A structural comparison of salt forms of dopamine with the structures of other phenylethylamines

In four new dopamine salts, the dopamine cation adopts an extended conformation. Intermolecular interaction motifs that are common in the salt forms of tyramine can be found in related dopamine structures, but hydrogen bonding in the dopamine structures appear to be more variable and less predictable than for tyramine.


Introduction
The generation of salt forms of an active pharmaceutical ingredient (API) is a well-known process used by the pharmaceutical industry to change important material properties of the API.Idealizing properties such as solubility, stability or hygroscopicity is important to the development of an effective and commercially successful API (Stahl & Wermuth, 2008).It is generally accepted that there are links between the solidstate structure and the material properties of interest, and that a greater understanding of such structure-to-property correlations should help to rationalize salt screening and other form-choice processes.
Phenylethylamine (PEA) compounds (Scheme 1) have long been known to have a large variety of pharmaceutical and biological roles (e.g. Brown et al., 1979;Drew et al., 1978;Broadley, 2010;Dennany et al., 2015).Due to their favourable handling characteristics, several have been used in studies where relatively large numbers of salt forms of a given API have been crystallographically characterized and the structures then used to systematically investigate material properties.The earliest examples of this are the studies by Davey investigating the structures and crystal properties of pseudoephedrine salts forms and their relationships to solubility (Black et al., 2007;Collier et al., 2006).A problem with similar studies using large numbers of crystal structures is how to simply compare and contrast multiple structures.One solution to this are the packing similarity tools available within Mercury (Taylor & Wood, 2019;Childs et al., 2009;Macrae et al., 2020).In the area of PEA salt forms, these tools have been used to investigate hydrate formation in tyramine salt forms (Briggs et al., 2012), and density and melting point in pairs of enantiopure and racemic methylephedrine salt forms (Kennedy et al., 2011).An intriguing result using this approach was that groups of methylephedrine salt forms that showed isostructural cation packing also showed tighter correlation between aqueous solubility and melting point than did similar salt forms that were not part of isostructural packing groups (de Moraes et al., 2017).Dopamine is a biologically significant member of the PEA family and arguably the most well known.In the brain it is a neurotransmitter and it is known to play a role in a wide range of human bodily functions, including motor control, motivation, gastrointestinal tract function and operation of the immune system.It is well known that loss of the ability to secrete dopamine leads to Parkinson's disease (e.g.Wenzel et al., 2015;Schultz, 2007).Perhaps less well known is that dopamine in the form of its HCl salt is used as an API, for instance, in the treatment of neonatal shock (Noori et al., 2003).Some crystallographic work has been undertaken on forms of dopamine.Dopamine itself has been shown to exist in the solid as a zwitterionic form, with deprotonation of the OH group meta to the ethylamine substituent (Cruickshank et al., 2013).The structures of some simple salt forms of dopamine are also know.These include forms with inorganic anions [the halides DOPAMN01, QQQAEJ02 and ATOLUR04 (Giesecke, 1980;Pike & Dziura, 2013;Ivanova & Spiteller, 2017); the nitrate CIZYAN (Gatfaoui et al., 2014); and the perchlorate OGE-GAJ (Boghaei et al., 2008)] and four forms with small to medium sized organic anions (ATOLIF, ATOMAY, RAWDEB and MIYLOV; Ivanova & Spiteller, 2010;Feng et al., 2017;Ohba & Ito, 2002).This gives a total of ten relevant literature structures available from the Cambridge Structural Database (CSD, Version 5.43, update of November 2022, Groom et al., 2016).
To this data set we herein add the structures of the benzoate, 4-nitrobenzoate, ethanedisulfonate and 4-hydroxybenzenesulfonate salt forms of dopamine.The new structures are described and a comparative analysis of the packing of dopamine and its salt forms, and those of the closely related PEA species tyramine is presented.

Synthesis and crystallization
Dopamine hydrochloride was purchased from Sigma-Aldrich.Because of the well-known rapid oxidation of dopamine under basic conditions (Richter & Waddell, 1983), the HCl salt was converted to neutral dopamine under an N 2 atmosphere and in a Schlenk tube.This was done by addition of NaOH to ice-cooled aqueous solutions of dopamine HCl.Dopamine free base precipitated in 51-59% yield after 2 h.The white solid was separated by filtration and stored under N 2 before use.Salt forms I to IV were prepared by adding dopamine (0.2 g) and an equimolar amount of the appropriate acid to degassed water (5 ml).The mixtures were stirred and heated under N 2 to 313 K before being filtered to leave clear solutions.These solutions were left to evaporate slowly.Crystals suitable for single-crystal diffraction were obtained directly from these solutions within one week.For both I and II, crystals of the salt form grew alongside a small number of crystals of the parent benzoic acid.

Refinement
The anion of IV was found to be disordered, with the benzene ring rotated by approximately 52 � around an axis that runs through atoms S1, C9, C12 and O6.Thus, four aromatic C-H groups were each modelled as split over two sites with occupancies refined to a 50:50 ratio.No further restraints or constraints were required to satisfactorily model these disordered atoms.For I, II and III, all H atoms bonded to O or N atoms were positioned as found by difference synthesis and refined freely and isotropically.For IV, restraints on the O-H bond lengths were required and they were set to 0.88 (1) A ˚.For I to IV, H atoms bound to C atoms were placed in idealized positions and refined in riding modes.C-H bond lengths of 0.95 and 0.99 A ˚were used for CH and CH 2 groups, respectively, and U iso (H) values were set at 1.2U eq (C) of the parent atom.Further crystallographic details and refinement parameters are given in Table 1.

Results and discussion
The structures of I-IV are shown in Figs.1-4, with crystallographic parameters detailed in Table 1 and hydrogenbonding parameters detailed in Tables 2-5.The asymmetric units of both I and II consist of a dopamine cation and a (substituted) benzoate anion.The asymmetric unit of III consists of a dopamine cation and half of an ethanedisulfonate dianion.Here the dianion has a crystallographic centre of symmetry in the middle of its C-C bond.Finally, IV is a monohydrate and so the asymmetric unit consists of a dopa-mine cation, a disordered hydroxybenzenesulfonate anion and a water molecule.In all four cases, the dopamine moiety has been protonated at the amine group and the H atom of the meta-hydroxy substituent is orientated towards the O atom of the para-hydroxy group to form an intramolecular hydrogen bond.All of the ethylammonium chains adopt extended conformations, with the N1-C1-C2-C3 torsion angles ranging from À 168.89 (14) to 176.39 (16) � .This corresponds to an anti arrangement of the large aromatic and NH 3 substituents on the C1-C2 fragment.The relevant literature salt forms as listed in Table 6 also adopt extended conformations, with the exception of the dinitrobenzoate salt MIYLOV.This is the only form to have a folded conformation, displaying an N-C-C-C torsion angle of 60.5 � (Ohba & Ito, 2002).This distribution of conformations resembles that found for the salt forms of the closely related tyramine cation.Of 42 tyramine salt forms, the majority displayed extended confor-   (Rigaku OD, 2019), SIR92 (Altomare et al., 1994), SHELXS (Sheldrick, 2015a), SHELXL2018 (Sheldrick, 2015b), Mercury (Macrae et al., 2020) and SHELXL in WinGX (Farrugia, 2012).

Figure 1
View of the asymmetric unit contents of I, with non-H atoms shown as 50% probability displacement ellipsoids.Here and in Figs.2-4, H atoms are drawn as spheres of arbitrary size.

Figure 2
View of the asymmetric unit contents of II, with non-H atoms shown as 50% probability displacement ellipsoids.
mations and only four displayed a folded conformation (Briggs et al., 2012).
The dopamine cations of I-IV utilize all three NH groups and both OH groups as hydrogen-bond donors, but apart from that, there is little similarity between them and in detail each acts in a different manner.As shown in Table 7, in benzoate I all potential donors make a single hydrogen bond to an O atom of a benzoate COO group.Here, none of the atoms of the cation acts as an acceptor and hydrogen bonds exist only between cations and anions.In II, the number of potential hydrogen-bond acceptors is increased by the inclusion of an NO 2 group on the anion.This leads to the cation making extra donor interactions, with one NH group and the para-OH group both acting as bifurcated donors to two hydrogen bonds.Again, no atom of the cation acts as an acceptor and all hydrogen bonds are formed between cations and anions.In III, all five cation donor groups make single hydrogen bonds, but in contrast to I and II, the para-OH group also acts as an acceptor, accepting a hydrogen-bond contact from a neighbouring RNH 3 group.Thus, in III, there are hydrogen bonds both between cations and anions, and between pairs of cations.In the hydrate IV, one of the NH groups makes a bifurcated donor interaction with two neighbouring SO 3 groups and all other cation donor atoms make single hydrogen bonds.That from the para-OH group donates to a water molecule, but all others are to anions.The para-OH group also accepts a hydrogen bond from a water molecule.In IV, hydrogen bonds link cations to anions, and both cations and anions to water.However, unlike III, there are no cation-to-cation hydrogenbond contacts.
A large-scale structural study on tyramine salt forms identified two common hydrogen-bonding motifs that co-existed in 19 of 24 benzoate and sulfonate salts of that compound (Briggs et al., 2012).These motifs were both one-dimensional (1D) chain structures, one of graph set C 2 2 (6) corresponding to an (� � �OXO� � �HNH� � �) n (X = C or S) linkage and one of graph set C 2 2 (13) corresponding to COO or SO 3 groups bonding to both the NH 3 head and the para-OH tail of the cation.Here only structures I and III show both motifs.They also have an additional C 2 2 (12) motif.This latter is equivalent    98 (3)  1.87 (4)  2.834 (3)  167 (3)  N1-H2N� � �O3  0.95 (3)  1.93 (3)  2.867 (3)  171 (3)  N1-H3N� � �O3 iv  0.87 (4)  2.04 (4)  2.866 (3)  156 (3) Symmetry codes: to the C2 2 (13) motif, but utilizes the extra meta-OH group of dopamine rather than the para-OH group which is common to both dopamine and tyramine.Figs. 5 and 6 illustrate these hydrogen-bonded-chain features.Structure IV contains both the C 2 2 (6) and the C 2 2 (12) motifs, but the para-OH group of this hydrate only hydrogen bonds to water molecules and thus the C 2 2 (13) motif does not occur here.In contrast, of the three motifs described above, the nitrobenzoate salt II only displays the C 2 2 (13) chain.In the hydrogen bonding of structure II, ring motifs become prevalent, including that formed by a tetramer consisting of two cations and two anions.These are linked by hydrogen bonding between the catechol moieties and the carboxylate groups in an R 4 4 ( 18) motif.This coplanar tetramer is then capped on each side of the plane through hydrogen bonds to the RNH 3 groups of two further cations, as shown in Fig. 7.

Figure 5
Part of the 1D C 2 2 (6) motif found in III.The hydrogen-bonded chain propagates parallel to the a direction.

Figure 6
An illustration showing the repeating core of the C 2 molecule sites.Thus, before analysis, these H atoms were also added in geometrically reasonable expected positions.All further discussion of the hydrogen bonding of these three compounds thus refers to the edited structures.Atomic structures for these edited structures are given in CIF format in the supporting information.
When examining all 13 available salt forms of dopamine in Table 7, it becomes apparent that the hydrogen-bonding behaviour of the cation is very variable.Of 14 crystallographically independent dopamine fragments, only two, those of the chloride DOPAMN01 and the bromide QQQEAJ01, have the same set of interactions originating from the dopamine cation.Furthermore, none of the literature carboxylate or sulfonate structures feature the combination of C 2 2 (6) and C 2 2 (13) chains that is found to be prevalent in tyramine salt forms (Briggs et al., 2012).The halide salt forms of dopamine (Cl, Br and I) do though present the C 1 2 (4), C 1 2 (11) and C 1 2 (10) chains that are the monoatomic ion equivalent of the three motifs discussed above for COO-and SO 3 -based ions.Finally, it is noted that the ladder-like structures commonly seen for other carboxylate salt forms of RNH 3 + species (Kinbara et al., 1996) are found for neither dopamine salt forms nor for tyramine salt forms.
In an attempt to find further comparable features across the structural group, use was made of the 'crystal packing similarity' module within Mercury (Macrae et al., 2020;Childs et al., 2009).This was used to investigate similarity in the cation packing across the available dopamine forms by investigating

Table 7
Selected hydrogen-bonding features in the structures of salt forms of dopamine.
The table shows the various potential acceptor (A) and donor (D) groups of the dopamine cation (first row) and details the types of fragment that form hydrogen bonds with these groups (body of table ).geometrical similarity between small clusters of dopamine cations.In doing so other species present, such as anions and solvent molecules, were ignored.An initial calculation using only the dopamine structures identified that the chloride and bromide salts of dopamine were isostructural at a cluster size of 15 cations, and that the iodide and perchlorate salt forms were similarly isostructural (Figs. 9 and 10).For the Cl/Br pair, the reported unit cells and space groups clearly indicate that the complete structures are both isostructural and isomorphous (Giesecke, 1980;Pike & Dziura, 2013).However, there is no such similarity in the unit cells of the I/ClO 4 pair (Ivanova & Spiteller, 2017;Boghaei et al., 2008).More interesting results were obtained when the packing similarity module was applied to a data set that included both the available dopamine forms and those of tyramine.This time six groups of structures with similar cation packing arrays at the level of a 15 from 15 match were identified (Table 8).Group 1 contains only the dopamine I/ClO 4 pair as already seen, and groups 4, 5 and 6 contain only tyramine structures.However, groups 2 and 3 are interesting as they contain both dopamine and tyramine structures.Group 2 contains I, the benzoate salt of dopamine, and both the 4-amino-and 4-methylbenzoate salt forms of tyramine.Group 3 is an expanded version of the dopamine Cl/Br grouping that now also contains III, the ethanedisulfonate salt of dopamine, and six forms of tyramine.These are the chloride, bromide, perchlorate, BF 4 and dihydrogen phosphate salts of tyramine, and also the neutral hemihydrate of tyramine.(Note: when assessing dopamine structures alone, the ethanedisulfonate structure III was found to be related to the Cl/Br group, but only at a level with 7 from 15 matches.However, the larger and more varied dopamine/tyramine group appears to allow a fuller match.)Each group of Table 8 is composed of structures with broadly similar anion types.Thus, for example, group 2 contains only structures with benzoate or para-benzoate anions, and group 3 is composed of species with simple inorganic anions or coformers.Beyond this basic similarity though lies a great deal of variation.For example, group 3 encompasses structures with different cations, with different anions, with and without solvent present, and with neutral PEA species rather than charged ones, see Fig. 11 as an example.

CSD refcode Anion para-OH D para-OH A meta-OH D meta-OH
This, of course, leads to very different hydrogen bonding throughout the structures of these compounds.From a chemical identity point of view, the two most different structures of group 3 are the ethanedisulfonate salt of dopamine, III, and the hemihydrate of tyramine, TIRZEB (Cruickshank et al., 2013).The ethanedisulfonate dianion does not fit well with the descriptor used above of a 'simple inorganic anion' being as it is both larger than the other anions in this group and doubly charged.This is reconciled simply.The ethanedisulfonate ion lies upon a crystallographic centre of symmetry, thus making the unique repeating structural part the much smaller 'O 3 SCH 2 ' fragment which is a reasonable match to a 'simple inorganic anion'.The ethanedisulfonate anion takes the structural place of two anions in other group  member structures, such as that of dopamine chloride, DOPAMN01.The intramolecular S� � �S separation of 4.338 A in III compares well with the intermolecular Cl� � �Cl distance of 4.303 A ˚in the chloride.Tyramine hemihydrate, TIRZEB, is an interesting structure.Disorder of the phenol H-atom positions in this structure means that the tyramine fragments present are best thought of as a mix of neutral, cationic and zwitterionic forms of tyramine (Cruickshank et al., 2013).This presents some difference to the cationic PEA forms that make up the rest of group 3. Water is obviously a neutral coformer rather than the small anions found in the rest of group 3, but a further difference is stoichiometry.There is only one water molecule per two tyramine fragments in TIRZEB, as opposed to one monoanionic fragment per organic cation in all the other structures of group 3. Despite all this variation in chemical identity and in the type and number of the strong hydrogen-bonding intermolecular interactions, the cations of these groups still adopt similar packing arrangements.Conversely, similarities in hydrogen bonding do not necessarily seem to lead to similarity in cation packing.One of the few patterns in the hydrogen-bonding behaviour of the dopamine salts is that all three halides have structures based around the same chain-type interactions (see above).Despite this hydrogen-bonding similarity, only the Cl and Br salt forms are found in group 3, with the iodide salt grouping with the perchlorate in group 1.A similar observation that PEA cation packing was not governed by hydrogen-bond formation, though one from a data set that did not feature different cations, was made in a study on methylephedrine salt forms (Kennedy et al., 2011).In a related point, Collier et al. (2006) noted that it was simply the gross amphiphilic nature of the ephedrine cation that dominated packing in structures of its salt forms, rather than the detail of the functional groups or individual interaction types.For all structures, data collection: CrysAlis PRO (Rigaku OD, 2019); cell refinement: CrysAlis PRO (Rigaku OD, 2019); data reduction: CrysAlis PRO (Rigaku OD, 2019).Program(s) used to solve structure: SIR92 (Altomare et al., 1994) for (I); SHELXS (Sheldrick, 2015a) for (II), (III), (IV).For all structures, program(s) used to refine structure: SHELXL2018 (Sheldrick, 2015b); molecular graphics: Mercury (Macrae et al., 2020).Software used to prepare material for publication: (Farrugia, 2012) for (I), (II); SHELXL in WinGX (Farrugia, 2012) for (III), (IV).

Special details
Geometry.All esds (except the esd in the dihedral angle between two l.s.planes) are estimated using the full covariance matrix.The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry.An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s.planes.Refinement.All measurements were made with Oxford Diffraction instruments using Crysalis PRO software for data collection and reduction (Rigaku OD, 2019).Solution was by direct methods, SIR92 or SHELXS (Altomare et al., 1994;Sheldrick, 2015a).All structures were refined to convergence against F 2 using all unique reflections and the program SHELXL2018 as implemented within WinGX (Sheldrick, 2015b;Farrugia, 2012).Hydrogen-bond geometry (Å, º)

Special details
Geometry.All esds (except the esd in the dihedral angle between two l.s.planes) are estimated using the full covariance matrix.The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry.An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s.planes.Refinement.All measurements were made with Oxford Diffraction instruments using Crysalis PRO software for data collection and reduction (Rigaku OD, 2019).Solution was by direct methods, SIR92 or SHELXS (Altomare et al., 1994;Sheldrick, 2015a).All structures were refined to convergence against F 2 using all unique reflections and the program SHELXL2018 as implemented within WinGX (Sheldrick, 2015b;Farrugia, 2012 Refinement.All measurements were made with Oxford Diffraction instruments using Crysalis PRO software for data collection and reduction (Rigaku OD, 2019).Solution was by direct methods, SIR92 or SHELXS (Altomare et al., 1994;Sheldrick, 2015a).All structures were refined to convergence against F 2 using all unique reflections and the program SHELXL2018 as implemented within WinGX (Sheldrick, 2015b;Farrugia, 2012).
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å

Figure 3
Figure 3View of the asymmetric unit contents of III, extended to show the complete dianion generated by the inversion centre in the C-C bond.Non-H atoms are shown as 50% probability displacement ellipsoids.

Figure 4
Figure 4View of the asymmetric unit contents of IV, with disorder of atoms C10, C11, C13 and C14 hidden for clarity.Non-H atoms are shown as 50% probability displacement ellipsoids.

Figure 7 A
Figure 7A central hydrogen-bonding motif in II consisting of four coplanar groups linked via the catechol and carboxylate groups.This unit is capped top and bottom by hydrogen bonds to the RNH 3 group of the cation.

Figure 8 (
Figure8(a) The structure of ATOMAY as recovered from the CSD.Note the unusual out-of-plane geometry of the H atoms of the OH substituents.These out-of-plane H atoms do not form hydrogen bonds with neighbouring ions.(b) The structure of ATOMAY edited so as to place H atoms in-plane and in geometries that maximize hydrogen bonding.

Figure 9
Figure 9Overlay diagram showing the packing of 15 dopamine cations of the chloride structure (multicoloured) and 15 dopamine cations of the bromide structure (green).The r.m.s.value is 0.210 A ˚. Anions have been omitted for clarity.

Figure 10
Figure 10Overlay diagram showing the packing of 15 dopamine cations of the perchlorate structure (multicoloured) and 15 dopamine cations of the iodide structure (green).The r.m.s.value is 0.451 A ˚. Anions have been omitted for clarity.

Figure 11
Figure 11Overlay diagram showing the packing of 15 dopamine cations of the chloride structure (green) and 15 tyramine units of the hemihydrate structure.The r.m.s.value is 0.566 A ˚. Anions and water molecules have been omitted for clarity.

Table 1
Rigaku OD, 2019)ails.For all structures: Z = 4. Experiments were carried out at 123 K. Absorption was corrected for by multi-scan methods (CrysAlis PRO;Rigaku OD, 2019).H atoms were treated by a mixture of independent and constrained refinement.

Table 6
Available crystal structures of dopamine forms.

Table 8
Groups identified as having isostructural packing of cations. ).