Correlation Among Crystal Structure, Mechanical Behavior, and

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Correlation Among Crystal Structure, Mechanical Behavior, and Tabletability in the Co-Crystals of Vanillin Isomers G. Rama Krishna, Limin Shi, Partha P. Bag, Changquan Calvin Sun, and C. Malla Reddy Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/cg5018642 • Publication Date (Web): 12 Feb 2015 Downloaded from http://pubs.acs.org on February 18, 2015

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Crystal Growth & Design

Correlation Among Crystal Structure, Mechanical Behavior, and Tabletability in the Co-Crystals of Vanillin Isomers G. Rama Krishna,1 Limin Shi,2 Partha Pratim Bag,1 Changquan Calvin Sun,2,* and C. Malla Reddy1,* 1

Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER) Kolkata, Mohanpur campus, Mohanpur, 741246, India, Fax: +91-(0)33-25873020; Tel: +91-3325873119; Email:[email protected]; [email protected] 2 Department of Pharmaceutics, University of Minnesota, Minneapolis, MN 55455, USA; [email protected] KEYWORDS: Co-crystals, mechanical properties, crystal engineering, nanoindentation, tabletability, and tensile strength.

ABSTRACT: Tuning mechanical performance of molecular materials is currently attractive owing to their practical applications in pharmaceutical, food and fine chemical industries and optoelectronics. Here we employed crystal engineering approach to transform four food flavouring agents, vanillin isomers, from brittle to soft solids by forming co-crystals with 6-chloro-2,4-dinitroaniline (cda). The series includes vanillin (van), ethylvanillin (evan), iso-vanillin (ivan), as well as a Schiff base of ortho-vanillin (ovan) with ethylene diamine (sb-ovan). All the co-crystals adopt flat two dimensional (2D) layer packing, except the sb-ovan:cda, which adopts a corrugated layer packing with the presence of slip planes. The mechanical properties of the co-crystals were studied by (1) a qualitative method, (2) nanoindentation and (3) powder compaction techniques, which allowed successfully establishing the relationship among crystal structure, mechanical properties, and tablet tensile strength. The simple qualitative mechanical (deformation) tests confirmed plastic shearing deformation behavior in the cda co-crystals with van, evan and ivan, while the co-crystal of sb-ovan:cda showed plastic bending due to the presence of slip planes formed by van der Waals interactions in the structure. The measured tensile strengths of the vanillin isomers and their respective co-crystals, which followed the order: sb-ovan:cda > evan > van > ivan:cda > evan:cda > van:cda > sb-ovan > ivan, confirmed that the plastically bendable co-crystal, sb-ovan:cda shows a significant improvement in the compaction properties compared to any other form studied. In contrast to the initial brittle forms with isotropic structures, the new co-crystal solids show improved plasticity due to their anisotropic 2D-layer structures with active slip planes that facilitate the plastic deformation, which enhances tabletability, particularly in the plastic bendable solid. The study also suggests that the bending type crystals are potentially far better suitable for tabletability than the shearing and brittle type crystals.

1. Introduction For successful applications of organic materials, such as pharmaceuticals, food and fine chemicals, optoelectronics, and explosives, their mechanical properties must meet certain criteria. For example, in pharmaceutical industry, a poor plastic behaviour of an API may greatly limit its tablet strength, while a very high plasticity may cause problems in filtering, transferring and various other processes.1, 2, 3 Plastically bendable crystalline fluorophores have been shown to exhibit superior mechanochromic luminescence (change of emission color upon mechanical action) compared to that of the brittle forms.4 The mechanical properties of organic materials are also vital for achieving efficient organic opto-electronics,5 mechanical actuators, etc.6, 7, 8 However, despite the great needs, tailoring mechanical properties of organic solids currently remains a challenge. In recent times, crystal engineering approach has been used effectively to alter the properties of pharmaceuticals,8, 9, 10 metal-organic frameworks,11 and photoluminescent materials.12, 13, 14 Particularly, the co-crystallization approach has been successfully utilized to alter the physicochemical properties such as solubility, bioavailability, tabletability, and stability in active pharmaceutical ingredients (APIs) by carefully choosing the co-formers based on crystal engineering

principles.15, 16, 17, 18 But the systematic studies on mechanical properties, structure – mechanical property relationship, in organic solids is still a rarity.19, 20, 21 Consequently, the current pharmaceutical product development, to a large extent, still depends on empirical methods.3, 22 In this regard, detailed studies of a large number of compounds, using multiple techniques, for establishing a reliable structure-mechanical property correlation in molecular crystals is needed for effective development of functional materials.7 As a part of our ongoing studies on mechanical properties of molecular crystals, we investigated a series of cocrystals between 6-chloro-2,4-dinitro aniline (cda) and isomeric compounds (Scheme 1), namely, vanillin (van), ethyl vanillin (evan), iso-vanillin (ivan) and a Schiff base of orthovanillin (ovan) with ethylene diamine (sb-ovan). This series was chosen as the single crystals of all vanillin isomers display brittle nature, which is expected from their isotropic structures with 3D-interlocked packing.23, 24, 25, 26 They, therefore, offer an opportunity to test the effectiveness of co-crystallization approach in converting brittle crystals to soft forms through crystal structure engineering. We used cda as a co-crystallizing agent because it has functional groups that can form both strong and weak intermolecular interactions. Interplay of these interactions profoundly influences the mechanical properties

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of its polymorphs.27 Application of a mechanical stress on crystals of cda Forms I (2D-flat layer structure) and II (corrugated sheets) causes shearing and bending, respectively. However, Form III is brittle due to its interlocked structure with strongly hydrogen bonded layers. With this in mind, we intended to prepare both shearing and bendable co-crystals of the brittle vanillin’s using cda.

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Scheme 2. Two most common synthons observed in the cocrystals of cda with vanillin isomers.

Scheme 1. Chemical structures of the compounds used in this study. These vanillin isomers have similar shape and size to that of cda with complimentary functional groups, hence, shall favour the formation of co-crystals with 2D layer structure due to their disk like molecular shape.28 Successful preparation and characterization of this series of co-crystals allow systematic probe of the impact of changes in crystal structures on mechanical properties of organic crystals. In addition, van is a naturally occurring flavouring agent used in foods (chacolate, ice-creame), beverages and pharmaceuticals. It is the primary component of the vanilla bean extract, also found in roasted coffee and the Chinese red pine. The evan, also used as a food additive, has a stronger flavour than vanillin. The iso-vanillin is a selective inhibitor of aldehyde oxidase. 2. Results and Discussion The 1:1 co-crystals of cda were obtained with all four vanillin isomers, namely van, evan, ivan and sb-ovan, from their equimolar solutions in diethyl ether with a few drops of methanol or hexane:ethyl acetate mixture (in 1:1 ratio), by slow evaporation method at ambient conditions (Figure S1). All the co-crystals were characterized by powder Xray diffraction (PXRD), single crystal (SC) XRD, IR, DSC and TGA experiments. Structure-Mechanical Property Correlation The X-ray crystal structure analysis (see Table S1 in supporting information) revealed that the co-crystals van:cda, evan:cda, ivan:cda adopt the 2D flat layer packing, similar to that in cda Form I (shearing type). The sb-ovan:cda co-crystal adopts the corrugated layer structure, somewhat similar to that in cda Form II (bending type).27 Notably, none of the cocrystals adopted 3D interlocked structure as in cda Form III (brittle type). The 2D-layers in the co-crystals of van:cda, evan:cda and ivan:cda are stabilized by a combination of strong and weak intralayer interactions. In these three structures, the molecules within the layer form trimeric synthon I (Scheme 2) via strong N−H···O and O−H···O hydrogen bonds (Figure 1a).

Figure 1. Crystal packing in van:cda; (a) top view of a layer and (b) side view of multiple layers parallel to (100). (c) As grown crystal of van:cda with natural stair-case-like-edges. (d) Shear deformation of the crystal upon application of a mechanical stress parallel to the layers. (e) Further mechanical deformation leading to the cleavage of crystal into slices.

Co-crystal van:cda crystallizes in the triclinic P21/n space group with two molecules of each co-former in the asymmetric unit. In the crystal structure, one cda and two van molecules, which interact in a head to tail fashion, form synthon 1 via O−H···O (2.632(2) Å, 143°) and N−H···O (2.878(3) Å, 137°) leading to formation of zipper type 1D tapes nearly along the c-axis (Figure 1a). The cda molecules placed alternatively on either sides of 1D tape allow zipper type locking with the adjacent 1D tapes within the same layer via van der Waals and (sp2)C−H···O interactions (3.499(3) Å, 172°). These 2D sheets, which are parallel to (100), further stack in an antiparallel fashion via the weak π-stacking interactions with a layer separation of 3.274 Å (Figure 1b). We examined the macroscopic deformation behaviour of van:cda crystals by applying mechanical stress nearly parallel to the layers, using a pair of forceps and needle under a stereo microscope at ambient atmospheric conditions. In this simple quali-


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tative test, the crystal underwent shear deformation through the slip planes parallel to (100) as shown in Figure 1(c-e). Shearing in 2D structures generally occurs when intralayer interactions among the molecules are strong and interlayer interactions are weak; and when shear stress becomes significantly less than the fracture stress.29, 30 Although the intralayer interactions between the 1D tapes within the layer are considerably weak, the zipper-type interlocking of molecules from either side of the 1D tapes strengthens the layers. Moreover, there are no competing slip-planes orthogonal to the 2D layers (Figure 1a, b).29 Hence, in these crystals, the shear deformation is favoured over the brittle fracture.

Figure 2. Crystal packing in evan:cda. Formation of 2D layers via the synthon I (trimer) by O−H···O and N−H···O hydrogen bonds. (b) Overlay diagram of the two independent evan molecules in the asymmetric unit of co-crystal. Notice the conformational variations of -OEt groups in the blue and green molecules.

The evan:cda crystallizes in triclinic P-1 space group with two molecules of each co-former in the asymmetric unit. The packing of molecules within a layer in evan:cda (Figure 2a) is very similar to that of layers in van:cda (Figure 1a). The two symmetry independent molecules of evan differ in conformation at the -OEt groups as evident from the overlay diagram (Figure 2b). The -OEt group on the first evan molecule is co-planar with its phenyl (Ph) ring but on the second evan molecule, it is out of the plane and part of the –OEt group (-Me group) protrudes into the interlayer region. This latter structural feature does not appear to prevent the sliding of layers under shear because of the observed smooth shearing of evan:cda crystals. This is reasonable since the larger inter planar distance (3.375 Å) compared to that of van:cda (3.160 Å) compensates the potential hindrance on sliding by the proturding methyl group.

Figure 3. (a) Formation of 2D layers in ivan:cda via the synthon I (trimer) by O−H···O and N−H···O hydrogen bonds. (b) A crystal of ivan:cda. (c) Brittle deformation of the crystal upon application of a mechanical stress parallel to the layers i.e. along the

crystal length. (d) Further mechanical deformation leading to the cleavage of crystal.

The ivan:cda crystallizes in the orthorhombic Pnma space group with one molecule of each co-former in the asymmetric unit. The molecular packing of 2D layers in this structure is also somewhat similar to that of van:cda. However, the ivan molecule shows some disorder in the hydrogens of -OMe and the -OH groups as the molecule sits on a mirror plane. Seemingly the observed disorder is not because of a wrong space group assignment since our efforts to solve the structure in other space groups were unsuccessful. The qualitative mechanical tests on the ivan:cda crystals did not show any sign of shearing upon application of a mechanical stress perpendicular to the length of the prism shaped crystals. Although the crystal possesses a similar packing to that of the shearing type van:cda, they appeared hard and brittle. Face indexing using SCXRD revealed that the layers are not oriented perpendicular, but parallel to the length of the crystal. When the stress was applied along the crystal length, i.e., parallel to the layers, the crystal cleaved easily instead of shearing as shown in the Figure 3d.29 This observation illustrates the potentially dramatic influence of morphology over the mechanical response of anisotropic crystalline solids to an external stress. It also points out the opportunities to alter the bulk mechanical behavior by controlling morphology, without changing the crystal form. As all three above co-crystals adopt the similar layer packing, expected from the disk like shape of the co-formers,30 we decided to change the shape of the co-former by coupling the aldehyde group of vanillin isomers with ethylene diamine to obtain Schiff bases with elongated molecular shape. Among the four isomers, only Schiff base of ovan (sb-ovan), could be synthesized under the conditions attempted (SI, Scheme S1). Crystallization of the sb-ovan with cda resulted in a 1:2 co-crystal with the monoclinic space group P21/c. Compared to ovan, the molecular shape in sb-ovan is greatly changed from disc to a linear type with a z-kink at the center of the –CH2-CH2– group, but the synthon forming groups remain unaltered. In this crystal, synthon II holds the molecules to form 1D tapes along b-axis. Between the adjacent tapes, only weak interactions ((sp3)C− −H···O: 3.290(3) Å, 132°) are present. The z-type kink leads to a corrugated sheet structure. The weak interaction planes in the structure serve as active slip planes. As expected, the mechanical tests on the crystals revealed their excellent bending nature on (0 –2 –1) face. The crystal packing with slip planes perpendicular to the stacking interactions, is consistent with the bending model.31, 32, 33

(a)

(b)

(c)

Figure 4. Crystal morphology of sb-ovan:cda (a) before and (b), (c) after bending on (0 –2 –1) face.



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highest plasticity among all co-crystals. This is consistent with its superior plastic bending behaviour. Table 1. Elastic modulus (E) and hardness (H) of the four cocrystals obtained from nanoindentation experiments.

(a)

Sample ID

Mechanical Behavior

E (GPa)

H (GPa)

van:cda

shearing

6.2 ± 0.8

0.14 ± 0.02

evan:cda

shearing

6.5 ± 0.3

0.21 ± 0.01

ivan:cda

shearing

5.5 ± 0.8

0.17 ± 0.01

sb-ovan:cda

bending

4.3 ± 0.2

0.15 ± 0.01

Tabletability of Co-Crystal Powders The tabletability of the bulk powders of the four new co-crystals was determined over a compaction pressure range of 25 to 350 MPa (Figure 6). They follow the order of sbovan:cda >> ivan:cda > evan:cda > van:cda. The variation in tableting performance of these materials can be interpreted based on the different intrinsic mechanical properties of the corresponding crystalline particles in the bulk. The highest tabletability of sb-ovan:cda is consistent with its highest plasticity. The tabletability of the other three co-crystals are comparable, but significantly lower than that of the bending type co-crystal, sb-ovan:cda. (b) Figure 5. Crystal packing in the co-crystal, sb-ovan:cda. (a) Side view of the corrugated structure showing the synthon-II formation via N−H···O interactions and formation of slip planes. (b) Formation of slip planes where only very weak (sp3)C−H···O (2.81 Å, 111.86°) intermolecular interactions are present (negligible as the angle is very low ( ivan:cda > sb-ovan:cda. The evan:cda co-crystal exhibit both highest E and H in this series, suggesting its lowest plasticity. On the other hand, both the E and H values of co-crystal, sbovan:cda is the lowest, suggesting that sb-ovan:cda has the

Figure 6. Tabletability curves of vanillin isomers co-crystals with cda.

As the packing of evan:cda is nearly the same to that of van:cda, it is not surprising that they have very similar tabletability. Here, the hardness of the sb-ovan:cda (0.15 ± 0.01 GPa) is slightly lower than that of sb-ovan (0.17 ± 0.01 GPa), which indicates that sb-ovan:cda has higher plasticity than sb-ovan. This is because the slip planes in sb-ovan:cda with corrugated sheet structure only interact very weakly. This is also the underlying reason for its bending deformation. The highest tabletability in the sb-ovan:cda suggests that the bending type crystals are far better suitable for tableting than shearing type of crystals, which supports our previous observation made in the trimorphs of single component cda system.2 Hence, the current work emphasizes the need for emulating crystal engineering strategies to deliberately achieve bendable functional organic crystals.


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Conclusions In conclusion, we have employed the co-crystal approach to successfully modify brittle crystals, three vanillin isomers and a Schiff base, into crystals exhibiting soft mechanical behaviour. Our detailed and systematic study carried out involving a range of characterization techniques allowed us to establish a correlation among crystal structure, mechanical behavior, and tableting properties. The quick and simple mechanical tests allowed us to categorize mechanical behavior of initial and co-crystal forms. The crystals of van:cda and evan:cda display mechanical shearing while such behavior was barely detectable in van:cda, even though all the three structures possessed 2D layer packing. The contrasting behavior of ivan:cda is attributed to the different orientation of layers with respect to the crystal morphology; the layers in ivan:cda crystal are parallel to the length of the crystal, hence the shearing was not possible by applying stress from perpendicular to the crystal length. These observations illustrate the potentially profound impact of crystal morphology on the mechanical properties of anisotropic crystalline solids. This reveals the opportunities to alter the bulk mechanical properties by controlling morphology. We have also shown that the soft mechanical properties may be achieved by carefully selecting the co-formers through targeting low dimensional structures (2D, 1D or 0D) in the co-crystals by carefully tuning the functional groups in co-formers. The study also emphasizes the potential of plastically bendable type crystals for siganificantly improving the tabletability compared to that of the shearing or brittle type crystals. Hence, this work provides a realistic test on the extent to which the mechanical properties could be altered by varying packing using the co-crystallization approach in molecular solids. Experimental Section Materials and methods 6-chloro-2,4-dinitro aniline (cda) and all other vanillin isomers (Scheme 1), namely, vanillin (van), ethyl vanillin (evan), iso-vanillin (ivan) and ortho-vanillin (ovan) were purchaged from Sigma Aldrich. Commercially available solvents were used as received without further purification. Synthesis of sb-ovan was followed by the same procedure as reported in the literature (see the supporting information).25 Experimental details of single crystal preparation of 1:1 cocrystals of cda and characterization techniques which we used in this study, are available in the supporting information.

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected] (C.M.R)

*E-mail: [email protected] (C.C.S.)

ACKNOWLEDGMENT GRK thanks IISER Kolkata for SRF. PPB thanks CSIR (New Delhi) for fellowship. CMR acknowledges financial support from the CSIR (02(0156)/13/EMR-II).

SUPPORTING INFORMATION Experimental procedures, methods, ORTEP diagrams, crystallographic table and characterization data from infrared spectroscopy, powder x-ray diffraction, differential scanning calorimetry and thermogravimetric analsis are included in this section. This infor-

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For Table of Contents Use Only

Correlation Among Crystal Structure, Mechanical Behavior, and Tabletability in the Co-Crystals of Vanillin Isomers G. Rama Krishna,1 Limin Shi,2 Partha Pratim Bag,1 Changquan Calvin Sun,2,* and C. Malla Reddy1,* 1

Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER) Kolkata, Mohanpur campus, Mohanpur, 741246, India, Fax: +91-(0)33-25873020; Tel: +91-3325873119; Email:[email protected]; [email protected] 2 Department of Pharmaceutics, University of Minnesota, Minneapolis, MN 55455, USA; [email protected]

Crystal engineering approach is employed to transform four food flavouring agents, vanillin isomers, from brittle to soft solids by forming co-crystals with 6-chloro-2,4-dinitroaniline (cda). Compaction studies suggest that the plastically bendable solid forms can potentially show better tabletting property compared to brittle (3D packing) or the shearing (2D layer packing) type solid forms.

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Correlation Among Crystal Structure, Mechanical Behavior, and

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