CRYSTAL GROWTH & DESIGN
Crystal Growth Mechanism in a Solution of Hollow Whiskers of Molecular Compounds Mallet,†
Petit,†
Lafont,‡
Franck Samuel Sylvaine Dany Lemarchand,⊥ and Ge´rard Coquerel*,†
Pascal
2004 VOL. 4, NO. 5 965-969
Billot,#
Unite´ de Croissance Cristalline, de Chromatographie et de Mode´ lisation Mole´ culaire (UC3M2), Sciences et Me´ thodes Se´ paratives (SMS), UPRES-EA 3233, IRCOF, Universite´ de Rouen, rue Tesnie` re, F-76821 Mont Saint-Aignan Cedex, France, Aventis Pharma, Centre de de´ veloppement des proce´ de´ s, laboratoire Qualite´ Physique, 31 quai Armand Barbe` s 69583 Neuville sur Saoˆ ne Cedex, France, Aventis Pharma, Process Development, 102, route de Noisy, F-93235 Romainville Cedex, France, and Groupe de Physique des Mate´ riaux, UMR 6634, Universite´ de Rouen, F-76801 Saint Etienne du Rouvray Cedex, France Received January 5, 2004
ABSTRACT: Hollow and solid whiskers are formed during the solvent exchange from the dimethyl sulfoxide or dimethylformamide solvates of dexamethasone acetate to the sesquihydrate by immersion of the initial phase in water. Detailed investigations using mainly optical and scanning electron microscopies lead us to propose a growth mechanism of the hollow whiskers. Six criteria appear to be necessary for the formation of thin tubular crystals during the solvent exchange. To reproduce the crystallization occurring at the surface of the initial crystal, an experimental assembly was made with a syringe and a glass filter. When the six conditions are fulfilled, this technique permits the production of 100% of hollow whiskers. Introduction The formation of whiskerlike crystals has been described several decades ago in the case of electronic equipment, when metallic whiskers have grown between electroplates of zinc, resulting in short circuits. These kinds of materials show several interesting physical properties, such as a high mechanical strength, and they are used as additives in composite materials. In his monograph, Evans1 presented different cases of whisker formation and proposed several growth mechanisms. More recently, a few research papers have been devoted to the formation of whiskers in molecular compounds2-5 and references therein. In the case of carbamazepine,2 the anhydrous form is immersed in water, and the dihydrated phase appears as whiskerlike crystals within a few minutes. In 1999, Nordhoff and Ulrich prepared whiskers of inorganic compounds.6 When single crystals of such inorganic hydrates were immersed in dry methanol, the formation of needlelike crystals was observed during dehydration. An interesting property of crystals exhibiting extreme morphologies is their high specific surface areas. In the frame of recent studies devoted to the desolvation and polymorphic behavior of dexamethasone acetate,7,8 we have prepared and identified several new solvates including dimethyl sulfoxide (DMSO), dimeth-
Figure 1. Molecular formula of dexamethasone acetate.
ylformamide (DMF), ethanol (EtOH), N-methylpyrrolidinone (NMP), and dimethyl carbonate (DMC) solvates. A monohydrate,9 two nonsolvated forms, as well as an unstable sesquihydrate were also previously described.10 From desolvation investigations, we observed that this pharmaceutical compound (belonging to the family of steroids, Figure 1) could be transformed rapidly (from 3 to 5 min) into whiskerlike particles of the sesquihydrate when single crystals of its DMSO solvate were immersed in water. On the basis of these preliminary data and the assumed mechanism of this solid-to-solid transformation, we report here more detailed results and observations concerning the formation of whiskers. With the aim to complete and to confirm our hypotheses, we also present new results obtained with an experimental assembly designed to reproduce the nucleation and growth mechanism of hollow whiskers. Experimental Section
* To whom correspondence should be addressed. Prof. Ge´rard Coquerel, UPRES EA 3233, SMS, IRCOF, Universite´ de Rouen, Rue Tesnie`re, F-76821 Mont Saint Aignan Cedex, France. Tel/Fax: (33) 2-35-52-29-27. E-mail:
[email protected]. † Unite ´ de Croissance Cristalline, de Chromatographie et de Mode´lisation Mole´culaire (UC3M2), Sciences et Me´thodes Se´paratives (SMS), UPRES-EA 3233, IRCOF, Universite´ de Rouen. ‡ Aventis Pharma, Centre de de ´ veloppement des proce´de´s, laboratoire Qualite´ Physique. # Aventis Pharma, Process Development. ⊥ Groupe de Physique des Mate ´ riaux, UMR 6634, Universite´ de Rouen.
Materials. Dexamethasone acetate (DMA) monohydrate was supplied as a crystalline powder by Aventis Pharma (Romainville, France). Single crystals (size ≈ 1 mm) of the DMSO and DMF solvates of DMA were obtained by cooling to room-temperature solutions saturated at 40 °C in the corresponding solvents. Needlelike crystals were obtained by immersion of these single crystals in stagnant water at room temperature. The experimental setup designed to prepare “artificial” whiskers is presented in Figure 2 and consists of a “spray-in-
10.1021/cg030046e CCC: $27.50 © 2004 American Chemical Society Published on Web 08/17/2004
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Figure 2. Experimental assembly for the formation of whiskers according to the “spray-in-antisolvent” method. antisolvent” method. In this setup, a syringe (volume, 5 mL) is connected to a glass filter (porosity 4), and filled with a saturated solution of DMA in DMSO or DMF (solubilities >33%) at room temperature. The extremity of the glass filter is immersed in water, in which the saturated solution of DMA is injected at a constant rate (2 mL/s). Characterization Techniques. Crystalline phases were identified by means of X-ray powder diffraction (XRPD), using a Siemens D5005 diffractometer equipped with a copper source. All XRPD were carried out in ambient atmosphere. The raw spectra were processed by using EVA software V 8.0. The stoichiometry of the hydrated phases was determined by Karl Fisker titrations, and confirmed by gravimetric analyses. Scanning electron microscopy (SEM) observations were carried out under vacuum using a LEO 1530 apparatus at various magnifications. Optical microscopy observations were performed by using a Nikon SMZ-10A apparatus equipped with a CCD Sony Camera.
Results and Discussion The evolution of the aspect and the habit of single crystals of DMA‚DMSO and DMA‚DMF when they are immersed in water at room temperature was observed by optical and scanning electron microscopies. These
Mallet et al.
observations revealed that a large number of needlelike crystals (whiskers) appeared within a few minutes. These whiskers appear first at the corners, edges, and defects of the initial single crystal. If a flat face of the initial particle is damaged (by a sharp needle for instance), the resulting macroscopic defects also constitute preferential sites for the nucleation and growth of whiskers. During the formation of needlelike crystals, the initial particle becomes opaque, and XRPD analyses indicated that the final phase is the sesquihydrate. At the end of the transformation (a few minutes), the whole initial particle is actually constituted of a huge number of whiskers. Simultaneously, a second group of filamentary particles irradiates from the former particle. XRPD analyses reveal that this second group of particles has a fairly good crystallinity and corresponds also to the sesquihydrate. Upon heating, the sesquihydrate gives the anhydrous form II of DMA (Figure 3). The transformation begins at 35 °C and is completed at 40 °C, and there is no intermediate monohydrate phase. Figure 4 shows fragments of isolated whiskers protruding in the antisolvent, obtained from DMA‚DMF in water. They look like thin capillary tubes sealed at the top. To investigate the very first step of whisker formation, the transformation was stopped 30 s after immersion in water of a single crystal. Several scanning electron microscopy observations were carried out to observe whiskers at the surface of the initial particle, as well as inside the resultant sample. From these observations, it was established that the transformation proceeds through an inward moving interface (Figure 5). This transformation can be labeled as WET3 according to the Galwey classification11 and as type I-destructive-reconstructive in the Petit & Coquerel model.12 Careful observations of many whiskers revealed that they usually exhibit a polygonal section (often rectangular shape in the order 1-2 µm). Furthermore, an unexpected feature of whiskers which grow outward from the initial crystal is their hollow structure (Figures 4 and 6).
Figure 3. XRPD at various temperatures of the sesquihydrate of DMA.
Crystal Growth of Hollow Whiskers
Figure 4. Microscopic observation of whiskers (×500).
On the basis of these observations, a growth mechanism of hollow whiskers has been proposed. Figure 7 summarizes the main features of this interpretation, which consists of the following steps: (1) When a single crystal of solvate S1 (here DMSO or DMF) is immersed in solvent S2 (here water), the fast penetration of the S2 solvent primarily through the crystal defects induces an increase of the internal pressure within the crystal. (2) Owing to the high solubility of the solute in S1, the crystal lattice is progressively disrupted and tiny droplets of saturated solution in S1 tend to gather and to migrate toward the surface. (3) Because of the above-mentioned internal pressure, the saturated solution in S1 is rapidly evacuated outward, and as soon as it enters in contact with S2, the
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solute crystallizes, creating a wall that prevents further mixing of the S1 solution and in-going S2 solvent. (4) When a sufficient amount of saturated solution in S1 reaches the surface of the initial particle, a hollow whisker grows in the solvent S2 like an expanding chimney fed by an internal channel. (5) The growth stops when the pressure is insufficient to eject the solution of DMA in S1. At that time, the solution trapped in the tubular particle crystallizes and closes or at least reduces the section of the channel. The whiskers can even be obstructed at the protruding extremities. To reproduce steps 3-5 described above, an experimental assembly was made up with a glass filter and a syringe (see Experimental Section and Figure 2). A saturated solution of dexamethasone acetate in DMSO () S1) was injected rapidly (approximately 2 mL/s) in water (S2) at 20 °C without stirring through the glass filter. The phase obtained is that obtained from solidto-solid transformation. SEM observations revealed that the global habitus of the sedimented whiskers obtained by this spray-inantisolvent mechanism (Figure 8) is similar in size and in shape to that obtained by immersion of single crystals. Optical microscopy observations (Figure 9) showed straight particles only. By transparency, a black line can be seen, which testifies to the presence of a channel running all along the needle-shaped particle. The whiskers are not sealed at their extremities; this may be due to the pressure of the saturated solution S1 which
Figure 5. SEM of the experiment interrupted 30 s after the immersion of the DMA‚DMSO solvate in water.
Figure 6. (a) SEM of two types of whiskers; (b) detailed view of hollow whiskers.
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Figure 7. Proposed scheme of the growth mechanism of whiskers.
Figure 8. Global observation (SEM) of whiskers obtained by using the spray-in-antisolvent method.
Mallet et al.
Figure 10. SEM photograph of whiskers at high magnification.
Hence owing to our experimental data, six criteria seem to be required for the formation of whiskers: (1) The solute has a high solubility in the initial solvent S1, in which it crystallizes as a solvate. (2) The solute is almost nonsoluble in the final solvent S2 (note that the final phase can be another solvate with S2). (3) The two solvents are fully miscible. (4) The exchange proceeds through a destructivereconstructive process. (5) There is no liquid-liquid demixtion between S1 (saturated in organic material) and S2 (antisolvent). (6) The product crystallizes immediately in the antisolvent phase. Conclusion
Figure 9. Optical microscopy of whiskers produced by using the setup depicted in Figure 2 (×400).
might be greater in this simulation than that in the crystal undergoing the exchange of solvent molecules. Higher magnification SEM observations (Figure 10) indicated unambiguously that all whiskers obtained with this setup present a hollow structure. Most of them have a simple polygonal section. The analogy of little springs of solution S1 emerging from the pores of the glass filter into solvent S2 and creating elongated chimney-like crystals is reinforced by these observations. However, when other organic materials readily soluble in DMSO and almost nonsoluble in water have been tested with the “spray-in-antisolvent” assembly, other phenomena have been observed: (i) liquid-liquid demixtion between S1 saturated in organic material and S2 (antisolvent) (ii) stand still on supersaturated state.
To explain the formation of whiskers during the solvent exchange from DMSO or DMF to water in dexamethasone acetetate, six criteria are proposed. Criteria 5 and 6 (no liquid-liquid demixtion and high instability of the supersaturated state) correspond to the formation of whiskers almost immediately at the interface between the antisolvent and the initial saturated solution. Two types of whiskers have been distinguished: the solid type, which is formed within the former crystal, and the hollow type, which grows in water acting as an antisolvent phase. The growth mechanism of the hollow needlelike crystals has been confirmed by the formation of 100% hollow whiskers when using a “spray-inantisolvent” method. The thin tubular crystals are thus the remains of dissipative structures13 obtained by this far-from-equilibrium process. Future work will be devoted to determine if they are single crystals. References (1) Evans C. C.; In Whiskers; M&B Monographs ME/8, Mills and Boon: London, 1972. (2) Laine, E.; Tuomien, V.; Ilvessalo P.; Kahela P. Int. J. Pharm. 1984, 20, 307-314. (3) Yuasa, H.; Kanaya, Y.; Asahina, K. Chem. Pharm. Bull. 1986, 34, 850-857. (4) Yuasa, H.; Ooi, M.; Takashima, Y.; Kanaya, Y. Int. J. Pharm. 2000, 203, 203-210. (5) Garnier, S.; Petit, S.; Coquerel G. J. Therm. Anal. Calorim. 2002, 68, 489-502. (6) Nordhoff, S.; Ulrich, J. J. Therm. Anal. Calorim. 1999, 57, 181-192.
Crystal Growth of Hollow Whiskers (7) Mallet, F.; Petit, S.; Petit, M. N.; Cardinael, P.; Billot, P.; Lafont, S.; Coquerel, G. J. Phys. IV 2001, 11, 253-259. (8) Mallet, F.; Petit, S.; Lafont, S.; Billot, P.; Lemarchand, D.; Coquerel, G. J. Therm. Anal. Calorim. 2003, 73, 459-471. (9) Terzis, A.; Theophanides, T. Acta Crystallogr. 1975, B31, 590-601. (10) Kuhnert-Brandsa¨tter M.; Gasser P. Microchem. J. 1971, 16, 590-610.
Crystal Growth & Design, Vol. 4, No. 5, 2004 969 (11) Galwey, A. K. Thermochim. Acta 2000, 355, 181-238. (12) Petit, S.; Coquerel, G. Chem. Mater 1996, 8, 2247-2258. (13) Nicolis, G.; Prigogine, I. Self-Organization in None Equilibrium System: From Dissipative Structures to Order through Fluctuation; John Wiley: Interscience: New York, 1977.
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