Ketoconazole Salt and Co-crystals with Enhanced Aqueous Solubility

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Ketoconazole salt and co-crystals with enhanced aqueous solubility Flavia A Martin, Mihaela M Pop, Gheorghe Borodi, Xenia Filip, and Irina Kacso Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/cg400638g • Publication Date (Web): 30 Aug 2013 Downloaded from http://pubs.acs.org on September 2, 2013

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Crystal Growth & Design

Cover Page Ketoconazole salt and co-crystals with enhanced aqueous solubility Flavia A. Martin, Mihaela M. Pop*, Gheorghe Borodi, Xenia Filip, Irina Kacso National Institute for Research and Development of Isotopic and Molecular Technologies Crystal structures of ketoconazole oxalate salt (1) and three co-crystals with fumaric (2), succinic (3) and adipic (4) acids in 1:1 stoichiometry were determined by single-crystal X-ray diffraction. The salt and co-crystal nature of 1–4 was confirmed by combining single-crystal X-ray diffraction, ss-NMR and lattice energy calculations. Ketoconazole molecules show highly similar conformations and crystal packing in co-crystals 2 and 3, while different conformers are present in the 1, 2 and 4 structures. For all salt and cocrystals, powder dissolution measurements revealed a significant solubility improvement compared to ketoconazole, and the solubility of 1–4 is contrary to the solubility values of the corresponding acids. A 100 - fold solubility increase in water was obtained by ketoconazole co-crystallization with fumaric and adipic acids. Additionally, 1–4 are stable in suspensions for at least 1 week and on storage at 40oC/75% RH for at least 4 months. The melting points of 1, 3 and 4 are in line to their solubility, while the solubility difference between the highly similar co-crystals 2 and 3 is reflected in their different lattice energy. Our study emphasizes the benefit of crystal engineering in the landscape of the formulation techniques used to enhance the dissolution rate of poorly watersoluble drugs, such as ketoconazole.

Mihaela Maria Pop 65 - 103 Donath Street 400293 Cluj- Napoca Romania Phone: (+4)0264-584037 Fax: (+4)0264-420042 Web: www.itim-cj.ro

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Ketoconazole salt and co-crystals with enhanced aqueous solubility Flavia A. Martin, Mihaela M. Pop*, Gheorghe Borodi, Xenia Filip, Irina Kacso National Institute for Research and Development of Isotopic and Molecular Technologies, PO Box 700, Cluj-Napoca R-400293, Romania * E-mail: [email protected]

Abstract Crystal structures of ketoconazole oxalate salt (1) and three co-crystals with fumaric (2), succinic (3) and adipic (4) acids in 1:1 stoichiometry were determined by single-crystal X-ray diffraction, in which 1 forms oxalate dimers involved in ionic interaction with the imidazole ring of ketoconazole molecules, while 2 - 4 display 4-member circuit networks between hydrogen-bonded ketoconazole and co-former molecules. The salt and cocrystal nature of 1 - 4 was confirmed by combining single-crystal X-ray diffraction, ssNMR and lattice energy calculations. Ketoconazole molecules show highly similar conformations and crystal packing in co-crystals 2 and 3, while different conformers are present in the 1, 2 and 4 structures. For all salt and co-crystals, powder dissolution measurements revealed a significant solubility improvement compared to ketoconazole, and the solubility of 1–4 is contrary to the solubility values of the corresponding acids. A 100 - fold solubility increase in water was obtained by ketoconazole co-crystallization with fumaric and adipic acids. Additionally, 1 – 4 are stable in suspensions for at least 1 week and on storage at 40oC / 75% RH for at least 4 months. The melting points of 1, 3 and 4 are in line to their solubility, while the solubility difference between the highly similar co-crystals 2 and 3 is reflected in their different lattice energy. Our study emphasizes the benefit of crystal engineering in the landscape of the formulation techniques used to enhance the dissolution rate of poorly water-soluble drugs, such as ketoconazole.


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Introduction Although drug absorption from the gastro-intestinal (GI) tract is a complex process, drug permeability through the GI membrane and the solubility/dissolution of the drug dose in the GI environment are playing determinant roles

[1]. As a consequence, drug

substances have been classified into four categories based on their solubility and membrane permeability characteristics. The derived Biopharmaceutics Classification System (BCS) adopted by the US Food and Drug Administration (FDA), the European Medicines Agency (EMEA), and the World Health Organization (WHO) is extensively used by the pharmaceutical industry throughout drug discovery and development processes [2 – 4]. In the case of the BCS class II drugs with low solubility and reasonable permeability, drug dissolution step is the rate-limiting process of drug absorption. For these drug substances, the choice of the solid form plays a critical role in their absorption from the GI tract. Besides salts, pharmaceutical co-crystals open a new dimension to search for solid forms that can enable substantial modification of properties such as solubility, dissolution rate, stability, shelf life of active pharmaceutical ingredients (APIs) [5 – 10] without affecting their inherent pharmacological properties [11 –13]. Pharmaceutical co-crystals are multi-component crystalline structures made of neutral APIs and co-crystal formers that are solid at ambient conditions and that are bound via non-covalent interactions [14]. The co-crystallization of APIs with pharmaceutically acceptable co-crystal formers is nowadays a recognized technique in pharmaceutical science for improving the drug physico-chemical properties leading to an enhanced oral bioavailability [15 – 17]. Additionally, co-crystals have great potential in the pharmaceutical industry by creating intellectual property (IP) protection and extending the life cycles of the APIs [18]. A recent study showed that in the case of poorly-water soluble drugs that are weak bases, co-crystallization seems a better choice to the classic HCl salt formation for the dissolution rate improvement and achieving suitable stability of the solid form [19]. Ketoconazole, cis-1-acetyl-4[4-(2-(2,4-dichlorophenyle]-2-(1H-imidazole- 1ylmethyl)-1,3dioxolon-4-yl]methoxy piperazin, is a highly effective, broad spectrum imidazole antifungal agent used to treat a wide variety of superficial and systematic mycoses [20, 21]. Being a BCS class II drug [22], ketoconazole has pronounced hydrophobic characteristics and weak basicity that contribute to its poor aqueous solubility [23].



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Although it is administered both orally and topically, the very low aqueous solubility of ketoconazole at pH > 3 represents a major disadvantage for its efficacy as an oral dosage form [24]. Besides the low, variable bioavailability [25], the risk of hepatotoxicity led to the re-evaluation of the oral drug for the risk/benefits effects followed by restriction of its therapeutic indications. An increase of the ketoconazole bioavailability would lower the dose required for the therapeutic effect, decreasing in the same time the risk of hepatotoxicity. Recently, there is increasing interest in formulation approaches for solubility and bioavailability enhancement of ketoconazole, including solid dispersions, hot-melt extrusion, inclusion complexes with beta-cyclodextrins and nanosuspensions [26-30]. These methods involve combinations of ketoconazole with other components, which might not be optimal from a regulatory point of view, in spite of the achieved increase in solubility, in some cases with factors of 100 and 172.5 [30] or even 600 [26]. Besides the formulation techniques, to our knowledge, the crystal engineering approach was hardly explored in the case ketoconazole, although it is known to work for other triazole antifungal drugs such as itraconazole [16] or fluconazole [31]. In a recent study [32], the enhanced solubility shown by the dihydrochloride salt of ketoconazole was correlated to both salt formation as well as the nano-particule structure of the compound. A careful literature and Cambrige Structural Database (CSD) [33] search showed that no salt or co-crystal structures of ketoconazole were reported so far. On the other hand, the Naromatic…COOH supramolecular heterosynthon exhibits a high occurrence in the CSD [34, 35] and its formation would also be expected for ketoconazole. In addition, considering the persistence of this synthon in co-crystals of similar drugs with dicarboxylic acids [16, 31, 36], we investigated the possibility of ketoconazole cocrystallization with a series of saturated and unsaturated dicarboxylic acids (oxalic, malonic, succinic, glutaric, adipic, fumaric, and maleic). By applying both solution crystallization and the solvent-drop grinding method, three of the screened acids in combination with ketoconazole led to clay materials under the applied crystallization conditions (Supporting information, Table S1), while four of them presented in the current work, resulted in crystalline materials (Scheme 1).


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Scheme 1. Structures of Ketoconazole and Coformers (a−d). O

R2

N

R1

R5

O

H3C

N

O

O

H Cl Ketoconazole

HO O Oxalic acid (a)

O Fumaric acid (b)

O

O

R4

O N

OH

HO

N R3

O

OH

Cl

HO

OH

O Succinic acid (c)

OH

HO O Adipic acid (d)

Experimental section Materials and General methods Ketoconazole, commercial form was purchased from Melone Pharmaceutical Co., Ltd. Oxalic, fumaric, succinic and adipic acids were purchased from Merck. Reagent grade solvents were used. Differential scanning calorimetry (DSC) was recorded on a Shimadzu DSC60 instrument, with a heating rate of 10 °C/min. The ss-NMR spectra were recorded on a Bruker AVANCE III wide bore spectrometer operating at a 1H Larmor frequency of 500.13 MHz. 15N CP-MAS data were acquired with a 4 mm CP-MAS probe, at 7 kHz spinning frequency, 4 ms contact time, proton decoupling (80 kHz) under TPPM, by averaging 15000 transients with a recycle delay of 10 s. The

15

N CP-MAS

spectra were calibrated relative to nitromethane using Glycine (-347.6 ppm) as an external standard. X-ray powder diffraction (XRPD) patterns were obtained on a D8 Advance Bruker AXS θ-2θ diffractometer with Cu Kα radiation (40 kV, 30 mA). Accelerated stability testing was conducted under the storage condition of 40 ± 2oC/75 ± 5% RH. Ketoconazole oxalate salt (1:1) (1) Crystals suitable for single crystal X-ray diffraction were prepared by dissolving a (1:1.1) mixture of ketoconazole and oxalic acid (10.0 mg) in 1 mL of acetone:methanol (1:1) with heating at 60oC. Slightly closed vials, allowing the vapors to escape, were put in the refrigerator for slow solvent evaporation at 4 oC, until colorless single-crystals of suitable size were formed. Ketoconazole fumaric acid co-crystal (1:1) (2) Crystals suitable for single crystal X-ray diffraction were prepared by dissolving a (1:1.1) mixture of ketoconazole and fumaric acid (15.0 mg) in 1 mL acetone:methanol (1:1) with heating at 60 oC. Slightly closed vials, allowing the vapors to escape, were put in the



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refrigerator for slow solvent evaporation at 4 oC, until colorless single-crystals of suitable size were obtained. Ketoconazole succinic acid co-crystal (1:1) (3) Crystals suitable for single crystal X-ray diffraction were prepared by dissolving a (1:1.1) mixture of ketoconazole and succinic acid (10.0 mg) in 1 mL chloroform with heating at 60 oC. Slightly closed vials, allowing the vapors to escape, were placed in the refrigerator for slow solvent evaporation at 4 oC, until yellow single-crystals of suitable size and quality grew. Ketoconazole adipic acid co-crystal (1:1) (4) Single-Crystal Growth: Crystals suitable for single crystal X-ray diffraction were prepared by dissolving a (1:1.1) mixture of ketoconazole and adipic acid (15.0 mg) in 1 mL chloroform or chloroform:ethanol (3 :1) with heating at 60 oC. Slightly closed vials, allowing the vapors to escape, were put in the refrigerator for slow solvent evaporation at 4 oC, until colorless single-crystals of suitable size and quality were formed. Single Crystal X-Ray Diffraction Single-crystal diffraction data for 1 – 4 were collected on an Oxford Diffraction SuperNova dual wavelength diffractometer with operating mirror monochromated CuKα radiation mode (λ=1.5418 A ). X-ray data collection was monitored and all the data were corrected for Lorentzian, polarization and absorption effects using CrysAlisPro program [37]. Olex2 program [38] was used for the crystal structures solution and refinement: SHELXS97 was used for structure solution [39] and SHELXL was used for full matrix least-squares refinement on F2 [40]. All non-hydrogen atoms were refined anisotropically and most hydrogen atoms were added in calculated positions and refined riding on their host atoms. The hydroxyl H-atoms of the fumaric acid were allowed to rotate to best fit the experimental electron density, whilst imposing O-H distance restraints to typical values. Crystallographic data and details of refinements of 1−4 are listed in Table 1, and the hydrogen bonding distances and angles are given in Table 2. Density Functional Theory (DFT) calculations Computations were carried out using CASTEP module of Materials Studio® package (Materials Studio, release 5.5., Accelrys Software Inc., San Diego, CA, USA, http://accelrys.com/products/materials-studio/). CASTEP code [41] is an implementation of density functional theory (DFT) [42, 43]. For all the DFT calculations, the plane-wave cut-off energy was 610 eV and Brillouin zone integrations were performed on a


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symmetrized Monkhorst-Pack k-point grid with a k-point spacing of 0.04 Å-1. The exchange-correlation functional was approximated at the generalised-gradient level, specifically that of Perdew, Burke and Ernzerhof (PBE) [44]. Ultrasoft pseudopotential [45] consistent with the PBE approximation was generated by CASTEP on the fly. H atoms positions were optimized using a BFGS variant [46] such that the computed atomic forces were less than 0.01 eV/ Å. Lattice parameters and heavy atoms positions were fixed at those given by X-ray diffraction experiments. NMR shielding tensor was computed using the fully periodic GIPAW method [47, 48]. The computed isotropic shielding constants σ where transformed to chemical shifts using the relationship δcalc = σref - σcalc, with reference value σref extracted from a linear fit of the computed shielding constants against the experimental shifts.

Powder Dissolution Experiments The absorbance values for Ketoconazole, salt and co-crystals 1−4 in deionized water at different times were detected by a µDISS ProfilerTM apparatus. The system consists of an integrated diode array spectrophotometer connected to a fiber optic UV probe located directly in the reaction vessel and is able of measuring the concentration as a function of time, without having to filter the solution. Measurement of dissolution kinetics and equilibrium solubility was carried out at 300 nm, where all the used di-carboxylic acids have no absorption, and the concentrations of 1 - 4 were calculated by means of a standard curve. The solids of Ketoconazole starting material and 1−4 were milled to powder and sieved using standard mesh sieves to provide sample with approximate particle size ranges of 150−200 µm. In a typical experiment, 15 mL of deionized water (pH 5.8) was added to a flask containing 20 mg of sample, and the resulting mixture was stirred at 25 °C and 600 rpm. The dissolution experiments were carried out in triplicates (Supplementary information, Figure S5).



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Results and discussion Crystal structures Table 1. Crystallographic data for 1- 4. 1

2

3

4

oxalic

fumaric

succinic

adipic

Notation Acid Formula

C28H30Cl2N4O8

C30H32Cl2N4O8

C30H33Cl2N4O8

C32H28Cl2N4O8

Formula weight (g/mol)

621.46

647.50

648.50

677.56

Crystal System

monoclinic

triclinic

triclinic

triclinic

Space group

P21/n

P-1

P-1

P-1

a, Å

10.51506(16)

10.5094(6)

10.5261(8)

5.8721(3)

b, Å

13.3330(2)

11.7425(6)

11.7297(9)

8.3797(4)

c, Å

20.3036(3)

13.4568(5)

13.4580(11)

34.4919(14)

α, deg

90

96.238(4)

95.287(6)

92.623(4)

β, deg γ, deg T, K 3 V, Å Z -3 Dc/g⋅cm F(000) Crystal size/mm Range of indices

96.6413(14) 98.973(4) 99.302(7) 93.859(4) 90 105.330(5) 104.429(7) 103.791(4) 293 293 293 293 2827.40(8) 1562.27(13) 1572.8(2) 1641.20(13) 4 2 2 2 1.460 1.374 1.369 1.371 1296 674 678 712 0.4x0.3x0.2 0.3x0.2x0.1 0.2x0.1x0.1 0.3x0.2x0.1 -12,12; -16,16; -10,12; -14,14; -12,12; -14,10; -7,6; -10,9; -19, 24 -15, 16 -16, 16 -16, 16 Rint 0.0217 0.0250 0.0278 0.0382 GOF 1.039 1.701 1.437 1.318 0.0435 0.0711 0.0749 0.0689 R1 [I>2σ(I)] wR2 [all data] 0.1172 0.2331 0.2341 0.2033 2 2 2 2 2 1/2 2 2 2 R1=ΣFo-Fc/ ΣFo. wR2=[ Σ [w(Fo -Fc ) ] / Σw(Fo ) ] , w=1 / [σ (Fo )+(aP) +bP], where 2

2

P=[(Fo )+2Fc ]/3

Structure 1 The crystal structure 1 contains one oxalic acid and one ketoconazole molecule in the asymmetric unit, with the oxalate moieties linked into dimers via O(1A)-H(1AA)…O(3A) bidentate intermolecular hydrogen bonds (Figure 1a, Table 2). Ketoconazole conformation is characterized by folding of the imidazole (R2) sidechain towards the R5 ring of the molecule (Scheme 1). The 5- and 6-membered rings (R1, R3) of the ketoconazole molecule adopt an envelope and a chair conformation, respectively.


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a)

b)

c) Figure 1. Structure 1 hydrogen bonding (a, b) and crystal packing (c, view along the c-axis).



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Table 2. Hydrogen bonding geometry details Structure Symmetry D-H···A d (D···H) Codes (Å) 1 1-x,1-y,1-z N1-H1A…O4A 0.86 (oxalic) 1-x,2-y,1-z O1A0.82 H1AA…O3A 1+x,-1+y,z C1-H1…O2A 0.93 2 1-x,1-y,-1-z O4A-H4AA…N1 1.04(5) (fumaric) x, y, z O2A-H2A…O4 0.91(5) -1+x,1+y,1+z C4-H4B…O3A 0.97 3 -x,2-y,4-z O4A-H*…N1 1.04 (succinic) x, y, z O2A-H2A…O4 0.82 1+x,-1+y,-1+z C4-H4A…O3A 0.97 x,1+y,1+z C3A-H3AA...O3 0.97 4 2+x,1+y,z O4A-H4AA…N1 0.81 (adipic) -x,-y,-z O2A-H2A…O4 0.82 -1+x,y,z C1-H1…O2 0.93 * H atom position from the DFT optimized structure

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d (H···A) (Å) 1.88 1.92

d (D···A) (Å) 2.737(3) 2.651(3)

(D-H-A) (deg) 178 148

2.30 1.59(5) 1.71(6) 2.25 1.64 1.81 2.27 2.56 1.88 1.79 2.47

3.144(3) 2.621(4) 2.597(4) 3.176(5) 2.675(6) 2.619(4) 3.199(5) 3.455(5) 2.693(4) 2.587(3) 3.311(3)

150 171(6) 166(6) 159 168 168 161 153 172 164 151

Structure 1 is an oxalate salt, since proton transfer occurs from the hydroxyl O-atom of the oxalic acid to the imidazole N-atom of the ketoconazole molecule. The resulting ionized ketoconazole and oxalate moieties are connected via a N(1)-H(1A)…O(4A) hydrogen bond. The imidazole ring (R2) of ketoconazole is further involved in a C-H…O hydrogen bond with the carbonyl O-atom of adjacent oxalate dimers (Figure 1b). The crystal packing of 1 highlighting the oxalate counter-ion and the imidazole ring involved in the ionic interaction is shown in Figure 1c. Structures 2 and 3 The crystal structures of 2 and 3 are very similar (Table 1), which is in line with the molecular similarity between fumaric and succinic acids (Scheme 1). The asymmetric units of 2 and 3 include one ketoconazole and one acid molecule connected via a O(2A)H(2A)…O(4) hydrogen bond between one acid hydroxyl group and the acetyl group of ketoconazole. The second hydroxyl O-atom of fumaric acid is hydrogen bonded to the imidazole N-atom of the ketoconazole molecule via the O(4A)-H(4AA)…N(1) hydrogen bond, without transferring the proton to the basic moiety. The co-crystal nature of 2 was determined based on locating the H-atoms in the difference Fourier map. The hydroxyl H-atoms of the fumaric acid were allowed to rotate to best fit the experimental electron density, whilst imposing distance restraints for achieving a stable refinement (d(O-H)=0.9 – 1.0 A ). All the other H atoms were located in a difference map, placed in the calculated ideal positions and refined in the riding model approximation [40]. In the case of 3, the hydroxyl H-atom related to the O-H…N hydrogen bond could not be located in the difference map due to the possible disorder, indicated by larger anisotropic


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displacement parameters of this hydroxyl O-atom of the succinic acid. However, based on crystal structure similarity with 2 and the evidence from DFT calculations and ss-NMR 15

N results (presented in the next section) it could be concluded that 3 is also a co-

crystal. In both co-crystals 2 and 3, the ketoconazole and the co-former molecules are connected via hydrogen bonding into a 4-member circuit network (Figure 2a). Moreover, ketoconazole molecules adopt almost identical conformations (Figure 2b) and highly similar crystal packing in the two structures (Figure 3a, 3b).

a)

b)

c) Figure 2. Structures 2 and 3: the 4-member circuit network (a) overlay of ketoconazole molecules in 2-red and 3-green (b) and overlay of ketoconazole molecules in structures 2-red and 1-blue (c).



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The high similarity between 2 and 3 was also evidenced by the crystal structure overlay (Figure 3c), leading to a root mean square (RMS) deviation in distance of 0.163, calculated for 30 molecules in common between the two structures [49].

a)

b)

c) Figure 3. Crystal packing viewed along the a-axis for: structure 2 (a), 3 (b) and the crystal structure overlay for 2-red and 3-green (c)


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The main difference between the crystal structures of 2 and 3 is the additional involvement of the succinic acid in weak hydrogen bonding with ketoconazole molecules from adjacent 4-member circuit networks (Table 2). Compared to the oxalate salt, the conformation of the ketoconazole molecule is substantially different in the co-crystals with fumaric and succinic acids, with a twisted conformation of the 5-membered ring R1 (whereas R1 adopts an envelope conformation in 1) and different orientations of the ring planes (Figure 2c, Supporting Information Table S2, S3). Structure 4 Similar to 2 and 3, the crystal structure of 4 is characterized by a 4-member circuit network involving hydrogen bonded ketoconazole and adipic acid molecules (Figure 4a). Structure 4 is also a co-crystal since hydrogen bonding takes place with no proton transfer between the hydroxyl group of the adipic acid and the imidazole N-atom of the ketoconazole molecule. Unlike the co-crystals with fumaric and succinic acids, the 4member circuit networks are inter-connected via a C(1)-H(1)-O(2) hydrogen bond (Figure 4b), leading to a different overall crystal packing (Figure 4c).

a)



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b)

c) Figure 4. Structure 4: the 4-member circuit network (a), H-bonded circuit networks (c) crystal packing viewed along the b axis (c).

Additionally, the ketoconazole molecule conformation in 4 is different from the cocrystals 2 and 3 with respect to both the R1 conformation (envelope in 4 versus twisted in structures 2 and 3) and the orientations of the ring planes (Figure 5a, Supporting Information Table S3). Compared to the oxalate salt, the conformation of the ketoconazole molecule in 4 shows the same R1 envelope conformation, but pronounced ring orientation differences (Figure 5b, Supporting Information Table S3).

a)

b) Figure 5. Overlay of ketoconazole molecules in structures 2-red and 4-orange (a) and in structures 1-blue and 4-orange (b).


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Despite the different ring orientations, a match between the ketoconazole conformations in 4 and 1 is achieved by the variation of the flexible torsion angles only, whereas this is not the case for the ketoconazole conformers in the structure pairs 4 versus 2/3 or 1 versus 2/3 (Supporting Information Figure S1, Table S4), probably due to the different puckering parameters of the R1 ring. Elucidation of the ionization states In the case of multi-component structures such as 1 – 4, the position of the hydroxyl H atom from the carboxylic acids plays an important role in judging the crystal form nature, namely a salt or a co-crystal. In the case of 1, 2 and 4 structures, the single-crystal X-ray diffraction data enabled the location of the proton either at the hydroxyl group of the acid or at the imidazole N-atom of the ketoconazole molecule, indicating that 1 is a salt, while 2 and 4 are co-crystals. For 3, the hydroxyl H atom could not be located due to the possible disorder present, such that a first indication of the ionization state was obtained from the structural characteristics of interacting functional groups, namely C−O bond lengths of carboxylic/ carboxylate group and endocyclic C−N−C bond angle in the triazole ring [31]. In a neutral carboxylic group C−O are longer bonds C=O, while in the carboxylate anion, depending on the extent of delocalization of negative charge between the oxygen atoms, there can be practically no difference between the C−O and C=O distances [50]. The C−N−C angle in N-heterocycles is also known to be sensitive to the protonation of nitrogen, such that cationic forms exhibit higher values than the corresponding neutral molecules [51, 52]. The characteristic bond lengths of carboxylic/carboxylate groups and the C−N−C bond angle in the imidazole rings were analyzed for all 1 – 4 determined structures (Table 3). In structure 1 the difference between d(C2A-O4A) and d(C2A-O3A) is very small (0.003 Å) and the value of the θ angle is 109 deg, indicating protonation of N1 and formation of a salt. On contrary, in structure 4 the difference d(C6A-O4A) and d(C6A-O3A) is significant (0.125 Å) and the value of θ angle is smaller, indicating a neutral compound and formation of a cocrystal. In the case of 2 and 3 similar structures, co-crystal formation is also indicated by smaller values of the θ angles and larger differences (of 0.08 Å) between the C-O and C=O bond lengths than in the oxalate salt 1.



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Table 3. Carbon-Oxygen Bond Distances of the Carboxylic/Carboxylate Groups and C1-N1-C2 angle value in N-heterocycles of 1 – 4. Structure (acid, n)

d(C1A-O1A) (Å)

d(C1A-O2A) (Å)

d(CnA-O3A) (Å)

d(CnA-O4A) (Å)

θ (C1-N1-C2) (deg)

1 (oxalic, n = 2)

1.204

1.313

1.228

1.231

109.12

2 (fumaric, n = 4)

1.223

1.295

1.204

1.284

105.69

3 (succinic, n = 4)

1.187

1.302

1.182

1.264

105.99

4 (adipic, n = 6)

1.185

1.311

1.198

1.323

105.15

In order to complement the results of the single-crystal analysis and to bring additional evidence on the ionization states of 1 – 4 the total DFT energies (Et) of the single crystal X-ray structures without any optimization were compared for two different cases: i) the H atom is bonded to O4A at a distance of 0.82 Å and ii) the H atom is bonded to N1 at a distance of 0.86 Å. Computations were performed with the CASTEP code, which uses a plane-wave basis-set to simulate the electronic wave functions, together with pseudopotentials to represent the core electrons [53]. The results are presented in Table 4 in terms of the relative energy ∆Et, were the reference energy is considered in each case as the minimum energy between the two computed structures (with H atom bonded to O4A, or to N1, respectively). One observed that the minimum energy of 3 belongs to the structure model with the H atom bonded to O4A, suggesting the presence of a cocrystal. The ∆Et values for the other structures (1, 2 and 4) are also in agreement with the salt and co-crystal nature of 1, 2 and 4 as determined from single-crystal analysis. Table 4. ∆Et values depending on the proton location in 1 - 4 crystal structures ∆Et (kcal/mol)

Structure (acid)

Co-crystal (O4A-H)

Salt (N1-H)

1 (oxalic)

90.99

0

2 (fumaric)

0

20.85

3 (succinic)

0

65.42

4 (adipic)

0

47.15

To further strengthen the assignment of the ionization states, the DFT analysis was extended with another type of calculations applied for structure 3 with succinic acid: the


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positions of all hydrogen atoms (with the heavy atoms fixed to their original positions) have been optimized using as input the crystal structure determined by single-crystal Xray diffraction, and also including the H atom of which position could not be determined by X-ray. Because of this uncertainty, two input structures were considered separately: H atom bonded to O4A in one case and to N1 in the other case, respectively. In both cases, the solutions after the geometry optimization converged to a unique structure, with the H atom bonded to O4A, indicating the co-crystal formation (even when H was initially bonded to N1, this was moved to O4A by optimization). For consistency reasons, these calculations have also been carried out for structures 1, 2 and 4, indicating for each of them the most stable structure, salt for 1, and co-crystals for 2 and 4. For these optimized structures we also computed the ss-NMR shielding and we acquired experimental ss-NMR 1H,

13

C and

15

N spectra of 1 – 4 with the purpose of validating the

crystal structures and confirming their ionization states (Suporting information – ss-NMR spectroscopy results and chemical shift calculations). Due to the poor resolution of the 1

H spectra, no information could be extracted regarding the ionization states of 1 – 4, but

the data corroborated with the hydrogen bond network described in the Crystal structures section. On the other hand, the comparison between experimental and computed 13C chemical shifts seemed acceptable (Supporting information Table S6, S7), although the particularly lower accuracy obtained for the carboxylic C atoms showed that no firm conclusions can be drawn on the ionization states of 1 – 4. The final confirmation of the ionization states was obtained from the ss-NMR 15N spectra (Figure 6). The protonation of N1 atom increases the magnetic shielding, which results in a decrease of its chemical shift. Comparison of the

15

N CP-MAS spectra of 1 – 4

evidences a significant shift only in the N1 resonance of structure 1, confirming the N1 atom protonation and the salt character of the crystal form. The other structures where no shift of the N1 resonance occurred are all co-crystals. Spectral assignments of the 15

N CP-MAS data were determined by ss-NMR shielding calculations (Supporting

information, Table S5) and within the error limits of the method showed good agreement between experimental and computed values, confirming the ionization states of 1 – 4.



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Figure 6.

15

N CP-MAS spectra for structures 1 – 4.

The proposed ionization states are in line with the ∆pKa values between ketoconazole and the respective acids for structures 1, 3 and 4 (∆pKa for 1, 3 and 4 are: 5.24, 2.31 and 2.07). In the case of structure 2 with fumaric acid, a salt would be expected to occur based on the ∆pKa rule proposed by Childs, et. al, [54] (∆pKa with respect to ketoconazole > 3). In this case, the crystal environment is likely having a strong impact on the ionization state, leading to a fumaric acid co-crystal. A highly similar crystal structure environment is also present in the succinic acid co-crystal where ∆pKa = 2.31. DSC Analyses, Powder Dissolution and Stability The DSC traces of ketoconazole, carboxylic acids, salt 1 and cocrystals 2 − 4 are shown in Figure 7. The melting points of 1 − 4, are different from those of ketoconazole and corresponding acids. It is interesting to note that the melting points of 2 and 3 are in between those of ketoconazole and the corresponding co-formers, while the melting point for 1 is higher and of 4 lower than those of the components (Figure 7).


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Figure 7. DSC traces of ketoconazole, di-carboxylic acids and 1 – 4.

In addition, the melting points of 2 and 3 are closely matching (171oC versus 165oC, Supporting information, Table S10), which is in agreement with their crystal structure similarity. On the other hand, the different crystal packing of 1 compared to 2 - 4 is reflected in its highest melting point (198oC versus 171oC, 165oC, 128oC). This is in agreement with the higher packing efficiency encountered in the salt 1 than in the cocrystals 2 – 4, as shown by its higher density and packing index values (Supporting information, Table S11). For all salt and co-crystals, powder dissolution measurements in water revealed a significant solubility improvement compared to ketoconazole (Figure 8). Considering the reported aqueous solubility of ketoconazole (0.017 mg/ml) [22], a 100-fold solubility increase was obtained by ketoconazole co-crystallization with fumaric and adipic acids. The solubility values of 1 and 4 are approximately 53 and 75 times as large as that of



ketoconazole, but it is interesting to note that a higher solubility increase is achieved by ketoconazole co-crystallization than by salt formation.

1.8

2 4

1.6 1.4

Concentration (mg/ml)

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3

1.2 1.0

1 0.8 0.6 0.4 0.2

Ketoconazole

0.0 0

20

40

60

80

100

120

Time (min) Figure 8. Powder dissolution profiles of ketoconazole and 1 – 4 in water.

After the dissolution experiments, the undissolved solids were filtered, air-dried and the solid form stability of 1 – 4 was confirmed by XRPD analyses. Additionally, slurry experiments in water and ethanol and accelerated stability testing showed that 1 – 4 are stable in suspensions for at least 1 week and on storage at 40oC / 75% RH for at least 4 months (Figure 9). The final pHs of the water dissolution experiments fall within a small pH interval (3.4 – 4.1, Supporting information, Table S12) where ketoconazole and the di-acids are partially ionized. This suggests that ionization is not the main contribution to the excellent solution stability of 1 - 4, but more likely the intrinsic crystallization behavior of ketoconazole is playing an important role, since ketoconazole is a relatively large molecule having a low crystallization tendency [55].


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Figure 9. XRPD patterns of ketoconazole, and 1 - 4 after crystallization and accelerated stability testing.

Although co-crystal melting point was shown to be a poor indicator of co-crystal aqueous solubility [56] in the case of ketoconazole the melting points of 1, 3 and 4 are in line with their solubility. When comparing the 2 and 3 co-crystals with very similar crystal structures and melting points, the solubility difference can be attributed to the higher lattice energy of the co-crystal with fumaric acid (Supporting information, Table S9). In addition, it is interesting to note that an inverse correlation is found when comparing the aqueous solubility sets of 1 – 4 and of the corresponding acids (aqueous solubility of acids: 90 mg/ml – oxalic, 80 mg/ml – succinic, 23 mg/ml – adipic and 6.3 mg/ml – fumaric, www.chemicalbook.com).



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Conclusions Similar to other azole antifungal drugs, ketoconazole is able to form salts and co-crystals with dicarboxylic acids, although in some cases the tendency of forming clays might interfere with their crystallization. One oxalate salt and three co-crystals of ketoconazole with fumaric, succinic and adipic acids were obtained, their crystal structures determined from single-crystal diffraction and the ionization states were confirmed by combining single-crystal X-ray diffraction, ss-NMR and lattice energy calculations. All solid forms were stable and showed significant solubility improvement compared to ketoconazole, with a 100 fold enhancement in the case of the co-crystals with fumaric and adipic acids. The results emphasize that salts are not necessarily more soluble than co-crystals and that correlations between salt/co-crystal solubility, melting points or co-former solubility are possible in specific cases. Our study evidences the benefit of crystal engineering in the landscape of the formulation techniques used to enhance the dissolution rate of poorly water-soluble drugs, such as ketoconazole.

Acknowledgement This work was supported by ANCS, project POSCCE ID536. The computing support was provided by the Data Center of INCDTIM, Cluj. Supporting Information Experimental details, structural characteristics and overlay analysis, lattice energy, NMR chemical shifts calculations, X-ray crystallographic information files (CIF), 1H MAS NMR, 13

C CP-MAS spectra are available for 1 - 4. Powder X-ray diffraction patterns from the

slurry experiments are included. This material is available free of charge via the Internet at http://pubs.acs.org.


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For table of contents use only Synopsis One oxalate salt and three co-crystals of ketoconazole with fumaric, succinic and adipic acids were obtained, their crystal structures determined from single-crystal diffraction and the ionization states were confirmed by combining single-crystal X-ray diffraction, ss-NMR and lattice energy calculations. All solid forms were stable and showed significant solubility improvement compared to ketoconazole, with a maximum of 100 times enhancement in the case of the co-crystals with fumaric and adipic acids.


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Ketoconazole Salt and Co-crystals with Enhanced Aqueous Solubility

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