Synthesis and structure of a 1:1 co-crystal of hexamethylenetetramine carboxyborane and acetaminophen

Acetaminophen assists as a co-former in the crystallization of hexamethylenetetramine carboacetaminophenborane, which may otherwise be challenging to form a crystal itself.


Chemical context
Crystal structures of pure drugs are of great interest in the pharmaceutical industry since these structures provide an understanding of the intermolecular interactions that explain the physical and chemical properties of the solid (Desiraju, 2007). Modifications made to the active pharmaceutical ingredients to enhance the biological availability often include crystal engineering. For instance, the recrystallization of acetaminophen, C 8 H 9 NO 2 (also known as paracetamol), gives crystal form II, which displays better solubility and compressibility than form I (Naumov et al., 1998;Agnew et al., 2016). Another approach that has been brought into attention is using crystal formers or co-formers to improve the physicochemical characteristics of the solids. Recent developments in co-crystallization show potential advantages of drug-coformer co-crystals as well as drug-drug co-crystals (Kaur et al., 2017;Cheney et al., 2011;Nugrahani et al., 2007;Dalpiaz et al., 2018).
A group of organo-boron compounds, namely amine carboxyboranes, have been studied extensively for their diverse biological effects such as anti-inflammatory, antineoplastic and anti-osteoporotic activities (Hall et al., 1995(Hall et al., , 1990Murphy et al., 1996). Their fundamental structure contains tetravalent amines connected to a boron atom of the carboxyborane moiety with an N-B coordinate covalent bond (Spielvogel et al., 1976). As a result of the ease of structural transformability, this group is very amenable to modification such as exchanging various amine groups and esterification on the carboxyborate. Our interest in amine carboxyboranes stemmed from their innate structure that undergoes decarbonylation to produce CO, H 2 , and the amine group when placed in aqueous solution. We have shown amine ISSN 2056-9890 carboxyboranes to be a group of molecules that can be used as carbon monoxide releasers (Ayudhya et al., 2017). Moreover, we have recently reported that this process is accelerated by reactive oxygen species (ROS) increasing the rate at which CO and the amine group is released (Ayudhya et al., 2018). Considering the amine compounds are drug molecules, carboxyboranes can be used as a system to deliver drugs that contain amino groups. Since we started our endeavor with drug-conjugated carboxyboranes (Ayudhya et al., 2018), we speculated that carboxyboranes may be able to carry more than one drug. In addition to the amine group on the boron atom, ester and amide derivatives at the carboxyborate end have been shown previously (Das et al., 1990).
As part of this work, we now describe the crystal structure of the title co-crystal, C 15 H 22 BN 5 O 3 ÁC 8 H 9 NO 2 , (I), which resulted from the synthetic concept that conjugating two different pharmacophores to the carboxyborate moiety may make a molecule that has multiple biological effects.

Structural commentary
The asymmetric unit of the resulting monoclinic crystal (space group P2 1 /c) contains one C 15 H 22 BN 5 O 3 ester (CORCB-1-APAP) and one C 8 H 9 NO 2 acetaminophen molecule (Fig. 1). The hexamethylenetetraamine (hmta) moiety of the ester is syn to the C9 O3 carboxy carbonyl group and the aromatic C3-C8 ring is approximately perpendicular to the plane of the B1/C9/O2/O3 ester carboxylate group [dihedral angle = 76.89 (9) ] while the C1/C2/N1/O1 acetylamino group is twisted out of plane of the ring by 65.42 (9) ; the dihedral angle between the pendant groups is 11.70 (10) .
Based on the observed geometry, we may assume that the bonding in this difunctionalized carboxyborate is very similar to that in the previously reported crystal structure of C 7 H 15 BN 4 O 2 or CORCB-1 [Ayudhya et al., 2017;Cambridge Structural Database (Groom et al., 2016) refcode UDAQOI]. The only significant difference is in the slightly longer C9-O2 single bond, 1.399 (2) Å in the difunctionalized title compound compared to 1.353 (3) Å in CORCB-1. This lengthening is expected to be due to the weak ester bond, which is confirmed by rapid hydrolysis. There are only small differences in B-N and B-C bond lengths between the two materials with some lengthening seen in the difunctionalized compound. In the co-crystallized acetaminophen molecule in (I), the dihedral angle between the C18-C23 benzene ring and the acetylamino C16/C17/N6/O5 grouping is 54.61 (10) .

Supramolecular features
During crystallization, the new difunctionalized molecule, CORCB-1-APAP, forms a co-crystal with acetaminophen at a 1:1 ratio with hydrogen-bonding interactions (Table 1) between them (Figs. 2 and 3). In comparison to the CORCB-1 crystal reported previously, which features hydrogen bonds between the amino and carboxylic acid groups (Ayudhya et al., 2017) The molecular structure of (I) with displacement ellipsoids drawn at the 50% probability level.
CORCB-1 region due to the replacement of carboxylic acid with an ester functional group. As a result, a co-crystal former such as acetaminophen is needed for crystal formation to provide stable hydrogen bonds: with acetaminophen molecules flanking CORCB-1-APAP; no interactions are observed between these difunctionalized compounds. The cocrystal shows three classical hydrogen bonds. The first is an N6-H6NÁ Á ÁO1 hydrogen bond (HÁ Á ÁO = 2.00 Å ) found between the N-H group of acetaminophen and the C=O acceptor from CORCB-1-APAP. This type of bond has been previously reported in the acetaminophen co-crystal with citric acid (Elbagerma et al., 2011). Pure acetaminophen crystals typically only form hydrogen bonds between N-HÁ Á ÁO-H and O-HÁ Á ÁO=C. The second interaction N1-H1NÁ Á ÁO4-H4O is between CORCB-1-APAP and another acetaminophen molecule. The bond length (2.18 Å ) of this hydrogen bond is similar to the N-HÁ Á ÁO-H bond (2.09 Å ) from the known acetaminophen crystal form II (Agnew et al., 2016;Thomas et al., 2011). The third hydrogen bond does not involve CORCB-1-APAP: it is exclusively formed between two acetaminophen molecules and this O4-H4OÁ Á ÁO5 C17 bond (1.85 Å ) is identical in length to that of acetaminophen crystal form II (1.85 Å ). Several weak C-HÁ Á ÁO hydrogen bonds may help to consolidate the structure.
A molecular packing projection of (I) is shown in Fig. 4 for clear representation of each pair of CORCB-1-APAP and its co-former, acetaminophen. As noted, the observed hydrogenbond lengths in this co-crystal are similar to those from acetaminophen form II packing while the overall packing looks similar to form I (Naumov et al., 1998  Detail of the packing of (I) showing hydrogen bonds (yellow lines) between the components of the co-crystal. Three acetaminophen molecules are shown but only the two on the left are hydrogen bonded with CORCB-1-APAP. The third acetaminophen molecule, which accepts a hydrogen bond from the second, is oriented in the same way as the first and repeats the pattern.    (2)  130 Symmetry codes: (i) x; Ày þ 3 2 ; z þ 1 2 ; (ii) x; Ày þ 1 2 ; z À 1 2 ; (iii) Àx þ 1; y À 1 2 ; Àz þ 3 2 ; (iv) Àx þ 1; Ày þ 1; Àz þ 1.

Figure 2
Unit cell packing of (I) viewed down the c-axis direction, with additional molecules added along the b-axis direction. Acetaminophen molecules are green; hydrogen bonds are shown as dashed yellow lines.

Synthesis and crystallization
The synthesis of amine carboxyborane derivatives such as methyl ester of various amine carboxyborates have been described previously. Several esterification methods of amine carboxyboranes with alcohols include using DCC to make 98% yield (Spielvogel et al., 1986) and using a catalytic amount of hydrogen bromide, which provides nearly quantitative yields (Gyo ri et al., 1995). In our process, esterification is completed before the amine exchange reaction and not vice versa. The synthesis of hexamethylenetetramine carboacetaminophenborane (CORCB-1-APAP) involves several steps using trimethylamine carboxyborane (CORCB-3) as the starting material. Trimethylamine carboxyborane, synthesized by the previously reported method (Spielvogel et al., 1976) is first esterified at the carboxyborate moiety with acetaminophen (APAP). The esterification was carried out in a mixed solvent system of chloroform and THF (1:1) at 313 to 318 K for five days and the crude product was purified by a series of recrystallizations. CORCB-1-APAP and acetaminophen cocrystals for X-ray data collection were grown in mixed solvents of hexane/chloroform using the solution crystallization method.

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.