New pharmaceutical cocrystal forms of flurbiprofen: structural

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New pharmaceutical cocrystal forms of flurbiprofen: structural, physicochemical and thermodynamic characterization Artem O. Surov, Alex N. Manin, Alexander P. Voronin, Denis Boycov, Oxana Magdysyuk, and German L. Perlovich Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.9b00781 • Publication Date (Web): 21 Aug 2019 Downloaded from pubs.acs.org on August 23, 2019

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Crystal Growth & Design

New pharmaceutical cocrystal forms of flurbiprofen: structural, physicochemical and thermodynamic characterization† Artem O. Surov1, Alex N. Manin1, Alexander P. Voronin1, Denis E. Boycov1, Oxana V. Magdysyuk2, German L. Perlovich1*

1G.A.

Krestov Institute of Solution Chemistry of the Russian Academy of Sciences, 1 Akademicheskaya St., 153045 Ivanovo, Russia;

2Diamond

Light Source Ltd, Harwell Science and Innovation Campus, Didcot, OX11 0DE, UK.

*To whom correspondence should be addressed: Telephone: +7-4932-533784; Fax: +74932- 336237; E-mail [email protected]

†In

memory of Oleg A. Raevsky

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Abstract

In this work, three new cocrystals of the nonsteroidal anti-inflammatory drug flurbiprofen with salicylamide, benzamide and picolinamide have been discovered using thermodynamic analysis of solid-liquid binary phase diagrams, and their crystal structures have been determined from the high-resolution synchrotron powder diffraction data. Periodic DFT calculations have been carried out to gain additional insight into energy differences between the cocrystal structures. The pH-solubility behavior and solubility advantage of the cocrystals have been examined via eutectic concentrations of the components, and the thermodynamic stability relationships between different solid phases have been rationalized in terms of Gibbs energies of the formation reactions. In addition, a new model has been proposed for estimating the solubility product (Ksp) of a cocrystal, based on the experimental intrinsic solubility of the drug and coformer complemented by calculated physicochemical HYBOT descriptors. The relationship between the change in Gibbs free energy and the molecular volume of cocrystal formation has been observed and discussed.

1. Introduction


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Flurbiprofen (FBP) belongs to an important class of nonsteroidal anti-inflammatory drugs (NSAIDs), and is widely used as an effective pain reliever and a medicine for treatment of rheumatoid arthritis and osteoarthritis.1,

2

In addition, recent studies have

revealed that flurbiprofen can be a promising therapeutic agent for Alzheimer’s disease treatment.3-5 However, poor bioavailability and low brain permeability of FBP requires the design of special delivery systems capable of overcoming the blood–brain barrier and transporting the drug into the brain.6 According to the Biopharmaceutics Classification System (BCS),7 FBP is a class II drug with high permeability and low solubility, and the latter limits both its therapeutic application and efficacy. Various formulation strategies have been reported to improve the solubility and dissolution rate of flurbiprofen, including solid dispersion,8 solid lipid nanoparticles,9 inclusion complex with

cyclodextrins10,

11

and

cycloamyloses,12

nanosuspensions13

and

self-

nanoemulsifying drug delivery systems.14 An alternative approach to improving the physicochemical profile of an active pharmaceutical ingredient (API) implies modification of its supramolecular structure, i.e. changing the packing arrangement of molecules in the solid state by introducing an acceptable second component (coformer) with good water solubility in order to form a pharmaceutical cocrystal. The cocrystallization strategy is nowadays recognized as a common approach to altering and tuning of the most critical physicochemical properties of drug compounds such as solubility, dissolution rate, stability, bioavailability, mechanical strength, permeability, etc.15-18 Compared to other related NSAID compounds, the ability of flurbiprofen ACS Paragon Plus Environment


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to form multicomponent solids is not well investigated. The reported examples include cocrystals with 4,4-bipyridine and trans-1,2-bis(4-pyridyl)ethylene.19 It has also been shown that cocrystallization of flurbiprofen with nicotinamide can simultaneously improve several key pharmaceutical properties such as dissolution rate, moisture sorption, and mechanical properties.20 Recently, the series of cocrystals of enantiopure and racemic flurbiprofen has been considerably extended by combining the API with amino acid proline, resulting in 18 novel solid forms.21 In this study, a series of complementary highly water soluble carboxamide compounds (salicylamide, benzamide, picolinamide), which are pharmaceutically acceptable or biologically safe, has been selected to react with flurbiprofen to improve the API poor solubility performance (Figure 1). Moreover, the cocrystal comprised of flurbiprofen and salicylamide (2-OHBZA) may be considered a drug-drug product,22, 23 as the coformer (2-OHBZA) is a mild analgesic with anti-inflammatory and antipyretic properties.24 The thermodynamic approach, which implies the construction of solid-liquid binary phase diagrams, has been used to form cocrystals between the components and to identify their stoichiometry. The crystal structures of the FBP cocrystals were solved from the high-resolution synchrotron powder diffraction data and their crystal lattice and cocrystallization energies were evaluated using periodic DFT calculations. The pHsolubility behavior and solubility advantage of the cocrystals were examined via eutectic concentrations of the components, and the thermodynamic stability relationships


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between different solid phases were rationalized in terms of Gibbs energies of the formation reactions. In addition, a new model has been proposed for estimating the solubility product (Ksp) of a cocrystal, based on experimental intrinsic solubility of the drug

and

coformer

complemented

with

calculated

physicochemical

HYBOT

descriptors.25 The database of the reported intrinsic solubility and Ksp values was also used to derive and analyze the Gibbs energies of formation for 41 cocrystals. We have also found that the molecular volume of cocrystal formation26-28 can be used as a numerical parameter to estimate the thermodynamic stability of the resulting cocrystal.

Figure 1. Molecular structures of flurbiprofen (FBP), benzamide (BZA), picolinamide (PicAm) and salicylamide (2-OHBZA)

2. Materials and Methods

2.1. Compounds and solvents ACS Paragon Plus Environment


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Flurbiprofen (C15H13FO2, 98%), salicylamide (C7H7NO2, 99%), benzamide (C7H7NO, 99%) and picolinamide (C6H6N2O, 98%) were purchased from Acros Organics. All the solvents were available commercially and used as received without further purification.

2.2. Construction of binary phase diagrams In the construction of binary (solid + liquid) phase diagrams for the studied systems, DSC measurements were performed on mixtures of different composition prepared by liquid-assisted grinding. The grinding was performed using a Fritsch planetary micro mill model Pulverisette 7 with 12 mL agate grinding jars and ten 5 mm agate balls at a rate of 500 rpm for 30 min. The solvent-drop grinding experiments were conducted by adding ca. 50 μL of ethanol to the physical mixture of FBP with the selected coformer (ca. 80 mg).

2.3. Differential scanning calorimetry (DSC) The thermal analysis was carried out using a differential scanning calorimeter with a refrigerated cooling system (Perkin Elmer DSC 4000, USA). The sample was heated in a sealed aluminium sample holder at a rate of 2 °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.


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2.4. Powder X-ray diffraction (PXRD) The laboratory PXRD data of the bulk materials were recorded under ambient conditions on a Bragg-Brentano diffractometer D8 Advance (Bruker AXS, Germany) with CuKα1 radiation (λ = 1.5406 Å). The synchrotron PXRD data were recorded on a beamline I12-JEEP29 (Diamond, UK) using a 2D area flat panel detector Pixium RF4343. The wavelength calibration (λ=0.23307 Å for the measurements of [FBP + BZA] (1:1) and λ=0.23307 Å for the measurements of [FBP+2-OHBZA] (1:1) and [FBP + PicAm] (1:1)) and 2D powder diffraction data reduction were performed with DAWN software.30, 31

2.5. Determination of cocrystal crystal structures by high-resolution synchrotron PXRD The indexing of powder patterns was performed with the software Topas 4.1.32-35 The subsequent structure solution36 and Rietveld refinement37,

38

of the solved structures

were also performed in TOPAS. For the structure solution, rigid body models were used for the corresponding molecules with free intramolecular rotations. Hydrogen atoms were placed at the geometrically calculated positions. The crystallographic data for [FBP+2-OHBZA] (1:1), [FBP + BZA] (1:1), [FBP + PicAm] (1:1) have been deposited by the Cambridge Crystallographic Data Centre as supplementary publications under the CCDC numbers 1920065, 1920066, 1920067, respectively. This information can be obtained free of



charge

from

the

Cambridge

Crystallographic

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Data

Centre

via

www.ccdc.cam.ac.uk/data_request/cif.

2.6. Solubility experiments 2.6.1. Solubility of pure compounds The solubility of flurbiprofen and cocrystal formers in the pH 2.0 hydrochloric buffer and the pH 6.8 phosphate buffer was measured by the shake-flask method at 25.0 0.1C. An excess of each solid was placed in an Eppendorf tube and 2 ml of the solvent was added. After 48 h, the suspension was filtered through a Rotilabo® syringe filter (PTFE, 0.2 m), diluted by a mobile phase and the concentration in the supernatant was determined by HPLC (see section 2.7). The solid phases at equilibrium were confirmed by DSC and PXRD.

2.6.2. Measurement of cocrystal solubility To obtain the aqueous solubility values of the FBP cocrystals, 80 - 150 mg of the cocrystal and 20 - 60 mg of the FBP were suspended in 2 ml of the aqueous solution with pH 2.0 or pH 6.8 at 25.0 0.1C for 72h, in order to reach the eutectic point between the drug and the cocrystal. After the equilibration, the final pH of each solution was measured and PXRD experiments confirmed that the samples had a mixture of two solid phases (FBP and cocrystal). The suspensions were filtered through a Rotilabo®


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syringe filter (PTFE, 0.2 m), diluted by a mobile phase and the concentration of each compound in the eutectic point was analyzed by HPLC, as described in section 2.7. The results are stated as the average of at least three replicated experiments.

2.7. High-Performance Liquid Chromatography (HPLC). HPLC was performed on a Shimadzu Prominence model LC-20AD equipped with a PDA detector and a Luna C-18 column (150 mm × 4.6 mm i.d., 5.0 μm particle size and 100 Å pore size). The elution of the samples was achieved by a mobile phase consisting of acetonitrile and water- 0.1% trifluoroacetic acid mixed in the 48:52 ratio (v/v) in an isocratic regime at a flow rate of 1.0 mL∙min-1. The UV detection of FBP, 2hydroxybenzamide, benzamide and picolinamide was carried out at the wavelengths of 246 nm, 302 nm, 223 nm and 264 nm, respectively.

2.8. DFT computations 2.8.1. Parameters of periodic DFT computations The periodic DFT computations with localized Gaussian basis sets were performed using the Crystal17 software suite39 at the B3LYP/6-31G** level of theory. It was demonstrated that this level of theory provided reliable and consistent results in studying the non-covalent interactions in organic crystals.40 London dispersion



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interactions were taken into account by introducing the D3 correction with Becke-Jones damping developed by Grimme et al.41 The space groups and the unit cell parameters of the crystals obtained from PXRD data were fixed and the structural relaxations were limited to the positional parameters of atoms. The experimental crystal structure with normalised X-H bond lengths was used as the starting point for geometry optimisation. Frequencies of normal modes were calculated within the harmonic approximation by numerical differentiation of the analytical gradient of the potential energy relative to the atomic position. All the optimized structures were found to correspond to the minimum point on the potential energy surface. The shrinking factor reflecting the density of the kpoints grid in the reciprocal space was set at least to 3. The tolerance on energy controlling the self-consistent field convergence during the geometry optimizations and frequency computations was set to 10−10a.u.

2.8.2. Crystal lattice energy evaluation The crystal lattice energy Elatt of the n-component crystal was estimated from periodic DFT as the difference between the sum of total electronic energies of isolated molecules in their relaxed conformations Emol and the total energy of the crystal Ecry calculated per asymmetric unit:


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n

E cry

i 1

Z

Elatt   E mol ,i 

(1)

For the sake of consistency with the periodic DFT, all the computations of isolated molecules were performed in Crystal17 with the same computation parameters using the keyword MOLECULE. The obtained lattice energy values were corrected against the basis set superposition error (BSSE) using the Boys–Bernardi counterpoise correction scheme with the MOLEBSSE option.42 The cocrystal formation energy Eform was estimated as the difference between the lattice energies of a cocrystal and its constituents:

E form  Elatt ( А)  Elatt ( В)  Elatt ( АВ)

(2)

3. Results and Discussion

3.1 Cocrystal screening and stoichiometry All the compounds under study (API and coformers) melt without decomposing. Therefore, for their preliminary screening, we used the DSC method as the simplest and fastest one for selecting systems which produce cocrystals.43-46 Moreover, a detailed interpretation of the DSC scans and construction of the solid–liquid phase diagrams allow identifying systems with multiple stoichiometry and other potentially useful binary compositions such as eutectic mixtures.47, 48



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The DSC heating curves obtained for the selected compositions are shown in Figures S1-S3. The solidus and liquidus lines of the phase diagram were obtained from the onset of the first peak observed and from the corrected maximum of the second one (if any) on the DSC curve.49, 50. The constructed phase diagrams are presented in Figures 2-4. The experimentally obtained liquidus lines in all the studied phase diagrams were compared with the theoretical Schroeder model,51 where the liquidus lines were calculated using the equations:

ln X A

A  ΔH fus  1  1  A R  T fus T fus 

   

A  2ΔH fus  1  1 ln 4 X (1  X )  cc R  T fus T fus 

   

(3)

(4)

where XA is the mole fraction of component A in the mixture melting at the temperature A A Tfus. ΔH fus , T fus are the enthalpy and temperature of fusion of the pure component,

cc respectively, and ΔH cc fus , T fus are the enthalpy and temperature of fusion of the

cocrystal. The phase diagram of FBP and 2-OHBZA is represented in Figure2. Single narrow peaks are observed in the thermogram of the XFBP=0.333; XFBP=0.4; XFBP=0.5 and 0.8. However, when the stoichiometric ratio of the components is 1:1, at the point XFBP=0.5, the temperature of the eutectic melting changes from TE1=117.5 °C toTE2=107.3 °C,


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which indicates the only stoichiometry of the cocrystal for this system is 1:1(Table S1). To confirm the cocrystal formation and its composition, the X-ray diffraction analysis for several samples after the liquid assisted grinding experiments was carried out. The PXRD analysis of the (FBP+2-OHBZA) samples revealed the presence of a new phase along with an excess of the initial compounds. (Figure S4)

Figure 2. Phase diagram showing the thermal behavior of the (FBP+2-OHBZA) binary system; the theoretical liquidus and solidus curves are represented by (-----).

These eutectic temperatures correspond to the solidus lines of 2-OHBZA/[FBP+2OHBZA] (1:1) and [FBP+2-OHBZA] (1:1)/FBP mixtures. In order to clarify the eutectic melting points for the mixture under study, we used the Schroeder model. It has been found that the theoretical model describes the experimental data well, so we did not draw the experimental interpolated curve and used only the theoretical one. The eutectic points for the studied system are at points XFBP=0.4 and XFBP=0.8.The single ACS Paragon Plus Environment


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peak on the DSC curve for XFBP=0.333 is due to the fact that the eutectic peak and the peak of 2-OHBZA excess are very close and cannot be separated. The phase diagram for the (FBP + BZA) system is shown in Figure 3. As for the [FBP+2-OHBZA] (1:1) cocrystal, the temperature change in the eutectic melting is observed at a stoichiometric ratio of 1:1, which indicates the existence of only one form of the [FBP+BZA] (1:1) cocrystal. The XPRD analysis of the grinded samples confirmed this stoichiometry (Figure S5). It should be noted that the difference in the eutectic melting temperatures (TE1=101.5 °C, TE2=99.0 °C) for this system is rather small. The Schroeder model for the studied system does not describe the phase diagram as accurately as it did with the [FBP+2-OHBZA] (1:1) cocrystal; the experimental and theoretical lines of the solidus and liquidus do not coincide. Unlike at the first eutectic point (XFBP=0.33), at the second eutectic point the composition of the system is difficult to determine from the DSC melting curves. Therefore, the refinement of the composition of the second eutectic point (E2) was made by constructing a Tamman triangle (Figure 3b). Tammann plots are normally used for determining the eutectic compositions and evaluating the possibility of solid solution formation.52,

53

We determined the system

composition at the eutectic point E2 and found it to be equal to XFBP=0.7, XBZA=0.3


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(Table S1). As Figure 3 shows that the predicted temperature of the eutectic mixture does not coincide with the experimentally obtained one, but the stoichiometric ratio of the components in the composition of the eutectic can be accurately determined using equations (3) and (4). The deviations of the model can be explained by the close values of the melting points of the mixture components.

(a)

(b)

Figure 3. (a) Phase diagram of (FBP+BZA); the theoretical liquidus and solidus curves are represented by (-----) and (b) the Tamman plot for the (FBP+BZA) system

The phase diagram for the (FBP+PicAm) system is represented in Figure 4. Single narrow peaks are observed in the thermogram of the XFBP=0.25; XFBP=0.5; XFBP=0.6 and 0.66. The temperatures of the eutectic melting TE1=78.2°C andTE2=82.2 °C are achieved when the stoichiometric ratio of the components is 1:1 (Table S1). The difference in eutectic melting temperatures for this system, as in the case of (FBP +



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BZA), does not exceed 5 °C. Equation (3) of the Schroeder model poorly predicts the liquidus lines, whereas, according to equation (4), the liquidus line in the center of the diagram almost perfectly coincides with the experiment. It is impossible to refine the system at the points of the eutectic composition by building a Tamman triangle for this system because in most cases it is not possible to separate the peaks of the eutectic melting and melting of the excess component. However, it is possible to determine that the first eutectic melting point corresponds to XFBP=0.25, and the second one XFBP=0.6 by crossing the liquidus line calculated by the Schroeder method – with the experimentally constructed solidus lines. The single peak in the diagram with a stoichiometry of 0.66 is explained by the API low melting intensity. The discrepancy between the theoretical and experimental data can be explained by the fact that, in addition to close values of the melting temperatures of coformers (TFBP=115 °C; TPicAm=107.5 °C), this system also has a close arrangement of temperatures of the eutectic melting and cocrystal melting (TCC=83.8 °C).


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Figure 4. Phase diagram of the (FBP+PicAm) system; the theoretical liquidus and solidus curves are represented by (-----)

Thus, the obtained phase diagrams unambiguously indicate that in all the studied systems the cocrystals are formed in 1:1 stoichiometry, which is also confirmed by XPRD analysis of the grinded samples (Figure S6). In addition, it can be concluded that the Schroeder model works well for predicting melting phase diagrams of the systems that form cocrystals, in the cases where the melting points of the components differ by at least 20 °C and the difference in the eutectic melting temperatures is not less than 10 °C. It has been shown in our previous works54, 55 that the melting temperature of a new cocrystal can be confidentially predicted by analysing experimental melting points for a



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cluster of cocrystals, in which one component remains the same (an API or a coformer), while the second one changes. The results of applying this approach to the cocrystals containing salicylamide, benzamide and picolinamide as a permanent component and different APIs are shown in SI (Figure S7). According to the obtained correlation equations, the calculated melting temperatures of the [FBP+2-OHBZA] (1:1), [FBP+BZA] (1:1) and [FBP+PicAm](1:1) cocrystals equal 112.4°C, 108.3°C and 69.0°C, respectively. The predicted values do not only follow the same trend as the experimental temperatures, but are also in good agreement with the measured data in terms of absolute values (Table S1).

3.2 Crystal structures of FBP cocrystals In this work, the crystal structures of the cocrystals have been determined from the high-resolution synchrotron powder diffraction data collected at the Diamond Light Source because numerous attempts to grow single crystals were unsuccessful. The final Rietveld refinement shows good agreement of the simulated and measured XRD patterns (Figure S8). The relevant crystallographic data for the FBP cocrystals are given in Table S2. The [FBP+2-OHBZA] (1:1) and [FBP+PicAm](1:1) cocrystals crystallize in


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the triclinic P

space group with one FBP and one coformer molecule in the

asymmetric unit. According to the Crystal Packing Similarity analysis56 performed in Mercury (ver. 4.1.0), these cocrystals contain the same principal substructure of the FBP molecules, resulting in a 15 molecule overlay with rmsdn of 0.289 Å (Figure S9). In the asymmetric unit of [FBP+PicAm] (1:1), the FBP and PicAm molecules are connected by two different hydrogen bonds (O2a–H14a···O2b and N4b–H12b···O1a) to form an acid-amide heterodimer with

R22 (8) graph

set notation

57, 58

(Figure S10). The

second N4b–H11b···O1a hydrogen bond between the amide and carboxylic groups of the molecules (the blue dash line) connects the neighboring dimers into a closed-ring supramolecular tetrameric unit across a crystallographic inversion center that may be described in graph set notation as

R42 (8) (Figure

5a). A similar H-bonded tetrameric unit is

also observed in [FBP+2-OHBZA] (1:1) (Figure 5b). In this case, however, the 2OHBZA molecules are additionally connected to each other by a N1b–H6b···O2b hydrogen bond to form the C(6) chain (the green dash line), which propagates along the a-axis and unites the adjacent tetramers into a distinct layer (Figure 5b). The [FBP+BZA] (1:1) cocrystal crystallizes in the monoclinic C2/c space group. In contrast to



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the above described structures, [FBP+BZA] (1:1) consists of discrete H-bonded heterodimers of the FBP and BZA molecules linked to each other via an N1b–H6b···O1b H-bond between the carbonyl and amide groups of BZA to form the C(4) chain (Figure 5c, the green dash line). In this case, the carbonyl oxygen of the BZA molecule rather than FBP acts as the acceptor of two hydrogen bonds, which results in a considerable change in the H-bond pattern organization. In all the structures, the components are packed in a layer-like manner, which is characterised by alternating hydrophobic and hydrophilic regions containing the FBP moieties and hydrogen bonded coformer molecules, respectively (Figure S11). Similar packing arrangements are observed in the reported cocrystals of FBP with nicotinamide59 and proline.21 It should be also noted that [FBP+2-OHBZA] (1:1) and [FBP+PicAm] (1:1) show a close resemblance in a relatively large cluster of molecules with the [FBP + L-proline] (1:1) cocrystal (VEVMUH) (n=9, rmsdn = 0.474). This leads to the suggestion that the spatial arrangement of FBP in these cocrystals is favorable in terms of packing energy, allowing various coformers to be placed within the 3D supramolecular framework of the drug molecules.


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(a)

(b)

(c) Figure 5. Illustration of hydrogen bond patterns in the crystals of (a) [FBP+PicAm]



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(1:1), (b) [FBP+2-OHBZA] (1:1) and (c) [FBP+BZA] (1:1). The supramolecular tetrameric units and infinite chains in the structures is shown in ball and stick style

3.3. Periodic DFT computations In order to validate the crystal structures of the FBP cocrystals determined from the PXRD data and calculate the crystal lattice energy, we carried out relaxation of the positions of all the atoms with fixed unit cell parameters, using periodic DFT computations in the Crystal17 software (Tables S3 and S4). The optimized and experimentally determined crystal structures were found to be in good agreement (Figure S12), indicating that the determined structures were close to the energy minima within the given space group and unit cell parameters. As Table 1 shows, the crystal lattice energy Elatt decreases in the series: [FBP+BZA] (1:1)> [FBP+2-OHBZA] (1:1)> [FBP+PicAm] (1:1). One can suppose that the chain hydrogen bond motifs in the [FBP+BZA] (1:1) cocrystal are slightly more energetically preferable than the tetrameric units in [FBP+2-OHBZA] (1:1) and [FBP+PicAm] (1:1). The energy of cocrystal formation estimated from the DFT computations equals -3.0 kJ∙mol-1 for [FBP+BZA] (1:1), -2.0 kJ∙mol-1 for [FBP+PicAm] (1:1) and +1.5 kJ∙mol-1 for [FBP+2-OHBZA] (1:1). Despite the isostructurality of the cocrystals with 2-OHBZA and PicAm, their Elatt and


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Eform values differ due to the non-planar conformation of the 2-OHBZA molecule. Literature data show that the cocrystal formation enthalpy does not exceed 20 kJ·mol1.60

This imposes strict requirements on the accuracy of the lattice energies for a

cocrystal and its constituents. The highest accuracy of lattice energy estimation reported so far was obtained by Yang et al.61 for a benzene crystal due to careful consideration of computational corrections and thermal contributions. In fact, a high computing power is required to estimate the lattice energy of a single-component crystal with chemical accuracy (1 kcal·mol-1 ≈ 4.2 kJ·mol-1) at least.62-64 Even at this level, the estimated error in the energy of cocrystal formation from two different molecular crystals exceeds 12 kJ·mol-1. For this reason, we can conclude that the obtained Eform values are equal within the error of the method.65 Table 1. Crystal lattice energies of cocrystals, FBP and coformers (CF) and formation energies (Eform) of the cocrystals (in kJ·mol-1) estimated using periodic DFT computations.

FBP [FBP+BZA] (1:1) [FBP+2OHBZA] (1:1) [FBP+PicAm] (1:1)

143.9

CF

[FBP+CF] (1:1)

Eform

113.4

260.3

-3.0

114.5

257.0

1.5

98.7

244.5

-2.0



Page 24 of 54

3.4 Solubility studies The ultimate goal of cocrystallisation for most APIs is to improve solubility because it usually enhances bioavailability of drug compounds.66-68 Therefore, the aim of the next part of the work was to explore the influence of cocrystallisation of the FBP with the selected coformers on its solubility in aqueous solutions with pharmaceutically relevant pHs (pH 2.0 and pH 6.8) at 25 °C. Preliminary dissolution experiments at pH 2.0 for 8 hours showed that the [FBP+2-OHBZA] (1:1), [FBP+BZA] (1:1) and [FBP+PicAm] (1:1) cocrystals dissolved incongruently in a buffer medium, resulting in precipitation of the pure drug in the bottom phase. The result is quite predictable, considering the large difference between the aqueous solubilities of the FBP and coformers (see Table 3). Taking into account the cocrystals’ instability in the aqueous medium, it would be incorrect to determine their thermodynamic solubility using the kinetic dissolution method. As demonstrated by Rodríguez-Hornedo, an alternative approach to assessing cocrystal equilibrium solubility is based on determining the eutectic points, which are characterized by the solution concentrations of the drug and the coformer ([drug]eu and [coformer]eu) at the point where the solution is doubly saturated with the drug and the


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cocrystal.69,

70

In this case, the cocrystal solubility (with a 1:1 stoichiometry) can be

calculated using the following equation:

Scc  [FBP]eu [CF]eu ,

(5)

where [FBP]eu and [CF]eu are the eutectic concentrations of the components corresponding to the isothermally invariant points where the cocrystal and FBP coexist in equilibrium with the liquid phase. The cocrystal solubilities calculated from the eutectic concentrations of the components at pH 2.0, pH6.8 and 25.0°C are provided in Table 2. The concentrations of the cocrystals’ components at the eutectic points are shown in Table S5. The experimental eutectic concentrations of FBP are closely comparable with the pure drug solubility in the respective medium, indicating that there is minor or no complexation of FBP with coformers in the solutions. As Table 2 shows, the highest solubility advantage (the SA parameter) in the acidic pH 2.0 buffer solution is observed for the [FBP+PicAm] (1:1) cocrystal (Scc/SFBP = 70.8). For [FBP+2-OHBZA] (1:1) and [FBP+BZA] (1:1), the SA values are smaller (9.7 and 20.8, respectively) and follow the trend in the coformer solubility (Table 2). It is known that SA is not expected to be equal to the observed supersaturation, but it is of great value for classifying cocrystals in terms of their



Page 26 of 54

conversion risk.71 In addition, for all the cocrystals, the observed values of the eutectic constant (Keu) significantly exceed unity (Keu = 105-3027, see Table 2), indicating low thermodynamic stability of the 1:1 cocrystals in comparison with the parent drug in a pH 2.0 buffer solution.69 Flurbiprofen is a weak acid (pKa = 4.5072) and its solubility strongly depends on the pH value of dissolution media. It is known that cocrystallization can alter the solubility−pH profile of an ionizable drug, resulting in a decrease in the API solubility above (for acidic APIs) or below (for basic APIs) a pHmax value.69-71,

73

The solubility

studies at pH 6.8 suggest that only two of the three FBP cocrystals (i.e. [FBP+BZA] (1:1) and [FBP+PicAm] (1:1)) remain more soluble than the drug. The [FBP+2-OHBZA] (1:1) cocrystal, however, is found to be less soluble compared to pure FBP. This fact also indicates that the latter cocrystal exhibits a pHmax where its solubility curve intersects with the drug solubility curve. It should be noted that the increasing pH considerably reduces the SA parameter for the [FBP+BZA] (1:1) and [FBP+PicAm] (1:1) forms, resulting in a moderate solubility improvement (1.8 and 3.9, respectively). Table 2. Experimental solubility (SCC) of FBP cocrystals, solubility advantage (SA), eutectic constants (Keu) and Ksp values at pH 2.0, pH 6.8 and 25.0°C


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SCC,a

Keuc

SAb

Ksp,d

mol·l-1

M2

pH 2.0, SFBP = (4.53±0.08)·10-5 mol·l-1 (4.4±0.2)·10-4

9.7

105

1.9·10-7

[FBP+BZA] (1:1)

(9.4±0.5)·10-4

20.8

400

8.9·10-7

[FBP+PicAm] (1:1)

(3.2±0.1)·10-3

70.8

3027

4.5·10-6

(6.6±0.2)·10-3

0.8

0.8

2.2·10-7

[FBP+BZA] (1:1)

(1.4±0.3)·10-2

1.8

3.2

9.6·10-7

[FBP+PicAm] (1:1)

(3.1±0.2)·10-2

3.9

14.4

4.8·10-6

[FBP+2-OHBZA] (1:1)

pH 6.8, SFBP = (7.89±0.05)·10-3mol·l-1 [FBP+2-OHBZA] (1:1)

acalculated

according to eq. (5);

bSA

= Scc/SFBP

cK

= [CF]eu / [FBP]eu70

eu

dcalculated

according to eq. (7) and eq. (9)

At the next stage, the Ksp values of the FBP cocrystals were calculated using the experimental solubility and ionization constants of the components. The solubility dependence on pH for the [FBP+2-OHBZA] (1:1) and [FBP+BZA] (1:1) cocrystals, containing only one ionizable, acidic component (FBP), is described by the following equation:

Scc  K sp (1  10

pH  pK a ,FBP

)

(6)

or

[FBP]eu [CC]eu  K sp (1  10

pH  pK a ,FBP

)

(7)

where Ksp and Ka,FBP are the solubility product of the cocrystal and the FBP ionization constant, respectively.



Page 28 of 54

The [FBP+PicAm] (1:1) cocrystal consists of acidic and basic components (the pKa of PicAm equals 2.1) components. Thus, the solubility dependence on pH for the cocrystal is given by:

Scc  K sp (1  10

pH  pK a ,FBP

)(1  10

pK a ,PicAm  pH

)

(8)

or [FBP]eu [CC]eu  K sp (1  10

pH  pK a ,FBP

)(1  10

pK a ,PicAm  pH

)

(9)

where Ksp, Ka,FBP and Ka,PicAm are the solubility product of the cocrystal, the FBP and PicAm ionization constants, respectively. The Ksp values for the cocrystals are summarized in Table 2. The theoretical solubility curves for the cocrystals and FBP calculated based on Ksp and pKa values are shown in Figure S13. The predicted and experimentally determined values at pH 6.8 agree well with each other. The predicted solubility curves indicate that the [FBP+BZA] (1:1) and [FBP+PicAm] (1:1) cocrystals are more soluble than parent FBP over the entire pH range. The [FBP+2-OHBZA] (1:1) crystal form, however, has the pHmax value at ca. pH 6.2, suggesting that the cocrystal is less soluble and thermodynamically more stable than the drug at pH >pHmax. This fact was verified by solubility measurements and analysis of the bottom phase.

3.5 Prediction of Ksp using HYBOT descriptors


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It has been recently shown by Avdeef74 that aqueous Ksp values of cocrystals correlate with the corresponding intrinsic solubilities of an API and coformer. And, combining experimental intrinsic solubility values with several Abraham hydrogen bond descriptors results in construction of a reliable model for the Ksp prediction. In this work, we have tested another set of physicochemical descriptors, i.e. HYBOT descriptors,25 to develop an alternative Ksp prediction model. The multiple linear regression equations were used to correlate pKsp (a dependent variable) and pS0(API), pS0(CF) and various HYBOT descriptors (independent variables). The following descriptors were taken into consideration:  СaAPI ,  СaCF – the sum of the free energy H-bond acceptor atom factor in the API and coformer molecules, respectively;  СdAPI ,  СdCF – the sum of the free energy H-bond donor atom factor in the API and coformer molecules, respectively. The donor-acceptor cross terms (  СaAPI   СdCF ,  СdAPI   СaCF ) were also included in the multiple linear regression analysis. The total data set of 41 experimental Ksp, S0 (API) and S0 (CF) values (in terms of –log10), including those for FBP cocrystals, is listed in Table S6. The results of different regression models and their statistical characteristics are summarized in Table S7. All the possible combinations of descriptors were fully analyzed to calculate the models considering a relatively small



Page 30 of 54

number of selected descriptors. The H-bond descriptors corresponding to the coformer molecule (  СaCF ,  СdCF ) were found incapable of improving the basic model, based solely on the API and conformer solubility, and, thus, statistically insignificant (Table S7). A similar result was obtained, when the donor-acceptor cross term descriptors were introduced into the model (Table S7). In fact, various combinations of the tested HYBOT descriptors have shown that  СaAPI is the only descriptor, which is able to provide a statistically meaningful correlation with the improved statistical characteristics (Table S7). Figure 6 shows the correlation between the observed data and those calculated from the model containing the  СaAPI descriptor (the total H-acceptor capacity of the API molecules).


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Figure 6. Correlation between experimental and calculated pKsp values (see text for details)

In a similar way (as in Avdeef’s study), the physicochemical descriptor has a minor weight in the prediction model, while the pS0 (API) and pS0 (CF) parameters account for most of the variances in the data. Nevertheless, adding the  СaAPI descriptor improves the statistics and, therefore, makes the prediction of the Ksp value for new cocrystals more reliable. Therefore, the solubility and solubility advantage of a cocrystal in a particular pH range can be estimated using the above relationship, avoiding timeconsuming cocrystal solubility measurements. It should be also noted, however, that the



Page 32 of 54

expansion of the existing database of the Ksp values will increase the accuracy and reliability of prediction models.

3.6 Free energy of cocrystal formation The standard free-energy change, G 0f , for the formation reaction of the FBP cocrystals can be expressed through the solubility data of each of the materials by the following equation:75  S0 S0 G 0f ([ FBP  CF ]cr (1:1))   RT  ln  FBP 1:1 CF  K sp 

  

(10)

0 0 where S FBP and SCF are the intrinsic solubility values of the FBP and coformer, respectively,

and Ksp is the solubility product of the cocrystal. The experimental solubility data, the Ksp values and the calculated Gibbs energies of the cocrystal formation are provided in Table 3.The negative values of the Gibbs energy suggest that formation of the cocrystals from individual components is a spontaneous process. It is evident that all the FBP cocrystals are closely comparable (within experimental errors) in terms of the Gibbs free energy change of the cocrystallization process. This result is expected from the similarity in the crystal structures and the calculated formation energies for all the obtained cocrystals. Table 3. Intrinsic solubility of parent FBP and coformers (S0), Ksp values for the cocrystals, and values of the Gibbs energy change associated with the cocrystal formation


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Cocrystal

S0 (FBP) mol·l-1

[FBP+2-OHBZA] (1:1)

S0 (CF) mol·l-1 (1.88±0.05)·10-2b

-5a [FBP+BZA] (1:1) (4.53±0.08)·10 (1.02±0.06)·10-1c

8.9·10-7

[FBP+PicAm] (1:1)

4.5·10-6

(6.10±0.08)·10-1d

aThe

literature value: 4.34·10-5 76

bThe


cThe


dMeasured

G0f kJ·mol–1

Ksp M2 1.9·10-7

-3.7±0.5 -4.1±0.6 -4.4±0.3

in the pH6.8 solution

As the next step, we calculated the formation Gibbs energies for all the cocrystals with known Ksp, S0 (API) and S0 (CF) parameters listed in Table S6, using relationship (10). Figure 6a shows the distribution of the G 0f values among the cocrystals. According to Figure 7a, the FBP cocrystals belong to the most abundant group of cocrystals, with the formation Gibbs energies lying within the interval of (-3.0) – (-6.0) kJ∙mol-1.

(a)

(b)



Page 34 of 54

Figure 7. Distribution of (a) the formation Gibbs energy and (b) the molecular volume of formation for the selected cocrystals

The formation Gibbs energy is a complex parameter, resulting from a combination of enthalpy and entropy terms, with each of them, in their turn, depending on the relative strength of the intermolecular forces and order in both the multicomponent system and the parent components. Therefore, it is hard to find a suitable descriptor for describing and predicting the Gibbs energy of cocrystal formation. In this work, we used the molecular volume of cocrystal formation (ΔVf(CC))26-28 as a parameter, which may help to rationalize the regularities between the driving force (i.e. the Gibbs free energy change) of the cocrystallization process and structural parameters (i.e. molecular volume) of participating solids. The ΔVf(CC) values were calculated by the following equation using the crystallographic data taken from the CSD: ΔVf(CC) = Vmol(CC) − (X1·Vmol(API) + X2·Vmol(CF)),

(11)

where Vmol(CC) = Vcell(CC)/Z, Vmol(API) = Vcell(API)/Z, and Vmol(CF) = Vcell(CF)/Z. Evaluation of the structural information has been carried out in the following way. We took all the crystal structures (found in the CSD at the moment, see Table S8) of the analyzed cocrystals and the individual components constituting them (including all the polymorphic forms at the temperatures published). It should be mentioned that it is difficult to predict what polymorphic modifications of the initial compounds take part in the co-crystal formation reaction. For this reason, we found all the structures (including the polymorphic forms) for both the individual ACS Paragon Plus Environment

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compounds and the co-crystals to obtain the ΔVf(CC) value which fits well in the G 0f vs.ΔVf(CC) dependence. The X-ray experimental data for these calculations were selected with the nearest maximal temperatures possible. According to Figure 7b, the formation process for most of the considered cocrystals is associated with the negative values of the ΔVf(CC) parameter. This fact indicates that the molecules in such cocrystals tend to form a more efficient packing arrangement than those in the individual component crystals. Nevertheless, in a many of the systems, cocrystallization results in volume expansion. It has been suggested by Zhang et al.26 that this effect may be due to the energy compensation of the inefficient molecular packing by strong intermolecular interactions (e.g. H-bonds) in the crystal structure.

Figure 8. Relationship between G 0f and ΔVf(CC) parameters (see text for details). The numbering corresponds to Table S8.

The dependence of the Gibbs energy of cocrystal formation on the molecular formation volume is shown in Figure 8. It can be seen that for 22 compounds, lying inside the 95% confidence interval (the shaded area), the Gibbs free energy change of ACS Paragon Plus Environment


Page 36 of 54

the cocrystallization process decreases linearly with the increase in the ∆Vf parameter. It might be reasonable to assume that a positive value of the formation volume can be considered a good indicator of low thermodynamic stability of the resulting cocrystal. This may also indicate the existence of alternative crystalline forms in such systems, such as polymorphic modifications or cocrystals with multiple stoichiometry. It should be noted that less than a half of the structures (red points) deviate from the general trend, which can be caused by one or more of the following factors: (i) uncertainties in the solubility values for the cocrystals and initial components, (ii) difference in the X-ray experimental temperatures, (iii) lack of the structural information concerning alternative polymorphs both for the individual compounds and the cocrystals. 4. Conclusions

In this work, three new cocrystals of the nonsteroidal anti-inflammatory drug flurbiprofen with salicylamide, benzamide and picolinamide have been discovered using thermodynamic analysis of the solid-liquid binary phase diagrams. Structural analyses have shown similar packing arrangements of the cocrystals that consist of conventional hydrogen bonded acid-amide heterodimers of the components assembled into either closed-ring supramolecular tetrameric units or infinite chains. The periodic DFT


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calculations have indicated that all the flurbiprofen cocrystals have small and closely comparable values of the cocrystallization energy. A similar trend was also observed for the Gibbs energy change in the cocrystallization process obtained from the thermodynamic solubility of the cocrystals and parent components in aqueous media. According to the solubility studies at different pH, the picolinamide and benzamide cocrystals were found to be more soluble than the flurbiprofen ones over the entire pH range. A reversal cocrystal-drug solubility ratio is observed for the flurbiprofen cocrystal with salicylamide at pH 6.8, suggesting that the cocrystal is a thermodynamically preferred solid form of the drug at pH > 6.2. The solubility parameters of flurbiprofen cocrystals follow the general correlation pattern between the solubility product (Ksp) and intrinsic solubilities of components recently reported by Avdeef.74 We have found that introduction of HYBOT descriptors25 into the correlation improves the model statistics and makes the prediction of the Ksp value for new cocrystals more reliable. We have also shown that the Gibbs free energy change of cocrystallization process could be estimated by using the difference in molecular volumes of participating solids (i.e. molecular volume of cocrystal formation).



Page 38 of 54

Supporting Information

The Supporting Information is available free of charge on the ACS Publications website at DOI: The DSC heating curves for binary systems, Rietveld refinement of the crystal structures, crystallographic data for the solid forms, results of the periodic DFT calculations, details of solubility studies (eutectic concentrations, theoretical solubility curves), the data set of experimental values of cocrystal solubility product and intrinsic solubilities of API and conformer, calculated HYBOT descriptors and Gibbs energy of cocrystal formation reaction, calculated formation volumes of cocrystals.

Acknowledgements

This work was supported by the Russian Foundation for Basic Research (project № 18-3300485) and Russian Science Foundation (project № 17-73-10351). We acknowledge Diamond Light Source for the time on Beamline I12-JEEP. We thank “the Upper Volga Region Centre of Physicochemical Research” for technical assistance with PXRD experiments. We are saddened to learn that the giant of computational chemistry, Prof. Oleg A. Raevsky, died 5 March 2019. We dedicate this paper to his memory.


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For Table of Contents Use Only New pharmaceutical cocrystal forms of flurbiprofen: structural, physicochemical and thermodynamic characterization Artem O. Surov, Alex N. Manin, Alexander P. Voronin, Denis E. Boitsov, Oxana V. Magdysyuk, German L. Perlovich Three new cocrystals of the nonsteroidal anti-inflammatory drug flurbiprofen with salicylamide, benzamide and picolinamide have been discovered using thermodynamic analysis of solid-liquid binary phase diagrams. The pH-solubility behavior and solubility advantage of the cocrystals have been examined. A new model has been proposed for estimating the solubility product (Ksp) of a cocrystal, based on the experimental intrinsic solubility of the drug and coformer complemented by calculated physicochemical HYBOT descriptors.


New pharmaceutical cocrystal forms of flurbiprofen: structural

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