Cocrystals of Pentoxifylline: In Silico and Experimental Screening

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Cocrystals of Pentoxifylline: in silico and experimental screening Dmitrijs Stepanovs, Mara Jure, Liudmila N. Kuleshova, Detlef W. M. Hofmann, and Anatolij Mishnev Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.5b00185 • Publication Date (Web): 26 Jun 2015 Downloaded from http://pubs.acs.org on July 1, 2015

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Crystal Growth & Design

Cocrystals

of

Pentoxifylline:

in

silico

and

experimental screening Dmitrijs Stepanovs1, 2*, Māra Jure2, Liudmila N. Kuleshova3, Detlef W.M. Hofmann3, and Anatoly Mishnev1, 2* 1

Latvian Institute of Organic Synthesis, 21 Aizkraukles street, Riga, LV-1006, Latvia

2

Faculty of Material Science and Applied Chemistry, Riga Technical University, 3 Paula

Valdena street, Riga, LV-1007, Latvia 3

CRS4, Parco Scientifico e Technologico, Sardegna Ricerca, Edificio 1, Loc. Piscina Mana,

Pula, Italy 09010

KEYWORDS Pentoxifylline, aspirin, benzoic acid, salicylic acid, pharmaceutical cocrystals, single crystal Xray crystallography, cocrystal screening in silico

ABSTRACT To obtain new crystal forms with altered physicochemical properties and to get insight into the driving forces guiding cocrystallization, we performed experimental and in silico screening of pentoxifylline with 11 pharmaceutically acceptable organic acids. Neat grinding, liquid-assisted grinding and slow solvent evaporation were used to obtain cocrystals of pentoxifylline. The free energy of experimental and hypothetical crystal structures have been calculated using FlexCryst program. Three cocrystals of pentoxifylline with aspirin, salicylic acid and benzoic acid in a 1:1

ACS Paragon Plus Environment 1


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molar ratio have been obtained and characterized by physical methods. The experimental and in silico results were found to match very well. Strong correlation between melting points of pentoxifylline cocrystals and coformers has been detected. A significant decrease in solubility of pentoxifylline cocrystals as compared to pure pentoxifylline was observed.

INTRODUCTION Cocrystallization is a flourishing research field with direct application in the pharmaceutical industry.1 Pharmaceutical cocrystallization represents a promising approach to generate novel crystal forms. In the past decade, cocrystals have been a focus of attention as valuable modified forms of active pharmaceutical ingredients (APIs) with the potential to improve physicochemical2 and pharmacokinetic3 properties. The most challenging property of newly discovered forms is the change in solubility of cocrystals in comparison with the pure components. Cocrystals can provide higher or lower solubility compared to the API. For poorly soluble compounds synthesis of cocrystals may be an effective approach for improving their solubility.4,5 Together with experimental methods,6–13 various theoretical calculations14–17 have been suggested to minimize the costs of experimental efforts and introduce a "virtual filter" for the selection of an appropriate coformer (CF) already at a very early stage of research. The theoretical approaches are mainly based on the comparison of thermodynamic characteristics (free energy, enthalpy, electrochemical potentials etc.) of pure compounds vs cocrystals (CC). The supramolecular synthons were also considered as a driving force for cocrystallization; they play an important role while planning the cocrystallization strategy.18–20 Pentoxifylline (pen), C13H18N4O3, (3,7-dimethyl-1-(5-oxohexyl)-3,7-dihydro-1Hpurine-2,6-dione)(pen), is a nonselective methyl xanthine phosphodiesterase inhibitor, which increases erythrocyte cAMP activity and improves blood flow by decreasing its viscosity.21 Due


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to rapid and extensive absorption, pentoxifylline is formulated as sustained-release 400 mg orally administrated tablets.22 The ability of (pen) to form cocrystals has been mentioned recently23. We have already reported24 the formation of (pen) cocrystals with furosemide. Notably, pentoxifylline, similarly to cocrystals of caffeine3,25,26 and theophylline,27,28 form the H-bonded 2 heteromolecular dimmers with the graph R2 (7) . The formation of this complex was assumed to

be a promising instrument in crystal engineering of cocrystals.26 Here we will present the results of experimental search for pentoxifylline cocrystals accomplished with theoretical calculations of free energy to get benefits from both approaches. The set of selected coformers (Scheme 1) includes carboxylic acids (except L-ascorbic acid) 2 capable of forming the H-bonded dimmers with graph-set description R2 (7) between the

imidazole and carboxylic group during cocrystallization. The coformer selection was carried out in order to obtain cocrystals for development of pharmaceutical dosage forms, therefore three coformers are APIs (aspirin, furosemide and diclofenac) and the others are ‘generally regarded as safe (GRAS)’.29

EXPERIMENTAL SECTION Materials The API, coformers and solvents were purchased from commercial suppliers and used without further purification. For pentoxifylline two polymorphic forms have been reported in the literature: monoclinic30 and triclinic.31 The triclinic polymorph has been used in all cocrystallization experiments.



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Scheme 1. Structural Formulas of Cocrystal Components

pentoxifylline (pen)

acetylsalicylic acid (aspirin) (asa)

salicylic acid (sa)

benzoic acid (ba)

furosemide (fur)

p-aminobenzoic acid (aba)

p-aminosalicylic acid (as)

cinnamic acid (ca)

nicotinic acid (na)

4-hydroxyphenylacetic acid (hpa)

diclofenac (dic)

-ascorbic acid (laa)

L

2 Scheme 2. Representative heteromolecular H-bonded dimer, described with the graph R2 (7)

Carboxylic acid fragment

Imidazole (purine) fragment


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Neat (NC) and liquid-assisted (LAC) cogrinding Pentoxifylline and coformers listed in Scheme 1 in the molar ratio of 1:1 were mixed and milled in a Retsch MM301 ball mill (30 Hz) for 40 minutes in NC or for 20 minutes with addition of few drops of solvent in LAC. Suitable solvents were dichloromethane, acetone, acetonitrile, methanol and ethanol.

Powder X-ray diffraction Powder diffraction was used to observe the results of NC and LAC cocrystallization experiments. Powder X-ray data were collected at room temperature with 0.02° step and scan speed of 0.5 s/step on Rigaku ULTIMA IV powder diffractometer (CuKα radiation, λ = 1.5418 Å) equipped with parallel beam geometry.

Single crystal synthesis by slow solvent evaporation (SSE) Taking into account that cocrystals formed when (pen) and coformer were in 1:1 molar ratio, 30 mg (0.11 mmol) of (pen) gave (pen)(asa) cocrystals with 19 mg of (asa), using dichloromethane as solvent; (pen)(sa) cocrystals with 15 mg of (sa), using acetone as solvent; and (pen)(ba) cocrystals with 13 mg of (ba), using ethanol as solvent. In all mentioned cases slow evaporation of the solvent gives colorless crystals suitable for single crystal X-ray analysis. (pen) and the rest of the coformers do not produce cocrystals by SSE, as the PXRD pattern shows a mixture of starting materials.

Single crystal X-ray diffraction X-Ray diffraction data were collected using a Nonius Kappa CCD diffractometer (CuKα



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radiation, λ = 0.71073 Å), equipped with low temperature Oxford Cryosystems Cryostream Plus device. Data were collected using KappaCCD Server Software, cell refined by SCALEPACK,32 data reduction performed by DENZO32 and SCALEPACK, 32 structures solved by direct method using SIR200433 and refined by SHELXL9734 as implemented in the program package WinGX.35 All non-hydrogen atoms were refined anisotropically. The hydrogen atoms bound to carbon atoms and the carboxyl groups were positioned geometrically, with C–H = 0.93–0.97 Å and O–H = 0.82 Å, and refined as riding, with Uiso(H) = 1.2 or 1.5Ueq(C,O). Software used to prepare CIF36 files was SHELXL97.34

Differential Scanning Calorimetry (DSC) and Thermogravimetry (TG) DSC and TG were conducted by use of a SETARAM Setsys 1750CS Evolution with DSC S-type rod using Gallium and Indium for calibration. Accurately weighed samples (7-10 mg) were placed in alumina crucibles and scanned from 12 °C to 300 °C at 10 °C/min under nitrogen purge. Results of DSC and TG are available in the Supporting information, Figure S3a-S3b.

Elemental analysis (EA) and Fourier-transform infrared spectroscopy (FT-IR) EA was performed on Carlo ERBA Instruments EA1108 elemental analyzer (results of EA are available in the Supporting information, Table S1). FT-IR was performed at room temperature on Shimadzu Corp. IRPrestige-21 spectrometer (FT-IR spectra available in the Supporting information, Figure S2).


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UV/vis spectrometry and solubility experiments The concentration of cocrystal aqueous solutions was determined by UV/vis using Camspec M501 UV/vis Spectrophotometer. UV/vis absorbtion spectra in the 200-400 nm range were recorded for all samples. One separate linear calibration curve was plotted for (pen). The absorption maxima at wavelength 274 nm was used to calculate the concentrations for all samples. Solubility Experiments. The cocrystal solubility was determined by dissolving excess cocrystal in 5 mL of deionized water at room temperature (23 ± 1 °C). Suspensions were mixed for 24 h. The concentration of the cocrystal in the solution was determined by UV/vis spectrometry, and composition of the solid phase was analyzed by PXRD. UV/vis measurements were performed in triplicate.

Crystal lattice energy calculation and crystal structure prediction In parallel to our experimental attempts of obtaining cocrystals we have done the in silico screening of cocrystal stability as it was described in ref.37 To obtain the free energy of crystal structures, G, the FlexCryst program suite was used (www.flexcryst.com).38 For screening purposes, the attractive features of this program are the rapid algorithm for crystal structure prediction and the data mining force field (DMFF).38,39 The energy function of the DMFF is calibrated to the free energy and possesses valuable qualities of parameters and acceptable CPU times both in crystal energy calculation and for crystal structure prediction.15 For the calculations, we used the FlexCryst program modules: SCORE – to calculate and minimize the energies of the experimental crystal structures (Gexp_min) and PREDICT – to predict the crystal structures of hypothetical cocrystals (Gpred). We check the goodness of the used energy function



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for a given set of crystals via estimation of the correlation between these values (Gexp_min and Gpred). Calculation of the correlation coefficient for coformers, the polymorphs of pentoxifylline and cocrystals obtained gave the value of 0.99, indicating proper accuracy of the calculations. The other important point follows from this consideration. The multiple blind tests of crystal structure prediction, organized by the Cambridge Crystallographic Data Centre,40 have shown that in the surrounding of the global minimum within the narrow energy range of 1-2 kJ/mol, hundreds of hypothetical polymorphs can be found. This obstacle of the crystal structure prediction method has, nevertheless, an obvious advantage for the aim of a quick screening. It gives the possibility to operate with the energy of the first rank of a predicted structure without the analysis of crystallographic characteristics of the structure. The following procedure for prediction was applied. As an input for the prediction, we used the molecular geometry of components taken from the experimental crystal structures and this geometry was kept rigid during the prediction. It should be noted that for the molecules with high degree of freedom the use of the fixed molecular conformation is clearly not appropriate. In the same time, for molecules with moderate or low degree of freedom the approach is feasible: the crystal structure prediction has to be carried out separately for any reasonable molecular conformation. Here for the prediction of pentoxifylline cocrystals we used molecular conformations of pentoxifylline and conformers from experimental crystal (or cocrystal) structures, so, in this case, the energy calculations were plausible. Five space groups were taken into account in the prediction: P 1 , P21, P21/c, C2/c, P212121, with 1 and 2 complexes in the asymmetric unit. Desired coverage of the energy landscape was chosen as 50%. The maximum CPU time for a prediction was restricted to 10 hours, but typically, it did not exceed several hours on a PC.


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RESULTS AND DISCUSSION Experimental detection of cocrystals The PXRD patterns for initial materials and (pen)(asa) cocrystal obtained by different synthetic methods are shown in Figure 1. As it follows from the superposition of starting powder diagrams the NC does not result in a new solid after 40 minutes of grinding, whereas the products from LAC and SSE give the same new PXRD patterns, indicating the appearance of a new solid.

Figure 1. Comparison of PXRD patterns of the starting materials and products from NC, LAC and SSE

Figure 2. Experimental (red) and calculated41 (blue) PXRD patterns of (pen)(asa)

The calculated* X-ray diffraction pattern of (pen)(asa) solid and experimental pattern of

LAC and SSE products are match very well (Figure 2) (calculated41 pattern is shifted a little to higher 2-Θ values, because PXRD pattern was measured at room temperature, while the single crystal X-ray measurement was carried out at low temperature of 173 K). In the same way the

*

A calculated PXRD patterns were generated from the single crystal structures using Mercury CSD 31.141 and compared with the patterns collected from the bulk sample



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(pen)(sa) and (pen)(ba) cocrystals † were obtained using NC, LAC, SSE experiments and confirmed with PXRD. In all other cocrystal screening experiments, for (aba), (as), (ca), (na), (hpa), (dic) and (laa), the superposition of PXRD patterns were observed, indicating failures in cocrystal formation during NC, LAC and SSE.

In silico screening and calculations of cocrystal stability To clear up the results of experimental screening we have accomplished our investigations with the theoretical estimation of cocrystal stability. Our approach to in silico screening of cocrystals, as the other similar approaches,16,42 is based on the simple thermodynamic arguments,‡ that a cocrystal can be formed if its total free energy GCC is lower than the sum of the lattice energies of its pure components (GAPI + GCF). According to the approach suggested in ref.37, the feasibility of cocrystal formation we link with the difference ∆G between the sum of free lattice energies of pure components (GAPI + GCF) and free lattice energy of cocrystal GCC : if ∆G is positive, the formation of a cocrystal is possible, if ∆G gets negative value, the formation of a cocrystal is unlikely. It should be noted that as the output of FlexCryst program the crystal lattice energy G is expressed in kJ/mol per molecule; therefore the sum of free lattice energies of the components has to be divided by the number of molecules in the asymmetric unit of the elementary cell of the cocrystal. ∆G for two-component cocrystals of (pen) with 1:1 stoichiometry can be calculated:

∆G = 1/2 (G(pen) + GCF) – GCC . †

The formation of these cocrystals was reported also in ref.,23 but the results of the X-ray analysis were neither published in scientific journals nor deposited in CCDC ‡ It is obvious that the crystallization process comprises both thermodynamics and kinetic aspects. Crystal structure prediction method, which we used in FlexCryst approach, takes into account only thermodynamics aspect. The inclusion of kinetic effects to the crystal structure prediction presently is out of the possibilities for the tremendous CPU-time and for the weakly developed theory.


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The results of the stability calculations are listed in the Table 1. We have also included the results for a cocrystal with furosemide (fur), whose structure we reported earlier.24 According to ref.37 the formation of a cocrystal is recognized as preferable if ∆G ≥ 0 kJ/mol. It was also noted that the more general criterion for cocrystal formation would be ∆G ≥ -3 kJ/mol, which takes into account the accuracy of the method, which we evaluate as ±3 kJ/mol. This criterion will be helpful to keep for further examinations of cocrystals, which can still be recognized as possible. In Table 1 the preferred cases are marked with , possible – , cases of unsuccessful cocrystallization – .

Table 1. The results of in silico screening for cocrystals of pentoxifylline. (The predicted G values of hypothetical cocrystals are marked with the asterisk; lattice energy of triclinic polymorph of (pen), Gexp_ min = –170.87 kJ/mol) Refcode43 (coformer)

Gexp_min kJ/mol

Cocrystallization result

ACSALA (asa) SALIAC(sa) BENZAC(ba)

-93.17 -78.71 -77.96

(pen)(asa) (pen)(sa) (pen)(ba)

FURSEM(fur) AMBNAC(aba) AMSALA(as) CINMAC(ca) NICOAC(na) DLMAND(hpa) SIKLIH(dic) LASCAC(laa)

-193.95 -120.75 -128.53 -90.96 -79.25 -87.17 -146.71 -82.24

(pen)(fur)24 (pen)(aba) (pen)(as) (pen)(ca) (pen)(na) (pen)(hpa) (pen)(dic) (pen)(laa)

Gexp_,min (*Gpred) kJ/mol -134.24 -124.65 -122.47 -125.62* -190.18 -135.19* -140.11* -125.46* -117.47* -122.31* -148.99* -118.11*

Gsumm kJ/mol -132.02 -124.79 -124.42 -182.41 -145.85 -149.67 -130.92 -125.06 -129.06 -158.79 -126.51

∆G kJ/mol 2.22 -0.14 -1.95 1.20 7.71 -10.66 -9.56 -5.46 -7.59 -6.75 -9.80 -8,40

In total, the results of experimental and in silico screening of cocrystals match very well. Cocrystals of (pen)(asa) and (pen)(fur) have been detected as preferable according to criterion



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∆G ≥ 0 kJ/mol, (pen)(sa) and (pen)(ba) as possible, according to criterion ∆G ≥ -3 kJ/mol. Other cocrystallization experiments, that failed, were appraised as unfavorable. It ensures both the completeness of experimental attempts and correctness of theoretical calculations of lattice energy. For (pen)(ba), which has four independent molecules in the asymmetric unit (2:2 stoichiometry), we have also estimated the energy of a hypothetical cocrystal with 1:1 stoichiometry. These data, marked with asterisk, are listed in the Table 1. As one can see, more “equilibrated” 1:1 structure would get somewhat (~3.2 kJ/mol) lower lattice energy and with positive ∆G can be considered as preferable. The same criteria of preferable and possible formation of cocrystals also proved to be valid for cocrystals of caffeine having the same purine fragment as pentoxifylline (Table 2). Among 23 experimentally available cocrystals in CSD,43 15 cocrystals were evaluated as preferable (∆G ≥ 0), 5 cocrystals were estimated as possible (∆G > -3 kJ/mol). Around half of the structures fall to the tolerance interval ±3 kJ/mol. Thus the data for caffeine cocrystals encourage the use of the more general criterion ∆G > -3 kJ/mol rather than ∆G ≥ 0.

Table 2. The results of in silico screening of cocrystals of caffeine (caf) (structural data from CSD, Version 5.34)43 N

Cocrystal/ refcode43

∆G

Cocrystal/ refcode43

N

∆G

1

(caf)(2-phthaliminoethanoic acid)/ AYOROW

-4.66 13 (caf)(4-fluoro-3-nitroaniline)/ LATGIJ

2.04

2

(caf)(methyl gallate)/ DIJVOH

5.42 14 (caf)(2-fluoro-5-nitrobenzoic acid)/ LATHIZ

-1.98

3

(caf)(glutaric acid)/ EXUQUJ

-1.82 15 (caf)(4-nitroaniline)/ LATGUK

4

(caf)(maleic acid)/ GANYEA

0

16 (caf)(2-fluoro-5-nitroaniline)/

1.1

2.26

LATHEV

5

(caf)(p-coumaric acid)/ IJEZUT

-0.96 17 (caf)(3-hydroxybenzoic acid)/ MOZCOU

6

(caf)(citric acid)/

-9.4 18 (caf)(2,5-dihydroxybenzoic acid)/

5.1

22.09


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KIGKER

MOZDIP

7

(caf)(1-hydroxy-2-naphthoic acid)/ KIGKIV

8.74 19 (caf)(D-tartaric acid)/ NEXWUJ

10.24

8

(caf)(3-hydroxy-2-naphthoic acid)/ KIGKOV

5.82 20 (caf)(isophthalic acid)/ PUPGUD

1.88

9

(caf)(2-hydroxy-1-naphthoic acid)/ LAKXUS

2.6

21 (caf)(N-acetylsulfanilamide)/

-2.04

SACCAF

10 (caf)(2-iodo-4-nitroaniline)/ LATFUJ

8,66 22 (caf)(1H-pyrazole-3,5-dicarboxylic

11 (caf)(4-iodo-3-nitroaniline)/ LATGAQ

8.86 23 (caf)(salicylic acid)/ XOBCAT

12 (caf)(4-chloro-3-nitroaniline)/ LATGEU

6.5

-0.28

acid)/UNISUG 2.54

It should be noted that in 3 cases (for cocrystals AYOROW (1), KIGKER (6), NEXWUJ (19)) the calculations did not predict the formation of cocrystals. We see several possible

reasons, which still to be checked in more detail, to avoid getting false negative results during in

silico screening in the future.

These three mentioned co-formers have shown the largest

discrepancy in accuracy check, performed as described in the Experimental Section. As the result the correlation coefficient (between Gexp_min and G pred) for the set of caffeine cocrystals was lowered to R2=0.85. On the other hand caffeine crystals are stable in hydrate form. Unhydrous form, which was used in our study, has 5 independent molecules in elementary unit cell and shows tendency to form disordered crystal structure.

3.3. The results of single crystal X-ray analysis Crystallographic data of (pen)(asa), (pen)(sa) and (pen)(ba) cocrystals and the details of structure refinement are listed in Table 3. ORTEP-335 drawings of the asymmetric units of the structures are given in Figure 3. Mercury41 drawings in Figure 4 show the heteromolecular dimers formation in the structures.



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Table 3. General and crystallographic data for the reported (pen) cocrystals molecular formula Mr crystal system space group a, Å b, Å c, Å α, ° β, ° γ, ° V, Å3 Z Dc/g cm-3 F(000) µ(Mo Kα)/mm-1 T/K crystal size/mm range of indices

collected reflections unique reflections Rint reflections with I > 2σ(I) no. parameters R(F), F > 4σ( F) wR(F2), F > 4σ( F) R(F), all data wR(F2), all data ∆ρ (max., min), eÅ-3 CCDC deposition number

(pen)(asa) (C13H18N4O3)·(C9H8O4) 458.46 triclinic P1 9.4429 (5) 10.5278 (5) 13.1342 (10) 76.258 (2) 77.904 (2) 64.958 (3) 1140.26 (12) 2 1.335 484 0.101 173 (2) 0.45 × 0.15 × 0.08 h = –11→12 k = –13→13 l = –17→15 7807 5133 0.044 2562 300 0.067 0.124 0.163 0.155 0.21 and –0.18 965846

(pen)(sa) (C13H18N4O3)·(C7H6O2) 416.43 triclinic P1 6.7116(3) 8.4599(4) 19.3789(10) 83.936(2) 82.982(2) 70.404(4) 1026.36(9) 2 1.347 440 0.101 173 (2) 0.45 × 0.15 × 0.10 h = –8→8 k = –8→10 l = –20→25 6627 4628 0.051 2325 274 0.070 0.166 0.165 0.132 0.31 and -0.31 965847

(pen)(ba) (C13H18N4O3)·(C7H6O) 800.86 triclinic P1 13.3663(3) 13.4558(3) 14.1787(5) 64.7180(10) 81.0520(10) 60.983(2) 2012.10(11) 2 1.322 848 0.097 296 (2) 0.45 × 0.35 × 0.15 h = –17→16 k = –15→17 l = –15→18 13569 9151 0.047 359 531 0.074 0.209 0.210 0.163 0.44 and -0.22 965848

Cocrystals of (pen)(asa) are triclinic, space group P 1 with one pair of (pen) and (asa) molecules in the asymmetric unit. The atoms forming the dimer lie in one plane with a maximum deviation of 0.052 Å from the least-squares plane. Hydrogen bonds forming the dimer are listed in Table 4. To decide whether (pen)(asa) is a cocrystal or a salt, two factors were taken into consideration4: 1) C–O and C=O bond length of (asa); 2) C2–N3–C4 angle in (pen). C–O and C=O bond length of (asa) are 1.216(3) and 1.314(4) Å, respectively, indicating that (asa) exists as a neutral molecule. Finally, the C2–N3–C4 angle in (pen) is 103.7(2)° smaller in comparison


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with the protonated methyl xanthines.44,45 Moreover, according to the difference Fourier synthesis of electron density, a hydrogen atom was located on a carboxylic group and refined in isotropic approximation. So, both considerations unambiguously confirm that (pen)(asa) solid is a cocrystal. π–π stacking interactions have been found in the cocrystals: one interaction takes place between purine systems of (pen) with centroid–centroid distance 3.49 Å. The second π–π stacking interaction is between purine systems of (pen) and benzene rings of (asa) with centroid–centroid distance 3.72 Å. The dihedral angle between least-squares planes of purine system of (pen) and benzene ring of (asa) is 15.3°.

Table 4. Hydrogen-bond geometry for (pen) cocrystals D–H⋅⋅⋅A

dD–H (Å)

dH⋅⋅⋅A (Å)

O22–H22⋅⋅⋅N3 C2–H2⋅⋅⋅O21

0.82 0.93

1.89 2.50

O22–H22⋅⋅⋅N3 C2–H2⋅⋅⋅O21 O30–H30⋅⋅⋅O21

0.82 0.93 0.82

1.84 2.51 1.85

O22–H22⋅⋅⋅N3 C2–H2⋅⋅⋅O21 O51–H51⋅⋅⋅N30 C31–H31⋅⋅⋅O50

0.82 0.93 0.82 0.93

2.01 2.52 1.92 2.57

dD⋅⋅⋅A (Å) (pen)(asa) 2.704(3) 3.140(4) (pen)(sa) 2.664(3) 3.134(4) 2.573(3) (pen)(ba) 2.815(3) 3.177(4) 2.738(3) 3.198(5)

∠ D–H⋅⋅⋅A (°)

Symmetry code

176 126

1 – x, 1 – y, 2 – z 1 – x, 1 – y, 2 – z

178 125 146

– x, 1 – y, 2 – z – x, 1 – y, 2 – z intra

169 128 174 125

1 – x, 1 – y, 1 – z 1 – x, 1 – y, 1 – z 1 – x, 1 – y, – z 1 – x, 1 – y, – z



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(pen)(asa)

(pen)(asa)

(pen)(sa)

(pen)(sa)

(pen)(ba)

(pen)(ba)

Figure 3. ORTEP-335 drawings of the asymmetric units of the cocrystals showing the atom-numbering scheme

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Figure 4. The structures showing heteromolecular dimers, described with the R22 (7) graph; atoms, which participate in dimer formation are highlighted as spheres (Mercury CSD 31.141)

Cocrystals (pen)(sa) and (pen)(ba) are triclinic, too. They crystallizes in space group P 1, with one molecule of (pen) and one (sa) in asymmetric unit for (pen)(sa) and two molecules of (pen) and two – (ba) in asymmetric unit for (pen)(ba). The formation of heteromolecular H-


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bonded dimer with graph set R22 (7) in both cocrystals is analogous to the case of (pen)(asa). The formation of cocrystal (instead of salt) was established in the same way as in case of (pen)(asa). The maximum deviation from R22 (7) least-squares plane is 0.012 Å in (pen)(sa) and [0.079/0.099] Å in (pen)(ba). Only one type of π–π stacking interaction is present in (pen)(sa): between purine system of (pen) and benzene ring of (sa) with centroid–centroid distance is 3.40 Å; in (pen)(ba): between purine system of (pen) and benzene ring of (ba) with centroid–centroid distance is 3.51, 3.52 and 3.66 Å. The angle between least-squares planes of purine system in (pen) and benzene ring in (sa) is 3.4° in (pen)(sa) and 4.2, 5.0 and 4.3° in (pen)(ba). In order to investigate the influence of the crystal environment on the molecular conformation of (pen) in single component and cocrystal structures the selected torsion angles (Scheme 3) are listed in Table 5.

Scheme 3. Selected torsion angles in (pen).

Table 5. Selected torsion angles of (pen) molecule in crystal structures Compound (pen) (triclinic)31 (pen) (monoclinic)30 (pen) (fur)24 (pen) (fur) CC hydrate24 (pen) (fur) CC acetone solvate24 (pen)(asa) (pen)(sa) (pen)(ba)

τ1 75.6(3) -175.8(2) -168.5(3) -179.2(4) 175.8(3) 170.3(2) 175.0(2) -178.0(3)/ 177.3(3)

τ2 173.7(2) 71.4(3) -160.3(3) 165.5(4) 169.9(3) 176.0(2) -170.6(2) 178.6(3)/ -179.8(3)

τ3 -176.6(2) 178.3(2) -69.3(4) -77.0(6) 67.7(4) -75.9(3) -171.5(3) 176.5(3)/ -176.0(4)



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From the data presented in Table 5, it can be seen that 5-oxohexyl group in (pen) is flexible and adopts different positions in known crystal structures.

Physicochemical properties and their correlations It is a well-established fact that cocrystals have altered physicochemical properties in comparison with APIs and coformers. According to statistics obtained on the basis of available examples 51% of cocrystals have melting points between those of API and coformer and 39% have lower than those of API and coformer.8 Table 6 summarizes some physicochemical properties of (pen) cocrystals, API and coformers measured in our work. As follows from Table 6 the melting points of (pen)(asa), (pen)(sa) and (pen)(ba) cocrystals are lower than those of the respective API and coformers. For (pen)(fur) cocrystal the melting point lies between melting points of API and coformer.

Table 6. Physicochemical properties of (pen) and (pen) cocrystals Cocrystal (pen)(asa) (pen)(sa) (pen)(ba) (pen)(fur)

Melting point (ºC) (pen) CF CC 106 142 84 106 158 98 106 121 91 106

206

163

(pen) 77 77 77 77

Water solubility, mg/ml (pen)§ CF CC 4.60 46.4 ± 1.3 28.2 ± 0.8 2.24 8.6 ± 1,4 5.7 ± 1.0 3.40 10.2 ± 0.6 7.1 ± 0.4 0.64 ± 0.29 ± 0.0724 0.030 0.014**

In our case (pen) is very well soluble in water. According to measured values (Table 6) (pen) cocrystals exhibit much lower solubility than API. It was already mentioned that pentoxifylline, when administrated orally, is rapidly absorbed and eliminated from the body within 1-2 hours.22 Therefore it is commercially available in the form of sustained-release §

Concentration of (pen) in (pen)(asa) solution Concentration of (fur) in (pen)(fur) solution is 0.35 ± 0.016

**


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tablets. Modified chitosan and alginate-based scaffolds aimed to improve pentoxifylline release properties are described.46 In our work we have varied the solubility by employing a cocrystalengineering approach. On the other hand the solubility of coformers is much improved, including furosemide, which itself is a diuretic drug with low solubility. It should be noted that solubility of (pen)(ba) and (pen)(sa) (equal to 8.18 and 9.03 mg/ml, respectively) published earlier19 is in good agreement with our data. Examination of solid phase after solubility experiments shows that in case of (pen)(asa) the precipitate contains a mixture of (asa) and cocrystal. In the rest of the cases solid phase precipitate contains only initial cocrystals. A search for the correlation between melting points of coformers and cocrystals, a topic actively discussed the past several years, can provide simple rules for rational coformer choice in design of cocrystals with desirable thermal properties.8,47,48 For AMG 517 (vanilloid receptor 1 antagonist) substance the authors found a 78% correlation between melting points of cocrystal and coformer.47 Strong correlation of 81% between melting points was observed for 2acetaminopyridine cocrystals.48 However, for cocrystals of diclofenac with substituted pyrazoles, pyridines and pyrimidines no direct correlation between melting points of individual components and cocrystals have

been found.49 These examples show that to some extent a design of

cocrystals with desirable thermal properties can be possible only within a definite series of coformers.



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Figure 5. Melting onset (pen) cocrystals versus coformer

In our work a very good correlation (86%) has been achieved already for 4 (pen) cocrystals (data marked in red in Figure 5). The correlation coefficient kept the value even after including the already mentioned23 data on cocrystals of pentoxifylline with the other aromatic carboxylic acids (marked in blue).

Figure 6. Correlation between free lattice energies of coformers and (pen) cocrystals The correlation within sets of cocrystals and coformers for a given API becomes even more pronounced if we consider the free lattice energies of cocrystals of pentoxifylline: R2 rises to


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0.9995 (Figure 6). At the same time, it is important to note that the correlation is kept just within the set of structurally similar coformers for a given API.

CONCLUSIONS Experimental and in silico screening of pentoxifylline with a series of pharmaceutically acceptable carboxylic acids having aromatic fragment and L-ascorbic acid allowed us to find three new pentoxifylline cocrystals which were characterized by PXRD, single crystal X-ray diffraction, DSC/TG, FT-IR and UV/vis. The results of liquid-assisted co-grinding and slow solvent evaporation experiments match very well with theoretical calculations of cocrystal stability. Failed cocrystallization experiments were appraised as unfavorable according to theoretical stability calculations. Experience obtained in prediction of cocrystal formation of (pen), caffeine and other compounds using FlexCryst software suggest a more general condition, namely, ∆G ≥ -3 kJ/mol, rather than ∆G ≥ 0 kJ/mol, for acceptance of predicted structures as feasible. Analysis of molecular conformation of (pen) in its polymorphs and cocrystals showed that 5-oxohexyl group in (pen) is flexible and adopts different conformations in different crystal structures. All (pen) cocrystal structures exhibited the presence of heteromolecular H-bonded dimers with graph set R22 (7) and intermolecular π-π stacking interactions. It has been found that melting points of (pen)(asa), (pen)(sa) and (pen)(ba) cocrystals are lower than those of API and coformer while for (pen)(fur) cocrystal the melting point lies between the melting points of API and coformer. Strong correlation between melting points of (pen) cocrystals and coformers has been detected. The correlation becomes even more pronounced if one considers the free lattice energies of (pen) cocrystals and coformers. However the results obtained in our work and by other authors suggest that normally correlations hold well only for a given API within a series of



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similar (or, better, homological) rows of coformers. We observed a significant decrease in solubility of (pen) cocrystals in comparison with pure (pen), which is very soluble in water.

ASSOCIATED CONTENT Supporting information X-ray crystallographic information files (CIF), results of the elemental analysis, FT-IR spectra for (pen)(asa), DSC/TG thermograms for (pen), (asa) and (pen)(asa). This material is available free of charge via the Internet at http://pubs.acs.org. Crystallographic data of (pen)(asa), (pen)(sa) and (pen)(ba) have been deposited in Cambridge Crystallographic Data Centre (CCDC 965846-965848). Copies of the data can be obtained free of charge on application to CCD via www.ccdc.cam.ac.uk/data_request/cif. AUTHOR INFORMATION Corresponding Author

Anatoly Mishnev, [email protected] Present Addresses

† Latvian Institute of Organic Synthesis, 21 Aizkraukles street, Riga, LV-1006, Latvia Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

ACKNOWLEDGEMENT


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The authors are pleased to express their gratitude to Dr V. Grekhov for DSC/TG measurements. This research was partially supported by EC 7th Framework Programme project REGPOT-CT2013-316149-InnovaBalt. D.S. thanks the European Social Fund (No. 1DP/1.1.1.2.0/13/APIA/VIAA/011) for the opportunity to attend International EXPO/SIR workshop.

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For Table of Contents Use Only Cocrystals of Pentoxifylline: in silico and experimental screening Dmitrijs Stepanovs, Māra Jure, Liudmila N. Kuleshova, Detlef W.M. Hofmann, and Anatoly Mishnev

Experimental and in silico screening of pentoxifylline with a series of pharmaceutically acceptable carboxylic acids resulted in synthesis of three pentoxifylline cocrystals. Unsuccessful cocrystallization experiments were evaluated as unfavorable according to theoretical calculations of stability. Strong correlation between melting points of pentoxifylline cocrystals and coformers has been detected. Significant decrease in solubility of cocrystals in comparison with pure pentoxifylline was observed.


Cocrystals of Pentoxifylline: In Silico and Experimental Screening

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