High-Solubility Salts of the Multiple Sclerosis Drug Teriflunomide

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High Solubility Salts of Multiple Sclerosis Drug Teriflunomide Anilkumar Gunnam, and Ashwini K. Nangia Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.9b00914 • Publication Date (Web): 30 Jul 2019 Downloaded from pubs.acs.org on August 5, 2019

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Crystal Growth & Design

High Solubility Salts of Multiple Sclerosis Drug Teriflunomide Anilkumar Gunnama and Ashwini K. Nangia*a, b

a

School of Chemistry, University of Hyderabad, Prof. C. R. Rao Road, Gachibowli, Central University P.O., Hyderabad 500 046, India b

CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India

E-mail: [email protected], [email protected]

Abstract: Teriflunomide (TFM) is an immunomodulatory pro-drug of leflunomide which is used for the treatment of Multiple Sclerosis (MS). It is a Biopharmaceutics Classification System Class (BCS) II drug with low solubility and high permeability. The X-ray crystal structure of TFM is stabilized by O–H···O, C–H···O, C–H···N and N–H···N interactions. In order to study the solubility and dissolution changes of this drug, five multicomponent crystal forms were prepared with amine and amide generally regarded as safe (GRAS) coformers to improve the physicochemical properties such as solubility, dissolution, diffusion and phase stability. Equimolar TFM-coformer 1:1 salts were crystallized, except cytosine which afforded a salt cocrystal toluene solvate TFM-CYT-TOL in 1:2:1 ratio. The multicomponent forms were crystallized by slow solvent evaporation and characterized by single crystal X-ray diffraction. TFM and coformer are bonded by N+–H···O-, N– H···O, O–H···O, C–H···O, C–H···N N–H···N, and C–H···F interactions. The bulk phase purity of the salts was characterized by powder X-ray diffraction, infrared and thermal techniques. Solubility, dissolution and diffusion experiments in pH 7.0 buffer exhibited significant improvement compared to the reference drug. The morphology and particle size of salts by FESEM was related with dissolution behavior. The highest solubility, dissolution and diffusion profile was observed for TFM-MEA and TFM-TEA salts (monoethanol amine and triethanol amine).

Introduction: Crystal engineering1-3 strategies can address solubility,4 stability5 and bioavailability6 issues of poorly water soluble as cocrystals assembled via supramolecular synthons.7 Multicomponent molecular crystals have been shown to improve the physicochemical properties of drugs compared to those of reference levels.8-10 Over 80% of drugs in market are solid dosage forms. Oral tablets are preferred due to ease of manufacture, transport, storage, stability, low cost and total drugpatient compatibility.11 Poorly water-soluble drugs may be modified supramolecularly as salts, 12,13 cocrystals, 14 solvates/hydrates,15-16 polymorphs,17 eutectics and solid solutions, 18,19 amorphous compounds20 supramolecular gels21 and nanoparticles.22 Salt formation is the most conventional and preferred practice in the pharmaceutical industry to improve physicochemical properties and 1 ACS Paragon Plus Environment

Crystal Growth & Design 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

stability of drugs.13,23 Salts are water soluble with fast dissolution, good stability, high bioavailability, and improved absorption rates. The aqueous solubility of ionized drug molecules in salts is higher than neutral drug molecules because of dipolar and charged interactions with water. Multiple Sclerosis (MS) is a chronic autoimmune disorder which effects the Central Nervous System (CNS).24 According to the Atlas of MS2013, there are 2.3 million people suffering from MS in about 174 countries.25 This is a demyelinating disease that damages the myelin sheath on the nerve cells of brain and spinal cord resulting in abnormal impulse transmission. There is no proper treatment for the complete cure of MS but disease modifying treatments (DMT) can reduce the pathogenesis of MS.26 One of the recently approved and effective disease modifying drug (DMG) for MS is Teriflunomide (TFM), which is an active metabolite of its prodrug Leflunomide.27 TFM is a pyrimidine synthesis inhibitor which blocks the de novo pyrimidine synthesis by non-competitive and reversible inhibition of the enzyme dihydroorotate dehydrogenase (DHODH), which limits the proliferation of T and B cells involved in the pathogenicity of MS.28 TFM is a BCS class II29 drug molecule with high permeability (log P 2.14) and low solubility (0.0124 mg/mL).30 There are very few reports on the solubility and dissolution improvement of TFM. Biaryl analogues and ion pairs of TFM with amines have been reported to improve the transdermal permeation of TFM.31,32 However solubility limitation of TFM is a challenge for its effectiveness because it limits bioavailability of the drug. We address in this study the solubility of TFM by crystal engineering of pharmaceutical salts using Generally Regarded as Safe (GRAS) coformers approved by the US-FDA.33 The pKa rule guides in the selection of coformers which will be ionized in hydrogen bonding with the drug functional groups.34 Solvent assisted co-grinding of TFM with several high solubility coformers which will ionize with the acidic and basic groups of TFM (-keto-enol-OH of drug, pyridine-N and NH of coformer). Crystal forms of TFM with isonicotinamide (INAM), cytosine (CYT), monoethanolamine (MEA), diethanolamine (DEA), and triethanolamine (TEA) were isolated (structures are represented in Figure 1). The drug TFM and multi-component products TFMINAM (1:1) salt, TFM-MEA (1:1) salt, TFM-DEA (1:1) salt, and TFM-TEA (1:1) salt, and TFMCYT-CYT (1:2:1) salt cocrystal toluene (TOL) solvate were characterized by powder X-ray diffraction (PXRD), thermal analysis (DSC) and vibrational spectroscopy (IR) to confirm novelty of the crystalline phases. Single crystals of the solid forms were obtained by solution crystallization in different solvents and their structures were characterized by X-ray diffraction (SC-XRD, Table 1).

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Figure 1: Structures of TFM and its coformers.

Crystal structures TFM: The crystal structure of TFM is not reported in the CCDC,35 and so TFM was crystallized from different solvents to obtain good quality crystals from acetone which solved in P-1 space group. In this crystal structure the two centrosymmetric molecules of TFM are connected by N-H···N hydrogen bonds (N1–H1A···N4, 2.25 Å, 164º and N3–H13A···N2, 2.30 Å, 158º) in R22 (12) ring motif between C≡N and amide N-H groups. Each TFM molecule is stabilized by intramolecular hydrogen bonding between enolic hydroxyl and amide carbonyl via O-H···O (O2–H2A···O1, 1.64Å, 158º and O3–H3A···O4, 1.60Å, 154º). Further C-H···O (C7–H7···O1, 2.47Å, 157º) forming R22 (14) ring motif extending in 1D chain. And also the C-H···O (C12–H12A···O4, 2.51Å, 139º and C24– H24C···O2, 2.59Å, 140º) interactions in 2D fashion. Hydrogen bonds are listed in Table 2.

In multicomponent crystals of TFM, the weaker hydrogen bonds in the structure of TFM are replaced by strong enolate-amine synthons, N–H···O hydrogen bonds and weak C–H···F interactions. The crystal packing in TFM salts induces conformational changes in TFM molecule (represented in overlay diagram of Figure S1 in Supporting Information) and torsion angles are listed (in Table S1of SI). Single crystals of TFM-TEA we could not be obtained after multiple crystallization attempts and so TFM-TEA was characterized by solid-state 13C NMR, and compared with that of TFM-MEA and TFM-DEA (which are salts by SC-XRD) (Figure S2a-S2d and Table S2 of SI).



(a)

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(b)

Figure 2: Crystal structure of TFM. (a) 1D chain extending via N-H···N synthon. The -keto-enol is engaged in intramolecular O-H···O bond. (b) Layered packing of TFM due to coplanar aromatic and -keto-enol fragments. TFM-INAM (1:1) salt: TFM-INAM crystalized from a 1:1 mixture of methanol and toluene and the structure was solved in monoclinic P21/c space group. TFM and INAM are connected by ionic N-H+···O- (N4–H4A···O2, 1.74 Å, 164º) H-bond between enolic hydroxyl group of TFM and protonated pyridine nitrogen of INAM. Two INAM molecules are connected by N-H···O amide dimer (N3–H3A···O3, 2.08 Å, 177º) in R22(8) ring motif (Figure 3). The crystal structure is extended in a 2D sheet via N-H···O (N3–H3B···O1, 2.16 Å, 164º) H-bond. The flat layers stack as shown in (b).

(b)

(a)

Figure 3: Crystal structure of TFM-INAM (a) connected by N-H+···O- and N-H···O H-bonds, and (b) layered packing of TFM-INAM sheets. TFM-CYT-TOL (1:2:1) Salt Co-crystal: TFM-CYT crystalized from a 1:2 mixture of ethyl acetate and toluene in the triclinic space group P-1 as the toluene solvate. TFM and CYT molecules are connected by N-H···O (N8–H8A···O2, 1.99 Å, 175º) H-bond between the amine donor of CYT ketone acceptor of TFM. These co-crystal molecules are connected by N-H···O dimer (N5– H5A···O1, 1.99 Å, 152º) of CYT molecules in a 1D chain. The CYT molecules are bonded in a three-point synthon via N-H···O (N5–H5B···O5, 1.91 Å, 154º; N8–H8B···O3, 2.08 Å, 154º) and N–H···N (N3–H3A···N6, 1.96 Å, 172º) H-bonds (Figure 4). Such three-point CYT dimeric units extend by amide dimer N–H···O (N4–H4A···O5, 1.82 Å, 169º; N7–H7A···O3, 2.06 Å, 168º) Hbonds. Toluene solvent molecules occupy the void space between the layers. Toluene molecules could not be modelled completely due to solvent disorder in the crystal structure. A satisfactory disorder model was not found and was used to mask out the diffuse electron density corresponding 4 ACS Paragon Plus Environment

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to 49 electrons, which is ascribed as one toluene molecule (toluene has 50 electrons). The presence of toluene was further confirmed by solid-state NMR spectroscopy (Figure S3a-b & Table S3) and supported by TGA weight loss (calculations listed in Figure S4 & Table S4).

(a)

(b)

Figure 4: Crystal structure of TFM-CYT-TOL to show (a)voids for toluene solvent, (b) TFMCYT connected via N-H···O synthons. TFM-MEA (1:1) salt: Crystals of TFM-MEA crystalized from methanol in orthorhombic space group P212121 as a 1:1 salt. TFM and MEA are connected by ionic N-H+···O (N3–H3A···O1, 1.81 Å, 165º) interaction between amide carbonyl group of TFM and amine group of MEA. Two TFMMEA molecules are bonded in a 1D chain via O–H···O ( O3–H3A···O2, 1.89 Å, 143º) between enolic oxygen of TFM and hydroxyl group of MEA, further the TFM-MEA is stabilized by NH···O (N3–H3C···O3, 1.92 Å, 171º) interaction between TFM and MEA and N-H···N (N3– H3C···N2, 2.18 Å, 153º) interactions between MEA (Figure 5).

(a)

(b)

Figure 5: Crystal structure of TFM-MEA salt to show (a) ionic O-H···O-, N-H+···O, N-H···O and N-H···N interactions (b) extended packing in TFM-MEA salt. The CF3 group is disordered. TFM-DEA (1:1): TFM-DEA crystalized from a 1:1 mixture of methanol and acetonitrile and solved in the monoclinic space group P21/c as a 1:1 salt. TFM and DEA are connected by O– H···O- (O3–H3A···O2, 1.82 Å, 173º) H-bond between the hydroxyl group of DEA and enolic oxygen of TFM. The structure is further stabilized by O–H···O (O4–H4A···O1, 1.97 Å, 152º) Hbond between the hydroxyl donor of DEA and amide carbonyl of TFA, and N–H···N (N3– H3B···N2, 2.31 Å, 134º) from secondary amine of DEA to the nitrile acceptor of TFM and the DEA coformer molecules are connected by N–H···O (N3–H3C···O3, 2.02 Å, 152º) interaction between secondary amine and hydroxyl groups (Figure 6). 5 ACS Paragon Plus Environment


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(a) (b)

Figure 6: Crystal structure of TFM-DEA salt to show (a) O–H···O- and N–H···N interactions and (b) overall packing in TFM-DEA salt. Table 1: TFA Crystallographic parameters. TFM-INAM TFM-CYTTOL

TFM-MEA

TFM-DEA

C21H18F3 N8O5

C14H14F3 N3O3

C16H20F3 N3O4

392.34

519.43

329.28

375.35

Triclinic

Monoclinic

Triclinic

Orthorhombic

Monoclinic

Sp. gr.

P-1

P21/c

P-1

P212121

P21/c

T (K)

100(2)

298(2)

298(2)

100(2)

100(2)

a (Å)

9.3951(5)

5.5287(7)

8.4165(4)

10.6929(16)

11.3915(2)

b (Å)

11.5161(7)

18.321(2)

11.5538(6)

29.804(5)

18.8723(4)

c (Å)

11.9447(8)

17.638(2)

14.2896(6)

4.8637(7)

8.4638(2)

α (º)

95.990(3)

90

75.510(2)

90

90

β (º)

105.839(2)

91.655(4)

75.429(2)

90

108.847(2)

γ (º)

110.753(2)

90

70.962(2)

90

90

Z

4

4

2

4

4

V (Å3)

1133.21(12)

1785.8(4)

1249.65(10)

1550.0(4)

1722.02(7)

Rflns collect 5014

3159

4779

2708

3038

Obsd rflns

5004

3154

4767

2639

3038

Unique rflns 3443

2081

2533

2516

2753

Parameters

361

294

357

253

260

R1

0.0505

0.0590

0.0773

0.0574

0.0396

Compound

TFM

Emp. form.

C12 H9 F3 C18H15F3 N2 O2 N4O3

Form. Wt.

270.21

Cryst. Syst.


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D∙∙∙A (Å)

H∙∙∙A (Å)

DH∙∙∙A (°)

symmetry code

N1H1A∙∙∙N4

3.0516(2)

2.25

164

1-x,1-y,1-z

O2H2A∙∙∙O1

2.5005(2)

1.64

158

---a

N3H3A∙∙∙N2

3.1079(2)

2.30

159

1-x,1-y,1-z

O4H4A∙∙∙O3

2.4774(2)

1.60

154

---a

C4H4∙∙∙N4

3.3078(2)

2.57

135

1-x,1-y,1-z

C7H7∙∙∙O1

3.3675(2)

2.47

157

2-x,-y,1-z

C12H12A∙∙∙O4

3.3201(2)

2.52

139

2-x,1-y,2-z

C16H16∙∙∙O3

2.8263(2)

2.21

121

---a

C18H18∙∙∙N2

3.2928(2)

2.49

142

1-x,1-y,1-z

C24H24C∙∙∙O2

3.4117(2)

2.60

141

2-x,1-y,2-z

N1H1A∙∙∙O2

2.6626(3)

1.92

143

---a

N3H3A∙∙∙O3

2.9434(4)

2.08

176

1-x,1-y,1-z

N3H3B∙∙∙O1

2.9849(4)

2.16

162

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

N4H4A∙∙∙O2

2.5862(3)

1.74

164

1+x,y,z

C4H4∙∙∙O1

2.9363(4)

2.35

121

---a

C17H17∙∙∙N2

3.0768(4)

2.32

139

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

C18H18∙∙∙O1

3.3795(4)

2.46

168

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

DH∙∙∙A TFM

TFM-INAM

TFM-CYT-TOL wR2

0.1277

0.1538

0.2511

0.1543

0.1004

GOF

1.039

1.104

1.075

1.069

1.095

Diffractome ter

Bruker Bruker APEX-II APEX-II CCD CCD detector detector

Bruker APEX-II CCD detector

Bruker APEX-II CCD detector

Rigaku XtaLAB Synergy

Table 2: Hydrogen bonds in TFM crystal forms. 7 ACS Paragon Plus Environment


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N1H1A∙∙∙O2

2.6555(1)

1.78

152

---a

N4H4A∙∙∙O5

2.8299(1)

1.84

170

2-x,1-y,-z

N5H5A∙∙∙O1

2.8415(1)

1.94

155

1-x,1-y,1-z

N5H5B∙∙∙O5

2.8479(1)

1.95

171

1-x,1-y,-z

N7H7A∙∙∙O3

2.8325(1)

2.04

170

2-x,1-y,-z

N8H8A∙∙∙O2

2.8507(1)

1.89

175

-1+x,y,z

N8H8B∙∙∙O3

2.9052(2)

2.07

158

1-x,1-y,-z

C6H6∙∙∙O1

2.8826(1)

2.29

121

---a

C15H15∙∙∙O1

3.1831(2)

2.49

131

1-x,1-y,1-z

N1H1A∙∙∙O2

2.6758(1)

1.95

139

---a

N3H3A∙∙∙O1

2.6749(1)

1.81

165

-1+ x, y, z

N3H3B∙∙∙N2

3.0285(1)

2.18

153

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

O3–H3A···O2

2.6219 (1)

1.89

143

x, y, 1+z

N3H3D∙∙∙O3

2.8133(1)

1.92

172

x, y, -1+z

C4H4∙∙∙O1

2.8543(1)

2.27

121

---a

N1H1A∙∙∙O2

2.6480(7)

1.83

149

---a

O3H3A∙∙∙O2

2.6608(7)

1.82

173

x, 1.5-y,1/2+z

N3H3B∙∙∙N2

3.0133(8)

2.31

134

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

N3H3B∙∙∙O4

3.1283(8)

2.42

133

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

N3H3C∙∙∙O3

2.8856(8)

2.02

152

x,1.5-y,-1/2+z

O4H4A∙∙∙O1

2.7479(7)

1.97

152

1-x,1-y,-z

C14H14A∙∙∙N2

3.4998(9)

2.50

162

1-x,-y,-z

C15H15B∙∙∙F1

3.1740(9)

2.42

135

1+x,y,z

TFM-MEA

TFM-DEA

a

intramolecular hydrogen bond


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Figure 7: Overlay of experimental PXRD line pattern of TFM and salts (black trace) to show excellent match with the calculated line profile from the X-ray crystal structure (red trace), indicating bulk purity and phase homogeneity.

PXRD analysis PXRD is a front-line characterization technique to measure the bulk phase purity and homogeneity of pharmaceutical solids from their unique diffraction pattern. It is a fast and accurate method to characterize multicomponent solids from their starting materials.36,37 The PXRD of novel multicomponent solid forms prepared in this work confirm the bulk phase purity and homogeneity of the crystalline phase by an overlay of the experimental powder pattern with the calculated lines from the X-ray crystal structure (Figure 7). The profile fitting parameters for each powder pattern with crystal data are listed in the Table 3.



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Table 3: Profile fitting parameters of TFM and its crystalline forms. Rp

Rwp

TFM

15.7

20.61

TFM-MEA

12.70

17.49

TFM-DEA

11.71

16.88

TFM-INAM

7.27

9.25

TFM-CYT-TOL

20.79

28.78

Thermal analysis A knowledge of the phase transformations and phase purity are two important parameters for an active pharmaceutical ingredient (API).38-41 Differential Scanning Calorimetry (DSC) of the novel multicomponent forms of TFM show unique thermal behavior compared to the starting materials. The melting point of TFM is at 228-230 °C, whereas the solid forms exhibit an endotherm below the melting point of TFM (Figure 8, Table 4).42 This is due to the lower melting point of the coformers INAM (155-157°C), MEA (10-11°C), DEA (28-29 °C) and TEA (21-23 °C). In case of TFM-CYT-TOL though the melting point of CYT is higher (321-324 °C) the resulting product has a lower melting temperature compared to TFM. This anomaly can be explained by the solvent voids in the crystal packing of TFM-CYT-TOL (weak interactions between TFM-CYT and TOL) compared to the strong hydrogen bonding in TFM structure.

Figure 8: DSC thermograms for salts and cocrystals of TFM. 10 ACS Paragon Plus Environment

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Table 4: Melting point table of TFM and its solid forms. Drug/Coformer Melting point (°C)

New Solid form

Melting point of Salt/Co-crystal (°C)

TFM

228-230

---

---

INAM

155-157

TFM-INAM

162-165

CYT

320-325

TFM-CYT-TOL

209-211

MEA

10-11

TFM-MEA

161-164

DEA

28-29

TFM-DEA

149-154

TEA

21-23

TFM-TEA

134-136

Vibrational spectra of TFM and its solid forms Vibrational spectroscopy shows clear changes in the shift of the wave number due to hydrogen bonding of functional groups.43 FT-IR spectra of TFM shows an amide carbonyl stretch at 1634 cm-1 as well as hydroxyl (O-H) and amine (N-H) stretching frequency at 3304 cm-1 as a broad band and nitrile stretch at 2220 cm-1. The amide carbonyl stretch at 1634 cm-1 of TFM is red shifted to 1644.3 cm-1, the nitrile stretch at 2220 cm-1 is blue shifted to 2204.0 cm-1 due to interaction between amide-amide interaction and nitrile-C-H interactions respectively in TFM-INAM. The amide carbonyl of TFM is red shifted to 1642.3 cm-1 is due to interaction between amide-amide interactions in TFM-CYT-TOL. The amide carbonyl of TFM is red shifted to 1646.0 cm-1 and the nitrile group is blue shifted to 2190.0 cm-1 due to interaction between amide-amide interaction and nitrile-C-H interactions respectively in TFM-MEA. The amide carbonyl of TFM is red shifted to 1638.6cm-1 and the nitrile group is blue shifted to 2192.2 cm-1 due to interaction between amideamide interaction and nitrile-C-H interactions respectively in TFM-DEA. The amide carbonyl of TFM is red shifted to 1637.4cm-1 and the nitrile group is blue shifted to 2204.2 cm-1 due to interaction between amide-amide interaction and nitrile-C-H interactions respectively in TFMTEA. All the N-H stretching frequencies in TFM are red shifted to higher wavenumbers in their respective salts due to intramolecular interaction with neighboring enolate oxygen. These functional groups show spectral shift in the binary solid forms44 (Table S5 and Figure S5a-f, SI).

Fe-SEM Morphology studies SEM is used to investigate and visualize the microstructure and surface topography of crystalline solids.45,46 It provides visual information at the m and nm scale of the size, shape and morphology.47-49 SEM photographs of TFM salts are shown in Figure 9. The morphology of TFM and its salt forms are irregular and contains both small and large particles, indicating the similar 11 ACS Paragon Plus Environment


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morphology and smooth surfaces of TFM-INAM, TFM-MEA and TFM-DEA. In contrast TFM having particles of 7-20 m range with sharp edges and clear separation among the particles. The FE-SEM morphology of TFM-CYT-TOL and TFM-TEA are different in nature. TFM-INAM shows 0.2-2 µm size particles with rough surface and smooth edges. The morphology of TFMCYT-TOL has small irregular shape and 1-2 µm size particles with rough adherent surfaces. The SEM micrographs of TFM-MEA and TFM-DEA shows bunches of irregular 2-10 µm size range particles with adhering smooth surfaces and curvy edges. In case of TFM-TEA, the SEM micrographs show heterogeneity in the size and morphology of the particles. It has rod shaped particles with 1-10 µm size range.

(a) TFM

(b) TFM-INAM

(c) TFM-CYT-TOL

(d) TFM-MEA

(e) TFM-DEA

(f) TFM-TEA

Figure 9: FESEM images at 2-10 µm resolution. (a) TFM shows 7-20 µm particle size, (b) TFMINAM shows small grains of 0.2-2 µm particle size (c) TFM-CYT-TOL has grains of about 1-2 µm (d) TFM-MEA shows irregular 2-10 µm particle size, (e) TFM-DEA has irregular 2-10 µm particle size and (f) TFM-TEA is rod-like morphology of 1-10 µm irregular shape.

Solubility measurements of TFM Solubility is the key parameter which regulates the bioavailability and efficacy of an API. The equilibrium solubility is the measure of concentration of the substance at equilibrium between solution and undissolved material which is a thermodynamic phenomenon.50 The equilibrium solubility measurements for TFM and its salts were carried out in phosphate buffer (pH 7) medium at 37° C for a period of 24 hours. Dissolution rate is the amount of drug soluble in a particular time period, which is a kinetic phenomenon. Dissolution experiments were carried out in pH 7 12 ACS Paragon Plus Environment

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phosphate buffer for 60 min by rotating disc intrinsic dissolution rate (RDIDR) method at 37 ° C at a constant RPM of 150.51 After the equilibrium solubility and dissolution experiments, the concentrations of TFM in each solid form measured by UV spectroscopy and the undissolved materials at the end of the experiment characterized by PXRD to confirm the phase stability. All the multicomponent forms of TFM exhibited the enhanced solubility after 24 hours compared to neutral TFM. Specifically, TFM-TEA (11.0 times), TFM-MEA (6.6 times), TFM-DEA (2.8 times), TFM-CYT-TOL (2.13 times) and TFM-INAM (1.9 times) more soluble at equilibrium conditions than pure TFM indicating that new multicomponent solid forms of TFM are having considerably higher solubility profiles than TFM (Table 5). The stability of the solid materials at the end of the equilibrium experiments analyzed by PXRD indicating that all the solid phases are stable after 24 hours (Figure S6a & S6d-S6f of SI) except TFM-INAM which is totally converting to TFM (Figure S6b of SI) and TFM-CYT-TOL is converting to a new phase (Figure S6c of SI). In IDR experiments almost all the multicomponent solids of TFM showed enhanced dissolution rate compared to neutral TFM except TFM-INAM (Figure 10). At the end of the experiment the solid material was collected from the dissolution disc and analyzed by PXRD (Figure S7a & S7dS7f of SI), indicating that all the solid forms are stable during the dissolution period of 1 h except TFM-INAM which partially converted to TFM (Figure S7b of SI) and TFM-CYT-TOL which completely converted to a new phase (Figure S7c of SI). The IDR rate is highest for TFM-TEA (x 15.70 times) followed by TFM-MEA (x 9.29 times), TFM-DEA (x 4.29 times) and TFM-CYTTOL (x 1.45 times). TFM-INAM showed lower IDR among all the solid forms including TFM neutral. The enhanced solubility and dissolution profiles of the new solid forms of TFM are likely following the particle size and morphology and solubility of the coformers supported by the melting point trends in the solid forms. The TFM salts with ethanolamine coformers TEA, MEA and DEA are showing the highest solubility and dissolution rate over the TFM salts with aromatic basic coformers INAM and CYT. During IDR experiments, TFM-TEA salt reached peak concentration in 25-30 min whereas TFM-MEA salt reaches its peak concentration in 45-50 min. The highest solubility of TFM-TEA is driven by high solubility of TEA and morphological advantage of rod-shaped particles of TFM-TEA which are having high surface area compared to other particles from SEM images of the salts.52 Along with the solubility and morphological advantage of TFM-TEA the low melting point also favors the high solubility of the TFM-TEA salt. The highest solubility and dissolution improvement for TFM in its salt form with ethanolamine coformers are 11.0 and 15.62 times respectively with triethanolamine coformer, which is a considerable improvement over the current marketed neutral form of TFM. Table 5: Equilibrium solubility and IDR comparison of TFM and its solid forms. Solid form

Coformer solubility (mg/mL)

Molar extinction coefficient (ε) (L

mol-1

cm-1)

Equilibrium solubility

IDRa

in pH 7 buffer

Cumulative amount dissolved per unit areaa

(mg/mL)a

(mg/500mL)


(mg/cm2/min)


TFM

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0.012

0.0283

0.637

0.77

12.15

TFM-INAM 0.191

0.0286

Unstable

0.70 (x 0.91)

10.29 (x 0.85)

TFM-CYTTOL

8.000

0.0263

Unstable

1.12 (x 1.45)

16.74 (x 1.37)

TFM-MEA

100

0.0270

4.202 (x 6.6)

7.15 (x 9.29)

111.01 (x 9.14)

TFM-DEA

100

0.0274

1.785 (x 2.8)

3.30 (x 4.29)

52.41 (x 4.31)

TFM-TEA

100

0.0299

7.045 (x 11.0)

12.09 (x 15.70) 161.21 (x 13.27)

a

indicates times higher solubility/ dissolution compared to TFM

Figure 10: IDR curves of TFM and its solid forms.

Diffusion Studies of TFM and Solid forms


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In addition to the solubility profile, the diffusion and permeability flux of a drug is an important parameter which determines the amount of drug reaches to site of action through systemic circulation after being administered orally for solid drugs.53,54 The drug absorption through the lipid membrane is primarily depends on the solubility and dissolution profile. Diffusion is measured by the Franz cell method to measure the permeability profile of a drug. Diffusion is the random thermal movement of the drug in solution across a concentration gradient and the flux of the drug is defined as the mass or number of molecules passing through the membrane of a unit cross section in given time. A typical Franz diffusion cell set up consists of an upper donor compartment with a specific volume and concentration of the drug solution whose diffusion and permeability profile are measured. The drug solution diffuses from the receiver compartment at the bottom through a barrier with specific cross section and thickness. The initial concentration in the receiver cell is zero and the drug solution from donor compartment continually diffuses through a specific barrier membrane. The concentration of the solution in the receiver compartment is measured at regular time intervals to know the diffusion profile and permeability flux of the drug. The diffusion and permeability flux studies of TFM and its salts were carried out in pH 7.0 phosphate buffer over a time period of 100 minutes with a total of 10 intervals. After measuring the concentration of solutions received at each interval for all the solid forms of TFM using the formulae J = m/(A*t) where J is the flux of the drug, m is the mass of the drug moving through the membrane having area of cross section A in time t, the results are plotted as cumulative drug diffused vs. time (Figure 11) and flux of the drug vs. time (Figure 12). These plots showing that all the multicomponent solid forms of TFM show higher diffusion rate over neutral TFM. Especially, TFM-MEA, TFM-TEA and TFM-DEA exhibit higher diffusion rate over the other solid forms and this is evidenced from the high solubility and high permeability of ethanol amines from the literature and also these amine coformers are used for topical drug delivery.



Figure 11: Cumulative amount of TFM solid forms diffused vs. time.

Figure 12: Flux of TFM solid forms vs. time.


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Conclusions Salts of TFM with amines were prepared by the solvent-assisted grinding method and characterized by X-ray crystallography, thermal techniques, spectroscopic and microscopic analysis such as PXRD, SXRD, DSC, IR, NMR and SEM. The crystal forms of TFM are stabilized by various non-covalent and ionic interactions such as N+–H···O-/ N–H···O, N–H···N, C–H···N, O–H···O, C–H···O and C–H···F interactions. The solubility, dissolution and diffusion experiments of TFM salts in pH 7.0 phosphate buffer showed improvement compared to neutral TFM. The TFM-TEA, TFM-MEA and TFM-DEA showed good solubility and dissolution profile of good stability. Diffusion experiments in Franz cell apparatus showed that TFM-MEA, TFMTEA and TFM-DEA showed higher diffusion profile. This solubility profile of TFM and salts follow the melting point order of the salt (low melting high solubility) and particle size from FESEM. The diffusion profiles of TFM and salts depends primarily on solubility and dissolution of that particular salt and further on the coformer solubility and its size (small size high diffusion rate). From FE-SEM micrographs, the particle size and shape of salts are characterized and further correlated to solubility and diffusion profiles. TFM-TEA and TFM-MEA showed better solubility and diffusion profile for new formulations of TFM.

Experimental Section Preparation of TFM solid forms TFM (purity 99.8%) is a gift sample from Hetero Pharma and all co-formers and salt formers were purchased from Sigma Aldrich. All solvents used for preparation of solid forms and crystallization were purchased from Finar chemicals. TFM: TFM 270.0 mg (0.1 mmol, >99.8% purity) obtained from Hetero Pharma Hyderabad and confirmed by PXRD, DSC and IR. About 30 mg of this material was dissolved in 5 mL of methanol and left for slow evaporation at room temperature. Good quality single crystals were harvested for SC-XRD analysis after 4 days. TFM-INAM: TFM 270.0 mg (0.1mmol, >99.8% purity) and 122.1 mg (0.1 mmol, 99% purity) of INAM were co-grinded with acetonitrile solvent. The formation of co-crystal was confirmed by PXRD, DSC and IR. About 30 mg of this material was dissolved in 5 mL of 1:1 mixture of methanol and toluene and left for slow evaporation at room temperature. Good quality single crystals were harvested for SC-XRD analysis after 2 weeks. TFM-CYT-TOL: TFM 270.0 mg (0.1mmol, >99.8% purity) and 111.1 mg (0.1 mmol, 98% purity) of CYT were co-grinded with acetonitrile solvent. The formation of salt was confirmed by PXRD, DSC and IR. About 30 mg of this material was dissolved in 5 mL of 1:1 mixture of ethyl acetate and toluene and left for slow evaporation at room temperature. Good quality single crystals were harvested for SC-XRD analysis after 2 weeks.



TFM-MEA: TFM 270.0 mg (0.1 mmol, >99.8% purity) and 60.1 µL (0.1 mmol, 97% purity) of MEA were co-grinded with acetonitrile solvent. The formation of salt was confirmed by PXRD, DSC and IR. About 30 mg of this material was dissolved in 5 mL of methanol and left for slow evaporation at room temperature. Good quality single crystals were harvested for SC-XRD analysis after 2-4 days. TFM-DEA: TFM 270.0 mg (0.1 mmol, >99.8% purity) and 105.0 µL (0.1 mmol, 97% purity) of DEA were co-grinded with acetonitrile solvent. The formation of salt was confirmed by PXRD, DSC and IR. About 30 mg of this material was dissolved in 5 mL of 1:1 mixture of methanol and acetonitrile and left for slow evaporation at room temperature. Good quality single crystals were harvested for SC- XRD analysis after 3-4 days. TFM-TEA: TFM 270.0 mg (0.1 mmol, >99.8% purity) and 149.8 µL (0.1mmol, 97% purity) of TEA were co-grinded with acetonitrile solvent. The formation of salt was confirmed by using PXRD, DSC and IR. About 30 mg of this material was dissolved in 5 mL of several common solvents and solvent mixtures. However, we could not obtain good quality crystals for diffraction analysis even after several crystallization attempts. TFM-TEA was characterized by PXRD and 13C ss-NMR techniques (Figure S2a-d and Table S2 of SI). Powder X-ray diffraction Powder X-ray diffraction was recorded on Bruker D8 Advance diffractometer (Bruker-AXS, Karlsruhe, Germany) using Cu-Kα X-radiation (λ = 1.5406 Å) at 40 kV and 30 mA power. X-ray diffraction patterns were collected over the 2θ range 3–50° at a scan rate of 3.9°/min. Powder Cell 2.455 (Federal Institute of Materials Research and Testing, Berlin, Germany) was used for Rietveld refinement of experimental PXRD and calculated lines from the X-ray crystal structure. Vibrational spectroscopy Thermo-Nicolet 6700 FT-IR-NIR spectrometer with NXR FT-Raman module (Thermo Scientific, Waltham, MA) was used to record IR spectra. IR spectra were recorded on samples dispersed in KBr pellets. Data were analyzed using the Omnic software (Thermo Scientific, Waltham, MA). Thermal analysis Thermal analysis was performed on a Mettler Toledo DSC 822e module calibrated with indium (Tm = 156.60 °C; ΔHf = 28.45 J g–1) and zinc (Tm = 419.50 °C; ΔHf = 107.50 J g–1) as per the manufacturer’s specifications. The typical sample size is 3-5 mg and samples were placed in sealed pin-pricked aluminum pans for DSC experiments. A heating rate of 10 °C min–1 in the temperature range 30-350 °C was applied. Samples were purged by a stream of dry nitrogen flowing at 60 mL min–1. X-ray crystallography X-ray reflections were collected on Bruker D8 QUEST, CCD diffractometer equipped with a graphite monochromator and Mo-Kα fine-focus sealed tube (λ = 0.71073 Å) and reduction was performed using APEXIII Software.56 Intensities were corrected for absorption using SADABS 18 ACS Paragon Plus Environment

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and the structure was solved and refined using SHELX2018 and Olex 2.57 All non-hydrogen atoms were refined anisotropically. Hydrogen atoms on hetero atoms were located from difference electron-density maps and all C–H hydrogen atoms were fixed geometrically. Hydrogen-bond geometries were determined in PLATON.58,59 X-Seed was used to prepare packing diagrams.60,61 Crystallographic cif files are available at www.ccdc.cam.ac.uk/data or as part of the Supporting Information (CCDC Nos. 1885431-1885435). Crystal data for TFM-TEA is not deposited with this publication due to incomplete structure solution and high R-factor of 0.25. FE-SEM analysis The morphology and size of the micro structures of TFM and its salts were examined on Carl Zeiss Field Emission Scanning Electron Microscope Model 6027 with MERLIN compact using a beam voltage of 5 kV. Solubility measurements The solubility of TFM and solid forms was measured using the Higuchi and Connor method62 in (phosphate buffer (pH 7) media at 37 °C. First, the absorbance of a known concentration of the TFM and its salts was measured at the given λmax (TFM 290 nm) in purified pH 7 phosphate buffer medium on Thermo Scientific Evolution 300 UV-vis spectrometer (Thermo Scientific, Waltham, MA) respectively. These absorbance values were plotted against several known concentrations to prepare the concentration vs. intensity calibration curve. From the slope of the calibration curves, molar extinction coefficients for TFM and its salts were calculated. The equilibrium solubility measurements of TFM was carried out in pH 7.0 phosphate buffer using the shake-flask method.63 An excess amount of the sample (TFM/salts) was added to 3 mL of purified pH 7 phosphate buffer medium. The supersaturated solution was stirred at 800 rpm using a magnetic stirrer at 37 °C. After 24 h, the suspension was filtered through Whatmann 0.45μm syringe filter. Then equilibrium solubility is calculated as per procedure and remaining residues of TFM/salts were characterized by PXRD. Intrinsic dissolution rate (IDR) of TFM and its solid forms were conducted on a USP certified Electro lab TDT-08L Dissolution Tester (Electro lab, Mumbai, MH, India). In intrinsic attachment unit 250 mg sample (TFM/salts) is compressed between the smooth surfaces under a pressure of 2.5 ton/inch2 for 4 min in an area of 0.5 cm2. Then the pellets were dipped into 500mL of pH7.0 phosphate buffer medium at 37 °C with rotating paddle of 100 rpm. A 5mL of dissolution medium was collected at an interval of 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 and 60 min by replacing each with same amount of fresh pH 7.0 phosphate buffer. The absorbance is plotted against time for samples collected at regular intervals for TFM/salts was calculated and remaining residues of TFM/salts were analyzed by PXRD. Diffusion study The diffusion studies were conducted using a diffusion apparatus (Model EMFDC-06, Orchid Scientific, Maharashtra, India). TFM/salts was carried out through a dialysis membrane-135 (dialysis membrane-135, average flat width 33.12 mm, average diameter 23.8 mm, capacity approx. 4.45 mL/cm) obtained from Hi-Media, India. The dialysis membrane was pre-treated with 19 ACS Paragon Plus Environment


2% NaHCO3 at 60 °C for 30 min to remove traces of sulphides, followed by 10 mM of EDTA at 60 °C for 30 min to remove traces of heavy metal and another 30 min of treatment with deionized water at 60 °C to remove glycerin. Then soaking the pretreated membrane in pH 7.0 phosphate buffer for 30 min and then mounted in clips and placed between the donor and acceptor compartment of diffusion cells with an effective surface area of 3.14 cm2. Suspensions of the drug TFM/salts were prepared and placed on the dialysis membrane in donor compartment. The temperature of diffusion medium was thermostatically maintained at 37 °C ± 1°C throughout the experiment. The drug and/or cocrystal solution was then allowed to stir at 600 rpm and diffuse through the membrane towards the receptor compartment containing 20 mL of phosphate-buffered solution (PBS, pH = 7.0). The compound was withdrawn at predetermined intervals (10, 20, 30, 40, 50, 60, 70, 80, 90 and 100 min; 0.5 mL each sample) and an equal volume was replaced. The samples collected from the receptor compartment through the dialysis tube were analyzed by UVVis spectrophotometer (JASCO Spectrophotometer V-730) at λmax of 292 nm. Associated Content Supporting Information contains table of conformational overlay of TFM and its salts (Figure S1 and Table S1), 13C ss-NMR of TFM-TEA in comparison with TFM-MEA and TFM-DEA (Figure S2a-S2d and Table S2), 13C ss-NMR of TFM-CYT-TOL (Figure S3a-S2b and Table S3)and DSC and TGA calculations of TFM-CYT-TOL(Figure S4 and Table S4), IR stretching frequencies (Table S4 and Figure S5a-S5f), PXRD of TFM and salts at the end of equilibrium solubility/ IDR experiment match with the calculated line pattern from the crystal structure (Figure S6 and Figure S7) and crystallographic information (.cif files). This material is available free of charge via the Internet at XXXXX. Author information Corresponding Author * E-mail: [email protected], [email protected] Notes The authors declare no competing financial interest.

Acknowledgements: Financial and infrastructure support from the University Grants Commission, New Delhi (through the UPE and CAS programs) and the Department of Science and Technology, New Delhi (through the PURSE and FIST programs), JC Bose Fellowship (SR/S2/JCB-06/2009), CSIR project on Pharmaceutical cocrystals (02(0223)/15/EMR-II), and SERB scheme on Multi-component cocrystals (EMR/2015/002075) are gratefully acknowledged. AG thanks CSIR for research fellowship. We thank Central NMR facility of CSIR-NCL for ssNMR spectra. 20 ACS Paragon Plus Environment

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TOC: High Solubility Salts of Multiple Sclerosis Drug Teriflunomide Anilkumar Gunnama and Ashwini K. Nangia*,a,b

a

School of Chemistry, University of Hyderabad, Prof. C. R. Rao Road, Gachibowli, Central University P.O., Hyderabad 500 046, India b

CSIR-National Chemical Laboratory, Dr.Homi Bhabha Road, Pune 411 008, India

E-mail: [email protected], [email protected]

A salt screen of multiple sclerosis drug Teriflunomide shows excellent solubility and permeability behavior for mono- and tri-ethanolamine salts which is explained by X-ray crystal structures and FESEM morphology analysis.


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High-Solubility Salts of the Multiple Sclerosis Drug Teriflunomide

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