722
Langmuir 2008, 24, 722-733
Crystallization of Carbamazepine Pseudopolymorphs from Nonionic Microemulsions Anna Kogan,†,‡ Inna Popov,§ Vladimir Uvarov,§ Shmuel Cohen,|| Abraham Aserin,† and Nissim Garti*,† Casali Institute of Applied Chemistry and Department of Inorganic and Analytical Chemistry, The Institute of Chemistry, and The Unit for Nanoscopic Characterization, The Center for Nanoscience and Nanotechnology, The Hebrew UniVersity of Jerusalem, Jerusalem 91904, Israel ReceiVed September 6, 2007. In Final Form: October 14, 2007 Crystallization of carbamazepine (CBZ), an antiepileptic drug, precipitated from confined spaces of nonionic microemulsions was investigated. The study was aimed to correlate the structure of the microemulsion [water-in-oil (W/O), bicontinuous, and oil-in-water (O/W)] with the crystalline structure and morphology of solid CBZ. The precipitated CBZ was studied by DSC, TGA, powder XRD, single-crystal XRD, SEM, and optical microscopy. The results suggest that the microstructure of the microemulsions influences the crystallization process and allows crystallizing polymorphs that exhibit different crystal structure and habits. W/O nanodroplets orient the crystallizing CBZ molecules to form a prismlike anhydrous polymorphic form with monoclinic unit cell and P21/n space group. Bicontinuous structures lead to platelike dihydrate crystals with orthorhombic unit cell and Cmca space group. The O/W nanodroplets cause the formation of needlelike dihydrate crystals with monoclinic unit cell and P21/c space group. The morphological features of solid CBZ remain predetermined by the basic symmetry and parameters of its unit cell. Precipitation of CBZ pseudopolymorphs from supersaturated microemulsion is discussed in terms of oriented attachment that provides perfect packing of numerous separately nucleated ordered nuclei of CBZ into microscale platelets and then into macroscopic crystals. Crystallization from microemulsion media enabling one to obtain the drug (CBZ) with predicted structure and morphology should be of great significance for pharmaceutical applications.
1. Introduction Preparation or processing of pharmaceutical solids frequently results in formation of polymorphs or solvates.1 Polymorphs are crystalline substances having the same chemical composition but different internal crystal structure.2 Solvates, also known as pseudopolymorphs, are crystalline solid adducts containing solvent molecules within the crystal structure.3 If the incorporated solvent is water, the solvate is termed a hydrate.2,3 Polymorphic modifications and various hydration states of a compound have different crystal structures, giving rise to unique differences in the physical and pharmaceutical properties of the drug. Different polymorphs and solvates will differ in their lattice energy and entropy, as well as in their density, vapor pressure, refractive index, melting point, and heat of fusion. The differences between polymorphs could result in significant differences in solubility and dissolution rate and as a result affect the drug release rate and its bioavailability.2,4-6 Crystallization within confined space is a new trend in crystallization of a variety of organic7-9 and inorganic * Corresponding author. Tel: +972-2-658-6574/5. Fax: +972-2-6520262. E-mail:
[email protected]. † Casali Institute of Applied Chemistry. ‡ The results presented in this paper are part of A.K.’s PhD dissertation in Applied Chemistry, The Hebrew University of Jerusalem, Israel. § The Unit for Nanoscopic Characterization. || Department of Inorganic and Analytical Chemistry. (1) Han, J.; Suryanarayanan. R. Int. J. Pharm. 1997, 157, 209-218. (2) Vippagunta, S. R; Brittain, H. G.; Grant D. J. W. AdV. Drug DeliVery ReV. 2001, 48, 3-26. (3) Qu, H.; Louhi-Kultanen, M.; Kallas, J. Int. J. Pharm. 2006, 321, 101-107. (4) Luhtala, S. Acta Pharm. Nord. 1992, 4, 85-90. (5) Murphy, D.; Rodriguez-Cintron, F.; Langevin, B.; Kelly, R. C.; RodriguezHornedo, N. Int. J. Pharm. 2002, 246, 121-134. (6) Kobayashi, Y.; Ito, S.; Itai, S.; Yamamoto, K. Int. J. Pharm. 2000, 193, 137-146. (7) Furedi-Milhofer, H.; Garti, N.; Kamyshny, A. J. Cryst. Growth. 1999, 198, 1365-1370.
materials.10-12 One way to achieve a controlled crystallization process is by precipitating the compound from a confined liquidphase such as microemulsion media. Microemulsions are clear, stable, isotropic mixtures of oil, water, and surfactant, frequently in combination with a cosurfactant. Microemulsions are nanosized droplets characterized by thermodynamic stability and high surface areas.13-17 In recent years, we have conducted studies related to controlled crystallization and polymorphism of drugs and nutraceuticals from confined reservoirs of dispersed liquid systems. Such controlled crystallization may lead to the formation of nonstable polymorphic structures with unusual crystal habits and properties.7,18,19 A strong correlation between the microemulsion droplet size and shape and phase structure of the drug was found. Formation of a new polymorph of the artificial sweetener (8) Sajjadi, S. Langmuir 2007, 23, 1018-1024. (9) Liu, J.; Nicholson, C. E.; Cooper S. J. Langmuir 2007, 23, 7286-7292. (10) Ethayaraja, M.; Dutta, K.; Muthukumaran, D.; Bandyopadhyaya, R. Langmuir 2007, 23, 3418-3423. (11) Caponetti, E.; Martino, D. C.; Saladino, M. L. Langmuir 2007, 23, 39473952 (12) Rassy, H. E.; Belamie, E.; Livage, J.; Coradin, T. Langmuir 2005, 21, 8584-8587. (13) Kogan, A.; Garti, N. AdV. Colloid Interface Sci. 2006, 123-126, 369385. (14) Kogan, A.; Aserin, A.; Garti, N. J. Colloid Interface Sci. 2007, 315, 637-647. (15) Sommer, C.; Deen, G. R.; Pedersen, J. S.; Strunz, P.; Garamus, V. M. Langmuir 2007, 23, 6544-6553. (16) James-Smith, M. A.; Shekhawat, D.; Moudgil, B. M.; Shah, D. O. Langmuir 2007, 23, 1640-1644. (17) Frank, C.; Frielinghaus, H.; Allgaier, J.; Prast, H. Langmuir 2007, 23, 6526-6535. (18) Garti, N.; Aserin, A. Microemulsions for solubilization and delivery of nutraceuticals and drugs. In Microencapsulation: Methods and Industrial Applications, Culinary and Hospitality Industry Publications SerVices, 2nd ed.; Benita, S., Ed.; Taylor and Francis Group, LLC: New York 2005; Vol. 158, pp 345-428. (19) Yano J.; Fu¨redi-Milhofer, H.; Wachtel, E.; Garti, N. Langmuir 2000, 16, 10005-10014.
10.1021/la702763e CCC: $40.75 © 2008 American Chemical Society Published on Web 12/29/2007
Crystallization of Carbamazepine Pseudopolymorphs
Figure 1. Chemical structure of carbamazepine.
aspartame solubilized in water/isooctane/AOT microemulsions with greatly improved dissolution kinetics has been reported.7 It was also found that morphology, polymorphism, and crystal size of amino acids (glycine and L-phenylalanine) were affected by solubilization within the microemulsion droplets.19 Carbamazepine (CBZ), an antiepileptic drug,20 was selected as the model compound in this work (Figure 1). Although carbamazepine has high intestinal permeability, the bioavailability is limited by its low water solubility (0.11 mg/mL).21 Carbamazepine is known to crystallize into at least four polymorphic forms and two dihydrates,22 and its solubility and dissolution rate have been found to be influenced by the polymorphic form.6 In our previous work, we reported a detailed structural study of CBZ solubilization within microemulsions composed of R-(+)limonene + EtOH 1:1 wt % ratio that serves as an oil phase, Tween 60 used as surfactant, and water + propylene glycol (PG) 1:1 wt % ratio used as an aqueous phase (Figure 2). We found that up to 20 wt % aqueous phase the droplets have water-in-oil (W/O) microstructure, in the region of 20-70 wt % the droplets were composed of a bicontinuous domain, and with further dilution with water, the structure inverts to oil-in-water (O/W) nanodroplets (Figure 3).14 In addition, we found that solubilized CBZ from a supersaturated nonionic O/W microemulsion (90 wt % aqueous phase) upon precipitation forms a dihydrate form of CBZ with monoclinic P21/c unit cell. The present report is an extended study of CBZ crystallization from the three microemulsion structures. The study was done to correlate the interface packing parameters of the microemulsion with the crystalline structure and morphological features of the final CBZ material. The mechanism and pathways that the molecules of the drug undergo from their interfacially solubilized stage to the growth of the hydrated crystals in the aqueous phase are suggested. 2. Experimental Section 2.1. Materials. Commercial carbamazepine (5H-dibenz[b,f]azepine-5-carboxamide; Figure 1) was obtained from Teva Pharmaceutical Industries, Ltd. (Kfar Saba, Israel) and used as received. Tween 60 [polyoxyethylene-(20)-sorbitan monostearate] and R-(+)-limonene (98%) were purchased from Sigma Chemical Co. (St. Louis, MO). Ethanol (EtOH) (99.8%) was obtained from Frutarom (Haifa, Israel). Propylene glycol (PG or 1,2-propanediol) (99.5%) was purchased from Merck KGaA (Darmstadt, Germany). All components were used without further purification. The water was triple-distilled. 2.2. Crystallization Procedure. The CBZ pseudopolymorphs were crystallized from a five-component system described in a pseudoternary phase diagram (Figure 2) that was previously constructed in our lab.23 (20) El-Zein, H.; Riad, L.; El-Bary, A. A. Int. J. Pharm. 1998, 168, 209-220. (21) Tian, F.; Saville, D. J.; Gordon, K. C.; Strachan, C. J.; Zeitler, J. A.; Sandler N.; Rades, T. J. Pharm. Pharmacol. 2007, 59, 193-201. (22) Kogan, A.; Popov, I.; Uvarov, V.; Cohen, S.; Aserin, A.; Garti, N. J. Disper. Sci. Technol. 2007, 28, 1008-1019.
Langmuir, Vol. 24, No. 3, 2008 723 CBZ was solubilized in a transparent structured mixture of R-(+)-limonene + EtOH (1:1)/Tween 60 at an 8:2 wt % ratio and different weight percent of water + PG (1:1) mixture. For complete CBZ dissolution, the formulation was heated to 60 °C and stirred until a transparent and slightly yellow mixture was obtained. Then the mixture was transferred to a room-temperature bath without agitation for time-dependent (continuous) optical observation. The crystals were extracted from the mother liquid at the moment at which their growth visually decelerated. CBZ crystals were accurately withdrawn from the microemulsion with a spatula, and excess mother liquid was carefully removed by absorbent paper. In this form the material was immediately analyzed with all the characterization techniques described below. An absence of any microemulsion components’ residues was verified by elemental analysis (Elemental Analysis Unit, The Department of Inorganic Chemistry). 2.3. X-ray Diffractometry Measurements. X-ray powder diffraction measurements were performed on a D8 Advance diffractometer (Bruker AXS GmbH, Karlsruhe, Germany) with parallel-beam optics, 2° Soller slits for incident and diffracted beams, and 0.2 mm receiving slit. Cu KR radiation (λ ) 1.5418 Å) was used. Freshly prepared powder samples manually ground in an agate mortar were mounted on low background quartz sample holders. XRD patterns were recorded in 4°-50° 2θ scale range at room temperature and 40 kV tube voltage, 40 mA tube current, step scan mode with a scanning rate of 0.02° 2θ s-1. X-ray powder pattern simulations were performed with the program Powder Cell 2.4.24 Profile matching and integrated intensity refinement were performed with the program WinPLOTR.25 A single crystal of carbamazepine withdrawn from the microemulsion solutions was immediately attached to a glass fiber with epoxy glue and transferred to a Bruker SMART APEX CCD X-ray diffractometer system controlled by a Pentium-based PC running the SMART software package.26 The crystal was mounted on the three-circle goniometer with χ fixed at +54.76°, at room temperature. The diffracted graphite-monochromated Mo KR radiation (λ ) 0.710 73 Å) was detected on a phosphor screen held at a distance of 6.0 cm from the crystal operating at -42 °C. The detector centroid and crystal-to-detector distance were calibrated from a least-squares analysis of the unit cell parameters of a carefully centered YLID reference crystal. After collection, the raw data frames were transferred to a second PC computer for integration by the SAINT software package.27 Checking the profile of the reflections did not show any splitting; therefore, there was no indication of twinning. The structure of the crystals obtained from 40 and 90 wt % aqueous phase were solved and refined using the SHELXTL software package.28 Details of data acquisition and processing are presented in the Supporting Information and in our earlier publication.22 2.4. Thermal Analysis. Differential scanning calorimetry (DSC) measurements were carried out on a Mettler Toledo DSC822 (Greifensee, Switzerland). The instrument was calibrated with indium, lauric acid, water, and ethyl acetate. Samples of 5-15 mg were weighed using a Mettler M3 microbalance in standard 40 µL aluminum pans and immediately sealed by a press.29 Thermal behavior was studied under a dry nitrogen purge (50 mL/min) at 25-200 °C at a heating rate of 5 °C/min. An empty pan was used (23) Yaghmur, A.; Aserin A.; Garti, N. Colloids Surf. A 2002, 209, 71-81. (24) Kraus, W.; Nolze, G. J. Appl. Crystallogr. 1996, 29, 301-303. (25) Roisnel, T.; Rodriguez-Carvajal. J. Mater. Sci. Forum Pr. EPDIC 2000, 7, 118-123. (26) SMART-NT V5.6, BRUKER AXS GMBH, D-76181 Karlsruhe, Germany 2002. (27) SAINT-NT V5.0, BRUKER AXS GMBH, D-76181 Karlsruhe, Germany 2002. (28) SHELXTL-NT V6.1, BRUKER AXS GMBH, D-76181 Karlsruhe, Germany 2002. (29) Yaghmur, A.; Aserin, A.; Tiunova, I.; Garti, N. J. Therm. Anal. Calorim. 2002, 69, 163-177. (30) Dugue, J.; Ceolin, R.; Rouland, J. C.; Lepage, F. Pham. Acta HelV. 1991, 66, 307-310. (31) Otsuka, M.; Ofusa, T.; Matsuda, Y. Colloids Surf. B. 1999, 13, 263-273. (32) Katzhendler, I.; Azoury, R.; Friedman, M. J. Controlled Release 2000, 65, 331-343.
724 Langmuir, Vol. 24, No. 3, 2008
Kogan et al.
Figure 2. Phase diagram of pseudoternary system [water/PG]/[R-(+)-limonene/EtOH]/Tween 60 at 25 °C with constant weight ratios of water/PG (1/1) and R-(+)-limonene/EtOH (1/1). Dilution line 82 is shown.23
as a reference. The enthalpy changes associated with thermal transition were obtained by integrating the area of each pertinent DSC peak. For the thermogravimetric analysis (TGA), a Mettler TC10A/ TC15 TA controller and Mettler M3 thermobalance (Greifensee, Switzerland) were used. Samples of 10-20 mg were weighed and heated to 25-200 °C at a rate of 5 °C/min. For each examined sample of solid CBZ, the DSC and TGA data were acquired at least three times and an average error of as-measured enthalpy value was defined as (3 J/g. 2.5. Microscopy. The morphology of the CBZ crystals that crystallized out of the microemulsions was studied by optical and scanning electron microscopy. The samples were examined immediately after removing them from the microemulsion medium. A Nikon FX-IIA reflection microscope equipped with a Nikon FX35W camera (Tokyo, Japan) was used for optical acquisition. Solid phases were also examined using an environmental scanning electron microscope ESEM Quanta 200 (FEI, Eindhoven, The Netherlands) operated in low vacuum mode (0.6 Torr pressure) at 15 kV accelerating voltage. The samples were prepared by transferring the CBZ solid from the microemulsion to a strip of double sided carbon tape attached to a standard SEM mounting stub. 2.6. Dynamic Light Scattering (DLS). The hydrodynamic diameter of microemulsion nanodroplets containing 90 wt % aqueous phase was determined to be 8 ( 0.07 nm using the Nano-S (λ ) 633 nm; Malvern Instruments, UK) instrument. The samples were filtered by a 0.2 mm PVDF filter (Millipore) into a polystyrene disposable cuvette, with no further dilution. The measurements were carried out at a scattering angle of 173° at 25 °C. Data were collected in three repeated measurements (10 scans for each repeat). The average size was reported by the volume distribution for each measurement. The hydrodynamic radius RH was calculated using the equation KBT RH ) 6πηDeff where KB is the Boltzmann constant, T is the absolute temperature, η is the viscosity of the continuous medium at a given temperature, and Deff is the effective particle diffusion constant.
3. Results and Discussion 3.1. Thermal Analysis. DSC heating thermograms of the commercial CBZ and samples crystallized from microemulsions lying along the dilution line 82 are presented in Figure 4. Detailed descriptions of all the thermal events occurring at heating of CBZ crystallized from microemulsions are summarized in Table 1. The DSC curve of commercial untreated CBZ (Figure 4) exhibited an endothermic peak at 175 °C (∆Hm ) 43 J/g), which is characteristic for melting of P-monoclinic form.33-36 Further heating of the sample revealed the existence of an exothermic peak known as melt transformation of a triclinic (R-form) that occurred at 178 °C (∆Hf ) 37 J/g). This polymorph melted at 191 °C (∆Hm ) 107 J/g).33-36 The observed sequence of solidmelt-solid phase transitions is very similar to the thermal behavior of commercial P-monoclinic CBZ that has been reported.6,31 However, it differs significantly from the results of Katzhendler et al.32,33 in which solid-solid phase transformation of the commercial P-monoclinic to triclinic form of CBZ was reported. As expected, TGA of the commercial CBZ showed no weight loss (Figure 5). Since the main purpose of this study was to crystallize CBZ from the microemulsion and compare it to the commercial product, we did not conduct a more detailed study of the commercial product. The thermograms presented in Figure 4 can be divided into three clearly distinguished groups that differ significantly in their thermal behavior. (33) Katzhendler, I.; Azoury, R.; Friedman, M. J. Controlled Release 1998, 54, 69-85. (34) Ono, M.; Tozuka, Y.; Oguchi, T.; Yamamura, S.; Yamamoto, K. Int. J. Pharm. 2002, 239, 1-12. (35) Andratschke, M. University of Regensburg, Germany, ICDD Grant-inAid 1999 (JCPDF card number 51-2106). (36) Harris, R. K.; Ghi, P. Y.; Puschmann, H.; Apperley, D. C.; Griesser, U. J.; Hammond, R. B.; Ma, C.; Roberts, K. J.; Pearce, G. J.; Yates, J. R.; Pickard, C. J. Org. Process Res. DeV. 2006, 9, 902-910.
Crystallization of Carbamazepine Pseudopolymorphs
Langmuir, Vol. 24, No. 3, 2008 725
Figure 4. DSC curves for CBZ crystals obtained from microemulsion samples whose compositions lie along dilution line 82. The numbers near the curves indicate aqueous phase weight percent. The curves have been displaced vertically for ease of visualization.
Figure 3. Schematic illustration (not to scale) of possible packing of CBZ along dilution line 73 at three different dilution regions: (top) W/O microemulsion, (middle) bicontinuous, and (bottom) O/W microemulsion.
The first group covers crystals obtained from microemulsions containing 0-20 wt % aqueous phase and exhibiting W/O microstructures14 (Figure 3). The drug is located within the interface region of the reversed micelles.14 Therefore, CBZ from such structure crystallizes as anhydrous crystalline matter in a polymorphic form closely resembling that of the commercial one. As shown in Table 1, examination of thermal behavior of CBZ crystallized from microemulsions with 0-20 wt % water generally shows the same solid-liquid-solid sequence of phase transitions. Nevertheless, somewhat different thermal behavior is observed at 169-176 °C. In addition to the endothermic peak usually appearing at 175 °C and referring to the melting of the P-monoclinic form (β-form), there are other endothermic events that occur at 173, 174, and 169 °C for samples crystallizing from microemulsions containing 0, 10, and 20 wt % aqueous phase, respectively. We assume that these endothermic peaks are of the melting of a polymorph that we termed the β′-form that seems to be a less stable form of β-CBZ, since its melting occurs at a lower temperature (Table 1, Figure 4) and the sum of the melting enthalpies for these β′- and β-forms is very close to that of the commercial β-CBZ. Considering the melting enthalpy values for the β′- and β-form, we see that at 0 and 10 wt % aqueous phase the β′-form prevails over the β, i.e., a phase that is less stable and, apparently having higher concentration of structural defects, is formed.
Further increase in the aqueous phase contents leads to droplet swelling14 that enables higher mobility of drug molecules and thus allows the drug to pack itself in a more stable polymorph. Therefore, with the increase of aqueous phase contents (20 wt %) the peaks of the β′-form disappear. As seen in Table 1, the crystallization enthalpy of the triclinic form (exothermic process observed at ca. 178 °C) varies for CBZ crystals obtained from different W/O microstructures, whereas its melting enthalpy remains constant (endothermic process at ca. 191 °C). We suggest that these high-temperature processes are most likely affected by the preceding phase transformations and are not correlated with the microemulsion microstructure. TGA results (Figure 5) reveal no weight loss upon heating for all the samples in this group. The second group of samples covers crystals formed from microemulsions containing 30-60 wt % aqueous phase (Figure 3). Their thermal behavior at heating is significantly different from that observed for anhydrous CBZ and material formed from W/O microemulsions. As is shown in Figure 4 and Table 1, a series of low-temperature broad endothermic events are observed at 61-118 °C, while no thermal events occurred at 169-179 °C. Observed differences in thermal behavior can refer to formation of notably differing crystalline material, which easily decomposes and loses part of its weight upon heating (Figure 5). The microstructure of microemulsions containing aqueous phase at 30-60 wt % is known as bicontinuous.14 In this region the drug molecules are assumed to be more exposed to water, and thus, a hydrated form of CBZ could be obtained. As seen from the TGA profile of these CBZ samples, weight loss occurring mainly at 40-120 °C was around 13.2 wt %, nearly equal to the stoichiometric value calculated for the CBZ-dihydrate.6,34 On the basis of this observation, we explain the observed low-temperature endo-processes as a water release from dihydrate structures, which occurs in several steps. Both DSC data of Figure 4 and the first derivative of TGA data presented in Figure 5b consistently indicate the stepwise process of dehydration observed up to 120 °C. As is seen in Table 1, the least aqueous phase content in this type of microemulsion (30 wt %) enables the strongest trapping of water molecules within the hydrated solid product, since its dehydration ends at the highest observed temperature of 118 °C. Therefore, we suggest that the structure of hydrated CBZ is influenced by the structure of the bicontinuous crystallization medium. The bicontinuous mesophases are
726 Langmuir, Vol. 24, No. 3, 2008
Kogan et al.
Table 1. Thermal Behavior from DSC Measurements of the CBZ Crystals Obtained from Different Microemulsion Compositions Along Dilution Line 82a peak 1 aqueous phase wt % 0 10 20 30 40 50 60 70 80 90 a
T
61 72 86 78 83 84 81
∆Hf
9 90 204 101 338 308 358
peak 2 T
91 90 88 90
∆Hf
110 154 88 92
peak 3 T
∆Hf
102
60
96
85
peak 4 T
108 108
∆Hf
36 65
peak 5 ∆Hf
T
118
3
peak 6
peak 7
peak 8
peak 9
T
∆Hf
T
∆Hf
T
∆Hf
T
∆Hf
174 173 169
25 25 15
176 175 174
13 15 30
179 178 178
34 16 18
191 192 191 192 192 191 191 191 192 191
77 79 78 79 79 77 83 94 87 88
T, temperature of fusion (in °C). b ∆Hf, heat of fusion (in J/g).
characterized by interconnected channels of water and oil short domains. The specific size of each domain type depends on the amount of dilution. The water contents are quite high and some water molecules are free, facilitating attachment of these water molecules to the CBZ and formation of the hydrated forms. Thus, at higher aqueous phase contents we obtained solid hydrated product which exhibited a lower temperature of dehydration, apparently because of weaker entrapping of water molecules. Nevertheless, since total weight loss and total enthalpy of all dehydration steps are practically the same, we conclude that a variety of pseudopolymorphs with dihydrate stoichiometry are formed within this set of samples. As is seen in Figure 4, for all these samples only one thermal event followed the multistep endothermic series discussed above. That was an endothermic process observed around 191 °C and attributed to well-known melting of triclinic CBZ. Its enthalpy was practically the same for all examined samples, about 78 J/g. Since no intermediate process was observed, we, therefore, conclude that lowtemperature multistep endo-processes preceding this event were not only dehydration but also a solid-state transformation of dihydrate-to-triclinic CBZ. The third group of samples includes those precipitated from the microemulsion with the highest content of aqueous phase of 70-90 wt % (oil-in-water microemulsions)14 (Figure 3). We distinguish this group of samples from the previous one because they exhibited only one low-temperature endothermic event at around 81-84 °C (Figure 4) and their weight loss at this temperature range occurred through a sharp one-step process (Figure 5). Since the value of weight loss was practically the same as for the previous group, around 13.2 wt %, we suppose formation of dihydrate CBZ in these samples as well. That is why we conclude that crystallization of CBZ from microemulsions containing more than 20 wt % of aqueous phase resulted in formation of hydrated crystals composed of one molecule of drug per two molecules of water (1/2 molar ratio), i.e., CBZ dihydrate. We have already reported14 that increasing the water content results in transition of the microemulsion structure from bicontinuous domains to oil-in-water nanodroplets. Such a structure is expected to allow more contact of drug molecules with water and, because of its lower viscosity, should enable higher mobility of dissolved CBZ. Therefore, the solid hydrated product precipitated from such liquid structure is expected to have the best packing and stoichiometry compared to the previous groups of samples. Observed one-step low-temperature decomposition of this product upon heating confirms these suggestions and also indicates that, unlike the previous case, this CBZ dihydrate was much more structurally uniform.
Although the thermal behavior of all the examined samples in this group was very similar, only for the samples crystallized from most diluted microemulsion (90 wt % aqueous phase) was the value of dehydration enthalpy 358 J/g (Table 1) in good agreement with the reported data.30,32,33 This fact points out the definite relation between the crystallization medium features and the structure, stoichiometry, and, finally, thermal behavior of solids precipitated from it. As the rest of the thermal curves in this group of samples were identical to those of previous group, we conclude that dehydration at around 81-84 °C was accompanied by solid-solid phase transition of dihydrate-to-triclinic (R-form) CBZ which then melted at around 191 °C. In order to identify the crystalline structure of the microemulsion-induced crystallized dihydrate CBZ, we performed detailed X-ray diffraction analysis. 3.2. X-ray Diffraction. Using XRD powder method, commercial CBZ was identified as single-phase β-CBZ. XRD pattern processing (the profile matching and refinement of the unit cell parameters)25 allowed more precise definition of the cell parameters of β-CBZ: a ) 7.54 Å, b ) 11.16 Å, c ) 13.91 Å, β ) 92.86°, space group P21/n (Table 2). The obtained experimental pattern is very similar to the β-CBZ pattern published in the literature35 (Figure 6). This pattern was used as a reference for comparison of CBZ crystals obtained from microemulsion media. Powder XRD patterns of the samples crystallized from microemulsions containing up to 20 wt % aqueous phase are presented in Figure 7. All of them look very similar, but they do not completely coincide with the reference pattern. Nevertheless, the positions and the relative intensities of the strongest peaks found in all these patterns are identical to those of the commercial β-CBZ; therefore, we conclude that the material obtained has a crystalline structure of anhydrous β-CBZ with P-monoclinic cell (space group P21/n, unit cell parameters a ) 7.54 Å, b ) 11.16 Å, c ) 13.91 Å, β ) 92.86°; Table 2). A single crystalline diffraction experiment performed on the samples crystallized from the microemulsions with 10 and 20 wt % water support this conclusion (Table 2) and, consequently, directly confirms our suggestion made in the previous section about the anhydrous nature of CBZ crystallized from the microemulsion having the water-in-oil structure. Powder diffraction patterns of the crystals grown from the microemulsion containing 30-90 wt % aqueous phase are presented in Figure 8. All of them exhibit very close similarity to each other, but they differ significantly from the reference pattern of β-CBZ shown in Figure 8. In our previous study,22 we reported the details of a thorough crystallographic study conducted
Crystallization of Carbamazepine Pseudopolymorphs
Figure 5. (a) TGA curves for CBZ crystals and (b) the first derivative of TGA curves for CBZ crystals obtained from microemulsion samples whose compositions lie along dilution line 82. The numbers near the curves indicate aqueous phase weight percent. Table 2. Crystal Structure Data Obtained from Single-Crystal X-ray Diffraction and Powder X-ray Diffraction Measurements X-ray diffraction measurements content of aqueous phase (wt %) 0-20
30-80
90
single crystal
powder
monoclinic (anhydrous) space group P21/n a ) 7.53 Å b ) 11.19 Å c ) 13.96 Å β ) 93.03° orthorhombic (dihydrate) space group Cmca a ) 19.74 Å b ) 4.92 Å c ) 28.66 Å R ) β ) γ ) 90° monoclinic (dihydrate) space group P21/c a ) 10.16 Å b ) 28.70 Å c ) 4.93 Å β ) 103.33°
monoclinic (anhydrous) space group P21/n a ) 7.54 Å b ) 11.16 Å c ) 13.91 Å β ) 92.86° monoclinic (dihydrate) space group P21/c a ) 10.21 Å b ) 28.73 Å c ) 4.95 Å β ) 103.9° monoclinic (dihydrate) space group P21/c a ) 10.21 Å b ) 28.73 Å c ) 4.95 Å β ) 103.9°
for CBZ crystallized from the oil-in-water microemulsion (90 wt % aqueous phase). It was found that CBZ dihydrate with monoclinic crystalline structure (space group P21/c, unit cell parameters a ) 10.16 Å, b ) 28.70 Å, c ) 4.94 Å, β ) 103.33°) is obtained. To more clearly compare the patterns, we show here the simulated XRD pattern of this structure (Figure 8a). All the experimental patterns are similar to the simulated pattern of
Langmuir, Vol. 24, No. 3, 2008 727
monoclinic CBZ dihydrate; therefore, we conclude that CBZ crystallized from microemulsions containing 30-90 wt % aqueous phase is the same crystalline dihydrate with monoclinic unit cell reported elsewhere.22,36 The results of the powder XRD study are summarized in Table 2 for all tested ranges of concentrations. By using a single crystalline diffraction technique we obtained somewhat different results (Table 2, Figure 9). For CBZ crystallized from 30-80 wt % aqueous phase, an orthorhombic37 Cmca space group rather than the monoclinic P21/c previously reported22,36 was obtained. Both of them have the same formula, CBZ·2H2O, of stoichiometric dihydrate. All non-hydrogen atoms were refined anisotropically, hydrogen atoms connected to carbon were included using the riding model at their idealized positions, and those of the NH2 group were refined freely in isotropic approximation. Water hydrogen atoms were not resolved. The discrepancy factors are R1 ) 0.0510 and wR2 ) 0.1464 for 1277 reflections with I > 2σ(I) and 102 parameters. Pertinent crystallographic data are summarized in the Supporting Information. As seen in Figure 9a, the molecular structure of CBZ obtained from 90 wt % aqueous phase microemulsion, two benzo wings of the CBZ are crystallographically independent, as are the positions of the oxygen atom and the amino group in the carboxamide moiety.22 In contrast, in the sample obtained from the microemulsion with 40 wt % aqueous phase (Figure 9b), there is an extra mirror plane passing through atoms N1 and C8 causing these two wings to reflect each other. Moreover, the locations of the carboxylic oxygen and amino group are disordered; each position has 50% probability to populate either O1 or N2, because we found that the C8-O1,N2 bond length, 1.282(2) Å, in this sample was an average of the C15-O1 and C15-N2 bonds [1.245(3) and 1.322(3)Å, respectively] as measured for the sample crystallized from 90 wt % aqueous phase medium.22 For final verification of the orthorhombic form, the appropriate raw data were forced to be reduced as monoclinic. The discrepancy factor between Laue equivalent reflections, Rint ) 0.0265, was lower than that of the orthorhombic setting (0.0381). The structure was then refined in the P21/c space group allowing the same disorder of O1 and N2 atoms. The results were R1 ) 0.0558, wR2 ) 0.1534 for 2322 reflections with I > 2σ(I) and 197 parameters. Checking this “monoclinic” CIF file with the PLATON program38 detected a missing mirror plane and a second glide plane. Therefore, the proposed solution for CBZ dihydrate obtained from 40 wt % aqueous phase microemulsion is Cmca space group with orthorhombic unit cell parameters a ) 19.74 Å, b ) 4.92 Å, c ) 28.66 Å, R ) β ) γ ) 90°. In conclusion, we suggest that two dihydrates of CBZ have a very close crystal structure. However, in the monoclinic form each carboxamide moiety is ordered, while in the orthorhombic form it is disordered. Considering the full set of XRD results obtained for CBZ crystallized from microemulsions, we conclude that CBZ grown from W/O microemulsions of up to 20 wt % aqueous phase is anhydrous crystalline material analogous to the commercial β-CBZ with P-monoclinic cell. When aqueous content of the microemulsion reaches 30 wt %, crystals of dihydrate CBZ phase are formed. Their crystalline structure is completely different from that of anhydrous β-CBZ and could be described as (37) Florence A. J.; Kennedy, A. R.; Shankland, N.; Johnston, A.; Private Communication, CCDC RefCode ) FEFNOT01, 2004. (38) Spek, A. L. PLATON, A Multipurpose Crystallographic Tool, Utrecht University, Utrecht, The Netherlands 2007.
728 Langmuir, Vol. 24, No. 3, 2008
Kogan et al.
Figure 6. X-ray powder diffractogram acquired from anhydrous commercial CBZ. Vertical ticks represent the peak file of β-CBZ.35
Figure 7. X-ray powder diffractograms for CBZ crystals obtained from commercial CBZ (a) and from microemulsion samples along dilution line 82 containing 0 wt % (b) and 20 wt % (c) aqueous phase.
monoclinic or orthorhombic depending on the aqueous content in microemulsion and XRD technique applied. Thus, precipitation from bicontinuous or O/W microemulsion structure allows formation of hydrated pseudopolymorphs of CBZ. Stability of the hydrated form and its crystalline packing (both structural perfectness and symmetry) are dependent on the microstructure of mother liquid. Considering the unit cells of CBZ dihydrate crystals with orthorhombic and monoclinic structure (Table 2), we find that two of three unit cell parameters are practically coinciding for both structures (corth ) bmono ) 28.7 Å, borth ) cmono ) 4.9 Å). Moreover, both unit cells are highly nonequiaxial with an axis ratio as high as 28.7/4.9 ) 5.85. This feature predetermines
formation of elongated crystals at any specific parameters of the crystallization path and is usually utilized if synthesis/growth of rodlike morphologies is required.39-43 Since this dominating feature is possessed by both alternative structural solutions, we (39) Hiruma, K.; Yazawa, M.; Katsuyama, T.; Ogawa, K.; Haraguchi, K.; Koguchi, M.; Kakibayashi, H. J. Appl. Phys. 1995, 77, 447-462. (40) Duan, X.; Huang, Y.; Cui, Y.; Wang, J.; Lieber, C. M. Nature 2001, 409, 66-69. (41) Gudiksen, M. S.; Lauhon, L. J.; Wang, J.; Smith, D. C.; Lieber, C. M. Nature 2002, 415, 617-620. (42) Huang, Y.; Duan, X.; Cui, Y.; Lauhon, L. J.; Kim, K. H.; Lieber, C. M. Science 2001, 294, 1313-1317. (43) Bjo¨rk, M. T.; Ohlsson, B. J.; Sass, T.; Person, A. I.; Thelander, C.; Magnusson, M. H.; Deppert, K.; Wallenberg, L. R.; Samuelson, L. Nano Lett. 2002, 2, 87-89.
Crystallization of Carbamazepine Pseudopolymorphs
Langmuir, Vol. 24, No. 3, 2008 729
Figure 8. X-ray powder diffractograms for CBZ crystals obtained from simulated monoclinic CBZ22 (a) and from microemulsion samples along dilution line 82 containing 30 wt % (b), 40 wt % (c), 60 wt % (d), and 90 wt % (e) aqueous phase.
accept that despite possible variations in local atomic arrangement, CBZ dihydrate is an intrinsically nonequiaxial crystal which is supposed to keep its quasi-two-dimensional structure up to microand even macroscale. In contrast, the monoclinic unit cell of anhydrous CBZ (a ) 7.53 Å, b ) 11.19 Å, c ) 13.96 Å, β ) 93.03°; Table 2) has a much smaller aspect ratio value c/a ) 1.85. Consequently, micro- and macroscopic crystals of anhydrous CBZ are expected to have close to equiaxial morphology. In addition, we wish to mention that noncoincidence in structural solutions obtained with two XRD techniques could be caused by structural changes which occurred during grinding applied for powder XRD, while single crystalline acquisition was performed for the crystals as-extracted from mother liquid.22 3.3. Light Microscopic Observations. The optical microscope images of CBZ precipitated from microemulsion are shown in Figure 10a-c. The anhydrous CBZ crystals crystallized from W/O structures have prismlike morphology (Figure 10a). A number of crystals 3-5 mm in length and 2-4 mm in width were formed in a test tube after the crystallization mixture aged 3 weeks at constant temperature (25 °C) without agitation. After 2 weeks of precipitation at the same external conditions, only a few platelike crystals of 2-10 mm length and 0.5-1.5 mm width had been formed within the microemulsions containing 30-60 wt % aqueous phase exhibiting bicontinuous microstructures (Figure 10b). The crystal size distribution (CSD) of these crystallites was broad compared to that for the anhydrous CBZ formed from W/O mother liquid. As is seen in Figure 10c, crystallization from the O/W microemulsion media (70-90 wt % aqueous phase) resulted in formation of large needlelike crystals. They reached 10-15 mm in length and ∼0.5 mm in width after 3-7 days crystallization. Considering the features of CBZ precipitated from microemulsion media, we conclude that their microscopic morphology generally meets the predictions we made in the previous section based on the crystallographic data. Anhydrous CBZ prisms are the closest to 3D polyhedral geometry as well as the largest
quantity and the narrowest CSD. Hydrated crystals have quasi2D morphology of elongated plates or even quasi-1D needlelike geometry. Lack of 3D morphology is generally predetermined by the high aspect ratio of unit cells specific for dihydrate CBZ, which we discussed in the previous section in detail. Still, CBZ dihydrate obtained from microemulsion containing 30-60 wt % aqueous phase has a platelike morphology with the broadest CSD (Figure 10b), whereas CBZ of the same stoichiometry obtained from the most diluted mother liquid (90 wt % aqueous phase) has needlelike structure and relatively narrow CSD (Figure 10c). All these differences could be explained if crystallization paths are taken into consideration as well. Being a somewhat amphiphilic molecule, CBZ is known to be accommodated14 at the interface of the water and oil in any type of microemulsion microstructure: W/O, bicontinuous, and O/W14. Since in our experiments CBZ was precipitated from oversaturated solutions, with cooling, we suggest that with the highest probability the nucleation events happened at the oilwater interface. Upon cooling, the interface undergoes thermal contraction, while diffusion of CBZ molecules is slowed down. Thus, fluctuation of CBZ concentration reaches its maximum amplitude, the solution becomes unstable, and solid nuclei of CBZ are formed at the oil-water interface. As we mentioned above, crystallization from oil- and surfactantrich nanodroplets (W/O microemulsions) produced the smallest crystals in the largest quantity. This probably implies that the nucleation was dominant in the crystallization of anhydrous CBZ.3 High viscosity exhibited in this kind of vehicle may inhibit mass and heat transfer during growth. The heat of crystallization is not dissipated efficiently by the oil continuous phase, leading to growth of many prismlike crystals. The crystallization of a hydrate is different from that of an anhydrous compound. In anhydrous compound crystallization, the solute molecules solely experience the phase changing from solution to solid through nucleation and crystal growth. For hydrate crystallization, however, the water molecules have to be incorporated with the solute molecules to form the growth unit cell of the hydrate crystal.3
730 Langmuir, Vol. 24, No. 3, 2008
Figure 9. Schematic illustrations of the crystalline molecular structure of CBZ dihydrate with monoclinic (a) and orthorhombic (b) symmetry structure. Close resemblance between the “ordered” monoclinic form and the “disordered” form of orthorhombic is observed along with the difference in the population of the O1 and N2 atoms (carbon atoms, black spheres; nitrogen, dark blue; alternating nitrogen/oxygen, violet; oxygen, red).
In the bicontinuous microstructure, the viscous oil channels do not dissipate the heat of crystallization fast enough but rather dissolve the crystallized CBZ. Such structure, first of all, apparently causes the growth to be oriented toward neighbor “runny” channels of aqueous phase, which dissipate the heat of crystallization. Second, the specific size and homogeneity and, consequently, crystallization behavior from bicontinuous microemulsions are most likely related to its internal structure that is characterized by interconnected channels of water and oil that differ in size. One can clearly observe that platelike crystals obtained from the bicontinuous region have large CSD among other CBZ precipitates, most likely caused by the microemulsion domain’s internal disorder.
Kogan et al.
Figure 10. Optical photomicroscopic images of CBZ dihydrate crystals obtained after crystallization from 10 wt % (a), 40 wt % (b), and 90 wt % (c) aqueous phase.
Oil-in-water domains (70-90 wt %) led to the crystallization of the needlelike crystals. The aqueous phase effectively dissipates the heat of crystallization; therefore, presumably, growth into the water phase yields relatively large and oriented crystals. These crystals do not exhibit large crystal size distribution, but did reach large size during the shortest crystallization time. The decrease in observed crystal number leads to the assumption that the nucleation process is inhibited in favor of the growth process as the water content increased. The crystals did not have large CSD, probably because all the crystals were oriented toward the water continuous phase when grown from O/W droplets having similar shapes and size. Such needle-shaped crystals are the result of an oriented growth of the prismatic habit, as was indexed by
Crystallization of Carbamazepine Pseudopolymorphs
Langmuir, Vol. 24, No. 3, 2008 731
Figure 11. SEM images of CBZ dihydrate crystals obtained after crystallization from 10 wt % (a), 40 wt % (b), and 90 wt % (c) aqueous phase. The numbers indicate where the picture was taken: (1) acquired in the middle part of the crystal, (2) acquired at the edge of the crystal.
the X-ray diffractometry (a ) 10.16 Å, b ) 28.70 Å, c ) 4.93 Å). It can be observed that the operating conditions clearly influence the crystal number, size, size distribution, and morphology of the CBZ crystals. At low aqueous phase contents (W/O nanodroplets), the nucleation process seemingly favors the growth process, leading to a large number of small crystals with small CSD. Water-in-oil nanodroplets orient the crystallizing CBZ molecules to form a prismlike anhydrous polymorphic form. With the increase in aqueous phase contents, an effective dissipation of the crystallization heat by the aqueous phase leads
to the increase of CBZ dihydrate crystal size and to the decrease in the number of crystals, leading to the assumption that the nucleation process is inhibited in favor of the growth process. CSD seems to be influenced mainly by the internal order of the microemulsion media. In W/O and O/W, the crystallization presumably occurs from ordered nanodroplets leading to narrow CSD, while in bicontinuous nanostructures the crystals mainly grow from disordered channels of water and oil that differ in size and shape, leading to large CSD. We wish to stress that crystallization from microemulsion media resulted in formation of large perfectly ordered single
732 Langmuir, Vol. 24, No. 3, 2008
Figure 12. Illustrative cartoon of crystallization occurring by oriented attachment: (a) molecular solubilization of CBZ within direct micelles, (b) nucleation stage, (c) oriented attachment of the obtained unit cells, and (d) final form of crystals exhibiting needlelike morphology. The cartoon is not to scale.
crystals, which are favored for fundamental research and unambiguous structural characterization as well as for technological processes and approval procedures accepted in pharmaceutics. 3.4. Scanning Electron Microscopy Observations. In order to clarify the factors determining the final morphology of CBZ crystals and, therefore, constituting the crystallization process, we used SEM (Figure 11). As SEM imaging reveals the microscopic features of the crystals, it allows bridging between the diffraction results characterizing both CBZ crystals and microemulsions and macroscopic observations of solid CBZ. As seen in Figure 11a, the surface of anhydrous CBZ looks practically smooth at microscale. The microsctructure of dihydrate CBZ looks very similar, whether it was crystallized from bicontinuous or O/W microemulsions (Figure 11b,c). In general, the examined crystals do not have smooth faces [Figure 11b(1),c(1)], but they consist of micrometer-sized platelets perfectly oriented parallel to the longitudinal axis of the needle/plate. The length of the platelet varies in the range 2-15 µm, while its width is about 1 order of magnitude less (0.3-0.5 µm). A cross-sectional view of the macroscopic crystal exhibits layers of platelets [Figure 11b(2),c(2)]. Thus, we suppose these nonequiaxial microscopic platelets are the elemental building blocks of the macroscopic needles and plates. Their specific packing within the quasi-2D layers signifies an oriented attachment mechanism of crystallization.44 Oriented attachment is known to be responsible for biomineralization and miscellaneous self-organization processes occurring in nature.45 (44) Niederberger, M.; Co¨lfen, H. Phys. Chem. Chem. Phys. 2006, 8, 32713287. (45) Dujardin, E.; Mann, S. AdV. Mater. 2002, 14, 776-777.
Kogan et al.
We should note here that the considered crystallization is essentially the precipitation of an excessive solute in the form of crystalline solid. In the simplest case, at the nucleation step of this process the excessive CBZ is released. Accordingly, growth is mainly the space redistribution of the released material within the liquid medium. Except for the first moment, nucleation and growth most probably take place simultaneously. We simplify the model of the crystallization process, leaving behind this consideration, with the compositional changes occurring in solid and liquid phases during the crystallization and the structural changes taking place within the mother liquid upon precipitation of solid drug. A cartoon of the different steps in the crystallization process is shown in Figure 12. As we mentioned above, heterogeneous nucleation at the oilwater interface most probably provides the primary release of excessive CBZ. A rough estimation of the process size-scale, based on DLS results for mother liquid containing solubilized CBZ and XRD data for crystalline CBZ dihydrate precipitated from it,22 shows that oil-in-water nanodroplets (8 nm) provide enough space for precipitation of a CBZ dihydrate cluster having at least short-range order (Figure 12a). Further enlargement of the nucleus (Figure 12b) to a micrometric-sized plate could be realized either through liquid-liquid interactions between the droplets carrying nuclei or through the normal growth of nuclei by diffusion transport of CBZ molecules through aqueous phase. The former process is highly probable at studied conditions46,47 when oil droplets are known to swell upon dilution.48,49 The crystals could bridge between two or more adjacent droplets in a way resembling sintering. Therefore, enlargement of the microscopic plate is supposed to be achieved through droplet coalescence, in which multiple initial nuclei are attached to each another in the presence of a flexible liquid “envelope”. This envelope should not restrict the relative movements of the stacking objects and, thus, should easily provide the lowest energy attachement, oriented as required by crystal symmetry (Figure 12c). Since macroscopic crystals (needle-shaped, Figure 12d) as-extracted from mother liquid have been recognized by single crystalline XRD as perfect single crystalline objects, we conclude that the oriented attachement was perfect up to microscale, i.e., microplatelets revealed by SEM study are simultaneously the product and the object of oriented attachment occurring from nano- to macroscale. On the other hand, these perfect crystals were easily destroyed by grinding,22 implying weak attachmenttype bonding rather than the monolithic continuous structure usually achieved with normal molecule-by-molecule growth (Figure 12).
4. Conclusions Interfacial crystallization from microemulsions can be an effective method for the formation of desired crystal structure and habit modifications. The fully dilutable microemulsions provide a thermodynamically stable, monodispersed nanometric reservoir for appropriate control of the crystallization process and, accordingly, the crystal structure and habit of the precipitating agent. These features could make microemulsions useful tools for “engineering” crystals with specific properties. This study showed that the microstructure of the microemulsion significantly affects the mechanism of crystal growth and, (46) Feldman, Y.; Kozlovich, N.; Nir, I.; Garti, N. Phys. ReV. E. 1995, 51, 478-491. (47) Feldman, Y.; Kozlovich, N.; Nir, I.; Garti, N.; Archipov, V.; Idiyatullin, Z.; Zuev, Y.; Fedotov, V. J. Phys. Chem. 1996, 100, 3745-3748. (48) Garti, N.; Avrahami, M.; Aserin, A. J. Colloid Interface Sci. 2006, 299, 352-365. (49) de Campo, L.; Yaghmur, A.; Garti, N.; Leser, M. E.; Folmer, B.; Glatter, O. J. Colloid Interface Sci. 2004, 274, 251-267.
Crystallization of Carbamazepine Pseudopolymorphs
consequently, influences the phase composition and structure of the solid precipitate. At the same time, the final morphology of the solid crystallization product is found to originate from the parameters of its unit cell. We found that crystallization from W/O microstructure resulted in precipitation of anhydrous CBZ having the same crystalline structure as a known commercial drug. The microscopic crystals of this polymorph appeared practically equiaxial because of the limited ability of crystallization medium to dissipate the heat of crystallization. Crystallization from bicontinuous and O/W microemulsions resulted in precipitation of CBZ dihydrate crystals having plate- and needlelike morphology, respectively. Hydrated CBZ pseudopolymorphs have the same stoichiometry of two molecules of water per one molecule of CBZ in all cases, although their thermal stability and crystalline structure varied significantly depending on the structure of liquid crystallization medium. CBZ dihydrate precipitated from bicontinuous microemulsions was less stable and less perfect as regards to its local atomic packing that formed from O/W microemulsion. The crystalline structure of the less stable dihydrate form was found to be best described as orthorhombic (space group Cmca, unit cell parameters a ) 19.74 Å, b ) 4.92 Å, c ) 28.66 Å, R ) β ) γ ) 90°). In contrast, the crystalline structure of the most stable CBZ dihydrate was confirmed to be best described as monoclinic (space group P21/ c, unit cell parameters a ) 10.16 Å, b ) 28.70 Å, c ) 4.94 Å, β ) 103.33°). In addition, the crystallization media influenced the size, crystal size distribution, number, and duration of
Langmuir, Vol. 24, No. 3, 2008 733
crystallization of the CBZ precipitates. CSD was found to depend on the internal structure of microemulsion media, leading to low CSD of crystals obtained from W/O and O/W microstructure and high CSD of precipitates crystallized from bicontinuous structures. An increase in aqueous phase contents leads to a decrease in the number of crystals, an increase in their sizes, and a decrease in crystallization time, probably due to effective dissipation of the crystallization heat by the aqueous phase. We explain crystallization of hydrated CBZ in terms of orientated attachment at which relatively fast multiple nucleation of CBZ at the oil-water interface is followed by the attachment of solid nuclei to each other aided by coalescence of their oil droplets. The latter process, taking place spontaneously without agitation, provides perfect mutual orientation of the attached clusters and allows enlargement of the precipitate to micro - and macroscopic dimensions. Acknowledgment. We would like to thank Zehava Cohen for graphical support. Supporting Information Available: Details of single-crystal X-ray diffraction data acquisition and processing of CBZ precipitated from a microemulsion containing 40 wt % aqueous phase. This information is available free of charge via the Internet at http: //pubs.acs.org. LA702763E
