Crystal structure of rac-4-[2-(tert-butylazaniumyl)-1-hydroxyethyl]-2-(hydroxymethyl)phenol benzoate

The title salt forms a racemate due to disorder of the hydroxy group [occupancy ratio 0.738 (3):0.262 (3)] at the stereogenic C atom.


Chemical context
Salbutamol {systematic name: 4-[2-(tert-butylamino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol} is known as a shortaction selective 2-adrenergic receptor agonist for the treatment of pulmonary diseases, including asthma attacks, exercise-induced bronchoconstriction and chronic obstructive pulmonary disease (Saleh et al., 2000). However, salbutamol shows poor solubility in aqueous solution, which limits its bioavailability. The production of salt forms is a usual approach to alter the physicochemical properties of pharmaceutical compounds (Surov et al., 2015). Salbutamol has been widely studied and some salts of salbutamol have been on the market, such as salbutamol sulfate.
We selected various acids and combined them with salbutamol and then investigated the properties of new salt forms. Salbutamol benzoate was found to dissolve and crystallize in water, and it might show different in vitro solubility and dissolution properties. In this work, we report on the crystal structure determination of the title molecular salt salbutamol benzoate, C 13 H 22 NO 3 ISSN 2056-9890

Structural commentary
The asymmetric unit of the title compound is shown in Fig. 1. The molecule of salbutamol (SAL) accepts one proton at the N1 atom from the benzoic acid (BA) and thus forms a 1:1 salt, SAL + BA À . The bond lengths of the carboxylate group of the BA À anion, C20-O4 and C20-O5, are 1.2617 (15) and 1.2604 (15) Å , respectively. The slight difference may be caused by the role of O4 as an acceptor atom of the O3-H3Á Á ÁO4 hydrogen bond with one of the hydroxy groups of SAL + . The SAL + cation also has an intramolecular hydrogen bond between the two hydroxy functions (O1-H1Á Á ÁO3), forming an S(6) ring motif ( Fig. 1 and Table 1). The BA À anion is not planar, indicated by the dihedral angle between the benzene ring and the carboxyl group of 11.30 (8) . There is some disorder at the stereogenic centre (C8) of the SAL + cation, but the space group is centrosymmetric and the SAL + cation is racemic.

Database survey
Six structures containing salbutamol were found in a search of the Cambridge Structural Database (Version 5.38; Groom et al., 2016). The structure of salbutamol was reported by Beale & Grainger (1972). Salbutamol sulfate was the first salt of salbutamol to be structurally determined some years later (Leger et al., 1978). Recently, a new salbutamol sulfate polymorph crystallizing in a different space group (C2/c) was determined (Xie et al., 2010). Paluch et al. (2011) investigated the co-crystal of a salbutamol hemiadipate salt with adipic acid and also the salbutamol hemisuccinate salt. Moreover, an oxaprozin-salbutamol salt was also reported (Aitipamula et al., 2016).

Synthesis and crystallization
Salbutamol (0.479 g, 2 mmol) and benzoic acid (0.244 g, 2 mmol) were added to 10 ml methanol and stirred for 3 h. The crystal packing of the title compound, viewed perpendicular to the bc plane. N-HÁ Á ÁO and O-HÁ Á ÁO hydrogen bonds are shown as dashed lines (Table 1 gives the numerical details). Both disorder components of the OH group are shown.

D-HÁ
salbutamol benzoate. After recrystallization from water, pure crystals were again dissolved in ethanol and the solution filtered. The neat filtrate was evaporated slowly to give colourless block-like single crystals of salbutamol benzoate.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. The hydroxy group at C8 is disordered over two sets of sites, with refined site occupancies of 0.738:0.262. H atoms were constrained to an ideal geometry, with C-H distances in the range 0.93-0.97 Å , and allowed to ride, with U iso (H) = 1.5U eq (C) for methyl H atoms and U iso (H) = 1.2U eq (C) for all other H atoms. The H atoms of the NH 2 group and the hydroxy group (except for O1-H1, which was refined freely) were also constrained to ideal values and allowed to ride in the refinement, with U iso (H) = 1.2U eq (N) and 1.5U eq (O).

Figure 3
The crystal packing of the title compound, viewed perpendicular to the ab plane. N-HÁ Á ÁO and O-HÁ Á ÁO hydrogen bonds are shown as dashed lines (Table 1 gives the numerical details).