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Article

The Solid-Phase Transition of Carbapenem CS-023 Polymorphs and the Change in Helicity Observed in the Transition

by
Shinji Matsuura
1,*,
Koichi Igarashi
1,
Masayuki Azuma
1 and
Hiroshi Ooshima
2,*
1
Department of Applied Chemistry and Bioengineering, Graduate School of Engineering, Osaka City University, Osaka 558-8585, Japan
2
Kansai Chemical Engineering Co., Ltd., Amagasaki 661-0024, Japan
*
Authors to whom correspondence should be addressed.
Crystals 2024, 14(1), 71; https://doi.org/10.3390/cryst14010071
Submission received: 19 December 2023 / Revised: 1 January 2024 / Accepted: 8 January 2024 / Published: 11 January 2024
Browse Figures
Versions Notes

Abstract

:
Anti-solvent crystallization of carbapenem CS-023 was performed at 25 °C. The following results were obtained: (1) A solvate crystal, Form A (5/2 Ethanol·1/2 H2O), was recovered from 80 v/v% ethanol solution; (2) Form A transformed to Form H (4H2O) through solid-phase transition through the solvate-free polymorph, Form A-2, and Form A also transformed into Form C (1Ethanol·3H2O) through solvent-mediated transformation. In the present study, we found that Form C also transforms to Form H through the solid-phase transition through the solvate-free polymorph Form C-2. The three polymorphs, Forms A, H, and C, were composed of helical chain structures. However, there was an incomprehensible affair in the solid-phase transition among the three polymorphs. Namely, Form A comprised a left-handed helix. On the other hand, Form C’s and Form H’s helix chains were in a left- and right-handed helix complex, respectively. The solid-phase transition of Form A into Form H suggested a switch in helicity in the solid. We attempted to explain the helicity change in the solid-phase transition. As a result, we suggest that the over-absorption of water by Form A-2 at high humidity plays a vital role in the helicity change.

1. Introduction

The characteristics of drug substance crystals conclusively influence a drug’s bioavailability because they possess various physicochemical properties (e.g., stability, solubility, and dissolution rate). Polymorphism is one of the most critical research matters. An optimal polymorph should be carefully selected and produced for drug development. The Good Manufacturing Practice (GMP), International Council for Harmonization, Q3C [1], and other quality standards regulate that all the organic solvents should be reduced below a certain level in crystals. Organic compounds in pharmaceuticals require the use of specific solvents based on their solubility for purification. And they often crystallize solvates with the organic solvents used for purification [2]. Solvent screening is conducted to minimize solvates, as solvents, while not contributing to the treatment, are undesirable. Therefore, research was conducted to remove the solvent if only solvates are obtained with no other options for the raw material form [3]. On the other hand, hydrates can be used as drugs. Crystalline doripenem, a carbapenem, exists as an anhydrate, monohydrate, and trihydrate [4]. Hickey et al. reported, based on Physician’s Desk References (2006), that ~45% of β-lactam compounds on the market (e.g., cephalosporin and penicillin) exist as crystalline hydrates [5]. Even in the case of hydrated crystals, the reproducibility of crystallization and the stability of drug substances must be guaranteed [6].
Furthermore, it is important to comprehend the transition phenomenon from one polymorph to another in the control of pharmaceutical polymorphism. Polymorphs may transform through solvent-mediated and solid-phase transitions. Solvent-mediated transformation is a vital research matter in the pharmaceutical industry. On the other hand, solid-phase transitions are also helpful in obtaining favorable polymorphs not necessarily captured by routine pharmaceutical polymorph screening. A novel polymorph of venlafaxine hydrochloride was discovered at 180–190 °C, and it was more stable than marked drug forms [7]. The solid-phase transition is induced by various factors in addition to temperature [8], the presence of defects in a crystal [9,10,11], the pressure [12], the photochromic reaction by the UV irradiation [13], the solvent vapor [14], etc.
Solid-phase transitions are helpful for the crystallization of substances intolerant to hydrolysis. In our previous work [15], we induced a hydrate crystal of the antibiotic carbapenem CS-023 with a β-lactam structure, the polymorph Form H (CS-023·4H2O), with the solid-phase transition of an ethanol (EtOH)-solvate polymorph, Form A (5/2EtOH·1/2H2O). The solid-phase transition from an ethanol-solvate crystal into a hydrate crystal avoided the quick hydrolysis of the β-lactam compound that is unavoidable in direct crystallization from an aqueous solution. Form A transformed into another solvate polymorph, Form C (1EtOH·3H2O), through solvent-mediated transformation under 40–80% (mainly 40–75%) ethanol [16].
This study investigated the solid-phase transition of the carbapenem CS-023 crystal from Form C to Form H. Then, the solid-phase transition mechanism of the solvate crystal to the hydrate crystal was investigated.

2. Materials and Methods

2.1. Materials

Carbapenem (CS-023), with the chemical structure shown in Figure 1, was supplied by Daiichi Sankyo Co., Ltd. (Tokyo, Japan) [17,18]. The purity was determined to be 99.5% using a reverse-phase column based on the HPLC analysis and was used without further purification. Analytical reagent-grade ethanol was bought from Wako Pure Chemical Industries (Osaka, Japan). Ultrapure water was prepared in the laboratory.

2.2. Crystallization

Form C was recovered from a 30–75% ethanol solution by anti-solvent crystallization at a constant temperature of 25 °C. The crystals were filtered with a 1.0 μm cellulose filter (ADVANTEC No.5). Then, crystals were washed with 96 v/v% ethanol solvent of three double volumes of crystals under 50% RH at 25 °C and dried at 25 °C and 1.6 kPa. The PXRD pattern, TG-analysis, and the water desorption and absorption isotherm confirmed the crystals as Form C (CS-023·1EtOH·3H2O) [15]. Form C was the product of the solvent-mediated transformation of Form A (5/2EtOH·1/2H2O) [16]. Form A was obtained from an 80% ethanol solution by anti-solvent crystallization. Namely, we failed to obtain Form C from an 80% ethanol solution. This was due to the slow solvent-mediated transformation of Form A to Form C. In the present work, Form C recovered from a 75% ethanol solution was used for the starting material of the solid-phase transition of Form C to Form H.

2.3. Phase Transition on Instrumental Analysis

The phase transition experiment used a powder X-ray diffraction (PXRD) device with adjustable temperature and humidity. The PXRD patterns were derived using BrukerD8 Advance (Bruker AXS GmbH, Karlsruhe, Germany) with Cu K_ radiation (1.5418 Å) at 40 kV and 40 mA. The patterns were recorded between 2° and 42°, with a step of 0.02°. A domed hot-stage DHS900 (Anton Paar, Graz, Austria) was attached for the in situ temperature and humidity diffraction measurements. Humidity was controlled using SRG-1R (SHINEI,) at 25 °C.

2.4. Phase Transition by Absorption and Desorption of Water and Ethanol

Vapor absorption and desorption isotherms of crystalline materials were determined using DVS advantage-1 (Surface Measurement Systems Ltd., London, UK) in a relative humidity range of 0–95% at intervals of 5%. The equilibrium criterion for each step was that the weight change should be less than 0.001% for 5 min.

2.5. Determination of Crystal Structure with Single-Crystal X-ray Diffraction

Single-crystal structure analysis was performed on crystals that could grow to a size available for structure analysis. Single-crystal X-ray diffraction data were collected using a Graphite Monochromator (Rigaku/MSC Mercury CCD, Tokyo, Japan) with Mo K radiation (0.7107 Å) at 150 K. All structures were solved by direct methods using SIR97 [19] as implemented in the program package CrystalClear Ver.1.3.6 SP3 (Rigaku, Tokyo, Japan). Refinement was carried out using the full-matrix least-squares method with the SHELXL-97 program [20]. All non-hydrogen atoms were refined anisotropically. The hydrogen atoms were located using difference Fourier methods. Hydrogen atoms were refined in the riding mode.

3. Results and Discussion

3.1. The Solid-Phase Transition of Form C to Form H

The direct immersion of Form C in water is an easy way to obtain the hydrate crystal Form H. However, this method has a risk of hydrolysis of the dissolved CS-023 molecules. Then, at present, we attempted the solid-phase transition of Form C to Form H by putting Form C under humidity and temperature control.
Figure 2 presents a diagram of the solid-phase transition of Form C (CS-023·1EtOH·3H2O) to Form H (4H2O). The dotted arrow directly tied to Form H is a result shown in the previous paper [16]. When Form C was placed under 5%RH, it lost 3H2O, as shown in the desorption isotherm (Figure 3). The XRD pattern of the dehydrated solid presented in Figure 4 showed that the dry solid holds the crystalline state. Then, the crystal was named Form C-1 (CS-023·EtOH). Form C-1 returned to Form C under RH values higher than 25%.
Then, we began the thermal transition at a high temperature. When Form C-1 was heated to 150 °C, it changed to Form C-2 by releasing one crystalline ethanol. The XRD pattern change is presented in Figure 4. When the temperature was raised to 180 °C for confirmation, the same XRD pattern as in Form C-2 was observed. Furthermore, by cooling down Form C-2 to under 110 °C, it changed to Form H-1. Form H-1 returned to Form C-2 over the temperature of 120 °C. Form H-1 transformed to Form H, as reported in the previous paper [15].

3.2. The Relationship of CS-023 Polymorphs, Form A, Form C, and Form H

We summarize the relationship of polymorphs of CS-023 by combining the diagram of the solid-phase transition of Form C to Form H with the diagram of the solid-phase transition of Form A to Form H [15] in Figure 5. We will explain the value of the transition map in Figure 5. We obtained a hydrate polymorph of the antibiotic carbapenem CS-023, Form H (CS-023·4H2O), with the cooling crystallization from an aqueous solution [15]. However, the cooling crystallization from the aqueous solution had a potential problem. Namely, the CS-023 dissolved in water was prone to hydrolysis. Then, we obtained a solvate polymorph, Form A (CS-023·5/2EtOH·1/2H2O), by anti-solvent crystallization using ethanol as an anti-solvent at 25 °C [15]. Form A was recovered from an 80% ethanol solution that directly added pure ethanol into the aqueous CS-023 synthesis reaction solution. Form A transformed into Form H through a solid-phase transition. Form H was obtained through another solid-phase transition route reported in the present work, from Form C (CS-023·1EtOH·3H2O) to Form H. Figure 5 shows that, in this case, it is possible to select the solid-phase transition of solvate crystals to anhydrous or hydrate crystals in the crystallization of water-unstable substances.

3.3. A Comparison of the Crystal Structure between Form A, Form C, and Form H

Table 1 presents Form A’s, C’s, and H’s crystallographic data. The data for Form A and Form C were reported in a previous paper [16]. The structures of Form C and Form H were similar except for the solvation. The similarity in the lattice structure suggests that the solid-phase transition of Form C into Form H is easy because it seems possible only by going in and out of the solvent. On the other hand, the structures of Form A and Form H were distinguishably different. However, it can be reconfirmed that Form A also transformed into the same hydrate polymorph, Form H. Then, we investigated how Form A transformed into Form H.
The three polymorphs are composed of similar helical chain structures as follows. Figure 6 presents the mutual relationship between three helix chains (named A-, B-, and C-chains) composed of the three polymorphs: (a) Form A, (b) Form C, and (c) Form H. However, solvent molecules, namely water and ethanol, are omitted here for the simple look of the three polymorph structures. Our eyes are on the ab-plane of the Form A crystal lattice (panel (a)) and the ac-plane in Form C’s and Form H’s crystal lattice (panels (b) and (c)). Each molecule in each helix is given a number from one to six. In Form A, the three-helix chains point in the same direction. The tail (as shown in Figure 1) is positioned in the background on the paper. The direction from tail to head is left-handed.
On the other hand, in Form C and Form H, the three-helix chains alternate. Namely, the mutual relationship between the neighboring helix chains in Form A differs from that in Form C and Form H. This observation also suggests that the solid-phase transition of Form C into Form H is easy because the CS-023 molecule does not need to move as much.

3.4. The Mechanism of the Solid-Phase Transition of Form A into Form H

Figure 6 shows that the mutual relationship between the neighboring helix chains of Form A must change to transition Form A into Form H. Figure 7a presents the imaginary 180° rotation of two CS-023 molecules (B-1 and B-6 in Form A). Each molecule rotates inversely. The rotation results in the relationship illustrated in Figure 7b. It seems similar to the structure of Form H, shown in Figure 7c, except for a slight difference in the conformation of the CS-023 molecule. The rotated B-1 and B-6 molecules in Form A correspond to the B-3 and B-4 molecules in Form H (Figure 6c). The newly formed mutual relationship between helix chains A, B, and C should induce the new stable conformation of each molecule: it should be Form H.
A question remains in the above explanation about the solid-phase transition of Form A into Form H: how did the rotation of molecules start in a solid crystal? Some polymorphic transition phenomena were interpreted as a rearrangement of weak intermolecular interactions caused by a slight molecular movement inside the crystal lattice [21,22]. The 180° rotation of a molecule in the crystal lattice shown in Figure 7 is not a little movement of a molecule. We discuss the role of the water molecules that Form B (CS-023·3/2H2O) excessively absorbs at high humidity. Figure 8 presents the water-absorption isotherm curve of Form A-2 (no solvent) to Form H via Form B (the solid red curve) and the water-desorption curve of Form H into Form H-1 (the solid blue curve). In Figure 8, the water-absorption isotherm curve of Form H-1 (no solvent) to Form H (the dotted red curve) and the water-desorption curve of Form H into Form H-1 (the dotted blue curve) are also presented. Here, it should be noted that Form A-2 absorbed water over a four- or five-equivalent level. The absorption reached a 7.4-equivalent level at high humidity and then dropped to a 6-equivalent level. After that, the level gradually decreased. This observation means that Form A-2 absorbed too much water over Form H’s level. The loosening of the helix chain of Form A-2 must have caused this water-absorption excess. We suppose that the loosening was caused by the movement of the CS-023 molecules in Form B, namely by the rotation of the molecules, as shown in Figure 7. We suppose the rotation started after forming Form B, namely after the 1.5-equivalent water was absorbed in Form A-2. The hydrogen bond formed between the carbonyl group of the CS-023 molecule (No. 1 in Figure 1) and one water molecule in Form B played an essential role as the rotation axis.

4. Conclusions

A solid-phase transition of Form C (CS-023·EtOH·3H2O) into Form H (CS-023·4H2O) was performed. At first, Form C-1 (CS-023·EtOH) was obtained by placing Form C under less than 5% RH. Then, by heating Form C-1 to 150–180 °C, the solvate-free polymorph, Form C-2, was obtained. Form C-2 was transformed into Form H-1 by cooling it down to 110 °C. Finally, Form H-1 changed to Form H as described in the previous paper [15]. As a result, the hydrate polymorph was recovered without exposing Form C to bulk water, with no risk of hydrolysis of CS-023′s β-lactam structure. This is a merit of adopting the solid-phase transition for the polymorph change.
It was confirmed that two solvate polymorphs, Form A and Form C, were transformed into the same hydrate polymorph. The three polymorphs, Forms A, H, and C, were composed of helical-chain structures, respectively. However, there was an incomprehensible affair in the solid-phase transition among the three polymorphs. Namely, Form A comprised a left-handed helix. On the other hand, Form C’s and Form H’s helix chains were in a left- and right-handed helix complex. In the case of the transition of Form A to Form H, a helicity change had to be involved. The solid-phase transition of Form A into Form H suggested a switch in helicity in the solid. We attempted to explain the helicity change in the solid-phase transition. As a result, we understood that the over-absorption of water by the no-solvent polymorph, Form A-2, induced from Form A, plays a vital role in the helicity change.

Author Contributions

Investigation, S.M. original draft preparation, S.M. and H.O.; writing—review and editing, K.I. and M.A. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Data Availability Statement

Data is contained within the article.

Acknowledgments

The authors would like to thank Daiichi Sankyo Co., Ltd. for supplying CS-023.

Conflicts of Interest

Author Hiroshi Ooshima was employed by the company Kansai Chemical Engineering Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Crystals 14 00071 g001
Figure 1. Chemical structure of CS-023. The carbonyl groups forming the hydrogen bond with solvent (ethanol or water) are numbered 1 to 4 in Form A and Form H structure. And the corresponding directions in a molecule are named “Head” and “Tail” for a helical chain.
Figure 1. Chemical structure of CS-023. The carbonyl groups forming the hydrogen bond with solvent (ethanol or water) are numbered 1 to 4 in Form A and Form H structure. And the corresponding directions in a molecule are named “Head” and “Tail” for a helical chain.
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Figure 2. Diagram of the solid-phase transition of Form C to Form H.
Figure 2. Diagram of the solid-phase transition of Form C to Form H.
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Figure 3. The water desorption and absorption curves between Form C and Form C-1.
Figure 3. The water desorption and absorption curves between Form C and Form C-1.
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Figure 4. The XRD patterns of the CS-023 crystal’s polymorphs observed in the solid-phase transition of Form C to Form H.
Figure 4. The XRD patterns of the CS-023 crystal’s polymorphs observed in the solid-phase transition of Form C to Form H.
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Figure 5. A solid-phase transformation map of CS-023 crystal polymorphs. (PE: the ethanol partial pressure, PE0: the ethanol saturated vapor pressure).
Figure 5. A solid-phase transformation map of CS-023 crystal polymorphs. (PE: the ethanol partial pressure, PE0: the ethanol saturated vapor pressure).
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Figure 6. A comparison of the three-helix chain’s mutual relationships observed in (a) Form A, (b) Form C, and (c) Form H, where the crystal solvents (ethanol and water) are omitted. The expansion ratios of the three lattices are the same. The unit cell is written as a black rectangle.
Figure 6. A comparison of the three-helix chain’s mutual relationships observed in (a) Form A, (b) Form C, and (c) Form H, where the crystal solvents (ethanol and water) are omitted. The expansion ratios of the three lattices are the same. The unit cell is written as a black rectangle.
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Figure 7. A possible mechanism of the solid-phase transition of Form A into Form H. The rotation of two CS-023 molecules (B-1 and B-6) in Form A results in the formation of a similar structure with Form H: (a) the B-1 and B-6 molecules shown in Figure 6a, (b) the relationship between the B-1 and B-6 molecules after those rotations, and (c) the mutual relationship between the three helix chains in Form H represented as a reference of Form 7 (b). The unit cell is written as a black rectangle.
Figure 7. A possible mechanism of the solid-phase transition of Form A into Form H. The rotation of two CS-023 molecules (B-1 and B-6) in Form A results in the formation of a similar structure with Form H: (a) the B-1 and B-6 molecules shown in Figure 6a, (b) the relationship between the B-1 and B-6 molecules after those rotations, and (c) the mutual relationship between the three helix chains in Form H represented as a reference of Form 7 (b). The unit cell is written as a black rectangle.
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Figure 8. The water absorption and desorption curves of Form A-2 (the solid line) and Form H-1 (the dotted line) at 25 °C.
Figure 8. The water absorption and desorption curves of Form A-2 (the solid line) and Form H-1 (the dotted line) at 25 °C.
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Table 1. Crystallographic data for Form A, Form C, and Form H.
Table 1. Crystallographic data for Form A, Form C, and Form H.
PolymorphForm AForm CForm H
Solvate5/2 Ethanol 1/2 H2O1 Ethanol 3 H2O4 H2O
Crystal system triclinic orthorhombicorthorhombic
Space groupP1 P212121P212121
Unit cell dimensions
a (Å)10.239.8579.879
b (Å)13.2113.113613.322
c (Å)14.0424.185923.45
α (°)78.079090
β (°)89.029090
γ (°)76.639090
Volume (Å3)1805.13113.23086
Z244
Density (calculated)1.125 g/cm31.361 g/cm31.351 g/cm3
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Matsuura, S.; Igarashi, K.; Azuma, M.; Ooshima, H. The Solid-Phase Transition of Carbapenem CS-023 Polymorphs and the Change in Helicity Observed in the Transition. Crystals 2024, 14, 71. https://doi.org/10.3390/cryst14010071

AMA Style

Matsuura S, Igarashi K, Azuma M, Ooshima H. The Solid-Phase Transition of Carbapenem CS-023 Polymorphs and the Change in Helicity Observed in the Transition. Crystals. 2024; 14(1):71. https://doi.org/10.3390/cryst14010071

Chicago/Turabian Style

Matsuura, Shinji, Koichi Igarashi, Masayuki Azuma, and Hiroshi Ooshima. 2024. "The Solid-Phase Transition of Carbapenem CS-023 Polymorphs and the Change in Helicity Observed in the Transition" Crystals 14, no. 1: 71. https://doi.org/10.3390/cryst14010071

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