Controlling Polymorphism by Crystallization on Self-Assembled Multilayers
CRYSTAL GROWTH & DESIGN 2007 VOL. 7, NO. 5 847-850
David H. Dressler and Yitzhak Mastai* Department of Chemistry, Bar-Ilan UniVersity, Ramat-Gan 52900, Israel ReceiVed September 20, 2006; ReVised Manuscript ReceiVed March 5, 2007
ABSTRACT: In this paper, we present a new approach based on crystallization onto self-assembled multilayers (SAMs) for the control of polymorphism. To demonstrate our approach, we studied the crystallization of L-glutamic acid on a self-assembled multilayer of a phenyalanine derivative. It is shown that crystallization of L-glutamic acid on SAMs resulted in stabilization of the metastable R-form of L-glutamic acid. Additionally, crystallization onto SAMs led to crystal growth with preferential orientation along the crystal direction. The possibility of using SAM surfaces to stabilize thermodynamically metastable structures as demonstrated in this work offers a powerful tool in the development of processes in polymorphic systems. Crystal polymorphism is the ability of a solid material to exist in different crystal structures with different unit-cell parameters while remaining chemically identical. Different polymorphs may be significantly different in terms of both their structural and physical properties.1 Controlling polymorphism is of great interest in fields such as solid-state chemistry, materials science, pharmacology, and other applications.2 In the last decades, many methods were developed and applied for controlling crystal polymorphs, such as the controlling of crystallization parameters, e.g., temperature,3 solvents,4 the use of “tailor-made” additives,5,6 and surfactants.7 Self-assembled monolayers (SAM)8 have been used as an interface9 to control crystal morphology and orientation. This is done by applying several principles, such as geometric matching,10 and force interactions, e.g., van der Waals forces and hydrogen bonding.11 The use of SAM as molecularly engineered surfaces to control crystal polymorphism was recently demonstrated.8 For example, J.A. Swift et al.12 used SAMs to control the growth of 1,3-bis(m-nitrophenyl) urea polymorphs. In this paper, we describe the use of self-assembled multilayers as a tool to direct crystal polymorphs during crystallization onto surfaces. Self-assembled monolayers (SAM)13 and LangmuirBlodgett films14 have been used for many years to study the influence of well-defined functionalized surfaces on nucleation, polymorphism, and selective orientation of crystals. For instance, crystals of many different materials have been grown on SAMs, including proteins, enantiomerically pure amino acids, semiconductors, and biominerals. Self-assembled monolayers have also been employed to control crystal morphology crystal polymorphism and orientation. The SAMs used in this work were easily prepared and did not require specific ordering or a defined orientation, but were still sufficient to direct specific polymorph crystallization on them. Our model crystallizing system is based on enantiomeric glutamic acid that has two known polymorphs, the metastable R-form15 and the stable β-form.16 Our new method involves the formation and stabilization of the metastable R-form of L-glutamic acid utilizing a SAM of an L-2-amino-N-{-[2-(2-amino-3-phenyl-propionylamino)ethyldisulfanyl]-ethyl}-3-phenyl-propionamide labeled as L-AAPP (see Figure 1). We selected AAPP as the SAM because it consists of a phenylalanine entity that was already shown to promote R-stabilization in solution crystallization.17 Our method presents a new and general approach to obtaining and stabilizing metastable crystal polymorphs on surfaces similar to the stabilization of metastable polymorphs in solution crystallization.17 From a technological point of view, the possibility to obtain the metastable R-L-glutamic acid during crystallization processes is of prime importance, particularly for the production of monosodium glutamate (MSG).18,7 A few groups have studied glutamic acid polymorphs. Hodnett et al. studied19,20 the solution-mediated transformation of glutamic * To whom correspondence should be addressed. E-mail: mastai@ mail.biu.ac.il. Tel: 972-3-5317681. Fax: 972-3-7384053.
Figure 1. Chemical structure of L-AAPP.
acid polymorphs. Their results show that the stable β-form emerges from the metastable R-crystals through a kinetic process. Kitamura et al.3 showed that this transformation process of the R-polymorph into the β-polymorph involves four kinetic steps. In their experiments, it was shown that the R-polymorph converts rapidly to the β-form at 45 °C, but at ca. 15 °C, the conversion process is very slow and almost nonexistent, so that the R-polymorph is obtained exclusively. Other methods for controlling and stabilizing the R-form of L-glutamic acid involve the use of “tailor-made” additives17 and crystallization in the presence of surfactants.7 This method is based on the stabilization of the R-form during the recrystallization process, which prevents and inhibits the transformation of the R-form to the thermodynamically stable β-form. In this work, we will demonstrate that the R-form is obtained at room temperature and above, without the need for crystallization at low temperatures; in other words, the SAMs surface inhibit the transformation between the polymorphs. This means that on our surfaces, the R-form is stabilized kinetically and no transformation of R to β occurs for days. Analytical grade reagents (>99.9%) were purchased from SigmaAldrich and used without further purification. L-AAPP was synthesized by a known coupling reaction.21 Substrates for SAM preparation were prepared by vacuum deposition of thin gold (111) films22,23 (ca. 1000 Å) onto glass slides and characterized by X-ray diffraction. Thereafter, the gold substrates were immersed in an ethanolic solution of L-AAPP (2 mM) for a period of ca. 24 h. The SAMs were characterized by a range of methods, such as grazing angle FTIR, XPS, ellipsometry, contact angle,and AFM. The results of all the above measurements proved the formation of multilayers with a typical thickness of ca. 10 molecular layers. The SAM substrates were kept under nitrogen before crystallization experiments. Commercial L-glutamic acid was purchased from Riedelde Haen (99.9% purity) and used without further purification for crystallization. Saturated solutions of L-glutamic acid (0.45 g/mL) were prepared at 80 °C and left to spontaneously cool to room temperature. The SAMs substrates were positioned in the solution
10.1021/cg0606287 CCC: $37.00 © 2007 American Chemical Society Published on Web 03/22/2007
848 Crystal Growth & Design, Vol. 7, No. 5, 2007
Figure 2. X-ray diffraction of L-glutamic acid crystals (A) grown on the surface of L-AAPP self-assembled multilayers, (B) grown on Au (111), and (C) grown from solution.
leaning against the side of the crystallization vial and left to crystallize for 2-4 h. Crystals crystallized from solutions were also collected for comparison. The large crystals on the surfaces were removed manually for DSC measurements, and even thin crystals were removed by simple solvents that did not cause the removal of the SAMs from the gold surfaces (as verified by induction coupled plasma (ICP) measurements). X-ray diffraction was performed with a Bruker AXS D8 Advance Diffractometer (using CuKR λ )1.5418 Å radiation) operating at 40 kv/40 mA, with a graphite-reflected beam monochromator and variable divergence slits. Raman measurements were done with a Jobin Yvon Micro Raman (model HR800, λ ) 514.532 nm at 20 mW, slit ) 150 µm, hole ) 300 µm, five 75 s scans) using different objectives. Scanning electron microscope (SEM) images were acquired from a JEOL 840 instrument at an acceleration voltage of 20 kV. Differential scanning calorimetry (DSC) was done with a Mettler Toledo DSC822 equipped with a liquid nitrogen cooling system. We performed a series of crystallization experiments on the SAMs surface and in solutions. To investigate the influence of our SAM on crystal polymorphs, we employed X-ray diffraction. Figure 2C displays the X-ray diffraction of L-glutamic acid crystallized from solution. The X-ray diffraction corresponds to the β-L-glutamic acid as reported in the literature;16 moreover, from X-ray diffraction, it is evident that no R-crystals were obtained under these conditions. In Figure 2A, the X-ray diffraction of L-glutamic acid crystallized on SAMs is shown. The X-ray diffraction measurements were taken directly on the surfaces in order to determine preferred orientation on the SAMs surface. These results of the X-ray diffraction show high-intensity reflection peaks at 2θ ) 18.3°,24 which corresponds to the (111) plane of the R-form of L-glutamic acid and at 2θ ) 37.0° corresponding to the (222) plane of the R-form. In addition, a low-intensity peak at 2θ ) 10.2°24 is observed and attributed to the (020) plane of the β-form of L-glutamic acid. Other X-ray diffraction peaks corresponding to the R-form of L-glutamic acid, e.g., 2θ ) 20.2, 23.6, 26.7° are observed; however, their intensity is relatively low because of crystal orientation along the crystal direction of the R form on the surface. From the X-ray diffraction results, it is evident that L-glutamic acid crystallizes on the SAM surfaces as the R-polymorph with preferential crystal growth along the -crystal plane. Diffraction peaks that match the crystal structure of the β form at 2θ ) 10.2° were also noticed but at a very low intensity, which indicates the presence of very small quantities of the β-form. The crystallization of the β-form onto the SAM surface is probably occurring because of the growth of the β-form on bare gold spots caused by the nonuniformity of our surfaces as seen by AFM and contact angle measurements of the SAM surfaces. Previous studies19 show that the (011) facet of the R-form is critical for secondary nucleation and transformation
Communications to the β form. In our case, because of crystal orientation on the SAM surface, the (011) facet of the R-form is absent and therefore the nucleation and transformation to the β-form is inhibited. Crystallization experiments were also completed on a bare gold surface, to compare with the SAMs results. The X-ray diffractions of crystals grown onto bare gold surfaces are shown in Figure 2B and expose a diffraction pattern matching the β-form of glutamic acid. These results verify the preference and stabilization of the R-polymorph of L-glutamic acid on the L-phenylalanine-terminated SAM. The formation of the R-polymorph of L-glutamic acid on the SAM surface can also be studied by scanning electron microscopy (SEM) because the polymorphs have different crystal habits. Figure 3 displays the SEM images of crystals grown from solutions and on the SAM. Crystals grown on the SAM surfaces revealed wellordered large prismatic structures typical to the R-form,19 whereas crystals crystallized from solution expose platelike structures characteristic of the β-form.19 Another proof for the formation of the R-polymorph of Lglutamic acid on the SAM surfaces comes form differential scanning calorimetry (DSC) measurements. DSC can be used as a method for the determination of crystal polymorphism and crystal phase transitions.25 Because of the different crystal structures of the polymorphs, their phase diagrams and melting points differ. In our system, the melting point of the metastable R-form is lower than that of the thermodynamically stable β-form, as reported previously.7 DSC measurements of crystals collected from the SAM surfaces (mp 197 °C) and of crystals from solution (mp 200 °C) show a difference of 3 °C in melting points. It should be mentioned that in other studies by N. Garti et al.,7 a difference of 7 °C in the melting points of the L-glutamic acid polymorphs was observed. The somewhat low difference in melting points of polymorphs measured in our work could be due to the fact that crystals collected from the SAM surfaces are not pure R-crystals and contain some amounts of the β-polymorph, as seen by XRD. Nevertheless, the DSC results clearly demonstrate that substantial amounts of R-form are crystallized on to the SAM surfaces. Finally, we carried out Raman spectroscopy as a method for characterizing the different polymorphs2,19,20,26 on SAM surfaces. The Raman spectrum of the pure β-form crystallized from solution is shown in Figure 4B with main peaks at 387, 708, 865, and a shoulder at 1060 cm-1.19 The spectrum of crystals on SAMs surfaces shown in Figure 4A display two significant peaks at 92 and 867 cm-1 fitting the R-form.19 It should be mentioned that we also performed Raman, SEM, and DSC measurements on crystals grown on bare gold and the results from those measurements showed the formation of the β-form solely. In addition, we were interested in investigating chiral interactions on the surfaces. Therefore, we decided to crystallize D-glutamic acid on the L-AAPP surfaces. X-ray diffraction and SEM images of D-glutamic acid grown on L-AAPP surfaces showed almost equal combination of the R- and β-forms. It is well-known that chiral recognition plays an important role in the crystallization of glutamic acid polymorphs from solution in the presence of chiral tailor-made additives.17 Our assumption is that chiral interactions and molecular recognition in two-dimensional arrays, namely in crystallization onto SAM, is possibly less-dominant in comparison with a threedimensional molecular recognition,27 which exhibits significant chiral recognition. Although on the molecular level interactions on SAMs and in solution both occur at the interface,27 host-guest interactions in solution are caused by specific fitting of the guest to the host molecules caused by their similar entities (both amino acids), whereas interactions on SAMs, that are bound to the surface will not cause complete host-guest matching, but usually only one bond interaction. Therefore, chiral interactions may require complete host-guest matching, which does not occur on surfaces. Nevertheless, interactions on SAM surfaces cause morphological changes,
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Crystal Growth & Design, Vol. 7, No. 5, 2007 849
Figure 3. Scanning electron microscopy images of L-glutamic acid crystals (scale bar ) 200 µm): (A) crystal morphology of crystals grown on the surface of L-AAPP self-assembled multilayers, and (B) crystal morphology of crystals grown from solution.
terminated SAMs led to crystals grown with preferential orientation along the crystal direction. Despite the extensive research carried out over the years, our ability to manipulate the crystallization of polymorphic systems is still poor and limits the level of process control available for high-performance specialty chemical production. The possibility of using SAM surfaces to stabilize metastable structures as demonstrated in this work may offer a new tool in the development of processes in polymorphic systems. In principle, the approach introduced in this work can by expanded to other polymorphic systems and can be developed into a general method to stabilize metastable forms of different crystals through surface interactions. Acknowledgment. We thank the German-Israeli Foundation for Scientific Research and Development (GIF) for financial support. D.H.D. acknowledges the Bar- Ilan President’s Ph.D. Scholarship Foundation.
References Figure 4. Raman spectroscopy of L-glutamic acid crystals: (A) grown on the surface of L-AAPP self-assembled multilayers (R-ploymorph), and (B) grown from solution (β-polymorph).
which prevent polymorph transformation, as seen in our work. We are currently studying chiral recognition in two-dimensional arrays.28,29 A previous study aimed at controlling polymorphism in crystallization processes has shown that additives can inhibit a solid-state transformation and hence lead to the kinetic stabilization of a metastable polymorph.30,6 The design of additives for the control of polymorphism is usually based on differences in crystal symmetry of the polymorphs. In a few examples, additives31,2d were designed to selectively inhibit the crystallization of the stable polymorph on the basis of conformational and molecular recognition, allowing kinetics to dominate the crystallization process, leading to the stabilization of a metastable phase. Overall, the results of our work are novel because we demonstrated for the first time that SAM surfaces can act in a manner similar additives, i.e., inhibiting the polymorphs crystal transformation, whereas stabilization of a metastable phase is obtained. Another important conclusion derived from this work refers to the nature of the SAM surfaces. Most previous studies12 aimed at controlling crystal polymorphism on self-assembled monolayers utilized well-oriented and molecularly designed SAMs. However, this work shows that control of crystal polymorphism can be achieved by simple amino acid residues, i.e., SAMs that are not specifically designed. Further studies may include long chain monolayers that produce uniform SAM surfaces that may control polymorphism in a manner superior to that shown here. In conclusion, we demonstrated that crystallization of L-glutamic acid on SAMs resulted in stabilization of the metastable R-form of L-glutamic acid. In addition, crystallization onto phenyalanine-
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