Crystallizing Ionic Cocrystals: Structural Characteristics, Thermal

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Crystallizing ionic cocrystals: structural characteristics, thermal behavior, and crystallization development of a Piracetam-CaCl Cocrystallization process 2

Lixing Song, Koen Robeyns, and Tom Leyssens Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.8b00352 • Publication Date (Web): 16 Apr 2018 Downloaded from http://pubs.acs.org on April 16, 2018

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Crystal Growth & Design

Crystallizing ionic cocrystals: structural characteristics, thermal behavior, and crystallization development of a Piracetam-CaCl2 Cocrystallization process Lixing Song, Koen Robeyns, Tom Leyssens* Institute of Condensed Matter and Nanosciences, Université catholique de Louvain, Louvain-La-Neuve, Belgium ABSTRACT: In this study, we aim at developing a robust crystallization process for the ionic cocrystal between piracetam and CaCl2. We discuss the structural characteristics of the piracetam-CaCl2 cocrystal and its thermal behavior, furthermore we develop a robust crystallization process by construction of appropriate phase diagrams. CaCl2 and piracetam form an ionic dihydrate cocrystal with formula piracetam2·CaCl2·2H2O, in which the Ca2+ cation adopts an octahedral coordination with the oxygens of 4 different molecules of piracetam and of two water molecules. According to the TGA, DSC and VT-XRPD, the cocrystal exhibits improved thermal stability compared to the parent drug compound. In this article we show how one can develop a robust, water-based cocrystallization process for ionic cocrystals, a relatively underexplored part of the cocrystal landscape. We also discuss the common ion effect on cocrystallization, and show how a common ion can strongly impact on the solubility of the cocrystal, as well as its constituting components. In addition, a common ion will also strongly impact the size of the cocrystal region in the ternary phase diagram.

INTRODUCTION A cocrystal is a solid form including a stoichiometric ratio of at least two different components, which are both solid under ambient conditions.1 Pharmaceutical cocrystals are cocrystals for which one of the two components is an active pharmaceutical ingredient (API).2-3 Cocrystallization is a potentially attractive method to improve physicochemical properties of APIs, such as solubility, (thermal) stability, hygroscopicity, dissolution rate and bioavailability, especially for non-ionizable APIs.4-6 Recently the FDA7 revised its viewpoint on cocrystals, now defining them as APIs in contrast to drug product intermediates (DPIs) in the 2013 guidance. Therefore, cocrystallization is regarded as a promising approach in the pharmaceutical industry. Ionic cocrystals (ICCs) form a particular type of subset in the cocrystal family, as the cocrystal former (coformer) is a salt.8-9 They have gained increasing popularity over recent years, as they combine characteristics of typical molecular crystals with those of ionic salts, like an alkali or alkaline earth halide. ICCs can improve the parent compound’s stability because of interactions between the organic moiety and the ions from the inorganic salt.6 For example, when an alkali or alkaline earth halide is used as coformer, the electron-rich atoms in the API interact directly with the metal cations, and the halide ions could interact with other molecules (like water) if the ligand has hydrogen bonding ability. Recently this type of cocrystals has been used in the context of chiral resolution.10-11 Typically, ICCs are obtained by methodologies common to cocrystals, such as solvent evaporation, mechanochemistry and melt cocrystallization. Inorganic salts are usually

GRAS compounds (Generally Regarded As safe), and economic reagents, and therefore, ICCs carry strong potential in the field of cocrystallization. Even though the research concerning ionic cocrystallization has greatly increased over the last years, the upscaling of an ionic cocrystallization process is rarely explored. Solution crystallization is still considered as the process of industrial relevance for the synthesis of endproducts which meet the regulatory requirements concerning purity and quality.12 In the context of cocrystallization, purity also implies solid form purity. Form mixtures of cocrystal with one of its pure constituents can occur during cocrystallization from solution, and a robust cocrystallization process is required to handle these issues. The goal of this paper is to develop a robust cocrystallization process of an ionic cocrystal from solution. This is done by first analyzing the different possible cocrystal forms as well as to identify the most stable cocrystal form under ambient conditions, by studying the thermal behavior of the cocrystal. After this, appropriate phase diagrams are introduced and constructed which is a requirement for robust process design. Finally, a robust upscaled cooling crystallization will be presented on Piracetam-CaCl2 dihydrate chosen as a model ionic cocrystal.

MATERIALS AND METHODS Materials. Piracetam was purchased at Xiamen Top Health Biochem Tech. Co. Ltd. Calcium chloride anhydrous powder was purchased from ACROS. All the solvents were reagent grade.

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Solid State Synthesis. The ICC can be obtained mechanochemically through liquid-assisted grinding of equimolar mixtures of piracetam and CaCl2, with the addition of 10 μL of methanol. The sample was ground in a RETSCH Mixer Mill MM 400 for 90 min with a beating frequency of 30 Hz. The powders were characterized by powder X-ray diffraction (XRPD) and the resulting diffraction pattern compared with the diffraction pattern of the pure phases. Single Crystal Synthesis. An equimolar mixture of Piracetam (14.2 mg, 1.oo mmol) and CaCl2 (11.1 mg, 1.00 mmol) was dissolved in ethanol (2 ml) and left to evaporate over three days to get suitable crystals for single crystal diffraction. Single crystals of piracetam2·CaCl2·2H2O were obtained, as confirmed by single crystal x-ray diffraction and powder diffraction experiments. Ternary Phase Diagram. Ternary phase diagrams were determined by creating suspensions of varying relative amounts of piracetam and CaCl2 using a fixed amount of water as solvent. The piracetam/ CaCl2 molar ratio was varied from 0 to 1, which yields the experimental starting points shown by the blue crosses in scheme 1. Experiments were carried out in several 2 ml sealed vials. The suspensions were seeded with cocrystal Piracetam2·CaCl2·2H2O and stirred at constant temperature over 48 h to make sure that the system reached thermodynamic equilibrium. Then samples were filtered over sintered glass, followed by XRPD analysis of the solid phases. To determine the solubility lines (red curves in scheme 1), samples with identical proportions as those mentioned above were prepared. After 48 h, the samples were diluted under continuous stirring, by addition of 30 µl water every 30 minutes. Upon total dissolution, observed visually, a given point on the solubility line is obtained. Alternatively, one could quantitatively analyze the supernatant solution. However, as this would imply quantifying an organic compound as well as an inorganic salt, the former approach is more practical in this specific case. When performing the dilution with sufficiently small solvent addition steps, and sufficiently low waiting times, accuracy of this method is comparable to other techniques. TPDs were drawn using ProSim Ternary Diagram software.

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Powder X-ray Diffraction (XRPD). X-ray powder diffraction measurements were performed on a Siemens D5000 diffractometer equipped with a Cu X-ray source operating at 40 KV and 40 mA and the secondary monochromater allowing to select the Kα radiation of Cu (λ = 1.5418 Å). A scanning range of 2θ values from 5° to 50° at a scan rate of 0.6° min-1 was applied. The results were analyzed by the FullProf Suite software package. Single Crystal X-ray Diffraction Single crystal X-ray diffraction was performed on a MAR345 image plate using monochromated MoKα radiation (λ = 0.71073 Å) (Xenocs Fox3D mirror) produced by a Rigaku UltraX 18S rotating anode. The structures were solved by SHELXT and refined on |F2| using SHELXL-2014/7. Non-hydrogen atoms were anisotropically refined and the hydrogen atoms in riding mode with isotropic temperature factors fixed at 1.2 times U(eq) of the parent atoms. Thermogravimetric Analysis (TGA). TGA measurements were performed on a Mettler Toledo TGA /SDTA851e using an alumina crucible. The heating profile applied starts at 30° C and goes up to 450 °C with a rate of 2 °C /min under continuous nitrogen flow of 50.0 ml/min. Differential Scanning Calorimetry (DSC). DSC measurements were performed on a Mettler Toledo DSC 821 e using 40 μL aluminum crucibles with a pierced cap. The temperature profile applied starts at 30 °C and increases up to 340 °C with a rate of 2 °C /min.

RESULTS AND DISCUSSIONS Model System. As a model compound, we chose Piracetam, 2-oxo-1-pyrrolidine acetamide, a nootropic agent marketed for the treatment of several neurodegenerative disorders such as Alzheimer’s disease. Fabbiani et al13-15 have discovered five polymorphic forms and two hydrate forms of piracetam. A search of the Cambridge Structural Database reports 9 cocrystals of piracetam with organic coformers: gentisic16, citric and L-tartaric acids17, mandelic, p-hydroxybenzoic18 and 4-hydroxybenzoic acids19, gallic acid20 as well as 2,6- diaminopyridine21 and myricetin.22 Piracetam is also prone to cocrystal formation with different inorganic salts, such as MnCl2, NiCl223, SrCl2, LiCl and LiBr24. In this paper, we used the piracetam-CaCl2 system as a model to develop a robust solution cocrystallization process for ionic cocrystals.

O

N

NH 2

O

Figure 1. Molecular structure of piracetam.

Scheme 1. Typical process for determining the ternary phase diagram of an ionic cocrystal.

Firstly, we studied the solid state of the model system and compared it to the literature reference.8 By liquidassisted grinding (LAG) of an equimolar mixture of piracetam and CaCl2 with 10 µL of methanol, one obtains a


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Crystal Growth & Design novel crystalline phase (Figure 2), different to any of the known forms of the parent compounds. The resulting pattern furthermore overlaps with that described for the Ca-Piracetam cocrystal system (Figure 2).

Figure 2. XRPD overlay of LAG of piracetam with CaCl2 using 10 µL of methanol (red) with the simulated XRPD of the cocrystal (blue).

Structural Analysis. The first report on the structure of the Ca-Piracetam cocrystal comes from Braga et al,8 solving the structure from powder X-ray diffraction. In this paper, we are first to obtain this structure from single crystal analysis. Piracetam2·CaCl2·2H2O crystallizes in a monoclinic space group P21/n with two molecules of piracetam, one molecule of CaCl2 and two H2O molecules in the unit cell (Z=2) (Figure 3). The Ca2+ cation is found on an inversion center coordinated by six ligands. It forms an octahedral coordination with the oxygens of 4 different molecules of piracetam occupying the equatorial positions, the axial positions are taken up by water molecules. Each piracetam interacts with two Ca2+ cations giving rise to 2D sheets of interconnected Ca2+ octahedra. The sheets expose the coordinated water molecules and NH2 groups (amide) on either side, efficiently hydrogen bonding the Cl- anions that are wedged between the coordination sheets. Crystallographic parameters and refinement details are listed in Table 1.

2+

Figure 3. Left: Coordination around the Ca cation in crystal2+ line piracetam2·CaCl2·2H2O. Right: A 2D-layer of Ca ions and coordinated water and piracetam molecules extending in the crystalline.

Table 1. Crystallographic data of piracetam2·CaCl2·2H2O Cocrystal piracetam2·CaCl2·2H2O empirical formula M T [K] crystal system space group a [Å] b [Å] c [Å] β [°] 3 V [Å ] Z −3 ρcalcd [Mg m ] F (000) −1 μ [mm ] crystal size [mm] θrange(deg) reflection collected/unique Rint GoF Threshold expression R1 (obsd) wR2 (all)

C12H24CaCl2N4O6 431.33 296(2) monoclinic P21/n 8.9057(4) 9.6203(4) 11.9399(5) 108.077(4) 972.47(7) 2 1.473 452 0.632 0.48 x 0.40 x 0.15 3.205 to 26.012° 6845/ 1861 0.0377 1.006 > 2σ(I) 0.0344 0.0805

Thermal Stability. TGA analysis (Figure S1) shows a 7.6 % weight loss between 140 and 160 °C, corresponding to the loss of two equivalents of water (theoretical w% =8.36). TGA analysis indicates a single step water loss. DSC analysis (Figure S2) confirms the water loss at 140 °C as seen by the large endothermic signal. Variabletemperature XRPD (Figure S3) was used to highlight the one-step dehydration to an anhydrate solid phase at 140 °C, leading to a phase which remains unchanged up to 220 °C. From 240 °C onwards degradation occurs. As piracetam melts at 127 °C25, the ICC allows improving the thermal stability of piracetam in the solid state. Ionic Cocrystallization Process Development. Phase diagrams are crucial tools for the development of a robust crystallization process. Ternary phase diagrams (TPD) describe the thermodynamically stable equilibrium for different overall compositions (solvent, coformer, API) at a specific temperature and for a given pressure.26-28 Therefore, TPDs can serve as a guide to decide the end point of a robust solution cocrystallization process as it is a guide to the conditions where the desired phase is also the thermodynamically stable one.29-30 In our case, we developed the TPD for the water-piracetam-CaCl2 system, with the experimental data shown in Table 2 and 3 at 298.15 K. Table 2 gives the overall initial composition of the experimental points selected, and the nature of the solid state obtained at equilibrium. Table 3 shows the amount of water that needs to be added to each of these initial compositions for total dissolution to occur, and hence yields a solubility point. All the experiments in this paper are performed under atmospheric pressure. Figure 4 represents the graphical TPD generated from this data.



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Table 2. Initial experimental data for system of water-piracetam-CaCl2 at 298.15 K. Initial components (mol%)

Initial components sample No. 1

Piracetam (mg) 100

CaCl2 (mg) 0

H2O (μL) 50

2

92.02

7.98

3

83.67

4

74.93

5

65.77

34.23

6

56.16

43.84

solid phase at equilibrium

Piracetam

CaCl2

H2O

0.202

0

0.798

Pi

50

0.185

0.021

0.794

Pi

16.33

50

0.168

0.042

0.790

Pi+ CC

25.07

50

0.150

0.064

0.786

50

0.131

0.087

0.782

CC CC

100

0.062

0.062

0.875

CC

7

46.06

53.94

100

0.051

0.076

0.873

CC

8

35.44

64.56

100

0.039

0.091

0.870

CC

9

24.26

75.74

100

0.027

0.107

0.867

CC

10

12.46

87.54

100

0.014

0.123

0.864

CC

11

0

100

50

0

0.245

0.755

CaCl2

Pi: piracetam; CC: Piracetam2·CaCl2·2H2O

Table 3. Experimental data for the dissolution points at 298.15 K. Composition at dissolution point Piracetam CaCl2 H2O (mg) (mg) (μL) 98 100 0 89 92.02 7.98

1

48

Total amount of H2O (μL) 98

2

39

89

3

34

84

83.67

4

56

106

74.93 65.77

sample No.

Amount of H2O added (μL)

Composition at dissolution point (mol%) Piracetam

CaCl2

H2O

0.115

0.000

0.885

0.114

0.013

0.873

16.33

84

0.109

0.027

0.864

25.07

106

0.079

0.034

0.886

34.23

133

0.057

0.038

0.905

0.041

0.041

0.917

0.031

0.046

0.923

5

83

133

6

58

158

56.16

43.84

158

7

75

175

46.06

53.94

175

8

98

198

35.44

64.56

198

0.021

0.049

0.930

9

98

198

24.26

75.74

198

0.014

0.058

0.928

10

85

185

12.46

87.54

185

0.008

0.071

0.921

11

49

99

100

99

0.000

0.141

0.859

As illustrated in Figure 4, the zone where the cocrystal is the only stable phase in suspension is rather large. Furthermore, the diagram shows the system to behave congruently in water, which means that starting from a stoichiometric ratio of piracetam vs CaCl2 (2:1), one can access the zone where the cocrystal is the only stable phase in suspension by mere solvent evaporation. Hence a stoichiometric amount of piracetam and CaCl2 can be used in the development of a robust cocrystallization process.31 Figure S4 and S5 shows the temperature to have little impact on the overall interpretation of the ternary system. Based on the TPD, a solution cocrystallization process was suggested starting with a stoichiometric amount of starting compounds. 15 g of piracetam and 5.86 g of CaCl2 (0.5 equivalent) were added to 18 ml of water. This corresponds to the large red dot shown in Figure 4. By heating to 75 °C all solid forms were dissolved, and under continuous stirring the solution was then brought back to 25 °C,

0

by removing the solution from its 75°C environment and placing it in a surrounding of 25°C. Crystallization occurred spontaneously during cooling. However, to assure that the thermodynamically stable co-crystal phase was obtained, cocrystal seeding material was added, and the suspension left to stir for 3 h. The suspension was then filtered, and the powder left to dry. 5.80 g of dried cocrystal material were recovered, and shown to correspond to the dihydrate cocrystal phase (Figure S7) by XRPD of the bulk material. This corresponds to a 25% yield, in alignment with the maximum theoretical yield of 29%, based on the TPD data. As mentioned above, the yield can be increased optimizing the process conditions (amount of water, changing the temperature, recycling the filtrate which contains a stoichiometric ration of CaCl2 and piracetam, …), but this goes beyond the scope of the current contribution.


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a

b

Figure 4. TPD of water-piracetam-CaCl2 at 298.15K (mol%). The green zone highlights the zone where the cocrystal is the only stable phase in suspension. a: the full image of ternary phase diagram; b: zoom on the upper part.

Ionic Cocrystallization and the Common Ion Effect. Contrary to cocrystallization between two organic components, using an inorganic salt as a coformer introduces a supplementary parameter that can be used to fine-tune process conditions and that, as a consequence, needs to be taken into account. Working with a polar solvent, the inorganic salt dissociates in solution into its composing ions. Doing so, a common ion effect due to ions initially present in the solvent could occur. Using the most simplistic model for cocrystal solubility, the cocrystal solubility product can be described as: Ksp= api2 . acacl2 . aH202ൎ api2 . aca++ . aCl-2 . cte. As shown by this equation, considering a constant solubility product at a given temperature, and a constant water activity (solvent) the amount of Piracetam (and hence cocrystal) that is soluble in solution is directly impacted by both the Ca++ and Clconcentrations in solution, even those not coming from cocrystal material, the so called common ion effect. Such a solubility product is a direct extension of the solubility product discussed by Rodriguez-Hornedo and co-workers. They found that such a simplified solubility product is often too simplistic to describe the entire system, in particular when strong solution interactions between cocrystal partners occur.32 In this study, we therefore limited to an experimental evaluation of the common ion effect of the Cl- ion. We thus decided to recreate the ternary phase diagram shown in Figure 4 working with a 30 g·L-1 concentration of NaCl water solution. Such a solution contains 1.025 mol·L-1 of Cl-, which according to the solubility product definition is supposed to have a non–negligible impact on the amount of cocrystal able to dissolve in solution. -1

Table 4. Initial experimental data for system of piracetam-CaCl2 in 30 g.L NaCl aqueous solution at 298.15 K. Initial components sample No.

Initial components (mol%)

solid phase at equilibrium

1

Piracetam (mg) 100

CaCl2 (mg) 0

Solvent (μL) 70

0.153

0

0.847

Pi

2

92.02

7.98

70

0.141

0.016

0.844

Pi

0.127

0.032

0.841

Pi+ CC

Piracetam

CaCl2

Solvent

3

83.67

16.33

70

4

74.93

25.07

70

0.114

0.049

0.838

5

65.77

34.23

70

0.099

0.066

0.834

CC CC

6

56.16

43.84

70

0.085

0.084

0.831

CC

7

46.06

53.94

70

0.069

0.104

0.827

CC

8

35.44

64.56

70

0.053

0.123

0.824

CC

9

24.26

75.74

70

0.036

0.144

0.820

CC

10

12.46

87.54

70

0.018

0.166

0.816

CC

11

0

100

70

0

0.188

0.812

CaCl2

pi: piracetam; CC: Piracetam2·CaCl2·2H2O

As shown by Figure 5, there is a clear common ion effect on the phase behavior of an ionic cocrystal. First of all, one already notices a strong effect on the solubility of piracetam, which decreases from 1.02 g·ml-1 to 0.76 g·ml-1, which can be seen as a salting out effect. Secondly one observes a more than 50% reduction of the solubility of

CaCl2 (from 1.0 to 0.42g.ml-1), due to the common ion effect of Cl-. There is also a strong decrease in the solubility of the cocrystal from 0.95 g·ml-1 to 0.63 g·ml-1, as would be expected. Finally we highlight, that the zone wherein the cocrystal remains the only stable phase in suspension remains rather large.



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-1

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Table 5. Experimental data for dissolution points in 30 g.L NaCl aqueous solution at 298.15 K. Components at dissolution point Piracetam CaCl2 Solvent (mg) (μL) (mg) 131 100 0

1

Amount of solvent added (μL) 61

Total amount of solvent (μL) 131

2

55

125

92.02

7.98

3

58

128

83.67

16.33

128

4

94

164

74.93

25.07

164

5

127

197

65.77

34.23

197

56.16

43.84

sample No.

Components at dissolution point (mol%) Piracetam

CaCl2

Solvent

0.088

0.000

0.912

0.085

0.009

0.906

0.075

0.019

0.906

0.054

0.023

0.923

0.040

0.026

0.934

222

0.030

0.030

0.940

0.023

0.034

0.943

125

6

152

222

7

173

243

46.06

53.94

243

35.44

64.56

262

0.016

0.038

0.946

0.011

0.043

0.947

0.006

0.051

0.943

8

192

262

9

203

273

24.26

75.74

273

10

193

263

12.46

87.54

263

11

163

233

0

233 0.000 0.065 0.935 100 CCDC 1827949 contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures.

AUTHOR INFORMATION Corresponding Author * Telephone: +3210472811. Fax: +3210472707. E-mail: [email protected]. Address: Place Louis Pasteur 1, Bte L4.01.03, 1348 Louvain-la-Neuve, Belgium. Website: http://www.uclouvain.be/leyssens-group. Figure 5. TPD zoom picture of piracetam-CaCl2 in H2O and NaCl aqueous solution at 298.15K (mol%). The green one is in H2O, and the red one is in NaCl aqueous solution.

CONCLUSION

ORCID: Lixing Song: 0000-0003-4874-3551

ACKNOWLEDGMENT

In this contribution, we developed a robust, waterbased co-crystallization process for an ionic cocrystal, choosing piracetam-CaCl2 as the model system. TGA, DSC and VT-XRD confirmed the dihydrated cocrystal Piracetam2·CaCl2·2H2O to be stable up to 135 °C. Using water as a solvent a ternary phase diagram was developed showing a rather large congruent zone with the cocrystal as only stable phase in suspension. Based on this diagram, we developed an upscaled process for the manufacturing of Piracetam2·CaCl2·2H2O. Finally, we illustrated the importance of the common ion effect on the crystallization of ICCs.

ASSOCIATED CONTENT Supporting Information. Supporting information files are available free of charge via the Internet at http://pubs.acs.org. TGA and DSC curves, VT-XRPD, additional experimental data and TPD images (PDF)

Lixing Song would like to thank the China Scholarship Council (CSC) for financial support.

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Crystallizing ionic cocrystals: structural characteristics, thermal behavior, and crystallization development of a Piracetam-CaCl2 Cocrystallization process Lixing Song, Koen Robeyns, Tom Leyssens*

This work focuses on the development of a cocrystallization process for an ionic cocrystal from water. Using ternary phase diagrams, we developed a robust up-scalable process for the water-piracetam-CaCl2 system. The ternary phase diagram shows the system to behave congruently in water, allowing the development of a robust cocrystallization process by a stoichiometric amount of piracetam and CaCl2s. Furthermore we discussed the commonion effects for these systems.


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Crystallizing Ionic Cocrystals: Structural Characteristics, Thermal

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