Quinine Acesulfamates - Crystal Growth & Design (ACS Publications)

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Quinine Acesulfamates Jianhui Li, Xue Fu, Jiaoyang Li, Minmin Kong, Huaguang Yu, Jianming Wang, Zongwu Deng, and Hailu Zhang Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.6b01145 • Publication Date (Web): 23 Nov 2016 Downloaded from http://pubs.acs.org on November 25, 2016

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Crystal Growth & Design

Cover Page Quinine Acesulfamates Jianhui Li,† Xue Fu,† Jiaoyang Li,‡ Minmin Kong,† Huaguang Yu,§ Jianming Wang,‡ Zongwu Deng† and Hailu Zhang*,†

†

Laboratory of Magnetic Resonance Spectroscopy and Imaging, Suzhou Institute of Nano-Tech and

Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, P.R. China. ‡

Crystal Pharmatech, Suzhou Industrial Park, Suzhou 215123, P.R. China.

§

College of Physics Science and Technology, Yangzhou University, Yangzhou 225002, P.R. China.

Abstract: Pharmaceutical salts have been traditionally used in drug formulation. As a salt former, acesulfame (AH), an aliphatic calorie-free sweetener, is actively being employed. Acesulfamates of active pharmaceutical ingredients (APIs) may provide pleasant sweet taste along with modified physicochemical properties. In this paper, four quinine (QN) salts were obtained with AH, including two 1:1 anhydrous forms (QNAH11a and QNAH11b), one monohydrate of 1:1 salt (QNAH111), and one 1:2 anhydrous forms (QNAH12). The resulting salts were fully characterized by a range of analytical methods. Crystal structures of QNAH11a, QNAH111, and QNAH12 were determined by single-crystal X-ray diffraction, and crystal structure of QNAH11b was solved from powder X-ray diffraction data by Rietveld refinement. Ionization states for all samples were confirmed by

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solid-state NMR spectra. The mutual transformation and thermodynamic relationships of these solid forms were revealed via slurry conversion experiments and differential scanning calorimetry (DSC) measurements. Additionally, enhanced solubility was observed for each acesulfamate when compared with the pure free base. This study should further highlight the potential of AH as a pharmaceutical salt/cocrystal former.

*

Corresponding author:

Tel.: +86-512-62872713, Fax: +86-512-62603079, E-mail address: [email protected]. ACS Paragon Plus Environment


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Title Page Quinine Acesulfamates Jianhui Li,† Xue Fu,† Jiaoyang Li,‡ Minmin Kong,† Huaguang Yu,§ Jianming Wang,‡ Zongwu Deng† and Hailu Zhang*,†

†

Laboratory of Magnetic Resonance Spectroscopy and Imaging, Suzhou Institute of Nano-Tech and

Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, P.R. China. E-mail address: [email protected] (HLZ). ‡

Crystal Pharmatech, Suzhou Industrial Park, Suzhou 215123, P.R. China.

§

College of Physics Science and Technology, Yangzhou University, Yangzhou 225002, P.R. China.

Abstract: Pharmaceutical salts have been traditionally used in drug formulation. As a salt former, acesulfame (AH), an aliphatic calorie-free sweetener, is actively being employed. Acesulfamates of active pharmaceutical ingredients (APIs) may provide pleasant sweet taste along with modified physicochemical properties. In this paper, four quinine (QN) salts were obtained with AH, including two 1:1 anhydrous forms (QNAH11a and QNAH11b), one monohydrate of 1:1 salt (QNAH111), and one 1:2 anhydrous forms (QNAH12). The resulting salts were fully characterized by a range of analytical methods. Crystal structures of QNAH11a, QNAH111, and QNAH12 were determined by single-crystal X-ray diffraction, and crystal structure of QNAH11b was solved from powder X-ray diffraction data by Rietveld refinement. Ionization states for all samples were confirmed by

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solid-state NMR spectra. The mutual transformation and thermodynamic relationships of these solid forms were revealed via slurry conversion experiments and differential scanning calorimetry (DSC) measurements. Additionally, enhanced solubility was observed for each acesulfamate when compared with the pure free base. This study should further highlight the potential of AH as a pharmaceutical salt/cocrystal former. Keywords: Pharmaceutical salts; polymorphism; sweet pharmaceuticals; acesulfame; solid-state NMR.

*

Corresponding author:

Tel.: +86-512-62872713, Fax: +86-512-62603079, E-mail address: [email protected]. ACS Paragon Plus Environment

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INTRODUCTION Solid dosage forms (e.g., tablets, capsules) of an active pharmaceutical ingredient (API) are desirable and often employed because of their evident advantages, such as ease of handling and production, as well as storage economy.1 For a solid API, it may exist in several different solid forms (e.g., polymorphs, hydrates, salts, and cocrystals), and different solid forms of same API often show distinct physicochemical properties.2‒7 Thus, solid-form screening should be carefully conducted to obtain adequate forms with satisfied physicochemical properties for the drug development. Pharmaceutical salts have been traditionally used in drug formulation, and more than 50% of drug compounds are marketed as salts. As a salt former, small molecule sweetener (e.g., saccharin, acesulfame (AH, Scheme 1b)), is actively being employed in this field.8‒14 Also, these sweeteners are used as cocrystal formers.12, 15‒20 Sweet pharmaceutical salts or cocrystals may provide both pleasant taste and improved physicochemical properties. AH was first used as salt former of pharmaceuticals by Velaga group in 2012.21 Up to now, several pharmaceutical acesulfamates have been reported, including the salts of 5-fluorocytosine (FC),11 haloperidol (HAL),13 berberine (BB),14 ciprofloxacin (CIP),21 norfloxacin (NOR),21 salinazid (SAL),22 and stanozolol (STAN)23. Examples of acesulfamates are limited and less than that of saccharinates hitherto, which may be attributed to the later usage of this salt former. In our opinion, there should be many pharmaceutical acesulfamates are waiting to be discovered. At least, the numbers of acesulfamates should be similar to saccharinates, because AH and saccharin hold similar functional groups and pKa (acid dissociation constant) values.11 The API discussed in this study is quinine (QN, Scheme 1a), a medicinally important alkaloid having antipyretic, antimalarial, analgesic, and anti-inflammatory properties.24 QN has a very bitter taste and low solubility in water. To achieve satisfied solubility, its sulfate form was employed in the commercial formulation.25 With the development of crystal engineering, new salt forms of QN have also been investigated.8, 26 In particular, the 1:1 saccharinate of QN shows both sweeter taste and obviously enhanced solubility.8 Following the structural resemblance strategy,27‒28 acesulfamate of QN may also be available. Thus, cocrystallization trials for QN-AH salt were performed in this contribution, and some interesting results were obtained.

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19

20

H

18

17 15

14 13 H H

2 O

S 11

1

16

4

3

R

H

5

3

9 4

8

N

12

O

O

O

1

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S

2

21

23

10 7

6

5

2

1

N

24

(a)

3

NH

O

22

O

6

(b)

Scheme 1. Chemical structures of QN (a) and AH (b). EXPERIMENTAL SECTION Materials. Quinine (BR) was purchased from Sinopharm Chemical Reagent Co., Ltd. (Shanghai, China). Potassium salt of Acesulfame (≥99.9%) was purchased from Xiya Chemical Reagent Co., Ltd. (Chengdu, China), and the free acid form of AH was prepared using the reported acidification-extraction procedure.29 Ultrapure water (18.2 MΩ cm) was used throughout the experiments. Other chemicals used were of analytical grade and used as received without any further purification. Preparation of Form A of 1:1 QN-AH salt (QNAH11a). Equimolar amounts of QN (162 mg, 0.5 mmol) and AH (82 mg, 0.5 mmol) were added to 9 and 2 mL of ethyl acetate and filtered through 0.22 µm PTFE syringe filters, respectively. Then the QN solution was mixed with the AH solution and precipitation occurred slowly at room temperature and relative humidity (RH) < 40%. The suspension was filtered and the isolated material was dried at 40 °C in a vacuum oven. The filtrate was left to evaporate slowly at 25 °C/40% RH. After two weeks, rod-shaped crystals of QNAH11a were obtained. Preparation of Form B of 1:1 QN-AH Salt (QNAH11b). Equimolar amounts of QN (162 mg, 0.5 mmol) and AH (82 mg, 0.5 mmol) were added to 2 and 4 mL of dichloromethane and filtered through 0.22 µm PTFE syringe filters, respectively. Then the QN solution was mixed with the AH solution in a glass vial and was left to evaporate slowly at 25 °C/40% RH. Once the solvent was completely evaporated, the resulting solids were dried at room temperature in a vacuum oven for 6 h. Single crystal sample of QNAH11b was not obtained. ACS Paragon Plus Environment

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Preparation of monohydrate of 1:1 QN-AH Salt (QNAH111). QNAH111 can be obtained by maintaining QNAH11a under high humidity condition (95% RH) at 25 °C for 24 h. Cultivation of single-crystal sample was conducted by slow evaporation of saturated ethyl acetate solutions of QNAH111 under controlled conditions of 25 °C/75% RH. Block-shaped crystals suitable for single-crystal X-ray analysis were obtained after two weeks. Preparation of 1:2 QN-AH Salt (QNAH12). QN (162 mg, 0.5 mmol) and AH (163 mg, 1mmol) were added to 18 and 4 mL of ethanol and filtered through 0.22 µm PTFE syringe filters, respectively. Then, the QN solution was mixed with the AH solution together in a glass vial and precipitation occurred slowly at room temperature. The suspension was filtered and the isolated solids of QNAH12 were dried under vacuum for 24 h. The filtrate was left to evaporate slowly at room temperature. After several days, needle-shaped crystals of QNAH12 were obtained. Single-crystal X-ray Diffraction (single-crystal XRD). Single-crystal XRD measurement was conducted using a Bruker APEX-II CCD diffractometer (Bruker AXS, Karlsruhe, Germany) with Mo Kα radiation (λ= 0.71073 Å) at 223 or 273 K. Diffraction data were processed (cell refinement and data reduction) using the Agilent CrysAlisPro software, and all crystal structures were solved by direct methods using OLEX2 program. A full-matrix least-squares refinement was used for the non-hydrogen atoms with anisotropic thermal parameters.30 Hydrogen atoms associated with carbon atoms were fixed in geometrically constrained positions. The hydrogen atoms on the N atoms were located using the difference Fourier maps. Relevant crystal data, collection parameters, and refinement results can be found in Table 1. Table 1. Crystallographic data of four acesulfamates of QN.



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Name

QNAH11a

QNAH11b

QNAH111

QNAH12

Formula

C24 H29 N3 O6 S

C24 H29 N3 O6 S

C24 H31 N3 O7 S

C28 H34 N4 O10 S2

Molecular weight

487.560

487.560

505.580

650.710

temperature/K

273

298

223

223

Crystal system

orthorhombic

monoclinic

orthorhombic

monoclinic

Space group

P 21 21 21

P 21

P 21 21 21

P 1 21 1

a (Å)

6.6336(3)

14.3997

6.9864(3)

12.1083(5)

b (Å)

15.8138(9)

6.6333

16.3105(8)

6.8457(3)

c (Å)

22.6531(13)

13.5549

21.9899(12)

18.1657(9)

α (º )

90

90

90

90

β (º )

90

110.9579

90

93.609(4)

γ (º )

90

90

90

90

Volume (Å3)

2376.4(2)

1209.08

2505.8(2)

1502.8(1)

Z/Z’

4/1

2/1

4/1

2/1

Dc/g·cm−3

1.363

1.339

1.340

1.438

F(000)

1032.0

-

1072.0

684

Reflns collected

22648

-

10111

6090

Unique reflns

5885

-

4657

4350

Observed reflns

4410

-

3818

3691

Number parameters

318

-

322

405

Absorption coeff (mm−1)

0.182

-

0.178

2.158

GOOF

0.805

-

1.024

0.828

R1 [I > 2σ(I)]/ R1

0.0466/0.0785

-

0.0536/0.0691

0.0476/0.0590

wR2[I > 2σ(I)]/wR2

0.1107/0.1309

-

0.1180/0.1283

0.1173/0.1290

CCDC

1491333

1516140

1491334

1491335

Powder X-ray Diffraction (powder XRD). All powder materials were identified by D8 Advance powder X-ray diffractometer (Bruker AXS, Germany) with Cu−Kα radiation (λ = 1.54056 Å). The voltage and current applied were 40 kV and 40 mA, respectively. The samples were scanned in the reflection mode from 3° to 40° 2θ with a scanning step size of 0.0194°. For QNAH11b, powder XRD pattern in transmission mode was also collected, which was used for structure refinement. The data were collected on a PANalytical X'Pert Pro X-ray powder ACS Paragon Plus Environment

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diffractometer (PANalytical B.V., Almelo, Netherlands) equipped with an X'Celerator Real Time Multi-Strip detector. Cu-Kα radiation was used at 45 kV and 40 mA. Powder sample of QNAH11b was wrapped in two pieces of Mylar film and scanned in the transmission mode from 3.0 to 70.0°. The step size and time per step were 0.0167113° and 60 s, respectively. The structure refinement from powder XRD data was carried out using MS Reflex program, and the refinement procedure is in line with our recent report.15 Firstly, the crystal class and approximate lattice parameters were derived from the peak positions in the powder diffraction pattern by using X-Cell algorithm. Next, Pawley refinement of the peak profiles, simulated annealing for structural model, and Rietveld refinement were performed. For Pawley refinement and Rietveld refinement, 10 cycles were used for each trial. For simulated annealing, 10 cycles were also used and each cycle contains 100000 calculation steps. Crystallographic details of the refined structure are presented in Table 1 and Table 2. Differential Scanning Calorimetry (DSC). DSC tests were performed on a TA Q2000 differential scanning calorimeter (TA Instruments, New Castle, DE). Approximately 3 mg of each powder sample was loaded in a hermetically sealed aluminum pan and heated from 25 °C to the proper temperature with a scan rate of 10.0 °C/min under continuously purged nitrogen atmosphere (50 mL/min). Solid-state Nuclear Magnetic Resonance (solid-state NMR). Solid-state NMR experiments were performed with a 4 mm double-resonance MAS probe on a 500 MHz Bruker spectrometer (Bruker BioSpin, Karlsruhe, Germany). Cross-polarization (CP) pulse program was used to collect the

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spectra at a magic angle spinning (MAS) speed of 8 kHz. For the CP/MAS spectra, a total sideband suppression (TOSS) frame was embedded into the conventional CP pulse sequence. Recycle delay and contact time were set to 8 s and 2 ms, respectively, and chemical shifts were externally referenced to tetramethylsilane (TMS, 0 ppm). Moisture Stability. QN and its salts were equilibrated under different RH conditions at 25 °C for 3 days, and the resulted solids were subjected to powder XRD measurements to monitor possible polymorphic transformation. Dynamic Vapor Sorption (DVS). DVS experiment was performed on an intrinsic dynamic gravimetric water sorption analyser (SMS Ltd., London, UK). 20 mg of QNAH11a was studied over a humidity range from 0 to 95% RH at 25 °C. For each step, sample was equilibrated with the criterion of either dm/dt ≤ 0.002 min−1 or a maximum hold time of 3 h. Solvent-mediated

Phase

Transformation

Experiments.


The

solvent-mediated

phase


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transformation experiments (slurry tests) of four QN salts were carried out in a 20-mL glass bottle under a constant agitation speed of 200 rpm. Single solvent of n-hexane or mixed solvent of n-hexane-water (10/1, v/v) were applied for a period of up to 7 days at room temperature. The residual solids were collected and analyzed by powder XRD. Saturation Solubility. The solubilities of QN and its salts were measured using the shake-flask method in water. Each sample equivalent to 75 mg of QN was added to the screw-capped test tubes with 5 mL of ultrapure water. The oversaturated suspension was treated at 37±0.5 °C in an incubator shaker rotating at 100 rpm. After 72 h, 0.1 mL of sample was taken from the solution and filtered through 0.22 µm polycarbonate filter. The concentration of QN was measured by using the Waters HPLC system (Waters2535) equipped with a photodiode array detector at 250 nm. The C18 HPLC column (GraceSmart RP C18, 4.6 mm × 250 mm, 5 µm) was employed, and acetonitrile and ultrapure water (20/80, v/v) were used as the mobile phase with a flow rate of 1 mL/min at 37 °C. The residual solids were verified by powder XRD measurements to monitor possible transformation. Each determination test was performed in triplicate. Dissolution curves of QNAH11a and QNAH11b were also collected by using a similar dissolution protocol.

RESULTS AND DISCUSSION QN is a basic molecule and contains two major ring systems: the aliphatic quinuclidine and the aromatic quinoline. The calculated pKa values of N1 and N2 sites (Scheme 1a) in these two rings are 9.05 and 4.02, rescetively.31 When QN interacts with acidic organic molecules, the more basic N1 site should be the preferential proton acceptor. Such results have been observed in the reported QN complexes.8, 26, 32 In fact, the N2 site in the quinolone group is also accessible, and can act as another proton acceptor. The acidic pKa value of AH is 2.0.11 According to the pKa rule, N1 site (∆pKa > 3) should be preferentially protonated and ionization state of N2 site (0 < ∆pKa < 3) is unpredictable, if they are employed in a really existed QN-AH crystalline complex. While, we must point out that larger pKa difference only offer a higher possibility, and cannot be regarded as either a necessary or a sufficient condition for the formation of salt crystals, for there are many contributors (e.g., hydrogen-bond, π-π, van der Waals, repulsive interactions, etc.) for the orderly arrangement of molecules. The salt formation should be revealed by experimental results. QNAH11a Crystal Structure. Single crystal sample of QNAH11a was harvested from ethyl acetate under controlled RH condition. Crystal structure analysis reveals that the complex is a salt and crystallizes in the orthorhombic P 21 21 21 space group with four asymmetric units in a unit cell and ACS Paragon Plus Environment

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each asymmetric unit contains one QN+ cation and one AH− anion (Figure 1a). As expected, an intermolecular proton transfer from –N3H– group of AH to the N1 site of QN was observed. QN+ cations and AH− anions are connected through N1+–H···O6 (1.85 Å, 159.3°) and O1–H···O6 (2.04 Å, 145.4°) interactions, forming a one-dimensional (1D) molecular chain structure (Table 2 and Figure 1b). Each hydrogen-bonding chain is infinitely extended along the a axis (Figure 1c). No other intermolecular hydrogen-bonding interaction was observed.

Figure 1. Asymmetric unit (a), hydrogen-bonding chain diagram (b), and three-dimensional (3D) packing view along the a axis (c) of QNAH11a. Table 2. Hydrogen bonding metrics for four acesulfamates of QN Name

D−H···A

D···A (Å)

H···A (Å)

D−H···A (deg)

QNAH11a

N1+–H···O6

2.724(3)

1.85

159.3

O1–H···O6

2.756(2)

2.04

145.4

N1+–H···O6

2.733

1.91

148.5

O1–H···O6

2.695

2.03

137.5

N1+–H···O6

2.716(4)

1.81

174.6

O1–H···O7 (H2O)

2.694(4)

1.88

174.4

O7–H···O6

2.731(4)

1.9

167

N2+–H···O6’

2.718(4)

1.95(7)

170.0(6)

QNAH11b

QNAH111

QNAH12



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N1+–H···O6

2.712(5)

1.81

170.8

O1–H···N3’−

2.862(4)

2.05

173.5

QNAH11b Crystal Structure. The crystal structure of QNAH11b was solved from powder XRD data by Rietveld refinement. The salt state of this sample was confirmed by the solid-state NMR spectrum (vide infra). This salt crystallizes in the monoclinic P 21 space group with two asymmetric units in a unit cell and each asymmetric unit contains one QN+ cation and one AH− anion (Figure 2a). QNAH11b structure holds similar intermolecular hydrogen-bonding interactions to QNAH11a, in which QN+ cations and AH− anions are connected through N1+–H···O6 (1.91 Å, 148.5°) and O1–H···O6 (2.03 Å, 137.5°) interactions, forming a 1D molecular chain structure (Table 2 and Figure 2b). Such hydrogen-bonding chain is infinitely extended along the b axis (Figure 2c).

Figure 2. Asymmetric unit (a), hydrogen-bonding chain diagram (b), and 3D packing view along the b axis (c) of QNAH11b. QNAH111 Crystal Structure. QNAH111 is a hydrate of QN-AH salt. Crystal sample of this hydrate can be obtained from ethyl acetate under higher RH condition. The structure was solved in the orthorhombic space group P 21 21 21 with four asymmetric units in a unit cell. Each asymmetric unit (Figure 3a) contains one QN+ cation and one AH− anion, with one water molecule playing a bridging role in the packing structure (Figure 3b). Each QN+ cation directly interacts with AH− anion via N1+–H···O6 (1.81 Å, 174.6°), and is indirectly connected with another AH− anion via the water molecule (O1–H···O7 and O7–H···O6, Table 2 and Figure 3b). Similar to the structure of QNAH11a ACS Paragon Plus Environment

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and QNAH11b, a hydrogen-bonding chain structure along a axis was also observed for this monohydrate (Figure 3c).

Figure 3. Asymmetric unit (a), hydrogen-bonding chain diagram (b), and 3D packing view along the a axis (c) of QNAH111. QNAH12 Crystal Structure. The crystal structure of QNAH12 belongs to monoclinic, P 1 21 1 space group. Each unit cell contains two asymmetric units and each asymmetric unit contains one QN2+ cation and two AH− anions. N1 and N2 sites of QN are both protonated as a consequence of proton transfer from –N3H– groups of two AH molecules. In each asymmetric unit, two AH− anions interact with QN2+ through N1+–H···O6 (1.81 Å, 170.8°) hydrogen bond and O1–H···N3’− (2.05 Å, 173.5°) hydrogen bond, respectively (Table 2 and Figure 4a). The asymmetric unit is extended along the b axis via N2+–H···O6’ (1.95 Å, 170.0°) interaction between QN2+ and one crystallographically non-equivalent AH− (Figure 4b and 4c).



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Figure 4. Asymmetric unit (a), hydrogen-bonding chain diagram (b), and 3D packing view along the b axis (c) of QNAH12. Summary of Intermolecular Hydrogen Bonding Interactions in Crystal Structures of Acesulfamates The intermolecular hydrogen bonding interactions in the reported crystal structures of acesulfamates are summarized in Scheme 2. It is not surprise that the –(O=)C–N–S(=O)2– group of AH− anion is always involved in the intermolecular hydrogen bonding interactions, for four potential proton acceptor sties may be utilized. Three ring motifs were observed in the crystal structures of FC-AH salt hydrate (Scheme 2a), CIP-AH/NOR-AH salt (Scheme 2e), and STAN-AH salt (Scheme 2f). For BB-AH salt14, only several weak S=O···H–C/C=O···H–C hydrogen bonds are present to stabilize the structure. In all these reported structures, interactions between O6=C– site and APIs were always present. Thus, O6 should be regarded as the best proton acceptor of AH− anion. Such conclusion is further confirmed by those O6 involved hydrogen bonds in the four structures of QN-AH salts.


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Scheme 2. Intermolecular hydrogen bonding interactions in the reported structures of acesulfamates. (a) 1:1 FC-AH salt hydrate,11 (b) 2:1 FC-AH conjugate acid–base (CAB) cocrystal,11 (c) 1:1 HAL-AH salts,13 (d) 1:1 SLZ-AH salt,22 (e) 1:1 CIP-AH or NOR-AH salt,21 and (f) 1:1 STAN-AH salt23. Powder XRD Analyses The experimental powder XRD patterns of QN, AH, and their complexes are shown in Figure 5. XRD pattern of each complex sample show distinguishable differences compared with other patterns, indicating the formation of new solid form. For example, feature peaks of QN at 2θ 3.9 and 5.9 are absent in the patterns of all salts. QNAH11a presents the characteristic peaks at 7.79°, 9.58°, 12.9°, 13.6°, 14.8°, 15.6°, and 16.1° 2θ. While for the other 1:1 salt, QNAH11b, the pattern is characterized by a set of new peaks at 6.5°, 7.66°, 12.4°, 13.1°, 13.9°, 15.0°, 15.3°, and 17.4° 2θ. For QNAH11a, QNAH111, and QNAH12, the experimental powder patterns conform to the simulated ones (SI Figure S1), confirming these bulk materials are identical to single-crystal samples for which the crystal structures have been solved. For QNAH11b, no single-crystal sample is available. Then, structure refinement was performed on the powder sample. The powder XRD pattern was collected in the transmission mode, which is less susceptible to preferred orientation. Thus, sample preferred orientation was not taken into account during the Rietveld refinement process to avoid the over-evaluation of the candidate structure. The final refined crystal structure shows favorable residual variances (Rwp = 5.96 and Rp = 4.26%), and restrained Rietveld fitting of the powder XRD data was provided in Figure S2 (SI).



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4.8

19.523.4

15.7

8.5

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QNAH12 18.1

14.3

8.0

24.4

QNAH111 17.4

13.1 15.3

7.66 6.5

12.4 13.9

QNAH11b

7.79 12.9 15.0 15.6 13.6 16.1 9.58

QNAH11a 23.4

14.8

16.1

20.7

AH

3.9 5.9

QN 5

10

15

20

25

30

35

40

2 Theta (degree)

Figure 5. Powder XRD patterns of QN, AH, and QN-AH salts. 13

C Solid-state NMR

The 13C CP/MAS TOSS NMR spectra of QN, AH, and their complexes are shown in Figure 6. For QN and AH, the spectra are in line with the reported ones,11, 15, 33 and their resonances were assigned according to the reported liquid and solid-state

13

C NMR data.11, 15, 34 Some important information

can be extracted from these spectra except for the formation of new solid forms. Characteristic chemical shifts of AH can be used to judge its tautomeric or ionization state. For the four crystalline complexes obtained in this study, the chemical shifts of C21 (172.6~174.4 ppm) and C22 (101.2~103.3 ppm) firmly confirm the formation of acesulfamates.11, 15 If a neutral AH molecule exists in the complex, more upfield C21 (~165 ppm) and C22 (~95 ppm) signals should be observed for its keto and enol forms, respectively.15 With respect to pure QN, C11 peaks in the acesulfamates also present obviously upfield shifts (from 71.4/70.7 ppm to 66.1~66.7 ppm). According the solved crystal structures, such upfield C11 signal should be an indicator of the presence of hydrogen-bonding interaction between the chiral carbon connecting –O1H group and other proton acceptor site. Additionally, each chemically distinct carbon in the new salts is represented by single resonance, indicating the numbers of molecules per asymmetric unit (Z’) of these samples are all equal to 1, which is in line with the crystallographic results. For QNAH11a and QNAH11b, the two polymorphs, some distinguishable feature resonances can be observed. For example, positions of C13 and C24 resonances are exchanged for these two salts. For C21 and C19 (a preliminary assignment), QNAH11b shows slight downfield chemical shifts (174.3 and 141.7 ppm) than QNAH11a (173.3 and 139.0 ppm). While for C20 (a preliminary ACS Paragon Plus Environment

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assignment), QNAH11a gives a slight larger chemical shift values (117.7 ppm). ,

,

21/21 23/23

22/22

Q NAH12 21

, 9

11

9

11

23 22

QNAH111 21 23 Q NAH11b

22

9

21 23

22

9

24

11

13 24 13

11

QNAH11a

AH

23/23,

8 3 QN

200

180

,

,

160

,

24/24

22/22

21/21

6 5 19 4 7 20 2 1

140

120

9

100

11

80

10 15 1217 16 1814 13

60

40

20

0

δ (ppm)

Figure 6. 13C CP/MAS TOSS NMR spectra of QN, AH, and QN-AH salts. Thermal Properties and Equilibrium Solubility DSC data of QN, AH, and the salts were also collected (Figure 7). The peak temperatures of melting processes (melting points) of QNAH11a, QNAH11b, QNAH111, and QNAH12 are 201.0, 199.6, 201.0, and 206.6 °C, respectively, which are all higher than that of pure QN (176.6 °C). For QNAH111, the dehydration peak appears at 77.4 °C, and QNAH11a phase can be formed after dehydration (confirmed by powder XRD, SI Figure S3). The enthalpies of fusion of QNAH11a and QNAH11b are 68.86 and 65.79 J/g, respectively. For QNAH12, the enthalpy value cannot be accurately provided because melting process is mixed with the decomposition process. Two polymorphs may be either monotropically or enantiotropically related. If they are enantiotropical related, the polymorphic transformation temperature should below the melting temperature. The theoretical polymorphic transformation temperature of these two form has been calculated from the thermal data mentioned above by using thermodynamic model proposed by Bauer-Brandl,35 which is higher than the melting temperatures. This evidence indicates that no polymorphic transformation would occur below the melting temperature, and QNAH11a and QNAH11b are monotropically related. Also, the thermodynamic relationships can be easily judged by using the heat of fusion rule.36 Since QNAH11a has a higher melting temperature and higher enthalpy of fusion than that of QNAH11b, then they should be in a monotropic relationship.



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QNAH12 206.6

QNAH111 77.4

201.0

QNAH11b

199.6

QNAH11a

201.0

AH 116.0

QN

176.9 50

75

100

125

150

175

200

225

250

T emperature (°C)

Figure 7. DSC curves of QN, AH, and QN-AH salts. As mentioned in the introduction section, the solubility of pure QN is not satisfied. Its equilibrium concentration in water at 37 °C is only 0.23 mg mL–1 (Figure 8). With the formation of the novel pharmaceutical salt, improved solubility is often obtained. For QNAH11a, QNAH11b, and QNAH111, the solubility values are all about 11 times (2.56, 2.59, and 2.58 mg mL–1, Figure 8) as large as that of free base. For anhydrous QNAH11a and QNAH11b, undissolved solids after solubility tests are completely transformed into hydrated form, QNAH111, leading to such same apparent equilibrium solubility values. For QNAH12, a much higher equilibrium solubility, 3.42 mg mL–1, is achieved, and no phase transformation was observed for the undissolved solids. Dissolution curves of QNAH11a and QNAH11b were also collected and given in SI (Figure S4). The results show that both forms have higher maximum apparent solubility values than their equilibrium solubility values. Also, the spring and parachute profiles further confirm the phase transitions from anhydrous forms to hydrated form.


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3.5

QN concentration (mg/mL)

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3.0 *

*

2.5 2.0 1.5 1.0 0.5 0.0 QN QNAH11a QNAH11b QN AH 111

QNAH12

Figure 8. Equilibrium solubility of QN and QN-AH salts in water at 37.0 °C. * Undissolved solids after solubility tests are completely transformed into QNAH111 form. The pH values of the aqueous solutions after solubility tests are 5.72±0.03 (for 1:1 salts) and 3.04±0.02 (for QNAH12), respectively. Moisture Stability As revealed in the DSC and solubility tests, phase transformations between anhydrous and hydrated 1:1 QN-AH salts may occur. Thus, the influence of humidity on the hydration stability of new QN salts should be disclosed. QN and its salts were equilibrated under different RH conditions for 3 days, and the results are summarized in Table 3. It can be found that anhydrous QN, QNAH11b, and QNAH12 have superior phase stability against high RH (95%). For QNAH11a, it can be transformed into monohydrate if RH is higher than 60%. And below such RH condition, QNAH111 sample trends to be dehydrated, forming the QNAH11a phase. From a view of practice, QNAH111 is not ideal for drug development for higher RH condition cannot be always maintained. Table 3. Moisture stability tests for QN and its salts at 25 °C. RH (%)

40

60

75

95

QN

-

-

-

QN

QNAH111

QNAH111

-

QNAH11b

QNAH111

QNAH111

QNAH11a (little)a/ QNAH11a

QNAH11a QNAH111

QNAH11b

-

QNAH11a(little)a

QNAH111

QNAH11a /QNAH111



QNAH12 a

-

-

-

QNAH12

confirmed by powder XRD patterns (SI Figure S5). Moisture stability tests indicate QNAH11a and QNAH111 are humidity sensitive. Then, DVS

experiment was carried out to further confirm the moisture induced phase transition between QNAH11a and QNAH111 (Figure 9). For QNAH11a, the moisture content is increased with the increment of RH. Only slight moisture content changes can be observed at the 0–50% RH range. Rapid water uptake occurs above 50% RH, indicating the phase transition from QNAH11a to QNAH111. During the desorption process of QNAH111, the profile reveals that QNAH11a should slightly appear if RH < 80%, and obvious phase transition from QNAH111 to QNAH11a would occur below 50% RH.

4

% Weight Change

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theoretical wt% change for the formation of QNAH111

3

2

1

0 0

20

40

60

80

100

% RH Figure 9 DVS curve of QNAH11a at 25 °C. Interconversion between Different Salt Forms Solvent-mediated slurrying tests were performed to investigate the interconversion between different QN-AH salts. QNAH11a and QNAH11b can be transformed into the hydrate form, QNAH111, by slurring in n-hexane-water mixed solvent (Scheme 3d). By using waterfree n-hexane, QNAH111 can be dehydrated into QNAH11a form (Scheme 3e). These outcomes are predictable according to the above demonstrated solubility and moisture stability tests. All 1:1 QN-AH salts, QNAH11a, QNAH11b, and QNAH111 can change into QNAH12 in a 1 equiv of AH contained n-hexane solvent (Scheme 3a). In the reverse direction, QNAH11b and QNAH111 can be obtained when QNAH12 and QN were whisked together in waterfree (Scheme 3b) and water contained (Scheme 3c) n-hexane, ACS Paragon Plus Environment

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respectively. QNAH11b may keep its solid phase in n-hexane solvent if there are no special inducing factors. While, if 1:1 solid mixtures of QNAH11a and QNAH11b were suspended in n-hexane solvent, all solid products were transformed into QNAH11a form (Scheme 3f), indicating QNAH11a, relative to QNAH11b, is the thermodynamically more stable polymorph at room temperature. The powder XRD patterns of resulting solids are given in SI (Figure S6-9), and the complete mutual transformation relationships of the four salt forms are summarized in Scheme 3.

Scheme 3. Schematic representation showing interconversion between the four QN-AH salts at room temperature. (a) 1 equiv of AH in n-hexane; (b) 1 equiv of QN in n-hexane; (c) 1 equiv of QN in n-hexane–water mixed solvent; (d) n-hexane–water mixed solvent; (e) n-hexane; (f) 1 equiv of QNAH11a in n-hexane.

CONCLUSIONS In this contribution, the salt formation behavior of poorly soluble API, QN, was investegated with a promising salt former, AH. Four novel acesulfamates of QN were successfully obtained and fully characterized, all of which show significant improved thermodynamic or apparent solubility. For the two anhydrous 1:1 QN-AH complexes, QNAH11a is thermodynamically more stable than QNAH11b. Interconversions between all these salts were also clearly described. QNAH11b and QNAH12 show superior physical stability against high RH. While for QNAH11a and QNAH111, phase transformation may occur under different RH conditions. All the crystal structures of these QN-AH salts were solved. The previous and current reported crystal structures of QN salts reveal that the more basic N site in the quinuclidine group of QN should be the preferential proton acceptor. And structure of QNAH12 reminds that the less basic N site in the quinoline ring is also accessible. Though AH and saccharin hold similar functional groups and pKa values, different results were obtained when they were used as sweet salt formers. Such phenomenon must prompt the comparing ACS Paragon Plus Environment


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usage of AH and saccharin for other pharmaceutical compounds.

ASSOCIATED CONTENT Supporting Information. The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.xxxxxx. 1. Experimental and simulated powder XRD patterns of four QN-AH salts, restrained Rietveld fitting of the powder XRD data of QNAH11b, powder XRD patterns of QN-AH salts after different tests, and dissolution curves of QNAH11a and QNAH11b in water. Accession Codes. CCDC 1491333−1491335 and 1516140 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif.

Acknowledgments This work was supported by the National Natural Science Foundation of China (No. 21673279), Natural Science Foundation of Jiangsu Province (No. BK2012191), and the Youth Innovation Promotion Association, CAS (No. 2012242). Authors also thank Platform for Characterization & Test, SINANO, CAS, and Supercomputing Center, CNIC, CAS for the calculation supporting.

Notes The authors declare no competing financial interest.

REFERENCES (1) Maddileti, D.; Swapna, B.; Nangia, A. Cryst. Growth Des. 2014, 14, 2557–2570. (2) Fabbiani, F.; Allan, D.; Parsons, S.; Pulham, C. CrystEngComm 2005, 7, 179–186. (3) Sanphui, P.; Goud, N.; Khandavilli, U.; Bhanoth, S.; Nangia, A. Chem. Commun. 2011, 47, 5013−5015. (4) Roy, S.; Goud, N. R.; Babu, N. J.; Iqbal, J.; Kruthiventi, A. K.; Nangia, A. Cryst. Growth Des. 2008, 8, 4343−4346. (5) Bhatt, P. M.; Ravindra, N. V.; Banerjee, R.; Desiraju, G. R. Chem. Commun. 2005, 1073−1075. (6) Thakuria, R.; Nangia, A. CrystEngComm 2011, 13, 1759−1764. (7) Schultheiss, N.; Newman, A. Cryst. Growth Des. 2009, 9, 2950–2967. (8) Banerjee, R.; Bhatt, P. M.; Ravindra, N. V.; Desiraju, G. R. Cryst. Growth Des. 2005, 5, ACS Paragon Plus Environment

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For Table of Contents Use Only Quinine Acesulfamates Jianhui Li, Xue Fu, Jiaoyang Li, Minmin Kong, Huaguang Yu, Jianming Wang, Zongwu Deng and Hailu Zhang 21/21

,

22/22

,

QNAH12 21 22

QNAH111 21 QNAH11b

22

21

22

QNAH11a 21/21

AH

,

22/22

,

QN

200

180

160

140

120

100

80

60

40

20

0

δ (ppm)

SYNOPSIS: Four quinine (QN) salts were obtained with acesulfame (AH), an aliphatic calorie-free sweetener, including two 1:1 anhydrous forms (QNAH11a and QNAH11b), one monohydrate of 1:1 salt (QNAH111), and one 1:2 anhydrous form (QNAH12).


Quinine Acesulfamates - Crystal Growth & Design (ACS Publications)

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