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DOI: 10.1039/C2NJ40379J (Paper) New J. Chem., 2013, 37, 97-104

From 3D channelled frameworks to 2D layered structures in molecular salts of L-serine and DL-serine with oxalic acid†‡

Dario Braga, Laura Chelazzi, Iacopo Ciabatti and Fabrizia Grepioni*
Dipartimento di Chimica G. Ciamician, Università degli Studi di Bologna, Via Selmi 2, 40126 Bologna, Italy. E-mail: fabrizia.grepioni@unibo.it; Fax: +39 051 2099456

Received (in Victoria, Australia) 10th May 2012, Accepted 1st August 2012

First published on 2nd August 2012

Abstract

L-Serine and DL-serine have been treated with oxalic acid under different experimental conditions, e.g. crystallization from solution and slurry, kneading and dry mixing, yielding the molecular salts [L-serH]2[ox]·2H2O forms I and II, [L-serH][Hox] and [DL-serH]2[ox]·2H2O, all fully characterized by powder or single crystal X-ray diffractions; the relationship between the different crystal forms, relative thermal stability, dependence on relative humidity and possible interconversions have all been explored.

Introduction

One of the areas of most intense investigation in the broad field of crystal engineering1 is that of design, preparation and characterization of multiple crystal forms, especially co-crystals and molecular salts.2 Besides the implications of utilitarian nature (changes in solubility and dissolution rate, stability etc.3) of the use of co-crystals/salts with respect to separate components, the investigation of how different molecules recognize and assemble and whether they prefer to pack in homo-molecular or hetero-molecular crystals affords criteria for an adequate selection of supramolecular synthons and a choice of preparation strategies. Among these, the mechanical mixing (grinding or kneading (i.e. grinding in the presence of trace amounts of solvent)/liquid assisted grinding)4 has proved to be among the most efficient ways to prepare new co-crystalline materials and crystalline forms in general.

A recent development of these strategies has arisen from the possibility of using co-crystallization to tackle enantiomer–racemate relationships when chiral molecules are involved.5 In a previous study we have reported the mechanochemical preparation of co-crystals of dextro- (R,R), levo- (S,S), meso- (R,S) and racemic (R,R–S,S) tartaric acid, C4O6H6, with pyrazine, C4N2H4. Pyrazine was chosen not only because it would easily bind to tartaric acid via N⋯H–O hydrogen bonds, but also because any unreacted pyrazine can easily sublimate at room temperature as a pure component,6 thus simplifying analysis and characterization of the reaction product. In a related experiment Friščić et al. had previously investigated the reaction of chiral co-crystals of caffeine·D-tartaric acid with co-crystals of caffeine·L-tartaric acid in the presence of a few drops of nitrobenzene.7

In this paper we report the result of co-assembly processes between L-serine [2(S)-amino-3-hydroxypropanoic acid] and DL-serine [2(RS)-amino-3-hydroxypropanoic acid] with oxalic acid (Scheme 1). Depending on stoichiometric ratio and/or preparation conditions, two polymorphic modifications of the dihydrated 2[thin space (1/6-em)]:[thin space (1/6-em)]1 salt [L-serH]2[ox]·2H2O (form I and form II), one crystal form of the anhydrous 1[thin space (1/6-em)]:[thin space (1/6-em)]1 molecular salt [L-serH][Hox] obtained by direct mixing (grinding and kneading) and the dihydrated 2[thin space (1/6-em)]:[thin space (1/6-em)]1 salt of racemic DL-serine, namely [DL-serH]2[ox]·2H2O, have been obtained. Structural characterization has been possible, for the last salt and polymorph II of [L-serH]2[ox]·2H2O, via powder data.


Serine molecule (left) and serinium cation (right).
Scheme 1 Serine molecule (left) and serinium cation (right).

It is important to stress here that distinction between molecular salts and co-crystals is usually made on the basis of H-atoms positions along the O–H⋯O or N–H⋯O hydrogen bonds. When COOH groups are involved, as in the case of oxalic acid as the co-former of choice, an analysis of C–O distances helps in distinguishing between COOH and COO− groups; chemical sense and a careful study of hydrogen bonding patterns are also needed before a sound conclusion can be reached. Although, in our experience, molecular salts and co-crystals can show extremely similar behaviour,8 the implications, especially in the pharmaceutical field, can be of outmost relevance.§ An adequate choice of the “co-former” may strongly depend on the task at-hand.

All solid-state materials have also been investigated by differential scanning calorimetry and variable temperature X-ray powder diffraction, as well as by a series of experiments in solution, in slurry and under different humidity conditions, in order to ascertain relative stability and possible interconversion pathways.

Results and discussion

Crystallization from solution of L-serine with oxalic acid in a 2[thin space (1/6-em)]:[thin space (1/6-em)]1 stoichiometric ratio yielded the 2[thin space (1/6-em)]:[thin space (1/6-em)]1 molecular salt [L-serH]2[ox]·2H2O form I. By grinding and kneading experiments we obtained [L-serH]2[ox]·2H2O form II and [L-serH][Hox], depending on the reagents molar ratio. The use of DL-serine invariably yielded [DL-serH]2[ox]·2H2O, irrespective of the synthesis methods. All crystallizations were carried out from water, while ethanol was utilized in the kneading and slurry experiments (Table 1).
Table 1 Molecular salts obtained as a function of the preparation method (c = crystallization, g = grinding, k = kneading, s = slurry)
Reagents ratioMethodProduct
L-ser[thin space (1/6-em)]:[thin space (1/6-em)]H2ox·2H2O 2[thin space (1/6-em)]:[thin space (1/6-em)]1c, k, s[L-serH]2[ox]·2H2O I
L-ser[thin space (1/6-em)]:[thin space (1/6-em)] H2ox·2H2O 2[thin space (1/6-em)]:[thin space (1/6-em)]1g[L-serH]2[ox]·2H2O II
L-ser[thin space (1/6-em)]:[thin space (1/6-em)] H2ox·2H2O 1[thin space (1/6-em)]:[thin space (1/6-em)]1g, k[L-serH][Hox]
DL-ser[thin space (1/6-em)]:[thin space (1/6-em)] H2ox·2H2O 2[thin space (1/6-em)]:[thin space (1/6-em)]1c, g, k, s[DL-serH]2[ox]·2H2O
DL-ser[thin space (1/6-em)]:[thin space (1/6-em)] H2ox·2H2O 1[thin space (1/6-em)]:[thin space (1/6-em)]1c, g, k, s[DL-serH]2[ox]·2H2O + DL-ser

In order to establish a sequence of relative stability for the molecular salts obtained with L-serine, slurry experiments were performed. The results are summarized in Table 2, and show that [L-serH]2[ox]·2H2O form I is the most stable form under ambient conditions.

Table 2 Results of the slurry experiments at RT in EtOH
Starting materialProduct
[L-serH]2[ox]·2H2O I[L-serH]2[ox]·2H2O I
[L-serH]2[ox]·2H2O II[L-serH]2[ox]·2H2O I
[L-serH][Hox] + L-ser[L-serH]2[ox]·2H2O I

Direct mixing of L-serine and oxalic acid by grinding or kneading in molar ratio 1[thin space (1/6-em)]:[thin space (1/6-em)]1 invariably leads to the formation of the anhydrous species [L-serH][Hox]. In the slurry tests, crystallization from solution yields instead the 2[thin space (1/6-em)]:[thin space (1/6-em)]1 dihydrated adduct [L-serH]2[ox]·2H2O form I, while the excess of oxalic acid is recovered as H2ox·2H2O. The structure of the anhydrous 1[thin space (1/6-em)]:[thin space (1/6-em)]1 compound has been determined directly from powder diffraction data (see below).

We also performed direct reactions in the solid state in order to see whether the forms obtained could be further converted. The results are summarized in Table 3.

Table 3 Results of direct reactions in the solid state
ReagentsaKneadingGrinding
a Molar ratio 1[thin space (1/6-em)]:[thin space (1/6-em)]1.
[L-serH]2[ox]·2H2O I + H2ox·2H2O [L-serH][Hox] No change
[L-serH]2[ox]·2H2O I + L-ser [L-serH]2[ox]·2H2O I No change
[L-serH]2[ox]·2H2O I + II [L-serH]2[ox]·2H2O I II

Preparative attempts with DL-serine invariably yielded the molecular salt [DL-serH]2[ox]·2H2O; even the direct reaction of L-serine, D-serine and oxalic acid in a 1[thin space (1/6-em)]:[thin space (1/6-em)]1[thin space (1/6-em)]:[thin space (1/6-em)]1 molar ratio resulted in formation of the racemic crystal [DL-serH]2[ox]·2H2O plus DL-serine, instead of the alternative products constituted by a racemic conglomerate of [L-serH]2[ox]·2H2O and [D-serH]2[ox]·2H2O (Fig. 1).


Schematic representation of the relationship between the different crystal forms obtained by reacting l-serine with oxalic acid.
Fig. 1 Schematic representation of the relationship between the different crystal forms obtained by reacting L-serine with oxalic acid.

A further point of interest is represented by the results of the dehydration processes on forms I and II of [L-serH]2[ox]·2H2O. Dehydration of [L-serH]2[ox]·2H2O does not result in formation of the anhydrous phase [L-serH]2[ox], either under thermal treatment or in the presence of P2O5. As shown by variable temperature powder diffraction, loss of water results in phase transition to the 1[thin space (1/6-em)]:[thin space (1/6-em)]1 molecular salt [L-serH][Hox], accompanied by extrusion of L-serine from the crystalline material (see ESI‡); more accurate data on the transitions have been obtained from DSC (see Table 4).

Table 4 Results of the differential scanning calorimetry (DSC) measurements in open and sealed pans, and of variable temperature X-ray diffraction on the molecular salts containing [L-serH]+
DSC
Starting materialPhase trans.a open panmpb sealed pan
a Extrusion of L-ser, following water loss, and transformation into [L-serH][Hox].b Congruent melting.
[L-serH]2[ox]·2H2O I84 °C (onset)87 °C (onset)
[L-serH]2[ox]·2H2O II73 °C (onset)77 °C (onset)
[L-serH][Hox]125 °C (onset)—
Variable temperature X-ray powder diffraction
 Phase trans.aProduct
[L-serH]2[ox]·2H2O I80–85 °C [L-serH][Hox] + L-ser
[L-serH]2[ox]·2H2O II70–75 °C[L-serH][Hox] + L-ser

Thermal behaviour of the molecular salts was examined by DSC measurements (see ESI‡), both in open and sealed pans. Measurements in sealed pans allow us to determine congruent melting of the hydrated phases, while in open pans loss of water is observed upon heating the hydrated samples, and the 1[thin space (1/6-em)]:[thin space (1/6-em)]1 anhydrous phase is formed, accompanied by extrusion of L-ser. DSC measurements in sealed pans also allow us to characterize the dimorphic system as a monotropic system, because no solid–solid phase transition is observed before melting, which occurs at 87 °C for form I and at 77 °C for form II (onset values). Thermal stability of the anhydrous molecular salt [L-serH][Hox] is much higher, as melting point is observed at ca. 125 °C (onset), followed by decomposition (see ESI‡).

The behaviour of [L-serH]2[ox]·2H2O forms I and II under controlled humidity at RT was also investigated (see Table 5). If form II is exposed to high humidity (RH 84% in the presence of a supersaturated solution of KCl), it converts into the more stable form I, while no transition is observed under low humidity conditions (RH 11% with a supersaturated solution of LiCl). Exposure to a dry atmosphere, i.e. to P2O5, does not result in dehydration; this fact is better understood if the packing features of forms I and II are investigated (see below).

Table 5 Behaviour of [L-serH]2[ox]·2H2O under controlled humidity conditions
ReagentsRH% = 11aRH% = 84bP2O5c
a Obtained with LiCl.b Obtained with KCl.c All attempts to solve the structure from powder diffraction data have been thus far unsuccessful.
[L-serH]2[ox]·2H2O INo changeNo changeNo change
[L-serH]2[ox]·2H2O IINo changeForm INo change
[L-serH][Hox]No changeNew phasecNo change

Structural characterization

Crystal structures of all solids were determined by X-ray single crystal or powder diffraction. Crystallographic data are listed in Table 6.
Table 6 Details of X-ray data measurements and refinements
 [DL-serH]2[ox]·2H2O [L-serH]2[ox]·2H2O form I[L-serH]2[ox]·2H2O form II (powder data) [L-serH][Hox] (powder data)
Chemical formulaC8H16N2O10·2H2OC8H16N2O10·2H2OC8H16N2O10·2H2OC5H9NO7
Mr336.26336.26336.24195.13
T/K293293293293
λ (Å)0.710730.710731.540561.54056
Crystal systemMonoclinic MonoclinicMonoclinicMonoclinic
Space groupP21/CP21P21P21
a/Å4.8685(3)4.8832(6)12.5711(6)14.3723(8)
b/Å17.2207(12)11.9276(14)11.2144(5)6.2614(4)
c/Å17.2062(15)12.4798(15)5.2079(2)9.1815(5)
α/degrees90909090
β/degrees91.668(7)92.018(10)100.529(3)92.112(4)
γ/degrees90909090
V/Å31441.94(18)726.43(15) 721.84(3)825.69(8)
Z4224
dcalc/mg cm−31.5491.528——
μ/mm−10.1480.147——
Measd reflns109025125  
Unique reflns 35022878——
Rint0.0510.073——
GoF1.2551.149——
R1 (I>2σ(I)0.10650.0963——
wR2 (all)0.24650.1693——
Rwp——9.3110.28
χ2——3.95.95

The formation of all molecular salts is the result of a one- or two-proton transfer process from oxalic acid to the amino acid serine, as evidenced by an analysis of all C–O distances. On the basis of pKa values for the second deprotonation of oxalic acid (pK = 4.14) and deprotonation of the COOH group on serine (pK = 2.19), it is clear that complete deprotonation of oxalic acid is possible only in the presence of an excess of serine, and the resulting salts show indeed a 2[thin space (1/6-em)]:[thin space (1/6-em)]1 stoichiometric ratio of serine[thin space (1/6-em)]:[thin space (1/6-em)]oxalic acid. Monodeprotonation of the oxalic acid is observed only in anhydrous [L-serH][Hox], in keeping with a stoichiometric ratio of 1[thin space (1/6-em)]:[thin space (1/6-em)]1.

Relevant crystal packing features for the four molecular salts will now be discussed and compared, starting with [DL-serH]2[ox]·2H2O and the two polymorphic forms of [L-serH]2[ox]·2H2O, which will be described together due to their packing similarities; this will be followed by a description of anhydrous [L-serH][Hox].

Crystal structures of [DL-serH]2[ox]·2H2O, [L-serH]2[ox]·2H2O form I and [L-serH]2[ox]·2H2O form II

Crystalline [DL-serH]2[ox]·2H2O9 can be ideally built up by piling serinium cations parallel to the a-axis direction, thus forming a first “pillared” scaffold, as shown in Fig. 2a. The serinium cations along the piles interact with each others only via CH⋯O interactions (C⋯OCO 3.211(6) Å, see Fig. 2b). This arrangement results in the formation of two kinds of channels, in a sort of a chessboard disposition (white and light blue squares in Fig. 2a).
(a) Chessboard disposition of channels, formed by piling serinium cations parallel to the a-axis direction in crystalline [dl-serH]2[ox]·2H2O. (b) The serinium cations along the piles interact with each others only via CH⋯O interactions.
Fig. 2 (a) Chessboard disposition of channels, formed by piling serinium cations parallel to the a-axis direction in crystalline [DL-serH]2[ox]·2H2O. (b) The serinium cations along the piles interact with each others only via CH⋯O interactions.

The channels evidenced in light-blue are filled with water of crystallization (blue spheres in Fig. 3a); the water molecules along the channels are linked via hydrogen bonds in infinite zig–zag chains, as shown in Fig. 3b [Ow⋯Ow 2.750(5) and 2.838(5) Å]. The role of water in this structure is not limited to its filler capacity: the water act as a hydrogen bonding “glue” towards the serinium cations, as it can be seen in Fig. 4, thus stabilizing the cationic 3D-network. For this task each serinium cation makes use of both the –OH and the –NH3+ groups, one of which is bound by water in one channel, while the second is bound to water molecules in the adjacent channel; in this way each cation bridges two water-filled channels [Ow⋯OOH 2.751(6) and 2.791(5) Å; Ow⋯NNH3+ 2.826(6) and 2.838(5) Å].


(a) Filling of light-blue channels from Fig. 2a with water of crystallization (blue spheres); (b) the water molecules along the channels are linked to each other via hydrogen bonds in infinite zig–zag chains, and also interacts with the serinium cations.
Fig. 3 (a) Filling of light-blue channels from Fig. 2a with water of crystallization (blue spheres); (b) the water molecules along the channels are linked to each other via hydrogen bonds in infinite zig–zag chains, and also interacts with the serinium cations.

Water-filled channels in crystalline [dl-serH]2[ox]·2H2O: the water molecules act as a hydrogen bonding “glue” towards the serinium cations, thus stabilizing the cationic 3D-network.
Fig. 4 Water-filled channels in crystalline [DL-serH]2[ox]·2H2O: the water molecules act as a hydrogen bonding “glue” towards the serinium cations, thus stabilizing the cationic 3D-network.

The empty channels are then filled with the oxalate dianions (Fig. 5a); the carboxylate oxygen atoms on each dianion interact via charge-assisted hydrogen bonds with six serinium cations, as shown in Fig. 5b [OCOO−⋯OCOOH 2.518(5) and 2.536(5) Å, OCOO−⋯OOH 2.777(5) and 2.779(5) Å, OCOO−⋯NNH3+ in the range 2.798(5)–2.947(5) Å].


(a) View down the a-axis of the cationic framework, constituted of serinium cations and water molecules, with oxalate dianions (in orange) filling the channels. (b) Each oxalate dianion interacts via charge-assisted hydrogen bonds with six serinium cations.
Fig. 5 (a) View down the a-axis of the cationic framework, constituted of serinium cations and water molecules, with oxalate dianions (in orange) filling the channels. (b) Each oxalate dianion interacts via charge-assisted hydrogen bonds with six serinium cations.

The same description of the packing features in crystalline [DL-serH]2[ox]·2H2O also applies to the two polymorphic modifications of crystalline [L-serH]2[ox]·2H2O. Both form I and form II are characterized by the presence of channels extending along the a- and c-axis direction, respectively, which are filled with water molecules and oxalate dianions; a schematic comparison of the three crystal packings is presented in Fig. 6.


Comparison of crystal packings, all viewed down the channels direction, for (top) [(dl)-serH]2[ox]·2H2O, (bottom left) [l-serH]2[ox]·2H2O form I and (bottom right) [l-serH]2[ox]·2H2O form II.
Fig. 6 Comparison of crystal packings, all viewed down the channels direction, for (top) [(DL)-serH]2[ox]·2H2O, (bottom left) [L-serH]2[ox]·2H2O form I and (bottom right) [L-serH]2[ox]·2H2O form II.

As observed in [(DL)-serH]2[ox]·2H2O, the water molecules accommodated within the channels form infinite hydrogen bonded chains [Ow⋯Ow 2.866(9), 2.775(8) Å; 2.84(1), 2.70(1) Å in forms I and II, respectively], which are then bound to the serinium cations [Ow⋯OOH 2.721(8), 2.851(9) and 2.84(1), 2.70(1) Å; Ow⋯OCO 2.928(9) and 3.19(1) Å; Ow⋯NNH3+ 2.855(9), 2.828(9) and 2.771(9) Å in forms I and II, respectively], as it is shown in Fig. 7. The most notable difference with respect to [DL-serH]2[ox]·2H2O is that in [L-serH]2[ox]·2H2O forms I and II the cationic frameworks are now chiral.


Water-filled channels in [l-serH]2[ox]·2H2O form I (top left) and form II (top right); side-view of the channels, showing the zig–zag water chains in forms I (bottom left) and II (bottom right) (H atoms in form II not observed, as these are powder data).
Fig. 7 Water-filled channels in [L-serH]2[ox]·2H2O form I (top left) and form II (top right); side-view of the channels, showing the zig–zag water chains in forms I (bottom left) and II (bottom right) (H atoms in form II not observed, as these are powder data).

The oxalate dianions interact with the cationic framework via charge-assisted hydrogen bonds; as observed in [(DL)-serH]2[ox]·2H2O, each dianion is bound to six serinium cations, but the conformation and the orientation of the cations around the oxalate dianion are markedly different within the polymorphic pair, as it can be observed in Fig. 8 [OCOO−⋯OOH/COOH 2.502–2.701 and 2.50(1)–2.95(1) Å; OCOO−⋯NNH3+ 2.773(8)–2.909(8) and 2.68(1)–2.988(9) Å for forms I and II, respectively]. Fig. 9 shows how forms I and II can be easily differentiated on the basis of their X-ray powder patterns.


Hydrogen bond interactions between oxalate dianions and the surrounding serinium cations in [l-serH]2[ox]·2H2O forms I (left) and II (right); H atoms not observed in form II (powder data, see Experimental section).
Fig. 8 Hydrogen bond interactions between oxalate dianions and the surrounding serinium cations in [L-serH]2[ox]·2H2O forms I (left) and II (right); H atoms not observed in form II (powder data, see Experimental section).

Comparison of calculated XRPD patterns for [l-serH]2[ox]·2H2O form I (bottom) and form II (top).
Fig. 9 Comparison of calculated XRPD patterns for [L-serH]2[ox]·2H2O form I (bottom) and form II (top).

Crystal structure of [L-serH][Hox]

Crystalline [L-serH][Hox] can be seen as formed by an alternation of layers of hydrogen bonded hydrogen oxalate anions and layers of serinium cations, also interconnected via hydrogen bonds (N⋯O distances in the range 2.69(1)–2.974(9) Å for intra- and inter-layer hydrogen bonds), as it can be appreciated in Fig. 10a. An alternating sequence of the ABCB′ type is observed, due to the fact that the two independent cations are “segregated” within distinct layers (see Fig. 10b and c).
(a) View down the b-axis: the structure can be described as a sequence of ABCB′ layers formed alternately by serinium cations and oxalate anions bonded together by hydrogen bonds. (b) View down the a-axis – left: serinium cations belonging to layer A; right: serinium cations belonging to layer B. N⋯O and O⋯O hydrogen bonds between adjacent layers not shown for clarity.
Fig. 10 (a) View down the b-axis: the structure can be described as a sequence of ABCB′ layers formed alternately by serinium cations and oxalate anions bonded together by hydrogen bonds. (b) View down the a-axis – left: serinium cations belonging to layer A; right: serinium cations belonging to layer B. N⋯O and O⋯O hydrogen bonds between adjacent layers not shown for clarity.

It is not surprising that [L-serH]2[ox]·2H2O, both as form I and form II, converts into [L-serH][Hox] upon water loss in a heating process: if water is removed from the channels, the cationic framework becomes unstable, and the crystal “solves” the problem by eliminating also one cation as a serine molecule; the extra H-atom on the hydrogen oxalate can thus be employed to form infinite chains of anions placed side by side as to form layers, which in turn are stabilized by close interactions with the remaining serinium cations layers.

Experimental

All reagents and solvents were purchased from Sigma-Aldrich and used without further purification.

Crystallization from solution

[L-serH]2[ox]·2H2O (polymorph I) and [DL-serH]2[ox]·2H2O salts were grown by crystallization from ethanol–water solution. 0.3 mmol of oxalic acid was dissolved in demineralised water and 0.3 mmol of serine was dissolved in ethanol and then mixed. The solution was allowed to evaporate at room temperature.

Kneading and grinding experiments

[L-serH]2[ox]·2H2O form II was obtained by grinding, while form I, [L-serH][Hox] and [DL-serH]2[ox]·2H2O were obtained by kneading experiments using ethanol. For [L-serH]2[ox]·2H2O forms I and II, 0.6 mmol of L-ser and 0.3 mmol of oxalic acid were ground using a Retsch MM200 grinder mill operated at a frequency of 20 Hz for 3 hours adding a few drops of solvent. For [L-serH][Hox] salt, the same experimental setting was used by mixing serine and oxalic acid in the ratio 1[thin space (1/6-em)]:[thin space (1/6-em)]1. For the [DL-serH]2[ox]·2H2O salt, two experiments with different starting molar ratios 2[thin space (1/6-em)]:[thin space (1/6-em)]1 and 1[thin space (1/6-em)]:[thin space (1/6-em)]1 were carried out. In the 1[thin space (1/6-em)]:[thin space (1/6-em)]1 case excess oxalic acid was detected.

Single crystal structural determination of [DL-serH]2[ox]·2H2O and [L-serH]2[ox]·2H2O form I

Single crystal X-ray diffraction data were collected at room temperature using an Oxford Diffraction X'Calibur diffractometer equipped with a CCD detector. MoKα radiation (λ = 0.71073 Å) was used. SHELX9710a was used for structure solution and refinement. In the asymmetric unit of [DL-serH]2[ox]·2H2O two half oxalate ions are present, lying about independent inversion centres. Non-hydrogen atoms were refined anisotropically. Hydrogen atoms were either added at calculated positions (HC atoms) or located from a Fourier map and their positions refined. PLATON10b was used for hydrogen bonding analysis; SCHAKAL9910c and MERCURY 3.010d were used for molecular graphics, respectively. Relevant crystallographic details are listed in Table 2.

X-ray powder diffraction

X-ray powder diffractograms in the 2θ range 5–70° (step size 0.01°, time/step 50 s, V × A 40 × 40) were collected on a PANalytical X'Pert PRO automated diffractometer equipped with a X'celerator detector. The data were collected in Bragg–Brentano geometry, using Cu–Kα radiation without a monochromator. The program PowderCell11 was used for calculation of X-ray powder patterns on the basis of single crystal data. The identity between the bulk material obtained via the solution and solid-state processes was verified by comparing calculated and observed powder diffraction patterns.

Structure solutions of [L-serH]2[ox]·2H2O form II and [L-serH][Hox]

Powder diffraction data for [L-serH]2[ox]·2H2O II and [L-serH][Hox] were analyzed with the software Highscore plus. 30 peaks were chosen in the 2θ range 5–40°, and unit cell parameters were found thanks to the algorithm DICVOL.12 For [L-serH]2[ox]·2H2O II salt was found a monoclinic unit cell with a volume of 722.01(3) Å3, compatible with the presence of 4 serinium cations and 2 oxalate anions plus 4 water molecules. Space group determination with Highscore plus resulted in space group P21, with Z = 2. In the case of [L-serH][Hox] a monoclinic unit cell was found with a volume of 821.8(2) Å3, compatible with the presence of 4 serinium cations and 4 hydrogen oxalate anions. Space group determination with Highscore plus resulted in space group P21, with Z = 4. Powder data for [L-serH][Hox] showed the presence of [L-serH]2[ox]·2H2O II impurities. The two structures were solved by simulated annealing using all independent ions and molecules. Simulated annealing runs with structure fragments were performed with EXPO2010, the updated version of EXPO2009.13 All options were left as default if not specifically stated. Best solutions were chosen for Rietveld refinements. As hydrogen atoms are not observed in these two structures, salt vs. co-crystal attribution was made on the basis of similarity with the single crystal structures, given that in all cases where L-ser is involved the same acid is employed, i.e. the acid–base relative behaviour is analogous.

Structure refinements of [L-serH]2[ox]·2H2O II and [L-serH][Hox]

Rietveld refinement (see Fig. S5 and S6, ESI‡ for plots) was performed with the software GSAS.14 Rietveld analyses were conducted starting from the solution obtained by EXPO and treating the single molecules as rigid bodies. A shifted Chebyshev function with 8–10 parameters and a Pseudo-Voigt function (type 4) were used to fit background and peak shape, respectively. A spherical harmonics model was used to describe preferred orientation. Restraints (“soft” rigid body) were applied on bond distances and angles of serinium cations and oxalic acid/oxalate anions. An overall thermal parameter for each atomic species of the molecules was adopted. Refinements converged with χ2 = 3.90% and Rwp = 10.39% for [L-serH]2[ox]·2H2O form II and with χ2 = 5.95% and Rwp = 10.28% for [L-serH][Hox]. O⋯O distances along the [Hox]−⋯[Hox]− chain 2.384(9)–2.625(9) Å show very short values, partly due to the fact that the anionic chain is “compressed” by the surrounding cations, and partly to the fact that data from powder are not of excellent quality; unfortunately no hydrogen position can be observed from powder data.

Variable temperature X-ray diffraction

X-ray powder diffractograms of [L-serH]2[ox]·2H2O forms I and II in the 2θ range 5–50° were collected on a PANalytical X'Pert PRO automated diffractometer equipped with an X'Celerator detector and an Anton Paar TTK 450 system for measurements at controlled temperature. The data were collected in open air in Bragg–Brentano geometry using Cu–Kα radiation without a monochromator.

Differential scanning calorimetry (DSC)

DSC measurements were performed with a Perkin–Elmer Diamond. Samples (3–5 mg) were placed in hermetic aluminium pans. Heating was carried out at 5 °C min−1 for all salts.

Conclusions

In this paper we have shown that different routes of preparation yield different crystal forms and with different hydration extent when L-serine is reacted with oxalic acid while only the dihydrated form [DL-serH]2[ox]·2H2O has been obtained by treatment of DL-serine with oxalic acid. The dihydrated [L-serH]2[ox]·2H2O, on the other hand, has been characterized in two different polymorphic modifications in monotropic relationship. Form I has been ascertained to be the most thermodynamically stable form. Conversion to the anhydrous form [L-serH][Hox] together with molar excess of L-serine is observed on heating the crystals up on a variable temperature diffraction experiment.

The solid–solid reactions with co-crystals or between co-crystals can be used not only to produce new crystal forms with respect to conventional reactions in solution, but also to interconvert crystal forms, in a sort of supramolecular metathesis. The combined experiments suggest a scale of solid state stability, form I > form II > anhydrous DL-serine. The structures of form I of [L-serH]2[ox]·2H2O and that of [DL-serH]2[ox]·2H2O have been determined by single-crystal X-ray diffraction while those of [L-serH]2[ox]·2H2O form II and that of [L-serH][Hox] have been determined from powder diffraction data alone.

Undoubtedly the increasing capacity in determining crystal structures from good quality powder diffraction data collected on laboratory equipment is of paramount importance in tackling structural problems related to the mechanical mixing of reactants, which is, in the case of co-crystals and very recently also in the cases of ionic co-crystals,15 the most efficient way to prepare new materials with active pharmaceutical ingredients.

Acknowledgements

We acknowledge the University of Bologna and MiUR (PRIN 2008) for financial support.

Notes and references

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Footnotes

† This article is included in the All Aboard 2013 themed issue.
‡ Electronic supplementary information (ESI) available: Comparisons between experimental and calculated XRPD diffractograms, Rietveld refinement plots, DSC measurements, variable temperature XRPD diffractograms for [L-serH]2[ox]·2H2O forms I and II. CCDC 881344–881347. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c2nj40379j
§ Co-crystals of an active pharmaceutical ingredient (API) are seen as pure “API-excipient” associations, and “an API that has been processed with a co-crystallizing excipient to generate an API-excipient co-crystal may be treated as a drug product intermediate”; in contrast, “per current regulatory scheme, different salt forms of the same active moiety are considered different active ingredients” http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM281764.pdf
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