Chiral Resolution of RS-Praziquantel via Diastereomeric Co-Crystal

Article pubs.acs.org/crystal

Chiral Resolution of RS-Praziquantel via Diastereomeric Co-Crystal Pair Formation with L‑Malic Acid Obdulia Sánchez-Guadarrama,† Fabiola Mendoza-Navarro,† Alberto Cedillo-Cruz,‡ Helgi Jung-Cook,‡ Jenniffer I. Arenas-García,† Alejandra Delgado-Díaz,§ Dea Herrera-Ruiz,*,§ Hugo Morales-Rojas,† and Herbert Höpfl*,† †

Centro de Investigaciones Químicas, IICBA, and §Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Av. Universidad 1001, Cuernavaca 62209, México ‡ Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Cd. Universitaria, Coyoacán 04510, México S Supporting Information *

ABSTRACT: Praziquantel (PZQ) is an important chiral active pharmaceutical ingredient for the treatment of gastrointestinal parasites, which is commercially available only in the form of its racemate. In this article, on the basis of co-crystallization experiments a convenient two-step protocol for the chiral resolution of RS-PZQ is described. Screening experiments with RS-PZQ using the liquid-assisted grinding technique revealed the formation of a diastereomeric co-crystal pair with L-malic acid (L-MA) of the compositions R-PZA:L-MA and S-PZQ:L-MA. Both co-crystals have been examined by single-crystal X-ray diffraction analysis, revealing similar unit cell parameters but differences in the supramolecular organization. Particularly the analysis of the hydrogen bonding patterns indicated overall stronger intermolecular interactions in the case of R-PZA:L-MA, which was confirmed by thermogravimetric−differential scanning calorimetry analysis giving a substantial difference in the melting point when compared to S-PZA:L-MA. After synthesis of R- and S-PZQ in enantiomerically pure form for the selective preparation of both R-PZA:L-MA and S-PZQ:L-MA, comparative solubilization experiments were carried out. Since significant variations in the solubility were found in some solvents, a procedure could be established allowing for the separation of R-PZA:L-MA by fractional crystallization. In a subsequent reaction step, the biologically active enantiomer R-PZQ was liberated from the co-crystal in the form of its hemihydrate by stirring with water. Comparison of the intrinsic dissolution rates for RS-PZQ, R-PZA·0.5H2O, and R-PZA:L-MA indicated that the co-crystalline phase exhibits a significantly larger rate constant than praziquantel in its enantiomerically pure form or as a racemate.

1. INTRODUCTION For biologically active compounds with chiral carbon atoms, frequently only one enantiomer is functional. Since the complementary stereoisomer can constitute an unnecessary burden for the metabolism of the organism or even be harmful, it is preferable to distribute such substances in enantiomerically pure form. For active pharmaceutical ingredients (APIs), this principle is strongly recommended by the most representative drug-regulatory instances.1 The main strategies for the preparation of enantiomerically pure chemicals consist of asymmetric synthesis2,3 and chiral resolution of the racemic mixture,4 which can increment the production costs significantly. Chiral resolution can be achieved via column chromatography or chemical transformation of the racemate to diastereomeric substances having different physical and physicochemical properties. For the latter, a common strategy consists of salt formation using chiral Brønsted acids or bases followed by fractional crystallization or solvent extraction.4 Nevertheless, the exposure to acids/bases can cause partial or complete chemical racemization5 and, most importantly, is not effective for compounds that lack functional groups suitable for © 2015 American Chemical Society

salt formation, which is common for APIs. In this context, chiral resolution via co-crystal formation, viz. the incorporation of two or more solid compounds into a single-phase crystalline solid, becomes an interesting alternative, which has been little explored so far.6−20 For chiral resolution via co-crystallization two strategies are envisioned. The first one consists of the generation of a host matrix from a chiral compound with cavities for the selective inclusion of only one enantiomer of the target molecule.6−12 The second aims at the formation of a true two-component crystal lattice, in which an enantiopure coformer such as L-malic acid, L-mandelic acid, L-lactic acid, L-tartaric acid, etc. coexists with the desired enantiomer.12−20 For this option two scenarios are possible: (i) the enantiopure coformer forms a co-crystal only with one enantiomer of the target (enantiospecific co-crystal formation) or (ii) it forms co-crystals with each enantiomer giving a diastereomeric co-crystal pair.19,20 In a theoretical study Received: August 28, 2015 Revised: November 4, 2015 Published: November 9, 2015 307

DOI: 10.1021/acs.cgd.5b01254 Cryst. Growth Des. 2016, 16, 307−314

Crystal Growth & Design

Article

Sample Characterization. IR Spectroscopy. IR spectra have been recorded on a FT-IR NICOLET 6700 ThermoScientific spectrophotometer and measured in the range of 4000−400 cm−1 using the Smart iTR accessory with a diamond ATR crystal. UV−vis Spectroscopy. UV−vis spectra have been acquired using a VARIAN UV CARY 50 spectrophotometer. Thermogravimetric Analysis and Differential Scanning Calorimetry. Measurements were realized with a SDT Q600 TA Instrument. Samples of approximately 3 mg were placed into aluminum pans and analyzed in the temperature range of 25−400 °C with a heating rate of 10 °C/min and using a current of 50 mL/min nitrogen as inert gas purge. HPLC Analysis. The chiral HPLC analysis was performed with an Agilent 1100 system equipped with an online vacuum degasser model G1322A, a quaternary pump model G1311A, a variable wavelength detector model G1314A, a thermostated column compartment model G1316A, an autosampler model G1377A, and an autosampler thermostat model G1330A. A CHIRACEL OD-H column (length, 250 mm; internal diameter, 4.6 mm; particle size, 5 μm) was used at a temperature of 40 °C. The mobile phase consisted of heptane and isopropyl alcohol (82.5:17.5, v/v), which was employed at a flow rate of 1.5 mL/min. The column effluent was monitored at 210 nm. Data were collected and processed on a PC equipped with the ChemStation software. The measured retention times for R-PZQ and S-PZQ were 7.3 and 9.5 min, respectively (resolution 2.6). A standard stock solution was prepared as follows: 20.0 mg of S-PZQ were weighed into a 100 mL volumetric flask and diluted with ethanol. Then, the stock solution was diluted further with ethanol to generate standard working solutions of 0.1, 0.2, 0.5, 1.0, 2.0, 4.0, and 8.0%. For the preparation of the identification solutions, 20 mg of R-PZQ (28.6 mg for R-PZA:L-MA) were weighed into a 10 mL volumetric flask and diluted with ethanol. Twenty microliters of the samples was injected. All solutions were stored at 4 °C and protected from light. Powder and Single-Crystal X-ray Diffraction Analysis. Powder X-ray diffraction (PXRD) was performed in the transmission mode on a BRUKER D8-ADVANCE diffractometer equipped with a LynxEye detector (λCuKα1 = 1.5406 Å, monochromator: germanium). The equipment was operated at 40 kV and 40 mA, and data were collected at room temperature in the range of 2θ = 5−50°. Single-crystal X-ray diffraction studies were carried out on an Agilent Technologies SuperNova diffractometer equipped with a CCD area detector (EosS2) using Mο-Kα radiation (λ = 0.71073 Å) from a microfocus X-ray source and an Oxford Instruments Cryojet cooler. Frames were collected at T = 295 K. The measured intensities were reduced to F2 and corrected for absorption using spherical harmonics (CryAlisPro).37 Intensities were corrected for Lorentz and polarization effects. Structure solution, refinement, and data output were performed with the OLEX238 program package using SHELXL-201439 for the refinement. Nonhydrogen atoms were refined anisotropically. All hydrogen atoms were placed in geometrically calculated positions using the riding model. Simulated PXRD patterns and hydrogen-bonding interactions in the crystal lattice were calculated with the WINGX program package. DIAMOND was used for the creation of figures.40 Crystallographic data for the two crystal structures have been deposited with the Cambridge Crystallographic Data Centre as supplementary publications nos. 1419900−1419901. Copies of the data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: (+44) 1223-336-033; e-mail: [email protected], http://www.ccdc.cam.ac.uk). Solution Phase Stability. 500 mg of the respective co-crystalline solid phases were exposed directly to 100 μL of deionized water. The resulting suspension was stirred at room temperature for 60 min and then filtered under a vacuum and characterized by PXRD. All experiments were carried out in duplicate. Intrinsic Dissolution Rate. Samples (130 mg) of RS-PZQ, R-PZQ· 0.5H2O, R-PZQ:L-MA were compressed into a disk with a surface area of 0.5 cm2 using a hydraulic press (Zhermack, C305800 PO3) at a total force of 30 kg/cm2 (30 s). The resulting products were subsequently placed in Wood’s apparatus (VARIAN, VK7010) and

Habgood examined both options with the conclusion that potentially resolving coformers should form a strong primary interaction motif with the target and, additionally, energetically relevant second-level interaction patterns, which will be disrupted if one enantiomer is exchanged for the other.20 Because of structural modifications in the supramolecular assembly in enantiospecific and diastereomeric co-crystal pairs, the crystal lattice energy and related physical and physicochemical properties such as the melting point and the solubility will change, thus enabling separation. Enantiospecific and diastereomeric co-crystal formation can also be an interesting tool for other applications, such as the determination of the absolute stereochemistry.21 Pharmaceutical co-crystals have been studied extensively during the past decade, and it is now well-established that they can exhibit improved biopharmaceutically relevant properties, such as solubility, dissolution rate, stability, hygroscopicity, etc., and provide even pharmacotechnical advantages for the product.22−28 Praziquantel (PZQ) is an important API for the treatment of gastrointestinal parasites29,30 and classified by the WHO as an essential drug.31 In spite of the widespread use, PZQ is commercially available only as a racemate (RS-PZQ). The biologically active component is R-PZQ and the bitter taste of the drug has been attributed to the S-enantiomer.32 Moreover, PZQ exhibits low solubility under physiological conditions (0.40 mg/mL in water at 25 °C),33 which requires the prescription of relatively large doses in order to achieve effective levels in the systemic circulation making it particularly problematic for children.31,32 Since this API is employed in developing countries in preventive chemotherapy as part of the global strategy for the combat of schistosomiasis,34 the WHO’s Special Program for Research and Training in Tropical Diseases has established the low-cost preparation of R-PZQ as a key priority.35 Because of the lack of acid/base functional groups, chiral resolution of RS-PZQ cannot be achieved via salt formation, and attempts via chiral chromatography, asymmetric synthesis, or chemical transformation have apparently not been economically attractive for the pharmaceutical industry.30,35 Taking into account these aspects as well as the emerging interest in chiral resolution via co-crystal formation, the main objective of the present contribution consisted of achieving the chiral resolution of RS-PZQ via co-crystallization. Previously, it has been documented that RS-PZQ is an ideal candidate for co-crystal formation with aliphatic dicarboxylic acids,36 and we report now on an easy achievable and complete procedure for the chiral resolution of RS-PZQ via co-crystal formation with L-malic acid (L-MA), which in the future might be extended to other chiral APIs and biologically active compounds.

2. EXPERIMENTAL SECTION Sample Preparation. Chemicals. RS-PZQ, all co-crystal formers, and solvents were commercially available from Sigma-Aldrich Company and were used as received without further purification. Preparative Part. For the preparation of the co-crystals, liquidassisted grinding experiments were performed by mechanical grinding in a Retsch MM400 mixer mill (30 min at 25 Hz) using stainless steel grinding jars (1.5 mL). Before starting, 10 μL of acetone were added to approximately 50 mg of a 1:1 stoichiometric mixture of PZQ and the co-crystal former. The resulting powder was distributed on a filter paper and air-dried. Single-Crystal Growth. Crystals of R-PZQ:L-MA and S-PZQ:L-MA suitable for single-crystal X-ray diffraction analysis were grown from solutions in acetone by slow solvent evaporation at room temperature. 308



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rotated at 100 rpm in 300 mL of a vacuum-filtered and degassed medium (0.1 N HCl, pH = 1.2) at 37 °C. Experiments were carried out in triplicate. Aliquots of dissolution samples (3 mL) were taken at intervals of 1, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, and 180 min and analyzed by UV−vis spectroscopy at a wavelength of 217 nm. The amount of PZQ dissolved in the dissolution rate determinations was derived from a previously established calibration curve for PZQ (r = 0.999). For the generation of this curve, the co-crystal former L-MA was not considered, since the reagent does not absorb in this region. Each volume sample extracted from the dissolution experiment was replaced with an equal volume of fresh medium (3 mL). The resulting dissolution profiles were generated using the ORIGIN PRO 8.1 software package.

3. RESULTS AND DISCUSSION Screening and Co-Crystal Phase Identification. Following the strategy proposed by Jones et al., initial co-crystal screening experiments with RS-PZQ were performed using the liquid-assisted grinding technique17 in the presence of L-malic, L-lactic, L-tartaric, and L-mandelic acid. With exception of L-mandelic acid, all co-crystal formers exhibited reactivity, and the formation of novel solid phases was evidenced by PXRD analysis (Figure 1, Figure S1).

Figure 2. PXRD patterns of R-PZQ:L-MA, S-PZQ:L-MA, and the mixture of R-PZQ:L-MA and S-PZQ:L-MA obtained by LAG with 10 μL of acetone using 1:1 stoichiometry.

In the case of the co-crystallization experiments with L-tartaric (L-TA) and L-lactic (L-LA) acid, PXRD patterns different from those observed for the corresponding grinding experiments with enantiomerically pure R-PZQ and S-PZQ were measured (Figure 4 and Figure S2).41 Since peaks for the starting materials were absent, it is assumed that co-crystalline phases containing both R-PZQ and S-PZQ were formed. Because chiral resolution cannot be achieved from such phases, these samples were not further explored. Structural Analysis of the Diastereomeric Co-Crystal Pair. Fortunately, crystallization conditions could be established for the growth of single-crystals of R-PZQ:L-MA and S-PZQ:L-MA, and fragments of the crystal lattices are shown in Figures 5 and 6. A comparison of the experimental and PXRD patterns simulated from the SXRD analyses is given in Figure S3. R-PZQ:L-MA and S-PZQ:L-MA crystallized in the same space group (P21) and have similar unit cell parameters (Table 1). The primary supramolecular interactions in the diastereomeric co-crystal pair consist of CO···H−O hydrogen bonds formed between the amide functions of PZQ and the carboxylic acid groups of L-MA, which acquire some double-bridge character due to a secondary (N)C−H···OC interaction (motif I, Figure 5, Table 2). This heterosynthon seems to be characteristic for co-crystals of PZQ with aliphatic carboxylic acids, since it has been observed in almost all previously reported co-crystals with this API.36 Since both amide groups of the PZQ molecules are involved in the formation of motif I, 1D linear chains of similar topology are generated. Nevertheless, there are important differences regarding the second-level intermolecular connectivity. In R-PZQ:L-MA, the coformer molecules are connected through O−H···O hydrogen bonds into 1D chains of 21-symmetry along b, which are additionally stabilized by weaker C−H···O contacts (motif II, Figure 6, Table 2). In the third dimension, the crystal structure is stabilized by a total of five crystallographically independent C−H···O contacts and one C−H···π interaction (Figure S4a, Table 2). On the contrary, in S-PZQ:L-MA the coformer molecules do not exhibit short intermolecular contacts between each other, and the crystal structure is stabilized only by three C−H···O and two C−H···π contacts formed between the one-dimensional S-PZQ:L-MA strands (Figure S4b, Table 2).

Figure 1. PXRD patterns of RS-PZQ, L-MA and the mixture of R-PZQ:L-MA and S-PZQ:L-MA obtained by LAG with 10 μL of acetone using 1:1 stoichiometry.

Assuming co-crystal formation for at least one of the enantiomers of RS-PZQ and the absence of solvent in the crystal lattice, and considering that either enantiospecific or diastereomeric co-crystal formation can occur, at least three options arise for the composition of the resulting solid mixture: (i) R-PZQ:L-coformer + S-PZQ, (ii) S-PZQ:L-coformer + R-PZQ, and (iii) R-PZQ:L-coformer + S-PZQ:L-coformer. Because of this, for an undoubted determination of the correct composition of the solid phases, we synthesized R-PZQ and S-PZQ in enantiomerically pure form according to a previously reported synthetic strategy.30 The compounds were isolated as hemihydrates and enabled to establish the products formed from RS-PZQ and L-malic (L-MA). Mechanic liquid-assisted grinding experiments of L-MA with R-PZQ·0.5H2O and S-PZQ·0.5H2O, respectively, provided novel solid phases, which according to the PXRD patterns (Figure 2) and IR-spectra (Figure 3) do not exhibit residues of crystalline starting material. Moreover, as seen from Figure 2, these two phases represent the product obtained from the analogous grinding experiment with the RS-PZQ racemate, indicating that it comprises a mixture of the diastereomeric co-crystals R-PZQ:L-MA + S-PZQ:L-MA. 309



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Figure 3. IR spectra of L-MA, R-PZQ·0.5H2O, S-PZQ·0.5H2O, R-PZQ:L-MA, and S-PZQ:L-MA.

Figure 4. PXRD patterns of the following samples and experiments: RS-PZQ, R-PZQ·0.5H2O, S-PZQ·0.5H2O, L-TA, R-PZQ:L -TA, S-PZQ:L-TA, and RS-PZQ:L-TA. Note: R-PZQ:L-TA, S-PZQ:L-TA, and RS-PZQ:L-TA were prepared by LAG with 10 μL of acetone using 1:1 stoichiometry.

Separation of R-PZQ:L-MA and S-PZQ:L-MA. The larger thermodynamic stability of R-PZQ:L-MA is confirmed by the TG-DSC analysis given in Figure 7, which provided a larger melting point for this co-crystal diastereomer (Tpeak = 153.6 °C) when compared to S-PZQ:L-MA (Tpeak = 126.8 °C). As a consequence, differences in other biopharmaceutically relevant physical properties such as the solubility can be expected. Table 3 provides an overview of a qualitative examination of the solubility of R-PZQ:L-MA and S-PZQ:L-MA in solvents of varying polarity, showing that the phase mixture is insoluble in water and nonpolar solvents such as ethers and hexane. Good solubility was established in polar solvents such as alcohols and acetone, and medium to low solubility was observed in tetrahydrofuran, ethyl acetate, and chloroform. Moreover, when using acetone, ethyl acetate, and chloroform significant differences in the solubility were observed. On the basis of these observations and considering additional parameters relevant for industrial applications (cost and toxicity), acetone and ethyl acetate were chosen to establish a procedure suitable for the separation of the diastereomeric co-crystal mixture via fractional crystallization. For a more precise determination of the solubilization extent, 50 μL portions of acetone or EtOAc, respectively, were added under stirring at intervals of 5 min to vials containing either 50 mg of R-PZQ:L-MA or S-PZQ:L-MA until complete dissolution was achieved. As expected, R-PZQ:L-MA was less soluble in both solvents and required

Figure 5. Perspective views of the 1D chains in the crystal structures of (a) R-PZQ:L-MA and (b) S-PZQ:L-MA.

Figure 6. In R-PZQ:L-MA, the coformer molecules are connected through O−H···O hydrogen bonds (motif II) into 1D chains of 21-symmetry along b.

820 μL of acetone and 4200 μL of ethyl acetate for complete dissolution under these conditions (versus 600 and 2200 μL for S-PZQ:L-MA). On the basis of this marked difference, a fractional crystallization experiment could be set up. 1.00 g of 310



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Table 1. Crystallographic Data for Compounds S-PZQ:L-MA and R-PZQ:L-MA crystal dataa

S-PZQ:L-MA

R-PZQ:L-MA

formula MW (g mol−1) T (K) space group a (Å) b (Å) c (Å) β (deg) V (Å3) Z μ (mm−1) ρcalcd (g cm−3) Rb,c Rwd,e

C19H24N2O2·C4H6O5 446.49 295 P21 10.0451(5) 8.6712(5) 12.9992(7) 102.513(6) 1105.38(11) 2 0.099 1.341 0.0397 0.0899

C19H24N2O2·C4H6O5 446.49 295 P21 10.6543(10) 8.4144(7) 13.5321(11) 112.765(10) 1118.64(18) 2 0.098 1.326 0.0434 0.1028

λMoKα = 0.71073 Å. bF0 > 4σ(F0). cR = Σ∥F0| − |Fc∥/Σ|F0|. dAll data. Rw = [Σw(Fo2 − Fc2)2/Σw(Fo2)2]1/2.

a e

RS-PZQ and 0.43 g of L-MA (corresponding to a 1:1 stoichiometric mixture) were dissolved quantitatively during 60 min in 30 mL of boiling ethyl acetate, giving after 30 min crystalline R-PZQ:L-MA in yields of approximately 460 mg, which was then recrystallized from the same solvent (Figure 8). The purity of the R-PZQ:L-MA co-crystals was examined by HPLC using a chiral column and a solvent mixture of isopropyl alcohol and heptane that allowed for the separation of R-PZQ and S-PZQ. For this purpose five independent fractional crystallization experiments have been carried to obtain samples No. 1−5 (Table 4). The HPLC analysis evidenced the presence of S-PZQ in the samples, which indicates either simultaneous crystallization of S-PZQ:L-MA or the occurrence of solid

Figure 7. TGA-DSC curves for the co-crystals of the composition S-PZQ:L-MA (top) and R-PZQ:L-MA (bottom).

Table 2. Intermolecular Hydrogen Bonding Interactions and Short Contacts for Compounds S-PZQ:L-MA and R-PZQ:L-MA compound

H-bond

D−H [Å]

H···A [Å]

D···A [Å]

∠DHA [deg]

symmetry code

S-PZQ:L-MA

O4−H4···O1 C1−H1B···O3 O6−H6···O2 C4−H4A···O5 O7−H7···O3 C1−H1A···O7 C12−H12···O7 C15−H15A···C9 C18−H18B···O1 C19−H19A···C9 O4−H4···O1 C1−H1B···O3 O6−H6···O2 C4−H4B···O5 O7−H7···O3 O7−HH7···O4 C22−H22B···O3 C1−H1A···O7 C3−H3···O2 C9−H9···O5 C14−H14···O5 C14−H14···O7 C19−H19A···C9

0.82 0.97 0.82 0.97 0.82 0.97 0.93 0.97 0.97 0.97 0.82 0.97 0.82 0.97 0.82 0.82 0.97 0.97 0.98 0.93 0.98 0.98 0.97

1.76 2.49 1.81 2.62 2.08 2.43 2.68 2.76 2.66 2.84 1.76 2.66 1.84 2.49 2.19 2.60 2.70 2.44 2.64 2.49 2.60 2.63 2.87

2.576(3) 3.358(4) 2.622(3) 3.560(4) 2.729(3) 3.304(4) 3.364(4) 3.675(5) 3.484(4) 3.760(5) 2.565(3) 3.227(4) 2.650(3) 3.445(4) 2.622(4) 3.262(5) 3.490(5) 3.331(5) 3.538(5) 3.413(5) 3.275(5) 3.576(4) 3.788(6)

170 149 169 163 135 150 132 158 143 160 167 118 170 168 113 139 138 153 153 170 126 162 158

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

R-PZQ:L-MA

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Table 3. Solubility of R-PZQ:L-MA and S-PZQ:L-MA in Solvents of Different Polarity at Room Temperature solubility solvent

dielectric constant (ε)

S-PZQ:L-MA

R-PZQ:L-MA

water methanol ethanol acetone tetrahydrofuran ethyl acetate chloroform diethyl ether diisopropyl ether hexane

80.1 32.7 24.5 20.7 7.58 6.02 4.81 4.33 3.88 1.88

− +++ +++ +++ ++ ++ ++ − − −

− +++ +++ ++ ++ + + − − −

Figure 9. Dissolution profiles of RS-PZQ, R-PZQ·0.5H2O, and R-PZQ:L-MA in HCl at pH 1.2.

indicating that probably only solid solutions are present to some extent. Evaluation of the Intrinsic Dissolution Rate. The intrinsic dissolution rate is an important parameter for the evaluation of the biopharmaceutical properties of a potential API. The dissolution curves of RS-PZQ, R-PZQ·0.5H2O, and R-PZQ:L-MA were measured in a standard solution simulating physiological conditions (0.1 N HCl, pH 1.2), showing that the co-crystal exhibits a significantly larger intrinsic dissolution rate constant (6.1- and 12.5-fold increase) than R-PZQ·0.5H2O and RS-PZQ (Figure 9, Table 5). Thus, on the basis of the nontoxicity of L-MA, it might be most convenient to consider the co-crystal as option for a novel formulation of PZQ. Otherwise, R-PZQ can be liberated easily in the form of its hemihydrate from the co-crystal by stirring the solid at room temperature for 60 min with water followed by filtration. This methodology is based on the decomposition of R-PZQ:L-MA into R-PZQ·0.5H2O and L-MA in water (Figure 10). The enantiomeric excess of R-PZQ in the final product reaches 98.9−99.6% as shown by chiral HPLC (entry 3, Table 4). The increase in purity when compared to that achieved in the R-PZQ:L-MA co-crystal (entry 2, Table 4) can be probably explained by the viscous consistency of S-PZQ:L-MA in the presence of water, causing adherence to the glass surface of the flask used for the experiment and inhibiting its transference to the filtration apparatus.

Figure 8. PXRD pattern of R-PZQ:L-MA crystallized from a 1:1 stoichiometric mixture of RS-PZQ and L-MA in 30 mL of ethyl acetate followed by recrystallization. For comparison, the pattern of R-PZQ:L-MA simulated from the single-crystal X-ray diffraction analysis is included.

solution formation to some extent. Entry 1 in Table 4 shows the enantiomeric excess of R-PZQ corresponding to the cocrystalline phases initially formed in the fractional crystallization experiment. The ee-values for samples No. 1−5 in entry 1 reflect a significant variation when comparing samples 1−3 (ee = 85.2− 85.9%) to samples 4−5 (ee = 91.6 and 94.2%). These variations can be related to differences in the nucleation process during the crystallization. For samples 1−3, nucleation occurred faster, and the resulting microcrystalline material covered the bottom flask surface in a uniform manner. On the contrary, in samples 4−5 crystal growth occurred only in certain regions, giving larger crystal agglomerates (Figure S5). The larger quantity of S-PZQ in samples 1−3 indicates that a fast crystallization process should be avoided. Nevertheless, in all cases the amount of R-PZQ increases significantly after recrystallization from ethyl acetate, as shown by entry 2, giving ee values in the range of 95.9−97.8%. For the recrystallized samples, the PXRD patterns given in Figure 8 do not contain peaks for S-PZQ:L-MA,

4. CONCLUSIONS On the basis of the formation of a diastereomeric co-crystal pair with L-malic acid, chiral resolution of racemic RS-PZQ can be achieved in two steps via fractional crystallization from acetone or ethyl acetate in the presence of L-MA, followed by

Table 4. Enantiomeric Excess of R-PZQ (Determined by Chiral HPLC) in the Samples Obtained from the Fractional Crystallization Process (Entries 1−2) Followed by Treatment with Water (Entry 3) sample number entry

compound

1

2

3

4

5

average

1 2 3

R-PZQ:L-MA initial product R-PZQ:L-MA recrystallized from EtOAc R-PZQ·0.5H2O liberated from R-PZQ:L-MA

85.89 97.78 99.55

85.17 95.88 99.35

85.44 97.59 99.18

94.15 96.63 98.89

91.55 96.12 99.51

88.4 96.8 99.3

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Table 5. Intrinsic Dissolution Rate Constants for RS-PZQ, R-PZQ·0.5H2O, and R-PZQ:L-MA RS-PZQ R-PZQ·0.5H2O R-PZQ:L-MA

Kintrinsic (% diss/min·cm2)

Kint (cocrystal)/Kint (RS-PZQ)

Kint (cocrystal)/Kint (R-PZQ·0.5H2O)

0.016 0.033 0.200

1 2.06 12.50

1 6.06

this procedure can be extended to a large number of other APIs and chiral substances.

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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.5b01254. PXRD patterns for screening experiments of RS-PZQ with L-lactic, L-tartaric acid, and L-mandelic acid. Comparison of experimental and simulated PXRD patterns for R-PZQ:L-MA and S-PZQ:L-MA, respectively. Fragments of the single-crystal structures of R-PZQ:LMA and S-PZQ:L-MA. Photo of crystal agglomerates formed during one of the fractional crystallization assays for the formation of R-PZQ:L-MA (PDF) Crystallographic information files (CIF1 and CIF2)

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Figure 10. PXRD patterns of R-PZQ·0.5H2O prepared by asymmetric synthesis, R-PZQ:L-MA obtained from a 1:1 stoichiometric mixture of RS-PZQ and L-MA in 30 mL of boiling ethyl acetate, and R-PZQ· 0.5H2O liberated from RS-PZQ:L-MA by stirring for 60 min in water.

AUTHOR INFORMATION

Corresponding Authors

*(H.H.) Fax: (+52) 777 329 79 97. E-mail: hhopfl@uaem.mx. *(D.H.-R.) E-mail: [email protected].

Scheme 1. Racemic Resolution of RS-PZQ via Fractional Crystallization in the Presence of L-MA Followed by Treatment with Water

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work received financial support from Consejo Nacional de Ciencia y Tecnologia (CONACyT) through Grant Nos. 221455 and 229929 and Programa para el Desarrollo Profesional Docente (PRODEP).

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DEDICATION Dedicated to Prof. Dr. Eusebio Juaristi on occasion of his 65th birthday. REFERENCES

(1) http://www.fda.gov/Drugs/GuidanceComplianceRegulatory Information/Guidances/ucm122883.htm, U.S. Food and Drug Administration, 2011. (2) Lin, G. Q.; Sun, X. W. Chiral Drugs through Asymmetric Synthesis in Chiral Drugs: Chemistry and Biological Action; Lin, G. Q.; You, Q. D.; Cheng, J. F., Eds.; John Wiley & Sons: Hoboken, NJ, 2011. ́ (3) Juaristi, E. Sintesis Asimétrica; El Colegio Nacional: México D.F., 2013. (4) Kozma, D., Ed. CRC Handbook of Optical Resolutions via Diastereomeric Salt Formation; CRC Press: London, 2001. (5) Gonawan, F. N.; Yon, L. S.; Kamaruddin, A. H.; Uzir, M. H. Ind. Eng. Chem. Res. 2014, 53, 635−642. (6) Arad-Yellin, R.; Green, B. S.; Knossow, M.; Tsoucaris, G. Enantiomeric Selectivity of Host Lattices in Inclusion Compounds; Atwood, J. L.; Davies, J. E. D.; MacNicol, D. D., Eds.; Academic Press: New York, 1984. (7) Worsch, D.; Vögtle, F. Top. Curr. Chem. 1987, 140, 21−41. (8) Mori, K.; Toda, F. Tetrahedron: Asymmetry 1990, 1, 281−282. (9) Weber, E.; Wimmer, C.; Llamas-Saiz, A. L.; Foces-Foces, C. J. Chem. Soc., Chem. Commun. 1992, 10, 733−735. (10) Akazome, M.; Ueno, Y.; Ooiso, H.; Ogura, K. J. Org. Chem. 2000, 65, 68−76.

phase-decomposition of the R-PZQ:L-MA co-crystal by treatment with water (Scheme 1). Since the R-PZQ:L-MA co-crystal exhibits a significantly larger intrinsic dissolution rate constant than R-PZQ·0.5H2O and RS-PZQ, the co-crystal by itself might be considered as an alternative option for the drug formulation, which would require only one reaction path. We visualize that 313



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(11) Báthori, N. B.; Nassimbeni, L. R. Cryst. Growth Des. 2010, 10, 1782−1787. (12) Barton, B.; Caira, M. R.; Hosten, E. C.; McCleland, C. W.; Weitz, S. Chem. Commun. 2014, 50, 13353−13355. (13) Kawashima, M.; Hirayama, A. Chem. Lett. 1991, 20, 763−766. (14) Hanessian, S.; Gomtsyan, A.; Simard, M.; Roelens, S. J. Am. Chem. Soc. 1994, 116, 4495−4496. (15) Nemák, K.; Á cs, M.; Jászay, Z. M.; Kozma, D.; Fogassy, E. Tetrahedron 1996, 52, 1637−1642. (16) Thorey, P.; Bombicz, P.; Miklós-Szilágyi, I.; Molnár, P.; Bánsághi, G.; Székely, E.; Simándi, B.; Párkányi, L.; Pokol, G.; Madarász, J. Thermochim. Acta 2010, 497, 129−136. (17) Eddleston, M. D.; Arhangelskis, M.; Frišcǐ ć, T.; Jones, W. Chem. Commun. 2012, 48, 11340−11342. (18) Springuel, G.; Leyssens, T. Cryst. Growth Des. 2012, 12, 3374− 3378. (19) Springuel, G.; Robeyns, K.; Norberg, B.; Wouters, J.; Leyssens, T. Cryst. Growth Des. 2014, 14, 3996−4004. (20) Habgood, M. Cryst. Growth Des. 2013, 13, 4549−4558. (21) Eccles, K. S.; Deasy, R. E.; Fábián, L.; Maguire, A. R.; Lawrence, S. E. J. Org. Chem. 2011, 76, 1159−1162. (22) Trask, A. V.; Motherwell, W. D. S.; Jones, W. Int. J. Pharm. 2006, 320, 114−123. (23) McNamara, D. P.; Childs, S. L.; Giordano, J.; Iarriccio, A.; Cassidy, J.; Shet, M. S.; Mannion, R.; O’Donnell, E.; Park, A. Pharm. Res. 2006, 23, 1888−1897. (24) Blagden, N.; De Matas, M.; Gavan, P. T.; York, P. Adv. Drug Delivery Rev. 2007, 59, 617−630. (25) Shan, N.; Zaworotko, M. J. Drug Discovery Today 2008, 13, 440−446. (26) Schultheiss, N.; Newman, A. Cryst. Growth Des. 2009, 9, 2950− 2967. (27) Babu, N. H.; Nangia, A. Cryst. Growth Des. 2011, 11, 2662−2679. (28) Félix-Sonda, B. C.; Rivera-Islas, J.; Herrera-Ruiz, D.; MoralesRojas, H.; Höpfl, H. Cryst. Growth Des. 2014, 14, 1086−1102. (29) Cioli, D.; Pica-Mattoccia, L. Parasitol. Res. 2003, 90, S3−S9. (30) Cedillo-Cruz, A.; Aguilar, M. I.; Flores-Alamo, M.; PalomaresAlonso, F.; Jung-Cook, H. Tetrahedron: Asymmetry 2014, 25, 133−140. (31) Crompton, D. W. T.; Montresor, A.; Nesheim, M. C.; Savioli, L., Eds.; World Health Organization. Controlling Disease Due to Helminth Infections; WHO: Geneva, 2003. (32) Meyer, T.; Sekljic, H.; Fuchs, S.; Bothe, H.; Schollmeyer, D.; Miculka, C. PLoS Neglected Trop. Dis. 2009, 3, e357. (33) de La Torre, P.; Torrado, S.; Torrado, S. Chem. Pharm. Bull. 1999, 47, 1629−1633. (34) Olliaro, P. L.; Vaillant, M.; Diawara, A.; Coulibaly, J. T.; Garba, A.; Keiser, J.; King, C. H.; Knopp, S.; Landouré, A.; N’Goran, E. K.; Raso, G.; Scherrer, A. U.; Sousa-Figueiredo, J. C.; Stete, K.; Zhou, X.N.; Utzinger, J. PLoS Neglected Trop. Dis. 2015, 9, e0003821. (35) Woelfle, M.; Seerden, J.-P.; De Gooijer, J.; Pouwer, K.; Olliaro, P.; Todd, M. H. PLoS Neglected Trop. Dis. 2011, 5, e1260. (36) Espinosa-Lara, J. C.; Guzman-Villanueva, D.; Arenas-García, J. I.; Herrera-Ruiz, D.; Rivera-Islas, J.; Román-Bravo, P.; Morales-Rojas, H.; Höpfl, H. Cryst. Growth Des. 2013, 13, 169−185. (37) CrysAlisPro, Version 1.171.37.35; Agilent Technologies: Yarnton, Oxfordshire, United Kindom, 2014. (38) Dolomanov, O. V.; Bourhis, L. J.; Gildea, R. J.; Howard, J. A. K.; Puschmann, H. J. Appl. Crystallogr. 2009, 42, 339−341. (39) Sheldrick, G. M. Acta Crystallogr., Sect. A: Found. Adv. 2015, 71, 3−8. (40) Brandenburg, K. Diamond, Version 3.1c; Crystal Impact: Bonn, Germany, 1997. (41) In contrast to the grinding experiments with L-MA and L-TA, in the case of L-LA only the experiment with enantiomerically pure R-PZQ·0.5H2O provided a novel phase. The PXRD pattern for the experiment with enantiomerically pure S-PZQ·0.5H2O provided only peaks corresponding to the starting material. However, grinding of RS-PZQ with L-LA provided a novel phase different from that observed for R-PZQ:L-LA (Figure S2). 314


Chiral Resolution of RS-Praziquantel via Diastereomeric Co-Crystal

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