A new pseudopolymorph of berberine chloride: crystal structure and Hirshfeld surface analysis

The crystal structure of methanol solvate of berberine chloride, 9,10-dimethoxy-5,6-dihydro-2H-7λ5-[1,3]dioxolo[4,5-g]isoquinolino[3,2-a]isoquinolin-7-ylium chloride methanol monosolvate, was determined and its Hirshfeld surface analysis was performed.


Chemical context
The ability of co-crystals and polymorphs of active pharmaceutical ingredients (APIs) to change their physicochemical properties without modification of their biological activity has been pointed out in multiple publications, for instance, Shan & Zaworotko (2008), Bernstein (2002Bernstein ( , 2005 and Brittain (2009).
Currently, examples presented in the literature demonstrate that some attempts to grow co-crystals of organic compounds, including APIs, with particular coformers (additives) result in the formation of new polymorphs (Song & Cö lfen, 2011). In some cases, the combining of particular compounds with additives can increase the nucleation rate and thus lead to the development of a new crystalline form of the substance. Most likely, the additive suppressed formation of the general form, as a result of which a new polymorph begins to grow (Lee, 2014). For example, it was reported that combining different additives (trimesic acid, benzoic acid, phthalic acid, isophthalic acid, etc) with hexol (Co 4 H 42 N 12 O 18 S 3 ), allowed two different polymorphic and one new pseudopolymorphic forms of this substance to be obtained (Mehta et al., 2007).
New polymorph modifications are often obtained sporadically. For example, the second form of maleic acid was found only recently, in 2006, while the first form was reported in 1881. Interestingly, this new form was obtained during cocrystallization of maleic acid with caffeine (Day et al., 2006). Another example of this phenomenon was demonstrated by the well-known explosive 1,3,5-trinitrobenzene, which was cocrystallized with trisindane. Instead obtaining of a new cocrystal, two new polymorphs of the main compound were discovered (Thallapally et al., 2004). These examples demonstrate that sometimes applying additives to the compound of interest may lead to a new polymorph. In some cases, the polymorph modifications demonstrate improved properties compared to the previously known form of the substance. Kobayashi et al. (2000) compared the dissolution rate and bioavailability of carbamazepine dihydrate and its polymorphs. It was noted that one of the polymorphs showed a higher dissolution rate than the other species.
Berberine, a natural product belonging to the class of alkaloids, is extracted from the leaves, barks, or roots of various plants such as Coptis chinensis, Hydrastis canadensis, etc. (Babu et al., 2012). It was reported that berberine and its derivatives can be highly effective against inflammatory processes (Yeşilada & Kü peli, 2002), fungi (Silva et al., 2016), used as antioxidants (El-Wahab et al., 2013), or mutagens (Č erň á ková et al., 2002. Currently, berberine is available as a supplement. Berberine chloride (BCl) is a stable salt of berberine that is soluble in water (Battu et al., 2010). The primary goal of this study was to obtain co-crystals of berberine chloride with three different acids, glutaric, malonic, and succinic, in an attempt to increase its solubility. In addition, it was interesting to follow studies of BCl hydrates (Singh et al., 2018), demonstrating the mechanical responses of BCl single crystals on cooling and heating.

Crystallization
Berberine chloride (Alfa Aesar, lot No. R25HO28) was cocrystallized with glutaric (Alfa Aesar, lot No. D22Z032), malonic (Alfa Aesar, lot No. 10178800), and succinic (Spectrum, lot No. 1BK0179) acids. A slow evaporation technique was used for all three experiments. A molar ratio 1:1 for each pair was used; the compounds were dissolved separately in 5 mL of methanol with heating and ultrasonication. After that, those solutions were combined together and filtered. Then the three resulting solutions were left for evaporation at room temperature. After 7 days, small yellow needles were collected from the solutions with glutaric and malonic acids. The sample with succinic acid was not suitable for further characterization. The structure characterization showed that samples of BCl with glutaric and malonic acids gave two different species: one with two water molecules and another with one molecule of methanol. The obtained pseudopolymorph with two water molecules had been studied before (Kariuki & Jones, 1995). Crystals of the new BCl solvate with methanol were very fragile and dissipated very quickly in the air, most probably because of solvent loss. These crystals were used for diffraction studies with necessary precautions.

Structural commentary
Berberine chloride is a quaternary ammonium salt from the group of isoquinoline alkaloids. The berberine core ( Fig. 1) contains two almost planar aromatic fragments (N1/C1-C9 and C10-C15) with a dihedral angle of 13.91 (4) between them, which is similar to the corresponding values in other berberine cations presented in Molecular structure of the title compound with the atom labeling. Displacement ellipsoids are drawn at the 50% level.

Supramolecular features
The berberine cations in the structure of the title compound are not involved in the formation of any hydrogen bonds. The only short contact that might be considered as a specific interaction is the contact of Cl À with the methanol hydrogen atom H5A [2.23 (2) Å ]. This distance is quite close to the value of 2.079 Å that was presented in the review by Ková cs & Varga (2006). Details of the hydrogen-bond geometry are given in Table 2. In the crystal, the berberine cations form stacks along the a-axis direction. The neighboring cations within the stack are related by inversion (Fig. 2). The interplanar distance (only core atoms were included in plane calculation) to the cation related by the symmetry operation Àx + 1, Ày + 1, Àz + 1 is shorter than that to the other cation related by Àx + 2, Ày + 1, Àz + 1, being 3.564 (2) and 3.498 (2) Å , respectively. In general, the crystal packing can be described as 'stacks that are built of dimers'.

Database survey
A search of the Cambridge Structural Database (CSD version 5.42, last update November 2020; Groom et al., 2016) demonstrated the significant interest in berberine salts. The structure of BCl dihydrate has been determined three times [XUNFES (Tong et al., 2010); XUNFES01 (Singh et al., 2018); XUNFES02 (Fronczek, 2019)] with almost equal precision. The structure of BCl tetrahydrate has been determined twice [YUJHAM (Kariuki & Jones, 1995); YUJHAM01 (Singh et al., 2018)]. To the best of our knowledge, the only nonsolvated berberine salt to be characterized is the iodine derivative (YUJHUG; Kariuki & Jones, 1995). In addition, BCl ethanol solvate (YUJHIU; Kariuki & Jones, 1995), as well as berberine iodide monohydrate (KUZSAA; Grundt et al., 2010), bromide dihydrate (YUJHOA; Kariuki & Jones, 1995), and sulfate heptahydrate (YUJJAO; Kariuki & Jones, 1995) should be mentioned. The very interesting type of behavior exhibited by the BCl dihydrate and tetrahydrate at different temperatures was described by Singh et al. (2018). Depending on the chosen conditions, the crystals demonstrated unexpected mechanical responses: bending, cracking, and jumping. The explanation for these thermo-mechanical properties was linked to the presence of destabilizing interactions between the water molecules.
To estimate the similarities and differences between the crystal structures of pseudopolymorphs of BCl, we compared the hydrogen bonding and molecular packing for the four solvates presented in Table 1. All of the berberine cations in these structures are arranged in stacks, the space group for all compounds except for the dihydrate is P1; for the dihydrate, the space group is C2/c. The stacks are formed of the very similar dimers shown in Fig. 2. Table 1 demonstrates that the cations in stacks are situated in such a way that the distances between the mean planes (only core atoms were included in plane calculations) of the cations vary by ca 0.2 Å . The distances between the centroids of the aromatic rings characterizing the molecular slippage show more diversity than the interplanar distances.
As in the title structure, the water molecules in the dihydrate and in the ethanol solvate do not form hydrogen bonds with the berberine cation, but make short contacts with the Cl À anion. However, in the crystal structure of the tetrahydrate, one of the water molecules forms a bifurcated hydrogen bond with the berberine cation.

Hirshfeld surface analysis
The Hirshfeld surface analysis was performed using Crystal Explorer (Wolff et al., 2012). According to the Hirshfeld surface presented in Fig. 3 Table 2 Hydrogen-bond geometry (Å , ).

Figure 2
The dimers of berberine cations in the pseudopolymorphs with (a) two water molecules, (b) four water molecules, (c) one molecule of ethanol and 0.5 molecules of water, and (d) one methanol molecule (see text for references).
contacts are found for the hydrogen atoms attached to the nitrogen-containing C1-N1-C17 fragment. Fig. 4 gives the fingerprint plots for all the pseudopolymorphs presented in Table 1. There are 15 different types of interactions in these crystals between five elements -H, C, N, Cl, and O -from which 60 fingerprint plots can be generated. 20 plots for which the interactions contribute above 2% to the Hirshfeld surface are presented in Fig. 4. In spite of the different number and nature of the solvate/hydrate molecules in the pseudopolymorphs presented, the fingerprint plots allow generalization of the impact of the intermolecular interactions in these structures. In all structures, the HÁ Á ÁH contacts provide the largest contributions (44.0-48.3%). The presence of HÁ Á ÁO/OÁ Á ÁH interactions, corresponding to interactions between the solvate molecules, is also important (15.2-23.8%). The next highest contribution is by interactions involving the Cl À anion (8.6-13.6%). The fingerprint plot for the methanol solvate is different from the others since there are no water molecules in this structure, and no hydrogen bonds between the solvent and berberine cation. Hirshfeld surface for the berberine cation in the title structure plotted over d norm in the range À0.1877 to 1.1413 a.u.

Figure 4
The two-dimensional fingerprint plots for pseudopolymorphs of BCl with (a) two water molecules, (b) four water molecules, (c) one molecule of ethanol and 0.5 molecules of water, and (d) one methanol molecule.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 3. The O-bound H atom was refined freely. All other H atoms were positioned geometrically (C-H = 0.95, 0.98 and 0.98 Å for sp 2 -hybridized, methyl and methylene C atoms, respectively) and refined using a riding model, with U iso (H) = 1.5U eq (C) and 1.2U eq (C) for methyl and other H atoms, respectively.  Data collection: APEX2 (Bruker, 2016); cell refinement: SAINT (Bruker, 2016); data reduction: SAINT (Bruker, 2016); program(s) used to solve structure: SHELXT2014/5 (Sheldrick, 2015a); program(s) used to refine structure:

9,10-Dimethoxy-5,6-dihydro-2H-7λ 5 -[1,3]dioxolo[4,5-g]isoquinolino[3,2-a]isoquinolin-7-ylium chloride methanol monosolvate
Crystal data 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.