Improving Dissolution and Photostability of Vitamin K3 via

Nov 20, 2015 - Synopsis. With the objective to alter the topochemical photoreactivity of menadione, a cocrystallization approach was employed, and thr...
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Improving Dissolution and Photostability of Vitamin K3 via Cocrystallization with Naphthoic Acids and Sulfamerazine Bingqing Zhu, Jian-Rong Wang, Qi Zhang, and Xuefeng Mei* Pharmaceutical Analytical & Solid-State Chemistry Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China

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S Supporting Information *

ABSTRACT: Menadione (MD), also known as vitamin K3, has been widely applied in fortified food, feed, and the nutrition industry for its antihemorrhagic activity. However, the poor photostability in the solid state has greatly affected its biological performance and limited its applications. With the objective to alter the topochemical photoreactivity, a cocrystallization approach was employed, and three MD cocrystals with naphthoic acids and sulfamerazine were designed and prepared. Single crystal structures were determined, and solid-state characterization were performed. Solid-state UV−vis spectra revealed a significant red-shift of UV absorption in the cocrystal solids resulting in variant color differences. These physicochemical changes may be attributed to the enhanced π···π interactions and change-transfer interactions within these molecular complexes. More importantly, the newly synthesized cocrystals displayed better dissolution behavior and superior photostability with respect to MD itself. No obvious degradation was observed under stressed photoirradiation conditions. These findings may provide new possibilities to the application of this key vitamin.

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INTRODUCTION A cocrystal refers to a multiple crystalline molecular complex coexisting through noncovalent interactions.1 It has found applications in a number of fields such as active pharmaceutical ingredients (APIs),2,3 nonlinear optical4 and high energetic materials.5,6 Recently, cocrystals have gained increasing importance as an emerging class of solid forms in pharmaceutical materials. This relates, in a large part, to its potential ability to alter the physicochemical properties of APIs,7−10 wherein improving the solubility and dissolution rate has been a research hot spot, and so far a lot of exciting success has been obtained.11,12 However, relatively fewer studies have paid attention to the application of cocrystals to address the chemical stability of APIs. Nevertheless, the feasibility of this approach has been evidenced by a few cases.13−17 For example, Tan et al. demonstrated that the physicochemical and photostability of the 1:1 cocrystal of nitrofurantoin with 4-hydroxybenzoic acid was superior than that of the API itself.15 Our group reported the results of solving the stability challenge of vitamin D3 by conformational selective cocrystallization with cholesterol and cholertanol.16 Vitamins are a group of chemically diverse compounds that are widely used as feed supplements. Stability is especially important for these essential nutrients because they are normally added in small amounts to livestock diets, where the purity can remarkably affect animal performance and health.18 However, many vitamins have a delicate substance that can suffer loss of activity due to poor stability initiated by air, light, heat, moisture, minerals, oxidants, etc.19 Menadione (MD), © 2015 American Chemical Society

2-methyl-1,4-naphthoquinone, belongs to vitamin K3 and has been known for its antihemorrhagic activity for decades. In addition, recent studies reporting on its anticancer activity may also attract great attention of researchers.20,21 However, sensitivity to light and low water solubility (105.9 μg/mL) are the major hurdles on the road to market it in feed additives under its parent form (its derivative, menadione sodium bisulphite, is the currently used form).22 It was reported that MD is susceptible to dimerization when exposed to light under the solid state. The resulted adducts were identified as two cyclobutane photodimers depicted in Scheme 1.23,24 Therefore, MD has to be preserved in well-closed, light-resistant containers according to the United States Pharmacopeial specification.25 In order to address the photostability of MD, we turned to understand the mechanism that controls photoreaction of MD. Scheme 1. Chemical Structures of MD and Its Photoproducts

Received: October 21, 2015 Revised: November 18, 2015 Published: November 20, 2015 483

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Figure 1. Topological patterns of the molecular orientation during photoreaction.

Scheme 2. Chemical Structures of 1-Hydroxy-2-naphthoic Acid (1-HNA), 6-Hydroxy-2-naphthoic Acid (6-HNA), and Sulfamerazine (Sul)

The electron-deficient naphthoquinone ring in MD is typical for π···π stacking interactions to direct the supramolecular organization of cocrystals. Formation of alternate stacking of MD and the corresponding coformers may hinder the approaching of MD molecules, thus preventing photodimerization. We selected a series of electron-rich compounds (Scheme S1), most of which are hydroxyl or amino substituted benzene or naphthalene for complementary π···π stacking with MD. In addition, three sulfonamides were also included in the coformer library because they could provide rich hydrogen bond functionalities (donor: amine NH2 and imidine NH; acceptor: sulfonyl O and pyrimidine N), which makes them widely applied coformers to the synthesis of new cocrystals.28,29 Through extensive screening, we report herein the discovery of three cocrystals of MD with 1-hydroxy-2-naphthoic acid (1-HNA), 6-hydroxy-2-naphthoic acid (6-HNA), and sulfamerazine (Sul) (Scheme 2). Others only lead to a physical mixture of individual components according to PXRD results. Their crystal structures were determined by single-crystal X-ray diffraction (SXRD). A further comprehensive solid-state characterization including powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), Fourier transform-infrared (FTIR) spectroscopy, and Raman microscopy were performed. Solid state UV−vis spectra were also employed to study the color changes after cocrystallization. Finally, the photostability and dissolution behavior of the new cocrystals compared with MD were also investigated in this study.

Although the structures of photoproducts have been determined by single crystal X-ray diffraction, the reaction mechanism is still elusive due to the absence of the crystal structure of MD.24 The crystal structure of MD was not revealed until 2008,26 offering us an opportunity to get insight into the photoreaction mechanism. Irradiation of the crystalline MD results in [2 + 2] dimerization, which is one of the most extensively investigated topochemical reactions.27 It is influenced by molecular packing in the crystal lattice. The molecules must be organized with satisfactory orientations wherein the reactive double bonds of the neighboring molecules are within a certain proximal distance (3.5−4.2 Å according to empirical rules9,27) and also aligned with the small rotational angle (the ideal value is 0°).9 However, the molecular arrangement of MD apparently does not favor the formation of dimers. Apparently, the course of photoreaction must be involved in co-operative motions of MD molecules to reorient in proper geometry for dimerization. In order to accommodate the motion as the reactants transform to adducts, the molecular surroundings must contain a certain amount of free volume. Investigation of the crystal structure verifies the proposition. MD fits the gap rather than being opposite to the adjacent molecules, which allows certain rotation or translation with little steric hindrance. In addition, the relative symmetry, planarity and small volume of MD molecule may further facilitate the reorientation movement. To better visualize it, a simplified representation of the molecular orientation during photoreaction is shown in Figure 1 (take dimer B for example). The reactive double bonds are colored in black, and the hydrogen atoms are omitted for clarity. Dimerization involves directive rotation (indicated by red arrows) of each MD molecule, resulting in satisfying alignment for reaction.

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EXPERIMENTAL SECTION

Materials. The sample of MD used in the present work was purchased from Tokyo Chemical Industry Company Limited and used 484

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Differential Scanning Calorimetry (DSC). DSC experiments were performed on a PerkinElmer DSC 8500 instrument under a nitrogen gas flow of 20 mL min−1 purge. Ground samples weighting 3−5 mg were heated in sealed nonhermetic aluminum pans at a heating rate of 10 °C min−1. Two-point calibration using indium and tin was carried out to check the temperature axis and heat flow of the equipment. Fourier-Transform Infrared (FTIR) Spectroscopy. Fouriertransform infrared (FTIR) spectra were collected by a Nicolet-Magna FT-IR 750 spectrometer in the range from 4000 to 350 cm−1, with a resolution of 4 cm−1 at ambient conditions. Confocal Raman Microscope. Raman spectra were recorded with the Thermo Scientific DXR Raman microscope equipped with a 532 nm laser. Raman scans range from 3500 to 50 cm−1. Samples were analyzed directly in a glass sheet using 10 mW laser power and 50 μm pinhole spectrograph aperture. Calibration of the instrument was performed using polystyrene film standard. UV−vis Spectroscopy. UV−vis spectra of solid MD, coformers, and three cocrystals were recorded on Agilent Cary 500 spectrometer. Photostability Experiment. To minimize the size effect on photostability, samples were sieved through 100-mesh sieves and then were evenly spread across glass plates. Photostability experiments were conducted in a stability chamber (SHH-GD, China), which were carried out at 25 °C with an illuminance of 4500 lx. Ten milligrams of samples was taken out at various intervals during exposure (1, 2, 3, 4, and 5 days). The purity was determined by high performance liquid chromatography. Powder Dissolution. To minimize the size effect on dissolution results, MD and three cocrystals were sieved through 100-mesh sieves. Accurately weighed powders of (or corresponding to, for cocrystals) 10 mg MD (n = 3) were added to dissolution vessels containing 15 mL of pH 6.8 phosphate buffer. The dissolution studies were conducted at a rotation speed of 100 rpm at 37 °C. Sampling was performed at 5, 10, 15, 20, 30, 40, 60, 90, 120, 150, and 180 min. The withdraw suspensions were filtered with 0.22 μm PTFE filters prior to HPLC analysis. High Performance Liquid Chromatography (HPLC) Analysis. The contents of MD were determined by an Agilent 1260 series HPLC (Agilent Technologies), equipped with a quaternary pump (G1311C), diode-array detector (G1315D) set at 251 nm, and a 4.6 × 150 mm, 2.5 μm Agilent Eclipse plus C18 column. A mobile phase consisting of methanol and water (75/25, v/v) was run at 1.0 mL/min. The column temperature was set at 30 °C.

without further purification. All analytical grade solvents were purchased from Sinopharm Chemical Reagent Company and used without further purification. Preparation of MD·1-HNA. Equal moles of MD (172 mg, 1 mmol) and 1-HNA (188 mg, 1 mmol) were mixed with 5 mL of methanol, and the resulting suspension was stirred for 24 h. After filtration, the filtrate was allowed to evaporate slowly at room temperature in an opened glass vial. Yellow plate crystals with good quality for single crystal structure determination were harvested after 48 h. Preparation of MD·6-HNA. This cocrystal was prepared by a similar procedure to that of MD·1-HNA except with a different mole ratio of 1:2 (MD: 172 mg, 1 mmol; 6-HNA: 376 mg, 2 mmol). Orange block crystals were harvested for single crystal structure determination after 48 h. Preparation of MD·Sul. This cocrystal was prepared by a similar procedure to that of MD·1-HNA except using 20 mL of methanol to dissolve the substances. Orange block crystals were harvested for single crystal structure determination after 48 h. Powder X-ray Diffraction (PXRD). PXRD patterns were obtained using a Bruker D8 Advance X-ray diffractometer (Cu−Kα radiation). Voltage and current of the generator were set to 40 kV and 40 mA, respectively. Data over the range 3−40° 2θ were collected with a scan rate of 5°/min at ambient temperature. Data were imaged and integrated with RINT Rapid and peak-analyzed with Jade 6.0 from Rigaku. Single Crystal X-ray Diffraction (SCXRD). X-ray diffractions of all single crystals were carried out at 100(2) K on a Bruker Apex II CCD diffractometer using Mo−Kα radiation (λ = 0.71073 Å). Integration and scaling of intensity data were performed using the SAINT program. Data were corrected for the effects of absorption using SADABS. The structures were solved by direct methods and refined with full-matrix least-squares technique using SHELX-97 software. Non-hydrogen atoms were refined with anisotropic displacement parameters, and hydrogen atoms were placed in calculated positions and refined with a riding model. Crystallographic data in cif format have been deposited in the Cambridge Crystallographic Data Center, CCDC Nos. 1431599−1431601 for MD·1-HNA, MD·6-HNA, and MD·Sul, respectively. Crystallographic data and refinement details are summarized in Table 1.

Table 1. Crystallographic Data for MD Cocrystals formula crystal system space group temperature (K) a (Å) b (Å) c (Å) α (deg) β (deg) γ (deg) V (Å3) Dcal (g/cm3) Z λ (Mo−Kα) independent reflns S Rint R1 wR2

MD·1-HNA

MD·6-HNA

MD·Sul

C22H15O5 monoclinic C2/c 100(2) 33.788(2) 6.9012(5) 15.0424(11) 90 103.597(4) 90 3409.3(4) 1.400 8 0.71073 2993 0.961 0.1128 0.0881 0.2569

C33H24O8 monoclinic P21 100(2) 10.7294(19) 20.667(3) 12.357(2) 90 108.230(8) 90 2602.5(8) 1.400 4 0.71073 10504 0.920 0.0364 0.0649 0.1953

C22H20N4O4S triclinic P1̅ 100(2) 7.4250(7) 8.3806(8) 17.7795(16) 89.429(5) 85.939(5) 75.580(5) 1068.77(17) 1.356 2 0.71073 4880 1.028 0.0226 0.0388 0.1079

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RESULTS AND DISCUSSION Cocrystallization of MD with various electron-rich aromatic compounds, carboxylic acids, phenols, and amides was employed. Priorities of experimental trials were given to the coformers listed in Scheme S1. Three substituted naphthoic acids were employed to result in two successful examples. This highly successful rate may attributed to the shape/size resemblance between naphthalene and MD to adopt a better π···π stacking interactions in the expected cocrystals (Scheme S1). In the three sulfonamides employed, Sul was the only successful hit because of the subtle discrimination involved in the assembly of cocrystals.29 Cocrystal formation is not solely guided by the H-bonding and π···π interaction capability of both entities, but overall steric effects and less strong van der Waals interactions are also important factors in the cocrystal formation.30 Consistent with our earlier assumption, the crystal structures strongly suggest π···π interactions as the dominant driving force for cocrystallizaiton. In order to facilitate the comparison of three cocrystal structures, a table of H-bonding interactions (Table S1) and another of π···π contacts (Table S2) are presented. Single Crystal Structures. Cocrystallization of MD·1HNA in methanol gives yellow plate crystals (Scheme S2). The crystal structure reveals that MD·1-HNA crystallizes in the

Thermogravimetric Analysis (TGA). Thermogravimetric analysis was carried out on Netzsch TG 209F3 equipment. Samples were placed in open aluminum oxide pans and heated at 10 °C min−1 to 400 °C. Nitrogen was used as purge gas at 20 mL min−1. 485

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Figure 2. Columnar stacking of molecules in MD·1-HNA.

Figure 3. Packing view drawn along the column direction, showing the overlapping scheme in MD·1-HNA.

C2/c space group. In MD·1-HNA, two 1-HNA molecules form dimers via carboxylic acid pairs (O5−H···O4 distance of 2.628 Å), which is a reliable functional group that usually generates dimers (21% frequency in CSD, version 5.36, May 2015) without the presence of other strong H-bonding groups. The phenolic hydroxyl group in 1-HNA is involved in intramolecular H-bonding with the ortho-carbonyl group. Unlike the arrangement in MD crystal structure itself, the adjacent two MD molecules that would have dimerized under irradiation are isolated far apart in the MD·1-HNA cocrystal structure by filling with 1-HNA molecules. Two MD units and dimers of 1-HNA are alternately aligned, giving rise to columnar arrays shown in Figure 2. The interplanar distance defined by Cg−Cg (distance between ring centroids) between neighboring stacked molecules are ca. 3.66−3.82 Å, indicative of normal π···π interactions. All molecules within a stack are nearly, but not exactly, parallel, with dihedral angles of 1.4−2.9°. The molecules in one columnar stack lie close to those in the adjacent stack, but not exactly opposite to them. Such configuration is probably for the gain of packing density when a molecule fits the gap in the adjacent stack.31 Figure 3 presents the molecular overlapping viewed along the column direction, wherein the quinone ring of MD is stacked over the center of 1-HNA molecule. Cocrystallization of MD·6-HNA in methanol gives orange crystals showing a rod-like shape (Scheme S2). The crystal structure reveals that MD·6-HNA crystallizes in P21 space group with an asymmetric unit consisting of six molecules: two symmetrically nonequivalent MD and four symmetrically nonequivalent 6-HNA molecules (Figure S1). The connectivity motif is shown in Figure 4, in which we note the retention of

the carboxylic dimer synthon connecting two 6-HNA molecules. In contrast to 1-HNA molecule, however, yet can be expected, the free hydroxyl group in 6-HNA is involved in intermolecular H-bonding, leading to a 6-HNA chain structure along the b axis. This difference lies in the different substitution position of the hydroxyl group, where the 6-HNA is likely to form intermolecular H-bonding with less steric hindrance than 1-HNA. Unlike the MD·1-HNA cocrystal, MD in MD·6-HNA is involved in intermolecular H-bonding in addition to π···π stacking. MD is anchored to the chain via O−H···OC H-bonding every other 6-HNA molecule in two ways, either via O14−H14···O2 (2.810 Å) or O5−H5A···O3 (2.723 Å) (Figure 4). The chains are reinforced by intermolecular π···π interactions. Six molecules in an asymmetric unit of MD·6-HNA bring up six different types of π···π stacking, which can be best described as the relative orientation (overlap modes) of every two adjacent chains (Figure S2, i−iv), with an intercentroid distance in the range of 3.60−3.94 Å. Molecular arrangement along the c axis in MD·6-HNA is presented in Figure 5. Similar to MD·1-HNA, all MD molecules are spaced in between 6-HNA molecules, leading to two parallel 6-HNA chains with a MD layer between them (Figure 5). Cocrystallization of MD·Sul in methanol leads to orange crystals showing a rod-like shape similar to MD·6-HNA (Scheme S2). MD·Sul crystallizes in P1̅ space group with one Sul and one MD molecule in the asymmetric unit. Sul adopts a conformation in such a way that dihedral angle of the aniline ring with respect to the pyrimidine residue is determined to be 76.37°. Two Sul molecules connect each other through N2−H···N4 H-bonding (N2−H···N4 distance of 2.921 Å) to 486

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Figure 4. MD is anchored to 6-HNA chains via H-bonding in two ways.

Figure 5. Molecular arrangement along the c-axis, showing MD molecules (green) spaced in between 6-HNA molecules (red).

Figure 6. H-bonding generating Sul chains along the b axis.

generate an R2 2(8) motif. Such dimers are further linked together via N1−H···O3 H-bonding (N1−H···O3 distance of 3.040 Å), giving rise to a columnar chain along the b axis (Figure 6). Two parallel layers of MD molecules are sandwiched between two adjacent Sul columnar chains, with intermolecular H-bonding and π···π interaction as the packing cohesion. The interjacent MD layers form a slipped π stacked structure between benzene and quinone ring with an interplanar separation of 3.60 Å. Meanwhile, each MD layer is π stacked with the aniline ring of Sul molecule at an intercentroid

distance of 3.67 and 3.92 Å (Figure 7, viewed along the a axis). Besides, the amino group of Sul forms a relatively weak H-bonding with the carbonyl group of MD (N1−H···O1 distance of 3.117 Å), which further stabilizes the sandwichlike structure (Figure 8, viewed along the b axis). PXRD and Thermal Properties. The PXRD was used to preliminarily confirm the formation of cocrystals. The results show that the patterns of the products are different from either that of MD or those of the corresponding coformers (Figure 9). In addition, all of the peaks displayed in the measured patterns 487

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Figure 7. Crystal packing on the bc plane showing a sandwich-like assembly.

Figure 8. Crystal packing on the ac plane.

of the bulk powder are closely matched with those in the simulated patterns generated from single crystal diffraction data, confirming the formation of highly pure phases. Thermal behaviors of the cocrystals and the corresponding starting materials were investigated by TGA and DSC. TGA profiles show the absence of solvent molecules (Figure S3). The DSC patterns are presented in Figure S4, and the melting point (represented by onset temperature) results are listed in Table 2. The structural similarity of 1-HNA and 6-HNA leads to a similar packing coefficient and density. The much lower value of MD·Sul (packing coefficient: 70.0%; density: 1.356) may be attributed to the more degree of structural incompatibility between MD and Sul than between MD and 1-HNA/6-HNA. The melting points of the cocrystals are found to be proportional to that of their parent materials. Higher melting coformer resulted in higher melting cocrystal. The melting points of both MD·6-HNA and MD·Sul are between the values of the individual components, in agreement with most cocrystal cases.32

However, the melting point of MD·1-HNA is slightly lower than that of the individual components. The structural origin of this exception can be elucidated by less H-bonding involved in MD·1-HNA compared with 1-HNA and less interaction directionality (MD·1-HNA system shows disordered in the location of the ring methyl group on the MD molecule) compared with MD, resulting in its lower melting point. Thus, π···π interactions can be the main driving force for the formation of cocrystals in this particular case. FT-IR and Raman Spectroscopy. FT-IR and Raman spectra were used to identify the noncovalent interactions within the crystals. In FT-IR spectra (Figure S5), the signal corresponding to carbonyl CO stretching vibration (1665 cm−1) in MD is red-shifted to 1650 and 1660 cm−1 in MD·6-HNA and MD·Sul respectively, This is attributed to the strong H-bonding involving carbonyl group (O14−H···O2 distance of 2.810 Å, O5−H···O3 distance of 2.723 Å) in the former cocrystal and the weak H-bonding (N1−H···O1 distance of 488

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Figure 9. Comparison between experimental and simulated PXPD of three cocrystals: (a) MD·1-HNA, (b) MD·6-HNA, and (c) MD·Sul.

difference with respect to the starting materials. Neat MD and coformers are off-white or colorless powder (Figure 10). The resulting color difference must be characterized by considering intermolecular interactions within different cocrystals. According to the theory proposed by Mulliken,35 in complexes, one component behaves as an electron donor (D) and the other as an electron acceptor (A), wherein charge-transfer (CT) transitions occur from the highest occupied molecular orbital (HOMO) of the D to the lowest unoccupied molecular orbital (LUMO) of the A. In this case, the characteristic color can be ascribed to the CT transition in cocrystals consisting of the coformers as electron donors and the quinone ring of MD as a prototypical electron acceptor. A smaller HOMO/LUMO gap in MD·6-HNA and MD·Sul is likely to account for the redshifts in color. Accordingly, differences in solid state UV−vis spectra is also observed (Figure 10), which has been widely exploited to investigate the CT interaction of cocrystals.36 Compared with MD, a red-shift in the absorption band occurs to all three cocrystals. 1-HNA, 6-HNA, Sul, and MD are

Table 2. Structural Parameters and Melting Points of Three Cocrystalsa MD·1-HNA MD·6-HNA MD·Sul

mp (°C)

packing coefficient (%)

density (g/cm3)

102.7 174.0 157.2

74.6 74.0 70.0

1.400 1.400 1.356

a

Melting points of MD, 1-HNA, 6-HNA and Sul are 105.5, 198.8, 246.1, and 236.5 °C respectively.

3.117 Å) in the latter. This is also reflected in Raman spectra (Figure S6), wherein the CO at 1664 cm−1 in MD undergoes a slight shift to lower frequency of 1663 cm−1 in both MD·6-HNA and MD·Sul. Solid-State UV−vis Spectra. The appearance of strong color on bringing together two colorless, or different colored organic compounds, is well-known.33,34 In this work, we found that the color of three cocrystals evolved from yellow (MD·1HNA) to orange (MD·6-HNA and MD·Sul), which had clear 489

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Figure 10. (a) Photographs of MD, 1-HNA, 6-HNA, Sul, MD·1-HNA, MD·6-HNA, MD·Sul powders displaying various colors. (b) The visible region of the solid state reflectance spectra of individual components and cocrystals.

Figure 11. Powder dissolution profiles of MD and three cocrystals in pH 6.8 phosphate buffer.

transparent at wavelength λ > 500 nm. In contrast, cocrystals MD·6-HNA and MD·Sul show broad strong absorptions that extend to λ = 550 nm and thus crystallize as orange crystals. Compared with MD·6-HNA and MD·Sul, a smaller red-shift occurs in the absorption band of cocrystal MD·1-HNA, indicating a weaker degree of CT transition. Powder Dissolution and Photostability Studies. Powder dissolution profiles for MD and three cocrystals in pH 6.8 phosphate buffer are shown in Figure 11. Although MD·Sul displays a lower apparent solubility than pure MD, the apparent solubility of MD·1-HNA (146.8 μg/mL) and MD·6-HNA (164.1 μg/mL) is 34.8% and 50.7% higher than that of MD (108.9 μg/mL) respectively. Moreover, the higher concentration can be maintained for a considerable duration of time (at least 3 h). This is important for the development of cocrystal drugs to increase the solubility-limited bioavailability.37

PXRD results of the undissolved solids after dissolution experiments indicate that MD·Sul did not experience a form change at all, while a small fraction of MD·6-HNA and the majority of MD·1-HNA have dissociated into MD itself (Figure S7). Finally, the photostability of three cocrystals was investigated using pure MD as reference. MD and cocrystals in powder form were exposed to UV irradiation for up to 5 days. Sample appearance before and after the experiment is shown in Scheme 3. An obvious color change (from yellow to amber) was found with pure MD raw material after photostress for 5 days. This decoloring of MD is a good indication of chemical degradation and has been a long-known disadvantage to limit its applications. However, no obvious color change can be observed for the three cocrystals under the same stressed condition. Furthermore, time dependent change in MD content under irradiation was monitored, and the results are shown in 490

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Scheme 3. Change of Physical Appearance of MD and Its Three Cocrystals with an Illumination of 4500 lux for 5 Days

cocrystals with 1-HNA, 6-HNA, and Sul have been obtained and characterized. Notably, the three cocrystals develop a different color from MD and coformers due to CT transition. Most importantly, the cocrystallization was found to improve the apparent solubility and drastically enhance the photostability of MD. The alternate stacking between MD and the corresponding conformers via π···π interaction is responsible for the photostability improvement. The findings of this report may encourage the application of its cocrystals over the pure form in the future development of MD in the feed industry and provide valuable insight into the improvement of photostability by means of cocrystallization.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.5b01491. Schemes of library of conformers and polarizing microscopy pictures; tables of hydrogen bond lengths and angles and π···π interaction geometries; figures of asymmetric unit, π···π interactions, TGA diagrams, DSC diagrams, FT-IR spectra, Raman spectra, PXRD results, changes in MD assay values (PDF)

Figure 12. Comparison of MD assay values for pure MD powder and MD·1-HNA after an illumination of 4500 lx for 5 days.

Figure 12 (take MD·1-HNA as an example, the assay results for the other two cocrystals were shown in Figure S8). The assay value of MD was found to drastically decrease after only 1 day under irradiation, and the residual content was found to be only 15.6% for MD after 5 days UV treatment. However, neither obvious degradation nor any sign of decoloring was observed for the three cocrystals under the same illumination condition. The significant photostability improvement of MD is due to the alternate π···π stacking between MD and coformers, wherein coformers act as a blocker for MD approaching and photocyclization. In order to confirm the structure of photoproducts, the deteriorated powder sample of MD is dissolved in toluene for evaporation. After 3 days, colorless single crystals were obtained and determined to be cyclobutane photodimers (dimer B in Scheme 1) of MD. In conclusion, among the three cocrystals, both MD·1-HNA and MD·6-HNA displayed better dissolution behavior and superior photostability. It should be noted that 1-HNA is a pharmaceutical salt-forming reagent with proven low toxicity and good tolerability.38

Accession Codes

CCDC 1431599−1431601 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]; fax: +86-21-50807088; tel.: +86-21-50800934. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the National Natural Science Foundation of China (Grants 81273479 and 81402898), CAS Key Technology Talent Program, Youth Innovation Promotion Association CAS, and Shanghai Institute of Materia Medica New-Star Plan B for funding.

CONCLUSION We have investigated the cocrystallization behavior of MD by an appropriate crystal engineering strategy, attempting to identify new solid forms that could potentially improve the poor solubility and photostability of this vital ingredient. Three 491

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DOI: 10.1021/acs.cgd.5b01491 Cryst. Growth Des. 2016, 16, 483−492