 2011.02.047) (3) Mullin, J. W. In Crystallization, 4th ed.; Butterworth-Heineman: London, 1993; Chapter 6, pp 216288. (4) Meenam, P. A.; Anderson, S. R.; Klug, D. L. In Hanbook of Industrial Crystallization, 2nd ed.; Myerson, A. S., Ed.; Elsevier Science and Technology Books: Amsterdam, 2002; Chapter 3, pp 67100. (5) Kubota, N. Cryst. Res. Technol. 2001, 36, 749–769. (6) Myerson, A. S.; Kirwan, D. J. Ind. Eng. Chem. Fundam. 1977, 16, 420–425. (7) Kim, J. W.; Kim, J. K.; Kim, H. S.; Koo, K. K. Cryst. Growth Des. 2009, 9, 2700–2706. (8) Zhang, G. G. Z.; Grant, D. J. W. Cryst. Growth Des. 2005, 5, 319–324. (9) Berton, B.; Dupray, V.; Atmani, H.; Coquerel, G. J. Therm. Anal. Calorim. 2007, 90, 325–328. (10) Oliete, P. B.; Pena, J. I. J. Cryst. Growth 2007, 304, 514–519. (11) Jones, S. F.; Evans, G. M.; Galvin, K. P. Adv. Colloid Interface Sci. 1999, 80, 27–50. (12) Liu, X. Y.; Bennema, P.; van der Eerden, J. P. Nature 1992, 356, 778–780. (13) Coquerel, G. Chem. Eng. Proc. 2006, 45, 857–862. (14) Shindo, I. J. Cryst. Growth 1981, 51, 573–580. (15) Hu, X. B.; Jiang, S. S.; Huang, X. R.; Zeng, W.; Liu, W. J.; Chen, C. T.; Zhao, Q. L.; Jiang, J. H.; Wang, Z. G.; Tian, Y. L.; Han, Y. J. Cryst. Growth 1996, 163, 266–271. (16) Denbigh, K. G.; White, E. T. Chem. Eng. Sci. 1966, 21, 739–753. (17) Waldschmidt, A.; Rietveld, I.; Couvrat, N.; Dupray, V.; Sanselme, M.; Berton, B.; Nicolai, B.; Mahe, N.; Petit, S.; Ceolin, R.; Coquerel, G. Cryst. Growth Des. 2011submitted.
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