Improving the Solubility of Agomelatine via Cocrystals - Crystal Growth

Article pubs.acs.org/crystal

Improving the Solubility of Agomelatine via Cocrystals Yan Yan,† Jia-Mei Chen,*,‡ Na Geng,§ and Tong-Bu Lu*,†,‡ †

MOE Key Laboratory of Bioinorganic and Synthetic Chemistry/State Key Laboratory of Optoelectronic Materials and Technologies/School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, China ‡ School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China § School of Life Sciences, Sun Yat-Sen University, Guangzhou 510275, China S Supporting Information *

ABSTRACT: Four cocrystals of agomelatine with urea (1), glycolic acid (2), isonicotinamide (3), and methyl 4-hydroxybenzoate (4) in 1:1 stoichiometry were successfully synthesized via six kinds of synthons. The structures of 1−4 were determined by the single crystal X-ray diffraction, in which 1−3 form two-dimensional hydrogen bonded frameworks between agomelatine and coformers, while 4 displays a one-dimensional chain structure. The results of differential scanning calorimetry measurements indicate that the melting points of 1−3 are between those of agomelatine and coformers, while the melting point of 4 is below those of agomelatine and coformer. After the formations of cocrystals, the solubility of agomelatine is much improved, and the solubility values of 1−4 in phosphate buffer of pH 6.8 are approximately 2.2, 2.9, 4.7, and 3.5 times as large as that of agomelatine Form II, and 1.6, 2.1, 3.4, and 2.5 times as large as that of agomelatine Form I. The solids of 1−4 can keep their crystalline forms in phosphate buffer of pH 6.8 for 3.5, 2.0, 6.0, and 15.0 h, respectively.

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Scheme 1. Structures of Agomelatine and Coformers (a−d)

INTRODUCTION More than 70% of 1655 chemical pharmaceuticals are solidstate in the United States Pharmacopoeia (29th ed.), suggesting that the solid pharmaceutical forms screening is crucially important. The solid pharmaceutical forms include polymorphs, hydrates, salts, amorphous solids, solvates, and cocrystals.1,2 Pharmaceutical cocrystals were defined as structurally homogeneous crystalline materials that are constructed from at least two neutral molecules containing an active pharmaceutical ingredient (API) and other solid components (coformers) with a well-defined stoichiometry,3,4 in which APIs and coformers are not sustained by the covalent forces but by hydrogen-bond, halogen-bond, π···π, and other noncovalent interactions.5−14 The cocrystallization of an API with coformers profoundly affects its physical properties such as the melting point, stability, hygroscopicity, solubility, dissolution rate, and bioavailability.15−19 Like other solid forms, cocrystals possess intellectual property issues and can be protected by legal issues that confer cocrystals with unique commercial advantages and wide development space.20 Agomelatine (Scheme 1), under a trade name Valdoxan or Melitor, is an antidepressant for the treatment of major depressive disorder. It has been reported that agomelatine has a reduced level of sexual side effects as well as discontinuation effects compared to some other antidepressants.21,22 Furthermore, agomelatine has positive effects on sleep.23 However, agomelatine has poor solubility in water (1.1 mg/mL),24 so different solid pharmaceutical forms of agomelatine including polymorphs and solvates were screened to increase its solubility.25−31 © 2012 American Chemical Society

Up to now, six polymorphic forms of agomelatine (Forms I− VI) have been reported,25−30 while their solubility has not been investigated. In our previous study,31 two agomelatine cocrystals with acetic acid and ethylene glycol were synthesized and structurally characterized. The results of solubility measurements indicate that the solubility values of two cocrystals are approximately twice as large as that of agomelatine Form II. However, these two cocrystals are not stable in water, and agomelatine-acetic acid and agomelatineethylene glycol solvate are easy to transform to Form I and Form III respectively in water. In order to obtain cocrystals with higher aqueous solubility and stability, more cocrystals of agomelatine with coformers were screened in this study. Received: October 27, 2011 Revised: March 5, 2012 Published: March 28, 2012 2226

dx.doi.org/10.1021/cg201423q | Cryst. Growth Des. 2012, 12, 2226−2233

Crystal Growth & Design

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As the structure of agomelatine contains one 2° amide group, possible hydrogen bonding synthons containing 2° amide group are shown in Scheme 2. The Cambridge Structural

The pKa values of agomelatine and four coformers a−d are 9.50, 0.18, 3.83, 10.61, and 8.4, respectively.32 The coformers urea, isonicotinamide, and methyl 4-hydroxybenzoate are pharmaceutically acceptable, in which urea and methyl 4-hydroxybenzoate are approved by the Food and Drug Administration (FDA) as safe for internal administration,33 and isonicotinamide is an API. In addition, glycolic acid is also a low-level toxic material with rat oral LD50 of 1950 mg/kg.32c Thus, cocrystals 1−4 can be regarded as safe for oral dosage.

Scheme 2. Possible Hydrogen Bonding Synthons of Agomelatine with Coformers

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EXPERIMENTAL SECTION

Materials and General Methods. Agomelatine Form II was purchased from Nantong Chemical Co. Ltd. Urea, glycolic acid, isonicotinamide, and methyl 4-hydroxybenzoate were purchased from Aladdin reagent Inc. All of the other chemicals and solvents were commercially available and used as received. Elemental analyses were determined using Elementar Vario EL elemental analyzer. Differential scanning calorimetry (DSC) was recorded on a Netzsch STA 409PC instrument and aluminum sample pans in nitrogen atmosphere, with a heating rate of 10 °C/min. The infrared spectra were recorded in the 4000 to 400 cm−1 region using KBr pellets and a Bruker EQUINOX 55 spectrometer. X-ray powder diffraction (XRPD) patterns were obtained on a Bruker D8 Advance with Cu Kα radiation (40 kV, 40 mA). Agomelatine Form I. A methanol solution (3 mL) of agomelatine Form II (100 mg) was added dropwise to 30 mL of water. The precipitate formed was filtered off and dried in air. Yield, 99%. Anal. Calcd for C15H17NO2: C, 74.05; H, 7.04; N, 5.76%. Found: C, 74.14; H, 6.97; N, 5.84%. XRPD data, 2theta/°: 9.84, 12.4, 13.31, 15.14, 15.98, 16.62, 17.95, 18.88, 20.49, 20.99, 23.07, 23.44, 24.28, 25.1, 26.02, 26.82, 27.51. Agomelatine Form III. Form III was prepared according to the patent method.26 Yield, 98%. Anal. Calcd for C15H17NO2: C, 74.05; H, 7.04; N, 5.76%. Found: C, 73.98; H, 7.15; N, 5.68%. XRPD data, 2θ/°: 10.15, 12.93, 16.27, 17.38, 17.84, 18.55, 19.20, 19.89, 20.32, 21.15, 23.33, 23.84, 24.52, 24.88, 25.07, 26.27, 26.86, 27.97, 29.51. Agomelatine Urea Cocrystal (1:1), 1. A mixture of equimolar agomelatine (50 mg) and urea (12 mg) was melted at 120 °C for 20 min, and then dissolved in 3 mL of butanone. The solution was evaporated slowly at room temperature to get colorless column-shaped

Database (CSD) survey reveals that there are 6961 crystal structures that contain at least one 2° amide group, among which 851 (12%) entries exhibit the supramolecular homosynthon I. Analysis of the remaining amide containing compounds reveals that they are involved in supramolecular heterosynthons with different complementary functional groups such as carboxyl acid, ester, alcohol, etc. There are 1150 entries that contain both 2° amide and carboxyl acid containing moieties. 381 (33%) of these entries exhibit synthon II, whereas only 216 (19%) exhibit synthon III. The CSD contains 893 crystal structures with both 2° amide and ester moieties, and 108 entries (12%) exhibit heterosynthon IV. Moreover, 2° amide-alcohol heterosynthons V and VI occur in 260 (16%) and 551 (33%) of the 1646 crystal structures that contain both functional groups. The above survey indicates synthons I−VI (Scheme 2) can be used for the constructions of cocrystals of agomelatine. Therefore, a series of coformers that may form synthons I−VI with agomelatine were selected to cocrystallize with agomelatine, and four cocrystals of agomelatine with urea (1), glycolic acid (2), isonicotinamide (3), and methyl 4-hydroxybenzoate (4) were successfully obtained, and their structures, solubility, and stability of 1−4 were investigated. Table 1. Crystallographic Data for 1−4 formula formula weight crystal system space group a, Å b, Å c, Å α, deg β, deg γ, deg V, Å3 Z Dc/g·cm−3 F(000) crystal size/mm rang of indices Rint GOF R1 [I > 2σ(I)] wR2 [all data] a

1

2

3

4

C16H21N3O3 303.36 monoclinic P21/n 9.8643(2) 9.1412(2) 18.1501(4) 90 103.470(2) 90 1591.60(6) 4 1.266 648 0.20 × 0.15 × 0.10 −11,10; −10,10; −20,20 0.0245 1.086 0.0304 0.0852

C17H21NO5 319.35 monoclinic P21/c 13.3924(4) 7.1702(2) 18.0080(5) 90 111.240(3) 90 1611.77(8) 4 1.316 680 0.20 × 0.10 × 0.05 −16,15; −8,8; −21,15 0.0302 1.042 0.0384 0.1039

C21H23N3O3 365.42 orthorhombic P212121 7.9754(1) 8.9243(2) 27.7850(4) 90 90 90 1977.59(6) 4 1.227 776 0.20 × 0.20 × 0.05 −9,9; −10,10; −33,23 0.0272 1.077 0.0449 0.1424

C23H25NO5 395.44 triclinic P1̅ 9.4475(13) 11.1603(17) 11.2471(16) 94.415(12) 103.739 109.702 1068.4(3) 2 1.229 420 0.20 × 0.10 × 0.05 −11,11; −13,13; −13,13 0.0506 1.036 0.0607 0.1982

R1 = Σ∥ Fo| − | Fc∥/Σ| Fo|. wR2 = [Σ[w(Fo2 − Fc2)2]/Σw(Fo2)2]1/2, w = 1/[σ2 (Fo)2 + (aP)2 + bP], where P = [(Fo2) + 2Fc2]/3. 2227



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Table 2. Hydrogen Bonding Distances and Angles for 1−4 D−H···A 1a N3−H5N···O1#1 N2−H2N···O3#2 N2#3−H2N#3···O3 N1#4−H1N#4···O3 N2−H3N···O2 2b N1#1−H1N#1···O5 O3−H3···O1 O5−H5···O4#2 O5#3−H5#3···O4 3c N3−H1···O3 N2−H2A···N1#1 N2−H2B···O1#2 4d O3−H3A···O2#1 N1−H1N···O4

D···A (Å)

D−H···A (deg)

3.0613(16) 2.8994(15) 2.8994(15) 2.8616(13) 2.8828(15)

158.9(16) 173.8(15) 173.8(15) 177.0(15) 162.3(15)

2.8850(18) 2.5745(15) 2.8606(17) 2.8606(17)

174.4(18) 160.7 148.3 148.3

2.830(3) 2.966(3) 2.886(4)

175(3) 177.1 156.4

2.654(3) 2.984(3)

159.3 165(3)

a Symmetry codes: #1 −x + 2, −y − 1, −z + 2; #2 −x + 1, −y − 1, z + 2; #3 −x + 1, −y − 1, −z + 2; #4 x, y − 1, z. b#1 x, −y − 1/2, z + 1/2; #2 x − 1, −y + 1, −z − 2; #3 x − 1, −y + 1, −z − 2. c#1 x + 1, y, z; #2 x, y − 1, z. d#1 x, y − 1, z.

crystals of 1. Yield: 59 mg, 96%. Anal. Calcd for C16H21N3O3: C, 63.35; H, 6.98; N, 13.85%. Found: C, 63.46; H, 6.97; N, 13.92%. Agomelatine Glycolic Acid Cocrystal (1:1), 2. To a mixture of equimolar agomelatine (50 mg) and glycolic acid (16 mg) was added 2 mL of acetonitrile, and the resulting solution was refluxed for 2 h, cooled to room temperature, and then evaporated slowly to get colorless block-shaped crystals of 2. Yield: 61 mg, 93%. Anal. Calcd for C17H21NO5: C, 63.94; H, 6.63; N, 4.39%. Found: C, 64.23; H, 6.53; N, 4.22%. Agomelatine Isonicotinamide Cocrystal (1:1), 3. A mixture of equimolar agomelatine (50 mg) and isonicotinamide (25 mg) was

Figure 1. The structure of 1D chain (a) and 2D sheet (b) in 1. melted at 135 °C, cooled to room temperature, and then dissolved in 2 mL of tetrahydrofuran and evaporated slowly. After about one week, colorless block-shaped crystals of 3 were obtained. Yield: 74 mg, 98%.

Figure 2. (a) The structure of glycolic acid dimer in 2. (b) Side view and (c) top view of the 2D sheet containing 1D right-handed and left-handed helical chains. (d) The 3D structure of 2. 2228



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Figure 4. The structures of 1D chain (a) and the 3D framework (b) in 4. using the program of CrysAlis PRO. The structures were solved by the direct methods using the SHELX-97 program34 and refined by the fullmatrix least-squares method on F2. All non-hydrogen atoms were refined with anisotropic displacement parameters. The hydrogen atoms were placed in calculated positions with fixed isotropic thermal parameters and included in the structure factor calculations in the final stage of full-matrix least-squares refinement. Crystallographic data and details of refinements of 1−4 are listed in Table 1, and the hydrogen bonding distances and angles are given in Table 2. Powder Dissolution Experiments. The absorbance values for Forms I−III and cocrystals 1−4 in phosphate buffer of pH 6.8 at different times were detected by a Cary 50 UV spectrophotometry at 230 nm, where all the coformers have no absorption at this wavelength, and the concentrations of Forms I−III and cocrystals 1−4 were calculated by means of a standard curve (ε = 1.72 × 104 M−1). The solids of Form I−III and 1−4 were milled to powder and sieved using standard mesh sieves to provide sample with approximate particle size ranges of 75−150 μm. In a typical experiment, 50 mL of phosphate buffer (pH 6.8) was added to a flask containing 200 mg of sample, and the resulting mixture was stirred at 25 °C and 500 rpm. The solution was withdrawn from the flask at regular intervals and filtered through a 0.22 μm nylon filter. A 10 μm portion of the filtered aliquot was diluted to 1.0 mL with phosphate buffer (pH 6.8) and was measured with UV/vis spectrophotometry. After 2.5 h experiments, the undissolved solids were filtered and dried under a vacuum, and analyzed by powder X-ray diffraction (PXRD).

Figure 3. The structures of 1D chain (a), 2D sheet (b), and 3D framework (c) in 3 (the green and pink color are isonicotinamide and naphthalene groups of agomelatine, respectively). Anal. Calcd for C21H23N3O3: C, 69.02; H, 6.34; N, 11.50%. Found: C, 69.18; H, 6.57; N, 11.30%. Agomelatine Methyl 4-Hydroxybenzoate Cocrystal (1:1), 4. A mixture of equimolar agomelatine (50 mg) and methyl 4hydroxybenzoate (31 mg) were melted at 110 °C and then cooled to room temperature and dissolved in 1 mL of acetonitrile. The solution was allowed to evaporate slowly to get colorless columnshaped crystals of 4. Yield: 80 mg, 98%. Anal. Calcd for C23H25NO5: C, 69.86; H, 6.37; N, 3.54%. Found: C, 69.99; H, 6.20; N, 3.73%. Single Crystal X-ray Diffraction. Single-crystal X-ray diffraction data for cocrystals 1−4 were collected on an Agilent Xcalubur Nova CCD diffractometer with graphite monochromated Cu Kα radiation (λ = 1.54178 Å). Cell refinement and data reduction were applied

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RESULTS AND DISCUSSION Crystal Structures. The asymmetric unit of 1 contains one urea and one agomelatine molecule, in which the urea molecules alternately link the agomelatine molecules through 2229



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Figure 5. DSC curves for agomelatine Form II, coformers and cocrystals 1−4.

molecule forms five hydrogen bonds with adjacent urea and agomelatine molecules, and each agomelatine molecule forms three hydrogen bonds with adjacent three urea molecules (Figure 1b). The asymmetric unit of 2 contains one agomelatine and one glycolic acid molecules. In 2, two glycolic acid molecules form a dimer through two O(5)−H(5)···O(4)#2 and O(5)#3−H(5) #3···O(4) hydrogen bonds (Figure 1a), with the O···O distance of 2.861(2) Å. Along the ac plane, glycolic acid dimers alternately link the agomelatine molecules through the intermolecular hydrogen bonding interactions (synthons III and VI) to generate a 2D sheet, which contains helical chains with alternately right-handed and left-handed helicity (Figure 2b), with the O(3)−H(3)···O(1) and N(1)#1−H(1N) #1···O(5) hydrogen bonding distances of 2.575(2) and 2.885(2) Å, respectively. All the 2D sheets are packed along the b axis via interlayer C−H···π interactions between the adjacent naphthalene groups of agomelatine molecules to generate the 3D structure of 2 (Figure 2c), with a C−H···π distance of 3.604 Å. Similar to 1, the isonicotinamide molecules in 3 alternately link the agomelatine molecules through two N(2)−H(2B)···O(1)#2 and O(3)···H(1)−N(3) intermolecular hydrogen bonds (synthon I) to form a 1D chain along the b axis (Figure 3a), with the N···O distances of 2.886(4) and 2.830(3) Å, respectively. The 1D chains are further connected by the interchain hydrogen bonds between the pyridine nitrogen atom of isonicotinamide in one chain and the amine group of isonicotinamide in the adjacent chain to generate a 2D sheet (Figure 3b), with the N(2)−H(2A)···N(1)#1 distance of

Figure 6. Powder dissolution profiles for agomelatine Form I, Form II, Form III, and 1−4 in phosphate buffer of pH 6.8.

two N(2)−H(3N)···O(2) and O(3)···H(1N)#4−N(1)#4 intermolecular hydrogen bonds (synthon I) to form a onedimensional (1D) chain along the b axis (Figure 1a), with N···O distances of 2.883(2) and 2.862(1) Å, respectively. The adjacent chains are further connected via three additional interchain hydrogen bonds to generate a two-dimensional (2D) sheet (Figure 1b), in which two hydrogen bonds form between the adjacent two urea molecules (N(2)−H(2N)···O(3)#2 = O(3)···H(2N)#3−N(2)#3 = 2.899(2) Å, synthon I), and the third one forms between the urea N(3) atom within one chain and the O(1) atom of agomelatine within another chain (N(3)−H(5N)···O(1)#1 = 3.061(2) Å). In 1, each urea 2230



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Figure 7. XRPD patterns for 1 (a), 2 (b), 3 (c), and 4 (d) before and after powder dissolution experiments in phosphate buffer of pH 6.8.

packed along the b axis to generate the 3D structure of 4 (Figure 4b). DSC Analyses and Powder Dissolution. The DSC curves of agomelatine Form II, coformers and cocrystals are shown in Figure 5. It can be found that the melting points at 137, 92, 121, and 68 °C for 1−4, respectively, are different from those of agomelatine Form II and corresponding coformers. It is interesting to note that each melting point for 1−3 is between those of agomelatine Form II and corresponding coformers, while the melting point for 4 is lower than those of agomelatine Form II and methyl 4-hydroxybenzoate (Figure 5). This can be attributed to their different structures, as 1−3 form 2D hydrogen bonding linked frameworks, while 4 only forms 1D hydrogen bonding linked chains, and the weaker interchain interactions in 4 lead to its lower melting point. The results of XRPD measurements for 1−4 indicate that all the peaks displayed in the measured patterns closely match those in the simulated patterns generated from the singlecrystal diffraction data (Figure S1, Supporting Information), indicating single phases of 1−4 are formed. Powder dissolution profiles for agomelatine Forms I−III and 1−4 in phosphate buffer of pH 6.8 are shown in Figure 6. From Figure 6, it can be found that both the dissolution rate and solubility values of 1− 4 are larger than those of agomelatine Forms I−III, indicating the solubility of agomelatine can be indeed improved via forming the cocrystals. The solubility values of 1−4 are approximately 2.2, 2.9, 4.7, and 3.5 times as large as that of Form II, and 1.6, 2.1, 3.4, and 2.5 times as large as that of agomelatine Form I. After the dissolution experiments, the undissolved solids were filtered and dried under a vacuum, and

Figure 8. A correlation between the solubility of coformers and the stability of cocrystals in phosphate buffer of pH 6.8.

2.966(3) Å. The 2D sheets are linked by the C−H···π interactions between the pyridine groups of isonicotinamide molecules (green color), and the π···π interactions between the naphthalene groups of agomelatine molecules (pink color) to form the 3D structure of 3 (Figure 3c), with the C−H···π and π···π distances of 3.591 and 3.478 Å, respectively. In 4, the agomelatine molecules are alternately connected by the methyl 4-hydroxybenzoate molecules through two N(1)− H(1N)···O(4) and O(3)−H(3A)···O(2)#1 intermolecular hydrogen bonds (synthons IV and V) to form a 1D chain along the b axis (Figure 4a), with the N···O distances of 2.984(3) and 2.654(3) Å, respectively. All the 1D chains are 2231



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(2009ZX09501-022), and China Postdoctoral Science Foundation (Grant No. 20110490919).

the results of XPRD analyses indicate only 2 transformed to Form I, while 1, 3, and 4 remained unchanged. Indeed, the solids of 1−4 can keep their crystalline forms in phosphate buffer of 6.8 for 3.5, 2.0, 6.0, and 15.0 h, respectively (Figure 7), and then 1, 2, and 4 transformed to Form I, while 3 transformed to Form III. The above results indicate that both the solubility and stabilities of 1−4 in phosphate buffer are better than those of agomelatine with acetic acid and ethylene glycol we reported before. It is interesting to note that the stabilities of 1−4 in phosphate buffer are related to the solubility of corresponding coformers (Figure 8), as the solubility values of glycolic acid (b), urea (a), isonicotinamide (c), methyl 4-hydroxybenzoate (d), and agomelatine Form II in phosphate buffer of pH 6.8 are 1786, 873, 163, 30, and 0.51 mg/mL, respectively, and the stability of corresponding 2, 1, 3, and 4 is 2.0, 3.5, 6.0, and 15.0 h in phosphate buffer of pH 6.8, respectively, indicating the larger difference of solubility between the agomelatine and coformer in a given cocrystal leads to the lower stability of the cocrystal, as the coformer with larger solubility in a cocrystal is easier to dissolve in water and leads to the cocrystal decomposed more quickly in water.

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CONCLUSIONS Six kinds of synthons were used to construct the cocrystals of agomelatine, and four cocrystals of agomelatine with urea, glycolic acid, isonicotinamide, and methyl 4-hydroxybenzoate were obtained and determined by single crystal X-ray diffraction, in which 1−3 form 2D hydrogen bonded frameworks between agomelatine and coformers, while 4 displays a 1D chain structure. The melting points for 1−3 are between those of agomelatine Form II and corresponding coformers, while the melting point for 4 is lower than those of agomelatine Form II and coformer due to the weaker interchain interactions in 4. The aqueous solubility of agomelatine is increased after the formations of cocrystals 1−4, and 3 shows the highest solubility value, indicating the solubility of agomelatine can be improved via cocrystals. In addition, the stability of 1−4 in phosphate buffer of 6.8 is better than that of agomelatine cocrystals with acetic acid and ethylene glycol we reported before, and the stability of cocrystals is contrary to the solubility values of corresponding coformers. As solubility and bioavailability are often related, we believe that the bioavailability of agomelatine may also be increased after the formation of cocrystals 1−4, and this study is ongoing in our lab.

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ASSOCIATED CONTENT

S Supporting Information *

The XPRD patterns and IR spectra for 1−4. This material is available free of charge via the Internet at http://pubs.acs.org.

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REFERENCES

AUTHOR INFORMATION

Corresponding Author

*Fax: +86-20-84112921. E-mail: [email protected] (J.-M.C.); [email protected] (T.-B.L.). Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by 973 Program of China (2012CB821705), NSFC (20831005, 21101173, 91127002 and 21121061), the National Key Program of China 2232



Article

(30) Dan, H. B.; Zhang, P.; Yuan, Z. D.;, Jiang, X. D.; Huang, Y.; Wang, H. B.; Cao, X. F.; Cheng, X. D.; Yu, X. CN Patent, 101585779, 2009. (31) Zheng, S. L.; Chen, J. M.; Zhang, W. X.; Lu, T. B. Cryst. Growth Des. 2011, 11, 466−471. (32) (a) http://www.drugbank.ca/drugs?type=small_molecule (b) Kye, C. H.; Sung, O. K.; Seung, W. K. Bull. Korean Chem. Soc. 1999, 20, 953−956. (c) Stahl, P. H.; Wermuth, C. G. In Handbook of Pharmaceutical Salts; VHCA and Wiley-VCH: Zürich and Weinheim, 2002. (d) Dorn, T.; Fromm, M. K.; Janiak, C. Aust. J. Chem. 2006, 59, 22−25. (e) Breese, K.; Fuchs, G. Eur. J. Biochem. 1998, 251, 916−923. (33) http://www.cfsan.fda.gov/∼dms/opa-appa.html. (34) Sheldrick, G. M. SHELXTL-97, Program for Crystal Structure Solution and Refinement; University of Gottingen: Gottingen, Germany, 1997.

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