A Possible Infinite Number of Components in a Single Crystalline

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A possible infinite number of components in a single crystalline phase: on the isomorphism of brivaracetam – guest molecules Nicolas Couvrat, Morgane Sanselme, Yohann Cartigny, Frédéric De Smet, Sandrine Rome, Luc Aerts, Luc Quéré, Johan Wouters, and Gérard Coquerel Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.8b00331 • Publication Date (Web): 20 Aug 2018 Downloaded from http://pubs.acs.org on August 22, 2018

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Crystal Growth & Design

A possible infinite number of components in a single crystalline phase: on the isomorphism of brivaracetam – guest molecules Nicolas Couvrat†, Morgane Sanselme†, Yohann Cartigny†, Frederic De Smet‡, Sandrine Rome‡, Luc Aerts‡, Luc Quéré‡, Johan Wouters#*, Gérard Coquerel†* †

Normandie Univ, UNIROUEN-Normandie, EA3233, Laboratoire Science et Méthodes

Séparatives, 76821 Mont Saint Aignan, France. ‡

UCB Pharma S.A., 1420 Braine l’Alleud, Belgium.

#

Université de Namur Unité de chimie physique, théorique et structurale 5000 Namur, Belgium.

* [email protected]

Tel: +33 (0)2 35 52 29 27

* [email protected]

Tel: +32 (0)81 72 45 50

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A possible infinite number of components in a single crystalline phase: on the isomorphism of brivaracetam – guest molecules Nicolas Couvrat†, Morgane Sanselme†, Yohann Cartigny†, Frederic De Smet‡, Sandrine Rome‡, Luc Aerts‡, Luc Quéré‡, Johan Wouters#*, Gérard Coquerel†* †

Normandie Univ, UNIROUEN-Normandie, EA3233, Laboratoire Science et Méthodes

Séparatives, 76821 Mont Saint Aignan, France. ‡

UCB Pharma S.A., 1420 Braine l’Alleud, Belgium.

#

Université de Namur Unité de chimie physique, théorique et structurale 5000 Namur, Belgium.

KEYWORDS. Brivaracetam • channel solvate/co-crystal • syntectic equilibrium • isomorphous phases • aperiodic crystals

ABSTRACT. This article highlights the unusual behavior of Brivaracetam (BRV: an active pharmaceutical ingredient against epilepsy), which leads to a unique phase -ranging from clathrate to solvate to co-crystal- formed with an impressive number of apolar guest molecules (any linear alkanes to esters of fatty acids/alcohols, or waxes.). Moreover, the investigation of binary systems between linear alkanes and BRV displayed the systematic existence of a syntectic invariant (one solid melts into two non-miscible liquids) for CnH2n+2 with n> 7.


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Since decades, solid state characterization of organic molecules has become a major subject in physical-chemistry science (1,2). The ability of a given molecule to assemble on its own, or with partners, in several crystal packings (such as polymorphs, co-crystals or solvates) needs to be thoroughly investigated (3,4). In the specific class of solvates, isomorphism is generally encountered in channel structures and the so-called mixed solvates can be obtained (5). Nevertheless, in order to accept a solvent exchange on the same crystallographic site without impairing the stability of the solid phase, there are critical limitations such as nature and length of the solvent molecule and polarity or steric hindrance. Moreover, the existence of “real” isomorphous desolvates (i.e. stable solid phase without any trace of solvent) is still matter of debate (6-9). In this work, we report the unusual case of brivaracetam ((2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl] butanamide, BRV hereafter, see Figure 1), a chiral Active Pharmaceutical Ingredient (API) used against epilepsy and developed by UCB Pharma (marketed under the name BRIVIACT®) (10). This molecule shows an extensive ability to form a single isomorphous phase with a virtually infinite number of guest molecules.

Figure 1. Developed formula of Brivaracetam (BRV)


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Pure BRV crystallizes in its thermodynamic stable form as Phase 1, with a P21 space group (see Table 1) and a prismatic crystal shape (Tmelting ~76°C) (11). A solvate screening revealed the existence of an isomorphous channel phase which is obtained with numerous apolar solvents and called: Phase 2. The latter crystallizes in a needle shape with a P61 space group, as depicted in Figure 2. Through deeper investigations on Phase 2, a non-exhaustive list of guests has been identified. This phase clearly shows a “host-guest structure”, meaning that, whatever the guest included, the crystallographic data of Phase 2 are not significantly affected (see Table 1) (12). So far, Phase 2 was isolated by combining BRV with every linear alkane tested, isopropyl acetate, several fatty acids, esters of fatty acids, fatty alcohols, fatty ketones, several waxes and oils, or polyethers. (the list of tested guests is available in Table S3, Supporting Information). By contrast to some APIs which are known to form numerous structures with different guests (1317), in the case reported here the resulting association, whatever the guest molecule, is just the same phase from a thermodynamic point of view (as Gibbs defined this term (18)).The formation (or not) of Phase 2 seems to be directed by two parameters: i) the global polarity of the guest used (due to the hydrophobic character of the inner channel of Phase 2) and ii) the possible steric hindrance in the channels. Outstandingly, BRV seems to be able to form Phase 2 by wrapping around linear alkanes CnH2n+2 from n=1 up to potentially infinity (the longest tested alkane here was C50H102). Note that the diastereomer of BRV (called UCB34713, (2S)-2-[(4S)-2-oxo-4-propylpyrrolidin-1-yl] butanamide) did not form Phase 2 with every guest molecule tested so far.


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Table 1. Crystallographic data of BRV Phase 1, BRV Phase 2 with Isopropyl acetate (iPrAc) and BRV Phase 2 with PEG100 stearate

Phase 2 with iPrAc

Phase 2 with PEG100 stearate[a]

CCDC 1572556

CCDC 1553038

C11H20N2O2 + C2[b]

C11H20N2O2 +C[b]

Molecular Weight / 212.15 g.mol-1

236.31

224.31

Crystal System

Monoclinic

Hexagonal

Hexagonal

Space Group

P21 (n°4)

P61 (n°169)

P61 (n°169)

Z (Z’)

2 (1)

6 (1)

6 (1)

a/Å

8.930(1)

15.910(1)

15.787(2)

b/Å

7.350(1)

/

/

chost / Å

10.107(1)

9.529(1)

9.540(2)

β/°

98.753(3)

/

/

V / Å3

655.8(2)

2089.1(3)

2059.2(2)

dcalc / g.cm-3

1.074

1.010 / 1.127[c]

1.028 / 1.085[c]

Temperature

RT

RT

RT

Crystal information

Phase 1 CCDC 1572555,

CSD reference code NASROP (11) Chemical Formula

C11H20N2O2

Final R indices R1 = 0.0416, wR2 = R1= 0.0804, [I>2sigma(I)] 0.1139 0.1763 R indices (all data)

R1 = 0.0441, wR2 = R1=0.1672, 0.1173 wR2=0.2150

wR2= R1= 0.0587, 0.1593

wR2=

R1=0.0652, wR2=0.1650

[a] crystallization from the melt with PEG100 stearate, [b] residual electronic densities inside channels were considered as carbons, [c] empty channel / with the guest carbon atoms In Phase 2, the channel is oriented along the 61 screw axis (Figure 2). The diameter of the inner cavity is circa 8.2 Å. For every single crystal analyzed, the location of the guest molecules in the channels could not be accurately determined due to a high disorder mainly consistent with the


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weak interactions established between the host and the guest molecules. But always some residual electronic density could be spotted inside the channel. It is noteworthy that these crystallographic features present some similarities with urea and thiourea inclusion compounds (19-21). Indeed, Phase 2 can be considered as an aperiodic composite crystal, where a and b parameters are shared by both host and guest subsystems, but a misfit parameter (which can be irrational) α= chost/cguest exists (22). cguest will depend on the guest nature and conformation, and an incommensurate modulation is expected at very low temperature due to host-guest interactions (23). So far, only chost parameter could be determined from SC-XRD data. The translational disorder is significant and thus the concept of monodimensional liquid can be considered in this case (24-25). The limits of similarities between Phase 2 and urea inclusions compounds mainly reside in the chemical nature of co-formers, which seems to be more restrictive for urea inclusions compounds than for BRV system (see Table S3, Supporting Information). Note that we never obtained Phase 2 free from any residual molecules inside the channels (one can even wonder if that is possible under normal pressure). It indicates that the presence of the guest molecule is probably mandatory to ensure a sufficient stability of Phase 2. Therefore, it is likely that if the channels are empty, the whole structure might collapse and could not result in a topotactic desolvation leading to an isomorphous desolvate even under smooth experimental conditions (6) (26).


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Figure 2. Structural representation of BRV Phase 2 (crystallized in iPrAc), left: along c axis; right: along a axis. Yellow dots display the residual electronic density detected inside the channels Interestingly Phase 2 reaches a higher calculated density (1.085) than Phase 1 (1.074) when one carbon atom only (per BRV molecule) is inserted in the cavity according to residual electronic density in SC-XRD (data extracted from Phase 2 with PEG 100 stearate as a guest molecule). This observation highlights the remarkable stability of the non-stoichiometric compound. Indeed, when BRV is put in contact with a convenient filling agent, the crystallization of Phase 2 is always favored. Phase 2 is remarkable by the diversity of the solvents and guest molecules it can accommodate and this large panel of guest molecules brings different physical properties. Indeed, when crystallized in solvents with a low molecular weight (n-pentane for example), Phase 2 shows a highly efflorescent character (the spontaneous transformation to Phase 1 may be observed after a few seconds upon drying under ambient conditions). In isopropyl acetate, Phase 2 displays a non-congruent melting at circa 18°C (i.e. peritectic transformation), classically observed for organic solvates (27,28). When formed with long hydrophobic organic chains; Phase 2 becomes


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more stable and its melting temperature will depend of the guest length and its chemical nature. Along with the increasing melting temperature for Phase 2 formed with linear alkanes, a concomitant stable liquid-liquid separation in from a chain length Cn n≥ 7 onwards. This transformation is thus a syntectic equilibrium (27): ⇌ liquid 1 + liquid 2 (positive enthalpy from left to right)

Due to the very poor solubility of the API in liquid alkanes (

A Possible Infinite Number of Components in a Single Crystalline

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