Racemic Salts and Solid Solutions of Enantiomers of the

Jun 27, 2019 - The R and S enantiomers of the antihypertensive drug carvedilol (CVD) can display remarkable miscibility in the crystalline state allow...
0 downloads 0 Views 5MB Size
Article pubs.acs.org/crystal

Cite This: Cryst. Growth Des. XXXX, XXX, XXX−XXX

Racemic Salts and Solid Solutions of Enantiomers of the Antihypertensive Drug Carvedilol Luan F. Diniz,†,‡ Paulo S. Carvalho, Jr.,§ Wagner da Nova Mussel,‡ Maria Irene Yoshida,‡ Renata Diniz,‡ and Christian Fernandes*,† †

Downloaded via BUFFALO STATE on July 18, 2019 at 06:31:15 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

Laboratório de Controle de Qualidade de Medicamentos e Cosméticos, Departamento de Produtos Farmacêuticos, Faculdade de Farmácia and ‡Departamento de Química, Instituto de Ciências Exatas (ICEx), Universidade Federal de Minas Gerais, 31270-901, Belo Horizonte, Minas Gerais, Brazil § Instituto de Química, Universidade Federal do Mato Grosso do Sul, 79074-460, Campo Grande, Mato Grosso do Sul, Brazil S Supporting Information *

ABSTRACT: The R and S enantiomers of the antihypertensive drug carvedilol (CVD) can display remarkable miscibility in the crystalline state allowing this active pharmaceutical ingredient (API) to form a solid-solution of enantiomers (SSEs) as well as racemic compounds. Although rare and still little explored, these intriguing systems can also be used to design racemic multicomponent crystal forms toward the improvement of undesirable pharmaceutical properties of APIs. In this study, aiming to understand why there is miscibility between the enantiomers during the supramolecular recognition and crystallization processes of the CVD in the presence of salt formers, two SSEs and one racemic salt were prepared from the reaction of CVD with pharmaceutically acceptable HCl, HBr, and oxalic acids. Two monohydrated isostructural salts, hydrochloride (CVD-HClH2O) and hydrobromide (CVD-HBr-H2O), crystallize as racemic SSEs. These unique systems are formed from the miscibility of the R···R and S···S homochiral units that propagate into enantiomerically enriched one-dimensional chains through H-bonds with water molecules along the crystal. The oxalate salt (CVD-OXA), in turn, crystallizes as a standard racemic compound since the oxalate anions, which lie in the inversion center, are directly H-bonded to both R and S CVD enantiomers, forming racemic ionic units that extend along the structure. Complementary to the crystallographic study, conformational and Hirshfeld surface analysis were also performed based on the single-crystal X-ray diffraction data. The salt formations were confirmed from the Fourier transform infrared spectroscopy as well as powder X-ray diffraction patterns, and their thermal behaviors were investigated by a combination of differential scanning calorimetry, thermogravimetric, and hot-stage microscopy techniques.

1. INTRODUCTION The design of multicomponent crystal forms, e.g., salts and cocrystals, represents an essential branch of pharmaceutical sciences and has been increasingly used as an alternative strategy to improve physicochemical properties of active pharmaceutical ingredients (APIs).1−4 Taking into account the chiral APIs, a diversity of solid forms can be formed depending on the enantiomeric excess present in the crystal.5,6 The crystallization of a racemic compound can lead to three systems (Figure 1). The first one, a racemic compound or true racemate (>90% of cases), occurs when R and S enantiomers are present in equal amounts within a crystalline lattice in a well-defined arrangement and related by symmetry. In its turn, conglomerates are an equimolar physical mixture of each © XXXX American Chemical Society

enantiomer crystallized as enantiomerically pure phases within the crystalline lattice. Finally, solid solutions of enantiomers (SSEs)a particular and rare system (99%) was obtained from commercial sources and used without any further purification. Hydrochloride (HCl), hydrobromide (HBr), and oxalic acids were purchased from Sigma-Aldrich. Organic solvents (analytical grade) were also obtained from commercial sources and used as received. 2.2. Preparation of Salts. Carvedilol Hydrochloride Monohydrate (CVD-HCl-H2O). A total of 50 mg (0.124 mmol) of racemic CVD were weighed and dissolved in 5 mL of ethanol/water (2:1, v/v) B

DOI: 10.1021/acs.cgd.9b00263 Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

Article

Figure 2. Packing view of the CVD-HCl-H2O and CVD-HBr-H2O isostructural salts along the bc planes (a). Purple spheres generically represented the anions (Cl− and Br−). The non-centrosymmetric unit which is stabilized by NH2+aliphatic···A− (where A− = Cl− or Br−) and CH···π interactions (b). Assembly of the 1D chains from miscible R···R and S···S homochiral units along the [001] direction (c). Sheet structure formed at the ac plane through NHring···A− interactions (d). Representation of the enantiomerically enriched chains forming racemic layers parallel to the b-axis (e). solution. Then, an equimolar amount of HCl acid (125 μL of 1 mol L−1, 0.124 mmol) was added, followed by the system stirring at 70 °C for 20 min. Light brown crystals (Figure S1b, Supporting Information) of the CVD-HCl-H2O salt were obtained within 5−7 days, with a yield of 85%, by slow evaporation of solvent at room temperature. Carvedilol Hydrobromide Monohydrate (CVD-HBr-H2O). Prepared upon grinding of a 1:1 drug/acid molar ratio system. First, 50 mg of racemic CVD (0.124 mmol) and 125 μL of 1 mol L−1 HBr acid solution (0.124 mmol) were mechanically reacted, upon grinding for 10 min by ethanol liquid-assisted grinding. Then, 20 mg of the ground material were dissolved in 6 mL of ethanol/water (2:1, v/v) solution at 70 °C. Light brown crystals (Figure S1c, Supporting Information) of the CVD-HBr-H2O salt were obtained within 5−7 days, with a yield of 82%, by slow evaporation of solvent at room temperature. Carvedilol Oxalate (CVD-OXA). A total of 50 mg (0.124 mmol) of racemic CVD and 11.2 mg (0.124 mmol) of oxalic acid were mixed in 5 mL of ethanol/water solution (1:1, v/v) and stirred at 70 °C for 20 min, giving rise to a suspension. This filtered system results in a dried solid under ambient conditions. Single crystals of CVD-OXA were obtained dissolving this material in isopropyl alcohol under stirring at 90 °C for 20 min. Colorless crystals (Figure S1a, Supporting Information) were observed within 3−5 days, with a yield of 78%, by slow evaporation of solvent at room temperature. 2.3. Single-Crystal X-ray Diffraction (SCXRD). Single crystal Xray diffraction data were collected at room temperature on an AgilentRigaku Super Nova diffractometer with CCD detector system using Mo−Kα radiation (λ = 0.71073 Å). Suitable crystals of appropriate dimensions were chosen and mounted on loops for the data collection. Preliminary unit cell parameters were obtained with three sets of 12 narrow frame scans. The CrysAlisPro41 data reduction package was used for acquisition, indexing, integration, absorption correction, and scaling of Bragg reflections. The final cell parameters were determined using all reflections. A Gaussian face-indexed

absorption correction was applied to the three data sets collected. CrysAlisPro41 software was also used for analysis of systematic absences and space group determination. Thereafter, using Olex2,42 the structures were solved by direct methods (SHELXT-14)43 and refined by full-matrix least-squares on F2 for all data (SHELXL-17).44 The non-hydrogen atoms were refined anisotropically. Then, all hydrogen atoms were located from electron-density difference maps and were positioned geometrically and refined using the riding model [Uiso(H) = 1.2Ueq or 1.5Ueq]. During the refinement of the CVDHCl-H2O and CVD-HBr-H2O structures, a Q-peak from the electrondensity difference maps was identified close to chiral center of CVD+ cation in almost a mirrored position to the hydroxyl group. In addition, the Ow-atom of water molecule exhibited voluminous thermal ellipsoid. Thus, the commands PART1 and PART2 were needed to split the disordered atoms. The occupation of parts attributed to the enantiomers in the crystalhave been refined freely. MERCURY 3.1045 and ORTEP46 were used for analysis and visualization of the structures and also for graphic material preparation. All deposited CIF files are in the Cambridge Structural Database47 under the CCDC numbers 1899518−1899520. 2.4. Powder X-ray Diffraction (PXRD). Powder X-ray diffraction (PXRD) data were collected in a Shimadzu Optima XRD-7000 diffractometer at room temperature under 40 kV, 30 mA, using CuKα (λ = 1.54056 Å) equipped with a Polycapillar focusing optics under parallel geometry coupled with a graphite monochromator. The sample was spinning at 60 rpm, scanned over an angular range of 4− 60° (2θ) with a step size of 0.01° (2θ) and a time constant of 2 s step−1. 2.5. Hirshfeld Surface (HS) and Derived Fingerprint Plots. The Hirshfeld surface (HS) and its associated two-dimensional (2D) fingerprint plot were generated by the software Crystal Explorer 3.148 using as input the experimental single-crystal X-ray diffraction data of the respective CVD salt. The color pattern on the HS shows the areas involved in interactions and which ones are susceptible to weak and C

DOI: 10.1021/acs.cgd.9b00263 Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

Article

Figure 3. Crystal packing of CVD-OXA salt along the ac plane (a). In the structure, the oxalate anions are in the inversion center connecting R and S enantiomers through NH···O and CH···π interactions (b). View of the 1D racemic chain that propagates along the [010] direction (c).

A− (A = Cl−, Br−, O−) H-bonds. It is noteworthy that throughout the salt screening experiments, only the reactions of CVD with HCl, HBr, and oxalic acids led to the formation of solid phases. The attempts to prepare new CVD salts using other acceptable pharmaceutical salts failed or resulted in the immediate crystallization of pure CVD phase. In addition, the salts formation attempts also failed when the syntheses were carried out in pure solvents due to the low solubility of the API. Nevertheless, once formed, the single crystals of all salts were obtained from the conventional solvent evaporative method (see section 2). Novel and unique phases of CVD salts were first identified through PXRD and DSC analysis. Then the SCXRD analysis revealed that the reactions between the racemic CVD with HCl and HBr acids yielded solid solutions between the enantiomers, while the reaction with the oxalic acid gave rise to a standard racemic compound. Toward understanding the formation of these systems, detailed structural and supramolecular descriptions of these salts are provided below. Packing perspective views are depicted in Figures 2a and 3a. Crystal data and refinement parameters are shown in Table 1. In Figure S2 and Table 2 are shown, respectively, the ORTEP46 diagrams of the ASUs and geometric parameters of the H-bonds of CVD salts. Carvedilol Hydrochloride Monohydrate (CVD-HCl-H2O) and Carvedilol Hydrobromide Monohydrate (CVD-HBrH2O). The crystallization of CVD with HCl and HBr acids leads to the formation of monohydrate isostructural phases (see Table 1). Prism-like crystals of CVD-HCl-H2O and CVDHBr-H2O (Figure S1) have been solved in the centrosymmetric monoclinic C2/c space group with Z′ = 1. The formation of these salts is associated with, among others, the hydration of the API as well as the miscibility of enantiomers in the solid state that results in a disorder structural model.

strong interactions. In the dnorm surfaces, the contacts shorter than the sum of the van der Waals radii appear as red areas, while the white areas represent the contacts with a length close to the van der Waals sum. The blue areas represent the longer contacts.49,50 2.6. FT-IR Vibrational Spectroscopy. FT-IR spectra were recorded on a PerkinElmer Spectrum One spectrometer equipped with ATR accessory in the range of 4000−650 cm−1, with an average of 64 scans and 4 cm−1 of spectral resolution. 2.7. Differential Scanning Calorimetry (DSC). Differential scanning calorimetry (DSC) plots were obtained using a Shimadzu DSC-60 instrument. CVD and its salt samples (1.0 ± 0.5 mg) were placed in sealed aluminum pans and heated under a nitrogen atmosphere (50 mL min−1) from 25 to 400 °C at a heating rate of 10 °C min−1. Shimadzu TA-60 software was used in the data analysis. 2.8. Thermogravimetric (TG) Analysis. Thermogravimetric (TG) experiments were carried out with a Shimadzu DTG-60 thermobalance. Approximately 2.0 mg of the samples were placed in alumina pans and heated at 10 °C min−1 under a nitrogen flow (50 mL min−1) from 25 to 600 °C. The resulting data were also analyzed using the Shimadzu TA-60 software (version 2.2). 2.9. Hot-Stage Polarized Optical Microscopy (HSM). HSM experiments were carried out on a Linkam T95-PE device coupled to a Leica DM2500P optical microscope. Single crystals of CVD salts were heated at a constant rate of 10 °C min−1 over a temperature range from 30 °C until the melting or decomposition of the crystals. Recorded images use a CCD camera attached to the microscope in time intervals of 10 s via the Lynksys 32 software package (version 1.96).

3. RESULTS AND DISCUSSION 3.1. Crystal Structures of CVD Salts. CVD is a weakly basic molecule (pKa 7.8)51 and thus amenable to salt formation (see ΔpKa of the reactions in Table S2)52 with strong HCl, HBr, and oxalic acids (all listed as nontoxic salt former in the GRAS list).53 Taking this into account, we explored new salt phases of racemic CVD with salt formers able to form NH+··· D

DOI: 10.1021/acs.cgd.9b00263 Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

Article

Table 1. Crystallographic Data and Refinement Parameters of CVD Salts identification code

CVD-HCl-H2O

CVD-HBr-H2O

CVD-OXA

empirical formula formula weight temperature (K) crystal system space group a (Å) b (Å) c (Å) α (deg) β (deg) γ (deg) volume (Å)3 Z/Z′ ρcalc (g cm3) μ (mm−1) absorption correction F(000) crystal size/mm3 2θ range for data collection/° index ranges

C24H29ClN2O5 460.94 298(2) monoclinic C2/c 17.7925(11) 21.3203(12) 12.7668(6) 90 102.378(5) 90 4730.4(5) 8/1 1.294 0.199 Gaussian, Tmin = 1.000, Tmax = 0.817 1952.0 0.761 × 0.266 × 0.152 5.028 to 50.688 −16 ≤ h ≤ 21 −25 ≤ k ≤ 23 −15 ≤ l ≤ 15 13525 3372 4324 [Rint = 0.0222, Rsigma = 0.0238] 4324/0/318 R1 = 0.0508 wR2 = 0.1254 R1 = 0.0663 wR2 = 0.1354 1.029 0.43/−0.41

C24H29BrN2O5 505.40 298(2) monoclinic C2/c 18.0098(11) 21.0711(9) 13.0140(7) 90 103.049(6) 90 4811.1(5) 8/1 1.396 1.745 Gaussian, Tmin = 1.000, Tmax = 0.551 2096.0 0.652 × 0.348 × 0.081 5.028 to 50.698 −21≤ h ≤ 19 −25 ≤ k ≤ 24 −15 ≤ l ≤ 14 14160 3496 4409 [Rint = 0.0277, Rsigma = 0.0291] 4409/0/318 R1 = 0.0478 wR2 = 0.1104 R1 = 0.0637 wR2 = 0.1198 1.035 0.94/−0.72

C25H27N2O6 451.48 298(2) orthorhombic Pbca 19.793(2) 6.8279(8) 33.188(3) 90 90 90 4485.1(8) 8/1 1.337 0.096 Gaussian, Tmin = 1.000, Tmax = 0.752 1912.0 0.588 × 0.199 × 0.03 4.792 to 50.698 −19 ≤ h ≤ 23 −6 ≤ k ≤ 8 −39 ≤ l ≤ 27 13452 2680 4094 [Rint = 0.0529, Rsigma = 0.0611] 4094/0/300 R1 = 0.0558 wR2 = 0.1132 R1 = 0.0960 wR2 = 0.1315 1.077 0.17/−0.21

reflections collected reflections [I ≥ 2σ(I)] independent reflections data/restraints/parameters final R indexes [I ≥ 2σ(I)] final R indexes [all data] goodness-of-fit on F2 largest diff peak/hole/e Å−3

The crystal structures of these salts consist of layers of ionic pairs separated by domains where water molecules reside (Figure 2 and Figure S5). From the Table 2 and Figure S5, it is recognized that both crystal packings are stabilized by N−H··· O, O−H···O, C−H···O, C−H···π, O−H···A−, and N−H···A− (A− = Cl− or Br−) intermolecular interactions. In the structure, the anion is associated with 2-fold symmetry, and it is related to CVD+ cations via NH2+aliphatic···A− interactions (N2+− H2C···Cl2−, 3.247(2) Å, 142.16(11)° or N2+−H2D···Br2−, 3.395(3) Å, 136.98(19)°). As a result, a non-centrosymmetric unit appears which is further stabilized by CH···π (C17− H17···Cg3, 3.385(5) Å, 130.14(25)°/ 3.408(8) Å, 129.00(32)° and C19−H19···Cg4, 3.703(6) Å, 159.75(48)°/ 3.798(7) Å, 162.12(25)° for CVD-HCl-H2O and CVD-HBrH2O, respectively) interactions between the aromatic moieties of neighbor molecules (Figure 2b and Figure S4). Because of the symmetry, an homochiral assembly is formed, denoted by R···R or S···S. Thus, the solid solution occurrence comes from the miscibility of the R···R and S···S homochiral units throughout their propagation. Along the [001] direction, these units are held together into a 1D chain through two water molecules (Figure 2c). Interestingly, the hydroxyl group (which differ the enantiomers) is not directly involved in the formation of these units, and water is the molecule that has a crucial role in the chain formation. This feature agrees with the assumption that the 1D chain does not necessarily have to be homochiral and can be enantiomerically enriched because the

Throughout the CVD-HCl-H2O and CVD-HBr-H2O structural resolution processes, Q-peaks, from the difference electron-density map, were identified near the chiral center of CVD molecule, being attributed, at first, to substitutional disorder. However, these Q-peaks indicate, in fact, the existence of the hydroxyl group, as expected for molecule, but in an opposite configuration of the parent CVD. Furthermore, the O atom of the water molecule exhibited a high anisotropic displacement. The hydroxyl fragment and the water molecule were refined in two parts with site occupancies of 0.6675:0.3325 and 0.7188:0.2812 in the hydrochloride and hydrobromide salts, respectively. The CVD-HCl-H2O and CVD-HBr-H2O structures are racemic SSEs. Their ASUs (Figure S1) exhibit a CVD+ cation that is a superimposition of both enantiomers. Each of the enantiomers assumes a similar but not corresponding conformation. The CVD+ cations have the aromatic portions oriented about 12.77° to each other, so except for the aliphatic central chain, the molecule is almost planar (Figure S3). The ASUs comprise one CVD+ cation protonated on secondary aliphatic amine, two anions (Cl− or Br−), and one water molecule (see Figure S2). The halide anions lie on the 2-fold axes, being refined with 0.5 of occupancy; then the crystals have 1:1 CVD+/anion stoichiometry. On both salts’ crystal structure, the R-CVD+ and S-CVD+ enantiomers are present with opposite values of occupancies giving rise to an overall racemic composition to the crystals. E

DOI: 10.1021/acs.cgd.9b00263 Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

Article

Table 2. Geometric Parameters of the H-Bonds in the CVD Salts interaction

D···A (Å)

O2−H2···O5− N2+−H2A···O4 C24−H24A···O6− N2+−H2A···O6− N2+−H2A···O5− C15−H15A···O5− C16−H16B···O5− C9−H9···O6− C15−H15B···O2 C17−H17B···O3 C8−H8···Cg1a

2.605(2) 2.984(3) 3.517(3) 2.704(2) 2.927(2) 3.091(3) 3.175(3) 3.529(4) 3.353(3) 3.393(3) 3.900(4)

O2A−H2A···OwA O2A−H2A···OwB O2B−H2B···Cl2− N1−H1···Cl1− N2+−H2C···Cl2− N2+−H2C···O2A OwA−HwAB···Cl2− N2+−H2C···OwA OwB−HwAA···O4 OwB−HwBA···O3 OwA−HwAA···O4 OwB−HwBB···Cl1− C17−H17A···Cg3c C19−H19···Cg4d C24−H24C···Cg2b

2.892(5) 2.856(5) 3.161(4) 3.153(1) 3.247(2) 2.910(3) 3.326(7) 2.993(6) 3.014(5) 2.995(5) 2.941(8) 3.165(5) 3.385(5) 3.703(6) 3.914(7)

O2A−H2A···OwA O2A−H2A···OwB O2B−H2B···Br2− N1−H1···Br1− N2+−H2D···Br2− N2+−H2D···O2A OwB−HwBA···Br2− N2+−H2D···OwA OwA−HwAA···O4 OwA−HwAA···O3 OwB−HwBB···O4 OwA−HwAB···Br1− C17−H17B···Cg3c C19−H19···Cg4d C24−H24A···Cg2b

2.881(10) 2.904(24) 3.271(7) 3.272(4) 3.395(3) 2.915(4) 3.192(16) 2.986(11) 2.974(10) 3.010(9) 2.836(24) 3.536(7) 3.408(8) 3.798(7) 3.857(9)

H···A (Å)

D−H···A (deg)

CVD-OXA 1.790(2) 2.230(2) 2.700(2) 1.830(2) 2.425(2) 2.440(2) 2.551(2) 2.720(2) 2.485(2) 2.692(2) 3.049(3) CVD-HCl-H2O 2.076(5) 2.048(10) 2.447(1) 2.306(2) 2.498(3) 2.312(2) 2.478(1) 2.149(5) 2.095(2) 2.222(1) 2.095(2) 2.327(1) 2.678(2) 2.816(3) 2.968(2) CVD-HBr-H2O 2.062(10) 2.105(24) 2.595(3) 2.435(4) 2.690(9) 2.238(3) 2.343(1) 2.170(11) 2.168(3) 2.438(2) 2.005(3) 2.710(1) 2.714(3) 2.901(3) 2.917(3)

symmetry code

172.99(12) 142.20(13) 143.39(18) 166.90(13) 116.01(13) 124.21(14) 122.11(16) 145.94(20) 148.83(14) 129.56(15) 152.85(15)

x, y, z x, y, z x, y, z −x+1, −y+1, −z+1 x, +y−1, +z x, +y−1, +z x, +y−1, +z x, +y−1, +z −x+1/2 + 1, +y−1/2, +z −x+1/2 + 1, +y−1/2, +z x, +y−1, +z

172.61(20) 168.40(30) 146.11(30) 168.53(14) 142.16(11) 124.49(12) 175.57(48) 158.12(17) 146.14(37) 151.13(34) 173.10(67) 168.68(32) 130.14(25) 159.75(48) 168.72(28)

x, y, z x, y, z x, y, z x, y, z x, y, z −x+1, −y+1, −z+1 −x+1, −y+1, −z+1 −x+1, +y, −z+1/2 + 1 −x+1, +y, −z+1/2 + 1 −x+1, +y, −z+1/2 + 1 −x+1, +y, −z+1/2 + 1 −x+1/2 + 1, −y+1/2 + 1, −z+1 −x+1, −y+1, −z+1 −x+1, −y+1, −z+1 −x+1, −y+1, −z+1

177.07(33) 164.78(63) 140.74(47) 164.47(26) 136.98(19) 132.59(20) 176.60(93) 152.16(31) 158.34(68) 125.35(64) 165.32(22) 164.57(49) 129.00(32) 162.12(25) 166.21(21)

x, −y+1, +z+1/2 x, −y+1, +z+1/2 x, y, z x, y, z x, y, z −x+1, −y+1, −z+1 x, y, z −x+1, −y+1, −z+1 −x+1, −y+1, −z+1 −x+1, −y+1, −z+1 −x+1, −y+1, −z+1 x−1/2, +y+1/2, +z −x+1/2 + 1, −y+1/2 + 1, −z+1 −x+1/2 + 1, −y+1/2 + 1, −z+1 −x+1/2 + 1, −y+1/2 + 1, −z+1

a Cg1: C18−C19−C20−C21−C22−C23. bCg2: C1−C2−C3−C4−C5−C12. cCg3: C6−C7−C8−C9−C10−C11. dCg3: C5−N1−C6−C11− C12.

2e) that are further connected by the water molecules via OwH···A− (OwB−HwBB···Cl1−, 3.165(5) Å, 168.68(32)° or OwA−HwAB···Br1−, 3.536(7) Å, 164.78(57)°). By comparing the structures of SSEs reported here with the enantiopure salt described by Vogt et al.,40 it is noticed that the CVD+ cations have distinct molecular conformations and supramolecular patterns. Nevertheless, they share an interesting feature: the occurrence of the enantiomeric units formed by the 2-fold symmetry related molecules. In the SSEs, the enantiomeric units are held together by the halide anions, while in the phosphate salt they are connected by the water molecule. In summary, from the crystallographic analysis, the main characteristics of the SSEs studied are (i) both CVD-

water molecule cannot differ in diastereoisomers units (R···R from S···S). The water molecules are tetragonally coordinated to CVD+ cations when they bind enantiomeric units (Figure 2c). However, the construction of the chain is not broken if a diastereoisomeric assembly occurs along the chain (Figure 2c). At the ac plane, a sheet structure is formed by the association of chains through NHring···A− (N1−H1···Cl1−, 3.153(1) Å, 168.53(14)° or N1−H1···Br1−, 3.272(4) Å, 164.47(26)°) interactions (Figure 2d). Finally, parallel to the b-axis, the enriched chains are centrosymmetrically related to each other via CH···π (C24−H24···Cg2, 3.914(7) Å, 168.72(28)°/ 3.857(9) Å, 166.21(21)° for CVD-HCl-H2O and CVD-HBrH2O, respectively) interactions forming racemic layers (Figure F

DOI: 10.1021/acs.cgd.9b00263 Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

Article

HCl-H2O and CVD-HBr-H2O salts are racemic compounds that behave as a partial SSEs and not as conglomerate (in both structures the enantiomers do not crystallize as enantiomerically pure phases within the crystal); (ii) the crystals studied are not in equilibrium since there is no variation of the enantiomeric composition (the proportion of each enantiomer in the crystal is related to the occupancy of substitutional disorder); and (iii) the solid solutions are type 2 because a partial enantioselectivity is present within the crystal structure. Carvedilol Oxalate (CVD-OXA). The CVD-OXA crystal grows as plates (Figure S1) and is readily obtained from the reaction of CVD with oxalic acid (see section 2.2). This salt belongs to the orthorhombic Pbca space group with Z′ = 1. The ASU (Figure S2) contains a CVD+ cation and a half of oxalate anion (OXA2−), and the crystal packing is stabilized by classical (N−H···O and O−H···O) and nonclassical (C−H···O and C−H···π) H-bonds formed mainly among amine, hydroxyl, and ether groups of the CVD+ cation and carboxylate of the oxalate anion. As a result, an interesting network of Hbonds is formed connecting both CVD+ enantiomers and oxalate anions into a supramolecular arrangement. Differently from CVD hydrochloride and hydrobromide salts, in the CVDOXA the ionic unit forms a dimer (Figure 3b). The OXA2− anions reside in the inversion center between two CVD+ cations, the R and S enantiomers, being connected via bifurcated NH 2 + ···COO − H-bonds (N2 + −H2A···O6 − , 2.704(2) Å, 166.90(13)° and N2+−H2A···O5−, 2.927(2) Å, 116.01(13)°) that is further stabilized by CH···π (C8−H8··· Cg1, 3.900(4) Å, 152.85(15)°) interactions. Furthermore, the anion is directly H-bonded to the chiral center through O−H··· COO− H-bonds (O2−H2···O5−, 2.605(2) Å, 172.99(12)°) arranging the dimers into 1D racemic chain along the [010] direction (Figure 3c). Along these racemic chains, the API molecules are also stabilized by π···π interactions (Cg2···Cg3, 4.141(3) Å), resulting in the formation of homochiral chains as shown in Figure 3c. Finally, along the [100] direction, the sheet structure assembles into a 3D network through CH···O interactions (C15−H15B···O2, 3.353(3) Å, 148.83(14)°). In comparison with the CVD-HCl-H2O and CVD-HBr-H2O crystal structures, in which the racemic feature is from the centrosymmetric assembly of enantiomerically enriched arrangements, the CVD-OXA structure is formed by the ability of the OXA2− anion to recognize the R and S enantiomers (Figure 3b). 3.2. Molecular Conformational Analysis. Conformational analysis is extensively used to indicate which conformations an API with flexible groups adopt within the crystal.54−56 The CVD+ cation is a conformationally flexible molecule. Figure 4 shows the overlay of conformations of the three R-CVD+ cations (arising from the CVD salts), obtained by the superimposing of the carbazol-4-yloxy moieties. It is important to note that the CVD+ conformations in the hydrochloride and hydrobromide salts are practically identical to each other and entirely different from those found in the oxalate salt. On the basis of the orientation of aromatic groups, CVD+ cations are almost planar in solid solutions. The mean planes of these groups in the molecules are approximately 12.60° to each other, whereas in oxalate salt, they are almost orthogonal to each other (∠82.00°). From Figure 4, it is possible to see that the orientation of the carbazol-4-yloxy group is similar in all salt forms. On the other hand, the aliphatic central chain adopts different orientations. In solidsolutions, the C23−C18−O3−C17 torsion angle is 176.81°,

Figure 4. Molecular overlay diagram of CVD+ cations (R enantiomers) from the hydrochloride (green) and hydrobromide (yellow) racemic SSEs and racemic oxalate (blue) crystal structures.

whereas in the oxalate the C23 and C17 atoms are synclinal oriented each other (∠79.62°). Furthermore, the O1−C13− C14−C15 torsion angle is −65.44° for CVD-OXA salt and 55.05° for the CVD-HCl-H2O and CVD-HBr-H2O ones. This difference is sufficient to drive different orientations for the remainder of the amino moiety. Taking the distance between the O atom of the hydroxyl and the centroid of the 2methoxyphenoxy ring as a reference, notice that based on the CVD+ conformation in the oxalate salt, this distance is smaller (5.697 Å) than in the hydrochloride salt (7.717 Å). This difference may be associated with the occurrence of an intramolecular NH···O H-bond (N2+−H2A···O4, 2.989(3) Å, 142.43(13)°) in the cation molecule of oxalate salt that is not observed in the CVD-HCl-H2O and CVD-HBr-H2O isostructural forms. 3.3. Powder X-ray Diffraction and Isostructurality Analysis. Powder X-ray diffraction is a powerful characterization tool and the most suitable to establish the formation of new crystalline solid forms.57,58 Changes in the 2θ peak positions in the experimental diffractograms of the new materials, when compared to the 2θ peak positions of the starting materials, indicate that new crystalline phases are formed. PXRD analysis also confirms if the single crystal chosen for the SCXRD data collection is representative of the whole sample. Thus, this technique was used to confirm the purity and representativity of the CVD salts. In all situations, the CVD salts synthesized displayed experimental diffraction patterns in excellent agreement with the simulated ones obtained from SCXRD analysis (Figure 5), indicating that the single crystals are representative and present high phase purity. CVD-HCl-H2O and CVD-HBr-H2O salts exhibit very similar unit cell parameters (Table 1), showing they are isostructural. Both salts crystallized in the centrosymmetric monoclinic space group C2/c with 1:1 salt stoichiometry. The parameters of mean elongation (ϵ) and unit cell similarity index (Π)59 are close to zero, ϵ = 0.0061 and Π = 0.0046 (Table S6). The internal arrangement similarity of salts was also analyzed using the “structural similarity” tools available in the Mercury 3.10.45 A 15 CVD+ cations overlay (Figure S6) was carried out showing 15 out of 15 CVD+ cations in common (RMSD = 0.9807 Å, 20% geometry tolerance and ignoring the smallest molecular component). As expected, the diffractograms analysis of CVD-HCl-H2O and CVD-HBr-H2O salts confirmed the isostructurality between them, once their G

DOI: 10.1021/acs.cgd.9b00263 Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

Article

replaced by the CH···O one (Figure S7b). Similarly, this situation is the same for the enantiomers in CVD-HBr-H2O salt (Figure S8). Noteworthy, the OwH···O interaction associated with the 2-methoxyphenoxy moiety is more evident than in the hydrochloride salt, so red spots are observed on these groups on the HS of the hydrobromide salt. For both CVD-HCl-H2O and CVD-HBr-H2O salts, the fingerprint plots of the enantiomers are very similar (Figure 6a,b), as these molecules are involved in a similar crystalline environment. It is important to note that, the (di, de) pairs are more scattered (i.e., di = de = 1.2 Å) in the R-CVD+ plots than in the S-CVD+ ones. This finding shows that the S enantiomer is in a slightly more crowded environment than the R form. Regarding the intermolecular contacts contribution for the HS area, we observed that, indeed, the replacement of the S by R enantiomer provides a significant change in the H···O/O···H contact contribution as shown in Table S7. However, the other contactsH···H, H···N, H···A (A = Br− or Cl−), H···C and C···Cdo not differ significantly between the enantiomers in both CVD hydrochloride and hydrobromide salts. As expected, the HS of the CVD+ cation from CVD-OXA salt exhibits size and shape different from the halide salts reported here, showing the different chemical environments surrounding this molecule. Also, the HS analysis reveals very close intermolecular interactions associated with the hydroxyl and amine groups once the red spot is still on the O2 and N2 atoms. From the 2D fingerprint plot (Figure 6c), the H···H contacts represent the most significant contribution covering 51.9% of the overall HS (Figure S9). Since the structure is stabilized by NH···O, OH···O, and CH···π interactions, a significant contribution can also be seen from O···H/H···O and H···C/C···H contacts (see Table S7). 3.5. Infrared Spectroscopy. FT-IR spectra of CVD and its salts are shown in Figure 7. The spectra interpretation and band assignments (Table S1) were performed taking into account the structural features observed in the crystallographic analysis and the spectroscopic data available for related CVD compounds found in the literature.61−64 The main functional groups of CVD molecule are hydroxyl, secondary amine (aliphatic and cyclic), and ether. They exhibit IR stretching frequencies at 3343 cm−1 (hydroxyl O−H stretch), 3343 and

Figure 5. Experimental and calculated PXRD patterns of CVD and CVD salts.

experimental PXRD patterns show the presence of the main characteristic peaks in the same position at 2θ (Figure 5). 3.4. Hirshfeld Surface (HS) Analysis. HS of a molecule is an excellent tool for contact analysis in crystal structures.50,60 The HS of both R and S enantiomers from CVD-HCl-H2O and CVD-HBr-H2O SSEs and their corresponding 2D fingerprint plot derived from the HS ones are shown in Figure 6. The HS of the hydrochloride and hydrobromide CVD+ cations are very similar since their packings are isostructural and their conformations are practically identical to each other (see Figure 4). However, some differences have been observed on the HS around the chiral center when the R and S forms of each salt are compared (Figure 6). The remainder of the HS is very similar for both enantiomers. In CVD-HCl-H2O salt, the HS of the S enantiomer shows more incidence of red spots on the region of chiral carbon than those of the R one. In the S configuration, the red spots on the hydroxyl group correspond to the OH···Ow and NH···O interaction (Figure S7a). In the R configuration, on the other hand, the hydroxyl groups have the OH···Ow interaction

Figure 6. Hirshfeld surfaces (HS) and fingerprint plots of the nearest internal distance (di) versus the nearest external distance (de) for the R- and S-CVD+ enantiomers from (a) CVD-HCl-H2O, (b) CVD-HBr-H2O racemic SSEs. HS and fingerprint plot of CVD+ cation from CVD-OXA salt are shown in (c). Red spots and yellow arrows represent OH···O, NH···O, and CH···O H-bonds. The colors represent the frequency of many points that share the same (di, de) coordinate (light blue: many; dark blue: few). Close contacts are labeled as follows: (1) H···A (A = Cl− or Br−), (2) H···H, (3) H···O and (4) H···C. H

DOI: 10.1021/acs.cgd.9b00263 Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

Article

Figure 7. FT-IR spectra of CVD (black) and CVD salts: CVD-OXA (blue), CVD-HCl-H2O (green), and CVD-HBr-H2O (red).

Figure 8. TG and DSC curves of CVD and CVD salts.

3305 cm−1 (secondary amine N−H stretches), and 1040 and 1021 cm−1 (ether C−O stretches) in the CVD spectrum. Part of these stretching frequencies appear shifted in the FT-IR salt spectra due to protonation of the CVD molecule, confirming the salt formation. As expected, all salt spectra are affected by the nitrogen atom protonation of the CVD aliphatic secondary amine. The bands at 3343 and 3305 cm−1, assigned to the N−H stretching mode in the CVD spectrum, appear red-shifted to 3160 cm−1 (CVDHCl-H2O), 3178 cm−1 (CVD-HBr-H2O), and 3180 cm−1 (CVD-OXA) in the salt spectra. Moreover, for the CVDOXA salt, we observe characteristic bands associated with the anion vibrations. The spectrum shows new bands at 1586 and 1413 cm−1 attributed to the carboxylate (COO−) antisymmetric and symmetric stretching modes, respectively, since CVD as well as its other salts have no absorption bands in this region. Concerning the hydrochloride and hydrobromide hydrate salts, two weak absorption bands at 3515 and 3505

cm−1 characterize both spectra. These bands are attributed to the O−H stretching modes of water molecules. 3.6. Thermal Characterization. The thermal analysis and phase purity of CVD salts were assessed by a combination of DSC, TG, and HSM techniques. The DSC curves and the corresponding TG thermograms for CVD salts are shown in Figure 8. Overall, a single phase was obtained for all CVD salts since only characteristics endothermic peaks were observed in the DSC curves, which rule out any phase and/or polymorphic transition in the evaluated temperature ranges. For comparison purposes, the DSC/TG curves of CVD are also included in the plot. According to the TG curve, CVD is thermally stable up to 265 °C, and its DSC curve exhibits a single endothermic melting peak at 117.6 °C (Tonset = 114.5 °C, ΔH = −118.72 J· g−1). It is known that the thermal stability can be understood in terms of rupture of the crystal structure upon exposure to the heating process in a certain environment. Considering the I

DOI: 10.1021/acs.cgd.9b00263 Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

Article

SCXRD revealed that the R and S enantiomers of CVD display notable miscibility in the solid state, fulfilling the primary criterion for the formation of SSEs. In the CVD-HCl-H2O and CVD-HBr-H2O structures, due to symmetry (inversion center) and classical H-bonds (NH···Ow and OH···Ow) with water molecules, the interaction between R···R and S···S homochiral units (miscible with each other) leads to the formation of racemic SSEs. On the other hand, in the CVD-OXA structure, the formation of a standard racemic compound is related to the ability of the oxalate anions to recognize the R and S enantiomers of CVD via O−H···COO− H-bonds. As expected, the HS of both CVD+ enantiomers of CVD-HCl-H2O and CVD-HBr-H2O solid solutions are similar, which indicates that the miscibility between them is indeed favored in the solid state. The vibrational spectroscopic study and PXRD analysis were found to be congruent with the crystallographic analysis once from FT-IR spectra it was possible to confirm the salt formation, and, through PXRD patterns, the isostructurality between CVD-HCl-H2O and CVD-HBr-H2O salts could be confirmed. Besides, the TG/DSC curves showed that the CVD-HCl-H2O and CVD-HBr-H2O SSEs undergo dehydration and then melting, while the CVD-OXA salt just melts. These results are in good agreement with the HSM images. It is noteworthy that all the new salt phases exhibit lower thermal stability when compared to the neutral CVD. Regarding the impact of the results on the salts’ application, the three salt structures reported here not only extend the diversity of solid forms of CVD, but also provide insights to understand the intriguing mechanism of enantiomeric discrimination in the crystalline state. Therefore, it can be concluded that the structural elucidation and solid-state characterization of these new SSEs and racemic salts of CVD introduce valuable contributions to the pharmaceutical field since these findings can be beneficial for the understanding of the mechanisms of enantiomeric discrimination in crystals and for the enhancement of the physicochemical properties of carvedilol as well as of other chiral APIs.

decomposition and dehydration temperatures of the compounds, all new CVD salt phases exhibited lower thermal stability when compared to CVD raw material (polymorphic form II). The CVD-OXA DSC curve is characterized by a broad endothermic peak centered at 188.7 °C (Tonset = 167.1 °C, ΔH = −222.42 J·g−1), which was assigned to the melting/ degradation process. This event agrees with the mass loss that occurs in the TG curve, which begins at around 190 °C for CVD oxalate. As expected, because of isostructurality, the DSC curves of CVD hydrochloride and hydrobromide salts are similar to each other, and both exhibit two endothermic peaks. The first one is attributed to the salt dehydration (Tonset = 80.56 °C and ΔH = −90.06 J·g−1 for CVD-HCl-H2O and Tonset = 81.87 °C and ΔH = −38.70 J·g−1 for CVD-HBr-H2O), while the second one is assigned to the melting process (Tonset = 130.08 °C and ΔH = −45.22 J·g−1 for CVD-HCl-H2O and Tonset = 133.64 °C and ΔH = −69.34 J·g−1 for CVD-HBrH2O). These findings are in agreement with the TG curves, which show a first step of mass loss (at around 100 °C) of about 3.0% in both curves (loss of one water molecule from the crystalline lattice) and a second one (at approximately 250 °C) attributed to the thermal degradation of the samples. HSM experiments successfully confirmed the thermal events observed in the DSC/TG curves. From HSM images (Figure 9), it is possible to confirm that a single crystal of CVD, CVD-



ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.9b00263. Additional tables and figures from crystal structure analysis (including ASUs), crystallization experiments (images of crystalline habits) and solid-state characterization (isostructurality, ΔpKa of the reactions, and IR band assignments), as well as complementary information about the Hirshfeld surface analysis (2D fingerprint plots and relative contributions of the intermolecular contacts) of CVD salts (PDF)

Figure 9. Hot-stage microscopy images of (a) CVD, (b) CVD-OXA, (c) CVD-HCl-H2O, and (d) CVD-HBr-H2O single crystals.

OXA, CVD-HCl-H2O, and CVD-HBr-H2O start to melt/ decompose at around 115 °C, 170 °C, 130 °C, and 135 °C, respectively, and that above the corresponding melting or decomposition temperatures they become entirely melted into a liquid droplet. The images also show the darkening of the CVD-HCl-H2O and CVD-HBr-H2O crystals between 100− 120 °C, which are related to their dehydration process.

Accession Codes

CCDC 1899518−1899520 contain 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.

4. CONCLUSIONS In this study, we presented three salts of the antihypertensive drug CVD, two being racemic SSEs (CVD-HCl-H2O and CVD-HBr-H2O) and one racemic compound (CVD-OXA), obtained from the reaction of racemic CVD with pharmaceutically acceptable acids (HCl, HBr, and oxalic). The crystallization of these solid forms has been achieved by slow evaporation of solvent, and their structure elucidation by



AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. J

DOI: 10.1021/acs.cgd.9b00263 Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

Article

ORCID

(18) Rollinger, J. M.; Burger, A. Polymorphism of Racemic Felodipine and the Unusual Series of Solid Solutions in the Binary System of Its Enantiomers. J. Pharm. Sci. 2001, 90, 949−959. (19) Zhang, G. G. Z.; Paspal, S. Y. L.; Suryanarayanan, R. A. J.; Grant, D. J. W. Racemic Species of Sodium Ibuprofen: Characterization and Polymorphic Relationships. J. Pharm. Sci. 2003, 92, 1356− 1366. (20) Rekis, T.; Berzinš, A.; Džabijeva, D.; Nakurte, I.; Orola, L.; Actinš, A. Structure and Stability of Racemic and Enantiopure Pimobendan Monohydrates: On the Phenomenon of Unusually High Stability. Cryst. Growth Des. 2017, 17, 1814−1823. (21) Goldberg, A. H.; Gibaldi, M.; Kanig, J. L. Increasing Dissolution Rates and Gastrointestinal Absorption of Drugs via Solid Solutions and Eutectic Mixtures II: Experimental Evaluation of a Eutectic Mixture: Urea-acetaminophen System. J. Pharm. Sci. 1966, 55, 482−487. (22) Goldberg, A. H.; Gibaldi, M.; Kanig, J. L.; Mayersohn, M. Increasing Dissolution Rates and Gastrointestinal Absorption of Drugs via Solid Solutions and Eutectic Mixtures IV: Chloramphenicolurea System. J. Pharm. Sci. 1966, 55, 581−583. (23) Goldberg, A. H.; Gibaldi, M.; Kanig, J. L. Increasing Dissolution Rates and Gastrointestinal Absorption of Drugs via Solid Solutions and Eutectic Mixtures III: Experimental Evaluation of Griseofulvinsuccinic Acid Solid Solution. J. Pharm. Sci. 1966, 55, 487−492. (24) Coquerel, G. Review on The Heterogeneous Equilibria Between Condensed Phases in Binary Systems of Enantiomers. Enantiomer 2000, 5, 481−498. (25) Kaemmerer, H.; Lorenz, H.; Black, S. N.; Seidel-Morgenstern, A. Study of System Thermodynamics and the Feasibility of Chiral Resolution of the Polymorphic System of Malic Acid Enantiomers and its Partial Solid Solutions. Cryst. Growth Des. 2009, 9, 1851− 1862. (26) Lodochnikova, O. A.; Kosolapova, L. S.; Saifina, A. F.; Gubaidullin, A. T.; Fayzullin, R. R.; Khamatgalimov, A. R.; Litvinov, I. A.; Kurbangalieva, A. R. Structural Aspects of Partial Solid Solution Formation: Two Crystalline Modifications of a Chiral Derivative of 1,5-dihydro-2 H-pyrrol-2-one Under Consideration. CrystEngComm 2017, 19, 7277−7286. (27) Bredikhin, A. A.; Bredikhina, Z. A.; Zakharychev, D. V.; Gubaidullin, A. T.; Fayzullin, R. R. Chiral Drug Timolol Maleate as a Continuous Solid Solution: Thermochemical andSingle Crystal X-ray Evidence. CrystEngComm 2012, 14, 648−655. (28) Fayzullin, R. R.; Zakharychev, D. V.; Gubaidullin, A. T.; Antonovich, O. A.; Krivolapov, D. B.; Bredikhina, Z. A.; Bredikhin, A. A. Intricate Phase Behavior and Crystal Structure Features of Chiral para-Methoxyphenyl Glycerol Ether Forming Continuous and Partial Solid Solutions. Cryst. Growth Des. 2017, 17, 271−283. (29) Rekis, T.; Berzinš, A.; Orola, L.; Holczbauer, T.; Actinš, A.; Seidel-Morgenstern, A.; Lorenz, H. Single Enantiomer’s Urge to Crystallize in Centrosymmetric Space Groups: Solid Solutions of Phenylpiracetam. Cryst. Growth Des. 2017, 17, 1411−1418. (30) Rekis, T.; Berzinš, A.; Sarceviča, I.; Kons, A.; Balodis, M.; Orola, L.; Lorenz, H.; Actinš, A. A Maze of Solid Solutions of Pimobendan Enantiomers: An Extraordinary Case of Polymorph and Solvate Diversity. Cryst. Growth Des. 2018, 18, 264−273. (31) Rekis, T.; D’Agostino, S.; Braga, D.; Grepioni, F. Designing Solid Solutions of Enantiomers: Lack of Enantioselectivity of Chiral Naphthalimide Derivatives in the Solid State. Cryst. Growth Des. 2017, 17, 6477−6485. (32) Ruffolo, R. R., Jr.; Feuerstein, G. Z. Pharmacology of Carvedilol: Rationale for Use in Hypertension, Coronary Artery Disease, and Congestive Heart Failure. Cardiovasc. Drugs Ther. 1997, 11, 247−256. (33) Hamed, R.; Awadallah, A.; Sunoqrot, S.; Tarawneh, O.; Nazzal, S.; AlBaraghthi, T.; Al Sayyad, J.; Abbas, A. pH-Dependent Solubility and Dissolution Behavior of CarvedilolCase Example of a Weakly Basic BCS Class II Drug. AAPS PharmSciTech 2016, 17, 418−426.

Luan F. Diniz: 0000-0003-4702-9065 Paulo S. Carvalho, Jr.: 0000-0002-5551-9155 Christian Fernandes: 0000-0002-3905-3674 Notes

The authors declare no competing financial interest.



ACKNOWLEDGMENTS The authors acknowledge the Brazilian funding agencies CAPES, FAPEMIG, and CNPq (420052/2018-6 and 307599/2017-5) for financial support. The authors would like to thank Dra. Charlane Cimini Correa (Federal University of Juiz de Fora) for allowing access to the single-crystal X-ray diffraction facility. We also thank Matheus da Silva Souza (IFSC/USP) for his help in the Hot-Stage Microscopy analyzes.



REFERENCES

(1) Serajuddin, A. T. M. Salt Formation to Improve Drug Solubility. Adv. Drug Delivery Rev. 2007, 59, 603−616. (2) Schultheiss, N.; Newman, A. Pharmaceutical Cocrystals and Their Physicochemical Properties. Cryst. Growth Des. 2009, 9, 2950− 2967. (3) Duggirala, N. K.; Perry, M. L.; Almarsson, O.; Zaworotko, M. J. Pharmaceutical Cocrystals: Along the Path To Improved Medicines. Chem. Commun. 2016, 52, 640−655. (4) Davies, G. Changing the Salt, Changing the Drug. Pharm. J. 2001, 266, 322−323. (5) Kitaigorodsky, A. Mixed Crystals; Springer, 1984, 1−390. (6) Wermester, N.; Aubin, E.; Pauchet, M.; Coste, S.; Coquerel, G. Preferential Crystallization in an Unusual Case of Conglomerate with Partial Solid Solutions. Tetrahedron: Asymmetry 2007, 18, 821−831. (7) Jacques, J.; Collet, A.; Wilen, S. Enantiomers, Racemates and Resolutions; Wiley, 1981; pp 1−447. (8) Srisanga, S.; Ter Horst, J. H. Racemic Compound, Conglomerate, or Solid Solution: Phase Diagram Screening of Chiral Compounds. Cryst. Growth Des. 2010, 10, 1808−1812. (9) Huang, J.; Chen, S.; Guzei, I. A.; Yu, L. Discovery of a Solid Solution of Enantiomers in a Racemate-Forming System by Seeding. J. Am. Chem. Soc. 2006, 128, 11985−11992. (10) Chion, B.; Lajzerowicz, J.; Bordeaux, D.; Collet, A.; Jacques, J. Structural Aspects of Solid Solutions of Enantiomers. The 3Hydroxymethyl- and 3-Carboxy-2,2,5,5-Tetramethylpyrrolidinyl 1Oxyl Systems as Examples. J. Phys. Chem. 1978, 82, 2682−2688. (11) Rekis, T.; Berzinš, A. On the Structural Aspects of Solid Solutions of Enantiomers: An Intriguing Case Study of Enantiomer Recognition in the Solid State. CrystEngComm 2018, 20, 6909−6918. (12) Brandel, C.; Petit, S.; Cartigny, Y.; Coquerel, G. Structural Aspects of Solid Solutions of Enantiomers. Curr. Pharm. Des. 2016, 22, 4929−4941. (13) Murakami, H. From Racemates to Single Enantiomers − Chiral Synthetic Drugs over the Last 20 Years. Top. Curr. Chem. 2006, 269, 273−299. (14) An, G.; Yan, P.; Sun, J.; Li, Y.; Yao, X.; Li, G. The Racemate-toHomochiral Approach to Crystal Engineering via Chiral Symmetry Breaking. CrystEngComm 2015, 17, 4421−4433. (15) Bredikhin, A. A.; Zakharychev, D. V.; Gubaidullin, A. T.; Fayzullin, R. R.; Pashagin, A. V.; Bredikhina, Z. A. Crystallization Features of the Chiral Drug Timolol Precursor: The Rare Case of Conglomerate with Partial Solid Solutions. Cryst. Growth Des. 2014, 14, 1676−1683. (16) Lorenz, H.; Seidel-Morgenstern, A. Processes to Separate Enantiomers. Angew. Chem., Int. Ed. 2014, 53, 1218−1250. (17) de Diego, H. L.; Bond, A. D.; Dancer, R. J. Chirality 2011, 23, 408−416. K

DOI: 10.1021/acs.cgd.9b00263 Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

Article

New Modeling Approach for Solubility and Supersaturation. Chem. Eng. Sci. 2011, 66, 88−102. (56) Hursthouse, M. B.; Huth, L. S.; Threlfall, T. L. Why Do Organic Compounds Crystallise Well or Badly or Ever so Slowly? Why Is Crystallisation Nevertheless Such a Good Purification Technique? Org. Process Res. Dev. 2009, 13, 1231−1240. (57) Remenar, J. F.; Peterson, M. L.; Stephens, P. W.; Zhang, Z.; Zimenkov, Y.; Hickey, M. B. Celecoxib:Nicotinamide Dissociation: Using Excipients to Capture the Cocrystal’s Potential. Mol. Pharmaceutics 2007, 4, 386−400. (58) Thakral, N. K.; Zanon, R. L.; Kelly, R. C.; Thakral, S. Applications of Powder X-Ray Diffraction in Small Molecule Pharmaceuticals: Achievements and Aspirations. J. Pharm. Sci. 2018, 107, 2969−2982. (59) Wood, P. A.; Oliveira, M. A.; Zink, A.; Hickey, M. B. Isostructurality in Pharmaceutical Salts: How Often and How Similar? CrystEngComm 2012, 14, 2413−2421. (60) Wood, P. A.; McKinnon, J. J.; Parsons, S.; Pidcock, E.; Spackman, M. A. Analysis of the Compression of Molecular Crystal Structures Using Hirshfeld Surfaces. CrystEngComm 2008, 10, 368− 376. (61) Marques, M. P. M.; Oliveira, P. J.; Moreno, A. J. M.; Batista De Carvalho, L. A. E. Study of Carvedilol by Combined Raman Spectroscopy and Ab Initio MO Calculations. J. Raman Spectrosc. 2002, 33, 778−783. (62) Jagannathan, L.; Meenakshi, R.; Gunasekaran, S.; Srinivasan, S. FT-IR, FT-Raman and UV-Vis Spectra and Quantum Chemical Investigation of Carvedilol. Mol. Simul. 2010, 36 (4), 283−290. (63) Hiendrawan, S.; Widjojokusumo, E.; Veriansyah, B.; Tjandrawinata, R. R. Pharmaceutical Salts of Carvedilol: Polymorphism and Physicochemical Properties. AAPS PharmSciTech 2017, 18, 1417−1425. (64) Prado, L. D.; Santos, A. B. X.; Rocha, H. V. A.; Ferreira, G. B.; Resende, J. A. L. C. Vibrational Spectroscopic and Hirshfeld Surface Analysis of Carvedilol Crystal Forms. Int. J. Pharm. 2018, 553, 261− 271.

(34) Morgan, T. Clinical Pharmacokinetics and Pharmacodynamics of Carvedilol. Clin. Pharmacokinet. 1994, 26, 335−346. (35) Zhang, Y.; Zhi, Z.; Li, X.; Gao, J.; Song, Y. Carboxylated Mesoporous Carbon Microparticles as New Approach to Improve the Oral Bioavailability of Poorly Water-Soluble Carvedilol. Int. J. Pharm. 2013, 454, 403−411. (36) Wei, L.; Sun, P.; Nie, S.; Pan, W. Preparation and Evaluation of SEDDS and SMEDDS Containing Carvedilol. Drug Dev. Ind. Pharm. 2005, 31, 785−794. (37) Wen, X.; Tan, F.; Jing, Z.; Liu, Z. Preparation and Study the 1:2 Inclusion Complex of Carvedilol with β-Cyclodextrin. J. Pharm. Biomed. Anal. 2004, 34, 517−523. (38) Liu, D.; Xu, H.; Tian, B.; Yuan, K.; Pan, H.; Ma, S.; Yang, X.; Pan, W. Fabrication of Carvedilol Nanosuspensions Through the Anti-Solvent Precipitation−Ultrasonication Method for the Improvement of Dissolution Rate and Oral Bioavailability. AAPS PharmSciTech 2012, 13, 295−304. (39) Prado, L. D.; Rocha, H. V. A.; Resende, J. A. L. C.; Ferreira, G. B.; De Figuereido Teixeira, A. M. R. An Insight into Carvedilol Solid Forms: Effect of Supramolecular Interactions on the Dissolution Profiles. CrystEngComm 2014, 16, 3168−3179. (40) Vogt, F. G.; Copley, R. C. B.; Mueller, R. L.; Spoors, G. P.; Cacchio, T. N.; Carlton, R. A.; Katrincic, L. M.; Kennady, J. M.; Parsons, S.; Chetina, O. V. Isomorphism, Disorder, and Hydration in the Crystal Structures of Racemic and Single-Enantiomer Carvedilol Phosphate. Cryst. Growth Des. 2010, 10, 2713−2733. (41) CrysAlisPRO; Agilent Technologies UK Ltd: Yarnton, England, 2014. (42) Dolomanov, O. V.; Bourhis, L. J.; Gildea, R. J.; Howard, J. A. K.; Puschmann, H. OLEX2: A Complete Structure Solution, Refinement and Analysis Program. J. Appl. Crystallogr. 2009, 42, 339−341. (43) Sheldrick, G. M. SHELXT−Integrated Space-group and Crystal-Structure Determination. Acta Crystallogr., Sect. A: Found. Adv. 2015, 71, 3−8. (44) Sheldrick, G. M. Crystal Structure Refinement with SHELXL. Acta Crystallogr., Sect. C: Struct. Chem. 2015, 71, 3−8. (45) Macrae, C. F.; Edgington, P. R.; McCabe, P.; Pidcock, E.; Shields, G. P.; Taylor, R.; Towler, M.; Van De Streek, J. Mercury: Visualization and Analysis of Crystal Structures. J. Appl. Crystallogr. 2006, 39, 453−457. (46) Farrugia, L. J. WinGX and ORTEP for Windows: An Update. J. Appl. Crystallogr. 2012, 45, 849−854. (47) Groom, C. R.; Bruno, I. J.; Lightfoot, M. P.; Ward, S. C. The Cambridge Structural Database. Acta Crystallogr., Sect. B: Struct. Sci., Cryst. Eng. Mater. 2016, 72, 171−179. (48) Spackman, M. A.; Jayatilaka, D. Hirshfeld Surface Analysis. CrystEngComm 2009, 11, 19−32. (49) McKinnon, J. J.; Jayatilaka, D.; Spackman, M. a. Towards Quantitative Analysis of Intermolecular Interactions with Hirshfeld Surfaces. Chem. Commun. 2007, 37, 3814−3816. (50) McKinnon, J. J.; Spackman, M. A.; Mitchell, A. S. Novel Tools for Visualizing and Exploring Intermolecular Interactions in Molecular Crystals. Acta Crystallogr., Sect. B: Struct. Sci. 2004, 60, 627−668. (51) Stojanović, J.; Vladimirov, S.; Marinković, V.; Veličković, D.; Sibinović, P. Monitoring of the Photochemical Stability of Carvedilol and Its Degradation Products by the RP-HPLC Method. J. Serb. Chem. Soc. 2007, 72, 37−44. (52) Childs, S. L.; Stahly, G. P.; Park, A. The Salt-Cocrystal Continuum: The Influence of Crystal Structure on Ionization State. Mol. Pharmaceutics 2007, 4, 323−338. (53) Saal, C.; Becker, A. European Journal of Pharmaceutical Sciences Pharmaceutical Salts : A Summary on Doses of Salt Formers from the Orange Book. Eur. J. Pharm. Sci. 2013, 49, 614−623. (54) Back, K. R.; Davey, R. J.; Grecu, T.; Hunter, C. A.; Taylor, L. S. Molecular Conformation and Crystallization: The Case of Ethenzamide. Cryst. Growth Des. 2012, 12, 6110−6117. (55) Derdour, L.; Pack, S. K.; Skliar, D.; Lai, C. J.; Kiang, S. Crystallization from Solutions Containing Multiple Conformers: A L

DOI: 10.1021/acs.cgd.9b00263 Cryst. Growth Des. XXXX, XXX, XXX−XXX