A new high-pressure benzocaine polymorph — towards understanding the molecular aggregation in crystals of an important active pharmaceutical ingredient (API)

Patyk-Kaźmierczak, E.; Kaźmierczak, M.

doi:10.1107/S2052520619016548

research papers

STRUCTURAL SCIENCE
CRYSTAL ENGINEERING
MATERIALS

ISSN: 2052-5206

Volume 76| Part 1| February 2020| Pages 56-64

https://doi.org/10.1107/S2052520619016548

A new high-pressure benzocaine polymorph — towards understanding the molecular aggregation in crystals of an important active pharmaceutical ingredient (API)

Ewa Patyk-Kaźmierczak ^a ^* and Michał Kaźmierczak ^a ^*

^aFaculty of Chemistry, Adam Mickiewicz University in Poznań, Uniwersytetu Poznańskiego 8, Poznań, 61-614, Poland
^*Correspondence e-mail: ewapatyk@amu.edu.pl, kax@amu.edu.pl

Edited by J. Lipkowski, Polish Academy of Sciences, Poland (Received 20 September 2019; accepted 8 December 2019; online 16 January 2020)

Benzocaine (BZC), an efficient and highly permeable anaesthetic and an active pharmaceutical ingredient of many commercially available drugs, was studied under high pressure up to 0.78 GPa. As a result, new BZC polymorph (IV) was discovered. The crystallization of polymorph (IV) can be initiated by heating crystals of polymorph (I) at a pressure of at least 0.45 GPa or by their compression to 0.60 GPa. However, no phase transition from polymorph (I) to (IV) was observed. Although polymorph (IV) exhibits the same main aggregation motif as in previously reported BZC polymorphs (I)–(III), i.e. a hydrogen-bonded ribbon, its molecular packing and hydrogen-bonding pattern differ considerably. The N—H⋯N hydrogen bonds joining parallel BZC ribbons in crystals at ambient pressure are eliminated in polymorph (IV), and BZC ribbons become positioned at an angle of about 80°. Unfortunately, crystals of polymorph (IV) were not preserved on pressure release, and depending on the decompression protocol they transformed into polymorph (II) or (I).

Keywords: benzocaine; high-pressure polymorphism; data-mining; hydrogen bonds.

CCDC references: 1949574; 1949575; 1949576; 1949577; 1949578; 1949579; 1949580; 1949581

1. Introduction

Benzocaine (BZC), 4-aminobenzoic acid ethyl ester, is a local anaesthetic almost exclusively administered topically. Its pain-relief action is associated with BZC molecules binding to the phenylalanine residue in Na⁺ neuron channels via N—H⋯π and π⋯π interactions, preventing the transmission of impulses at nerve endings and along nerve fibres (Butterworth & Strichartz, 1990 ; Hanck et al., 2009 ; Aguado et al., 2013 ). BZC is an active pharmaceutical ingredient (API) of 583 over-the-counter drugs, commercially available in the USA and Canada, in the form of gels (402), liquids (63), swabs (25), creams (20), ointments (15), sprays (15), etc. (Law et al., 2014 ). It belongs to class II of the Biopharmaceutical Classification System (Amidon et al., 1995 ; Mehta, 2017 ) and as such has high permeability (1.11 × 10⁻⁴ cm s⁻¹; Juni et al., 1977 ) and low water solubility (0.131 mg ml⁻¹ in 30°C; Bottari et al., 1977 ). Therefore, in a similar way to other bioactive compounds from class II, BZC bioavailability is limited by its solubility.

The solubility of all compounds strongly depends on the hydrogen-bonding pattern formed in a solid state. Therefore, analysis of intermolecular interactions present in solid forms of APIs is an important aspect of drug development (Gao et al., 2017 ). Such insight not only enables a better understanding of the physicochemical properties of APIs, but also provides information about the hierarchy of supramolecular synthons, which is essential for the design of novel cocrystals of biologically active compounds (Bis et al., 2007 ; Shattock et al., 2008 ; Cheney et al., 2010 ; Bučar et al., 2014 ). This crystal engineering approach to the modification of intermolecular interactions by incorporation of coformer molecules allows for the fine-tuning of the properties of the final drug product, such as solubility (Smith et al., 2011 ; Geng et al., 2013 ) and stability (Gadade & Pekamwar, 2016 ). Even slight changes in the hydrogen-bonding pattern supporting the crystal structure, as observed between polymorphs, can result in varied properties of different solid forms of the same compound (Braga et al., 2009 ). In fact, it was recently reported that polymorphs (I)–(III) of BZC differ in solubility and permeability (Paczkowska et al., 2018 ). Until now three polymorphs of BZC were known. At ambient conditions, BZC exists in two forms: monoclinic polymorph (I) (space group P2₁/c, Lynch & McClenaghan, 2002 ) and orthorhombic polymorph (II) (space group P2₁2₁2₁; Sinha & Pattabhi, 1987 ). On cooling to 150 K, polymorph (II) undergoes a solid-to-solid phase transition to polymorph (III) of monoclinic symmetry, space group P112₁ (Chan et al., 2009 ). Depending on the milling protocol, polymorph (III) can transform to polymorph (I) (ball milling) or polymorph (II) (micro milling; Paczkowska et al., 2018). In all reported forms of BZC, molecules are hydrogen-bonded via N—H⋯O hydrogen bonds into ribbons, and a similar positioning of so-formed ribbons in respect to each other is observed.

Investigation of polymorphism is an important stage of drug development. It provides information on the stability of the solid forms of the API that can affect the properties of the final product (Lee, 2014 ). It is also an important legal matter, as each polymorph is considered a new material by the US Food and Drug Administration (FDA, 2007 ) and as such a patent-eligible subject matter. However, the search for polymorphs is often limited to varied-temperature conditions at ambient pressure and modification of solvent systems. Meanwhile, the application of high pressure for polymorph screening can significantly broaden the spectrum of experimental conditions, leading to the discovery of new crystal forms (Fabbiani et al., 2004 , 2007 ; Fabbiani & Pulham, 2006 ; Boldyreva, 2007 , 2016 ; Johnstone et al., 2010 ; Patyk & Katrusiak, 2015 ; Patyk et al., 2015a ,b , 2016 ; Marciniak et al., 2016a ,b ; Zakharov et al., 2016 ; Zakharov & Boldyreva, 2019 ). Previous research showed that pressure can provide a sufficiently strong stimulus to enforce phase transitions in compounds considered to exist only in one crystal form (e.g. sucrose; Patyk et al., 2012 ), or to allow access to theoretically predicted metastable phases (Neumann et al., 2015 ). In this work, a study of high-pressure polymorphism of BZC is presented and its new polymorph (IV) is introduced. Results are complemented with analysis and comparison of the crystal structure of polymorph (IV) with the three previously reported crystal forms.

2. Experimental

2.1. High-pressure crystallization and X-ray measurements

In all experiments, as-received benzocaine from Sigma-Aldrich was used. The powder X-ray diffraction (PXRD) confirmed that the received sample was a mixture of polymorphs (I) and (II) (Fig. S1). A small number of crystals of BZC, alongside small ruby chip, were loaded into an opening (0.4–0.5 mm diameter) in steel gasket (0.3 mm thick) mounted in modified Merrill–Bassett diamond anvil cell (DAC; Merrill & Bassett, 1974 ). For the experiments two types of BZC-saturated hydrostatic medium were used: 97.5% DMSO solution in water and MeOH:EtOH:H₂O mixture (16:3:1 volume). After loading, the pressure inside the DAC was gradually increased up to 0.78 GPa. The sample was recrystallized in situ (Figs. S3–S6, S8–S10) at each step before X-ray diffraction measurement (except for the measurement at 0.65 GPa, where the sample was obtained after releasing pressure from 0.78 GPa, Fig. S7). The pressure inside the DAC was measured by the ruby fluorescence method (Piermarini et al., 1975 ) with a Photon Control Inc. spectrometer affording a 0.02 GPa accuracy. Two series of experiments in the different hydrostatic medium were performed: (i) when DMSO was used as hydrostatic medium, crystals were grown and measured at 0.22 (2), 0.41 (2), 0.50 (2), 0.52 (2) GPa (the measurement at 0.22 GPa was used only for unit-cell parameters measurement due to the insufficient quality of the collected data), and (ii) when MeOH:EtOH:H₂O was used at 0.10 (2), 0.30 (2), 0.55 (2), 0.65 (2) and 0.78 (2) GPa. The X-ray diffraction experiments were performed with Mo Kα graphite-monochromated radiation and the four-circle Xcalibur diffractometer equipped in the EOS CCD detector. The CrysAlis PRO software (2015 $[Rigaku Oxford Diffraction (2015). CrysAlis PRO. Rigaku Oxford Diffraction, Yarnton, England.]$ ) was used for data collection, determination of the UB-matrix, absorption corrections and data reduction. The crystal structures were solved by intrinsic phasing with SHELXT (Sheldrick, 2015a ) and refined by least-squares with program SHELXL (Sheldrick, 2015b ). The positions of hydrogen atoms were determined based on hybridization of carrier atoms with U_iso equal to 1.2U_eq for aromatic and secondary C carriers, as well as N carriers, and equal to 1.5U_eq for primary C carriers. The length of N—H and C—hydrogen bonds was fixed to the distances of 0.93 Å for aromatic carbon atoms, 0.96 or 0.97 Å for primary and secondary carbon atoms, respectively, and 0.87 Å for nitrogen atoms. All crystal structures have been deposited with the Cambridge Crystallographic Data Centre (Groom et al., 2016 ; CCDC Nos. 1949574–1949581). Copies of the data can be accessed, free of charge, by filling online the application form at https://www.ccdc.cam.ac.uk/structures/. Selected crystallographic data for polymorphs (I) and (IV) at 0.10 and 0.55 GPa, respectively, alongside data for polymorphs (II) and (III), are listed in Table 1. Detailed crystallographic data for BZC polymorphs are presented in the supporting information (Table S1).

Table 1
Crystallographic data for BZC polymorphs

For full version of the table please refer to Table S1.

Phase	(I)	(II)†	(III)†	(IV)
T (K)	298	300	150	298
p (GPa)	0.10	0.0001	0.0001	0.55
Crystal system	Monoclinic	Orthorhombic	Monoclinic	Monoclinic
Space group	P2₁/c	P2₁2₁2₁	P112₁	P2₁/c
a, b, c (Å)	8.193 (1), 5.454 (1), 20.07 (5)	8.2424 (4), 5.3111 (3), 20.904 (1)	8.1883 (4), 10.640 (1), 20.476 (1)	6.305 (1), 5.1839 (4), 24.94 (8)
α, β, γ (°)	90, 91.47 (4), 90	90, 90, 90	90, 90, 99.370 (2)	90, 96.25 (8), 90
Unit-cell volume (Å³)	896 (2)	915.12 (9)	1760.05 (15)	810 (3)
Z, Z′	4, 1	4, 1	8, 4	4, 1
D_x (g cm⁻³)	1.224	1.199	1.247	1.354
R₁, wR₂ [I > 4σ(I)], GooF	0.0610, 0.1485, 1.000	0.0392, 0.1035, 1.059	0.065, 0.091, 2.103	0.0910, 0.2073, 1.157

†Crystallographic data cited after Chan et al. (2009

), structure refcodes: polymorph (II)-QQQAXG05; polymorph (III)-QQQAXG03.

In order to establish pressure limits for the crystallization of BZC polymorphs, a visual observation of its crystal compressed in the DAC was performed (Figs. S11 and S12). The pressure of 0.60 (2) GPa was the lowest at which initiation of the crystallization was observed (Fig. S12, Movie S1). During the growth of the new crystal, the dissolution of primary crystal was observed. The recrystallization was completed at pressure of 0.48 (2) GPa and the single-crystal X-ray diffraction (SCXRD) method was used to determine the lattice parameters.

Stability of new BZC polymorph was investigated by visual observation, on the pressure release at various rates: (i) slowly, followed by 40-days delay in DAC opening (Figs. S13 and S14); (ii) rapidly, followed by immediate DAC opening. In both cases, recovered samples were studied via SCXRD and/or PXRD techniques (Fig. S2).

2.2. Structural analysis

The Cambridge Structural Database (CSD version 5.40; May 2019; Groom et al., 2016) and DrugBank (version 5.1.3; April, 2nd 2019; Law et al., 2014) has been data-mined for structures of esters of p-aminobenzoic acid (PABA) and its derivatives using ConQuest (Bruno et al., 2002 ) and CSD Python API (here: Application Programming Interface). The following restrictions have been used for the CSD survey: (i) 3D coordinates determined; (ii) one chemical unit in the entry; (iii) disordered, ionic and metal–organic structures have been excluded. Search in the DrugBank was limited to entries marked as approved. In both cases of data mining, compounds containing nitrile, hydroxyl, aldehyde, and carbonyl (except ester) groups were omitted. Moreover, depositions with more than one ester or primary amine group, or lactone ring were excluded from statistical analysis. Additionally, the CSD has been surveyed for primary amine⋯ester synthons.

The D—H⋯A intermolecular hydrogen bonds were assigned using following criteria: (i) the distance between hydrogen and acceptor atoms must be smaller than the sum of van der Waals radii of involved atoms (Bondi, 1964 ); (ii) hydrogen atoms must be directed towards acceptor atoms.

Enthalpies of formation were calculated for crystals of polymorphs (I) and (IV) (in the whole investigated pressure range) using MOPAC2016:Hamiltonian PM7 (Stewart, 2016 ).

3. Results and discussion

We have shown that during recrystallization under the pressure of up to 0.41 GPa, polymorph (I) is a preferred form of BZC. Even if BZC crystals were dissolved entirely, on cooling, the crystals of polymorph (I) emerged. Above 0.45 GPa, on recrystallization via heating and subsequent cooling, BZC crystallizes in a new form, polymorph (IV), of monoclinic symmetry, space group P2₁/c, and it exists up to 0.78 GPa at least. Polymorph (IV) can be also obtained isothermally by increasing pressure to 0.60 GPa. Above this pressure, polymorph (I) crystals gradually dissolve and growth of polymorph (IV) crystals can be observed (Movie S1). After completion of the crystallization, the pressure was stabilized at 0.48 GPa, and polymorph (IV) crystals remained stable. Only when pressure is released, crystals of polymorph (IV) undergo a destructive phase transition to polymorph (II), observed visually and confirmed by PXRD measurement of the sample immediately recovered from the DAC (Fig. S2). Interestingly, when pressure was released slowly to 0.2 GPa and left for 40 days, recrystallization of sample to polymorph (I) occurred. The current state of knowledge on the relationship between four BZC polymorphs was mapped in Scheme 1. Methods for ambient-pressure crystallization of polymorphs (I)–(III) are cited after previous reports (Sinha & Pattabhi, 1987; Lynch & McClenaghan, 2002; Chan et al., 2009; Paczkowska et al., 2018).

Although newly obtained polymorph (IV) crystallizes in the same space group as polymorph (I), the behaviour of their crystals on compression differ. The unit-cell volume of polymorph (I) decreases of 46 Å³ (approx. 5% of the ambient-conditions one) in the span of 0.40 GPa. Meanwhile, the decrease of only 12 Å³ (1.5%) is noted for polymorph (IV), when pressure is increased from 0.50 to 0.78 GPa. The difference in susceptibility of crystals to compression is also reflected in the unit-cell volume compressibility (β_V). Initially, β_V is more than twice as high for polymorph (I) than for (IV). However, polymorph (I) crystals lose their softness with increasing pressure, as showed by the decrease in β_V value, but up to 0.41 GPa, they remain softer than crystals of polymorph (IV) [β_V = 0.70 GPa⁻¹ for polymorph (I) at 0.41 GPa, compared to β_V = 0.55 GPa⁻¹ for polymorph (IV) at 0.50 GPa]. It can be expected that on compression of polymorph (I) crystals above 0.41 GPa its compressibility β_V will decrease further, eventually becoming lower than for polymorph (IV). The decrease of β_V reflects the inability of molecular packing to adapt, resulting in increased structural strain. This, in turn, moves crystallization preference toward the new high-pressure polymorph (IV), of compressibility β_V hardly affected by the pressure in the range of 0.50–0.78 GPa [Fig. 1(a)]. Although compression of crystals of polymorph (I) to 0.60 GPa increases the strain, no phase transition was observed, and crystallization of polymorph (IV) was initiated instead. Similar cases, where polymorph formation required recrystallization, were described previously. Polymorphs formed during in situ high-pressure recrystallization that cannot be obtained as a result of solid-state phase transition were even termed hidden, as they can be easily missed when only the compression of sample crystals is performed (Paliwoda, 2012 ; Anioła & Katrusiak, 2015 ; Sobczak & Katrusiak, 2017 ).

Figure 1
The pressure dependence of (a) unit-cell volume, molecular volume, and compressibility, as well as, (b) unit-cell parameters for BZC polymorphs (I) (circles) and (IV) (triangles). Unit-cell parameters for BZC polymorphs (II) (at 300 K, squares) and (III) (at 150 K, diamonds) have been included for comparison. Unit-cell volume and parameter b for polymorph (III) have been divided by two. High-pressure data collected for sample in MeOH:EtOH:H₂O 16:3:1 volume hydrostatic medium is marked with full symbols, while open symbols mark data collected with the use of DMSO as a hydrostatic medium. Trend lines were extended beyond data points as dashed lines to mark pressure regions where the form of BZC crystals was preserved on compression [polymorph (I)] or decompression [polymorph (IV)].

Interestingly, crystals of both polymorphs, (I) and (IV), were found to compress anisotropically, with initial linear compressibility higher for directions [b] and [c] than for [a] (β_b, β_c and β_a, respectively). For polymorph (I), parameters β_b and β_c decrease with pressure, similarly to β_V, while β_a increases. As a result direction [a] becomes softer than [b] above 0.28 GPa, and equates with [c] at 0.41 GPa. Meanwhile, in polymorph (IV), linear compressibility of crystal in directions [a], [b] and [c] is affected in a lesser way, with an only slight decrease of β_b, and an increase of β_a and β_c observed in 0.50–0.78 pressure range.

The preference for the compression in [010] and [001] directions can be correlated with molecular aggregation in BZC crystals. It is worth noting that the primary aggregation motif of BZC molecules (N—H⋯O bonded ribbon) is common for all four polymorphs. For polymorphs (I)–(III) ribbons are positioned in a similar way (Fig. 2), all propagating parallel and antiparallel to the [100] direction. Only polymorph (IV) exhibits different positioning of ribbons in respect to each other, with every two parallel ribbons fitted on side of ethylene residue in a chainsaw mode, and then inclined in respect to the next adjacent ribbons at ca 80°. Therefore, two directions of parallel and antiparallel propagation can be distinguished: [ $[\bar 1\bar 10]]$ and [ $[1\bar 10]]$ .

Figure 2
Molecular packing for four benzocaine polymorphs shown along with selected crystallographic directions. The ribbons are distinguished by different colours. Packing for polymorphs (I)–(III) are shown for previously reported structures (Chan et al., 2009

): QQQAXG04 [polymorph (I)], QQQAXG05 [polymorph (II)] and QQQAXG03 [polymorph (III)].

In polymorph (I), hydrogen-bonded ribbons are either stacked or create a herringbone arrangement in the direction [010] and are stacked or positioned in a zigzag mode in the direction [001] (Fig. 2). It leaves a void space between ribbons that can be gradually eliminated when pressure is increased, making the crystal initially softer in [010] and [001] directions. However, as the volume of the voids is reduced and hydrogen-bonded ribbons are forced to become closer, steric hindrance and repulsive interactions become more meaningful, hindering further compression. Meanwhile, the ribbon propagation direction coincides with direction [100]. Due to the molecules in the ribbon being already close to each other, as a result of short hydrogen bonds formation, [100] is initially the hardest direction in the crystal. Nevertheless, the approach of the molecules within ribbons coincides with favourable shortening of hydrogen bonds, hence increase of the linear compressibility in [100] direction can be observed.

In polymorph (IV), the directions of ribbons propagation are interdependent with directions [100] and [010]. Because the linear compression along the ribbon axis is limited (due to the proximity of BZC molecules within ribbons), linear compression of crystals of polymorph (IV) in directions [100] and [010] is restricted, making direction [001] the softest. However, the inclined orientation of ribbons provides more compact packing compared to polymorphs (I)–(III). Therefore, a smaller void space that can be clenched on pressure increase is available. As a result, crystals of polymorph (IV) show lower compressibility in respect to polymorph (I).

The supramolecular heterosynthon (primary amine⋯ester synthon) formed in crystals of BZC coincide with the preference shown in crystal structures of compounds structurally similar to it reported so far. The CSD survey revealed that such synthon is formed in > 96% of structures in the absence of other oxygen or nitrogen atoms. The investigated group contains 60 depositions. In 51, moieties are connected by NH⋯O=C contacts, in four by NH⋯O—C, and in three structures both types of contacts are observed.

Similar to BZC, its analogous compounds show the tendency to form N—H⋯O contacts between primary amine and carboxyl atom of ester group leading to the creation of ribbon motif. In fact, this is the most common motif (60%) in crystal structures of esters of 4-aminobenzoic acid and its derivatives reported so far (including all BZC polymorphs). Further analysis showed that ribbons can be distinguished into three variations (Fig. S15). Most commonly molecules arrange in the flat [BZC polymorphs (I)–(IV)] or step-like [polymorph (III)] way. However, if substituents are present in the meta position of the aromatic ring of the benzoic acid, ribbons can become twisted due to the steric and/or electrostatic effects (e.g. BIZFIA, HOCJAM; Xie et al., 2014 ). Moreover, in most of the deposited structures, including BZC polymorphs (I)–(III), there is a tendency for ribbons to propagate in only one direction. Although the ribbon is the most common motif, there are seven deposits exemplifying alternative N—H⋯O bonded molecular arrangement: (i) five where molecules are forming tetramers; (ii) one exemplifying 2D net; (iii) one with zig-zag chain motif (Fig. S15). Intriguingly, methyl 4-aminobenzoate, structurally very close to BZC, is so far the only ester of 4-aminobenzoic acid with two solid forms reported, each one exemplifying different aggregation motif: ribbon (CEBGUL01) and tetramer (CEBGUL; Lin, 1983 ), both shown in Fig. S15. It is surprising that despite the molecular similarity of BZC, the tetramer motif occurred in none of its known polymorphs.

Due to the way molecules are oriented to form the of N—H⋯O hydrogen bonds, the ribbon motif can be additionally supported by C—H⋯O contacts, formed by an aromatic hydrogen atom (in ortho position in respect to the amine group) and carbonyl of the adjacent BZC molecule. However, despite adequate molecular orientation, in case of polymorphs (I) and (II), aromatic hydrogen atoms and carbonyl groups of neighbouring molecules are too far apart, and no such contact can be distinguished. Only when crystals of polymorph (I) are compressed in the DAC, molecules approach each other and the distance between hydrogen and oxygen atoms decrease leading to the formation of the C—H⋯O contact (Figs. 3 and S16, and Table S3). Such hydrogen-bond is also present in polymorphs (III) and (IV), but its formation can be explained in terms of thermal contraction [polymorph (III)] or compression [polymorph (IV)]. Interestingly, in polymorph (IV), the geometry of both, N—H⋯O hydrogen bond and C—H⋯O contact, becomes less favourable, as showed by them becoming longer than in polymorph (I) at the pressure of 0.41 GPa (Fig. 3).

Figure 3
The pressure dependence of: (a) D⋯A and (b) H⋯A distances for N—H⋯O, N—H⋯N and C—H⋯O contacts in crystals of BZC polymorphs (I) (circles) and (IV) (triangles), shown in red, blue and green, respectively. The sums of van der Waals radii are shown with dotted lines in corresponding colours. Data for samples obtained from MeOH:EtOH:H₂O 16:3:1 volume solution are marked with full symbols, while open symbols mark data collected using DMSO. The ORTEP symmetry codes (Farrugia, 2012

) are explained in Table S2. Data points at 0.1 MPa were calculated based on the previously reported structure, refcode QQQAXG04 (Chan et al., 2009

Alongside N—H⋯O hydrogen bonds, and occasional C—H⋯O contacts connecting BZC molecules into ribbons, we can distinguish additional contacts between ribbons. The major cohesion force connecting ribbons in polymorphs (I)–(III) are N—H⋯N hydrogen bonds, additionally supported by C—H⋯π interactions. The reorientation of ribbons in polymorph (IV) prevents the formation of any N—H⋯N contacts (Figs. 3, 4 and S16, and Table S3), making weak C—H⋯π interactions the major cohesion force bonding BZC ribbons together (Fig. S17 and Table S4).

Figure 4
Intermolecular distance between nitrogen–nitrogen (blue) and hydrogen–nitrogen (red) atoms in N—H⋯N hydrogen bonds in all four BZC polymorphs. The sums of van der Waals radii are shown with dotted lines in corresponding colours. Due to the Z′ = 4 for polymorph (III), values for three symmetry-independent N—H⋯N hydrogen bonds were included. Distances for polymorphs (I)–(III) are shown for previously reported structures (Chan et al., 2009

): QQQAXG04 [polymorph (I)], QQQAXG05 [polymorph (II)] and QQQAXG03 [polymorph (III)].

The distortion of the hydrogen-bonding pattern in polymorph (IV) can be observed in the comparison of Full Interaction Maps (FIMs; Wood et al., 2013 ). Polymorph (I) clearly fulfils the desired interactions to a higher extent than polymorph (IV), with all regions of preferred geometry for intermolecular contacts coinciding with the positioning of acceptor and donor groups of adjacent molecules (Fig. 5). However, in case of interacting amine groups, the primary amine donor and acceptor groups lay on the borderlines of the propensity regions. In polymorph (IV) only the regions within hydrogen-bonded ribbon are fulfilled, and two propensity regions in proximity of BZC amine group remain vacant, with amine groups of adjacent molecules visibly beyond them. Interestingly, the FIMs are used to investigate the propensity of a given compound to polymorphism based on the fulfilment of the interaction landscape in the known crystal forms (Wood et al., 2013). Therefore, polymorphs exhibiting hydrogen-bonding pattern of more preferred geometry than that observed in the ambient-condition BZC polymorph (I), should be expected. Instead, crystallization in the form of the polymorph (IV) leads to weakening of the hydrogen bonds between hydrogen-bonded BZC ribbons, leaving interaction landscape unfulfilled.

Figure 5
Full interaction maps (FIMs) calculated with programme Mercury (Bruno et al., 2002

; Wood et al., 2013

) for BZC polymorphs (I) and (IV) at 0.10 and 0.55 GPa, respectively. The propensity regions of preferred geometry for the position of carbonyl H-acceptors and amine H-donors/acceptors are shown in red and blue, respectively. Hydrogen bonds are shown in cyan.

The precise comparison of the significance of different types of contacts in supporting the crystal structure can be assessed from the overlap of their van der Waals radii. The overlap can be expressed as δ parameter:

$[\delta = r_{\rm AB} - {\rm vdW}_{\rm A} - {\rm vdW}_{\rm B}, \eqno(1)]$

where r_AB is the distance between atoms A and B, and vdW_A and vdW_B are their van der Waals radii (Kaźmierczak & Katrusiak, 2013 , 2014 , 2015 ).

When all contacts in crystal structures of BZC polymorphs (I) and (IV) are analysed in terms of their δ parameter, N—H⋯O hydrogen bond is the contact with the smallest δ value in both cases, even despite it becoming slightly longer in polymorph (IV) (Fig. 6). This is in agreement with the previously reported analysis of the shortest contacts hierarchy in crystals of compounds manifesting high-pressure polymorphism, showing that the nature of the shortest contact, relative to the sum of van der Waals radii, remains unchanged (Kaźmierczak & Katrusiak, 2015). At the same time, a significant rearrangement in contacts of larger δ value can be observed (Kaźmierczak & Katrusiak, 2015; Marciniak et al., 2016a), and such tendency is present in BZC (Fig. 6). Notably, the N—H⋯N hydrogen bond is the contact with the second smallest δ value in BZC polymorph (I) up to 0.41 GPa, while in polymorph (IV) it is not even the tenth contacts with the smallest δ value.

Figure 6
The short contacts sorted by increasing value of δ parameter in the function of pressure. The dotted line divides polymorphs (I) and (IV). Analysis of ambient-condition structure was performed using previously reported data (CSD refcode: QQQAXG09; Patel et al., 2017

). Where required, the positions of hydrogen atoms were normalized to C—H = 1.083 Å, N—H = 1.009 Å (Groom et al., 2016

Besides the more favourable hydrogen-bonding pattern, the enthalpy of formation also gives an indication that BZC polymorph (I) is thermodynamically more stable than polymorph (IV) (Fig. 7), with the energy calculated for unit cells of each form differing of about −15 kJ mol⁻¹. Such difference might originate from the reduction and attenuation of contacts supporting crystal structure, especially the elimination of N—H⋯N hydrogen bonds. In these terms, it would appear that preference for crystallization of BZC polymorph (IV) is kinetically driven, and can be associated with achieving more dense packing under high pressure.

Figure 7
Enthalpy of formation of high-pressure structures of polymorphs (I) (blue) and (IV) (red). Data for samples obtained from MeOH:EtOH:H₂O 16:3:1 volume solution are marked with full symbols, while open symbols mark data collected with the use of DMSO.

4. Conclusions

A new, high-pressure benzocaine polymorph (IV) has been discovered above 0.45 GPa, and it can be obtained either by isochoric or isothermal crystallization. The molecules of BZC in polymorph (IV) form N—H⋯O bonded ribbons similar to those found in the polymorphs (I)–(III). It shows that even increased pressure was not able to enforce a change of the major aggregation motif of BZC molecules. Nevertheless, the respective orientation of ribbons in the newly obtained crystal form was altered: hydrogen-bonded ribbons propagate parallel and antiparallel to only one direction, [100], in polymorphs (I)–(III), and to two distinctive directions, [ $[\bar 1\bar 10]]$ and [ $[1\bar 10]]$ , in polymorph (IV). Despite the fact that the shortest contact, i.e. N—H⋯O hydrogen bond, is preserved above 0.45 GPa, a significant change in the hierarchy of longer contacts can be observed. The most prominent change concerns N—H⋯N hydrogen bonds. Those bonds are the major cohesion force connecting ribbons in polymorphs (I)–(III), but they are eliminated in high-pressure polymorph (IV). Impairment of the hydrogen-bonding pattern is reflected in enthalpy of formation, that is about 15 kJ mol⁻¹ higher for polymorph (IV) than for polymorph (I), indicating its lower thermodynamic stability. This suggests that crystallization of polymorph (IV) is kinetically driven and it can be associated with achieving more dense packing under high pressure. Unfortunately, crystals of polymorph (IV) are not preserved on pressure release. On rapid decompression to ambient pressure, transformation to polymorph (II) occurs. However, if the sample remains in DAC after pressure decreases below 0.2 GPa, over the time BZC recrystallizes in the form of polymorph (I).

5. Related literature

References cited in the supporting information include: Arunan et al. (2011 ), Brandl et al. (2001 ), Katrusiak (2003 ).

Supporting information

CCDC references: 1949574; 1949575; 1949576; 1949577; 1949578; 1949579; 1949580; 1949581

Crystal structure: contains datablocks global, BZC_a1, BZC_a2, BZC_a3, BZC_a4, BZC_a5, BZC_b1, BZC_b2, BZC_b3. DOI: https://doi.org/10.1107/S2052520619016548/lo5062sup1.cif

Movie recording of sample recrystallisation on compression in diamond-anvil cell. DOI: https://doi.org/10.1107/S2052520619016548/lo5062sup2.wmv

Structure factors: contains datablock BZC_a1. DOI: https://doi.org/10.1107/S2052520619016548/lo5062BZC_a1sup3.hkl

Structure factors: contains datablock BZC_a2. DOI: https://doi.org/10.1107/S2052520619016548/lo5062BZC_a2sup4.hkl

Structure factors: contains datablock BZC_a3. DOI: https://doi.org/10.1107/S2052520619016548/lo5062BZC_a3sup5.hkl

Structure factors: contains datablock BZC_a4. DOI: https://doi.org/10.1107/S2052520619016548/lo5062BZC_a4sup6.hkl

Structure factors: contains datablock BZC_a5. DOI: https://doi.org/10.1107/S2052520619016548/lo5062BZC_a5sup7.hkl

Structure factors: contains datablock BZC_b1. DOI: https://doi.org/10.1107/S2052520619016548/lo5062BZC_b1sup8.hkl

Structure factors: contains datablock BZC_b2. DOI: https://doi.org/10.1107/S2052520619016548/lo5062BZC_b2sup9.hkl

Structure factors: contains datablock BZC_b3. DOI: https://doi.org/10.1107/S2052520619016548/lo5062BZC_b3sup10.hkl

Supporting information file. DOI: https://doi.org/10.1107/S2052520619016548/lo5062sup11.pdf

Computing details top

For all structures, data collection: CrysAlis PRO 1.171.38.41 (Rigaku OD, 2015); cell refinement: CrysAlis PRO 1.171.38.41 (Rigaku OD, 2015); data reduction: CrysAlis PRO 1.171.38.41 (Rigaku OD, 2015). Program(s) used to solve structure: SHELXS (Sheldrick, 2008) for BZC_a1, BZC_a3, BZC_b3; ShelXT (Sheldrick, 2015) for BZC_a2, BZC_a4, BZC_a5, BZC_b1, BZC_b2. For all structures, program(s) used to refine structure: SHELXL (Sheldrick, 2015); molecular graphics: Olex2 (Dolomanov et al., 2009); software used to prepare material for publication: Olex2 (Dolomanov et al., 2009).

4-aminobenzoic acid ethyl ester (BZC_a1) top

Crystal data top

C₉H₁₁NO₂	F(000) = 352
M_r = 165.19	D_x = 1.224 Mg m⁻³
Monoclinic, P2₁/c	Mo Kα radiation, λ = 0.71073 Å
a = 8.1928 (6) Å	Cell parameters from 592 reflections
b = 5.4539 (5) Å	θ = 4.5–21.5°
c = 20.07 (5) Å	µ = 0.09 mm⁻¹
β = 91.47 (4)°	T = 295 K
V = 896 (2) Å³	Needle, colourless
Z = 4	0.43 × 0.1 × 0.1 mm

Data collection top

Xcalibur, Eos diffractometer	238 reflections with I > 2σ(I)
Radiation source: fine-focus sealed X-ray tube, Enhance (Mo) X-ray Source	R_int = 0.099
Graphite monochromator	θ_max = 27.0°, θ_min = 3.9°
Detector resolution: 16.2413 pixels mm^-1	h = −10→10
ω and φ scans	k = −6→6
442 measured reflections	l = −4→4
442 independent reflections

Refinement top

Refinement on F²	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Hydrogen site location: mixed
R[F² > 2σ(F²)] = 0.061	H-atom parameters constrained
wR(F²) = 0.168	w = 1/[σ²(F_o²) + (0.1127P)²] where P = (F_o² + 2F_c²)/3
S = 0.96	(Δ/σ)_max < 0.001
442 reflections	Δρ_max = 0.09 e Å⁻³
100 parameters	Δρ_min = −0.07 e Å⁻³
123 restraints

Special details top

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. Refined as a 2-component twin.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
O1	0.2304 (6)	0.4101 (11)	0.1336 (12)	0.090 (19)
N1	0.9728 (8)	0.1430 (11)	0.2044 (11)	0.07 (3)
H1A	1.0542	0.1890	0.1786	0.086*
H1B	0.9737	−0.0196	0.2046	0.086*
C4	0.5209 (5)	0.4076 (11)	0.1421 (8)	0.091 (19)
C3	0.6626 (7)	0.5269 (10)	0.1235 (8)	0.096 (19)
H3	0.6559	0.6666	0.0970	0.115*
C2	0.8142 (5)	0.4375 (12)	0.1446 (8)	0.098 (19)
H2	0.9090	0.5174	0.1322	0.118*
C1	0.8241 (6)	0.2288 (11)	0.1842 (8)	0.095 (19)
C6	0.6824 (9)	0.1094 (10)	0.2028 (8)	0.096 (19)
H6	0.6891	−0.0303	0.2293	0.115*
C5	0.5308 (6)	0.1988 (12)	0.1817 (8)	0.102 (19)
H5	0.4361	0.1189	0.1942	0.122*
C7	0.3627 (11)	0.4953 (15)	0.1216 (12)	0.076 (18)
O2	0.3664 (7)	0.6853 (10)	0.0791 (13)	0.086 (18)
C8	0.2142 (9)	0.7863 (16)	0.055 (2)	0.074 (18)
H8A	0.1562	0.8611	0.0910	0.089*
H8B	0.1462	0.6578	0.0354	0.089*
C9	0.2526 (9)	0.9823 (17)	0.0009 (19)	0.076 (18)
H9A	0.2862	0.9020	−0.0391	0.114*
H9B	0.3386	1.0875	0.0172	0.114*
H9C	0.1565	1.0781	−0.0086	0.114*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
O1	0.057 (4)	0.100 (4)	0.11 (6)	0.000 (3)	−0.008 (11)	0.023 (10)
N1	0.076 (5)	0.076 (4)	0.06 (10)	0.004 (3)	0.029 (14)	0.022 (10)
C4	0.050 (5)	0.056 (5)	0.17 (6)	0.002 (4)	0.035 (13)	−0.008 (11)
C3	0.063 (5)	0.065 (5)	0.16 (6)	−0.005 (4)	−0.003 (13)	0.013 (15)
C2	0.068 (6)	0.062 (5)	0.17 (6)	−0.007 (4)	0.026 (14)	−0.006 (14)
C1	0.064 (5)	0.054 (5)	0.17 (6)	−0.003 (4)	0.027 (12)	−0.035 (13)
C6	0.078 (6)	0.057 (5)	0.15 (6)	−0.012 (5)	0.041 (17)	−0.015 (13)
C5	0.096 (7)	0.051 (5)	0.16 (6)	−0.004 (5)	0.062 (16)	−0.024 (15)
C7	0.060 (5)	0.058 (4)	0.11 (5)	0.001 (4)	0.008 (12)	0.006 (12)
O2	0.069 (4)	0.081 (4)	0.11 (5)	0.013 (3)	0.020 (9)	0.021 (11)
C8	0.058 (5)	0.091 (6)	0.07 (6)	0.009 (5)	−0.014 (12)	0.000 (16)
C9	0.080 (6)	0.084 (5)	0.06 (6)	0.006 (4)	−0.046 (15)	−0.005 (16)

Geometric parameters (Å, º) top

O1—C7	1.210 (10)	C6—H6	0.9300
N1—H1A	0.8914	C6—C5	1.3900
N1—H1B	0.8871	C5—H5	0.9300
N1—C1	1.357 (8)	C7—O2	1.34 (2)
C4—C3	1.3900	O2—C8	1.44 (2)
C4—C5	1.3900	C8—H8A	0.9700
C4—C7	1.432 (12)	C8—H8B	0.9700
C3—H3	0.9300	C8—C9	1.56 (3)
C3—C2	1.3900	C9—H9A	0.9600
C2—H2	0.9300	C9—H9B	0.9600
C2—C1	1.3900	C9—H9C	0.9600
C1—C6	1.3900

H1A—N1—H1B	106.0	C6—C5—C4	120.0
C1—N1—H1A	114.1	C6—C5—H5	120.0
C1—N1—H1B	110.7	O1—C7—C4	128.5 (12)
C3—C4—C5	120.0	O1—C7—O2	117.3 (11)
C3—C4—C7	121.5 (7)	O2—C7—C4	113.9 (9)
C5—C4—C7	118.5 (7)	C7—O2—C8	118.6 (13)
C4—C3—H3	120.0	O2—C8—H8A	110.1
C4—C3—C2	120.0	O2—C8—H8B	110.1
C2—C3—H3	120.0	O2—C8—C9	108.1 (13)
C3—C2—H2	120.0	H8A—C8—H8B	108.4
C1—C2—C3	120.0	C9—C8—H8A	110.1
C1—C2—H2	120.0	C9—C8—H8B	110.1
N1—C1—C2	119.5 (5)	C8—C9—H9A	109.5
N1—C1—C6	120.5 (5)	C8—C9—H9B	109.5
C6—C1—C2	120.0	C8—C9—H9C	109.5
C1—C6—H6	120.0	H9A—C9—H9B	109.5
C1—C6—C5	120.0	H9A—C9—H9C	109.5
C5—C6—H6	120.0	H9B—C9—H9C	109.5
C4—C5—H5	120.0

4-aminobenzoic acid ethyl ester (BZC_a2) top

Crystal data top

C₉H₁₁NO₂	F(000) = 352
M_r = 165.19	D_x = 1.264 Mg m⁻³
Monoclinic, P2₁/c	Mo Kα radiation, λ = 0.71073 Å
a = 8.24 (3) Å	Cell parameters from 690 reflections
b = 5.4015 (9) Å	θ = 4.1–20.6°
c = 19.519 (3) Å	µ = 0.09 mm⁻¹
β = 91.55 (6)°	T = 298 K
V = 868 (3) Å³	Plate, colourless
Z = 4	0.44 × 0.44 × 0.1 mm

Data collection top

Xcalibur, Eos diffractometer	292 independent reflections
Radiation source: fine-focus sealed X-ray tube, Enhance (Mo) X-ray Source	197 reflections with I > 2σ(I)
Graphite monochromator	R_int = 0.038
Detector resolution: 16.2413 pixels mm^-1	θ_max = 26.8°, θ_min = 3.9°
ω and φ scans	h = −1→1
Absorption correction: multi-scan CrysAlisPro 1.171.38.41 (Rigaku Oxford Diffraction, 2015) Empirical absorption correction using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm.	k = −6→6
T_min = 0.650, T_max = 1.000	l = −23→24
2925 measured reflections

Refinement top

Refinement on F²	Primary atom site location: dual
Least-squares matrix: full	Hydrogen site location: mixed
R[F² > 2σ(F²)] = 0.044	H-atom parameters constrained
wR(F²) = 0.131	w = 1/[σ²(F_o²) + (0.0682P)² + 0.2839P] where P = (F_o² + 2F_c²)/3
S = 1.16	(Δ/σ)_max < 0.001
292 reflections	Δρ_max = 0.05 e Å⁻³
99 parameters	Δρ_min = −0.09 e Å⁻³
132 restraints

Special details top

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
O1	0.226 (3)	0.4063 (13)	0.1335 (4)	0.064 (7)
C1	0.825 (2)	0.2176 (12)	0.1825 (3)	0.055 (4)
C6	0.684 (2)	0.0959 (7)	0.2010 (2)	0.050 (4)
H6	0.6908	−0.0471	0.2274	0.061*
C5	0.533 (2)	0.1879 (11)	0.1798 (3)	0.051 (4)
H5	0.4391	0.1064	0.1922	0.062*
C4	0.524 (2)	0.4016 (12)	0.1403 (3)	0.053 (3)
C3	0.665 (2)	0.5233 (7)	0.12184 (19)	0.056 (4)
H3	0.6579	0.6663	0.0954	0.068*
C2	0.815 (2)	0.4314 (11)	0.1430 (3)	0.057 (4)
H2	0.9096	0.5128	0.1306	0.069*
N1	0.979 (4)	0.1356 (12)	0.2039 (4)	0.060 (7)
H1A	1.0555	0.1379	0.1724	0.072*
H1B	0.9731	−0.0207	0.2170	0.072*
O2	0.364 (2)	0.6840 (9)	0.0745 (2)	0.074 (8)
C8	0.210 (4)	0.7862 (16)	0.0502 (4)	0.098 (19)
H8A	0.1498	0.8514	0.0884	0.117*
H8B	0.1445	0.6586	0.0279	0.117*
C9	0.246 (2)	0.9909 (11)	0.0001 (3)	0.09 (3)
H9A	0.3098	0.9258	−0.0363	0.131*
H9B	0.3059	1.1200	0.0233	0.131*
H9C	0.1463	1.0567	−0.0186	0.131*
C7	0.358 (2)	0.4900 (19)	0.1180 (6)	0.056 (5)

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
O1	0.02 (2)	0.092 (5)	0.074 (4)	0.004 (11)	−0.003 (12)	0.012 (3)
C1	0.057 (9)	0.058 (4)	0.050 (4)	−0.002 (7)	0.005 (8)	−0.004 (3)
C6	0.054 (9)	0.044 (3)	0.053 (3)	−0.016 (7)	0.007 (7)	0.009 (2)
C5	0.055 (9)	0.049 (3)	0.050 (3)	−0.019 (7)	0.002 (7)	0.001 (2)
C4	0.059 (9)	0.051 (4)	0.047 (4)	−0.007 (8)	0.000 (8)	−0.003 (3)
C3	0.059 (9)	0.052 (4)	0.059 (4)	−0.013 (7)	0.007 (7)	0.010 (3)
C2	0.057 (9)	0.053 (4)	0.062 (4)	−0.011 (8)	0.012 (8)	0.007 (3)
N1	0.03 (2)	0.072 (4)	0.074 (4)	−0.032 (11)	0.010 (11)	0.007 (3)
O2	0.07 (2)	0.073 (3)	0.079 (3)	0.012 (7)	0.015 (7)	0.018 (2)
C8	0.13 (6)	0.083 (5)	0.082 (5)	0.039 (13)	0.020 (12)	0.006 (4)
C9	0.11 (9)	0.075 (4)	0.077 (4)	0.04 (5)	0.03 (5)	0.011 (3)
C7	0.053 (12)	0.061 (5)	0.054 (5)	−0.019 (8)	0.020 (9)	−0.004 (4)

Geometric parameters (Å, º) top

O1—C7	1.22 (2)	C2—H2	0.9300
C1—C6	1.3900	N1—H1A	0.8940
C1—C2	1.3900	N1—H1B	0.8837
C1—N1	1.39 (2)	O2—C8	1.45 (3)
C6—H6	0.9300	O2—C7	1.351 (11)
C6—C5	1.3900	C8—H8A	0.9700
C5—H5	0.9300	C8—H8B	0.9700
C5—C4	1.3900	C8—C9	1.513 (13)
C4—C3	1.3900	C9—H9A	0.9600
C4—C7	1.501 (8)	C9—H9B	0.9600
C3—H3	0.9300	C9—H9C	0.9600
C3—C2	1.3900

C6—C1—C2	120.0	C1—N1—H1B	109.6
C6—C1—N1	122.0 (8)	H1A—N1—H1B	104.9
C2—C1—N1	118.0 (8)	C7—O2—C8	116.8 (18)
C1—C6—H6	120.0	O2—C8—H8A	110.2
C1—C6—C5	120.0	O2—C8—H8B	110.2
C5—C6—H6	120.0	O2—C8—C9	107.5 (19)
C6—C5—H5	120.0	H8A—C8—H8B	108.5
C4—C5—C6	120.0	C9—C8—H8A	110.2
C4—C5—H5	120.0	C9—C8—H8B	110.2
C5—C4—C3	120.0	C8—C9—H9A	109.5
C5—C4—C7	117.6 (6)	C8—C9—H9B	109.5
C3—C4—C7	122.3 (6)	C8—C9—H9C	109.5
C4—C3—H3	120.0	H9A—C9—H9B	109.5
C2—C3—C4	120.0	H9A—C9—H9C	109.5
C2—C3—H3	120.0	H9B—C9—H9C	109.5
C1—C2—H2	120.0	O1—C7—C4	128.2 (10)
C3—C2—C1	120.0	O1—C7—O2	119.5 (15)
C3—C2—H2	120.0	O2—C7—C4	112.2 (13)
C1—N1—H1A	116.2

4-aminobenzoic acid ethyl ester (BZC_a3) top

Crystal data top

C₉H₁₁NO₂	F(000) = 352
M_r = 165.19	D_x = 1.354 Mg m⁻³
Monoclinic, P2₁/c	Mo Kα radiation, λ = 0.71073 Å
a = 6.305 (1) Å	Cell parameters from 982 reflections
b = 5.1839 (4) Å	θ = 4.0–26.2°
c = 24.94 (8) Å	µ = 0.10 mm⁻¹
β = 96.25 (8)°	T = 298 K
V = 810 (3) Å³	Plate, colourless
Z = 4	0.42 × 0.34 × 0.1 mm

Data collection top

Xcalibur, Eos diffractometer	270 independent reflections
Radiation source: fine-focus sealed X-ray tube, Enhance (Mo) X-ray Source	225 reflections with I > 2σ(I)
Graphite monochromator	R_int = 0.052
Detector resolution: 16.2413 pixels mm^-1	θ_max = 26.5°, θ_min = 4.0°
ω and φ scans	h = −7→7
Absorption correction: multi-scan CrysAlisPro 1.171.38.41 (Rigaku Oxford Diffraction, 2015) Empirical absorption correction using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm.	k = −6→6
T_min = 0.111, T_max = 1.000	l = −6→6
2490 measured reflections

Refinement top

Refinement on F²	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Hydrogen site location: mixed
R[F² > 2σ(F²)] = 0.063	H-atom parameters constrained
wR(F²) = 0.172	w = 1/[σ²(F_o²) + (0.1321P)² + 0.4918P] where P = (F_o² + 2F_c²)/3
S = 1.06	(Δ/σ)_max < 0.001
270 reflections	Δρ_max = 0.11 e Å⁻³
99 parameters	Δρ_min = −0.10 e Å⁻³
125 restraints

Special details top

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
O1	0.0175 (9)	1.1815 (8)	0.1293 (13)	0.042 (17)
O2	0.0058 (7)	0.8460 (8)	0.0760 (8)	0.063 (14)
N1	0.9037 (10)	0.6236 (12)	0.2110 (15)	0.062 (18)
H1A	0.8974	0.5688	0.2436	0.074*
H1B	0.9428	0.4992	0.1912	0.074*
C4	0.3036 (5)	0.8802 (7)	0.1418 (5)	0.039 (13)
C5	0.4169 (6)	1.0146 (7)	0.1838 (5)	0.043 (13)
H5	0.3596	1.1635	0.1972	0.052*
C6	0.6159 (6)	0.9267 (8)	0.2057 (5)	0.047 (13)
H6	0.6917	1.0167	0.2338	0.057*
C1	0.7017 (6)	0.7043 (7)	0.1856 (5)	0.043 (13)
C2	0.5884 (6)	0.5698 (7)	0.1436 (5)	0.045 (13)
H2	0.6457	0.4209	0.1302	0.054*
C3	0.3893 (6)	0.6577 (7)	0.1217 (5)	0.046 (13)
H3	0.3136	0.5677	0.0936	0.055*
C7	0.0975 (12)	0.9848 (12)	0.1161 (11)	0.038 (14)
C8	−0.1941 (11)	0.9401 (11)	0.0464 (12)	0.043 (19)
H8A	−0.2986	0.9759	0.0712	0.051*
H8B	−0.1682	1.0975	0.0271	0.051*
C9	−0.2713 (13)	0.7389 (12)	0.0088 (14)	0.06 (2)
H9A	−0.1765	0.7223	−0.0186	0.096*
H9B	−0.4115	0.7830	−0.0077	0.096*
H9C	−0.2773	0.5783	0.0277	0.096*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
O1	0.043 (4)	0.046 (2)	0.04 (5)	0.012 (2)	−0.001 (14)	0.011 (9)
O2	0.026 (3)	0.043 (2)	0.11 (4)	0.000 (2)	−0.023 (9)	−0.016 (8)
N1	0.031 (4)	0.057 (3)	0.09 (6)	0.013 (3)	−0.006 (11)	0.014 (12)
C4	0.026 (3)	0.033 (2)	0.06 (4)	0.000 (2)	−0.001 (10)	0.008 (8)
C5	0.035 (4)	0.034 (3)	0.06 (4)	0.000 (2)	−0.009 (10)	0.009 (8)
C6	0.033 (3)	0.043 (3)	0.06 (4)	−0.004 (2)	−0.010 (10)	−0.002 (8)
C1	0.028 (3)	0.036 (3)	0.06 (4)	0.000 (3)	−0.004 (9)	0.014 (9)
C2	0.037 (4)	0.035 (3)	0.06 (4)	0.004 (2)	0.005 (10)	0.003 (9)
C3	0.033 (3)	0.037 (3)	0.07 (4)	−0.002 (2)	−0.003 (9)	−0.003 (8)
C7	0.029 (4)	0.037 (3)	0.05 (4)	−0.002 (3)	0.017 (10)	0.002 (9)
C8	0.033 (4)	0.049 (3)	0.05 (6)	0.007 (3)	0.008 (10)	0.021 (11)
C9	0.042 (5)	0.058 (4)	0.09 (7)	−0.012 (3)	0.000 (15)	−0.014 (12)

Geometric parameters (Å, º) top

O1—C7	1.199 (13)	C4—C7	1.487 (16)
O2—C7	1.31 (3)	C5—C6	1.3900
O2—C8	1.47 (2)	C6—C1	1.3900
N1—C1	1.422 (19)	C1—C2	1.3900
C4—C5	1.3900	C2—C3	1.3900
C4—C3	1.3900	C8—C9	1.45 (3)

C7—O2—C8	118.8 (9)	C2—C1—N1	123.4 (11)
C5—C4—C3	120.0	C3—C2—C1	120.0
C5—C4—C7	119.7 (8)	C2—C3—C4	120.0
C3—C4—C7	120.2 (9)	O1—C7—O2	120.8 (18)
C4—C5—C6	120.0	O1—C7—C4	124 (2)
C1—C6—C5	120.0	O2—C7—C4	114.8 (8)
C6—C1—N1	116.6 (11)	C9—C8—O2	107.2 (9)
C6—C1—C2	120.0

4-aminobenzoic acid ethyl ester (BZC_a4) top

Crystal data top

C₉H₁₁NO₂	F(000) = 352
M_r = 165.19	D_x = 1.365 Mg m⁻³
Monoclinic, P2₁/c	Mo Kα radiation, λ = 0.71073 Å
a = 6.3679 (8) Å	Cell parameters from 880 reflections
b = 5.1671 (6) Å	θ = 4.0–23.3°
c = 24.58 (8) Å	µ = 0.10 mm⁻¹
β = 96.25 (6)°	T = 298 K
V = 804 (3) Å³	Plate, colourless
Z = 4	0.43 × 0.31 × 0.1 mm

Data collection top

Xcalibur, Eos diffractometer	296 independent reflections
Radiation source: fine-focus sealed X-ray tube, Enhance (Mo) X-ray Source	223 reflections with I > 2σ(I)
Graphite monochromator	R_int = 0.049
Detector resolution: 16.2413 pixels mm^-1	θ_max = 26.5°, θ_min = 4.0°
ω and φ scans	h = −7→8
Absorption correction: multi-scan CrysAlisPro 1.171.38.41 (Rigaku Oxford Diffraction, 2015) Empirical absorption correction using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm.	k = −6→6
T_min = 0.054, T_max = 1.000	l = −5→5
2457 measured reflections

Refinement top

Refinement on F²	Primary atom site location: dual
Least-squares matrix: full	Hydrogen site location: mixed
R[F² > 2σ(F²)] = 0.044	H-atom parameters constrained
wR(F²) = 0.104	w = 1/[σ²(F_o²) + (0.0471P)² + 0.3983P] where P = (F_o² + 2F_c²)/3
S = 1.16	(Δ/σ)_max < 0.001
296 reflections	Δρ_max = 0.08 e Å⁻³
99 parameters	Δρ_min = −0.08 e Å⁻³
142 restraints

Special details top

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
O1	0.0184 (5)	1.1890 (6)	0.1315 (8)	0.039 (9)
O2	0.0069 (5)	0.8480 (7)	0.0763 (6)	0.046 (7)
N1	0.9040 (6)	0.6313 (10)	0.2074 (9)	0.072 (14)
H1A	0.9428	0.4999	0.1890	0.087*
H1B	0.8961	0.5852	0.2411	0.087*
C4	0.3031 (4)	0.8843 (6)	0.1408 (4)	0.029 (6)
C5	0.4160 (5)	1.0196 (6)	0.1832 (4)	0.032 (6)
H5	0.3586	1.1677	0.1972	0.039*
C6	0.6146 (5)	0.9337 (6)	0.2047 (4)	0.037 (6)
H6	0.6901	1.0242	0.2332	0.044*
C1	0.7004 (4)	0.7124 (6)	0.1838 (4)	0.035 (6)
C2	0.5875 (5)	0.5770 (6)	0.1413 (4)	0.032 (6)
H2	0.6449	0.4289	0.1273	0.038*
C3	0.3888 (4)	0.6630 (6)	0.1198 (4)	0.033 (6)
H3	0.3133	0.5724	0.0914	0.039*
C7	0.0974 (8)	0.9895 (10)	0.1165 (9)	0.033 (6)
C8	−0.1931 (7)	0.9444 (9)	0.0490 (8)	0.036 (9)
H8A	−0.1723	1.1097	0.0317	0.044*
H8B	−0.2948	0.9669	0.0753	0.044*
C9	−0.2724 (8)	0.7405 (10)	0.0057 (10)	0.040 (10)
H9A	−0.1716	0.7228	−0.0204	0.060*
H9B	−0.4058	0.7947	−0.0128	0.060*
H9C	−0.2893	0.5771	0.0233	0.060*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
O1	0.040 (2)	0.045 (2)	0.03 (3)	0.0096 (15)	−0.013 (7)	0.006 (6)
O2	0.0291 (19)	0.046 (2)	0.06 (2)	0.0050 (15)	−0.023 (5)	−0.012 (5)
N1	0.042 (3)	0.058 (3)	0.12 (4)	0.011 (2)	0.023 (9)	0.020 (8)
C4	0.027 (2)	0.032 (2)	0.029 (17)	−0.0028 (18)	0.007 (6)	0.003 (6)
C5	0.035 (2)	0.032 (2)	0.030 (18)	0.004 (2)	0.004 (6)	0.002 (7)
C6	0.036 (2)	0.042 (3)	0.032 (18)	−0.004 (2)	0.005 (6)	0.003 (6)
C1	0.030 (2)	0.038 (2)	0.035 (19)	0.001 (2)	−0.001 (7)	0.018 (7)
C2	0.038 (3)	0.029 (2)	0.030 (19)	0.004 (2)	0.008 (7)	0.009 (7)
C3	0.033 (2)	0.037 (2)	0.028 (18)	−0.0036 (18)	0.006 (6)	0.001 (6)
C7	0.030 (3)	0.038 (2)	0.031 (19)	−0.004 (2)	0.003 (6)	−0.001 (7)
C8	0.030 (2)	0.048 (3)	0.03 (3)	0.003 (2)	0.001 (6)	−0.002 (8)
C9	0.040 (3)	0.065 (3)	0.02 (3)	−0.004 (2)	−0.002 (8)	−0.004 (9)

Geometric parameters (Å, º) top

O1—C7	1.221 (11)	C6—C1	1.3900
O2—C7	1.313 (19)	C1—C2	1.3900
O2—C8	1.460 (11)	C2—H2	0.9300
N1—H1A	0.8662	C2—C3	1.3900
N1—H1B	0.8668	C3—H3	0.9300
N1—C1	1.425 (10)	C8—H8A	0.9700
C4—C5	1.3900	C8—H8B	0.9700
C4—C3	1.3900	C8—C9	1.54 (2)
C4—C7	1.481 (10)	C9—H9A	0.9600
C5—H5	0.9300	C9—H9B	0.9600
C5—C6	1.3900	C9—H9C	0.9600
C6—H6	0.9300

C7—O2—C8	116.4 (6)	C4—C3—H3	120.0
H1A—N1—H1B	109.4	C2—C3—C4	120.0
C1—N1—H1A	108.4	C2—C3—H3	120.0
C1—N1—H1B	109.0	O1—C7—O2	122.4 (11)
C5—C4—C3	120.0	O1—C7—C4	124.3 (15)
C5—C4—C7	118.6 (6)	O2—C7—C4	113.3 (7)
C3—C4—C7	121.3 (7)	O2—C8—H8A	110.4
C4—C5—H5	120.0	O2—C8—H8B	110.4
C4—C5—C6	120.0	O2—C8—C9	106.7 (6)
C6—C5—H5	120.0	H8A—C8—H8B	108.6
C5—C6—H6	120.0	C9—C8—H8A	110.4
C1—C6—C5	120.0	C9—C8—H8B	110.4
C1—C6—H6	120.0	C8—C9—H9A	109.5
C6—C1—N1	117.9 (7)	C8—C9—H9B	109.5
C6—C1—C2	120.0	C8—C9—H9C	109.5
C2—C1—N1	122.1 (7)	H9A—C9—H9B	109.5
C1—C2—H2	120.0	H9A—C9—H9C	109.5
C1—C2—C3	120.0	H9B—C9—H9C	109.5
C3—C2—H2	120.0

4-aminobenzoic acid ethyl ester (BZC_a5) top

Crystal data top

C₉H₁₁NO₂	F(000) = 352
M_r = 165.19	D_x = 1.375 Mg m⁻³
Monoclinic, P2₁/c	Mo Kα radiation, λ = 0.71073 Å
a = 6.3410 (7) Å	Cell parameters from 869 reflections
b = 5.1594 (5) Å	θ = 4.0–23.3°
c = 24.52 (6) Å	µ = 0.10 mm⁻¹
β = 96.05 (5)°	T = 298 K
V = 798 (2) Å³	Plate, colourless
Z = 4	0.43 × 0.31 × 0.1 mm

Data collection top

Xcalibur, Eos diffractometer	289 independent reflections
Radiation source: fine-focus sealed X-ray tube, Enhance (Mo) X-ray Source	224 reflections with I > 2σ(I)
Graphite monochromator	R_int = 0.054
Detector resolution: 16.2413 pixels mm^-1	θ_max = 26.5°, θ_min = 4.0°
ω and φ scans	h = −7→7
Absorption correction: multi-scan CrysAlisPro 1.171.38.41 (Rigaku Oxford Diffraction, 2015) Empirical absorption correction using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm.	k = −6→6
T_min = 0.020, T_max = 1.000	l = −5→5
2437 measured reflections

Refinement top

Refinement on F²	Primary atom site location: dual
Least-squares matrix: full	Hydrogen site location: mixed
R[F² > 2σ(F²)] = 0.043	H-atom parameters constrained
wR(F²) = 0.121	w = 1/[σ²(F_o²) + (0.0968P)²] where P = (F_o² + 2F_c²)/3
S = 1.08	(Δ/σ)_max < 0.001
289 reflections	Δρ_max = 0.08 e Å⁻³
111 parameters	Δρ_min = −0.08 e Å⁻³
132 restraints

Special details top

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
O2	0.0057 (5)	0.8484 (6)	0.0761 (6)	0.045 (6)
O1	0.0175 (4)	1.1903 (5)	0.1315 (7)	0.040 (9)
N1	0.9034 (6)	0.6310 (12)	0.2062 (9)	0.069 (15)
H1A	0.9271	0.4818	0.1927	0.083*
H1B	0.9065	0.6184	0.2410	0.083*
C4	0.3017 (7)	0.8884 (8)	0.1386 (7)	0.028 (6)
C2	0.5873 (8)	0.5781 (8)	0.1417 (9)	0.035 (6)
H2	0.6446	0.4304	0.1273	0.042*
C7	0.0977 (9)	0.9906 (9)	0.1167 (9)	0.034 (7)
C5	0.4163 (8)	1.0194 (9)	0.1824 (8)	0.032 (6)
H5	0.3575	1.1649	0.1973	0.038*
C6	0.6138 (7)	0.9359 (8)	0.2035 (8)	0.037 (6)
H6	0.6893	1.0310	0.2312	0.045*
C3	0.3893 (6)	0.6633 (7)	0.1211 (8)	0.033 (6)
H3	0.3115	0.5648	0.0943	0.040*
C8	−0.1935 (7)	0.9434 (8)	0.0494 (8)	0.033 (6)
H8A	−0.1729	1.1078	0.0315	0.040*
H8B	−0.2946	0.9680	0.0760	0.040*
C1	0.7026 (7)	0.7141 (8)	0.1844 (9)	0.036 (6)
C9	−0.2740 (8)	0.7394 (9)	0.0072 (10)	0.042 (9)
H9A	−0.1717	0.7154	−0.0186	0.063*
H9B	−0.4060	0.7959	−0.0119	0.063*
H9C	−0.2952	0.5784	0.0255	0.063*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
O2	0.0301 (19)	0.0454 (18)	0.053 (18)	0.0061 (14)	−0.019 (5)	−0.012 (5)
O1	0.0393 (19)	0.0428 (18)	0.03 (3)	0.0101 (13)	−0.012 (7)	0.013 (5)
N1	0.041 (2)	0.056 (2)	0.11 (5)	0.008 (2)	0.012 (8)	0.015 (8)
C4	0.026 (2)	0.034 (2)	0.026 (18)	−0.0043 (18)	0.014 (7)	0.013 (6)
C2	0.037 (3)	0.029 (2)	0.039 (18)	0.003 (2)	0.012 (7)	−0.002 (7)
C7	0.030 (3)	0.034 (2)	0.04 (2)	−0.005 (2)	0.005 (7)	−0.003 (7)
C5	0.032 (3)	0.032 (2)	0.032 (19)	0.0026 (19)	0.005 (8)	−0.009 (7)
C6	0.036 (3)	0.039 (3)	0.039 (19)	−0.0039 (18)	0.015 (7)	0.013 (6)
C3	0.037 (2)	0.035 (2)	0.029 (18)	−0.0038 (17)	0.014 (6)	−0.005 (6)
C8	0.030 (3)	0.044 (2)	0.027 (19)	0.0024 (19)	0.013 (6)	−0.001 (7)
C1	0.029 (2)	0.037 (2)	0.042 (19)	−0.001 (2)	0.004 (7)	0.020 (7)
C9	0.041 (3)	0.059 (3)	0.02 (3)	−0.008 (2)	−0.001 (8)	0.000 (8)

Geometric parameters (Å, º) top

O2—C7	1.322 (19)	C5—H5	0.9300
O2—C8	1.446 (12)	C5—C6	1.373 (12)
O1—C7	1.221 (10)	C6—H6	0.9300
N1—H1A	0.8576	C6—C1	1.379 (12)
N1—H1B	0.8535	C3—H3	0.9300
N1—C1	1.396 (12)	C8—H8A	0.9700
C4—C7	1.447 (12)	C8—H8B	0.9700
C4—C5	1.41 (2)	C8—C9	1.53 (2)
C4—C3	1.375 (10)	C9—H9A	0.9600
C2—H2	0.9300	C9—H9B	0.9600
C2—C3	1.375 (11)	C9—H9C	0.9600
C2—C1	1.40 (2)

C7—O2—C8	116.6 (6)	C4—C3—C2	122.6 (11)
H1A—N1—H1B	109.3	C4—C3—H3	118.7
C1—N1—H1A	108.5	C2—C3—H3	118.7
C1—N1—H1B	109.3	O2—C8—H8A	110.4
C5—C4—C7	118.6 (8)	O2—C8—H8B	110.4
C3—C4—C7	124.5 (12)	O2—C8—C9	106.7 (6)
C3—C4—C5	116.8 (8)	H8A—C8—H8B	108.6
C3—C2—H2	120.0	C9—C8—H8A	110.4
C3—C2—C1	119.9 (8)	C9—C8—H8B	110.4
C1—C2—H2	120.0	N1—C1—C2	121.1 (10)
O2—C7—C4	112.6 (8)	C6—C1—N1	120.9 (14)
O1—C7—O2	121.9 (11)	C6—C1—C2	118.0 (8)
O1—C7—C4	125.5 (15)	C8—C9—H9A	109.5
C4—C5—H5	119.5	C8—C9—H9B	109.5
C6—C5—C4	121.0 (9)	C8—C9—H9C	109.5
C6—C5—H5	119.5	H9A—C9—H9B	109.5
C5—C6—H6	119.3	H9A—C9—H9C	109.5
C5—C6—C1	121.4 (13)	H9B—C9—H9C	109.5
C1—C6—H6	119.3

4-aminobenzoic acid ethyl ester (BZC_b1) top

Crystal data top

C₉H₁₁NO₂	F(000) = 352
M_r = 165.19	D_x = 1.275 Mg m⁻³
Monoclinic, P2₁/c	Mo Kα radiation, λ = 0.71073 Å
a = 8.171 (13) Å	Cell parameters from 704 reflections
b = 5.3995 (9) Å	θ = 3.9–19.5°
c = 19.515 (3) Å	µ = 0.09 mm⁻¹
β = 92.00 (4)°	T = 298 K
V = 860.4 (14) Å³	Plate, colourless
Z = 4	0.34 × 0.29 × 0.1 mm

Data collection top

Xcalibur, Eos diffractometer	462 independent reflections
Radiation source: fine-focus sealed X-ray tube, Enhance (Mo) X-ray Source	228 reflections with I > 2σ(I)
Graphite monochromator	R_int = 0.069
Detector resolution: 16.1544 pixels mm^-1	θ_max = 26.9°, θ_min = 3.9°
ω and φ scans	h = −2→2
Absorption correction: multi-scan CrysAlisPro 1.171.38.41 (Rigaku Oxford Diffraction, 2015) Empirical absorption correction using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm.	k = −6→6
T_min = 0.526, T_max = 1.000	l = −24→24
3571 measured reflections

Refinement top

Refinement on F²	Primary atom site location: dual
Least-squares matrix: full	Hydrogen site location: mixed
R[F² > 2σ(F²)] = 0.087	H-atom parameters constrained
wR(F²) = 0.277	w = 1/[σ²(F_o²) + (0.1481P)²] where P = (F_o² + 2F_c²)/3
S = 1.10	(Δ/σ)_max < 0.001
462 reflections	Δρ_max = 0.14 e Å⁻³
99 parameters	Δρ_min = −0.15 e Å⁻³
133 restraints

Special details top

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
O1	0.222 (3)	0.4071 (13)	0.1341 (4)	0.104 (14)
O2	0.368 (2)	0.6836 (10)	0.0748 (3)	0.107 (6)
N1	0.972 (3)	0.1295 (11)	0.2035 (4)	0.104 (15)
H1A	1.0479	0.1668	0.1745	0.125*
H1B	0.9735	−0.0328	0.2080	0.125*
C4	0.5207 (16)	0.3999 (9)	0.1405 (3)	0.086 (7)
C3	0.6624 (17)	0.5218 (8)	0.1219 (2)	0.087 (7)
H3	0.6551	0.6642	0.0952	0.104*
C2	0.8148 (16)	0.4307 (10)	0.1433 (3)	0.091 (7)
H2	0.9096	0.5122	0.1309	0.109*
C1	0.8257 (16)	0.2178 (11)	0.1832 (3)	0.087 (7)
C6	0.6841 (16)	0.0959 (8)	0.2018 (2)	0.090 (7)
H6	0.6914	−0.0466	0.2285	0.108*
C5	0.5316 (16)	0.1870 (8)	0.1804 (3)	0.086 (7)
H5	0.4369	0.1054	0.1928	0.104*
C7	0.354 (3)	0.490 (2)	0.1176 (6)	0.091 (7)
C9	0.245 (3)	0.9909 (14)	−0.0004 (4)	0.131 (11)
H9A	0.2915	0.9206	−0.0404	0.197*
H9B	0.3207	1.1064	0.0205	0.197*
H9C	0.1449	1.0751	−0.0132	0.197*
C8	0.209 (3)	0.7854 (17)	0.0505 (5)	0.111 (7)
H8A	0.1496	0.8510	0.0887	0.133*
H8B	0.1430	0.6571	0.0284	0.133*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
O1	0.13 (5)	0.108 (6)	0.080 (5)	0.015 (8)	0.010 (11)	0.017 (3)
O2	0.14 (2)	0.086 (4)	0.090 (4)	0.016 (5)	0.005 (7)	0.009 (3)
N1	0.15 (5)	0.077 (5)	0.091 (6)	−0.008 (8)	0.028 (10)	0.010 (3)
C4	0.133 (19)	0.064 (5)	0.060 (4)	0.011 (7)	−0.004 (8)	0.001 (3)
C3	0.13 (2)	0.063 (4)	0.065 (4)	0.012 (7)	0.003 (9)	0.000 (3)
C2	0.13 (2)	0.076 (5)	0.067 (4)	0.011 (7)	0.012 (9)	0.000 (3)
C1	0.13 (2)	0.067 (5)	0.067 (5)	0.014 (8)	0.007 (9)	−0.006 (4)
C6	0.13 (2)	0.073 (5)	0.065 (4)	0.008 (7)	0.009 (9)	0.001 (3)
C5	0.13 (2)	0.066 (4)	0.060 (4)	−0.001 (6)	0.000 (8)	0.000 (3)
C7	0.137 (19)	0.077 (6)	0.061 (6)	0.009 (7)	0.007 (9)	−0.003 (4)
C9	0.22 (3)	0.084 (5)	0.092 (6)	0.017 (7)	−0.016 (13)	0.012 (4)
C8	0.15 (2)	0.085 (5)	0.099 (6)	0.011 (7)	0.001 (9)	−0.002 (5)

Geometric parameters (Å, º) top

O1—C7	1.22 (3)	C2—C1	1.3900
O2—C7	1.346 (14)	C1—C6	1.3900
O2—C8	1.47 (3)	C6—H6	0.9300
N1—H1A	0.8792	C6—C5	1.3900
N1—H1B	0.8807	C5—H5	0.9300
N1—C1	1.330 (19)	C9—H9A	0.9600
C4—C3	1.3900	C9—H9B	0.9600
C4—C5	1.3900	C9—H9C	0.9600
C4—C7	1.501 (19)	C9—C8	1.524 (12)
C3—H3	0.9300	C8—H8A	0.9700
C3—C2	1.3900	C8—H8B	0.9700
C2—H2	0.9300

C7—O2—C8	113.4 (18)	C4—C5—H5	120.0
H1A—N1—H1B	106.3	C6—C5—C4	120.0
C1—N1—H1A	112.0	C6—C5—H5	120.0
C1—N1—H1B	113.5	O1—C7—O2	122.9 (19)
C3—C4—C5	120.0	O1—C7—C4	127.3 (12)
C3—C4—C7	121.7 (7)	O2—C7—C4	109.8 (16)
C5—C4—C7	118.3 (7)	H9A—C9—H9B	109.5
C4—C3—H3	120.0	H9A—C9—H9C	109.5
C4—C3—C2	120.0	H9B—C9—H9C	109.5
C2—C3—H3	120.0	C8—C9—H9A	109.5
C3—C2—H2	120.0	C8—C9—H9B	109.5
C3—C2—C1	120.0	C8—C9—H9C	109.5
C1—C2—H2	120.0	O2—C8—C9	107.1 (17)
N1—C1—C2	120.1 (7)	O2—C8—H8A	110.3
N1—C1—C6	119.9 (7)	O2—C8—H8B	110.3
C2—C1—C6	120.0	C9—C8—H8A	110.3
C1—C6—H6	120.0	C9—C8—H8B	110.3
C5—C6—C1	120.0	H8A—C8—H8B	108.5
C5—C6—H6	120.0

4-aminobenzoic acid ethyl ester (BZC_b2) top

Crystal data top

C₉H₁₁NO₂	F(000) = 352
M_r = 165.19	D_x = 1.354 Mg m⁻³
Monoclinic, P2₁/c	Mo Kα radiation, λ = 0.71073 Å
a = 6.3608 (8) Å	Cell parameters from 667 reflections
b = 5.1830 (7) Å	θ = 3.2–21.3°
c = 24.75 (5) Å	µ = 0.10 mm⁻¹
β = 96.66 (5)°	T = 298 K
V = 810.4 (17) Å³	Plate, colourless
Z = 4	0.34 × 0.31 × 0.1 mm

Data collection top

Xcalibur, Eos diffractometer	396 independent reflections
Radiation source: fine-focus sealed X-ray tube, Enhance (Mo) X-ray Source	197 reflections with I > 2σ(I)
Graphite monochromator	R_int = 0.146
Detector resolution: 16.1544 pixels mm^-1	θ_max = 27.0°, θ_min = 3.2°
ω and φ scans	h = −8→8
Absorption correction: multi-scan CrysAlisPro 1.171.38.41 (Rigaku Oxford Diffraction, 2015) Empirical absorption correction using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm.	k = −6→6
T_min = 0.606, T_max = 1.000	l = −6→6
3446 measured reflections

Refinement top

Refinement on F²	Primary atom site location: dual
Least-squares matrix: full	Hydrogen site location: mixed
R[F² > 2σ(F²)] = 0.091	H-atom parameters constrained
wR(F²) = 0.260	w = 1/[σ²(F_o²) + (0.125P)² + 0.275P] where P = (F_o² + 2F_c²)/3
S = 1.16	(Δ/σ)_max < 0.001
396 reflections	Δρ_max = 0.17 e Å⁻³
99 parameters	Δρ_min = −0.17 e Å⁻³
141 restraints

Special details top

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
O1	0.0199 (8)	1.1797 (11)	0.1328 (10)	0.077 (9)
O2	0.0077 (9)	0.8470 (11)	0.0754 (9)	0.067 (5)
N1	0.9002 (11)	0.6224 (16)	0.2044 (13)	0.082 (19)
H1A	0.9401	0.4997	0.1843	0.098*
H1B	0.8934	0.5652	0.2369	0.098*
C4	0.3037 (7)	0.8806 (11)	0.1415 (6)	0.061 (6)
C5	0.4173 (9)	1.0132 (11)	0.1841 (6)	0.064 (6)
H5	0.3606	1.1610	0.1981	0.077*
C6	0.6156 (9)	0.9250 (11)	0.2059 (5)	0.071 (7)
H6	0.6915	1.0138	0.2344	0.085*
C1	0.7002 (7)	0.7042 (11)	0.1850 (5)	0.066 (7)
C2	0.5867 (8)	0.5715 (9)	0.1424 (5)	0.064 (7)
H2	0.6433	0.4237	0.1284	0.077*
C3	0.3884 (8)	0.6597 (10)	0.1206 (5)	0.063 (6)
H3	0.3124	0.5709	0.0920	0.076*
C7	0.0988 (10)	0.988 (2)	0.1146 (8)	0.061 (5)
C8	−0.1926 (12)	0.9395 (16)	0.0499 (13)	0.065 (6)
H8A	−0.1754	1.1031	0.0319	0.079*
H8B	−0.2911	0.9625	0.0767	0.079*
C9	−0.2712 (15)	0.737 (2)	0.0094 (14)	0.087 (12)
H9A	−0.1721	0.7171	−0.0168	0.130*
H9B	−0.4061	0.7883	−0.0089	0.130*
H9C	−0.2858	0.5762	0.0278	0.130*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
O1	0.060 (4)	0.067 (4)	0.10 (3)	0.011 (3)	−0.003 (9)	−0.006 (8)
O2	0.049 (3)	0.070 (3)	0.078 (13)	0.002 (3)	−0.013 (6)	−0.003 (6)
N1	0.063 (5)	0.080 (5)	0.11 (6)	0.018 (4)	0.022 (13)	0.025 (12)
C4	0.051 (4)	0.054 (4)	0.080 (17)	0.000 (3)	0.021 (8)	0.001 (7)
C5	0.055 (4)	0.056 (4)	0.083 (19)	0.003 (3)	0.013 (8)	0.009 (8)
C6	0.064 (4)	0.063 (4)	0.09 (2)	−0.004 (3)	0.013 (8)	0.008 (8)
C1	0.054 (4)	0.058 (4)	0.09 (2)	−0.001 (3)	0.012 (9)	0.002 (8)
C2	0.056 (4)	0.054 (4)	0.08 (2)	0.005 (3)	0.022 (9)	−0.013 (8)
C3	0.055 (4)	0.055 (4)	0.082 (19)	−0.003 (3)	0.022 (8)	−0.012 (7)
C7	0.046 (4)	0.059 (4)	0.078 (15)	−0.002 (4)	0.007 (8)	0.006 (8)
C8	0.043 (4)	0.073 (5)	0.078 (17)	0.002 (4)	0.000 (9)	−0.009 (9)
C9	0.068 (6)	0.090 (6)	0.10 (4)	−0.017 (5)	−0.003 (14)	−0.013 (13)

Geometric parameters (Å, º) top

O1—C7	1.222 (16)	C6—C1	1.3900
O2—C7	1.30 (2)	C1—C2	1.3900
O2—C8	1.436 (17)	C2—H2	0.9300
N1—H1A	0.8644	C2—C3	1.3900
N1—H1B	0.8614	C3—H3	0.9300
N1—C1	1.374 (13)	C8—H8A	0.9700
C4—C5	1.3900	C8—H8B	0.9700
C4—C3	1.3900	C8—C9	1.50 (3)
C4—C7	1.500 (2)	C9—H9A	0.9600
C5—H5	0.9300	C9—H9B	0.9600
C5—C6	1.3900	C9—H9C	0.9600
C6—H6	0.9300

C7—O2—C8	115.9 (10)	C4—C3—H3	120.0
H1A—N1—H1B	109.6	C2—C3—C4	120.0
C1—N1—H1A	110.3	C2—C3—H3	120.0
C1—N1—H1B	106.7	O1—C7—O2	124.6 (9)
C5—C4—C3	120.0	O1—C7—C4	120.8 (14)
C5—C4—C7	120.0 (7)	O2—C7—C4	114.3 (10)
C3—C4—C7	119.7 (7)	O2—C8—H8A	110.6
C4—C5—H5	120.0	O2—C8—H8B	110.6
C4—C5—C6	120.0	O2—C8—C9	105.7 (10)
C6—C5—H5	120.0	H8A—C8—H8B	108.7
C5—C6—H6	120.0	C9—C8—H8A	110.6
C1—C6—C5	120.0	C9—C8—H8B	110.6
C1—C6—H6	120.0	C8—C9—H9A	109.5
N1—C1—C6	120.5 (11)	C8—C9—H9B	109.5
N1—C1—C2	119.4 (11)	C8—C9—H9C	109.5
C6—C1—C2	120.0	H9A—C9—H9B	109.5
C1—C2—H2	120.0	H9A—C9—H9C	109.5
C3—C2—C1	120.0	H9B—C9—H9C	109.5
C3—C2—H2	120.0

4-aminobenzoic acid ethyl ester (BZC_b3) top

Crystal data top

C₉H₁₁NO₂	F(000) = 352
M_r = 165.19	D_x = 1.356 Mg m⁻³
Monoclinic, P2₁/c	Mo Kα radiation, λ = 0.71073 Å
a = 6.3399 (8) Å	Cell parameters from 1183 reflections
b = 5.1789 (6) Å	θ = 3.2–26.2°
c = 24.80 (7) Å	µ = 0.10 mm⁻¹
β = 96.58 (6)°	T = 298 K
V = 809 (2) Å³	Plate, colourless
Z = 4	0.47 × 0.31 × 0.1 mm

Data collection top

Xcalibur, Eos diffractometer	328 independent reflections
Radiation source: fine-focus sealed X-ray tube, Enhance (Mo) X-ray Source	209 reflections with I > 2σ(I)
Graphite monochromator	R_int = 0.118
Detector resolution: 8.0772 pixels mm^-1	θ_max = 25.9°, θ_min = 3.2°
ω and φ scans	h = −7→7
Absorption correction: multi-scan CrysAlisPro 1.171.38.41 (Rigaku Oxford Diffraction, 2015) Empirical absorption correction using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm.	k = −6→6
T_min = 0.415, T_max = 1.000	l = −6→6
2846 measured reflections

Refinement top

Refinement on F²	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Hydrogen site location: mixed
R[F² > 2σ(F²)] = 0.093	H-atom parameters constrained
wR(F²) = 0.280	w = 1/[σ²(F_o²) + (0.164P)² + 0.695P] where P = (F_o² + 2F_c²)/3
S = 1.16	(Δ/σ)_max < 0.001
328 reflections	Δρ_max = 0.18 e Å⁻³
99 parameters	Δρ_min = −0.14 e Å⁻³
134 restraints

Special details top

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
O1	0.0201 (9)	1.1775 (12)	0.1332 (12)	0.085 (11)
O2	0.0096 (10)	0.8475 (13)	0.0772 (10)	0.080 (9)
N1	0.8999 (11)	0.6219 (15)	0.2049 (14)	0.060 (9)
H1A	0.9423	0.5084	0.1831	0.072*
H1B	0.8941	0.5521	0.2364	0.072*
C4	0.3060 (8)	0.8825 (11)	0.1428 (6)	0.059 (9)
C5	0.4199 (9)	1.0134 (11)	0.1856 (6)	0.061 (9)
H5	0.3638	1.1618	0.1996	0.073*
C6	0.6176 (10)	0.9225 (12)	0.2075 (6)	0.067 (9)
H6	0.6937	1.0101	0.2362	0.080*
C1	0.7014 (8)	0.7008 (11)	0.1867 (6)	0.063 (9)
C2	0.5875 (8)	0.5699 (10)	0.1439 (6)	0.061 (9)
H2	0.6436	0.4216	0.1299	0.073*
C3	0.3898 (8)	0.6608 (11)	0.1219 (6)	0.064 (9)
H3	0.3137	0.5732	0.0933	0.076*
C7	0.0998 (11)	0.9916 (19)	0.1168 (8)	0.075 (10)
C8	−0.1959 (13)	0.9394 (17)	0.0463 (12)	0.079 (10)
H8A	−0.3004	0.9728	0.0711	0.094*
H8B	−0.1727	1.0976	0.0269	0.094*
C9	−0.2717 (17)	0.731 (2)	0.0075 (17)	0.101 (12)
H9A	−0.1570	0.6759	−0.0119	0.151*
H9B	−0.3855	0.7957	−0.0178	0.151*
H9C	−0.3213	0.5878	0.0271	0.151*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
O1	0.053 (4)	0.058 (3)	0.14 (3)	0.005 (3)	0.003 (11)	−0.026 (9)
O2	0.043 (4)	0.062 (4)	0.13 (3)	0.004 (3)	0.002 (8)	−0.024 (7)
N1	0.052 (4)	0.070 (4)	0.06 (3)	0.021 (3)	0.024 (11)	0.051 (11)
C4	0.039 (5)	0.058 (5)	0.09 (3)	0.005 (3)	0.034 (11)	0.003 (10)
C5	0.045 (5)	0.051 (4)	0.09 (3)	−0.002 (3)	0.012 (11)	0.018 (10)
C6	0.055 (5)	0.061 (5)	0.09 (3)	−0.003 (4)	0.043 (10)	0.021 (11)
C1	0.045 (4)	0.059 (5)	0.09 (3)	−0.001 (4)	0.018 (10)	0.005 (11)
C2	0.049 (5)	0.049 (4)	0.09 (3)	0.004 (4)	0.026 (11)	0.006 (11)
C3	0.051 (5)	0.053 (5)	0.09 (3)	−0.002 (3)	0.026 (11)	0.001 (10)
C7	0.040 (4)	0.055 (5)	0.13 (3)	−0.003 (4)	0.010 (10)	−0.025 (10)
C8	0.044 (4)	0.062 (5)	0.13 (3)	0.001 (4)	0.022 (9)	−0.029 (9)
C9	0.056 (5)	0.093 (7)	0.15 (4)	−0.014 (5)	0.009 (14)	−0.012 (14)

Geometric parameters (Å, º) top

O1—C7	1.181 (17)	C4—C7	1.500 (3)
O2—C7	1.31 (2)	C5—C6	1.3900
O2—C8	1.51 (2)	C6—C1	1.3900
N1—C1	1.351 (14)	C1—C2	1.3900
C4—C5	1.3900	C2—C3	1.3900
C4—C3	1.3900	C8—C9	1.49 (3)

C7—O2—C8	118.5 (9)	C6—C1—C2	120.0
C5—C4—C3	120.0	C3—C2—C1	120.0
C5—C4—C7	119.7 (7)	C2—C3—C4	120.0
C3—C4—C7	120.2 (7)	O1—C7—O2	123.7 (11)
C6—C5—C4	120.0	O1—C7—C4	123.0 (15)
C5—C6—C1	120.0	O2—C7—C4	113.0 (9)
N1—C1—C6	120.4 (12)	C9—C8—O2	107.2 (10)
N1—C1—C2	119.4 (12)

Acknowledgements

We are grateful to Professor Andrzej Katrusiak, Dr Marcin Podsiadło and Dr Anna Olejniczak from Faculty of Chemistry, Adam Mickiewicz University in Poznań for useful discussions. We would also like to thank Dr Joanna Gościańska from Faculty of Chemistry, Adam Mickiewicz University in Poznań for supplying the sample of benzocaine.

References

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Volume 76| Part 1| February 2020| Pages 56-64

https://doi.org/10.1107/S2052520619016548

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research papers\(\def\hfill{\hskip 5em}\def\hfil{\hskip 3em}\def\eqno#1{\hfil {#1}}\)

A new high-pressure benzocaine polymorph — towards understanding the molecular aggregation in crystals of an important active pharmaceutical ingredient (API)

1. Introduction

2. Experimental

2.1. High-pressure crystallization and X-ray measurements

2.2. Structural analysis

3. Results and discussion

4. Conclusions

5. Related literature

Supporting information

Acknowledgements

References

research papers