Three Polymorphic Forms of Ciprofloxacin Maleate: Formation

Article pubs.acs.org/crystal

Three Polymorphic Forms of Ciprofloxacin Maleate: Formation Pathways, Crystal Structures, Calculations, and Thermodynamic Stability Aspects Artem O. Surov,† Andrei V. Churakov,‡ and German L. Perlovich*,† †

Institution of Russian Academy of Sciences, G. A. Krestov Institute of Solution Chemistry RAS, 153045, Ivanovo, Russia Institute of General and Inorganic Chemistry RAS, Leninskii Prosp. 31, 119991, Moscow, Russia

‡

S Supporting Information *

ABSTRACT: Polymorphism of the pharmaceutical salt of ciprofloxacin with maleic acid has been investigated. Ciprofloxacin maleate was found to exist in three polymorphic forms and one hydrate. The formation pathways of the salt polymorphs were elucidated by using solvent screening of the mechanochemical synthesis. It has been found that the mechanochemical reaction of the salt formation consists of two steps, including the formation of a kinetic polymorph as a transitional stage and its conversion into a thermodynamically favorable form. The thermodynamic relationships between the polymorphs were rationalized based on solubility and solution calorimetry measurements. The pattern of intermolecular interactions and crystal lattice energies of the polymorphs were quantified by solid-state density functional theory followed by Bader analysis of periodic electron density. Despite a considerable diversity of the reported CIP salts3−10 (and of fluoroquinolone multicomponent crystals in general), only one is known to be polymorphic.11 Meanwhile, according to a recent review of Cruz-Cabeza et al.,12 37% of unhydrated salts and 28% of hydrated salts deposited in the Cambridge Structural Database have two or more polymorphic modifications. This indicates that polymorphism of the fluoroquinolone multicomponent crystals has not been thoroughly studied yet, and further investigations are needed to explore the polymorphic potential of these systems. In fact, description of polymorphism is limited to the paper by Romanuk et al., who studied two polymorphs of the CIP salt with saccharin.11,13 However, it is only the crystal structure of form II of ciprofloxacin saccharinate that has been reported, while form I has been characterized only by spectroscopic methods (IR and solid-state NMR spectroscopy). Ciprofloxacin maleate was first described in our paper along with other salts of the drug, including fumarate monohydrate and adipate dehydrate.9 The idea to revise the ciprofloxacin maleate more carefully was inspired by the very recent paper of Zhang et al.,14 who had also obtained CIP salt with maleic acid and determined its crystal structure. However, the X-ray crystallographic parameters of the salt reported in our work9 and in the paper by Zhang et al.14 are found to be considerably

1. INTRODUCTION Polymorphism is of great importance in the pharmaceutical industry as different polymorphs of a given crystalline drug substance may have different physicochemical properties such as melting temperature, solubility, stability, dissolution rate, and bioavailability.1 Although polymorphism is of constant interest for researchers worldwide,2 the phenomenon remains largely unpredictable, especially for multicomponent crystals. Therefore, identification and characterization of all polymorphic forms that potentially exist and their thermodynamic stability are a crucial step at all stages of pharmaceuticals development and manufacture. In this paper, we describe the polymorphic behavior of the pharmaceutical salt of ciprofloxacin (CIP) with maleic acid (Figure 1). CIP belongs to a family of broad-spectrum oral antibiotics called fluoroquinolones, drugs that are widely prescribed for treatment of several types of bacterial infections.

Received: August 29, 2016 Revised: September 27, 2016 Published: October 10, 2016

Figure 1. Molecular structures of CIP and maleic acid. © 2016 American Chemical Society

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DOI: 10.1021/acs.cgd.6b01277 Cryst. Growth Des. 2016, 16, 6556−6567

Crystal Growth & Design

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been deposited with the Cambridge Crystallographic Data Centre as supplementary publications under the CCDC numbers 1501151− 1501153. This information can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/ data_request/cif. PXPD data of the bulk materials were recorded under ambient conditions in Bragg−Brentano geometry with a Bruker D8 Advance diffractometer with CuKα1 radiation (λ = 1.5406 Å). 2.5. DSC Experiments. Thermal analysis was carried out using a PerkinElmer DSC 4000 differential scanning calorimeter with a refrigerated cooling system (USA). The sample was heated in sealed aluminum sample holders at the rate of 10 °C·min−1 in a nitrogen atmosphere. The unit was calibrated with indium and zinc standards. The accuracy of the weighing procedure was ±0.01 mg. 2.6. Thermogravimetric Analysis (TGA). TGA was performed on a TG 209 F1 Iris thermomicrobalance (Netzsch, Germany). Approximately 10 mg of the sample was added to a platinum crucible. The samples were heated at a constant heating rate of 10 °C·min−1. The samples were purged with a stream of flowing dry Ar at 30 mL· min−1 throughout the experiment. 2.7. Aqueous Solubility Experiments. Dissolution measurements were carried out by the shake-flask method in hydrochloric buffer with pH 1.2 at 25.0 ± 0.1 °C. The medium at pH 1.2 was prepared with 0.1 N aqueous hydrochloric acid solution and potassium chloride. The excess amount of each polymorph was suspended in 2 mL of the solvent and allowed to equilibrate under shaking at 25.0 °C for 48 h. An aliquot of the suspension was filtered using a 0.2 μm filter (Rotilabo syringe filter, PTFE), and the concentration of CIP was determined with a suitable dilution by a Cary 50 UV−vis spectrophotometer (Varian, Australia) at the reference wavelength. The results are stated as the average of at least four replicated experiments. The polymorphs stability during the solubility experiments was monitored by analyzing samples of the bottom phase at 6, 12, 24, and 48 h using PXRD. 2.8. Solution Calorimetry Experiments. The polymorhs solution enthalpies were measured by using an ampule-type isoperibolic calorimeter with a 50 cm3 titanium reaction vessel at 25.0 °C.18 The automated control scheme allowed the temperature to be maintained with the accuracy over 6 × 10−4 °C. The temperature and thermal sensitivities of the calorimeter measuring cell were 10−4 K and 10−3 J, respectively. The instrumental errors were 0.6−1%. The accuracy of weight measurements corresponded to ±10−5 g. Because of small values of the solution heat effects, a correction (q(T)) was introduced to account for the heat of ampule breaking and evaporation of the solvent in the ampule free volume: q(20.0 °C) = 0.034 J, q(30.0 °C) = −0.018 J, q(45.0 °C) = −0.059 J. Other corrections were negligibly small. The calorimeter was calibrated using KCl (Merck analysis grade >99.5%) in water over a wide concentration interval with more than 20 measurements made. The obtained standard value of solution enthalpy was 17240 ± 36 J·mol−1, which is in good agreement with the value 17241 ± 18 J·mol−1 recommended by IUPAC.19 The results are stated as the average of at least six replicated experiments. 2.9. Solid-State DFT Calculations and Energy of Intermolecular Interactions. The DFT computations with periodic boundary conditions (solid-state DFT calculations) were performed using the Crystal14 program20 in B3LYP-D2/6-31G** approximation. The details of the DFT computation procedures are given in the Supporting Information. The periodic electron density obtained from the crystalline wave function was analyzed according to the quantum theory of atoms in molecules and crystals (QTAIMC)21,22 using TOPOND 14.23,24 The calculation methodology is presented elsewhere.25−27 The following electron-density features at the (3;− 1) bond critical point (BCP) are computed: (i) the values of the electron density, ρb, (ii) the Laplacian of the electron density, ∇2ρb, and (iii) the positively defined local electronic kinetic energy density, Gb. Within the QTAIMC, the particular noncovalent intermolecular interaction is associated with the existence of the bond path (i.e., the bond critical point) between the pair of atoms. The absence of the bond critical point implies that the two atoms do not interact. The

different, which indicates that the structures should be considered as two polymorphs of ciprofloxacin maleate. The mechanochemical approach has been demonstrated as a powerful technique for screening cocrystals, salts, and their polymorphs.15 In this context, solvent screening of the liquidassisted grinding (LAG) synthesis of ciprofloxacin maleate accompanied by powder X-ray diffraction (PXRD) was conducted to explore the polymorphic behavior of the ciprofloxacin maleate salt and investigate the formation pathways of its polymorphs. Single-crystal X-ray diffraction, differential scanning calorimetry (DSC), and thermogravimetric (TG) analysis were carried out to obtain a complete solid state characterization of the polymorphic forms. The thermodynamic relationships between the polymorphs were rationalized based on solubility and solution calorimetry measurements. In addition, analysis of intermolecular interactions and crystal lattice energies of the polymorphs was performed using the density functional theory (DFT) computations complemented with Bader analysis of the periodic electron density.

2. MATERIALS AND METHODS 2.1. Compounds and Solvents. Ciprofloxacin (C17H18FN3O3, anhydrous, 98%) and maleic acid (C4H4O4, 99%) were purchased from Acros Organics. All the solvents were available commercially and used as received without further purification. 2.2. Grinding Experiments. The grinding experiments were performed using a Fritsch planetary micro mill, model Pulverisette 7, in 12 mL agate grinding jars with 10 agate balls of 5 mm at a rate of 500 rpm for 30 min. In the typical experiment, 60 mg of CIP and 21 mg of maleic acid (1:1 molar ratio) were placed in a grinding jar, and 50 μL of solvent was added with a micropipette. In the case of competitive grinding, 100 mg of an equimolar mixture of polymorphic form I and form II and 60 μL of solvent was ground for 40 min at 500 rpm. 2.3. Solution Crystallization. In the solution crystallization evaporation experiments, CIP (80 mg) was dissolved with maleic acid in a 1:1 molar ratio in 10 mL of an organic solvent−water mixture (1:1 v:v) and stirred at 60−70 °C until a clear solution was obtained. The solution was slowly cooled and kept in a fume hood at room temperature until a crystalline material was formed. Ciprofloxacin Maleate Form I. Crystals of form I (blocks) can be obtained from the water mixtures with methanol, ethanol, isopropyl alcohol, and dioxane. Ciprofloxacin Maleate Form II. Form II (blocks) crystallizes from a acetonitrile−water mixture (1:1 v:v). Form II could also be produced from each of the mentioned solvent systems by seeding a solution with the powder of form II. Ciprofloxacin Maleate Form III. Single crystals of form III (plates) were accidently obtained from a methanol−water solution (1:1 v:v) concomitantly with form I. Ciprofloxacin Maleate Monohydrate. Needle-shaped crystals of ciprofloxacin maleate monohydrate were obtained by placing a hot solution of the components in a methanol−water solution (1:1 v:v) in a freezer and storing at 5 °C. Monohydrate can also be produced by evaporation of an acetone−water solution (1:1 v:v) at room temperature. In this case, however, the resulting material is contaminated by the anhydrous form of the salt. 2.4. X-ray Diffraction Experiments. Single-crystal X-ray diffraction data were collected on a Bruker SMART APEX II diffractometer using graphite-monochromated MoKα radiation (λ = 0.71073 Å) at 150 K. Absorption corrections based on measurements of equivalent reflections were applied.16 The structures were solved by direct methods and refined by full matrix least-squares on F2 with anisotropic thermal parameters for all non-hydrogen atoms.17 All hydrogen atoms were found from a difference Fourier map and refined isotropically. The crystallographic data for form II, form III of ciprofloxacin maleate, and ciprofloxacin maleate monohydrate have 6557



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Figure 2. Calculated PXRD patterns of ciprofloxacin maleate form I, form II, and measured patterns of physical mixture of CIP and maleic acid and new form III.

Figure 3. Experimental XRPD patterns of (a) ciprofloxacin maleate polymorphs obtained by LAG with different solvents, (b) ciprofloxacin maleate form II. where j and i denote the atoms belonging to different molecules. Equation 2 is BSSE free. For the sake of simplicity, indexes j and i will be omitted below.

network of the bond paths yields the comprehensive bond picture, the energy of each specific interaction (in our case it is the intermolecular hydrogen bonds, C−H···O contact, etc.) is considered to be totally independent of the others. The effects of crystal environment, longterm electrostatic effects, etc. are taken into account implicitly, via the periodic electronic wave function, and are coded in the bond critical point features. The energy of the particular noncovalent interaction, Eint, is evaluated according to Mata et al.28 as E int = 0.429G b (in atomic units)

3. RESULTS AND DISCUSSION 3.1. Liquid-Assisted Grinding (LAG) Experiments and Discovery of Form III. As mentioned in the Introduction, comparison of the X-ray crystallographic parameters of ciprofloxacin maleate reported in our work9 and in the paper by Zhang et al.14 has revealed that the structures are two polymorphs of the salt. To simplify the discussion, the following nomenclature will be applied: form I9 and form II.14 Despite the fact that the preparation procedures of the salt described in ref 9 and ref 14 are similar, they lead to different polymorphic outcomes. In the work of Zhang et al., the components initially underwent mechanochemical treatment, which was followed by dissolution and crystallization from the ethanol−water mixture. In our paper, ciprofloxacin maleate was obtained by simple crystallization from the methanol−water solution. We reproduced the preparation procedure suggested

(1)

It has been reported that eq 1 yields reasonable values of Eint for intermolecular interactions with different strength from strong chargeassisted hydrogen bonds to weak van der Waals contacts.29−33 In addition, this approach allows estimating the lattice energy of a crystal as a sum of energies of noncovalent interactions between the considered molecule and its neighbors:34

E latt =

∑ ∑ Eint,j ,i i

j 2σ(I)) final wR(F2) values (I > 2σ(I)) final R1 values (all data) final wR(F2) values (all data) goodness of fit on F2 largest diff peak and hole, e·Å−3 a

Form Ia

Form II

monoclinic 9.1709(3) 16.1160(5) 14.0148(5) 90.00 106.4203(4) 90.00 1986.88(11) P21/n 4 0.119 20279 4792 0.0185 0.0331 0.0924 0.0363 0.0953 1.028 0.384/−0.217

C17H19FN3O3·C4H3O4 447.42 monoclinic 13.9442(5) 10.4033(4) 15.0674(6) 90.00 108.774(1) 90.00 2069.47(14) P21/c 4 0.115 22891 5494 0.0223 0.0355 0.0928 0.0420 0.0981 1.033 0.359/−0.267

Form III

[CIP + maleic + H2O] (1:1:1)

triclinic 7.0657(4) 9.2052(5) 15.6818(9) 88.7004(8) 86.4983(8) 75.5522(8) 985.83(10) P1̅ 2 0.120 8291 3810 0.0173 0.0326 0.0822 0.0403 0.0869 1.028 0.199/−0.231

C17H19FN3O3·C4H3O4·H2O 465.43 triclinic 6.9959(5) 10.3357(7) 14.7102(10) 94.0847(9) 90.5631(9) 105.6486(9) 1021.16(12) P1̅ 2 0.123 11404 5404 0.0204 0.0385 0.0978 0.0489 0.1041 1.040 0.395/−0.290

Data taken from ref 9.

hydrates of ciprofloxacin and norfloxacin maleates, [CIP + maleic + H2O] (1:1:1) seems thermodynamically less stable than the anhydrous salt at room temperature, while norfloxacin maleate demonstrates the opposite rank order of stabilities of anhydrous and hydrated forms of the salt (at least at room temperature). The overlay of conformations of the CIP ion molecules in different crystal forms is shown in Figure 10. Conformations of CIP in form I, form II, and monohydrate are closely comparable. An alternative orientation of the piperazinium ring with respect to the cyclopropyl group is observed for CIP ions in form III

centrosymmetric unit (Figure 9a). The crystal structure of [CIP + maleic + H2O] (1:1:1) consists of conventional layers of columnar π-stacks of the drug separated by domains where maleate ions and water molecules reside (Figure 9b). A search of the CSD for the maleate salts of fluoroquinolones has shown that the structure of ciprofloxacin maleate monohydrate is similar to that of norfloxacin maleate monohydrate (VETWIB) in terms of hydrogen bonding and packing arrangements (Figure S4). Our investigations have shown that being stored in mother liquor at room temperature, the crystals of [CIP + maleic + H2O] (1:1:1) gradually change their morphology and convert into anhydrous form of the salt (form II) in a week. Therefore, despite the similarity in the crystal structures of 6561



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Figure 7. Hydrogen bonded supramolecular units in the crystal structures of (a) form I, (b) form II, and (c) form III. The numbers correspond to the energies (in kJ·mol−1) of intermolecular hydrogen bonds (blue) and C−H···O contacts (green) derived from the Bader analysis of periodic electron density (see text).

3.5. Crystal Lattice Energy Calculations. In order to evaluate and compare crystal lattice energies (Elatt) of the ciprofloxacin maleate polymorphs, DFT computations complemented with the Bader analysis of the periodic electron density were performed. It has to be pointed out that lattice energies are commonly determined using atom−atom potentials38,39 or the PIXEL method based on semiclassical density sums.40,41 In the case of crystals with proton transfer, however, the applicability of these schemes for Elatt evaluation is

not straightforward, at least for the Gavezzotti model as it was originally calibrated only for molecular crystals containing neutral atoms. Calculations with salts require preliminary parametrization of the force field. On the other hand, the QTAIMC concept is successfully used both for salts and neutral cocrystals as it has been shown in our previous works.32,42 The energies of selected intermolecular interactions (in kJ· mol−1) in the crystals of the ciprofloxacin maleate polymorphs are shown in Figure 7a−c. The theoretical values of the 6562



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form III, the second N+3−H31···O−22 hydrogen bond between CIP and maleate ions is found to equal ca. 20% and ca. 30%, respectively, weaker than the first one (i.e., N+3−H32···O22). The remarkably high electron density in the bond critical point for the O24−H24···O−21 intramolecular hydrogen bond in the maleate ion (ρb ≈ 0.090 au) and short O24··· O21 distance (∼2.400 Å) indicate its partially covalent nature.43 The QTAIMC analysis has also revealed that, in the structures of form I and form III, the O21 atom of maleate acts as the acceptor of weak C−H···O interaction from the neighboring CIP molecule. It should be noted that in forms I and III only one of the carboxylic groups of the maleate ion participates in hydrogen bonding, while the second moiety accepts a number of C−H···O contacts from the neighboring molecules (Figures S5 and S7). Although, in form III, the QTAIMC analysis suggests the existence of a weak N+3−H31···O23 hydrogen bond with the energy of ca. 8.6 kJ·mol−1 (Figures S6). In form II, both carboxylic groups of the maleate are involved in hydrogen bonding. In this case, the energy of N+3−H32···O−22 hydrogen bond is slightly larger than that in forms I and III (Figure 7b). However, two other hydrogen bonds (N+3−H31··· O−23 and N+3−H31···O−24) are calculated to be considerably weaker (Figure 7b), so that their combined energy is comparable with the energy of N+3−H31···O−22 bond in forms I and III. In addition, the weak N+3−H31···O3 hydrogen bond (ca. 10 kJ·mol−1) connects CIP ions to each other (Figures S5). The QTAIMC analysis has located a number of the (3;−1) bond critical points corresponding to C−H···O contacts between the maleate and CIP ions in the crystal of form II. The energies of these interactions vary from ca. 4 to ca. 11 kJ·mol−1 (Figure S6). Considering the energies of all intermolecular interactions found in the crystal structure, it is possible to evaluate the lattice energies of the polymorphs (see eq 2). Relevant information can be also obtained by analyzing sums of the intermolecular interaction energies between the different types of constituents in the crystal structure (Table 3). According to the calculation results, form I of the salt has the largest value of the crystal lattice energy. The lattice energy of form II is found to be less stabilizing than form I, while form III is least stable. In forms I and III, the conventional hydrogen bonds comprise ca. 23% and ca. 27% of the lattice energy, while in form II they provide ca. 31% of the total energy. The most significant contribution in all the structures is made by C−H··· O interactions, the value of which reaches ca. 50% in form II, and in forms I and III such interactions comprise ca. 42 and ca. 36%, respectively. It would be interesting to note that a prominent contribution to the lattice energy of forms I and III is provided by C−H···F and F···F interactions. However, in form II, the QTAIMC analysis did not reveal the existence of the (3;−1) critical point corresponding to C−H···F and/or F··· F contacts. As Table 3 shows, in all the polymorphs, the Cip−maleic interactions provide the largest contribution to the lattice energy. The contribution of the Cip−maleic interactions are most prominent in form II (almost 70% of the total energy), while in form III their fraction is less than 60%. In all the structures, the Cip−Cip interactions comprise approximately a third of the total energy. The interactions between maleate ions (maleic−maleic) have a relatively small contribution. In forms I and III, they reach 3.6 and 6.3% of the lattice energy, respectively. However, no evidence of maleic−maleic contacts in the crystal of form II was found by the QTAIMC analysis. It

Figure 8. Packing arrangements of (a) form I, (b) form II, and (c) form III of ciprofloxacin maleate. The maleate ions are colored red.

electron density parameters in the critical points and energies of all the found intermolecular interactions in the polymorphs are collected in Tables S1−S3. The calculation shows that the N+3−H32···O22 hydrogen bond is the strongest noncovalent interaction in the crystals of all the polymorphs. In form I and 6563



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Figure 9. (a) Hydrogen bonded supramolecular unit in the crystal structures of ciprofloxacin maleate monohydrate, (b) packing arrangement of [CIP + maleic + H2O] (1:1:1). The maleate ions are colored red, and the water molecules are colored blue.

maleic interactions, on account of the decrease in the Cip−Cip and maleic−maleic interaction energies. 3.6. Thermal Analysis. DSC traces for the polymorphs and ciprofloxacin maleate monohydrate are shown in Figure S8, and the thermal data are given in Table 4. According to TG analysis, the melting process of ciprofloxacin maleate is accompanied by a weight loss which starts at Tfus (onset), indicating decomposition and/or sublimation of a sample (Figure S9). Unfortunately, this leads to a relatively large error in melting temperatures of the polymorhs. Moreover, due to the mentioned processes, melting enthalpies of the polymorhs derived from the DSC data are not reliable, since it is hard to separate thermal events corresponding to melting and decomposition (sublimation) processes. The DSC experiments suggest the highest melting point of form II. The melting temperature of form I, however, is ca. 6 °C lower than that of form II. Form III is found to be the least thermally stable. It should be also noted that the DSC studies propose the opposite rank order of stabilities of polymorphs I and II compared to the results of lattice energy calculations. 3.7. Thermodynamic Relationships between Polymorphs. In order to rationalize the thermodynamic relationships between the polymorphs of ciprofloxacin maleate, a set of experimental techniques has been applied, including solubility and solution calorimetry measurements. All the experiments were performed in the hydrochloric buffer solution with pH 1.2 at 25 °C. It is well-known that the difference in free energy between polymorphs is directly proportional to their relative equilibrium solubilities1 as expressed by the following equation:

Figure 10. Overlay of CIP conformations in different crystal forms of ciprofloxacin maleate: form I − red, form II − blue, form III − green, [CIP + maleic + H2O] (1:1:1) − orange.

Table 3. Sums of Intermolecular Interaction Energies (kJ· mol−1) between Different Types of Constituents Calculated Using the Solid-State DFT Method Coupled with Bader Analysis of Periodic Wave-Function Form I Form II Form III

Cip−Cip

Cip−maleic

maleic−maleic

total

101.9 (35.6%) 81.5 (30.6%) 92.7 (35.8%)

174.0 (60.8%) 184.9 (69.4%) 149.6 (57.8%)

10.3 (3.6%) 0 (0.0%) 16.4 (6.3%)

286.2 266.4 258.6

is notable that the most and least stable polymorphs, i.e., form I and form III, show a similar distribution of the Cip−Cip, Cip− maleic, and maleic−maleic relative contributions to the total energy. In form II, though, the distribution pattern is different. In this case, the lattice energy is distributed toward the Cip−

Table 4. Thermophysical Data for Polymorphs of Ciprofloxacin Maleate and Ciprofloxacin Maleate Monohydratea [CIP + maleic + H2O] (1:1:1) Form I Form II Form III a

Tdehyd, °C (onset)

ΔHdehyd, J·g−1

ΔmS,%

60.1 ± 1.0 n/a n/a n/a

127.0 ± 3.0 n/a n/a n/a

4.68 n/a n/a n/a

Tfus, °C (onset) 216.0 222.0 228.0 209.0

± ± ± ±

1.0 2.0 1.5 2.0

(n (n (n (n

= = = =

ΔTfus, °C (onset) 4) 7) 6) 5)

13.0 (I → III) 6.0 (II → I) 19.0 (II→III)

n, number of independent DSC measurements. n/a, not available 6564



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Table 5. Solubilities (S), Solution Enthalpies (ΔHsol ° ) of Ciprofloxacin Maleate Polymorphs in pH 1.2 Media at 25.0 °C and Thermodynamic Parameters of Polymorphic Transitions S, mol·l−1 Form I Form II

(2.38 ± 0.05) × 10 (2.69 ± 0.04) × 10−2

Form III a

ΔHsol ° ,a kJ mol−1 −2

49.5 ± 0.2 47.0 ± 0.2

ΔGtr° kJ mol−1

ΔHtr° kJ mol−1

ΔStr° J·mol−1·K−1

−0.30 ± 0.09 (Form II → Form I)

−2.5 ± 0.4 (Form II → Form I) −8.5 ± 0.5 (Form III → Form I)

−7.4 ± 1.6 (Form II → Form I)

41.0 ± 0.3

See Table S4 in the Supporting Information for the full data set.

⎛S ⎞ ΔGtrT(I → II) = RT ln⎜ II ⎟ ⎝ SI ⎠

polymorphs is available. The formation pathways of the polymorphs of the salt were investigated under mechanochemical conditions. It was found that the mechanochemical reaction of the salt formation consists of two steps, namely, rapid formation of kinetic form III, which subsequently converts into stable polymorphic form II. Mechanochemical synthesis of form I, however, requires seeding, which indicates a high activation barrier of nucleation of form I. The stability relationships between the polymorphs were rationalized by using a number of experimental and theoretical methods. The crystal lattice energy calculations, solubility, and solution calorimetry experiments suggest the following order of stabilities of the polymorphs: form I is the thermodynamically most stable one, followed by form II, while form III is the least stable. Although the crystal structures of form I and form II are considerably different, these alternative packing arrangements of the salt are found to be closely comparable in terms of free and lattice energies, indicating almost equal stability of the polymorphs.

(3)

where SI and SII are the solubilities of polymorphs I and II, respectively. Solubility implies equilibrium between a solid phase and a solution. PXRD analysis of the residual material recovered after the experiment has revealed that form I and form II remain stable during the dissolution experiment (48 h). Form III, however, undergoes a solution-mediated transformation to polymorph form II in the bottom phase at least after 6 h of dissolution (Figure S10). One can conclude that form III of ciprofloxacin maleate is the least thermodynamically stable polymorph under the current conditions, which is in agreement with all the experimental and theoretical evidence described above. The results of solubility (S) and solution calorimetry (ΔHsol ° ) studies of the polymorphs in buffer solution with pH 1.2 and the calculated thermodynamic parameters for polymorphic transition between the different forms are summarized in Table 5. Again, Form III is confirmed to be the least enthalpically stable, namely, by 8.5 ± 0.5 kJ·mol−1 less stable than form I. The experimental data show that the solubilities of forms I and II are closely comparable, which results in the value of the free energy of polymorphic transition (ΔGtr°) reaching 0.3 kJ mol−1. The difference in the crystal lattice energies between the polymorphs, obtained from the solution calorimetry experiments (ΔH°tr), is also found to be small. However, despite the modest values of ΔGtr° and ΔHtr°, both experiments suggest that form I is thermodynamically more stable than form II, since the experimental errors are less than the absolute values of the free energy and enthalpy of polymorphic transition. This conclusion seems rather surprising since polymorph I does not form via grinding of the components (see section 3.1), it has an unusual packing arrangement (see section 3.4), and its melting temperature is lower than that of form II (see section 3.6). In fact, the same rank order of stabilities of the polymorphs (form I is most stable, followed by form II and then form III) is supported only by the DFT calculations.

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.6b01277. Complete tables of characteristics of the intermolecular (noncovalent) interactions in the ciprofloxacin maleate forms I, II, and III calculated by the solid-state DFT method coupled with Bader analysis of the periodic wave function; details of the DFT calculations; details of solution calorimetry experiments for the ciprofloxacin maleate polymorphs (I, II, and III) in pH 1.2 media at 25.0 °C; experimental PXRD patterns of ciprofloxacin maleate form I, form II, form III, and ciprofloxacin maleate monohydrate obtained by solution crystallization; experimental and calculated PXRD patterns of ciprofloxacin maleate polymorphs; DSC thermogram and TG analysis of ciprofloxacin maleate monohydrate; Hydrogen bonded supramolecular unit in the crystal structures of ciprofloxacin maleate monohydrate and norfloxacin maleate monohydrate; selected intermolecular C−H···O, N···O, and F···C contacts in the crystal structure of form I, II, and III derived from the Bader analysis of periodic electron density; DSC traces for the polymorphs of ciprofloxacin maleate and ciprofloxacin maleate monohydrate; DSC and TG analysis for ciprofloxacin maleate; PXRD analysis of residual materials after solubility of ciprofloxacin maleate form I, form II, and form III in the pH 1.2 solution (PDF)

4. CONCLUSIONS In some cases, the polymorphic behavior of a pharmaceutical compound may be overlooked by researchers. This, in turn, may lead to unpredictable changes of the physicochemical properties of a product, if a thermodynamically unstable polymorphic form of a compound is selected for drug processing. Pharmaceutical salt of CIP with maleic acid studied in this work is found to exist in three polymorphic forms and one hydrate. Crystal structures of all the forms were identified by single-crystal XRD. And to date, ciprofloxacin maleate is the only example of a polymorphic system among the fluoroquinolone salts, for which structural information for three

Accession Codes

CCDC 1501151−1501153 contain the supplementary crystallographic data for this paper. These data can be obtained free of 6565



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state NMR investigation of two polymorphic forms of Ciprofloxacinsaccharinate. Phys. Chem. Chem. Phys. 2011, 13, 6590−6596. (14) Zhang, G.; Zhang, L.; Yang, D.; Zhang, N.; He, L.; Du, G.; Lu, Y. Salt screening and characterization of ciprofloxacin. Acta Crystallogr., Sect. B: Struct. Sci., Cryst. Eng. Mater. 2016, 72, 20−28. (15) Tan, D.; Loots, L.; Frišcǐ ć, T. Towards medicinal mechanochemistry: evolution of milling from pharmaceutical solid form screening to the synthesis of active pharmaceutical ingredients (APIs). Chem. Commun. 2016, 52, 7760−7781. (16) Sheldrick, G. M. SADABS, Program for Scaling and Correction of Area Detector Data; University of Göttingen: Germany, 1997. (17) Sheldrick, G. M. A short history of SHELX. Acta Crystallogr., Sect. A: Found. Crystallogr. 2008, 64, 112−122. (18) Manin, N. G.; Fini, A.; Perlovich, G. L. Thermodynamics of potassium diclofenac salt aqueous solutions at various temperatures. J. Therm. Anal. Calorim. 2011, 104, 279−289. (19) Cox, J. D.; Pilcher, G. Thermochemistry of Organic and Organometallic Compounds; Academic Press: London, U.K., 1970. (20) Dovesi, R.; Orlando, R.; Erba, A.; Zicovich-Wilson, C. M.; Civalleri, B.; Casassa, S.; Maschio, L.; Ferrabone, M.; De La Pierre, M.; D’Arco, P.; Noël, Y.; Causà, M.; Rérat, M.; Kirtman, B. CRYSTAL14: A Program for the ab Initio Investigation of Crystalline Solids. Int. J. Quantum Chem. 2014, 114, 1287−1317. (21) Bader, R. F. W. Atoms in Molecules - A Quantum Theory; Oxford University Press: Oxford, 1990;. (22) Tsirelson, V. G. Interpretation of the Experimental Electron Densities by Combination of the QTAIM and DFT. In The Quantum Theory of Atoms in Molecules: From Solid State to DNA and Drug Design; Matta, C.; Boyd, R., Eds.; Wiley-VCH, Berlin, 2007; Chapter 10. (23) Gatti, C.; Saunders, V. R.; Roetti, C. Crystal field effects on the topological properties of the electron density in molecular crystals. The case of urea. J. Chem. Phys. 1994, 101, 10686−10696. (24) Tsirelson, V. G. The mapping of electronic energy distributions using experimental electron density. Acta Crystallogr., Sect. B: Struct. Sci. 2002, 58, 632−639. (25) Bertini, L.; Cargnoni, F.; Gatti, C. Chemical insight into electron density and wave functions: software developments and applications to crystals, molecular complexes and materials science. Theor. Chem. Acc. 2007, 117, 847−884. (26) Churakov, A. V.; Prikhodchenko, P. V.; Lev, O.; Medvedev, A. G.; Tripol’skaya, T. A.; Vener, M. V. A model proton-transfer system in the condensed phase: NH4+ OOH−, a crystal with short intermolecular H-bonds. J. Chem. Phys. 2010, 133, 164506. (27) Vener, M. V.; Medvedev, A. G.; Churakov, A. V.; Prikhodchenko, P. V.; Tripol’skaya, T. A.; Lev, O. H-Bond Network in Amino Acid Cocrystals with H2O or H2O2. The DFT Study of Serine−H2O and Serine−H2O2. J. Phys. Chem. A 2011, 115, 13657− 13663. (28) Mata, I.; Alkorta, I.; Espinosa, E.; Molins, E. Relationships between interaction energy, intermolecular distance and electron density properties in hydrogen bonded complexes under external electric fields. Chem. Phys. Lett. 2011, 507, 185−189. (29) Vener, M. V.; Egorova, A. N.; Churakov, A. V.; Tsirelson, V. G. Intermolecular Hydrogen Bond Energies in Crystals Evaluated Using Electron Density Properties: DFT Computations with Periodic Boundary Conditions. J. Comput. Chem. 2012, 33, 2303−2309. (30) Vener, M. V.; Shishkina, A. V.; Rykounov, A. A.; Tsirelson, V. G. Cl···Cl Interactions in Molecular Crystals: Insights from the Theoretical Charge Density Analysis. J. Phys. Chem. A 2013, 117, 8459−8467. (31) Shishkina, A. V.; Zhurov, V. V.; Stash, A. I.; Vener, M. V.; Pinkerton, A. A.; Tsirelson, V. G. Noncovalent Interactions in Crystalline Picolinic Acid N-Oxide: Insights from Experimental and Theoretical Charge Density Analysis. Cryst. Growth Des. 2013, 13, 816−828. (32) Vener, M. V.; Levina, E. O.; Koloskov, O. A.; Rykounov, A. A.; Voronin, A. P.; Tsirelson, V. G. Evaluation of the Lattice Energy of the

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AUTHOR INFORMATION

Corresponding Author

*Telephone: +7-4932-533784. Fax: +7-4932- 336237. E-mail [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the Russian Science Foundation (No. 14-13-00640). We thank “the Upper Volga Region Centre of Physicochemical Research” for technical assistance with the PXRD experiments. The authors would like to thank Ph.D. student Alexander P. Voronin for help with the DFT calculations.

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REFERENCES

(1) Bernstein, J. Polymorphism in Molecular Crystals; Clarendon Press: Oxford, U.K., 2002. (2) Aitipamula, S.; Chow, P. S.; Tan, R. B. Polymorphism in cocrystals: a review and assessment of its significance. CrystEngComm 2014, 16, 3451−3465. (3) Reddy, J. S.; Ganesh, S. V.; Nagalapalli, R.; Dandela, R.; Solomon, K. A.; Kumar, K. A.; Goud, N. R.; Nangia, A. Fluoroquinolone salts with carboxylic acids. J. Pharm. Sci. 2011, 100, 3160−3176. (4) Paluch, K. J.; McCabe, T.; Muller-Bunz, H.; Corrigan, O. I.; Healy, A. M.; Tajber, L. (). Formation and physicochemical properties of crystalline and amorphous salts with different stoichiometries formed between ciprofloxacin and succinic acid. Mol. Pharmaceutics 2013, 10, 3640−3654. (5) Bag, P. P.; Ghosh, S.; Khan, H.; Devarapalli, R.; Reddy, C. M. Drug−drug salt forms of ciprofloxacin with diflunisal and indoprofen. CrystEngComm 2014, 16, 7393−7396. (6) Romañuk, C. B.; Manzo, R. H.; Linck, Y. G.; Chattah, A. K.; Monti, G. A.; Olivera, M. E. Characterization of the solubility and solid-state properties of saccharin salts of fluoroquinolones. J. Pharm. Sci. 2009, 98, 3788−3801. (7) Basavoju, S.; Bostrom, D.; Velaga, S. P. Pharmaceutical Salts of Fluoroquinolone Antibacterial Drugs with Acesulfame Sweetener. Mol. Cryst. Liq. Cryst. 2012, 562, 254−264. (8) Florindo, C.; Costa, A.; Matos, C.; Nunes, S. L.; Matias, A. N.; Duarte, C. M. M.; Rebelo, L. P. N.; Branco, L. C.; Marrucho, I. M. Novel organic salts based on fluoroquinolone drugs: Synthesis, bioavailability and toxicological profiles. Int. J. Pharm. 2014, 469, 179−189. (9) Surov, A. O.; Manin, A. N.; Voronin, A. P.; Drozd, K. V.; Simagina, A. A.; Churakov, A. V.; Perlovich, G. L. Pharmaceutical salts of ciprofloxacin with dicarboxylic acids. Eur. J. Pharm. Sci. 2015, 77, 112−121. (10) Chadha, R.; Singh, P.; Khullar, S.; Mandal, S. K. Ciprofloxacin hippurate salt: crystallization tactics, structural aspects and biopharmaceutical performance. Cryst. Growth Des. 2016, 16, 4960. (11) Romañuk, C. B.; Linck, Y. G.; Chattah, A. K.; Monti, G. A.; Cuffini, S. L.; Garland, M. T.; Baggio, R.; Manzo, R. H.; Olivera, M. E. Crystallographic, thermal and spectroscopic characterization of a ciprofloxacin saccharinate polymorph. Int. J. Pharm. 2010, 391, 197− 202. (12) Cruz-Cabeza, A. J.; Reutzel-Edens, S. M.; Bernstein, J. Facts and fictions about polymorphism. Chem. Soc. Rev. 2015, 44, 8619−8635. (13) Linck, Y. G.; Chattah, A. K.; Graf, R.; Romanuk, C. B.; Olivera, M. E.; Manzo, R. H.; Monti, G. A.; Spiess, H. W. Multinuclear solid 6566



Article

Two-Component Molecular Crystals Using Solid-State DFT. Cryst. Growth Des. 2014, 14, 4997−5003. (33) Katsyuba, S. A.; Vener, M. V.; Zvereva, E. E.; Fei, Z.; Scopelliti, R.; Brandenburg, J. G.; Siankevich, S.; Dyson, P. J. Quantification of Conventional and Nonconventional Charge-Assisted Hydrogen Bonds in the Condensed and Gas Phases. J. Phys. Chem. Lett. 2015, 6, 4431− 4436. (34) Dominiak, P. M.; Espinosa, E.; Angyan, J. In Modern Charge Density Analysis; Gatti, C., Macchi, P., Eds.; Springer, Heidelberg, 2012; pp 387−433. (35) Etter, M. C. Encoding and Decoding Hydrogen-Bond Patterns of Organic Compounds. Acc. Chem. Res. 1990, 23, 120−126. (36) Bernstein, J.; Davis, R. E.; Shimoni, L.; Chang, N.-L. Patterns in Hydrogen Bonding: Functionality and Graph Set Analysis in Crystals. Angew. Chem., Int. Ed. Engl. 1995, 34, 1555−1573. (37) Brittain, H. G.; Byrn, S. R.; Lee, E. Structural Aspects of Polymorphism. In Polymorphism in Pharmaceutical Solids, 2nd ed.; Brittain, H. G., Eds.; Informa Healthcare: New York, 2009. (38) Pertsin, J.; Kitaigorodsky, A. I. The Atom-Atom Potential Method. Application to Organic Molecular Solids; Springer-Verlag: New York, 1987. (39) Gavezzotti, A. Efficient computer modeling of organic materials. The atom−atom, Coulomb−London−Pauli (AA-CLP) model for intermolecular electrostatic-polarization, dispersion and repulsion energies. New J. Chem. 2011, 35, 1360−1368. (40) Gavezzotti, A. Calculation of intermolecular interaction energies by direct numerical integration over electron densities. 2. An improved polarization model and the evaluation of dispersion and repulsion energies. J. Phys. Chem. B 2003, 107, 2344−2353. (41) Gavezzotti, A. Non-conventional bonding between organic molecules. The ‘halogen bond’in crystalline systems. Mol. Phys. 2008, 106, 1473−1485. (42) Surov, A. O.; Voronin, A. P.; Simagina, A. A.; Churakov, A. V.; Skachilova, S. Y.; Perlovich, G. L. Saccharin Salts of Biologically Active Hydrazone Derivatives. New J. Chem. 2015, 39, 8614−8622. (43) Gatti, C. Chemical Bonding in Crystals: New Directions. Z. Kristallogr. - Cryst. Mater. 2005, 220, 399−457.

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Three Polymorphic Forms of Ciprofloxacin Maleate: Formation

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