# Origin of phase relative stability and phase transformation in an S-ibuprofen-nicotinamide cocrystal

Mathieu Guerain, Hubert Chevreau, Erik Elkaim, Yannick Guinet, Laurent Paccou, Florence Danede, Alain Hedoux, Frédéric Affouard

## ► To cite this version:

Mathieu Guerain, Hubert Chevreau, Erik Elkaim, Yannick Guinet, Laurent Paccou, et al.. Origin of phase relative stability and phase transformation in an S-ibuprofen-nicotinamide cocrystal. Acta Crystallographica Section C: Structural Chemistry [2014-..], 2025, Acta Crystallographica Section C Structural Chemistry, 81 (11), pp.658-665. 10.1107/S2053229625008952. hal-05352900

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STRUCTURAL
CHEMISTRY

ISSN 2053-2296

# Origin of phase relative stability and phase transformation in an S-ibuprofen-nicotinamide cocrystal

Mathieu Guerain,ª* Hubert Chevreau,ᵇ Erik Elkaim,ᵇ Yannick Guinet,ª Laurent Paccou,ª Florence Danède,ª Alain Hedouxª and Frederic Affouardª

Received 30 June 2025
Accepted 14 October 2025

Edited by X. Wang, Oak Ridge National
Laboratory, USA

**Keywords:** crystal engineering; crystal structure; cocrystal; ibuprofen; nicotinamide; powder X-ray diffraction; PXRD; SOLEIL Synchrotron; DFT.

CCDC reference: 2495679

**Supporting information:** this article has
supporting information at journals.iucr.org/c

ªUniversité Lille, CNRS, INRA, ENSCL, UMR 8207 – UMET – Unité Matériaux et Transformations, F-59650 Villeneuve d'Ascq, France, and ᵇSoleil Synchrotron, L'Orme des Merisiers, Saint-Aubin, BP 48, 91192 Gif-sur-Yvette, France.

*Correspondence e-mail: mathieu.guerain@univ-lille.fr

The crystal structure of the metastable form of S-ibuprofen-nicotinamide cocrystals, C₁₃H₁₈O₂·C₆H₆N₂O, was solved from powder X-ray diffraction. This form was obtained by melting a molar mixture of S-ibuprofen and nicotinamide at 100 °C, and then cooling. The high-resolution powder X-ray diffraction pattern of this new phase was recorded at room temperature using synchrotron radiation at SOLEIL Synchrotron (France). A hypothetical structure was obtained from the Monte-Carlo simulated annealing method and confirmed by Rietveld refinement. The symmetry is monoclinic (space group P2₁, No. 4) and the unit cell contains four molecules, two of nicotinamide and two of S-ibuprofen. Density functional theory (DFT) energy minimization simulation was performed in order to locate the H atoms. The determination of the crystallographic structure of this metastable form allowed an explanation of the main mechanisms at the origin of the relative stability of the two forms of the S-ibuprofen-nicotinamide cocrystals. This also made it possible to explain the transition mechanism between the two forms with temperature.

## 1. Introduction

In recent years, the design of functional pharmaceutical molecular materials by the cocrystallization technique has attracted increasing interest (Friščić & Jones, 2010) when other classical approaches based, for example, on salt formation or metastable polymorphs are not possible. Designing cocrystals is mainly based on the concepts used in crystal engineering (Desiraju, 2010), i.e. on the formation of supramolecular hydrogen-bonded networks via various hydrogen-bond synths. The stability of the supramolecular organization is therefore highly dependant on the large variety of hydrogen-bond strengths. Pharmaceutical cocrystals generally consist of an active pharmaceutical ingredient (API) and a coformer present in the same crystal structure (Friščić & Jones, 2010; Vishweshwar et al., 2006; Schultheiss & Newman, 2009; Brittain, 2013; Childs et al., 2009), for example, para-cetamol-piperazine (Oswald et al., 2002), ibuprofen-nicotinamide (Berry et al., 2008), carbamazepine-saccharin (Fleischman et al., 2003), etc. These multicomponent materials in the crystalline solid state have an obvious interest in terms of stability, but also in improving many physicochemical properties of an API, such as aqueous solubility, dissolution, hygroscopicity or bioavailability (Higashi et al., 2017; Friščić & Jones, 2010). However, the discovery and preparation of new cocrystals remain empirical, and still based on trial and error (ter Horst et al., 2009). Cocrystallization can be achieved by

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Published under a CC BY 4.0 licence
<figure><img src="image_6.png" /><figcaption>**Figure 1**
Representation of the ibuprofen (IBP) molecule. The atoms are labelled according to the CIF file for the present structure and Berry *et al.* (2008).</figcaption></figure>

many different techniques (Vishweshwar *et al.*, 2006; Karimi-Jafari *et al.*, 2018), such as crystallization in solution, grinding, grinding assisted by a solvent, use of supercritical fluids, sonocrystallization, *etc.*, which may lead to different crystalline polymorphs in an uncontrolled manner (Schultheiss & Newman, 2009; ter Horst *et al.*, 2009). It is worth noting that using various cocrystallization synthesis methods should promote various hydrogen-bond types, and then various polymorphic or pseudopolymorphic forms of cocrystals, characterized by different degrees of stability.

Ibuprofen (IBP, C₁₃H₁₈O₂) is a well-known API used as a nonsteroidal anti-inflammatory drug (NSAID) to reduce fever and to treat pain or inflammation. It can be found in many formulations (powders, capsules, tablets, *etc*. ) and is listed in the World Health Organization's *Essential Drugs List* (WHO, 2007). Nevertheless, its low water solubility remains a challenge for oral use (Garzón & Martínez, 2004). Adding a second molecule, and thus forming a cocrystal, to increase its solubility, is thus of interest. The crystallographic structure of S-ibuprofen (*S*-IBP) is monoclinic (space group *P*2₁) and its lattice parameters are *a* = 12.456 (3), *b* = 8.0362 (3), *c* = 13.533 (4) Å and β = 112.86 (3)° [Cambridge Structural

<figure><img src="image_7.png" /><figcaption>**Figure 2**
Representation of the nicotinamide (N) molecule. The atoms are labelled according to the CIF file for the present structure and Berry *et al.* (2008).</figcaption></figure>

Database (CSD; Groom *et al.*, 2016) refcode JEKNOC10 (Freer *et al.*, 1993)]. The melting point of S-ibuprofen is 53 °C (Dwivedi *et al.*, 1992). The molecule of S-ibuprofen can be seen in Fig. 1.

Nicotinamide (N, C₆H₆N₂O), one of the components of vitamin B, is currently used as a food additive. It is also one of the most popular coformers used for designing cocrystals, due to its high aqueous solubility and generally regarded as safe (GRAS) status.

Nicotinamide has a rich polymorphism with nine different polymorphs already known (Fellah *et al.*, 2021). The crystallographic structure of nicotinamide at atmospheric pressure and ambient temperature is monoclinic (space group *P*2₁/*c*), and its lattice parameters are *a* = 3.975 (5), *b* = 15.632 (8), *c* = 9.422 (4) Å and β = 99.03 (7)° (NICOAM02 and NICOAM03; Miwa *et al.*, 1999). The molecule of nicotinamide can be seen in Fig. 2.

<figure><img src="image_8.png" /><figcaption>Scheme 1</figcaption></figure>

Cocrystals of S-ibuprofen and nicotinamide (SOGLAC), and of RS-ibuprofen and nicotinamide (SODDIZ) have been reported by Berry *et al.* (2008). The RS-ibuprofen and nicotinamide cocrystal structure has also been confirmed by Alshahateet (2010). The synthesis of nicotinamide-ibuprofen cocrystals provides the opportunity to combine the therapeutic effect of ibuprofen with the high solubility of nicotinamide. The cocrystals of S-ibuprofen and nicotinamide obtained by Berry *et al.* (2008) crystallize in monoclinic symmetry (space group *P*2₁) and the lattice parameters are *a* = 5.4110 (6), *b* = 55.883 (6), *c* = 11.9006 (13) Å and β = 90.004 (2)°.

Recently, we reported a metastable form of this cocrystal, with a different crystallographic structure compared to that obtained by Berry *et al.* (2008), the metastable form being obtained from melting a mixture of S-IBP and N in equimolar proportions (Guerain, Guinet *et al.*, 2020). More specifically, cocrystals were synthesized using three different methods: (1) by milling, (2) by recrystallization from the melt and (3) by evaporation from a solution. Methods (1) and (3) lead to the already-known crystallographic structure of Berry *et al.* (2008), named form B. Method (2) leads to a new metastable crystallographic form of the cocrystal, named form A. After heating, form A is transformed into form B at 60 °C. Then, form B melts at 85 °C. The present article aims to resolve the structure of the new S-ibuprofen-nicotinamide cocrystal
(S-IBP:N, Scheme 1), obtained by melting the molar mixture, and to explain the mechanisms behind the polymorphic transition A→B with temperature and the relative stability between forms A and B. The structure was solved *ab initio* from powder X-ray diffraction using a direct-space approach (simulated annealing) and refined by the Rietveld method. The positions of the H atoms were estimated from density functional theory (DFT) energy minimization.

## 2. Experimental

### 2.1. Cocrystal synthesis

S-Ibuprofen (molecular weight = 206.28 g mol⁻¹) was purchased from Sigma-Aldrich (lot number BCBH0229V, purity 99%). Powder X-ray diffraction and Rietveld analysis have shown that the commercial material is in the monoclinic crystalline form (Freer et al., 1993), as can be seen in Fig. S1 in the supporting information, and differential scanning calorimetry (DSC, Q1000, TA Instruments, 5 °C min⁻¹) reveals the melting of the material at T_m = 53 °C.

Nicotinamide (molecular weight = 122.12 g mol⁻¹) was purchased from Sigma-Aldrich (lot number BCBV2931, purity >99.5%). Powder X-ray diffraction and Rietveld analysis have shown that the commercial material is in the most stable monoclinic crystalline P2₁/c form (Miwa et al., 1999), as can be seen in Fig. S1 in the supporting information, and differential scanning calorimetry (DSC, Q1000, TA Instruments, 5 °C min⁻¹) reveals the melting of the material at T_m = 128 °C.

All the samples were analyzed without further purification.

The new cocrystal was obtained by the following methods.

An equimolar mixture (1:1), i.e. a mass of 61.89 mg of S-ibuprofen and 36.63 mg of nicotinamide, was firstly melted at 100 °C, and secondly cooled:

- either to room temperature for isothermal crystallization

- or below the glass transition temperature, T_g = -20 °C (Guerain, Guinet et al., 2020), for non-isothermal recrystallization upon heating from 25 °C (at a rate of 0.5 °C min⁻¹).

Each time, the experiment was carried out both under a cover slip and in a capillary. The same results were obtained for both methods. In all cases, a new crystallographic form of S-IBP:N cocrystals was obtained (Guerain, Guinet et al., 2020).

### 2.2. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 1. The powder X-ray diffraction patterns were measured at the Synchrotron SOLEIL, France, at the high-resolution powder diffraction beamline CRISTAL. The beamline is equipped with a 1D detector, 'MYTHEN2 X'. The beamline was set up at an energy of 17 keV and then the energy was calibrated using NIST standard LaB6660a corresponding to a wavelength (λ) of 0.728302 Å. The cocrystal powder was enclosed in a glass capillary (diameter 0.5 mm) and mounted on the diffractometer. The capillary was rotated during the experiments to

<caption>**Table 1**</caption>

Crystallographic data, profile and structural parameters for S-ibuprofen-nicotinamide cocrystal form A obtained after Rietveld refinement.

<table><thead><tr><th></th><th></th></tr></thead><tbody><tr><td>Crystal data</td><td></td></tr><tr><td>Chemical formula</td><td>C<sub>10</sub>H<sub>24</sub>N<sub>2</sub>O<sub>3</sub></td></tr><tr><td>M<sub>r</sub></td><td>328.4</td></tr><tr><td>Cell setting, space group</td><td>Monoclinic, P2<sub>1</sub></td></tr><tr><td>Temperature (K)</td><td>293</td></tr><tr><td>a,b,c (Å)</td><td>27.9925 (13), 5.5286 (2), 6.0213 (2)</td></tr><tr><td>β (°)</td><td>93.112 (2)</td></tr><tr><td>V (Å<sup>3</sup>)</td><td>930.48 (7)</td></tr><tr><td>Z</td><td>2</td></tr><tr><td>F(000)</td><td>352</td></tr><tr><td>μ (mm<sup>-1</sup>)</td><td>0.079</td></tr><tr><td>Specimen shape, size (mm)</td><td>Cylinder, 0.5</td></tr><tr><td>2θ range (°)</td><td>1.2–40.284°</td></tr><tr><td>Data collection</td><td></td></tr><tr><td>Beamline</td><td>CRISTAL (SOLEIL)</td></tr><tr><td>Specimen mounting</td><td>0.5 mm diameter Lindemann capillary</td></tr><tr><td>Data collection mode</td><td>Transmission</td></tr><tr><td>Scan method</td><td>Continuous scan</td></tr><tr><td>Radiation type</td><td>Synchrotron 17 KeV, λ = 0.728302 Å</td></tr><tr><td>Binning size (°2θ)</td><td>0.004</td></tr><tr><td>Refinement</td><td></td></tr><tr><td>R factors and goodness-of-fit</td><td>R = 0.0694, R<sub>wlp</sub>(nb) = 0.0847, R<sub>exp</sub> = 0.007</td></tr></tbody></table>

improve the grain-sampling statistics. Data were collected at room temperature (~20 °C) in the 1.2–40° 2θ range in 3 min.

The powder X-ray powder diffraction pattern of the new form of the cocrystal was compared to the most commonly used pattern databases for therapeutic materials. Coupling of the search/match functionalities of *Highscore* software with the CSD (Groom et al., 2016), crystallographic open database (COD; Gražulis et al., 2009) and the PDF-2 database of the International Center for Diffraction Data (ICDD) (Kabek-kodu et al., 2024) confirmed that this new form was not already known.

## 3. Structure determination and Rietveld refinement

First, we compared the synchrotron pattern with the reference diffraction patterns obtained in the laboratory (Guerain, Guinet et al., 2020). These observations showed that traces of pure nicotinamide remained in the sample analysed at the synchrotron. Indeed, as can be seen in Fig. S2 (see supporting information), the most intense peaks of pure nicotinamide can be observed on the cocrystal pattern between 6.8 and 6.9° and at 12.8°. Consequently, these peaks are not considered from the indexation stage.

For the indexation, the profiles of 20 reflections with a 2θ angle lower than 10° were refined individually with the programs *WinPlotr* (Roisnel & Rodríguez-Carvajal, 2001) and *DASH* (David et al., 2006) in order to obtain their 2θ angular positions. The 2θ values of these reflections were computed in the programs *DICVOL* (Boultif & Louër, 2004), *TOPAS* (Markvardsen et al., 2008; Coelho, 2000) and *McMaille* (Le Bail, 2004), and indexed. The best solution obtained with the
three software programs has a monoclinic cell with the following parameters: *a* = 27.9997, *b* = 5.5302, *c* = 6.0231 Å, *β* = 93.1097° and *V* = 931.27 Å³. The calculated figures of merit are *M*₂₀ = 26.7 and *F*₂₀ = 92.6 (de Wolff, 1968; Smith & Snyder, 1979).

The experimental powder X-ray diffraction pattern was used from 1.2 to 24°. The model was refined using the Le Bail method (Le Bail *et al.*, 1988) within the program *DASH*. A pseudo-Voight function, a linear combination of a Lorentzian and a Gaussian of the same full width at half maximum (FWHM), was used to fit the Bragg peaks. This FWHM has a *θ* dependence according to Caglioti's law (Caglioti *et al.*, 1958). The background was determined with a linear interpolation between 50 points regularly distributed from 1.2 to 24°. The parameters were refined in the following order: the lattice parameters *a*, *b* and *c*, the zero-shift, the Caglioti profile parameters *U*, *V* and *W*, the mixing parameter *η*₀ of the pseudo-Voight function and its 2*θ* dependence, and 50 points to define the background. Due to the high quality of the pattern, no parameters for the asymmetry of the Bragg peaks were used.

The *DASH* probabilistic approach to space-group determination, based on the systematic absences, was used and leads to the space group *P*2₁ (No. 4) and a unit cell containing four molecules. In order to obtain a starting structural model, the simulated annealing algorithm of the program *DASH* was used. The starting configuration of the *S*-IBP molecule was borrowed from the monoclinic model (Freer *et al.*, 1993). The starting configuration of the *N* molecule was borrowed from the monoclinic model (Miwa *et al.*, 1999). The molecules were introduced randomly in the unit cell. The restraint options used for the calculations did not modify the bond lengths and bond angles. The translation and orientation parameters of the molecule in the cell, as well as the torsion angles, were defined as variables in the calculation. From this structural model, rigid-body Rietveld refinement was performed using *DASH*.

The refinement was performed in three steps: first, the global isotropic temperature factor, second, the translation and orientation parameters of the molecule, and third, the torsion angles. The lattice parameters and the background parameters were set free.

Because H atoms are poorly located in powder X-ray powder diffraction data, such data were not used to independently refine the H-atom positions. They were optimized by density functional theory (DFT). The structural model was minimized using periodic density functional theory with fixed-cell dispersion-corrected density functional theory (DFT-D) (Giannozzi *et al.*, 2009, 2017). In this minimization, the positions of the heavy atoms were constrained, while the positions of the H atoms were let free. The Perdew-Burke-Ernzerhof (PBE) functional (Perdew *et al.*, 1996) was used with projector-augmented wave pseudopotentials and the Grimme D3 correction (Grimme *et al.*, 2010), as implemented in the pw.x executable of the *Quantum Espresso* program (Giannozzi *et al.*, 2009, 2017).

Then, from the structural model and the H-atom positions, atomic coordinates were introduced in the programs *MAUD* (Materials Analysis Using Diffraction) (Lutterotti, 2010) and *JANA2020* (Petríček *et al.*, 2014), in order to graphically compare the calculated and experimental X-ray diffraction diagram (*MAUD*) and to generate the most accurate and complete CIF possible (*JANA2020*). The lattice parameters are *a* = 27.9925 (13), *b* = 5.5286 (2), *c* = 6.0213 (2) Å, *β* = 93.112 (2)° and *V* = 930.48 (7) Å³. The final conventional *R* factors are *R* = 0.0694, *R*<sub>wp</sub>(nb) = 0.0847, and *R*<sub>exp</sub> = 0.007. The experimental and calculated diffraction patterns are shown in Fig. 3. Crystallographic data, profile and structural parameters are given in Table 1. The atomic positions from the final Rietveld refinement and DFT optimization can be seen in Table S1 in the supporting information. A comparison between the refined and the DFT-optimized structure can also be seen in Fig. S3.

<figure><img src="image_9.png" /><figcaption>Figure 3</figcaption></figure>

Final Rietveld plot of the *S*-ibuprofen–nicotinamide cocrystal at room temperature. The observed intensities are indicated by dots and solid lines represent the best-fit profile (upper trace) and the difference pattern (lower trace). The vertical bars correspond to the positions of the Bragg peaks.
<caption>**Table 2**</caption>

Lattice unit-cell parameters comparisons between S-ibuprofen-nicotinamide cocrystal form A and S-ibuprofen-nicotinamide cocrystal form B (Berry *et al.*, 2008).

<table><thead><tr><th>Structure</th><th>a (Å)</th><th>b (Å)</th><th>c (Å)</th><th>β (°)</th><th>V (Å³)</th><th>Symmetry</th><th>Reference</th></tr></thead><tbody><tr><td>S-IBP:N Form A</td><td>27.9925</td><td>5.5286</td><td>6.0213</td><td>93.112</td><td>930.48</td><td>P2<sub>1</sub></td><td>This work</td></tr><tr><td>S-IBP:N Form B</td><td>5.4110</td><td>55.883</td><td>11.9006</td><td>90.004</td><td>3598.5</td><td>P2<sub>1</sub></td><td>Berry *et al.* (2008)</td></tr></tbody></table>

The *R* factors are comparable to those obtained in the case of other cocrystals. In particular, similar factors are obtained with *R* = 0.1097 and *R*<sub>wp</sub>(nb) = 0.1547 for the RS-ibuprofen-nicotinamide cocrystal, and *R* = 0.0582 and *R*<sub>wp</sub>(nb) = 0.138 for the S-ibuprofen-nicotinamide form B cocrystal. It is also comparable to the results obtained for the carbamazepine-tartaric acid cocrystal (Guerain, Derollez *et al.*, 2020) with the following *R* factors: *R* = 0.1207 and *R*<sub>wp</sub>(nb) = 0.1725. The correlation between the calculated and experimental X-ray diagram could be better in the absence of spurious peaks, probably due to the presence of nicotinamide impurities. However, calculations involving the stable form of nicotinamide have been performed but do not significantly improve this correlation. Unfortunately, due to the rich polymorphism of nicotinamide, it is not possible to know unambiguously the polymorphic form of nicotinamide present, and it is also possible that multiple polymorphs are present, which makes the calculation difficult.

## 4. Discussion

According to our previous experiments (Guerain, Guinet *et al.*, 2020), the Raman spectroscopy analysis performed on new S-IBP:N cocrystal form A clearly indicates both N—H···O molecular associations and O—H···N associations. Fig. 4 shows the spectrum of X—H stretching vibrations (X = C, N and O) collected at 20 and —100 °C in a previous study

<figure><img src="image_10.png" /><figcaption>**Figure 4**</figcaption></figure>

Intramolecular C—H, N—H and O—H stretching region in form A at 20 and —100 °C (dashed line), and in Form B at 20 °C for S-IBP:N from Guerain, Guinet *et al.* (2020). The insert presents a zoom along the y axis of the N—H and O—H stretching region.

(Guerain, Guinet *et al.*, 2020). It clearly shows three stretching vibrations of bonds involved in intermolecular associations via hydrogen bonding, easily recognized by the positive temperature dependence of the Raman bands. The N—H stretching band around 3150 cm<sup>-1</sup> is distinctive of N—H···O molecular associations, while the temperature dependences of O—H stretching bands located at 3390 and 3400 cm<sup>-1</sup> reflect O—H···N associations.

The crystallographic structure found here is consistent with these previous results, as can be seen in Fig. 5. Indeed, for the S-IBP:N cocrystal form A obtained here, N—H···O associations form between nicotinamide molecules through their primary amide group. A nicotinamide molecule is linked to two others by N—H···O hydrogen bonds. The NH<sub>2</sub> group of the molecule is linked to the C=O groups of another nicotinamide molecule and its own C=O group is linked to the NH<sub>2</sub> group of a third nicotinamide molecule. Moreover, O—H···N associations bind the ibuprofen and nicotinamide molecules through bonds between the N atoms of the nicotinamide pyridine ring and the H and O atoms of the ibuprofen carboxyl group.

The structure of the new S-IBP:N cocrystal form A resolved in this work can also be compared to the already known (Berry *et al.*, 2008) cocrystal obtained by solvent evaporation or milling, namely form B (Guerain, Guinet *et al.*, 2020).

The lattice parameters of S-IBP:N cocrystal forms A and B are given in Table 2. Both structures exhibit a monoclinic symmetry and crystallize in the same space group P2<sub>1</sub> (No. 4). Form B has a small lattice parameter (~5 Å), an intermediate one (~12 Å) and a larger one (~56 Å), while form A has two

<figure><img src="image_11.png" /><figcaption>**Figure 5**</figcaption></figure>

Projection of the unit cell along the [001] direction for S-ibuprofen-nicotinamide cocrystal form A and visualization of the hydrogen-bond network. Colour key: O atoms red, N atoms blue, C atoms black and H atoms white.
small lattice parameter (~5 and 6 Å) and a larger one (~28 Å) which is half that of form B. This results in a division by four of the unit-cell volume for form B compared to form A reflecting the fact that the cell of form A contains two molecules of ibuprofen and two molecules of nicotinamide, while form B contains eight molecules of each. Moreover, there is a difference in the β angle of the two forms, the cocrystal obtained in this work having a β angle greater than that of form B, which is a little greater than 90°.

These differences are due to a slight difference in the structural arrangement of the molecules (see Figs. 6 and 7).

In both cocrystals, molecules of ibuprofen and molecules of nicotinamide are stacked along the *c* axis without mirror projection or rotation from one molecule to another. In cocrystal S-IBP:N form A, molecules of ibuprofen and molecules of nicotinamide are also stacked along the *b* axis without mirror projection or rotation from one molecule to another. Thus, in this cocrystal, lattice parameters *c* and *b* are similar in value.

In cocrystal S-IBP:N form B, molecules of ibuprofen and molecules of nicotinamide are stacked along the *c* axis, as mentioned previously, and along the *a* axis without mirror projection or rotation from one molecule to another.

The difference between the two cocrystals originates from the stacking of the molecules along the larger axis (*a* for form A and *b* for form B). For cocrystal form A, along the *a* axis, there is an alternation of two molecules of ibuprofen, reversed with respect to each other, followed by two molecules of nicotinamide, reversed with respect to each other, and so on.

<figure><img src="image_12.png" /><figcaption>**Figure 6**
Projection of 4 × 2 cells of S-IBP:N cocrystal form A along the [010] direction.</figcaption></figure>

<figure><img src="image_13.png" /><figcaption>**Figure 7**
Projection of 4 × 1 cells of S-IBP:N cocrystal form B (Berry *et al.*, 2008) along the [100] direction.</figcaption></figure>

For cocrystal form B, there is also an alternation of two molecules of ibuprofen, reversed relative to each other, followed by two molecules of nicotinamide, reversed relative to each other. However, the next two ibuprofen molecules are not in the same configuration as the two ibuprofen molecules preceding the nicotinamide molecules. Indeed, there is a 180° rotation compared to the front one. The same is true for the nicotinamide molecules, which are also rotated by 180° compared to the previous nicotinamide molecules. Consequently, the *b* axis of S-IBP:N form B is twice that of the *a* axis of S-IBP:N form A. Thus, the structures of forms A and B are similar and differ mainly in the orientations of the benzene rings of ibuprofen.

The small difference between the crystallographic lattice of form A and that of form B is in agreement with the observations made previously during differential scanning calorimetry (DSC) experiments (Guerain, Guinet *et al.*, 2020). The transformation A→B around 50 °C [revealed by Raman spectroscopy and X-ray diffraction in Guerain, Guinet *et al.* (2020)] was difficult to observe in DSC (see Fig. S4 in the supporting information). Thus, it had been hypothesized that this transformation during heating was subtle, with a low energy phase transition and fairly close crystallographic cell for forms A and B. In addition, such small differences between the crystal lattices of the two forms also lead to relatively similar diffraction patterns with a certain number of peaks of forms A and B located at the same positions. This point was also observed in our previous experiments (see Fig. S5 in the supporting information).
<figure><img src="image_14.png" /><figcaption>**Figure 8**</figcaption></figure>

Projection of the unit cell along the [100] direction for S-ibuprofen-nicotinamide cocrystal form B (Berry *et al.*, 2008) and visualization of the hydrogen-bond network.

Regarding the cocrystal stability, we previously demonstrated that form A, which has been resolved here, is a metastable form, while form B is stable (Guerain, Guinet *et al.*, 2020). This relative stability and the transition from form A to form B can be explained by the comparison between the structure obtained here and that obtained by Berry *et al.* (2008). For the structure of form A, as can be seen in Fig. 5, nicotinamide molecules are linked together by N-H···O hydrogen bonds. This is also true for form B, as can be seen in Fig. 8. However, for form A, one molecule of nicotinamide is linked to two different nicotinamide molecules by N-H···O hydrogen bonds, whereas in the case of form B, two molecules of nicotinamide are linked together by dimer associations. Moreover, the O2-H2O···N1 hydrogen bond exists for both forms, but this bond has a shorter distance between O2 and N1 for form B than for form A (2.652 versus 2.689 Å). Therefore, this bond is more energetic and stable for form B. This result is in agreement with previously published Raman data (Guerain, Guinet *et al.*, 2020), where we showed that, when the temperature increases, the frequency of Raman bands O-H at 3375 cm⁻¹ in form A is greater than in form B, reflecting weaker molecular interactions between nicotinamide and ibuprofen in form A than in form B. In this context, form A is less stable than form B, considering that hydrogen bonds are responsible for the crystalline stability [the Raman spectra analysis performed and published in Guerain, Guinet *et al.* (2020) is given in Fig. S6 in the supporting information].

Finally, form A has a single bond between the molecule of ibuprofen and that of nicotinamide (Fig. 5), while form B has two (Fig. 8). Indeed, the O1-H···H2A-N2 hydrogen bond does not exist in form A (see Figs. 5 and 8). Form B therefore has one more type of N-H···O hydrogen bond than form A. In addition, the O-H···N hydrogen bonds between the nicotinamide molecules and the ibuprofen molecules are more energetic for form B than for form A. This justifies the different degrees of stability of the two forms observed previously (Guerain, Guinet *et al.*, 2020).

The polymorphic transition A→B could therefore be explained by the fact that in form A, under the effect of molecular agitation, rotation of the -CONH₂ group of nicotinamide would lead to the formation of a dimer on the one hand and to the appearance of a new N-H···O hydrogen

bond between the ibuprofen molecule and that of nicotinamide on the other hand. This new configuration associated with a shorter O-H···N hydrogen bond would ensure a stronger interaction between the nicotinamide and ibuprofen molecules, and would stabilize the structure into form B, the most stable form. However, van der Waals bonds also play an important role in the stability of cocrystals (Cruz-Cabeza *et al.*, 2024) and it would be interesting to carry out calculations involving them to confirm the stated hypothesis.

The energies of forms A and B as determined by the present study and in Berry *et al.* (2008) have been computed using periodic density functional theory employing the same methods as described in Section 3. As expected, metastable form A possesses a higher energy than stable form B. The energy difference is about 23.6 kcal mol⁻¹, which is quite significant, but well in line with the trend reported in Nyman & Day (2015). It should be noted that this difference could be a little lower, since the structure of form A has been determined at *T* = 293 K, while form B was determined at *T* = 120 K.

## Acknowledgements

This project has received funding from the Interreg 2 Seas programme 2014-2020 co-funded by the European Regional Development Fund.

## Funding information

Funding for this research was provided by: European Regional Development Fund (subsidy contract No. 2S01-059_IMODE).

## References

Alshahateet, S. F. (2010). *Mol. Cryst. Liq. Cryst.* **533**, 152–161.

Berry, D. J., Seaton, C. C., Clegg, W., Harrington, R. W., Coles, S. J., Horton, P. N., Hursthouse, M. B., Storey, R., Jones, W., Friščić, T. & Blagden, N. (2008). *Cryst. Growth Des.* **8**, 1697–1712.

Boultif, A. & Louër, D. (2004). *J. Appl. Cryst.* **37**, 724–731.

Brittain, H. G. (2013). *J. Pharm. Sci.* **102**, 311–317.

Caglioti, G., Paoletti, A. & Ricci, F. P. (1958). *Nucl. Instrum.* **3**, 223–228.
Childs, S. L., Wood, P. A., Rodríguez-Hornedo, N., Reddy, L. S. & Hardcastle, K. I. (2009). *Cryst. Growth Des.* **9**, 1869–1888.

Coelho, A. A. (2000). *J. Appl. Cryst.* **33**, 899–908.

Cruz-Cabeza, A. J., Spackman, P. R. & Hall, A. V. (2024). *Commun. Chem.* **7**, 284.

David, W. I. F., Shankland, K., van de Streek, J., Pidcock, E., Motherwell, W. D. S. & Cole, J. C. (2006). *J. Appl. Cryst.* **39**, 910–915.

Desiraju, G. R. (2010). *J. Chem. Sci.* **122**, 667–675.

Dwivedi, S. K., Sattari, S., Jamali, F. & Mitchell, A. G. (1992). *Int. J. Pharm.* **87**, 95–104.

Fellah, N., Zhang, C. J., Chen, C., Hu, C. T., Kahr, B., Ward, M. D. & Shtukenberg, A. G. (2021). *Cryst. Growth Des.* **21**, 4713–4724.

Fleischman, S. G., Kuduva, S. S., McMahon, J. A., Moulton, B., Bailey Walsh, R. D., Rodríguez-Hornedo, N. & Zaworotko, M. J. (2003). *Cryst. Growth Des.* **3**, 909–919.

Freer, A. A., Bunyan, J. M., Shankland, N. & Sheen, D. B. (1993). *Acta Cryst.* **C49**, 1378–1380.

Friščić, T. & Jones, W. (2010). *J. Pharm. Pharmacol.* **62**, 1547–1559.

Garzón, L. C. & Martínez, F. (2004). *J. Solution Chem.* **33**, 1379–1395.

Giannozzi, P., Andreussi, O., Brumme, T., Bunau, O., Buongiorno Nardelli, M., Calandra, M., Car, R., Cavazzoni, C., Ceresoli, D., Cococcioni, M., Colonna, N., Carnimeo, I., Dal Corso, A., de Gironcoli, S., Delugas, P., DiStasio, R. A., Ferretti, A., Floris, A., Fratesi, G., Fugallo, G., Gebauer, R., Gerstmann, U., Giustino, F., Gorni, T., Jia, J., Kawamura, M., Ko, H.-Y., Kokalj, A., Küçükbenli, E., Lazzeri, M., Marsili, M., Marzari, N., Mauri, F., Nguyen, N. L., Nguyen, H.-V., Otero-de-la-Roza, A., Paulatto, L., Poncé, S., Rocca, D., Sabatini, R., Santra, B., Schlipf, M., Seitsonen, A. P., Smogunov, A., Timrov, I., Thonhauser, T., Umari, P., Vast, N., Wu, X. & Baroni, S. (2017). *J. Phys. Condens. Matter* **29**, 465901.

Giannozzi, P., Baroni, S., Bonini, N., Calandra, M., Car, R., Cavazzoni, C., Ceresoli, D., Chiarotti, G. L., Cococcioni, M., Dabo, I., Dal Corso, A., de Gironcoli, S., Fabris, S., Fratesi, G., Gebauer, R., Gerstmann, U., Gougoussis, C., Kokalj, A., Lazzeri, M., Martin-Samos, L., Marzari, N., Mauri, F., Mazzarello, R., Paolini, S., Pasquarello, A., Paulatto, L., Sbraccia, C., Scandolo, S., Sclauzero, G., Seitsonen, A. P., Smogunov, A., Umari, P. & Wentzcovitch, R. M. (2009). *J. Phys. Condens. Matter* **21**, 395502.

Gražulis, S., Chateigner, D., Downs, R. T., Yokochi, A. F. T., Quirós, M., Lutterotti, L., Manakova, E., Butkus, J., Moeck, P. & Le Bail, A. (2009). *J. Appl. Cryst.* **42**, 726–729.

Grimme, S., Antony, J., Ehrlich, S. & Krieg, H. (2010). *J. Chem. Phys.* **132**, 154104.

Groom, C. R., Bruno, I. J., Lightfoot, M. P. & Ward, S. C. (2016). *Acta Cryst.* **B72**, 171–179.

Guerain, M., Derollez, P., Roca-Paixão, L., Dejoie, C., Correia, N. T. & Affouard, F. (2020). *Acta Cryst.* **C76**, 225–230.

Guerain, M., Guinet, Y., Correia, N. T., Paccou, L., Danède, F. & Hédoux, A. (2020). *Int. J. Pharm.* **584**, 119454.

Higashi, K., Ueda, K. & Moribe, K. (2017). *Adv. Drug Deliv. Rev.* **117**, 71–85.

Kabekkodu, S. N., Dosen, A. & Blanton, T. N. (2024). *Powder Diffr.* **39**, 47–59.

Karimi-Jafari, M., Padrela, L., Walker, G. M. & Croker, D. M. (2018). *Cryst. Growth Des.* **18**, 6370–6387.

Le Bail, A. (2004). *Powder Diffr.* **19**, 249–254.

Le Bail, A., Duroy, H. & Fourquet, J. L. (1988). *Mater. Res. Bull.* **23**, 447–452.

Lutterotti, L. (2010). *Nucl. Instrum. Methods Phys. Res. B* **268**, 334–340.

Markvardsen, A. J., Shankland, K., David, W. I. F., Johnston, J. C., Ibberson, R. M., Tucker, M., Nowell, H. & Griffin, T. (2008). *J. Appl. Cryst.* **41**, 1177–1181.

Miwa, Y., Mizuno, T., Tsuchida, K., Taga, T. & Iwata, Y. (1999). *Acta Cryst.* **B55**, 78–84.

Nyman, J. & Day, G. M. (2015). *CrystEngComm* **17**, 5154–5165.

Oswald, I. D. H., Allan, D. R., McGregor, P. A., Motherwell, W. D. S., Parsons, S. & Pulham, C. R. (2002). *Acta Cryst.* **B58**, 1057–1066.

Perdew, J. P., Burke, K. & Ernzerhof, M. (1996). *Phys. Rev. Lett.* **77**, 3865–3868.

Petríček, V., Dusek, M. & Palatinus, L. (2014). *Z. Kristallogr. Cryst. Mater.* **229**, 345–352.

Roisnel, T. & Rodríguez-Carvajal, J. (2001). *Mater. Sci. Forum* **378–381**, 118–123.

Schultheiss, N. & Newman, A. (2009). *Cryst. Growth Des.* **9**, 2950–2967.

Smith, G. S. & Snyder, R. L. (1979). *J. Appl. Cryst.* **12**, 60–65.

ter Horst, J. H., Deij, M. A. & Cains, P. W. (2009). *Cryst. Growth Des.* **9**, 1531–1537.

Vishweshwar, P., McMahon, J. A., Bis, J. A. & Zaworotko, M. J. (2006). *J. Pharm. Sci.* **95**, 499–516.

WHO (2007). *Model lists of essential medicines*. Geneva: WHO. https://www.who.int/.

Wolff, P. M. de (1968). *J. Appl. Cryst.* **1**, 108–113.
supporting information

Acta Cryst. (2025). C81 [https://doi.org/10.1107/S2053229625008952]

# Origin of phase relative stability and phase transformation in an S-ibuprofen-nicotinamide cocrystal

Mathieu Guerain, Hubert Chevreau, Erik Elkaim, Yannick Guinet, Laurent Paccou, Florence Danède, Alain Hedoux and Frederic Affouard

## Computing details

(2S)-2-[4-(2-methylpropyl)phenyl]propanoic acid; pyridine-3-carboxamide

### Crystal data

C₁₃H₁₈O₂·C₆H₆N₂O

M_r = 328.4

Monoclinic, P2₁

Hall symbol: P 2yb

a = 27.9925 (13) Å

b = 5.5286 (2) Å

c = 6.0213 (2) Å

β = 93.112 (2)°

V = 930.48 (7) Å³

Z = 2

F(000) = 352

Dₓ = 1.172 Mg m⁻³

Synchrotron radiation

T = 293 K

white

### Data collection

Synchrotron diffractometer

Radiation source: synchrotron, synchrotron
2θₘₜₘ = 2°, 2θₘₜₘ = 40.284°, 2θₘₜₚ = 0.004°

### Refinement

Rₚ = 0.069

Rₖₚ = 0.085

Rₚₘ = 0.007

R(F) = 0.293

9572 data points

Profile function: Pseudo-Voigt

19 parameters

0 restraints

1 constraint

H-atom parameters constrained

Weighting scheme based on measured s.u.'s
(Δ/σ)ₘₜₘ = 0.021

Background function: 8 Legendre polynomials

Preferred orientation correction: none

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

<table><thead><tr><th></th><th>x</th><th>y</th><th>z</th><th>U<sub>iso</sub>*/U<sub>eq</sub></th></tr></thead><tbody><tr><td>C1</td><td>0.10542</td><td>0.78781</td><td>0.96105</td><td>0.038*</td></tr><tr><td>C2</td><td>0.0715</td><td>0.89643</td><td>0.81798</td><td>0.038*</td></tr><tr><td>C3</td><td>0.06348</td><td>0.79785</td><td>0.60733</td><td>0.038*</td></tr><tr><td>C4</td><td>0.09017</td><td>0.6005</td><td>0.5454</td><td>0.038*</td></tr><tr><td>C5</td><td>0.1233</td><td>0.50458</td><td>0.69961</td><td>0.038*</td></tr><tr><td>C6</td><td>0.04223</td><td>1.10996</td><td>0.87776</td><td>0.038*</td></tr><tr><td>N1</td><td>0.13085</td><td>0.59378</td><td>0.90493</td><td>0.038*</td></tr><tr><td>N2</td><td>-0.00513</td><td>1.09704</td><td>0.83783</td><td>0.038*</td></tr></tbody></table>
<table><tr><td>O1</td><td>0.06198</td><td>1.28875</td><td>0.96245</td><td>0.038*</td></tr><tr><td>H1</td><td>0.11221</td><td>0.85118</td><td>1.12828</td><td>0.045*</td></tr><tr><td>H2</td><td>0.03549</td><td>0.87684</td><td>0.49651</td><td>0.045*</td></tr><tr><td>H3</td><td>0.08505</td><td>0.52005</td><td>0.38215</td><td>0.045*</td></tr><tr><td>H4</td><td>0.14473</td><td>0.35115</td><td>0.65726</td><td>0.045*</td></tr><tr><td>H5</td><td>-0.0212</td><td>0.94052</td><td>0.79667</td><td>0.057*</td></tr><tr><td>H6</td><td>-0.02542</td><td>1.23961</td><td>0.88113</td><td>0.057*</td></tr><tr><td>O2</td><td>0.16899</td><td>0.95336</td><td>0.25132</td><td>0.038*</td></tr><tr><td>O3</td><td>0.21438</td><td>0.65622</td><td>0.13975</td><td>0.038*</td></tr><tr><td>H7</td><td>0.46113</td><td>1.10245</td><td>-0.52283</td><td>0.057*</td></tr><tr><td>H8</td><td>0.43613</td><td>0.73029</td><td>-0.15812</td><td>0.057*</td></tr><tr><td>H9</td><td>0.46217</td><td>1.34307</td><td>-0.34301</td><td>0.057*</td></tr><tr><td>H10</td><td>0.49269</td><td>1.08351</td><td>-0.24456</td><td>0.057*</td></tr><tr><td>H11</td><td>0.25627</td><td>1.11609</td><td>0.72662</td><td>0.057*</td></tr><tr><td>H12</td><td>0.39447</td><td>1.18708</td><td>-0.32484</td><td>0.045*</td></tr><tr><td>H13</td><td>0.44578</td><td>1.12008</td><td>0.07107</td><td>0.057*</td></tr><tr><td>H14</td><td>0.20411</td><td>1.03769</td><td>0.6767</td><td>0.057*</td></tr><tr><td>H15</td><td>0.41706</td><td>1.35289</td><td>-0.01217</td><td>0.057*</td></tr><tr><td>H16</td><td>0.37915</td><td>0.80001</td><td>-0.22382</td><td>0.057*</td></tr><tr><td>H17</td><td>0.41041</td><td>0.7791</td><td>-0.42849</td><td>0.057*</td></tr><tr><td>H18</td><td>0.36321</td><td>1.3927</td><td>0.20728</td><td>0.045*</td></tr><tr><td>H19</td><td>0.25054</td><td>0.75264</td><td>0.51399</td><td>0.045*</td></tr><tr><td>H20</td><td>0.38007</td><td>0.72943</td><td>0.07552</td><td>0.045*</td></tr><tr><td>H21</td><td>0.31025</td><td>0.63289</td><td>0.24243</td><td>0.045*</td></tr><tr><td>H22</td><td>0.28275</td><td>1.29856</td><td>0.36714</td><td>0.045*</td></tr><tr><td>H23</td><td>0.1904</td><td>0.65201</td><td>0.02652</td><td>0.057*</td></tr><tr><td>H24</td><td>0.21628</td><td>1.24069</td><td>0.53278</td><td>0.057*</td></tr><tr><td>C7</td><td>0.20574</td><td>0.83543</td><td>0.27205</td><td>0.038*</td></tr><tr><td>C8</td><td>0.24468</td><td>0.89242</td><td>0.44365</td><td>0.038*</td></tr><tr><td>C9</td><td>0.22863</td><td>1.08503</td><td>0.6075</td><td>0.038*</td></tr><tr><td>C10</td><td>0.28917</td><td>0.96305</td><td>0.3253</td><td>0.038*</td></tr><tr><td>C11</td><td>0.30315</td><td>1.20264</td><td>0.31605</td><td>0.038*</td></tr><tr><td>C12</td><td>0.34435</td><td>1.26828</td><td>0.21381</td><td>0.038*</td></tr><tr><td>C13</td><td>0.3731</td><td>1.09936</td><td>0.11913</td><td>0.038*</td></tr><tr><td>C14</td><td>0.35935</td><td>0.86131</td><td>0.13181</td><td>0.038*</td></tr><tr><td>C15</td><td>0.31843</td><td>0.79521</td><td>0.23264</td><td>0.038*</td></tr><tr><td>C16</td><td>0.41667</td><td>1.1768</td><td>-0.00151</td><td>0.038*</td></tr><tr><td>C17</td><td>0.41689</td><td>1.08938</td><td>-0.24017</td><td>0.038*</td></tr><tr><td>C18</td><td>0.41052</td><td>0.8192</td><td>-0.25505</td><td>0.038*</td></tr><tr><td>C19</td><td>0.46232</td><td>1.16374</td><td>-0.34906</td><td>0.038*</td></tr></table>

Atomic displacement parameters (Å²)

<table><tr><td></td><td>U<sup>11</sup></td><td>U<sup>22</sup></td><td>U<sup>33</sup></td><td>U<sup>12</sup></td><td>U<sup>13</sup></td><td>U<sup>23</sup></td></tr><tr><td>?</td><td>?</td><td>?</td><td>?</td><td>?</td><td>?</td><td>?</td></tr></table>
<table><caption>Geometric parameters (Å, °)</caption><tr><td>C1—C2</td><td>1.3844</td><td>H13—C16</td><td>0.9567</td></tr><tr><td>C1—N1</td><td>1.3412</td><td>H14—C9</td><td>0.8629</td></tr><tr><td>C1—H1</td><td>1.0736</td><td>H15—C16</td><td>0.976</td></tr><tr><td>C2—C3</td><td>1.388</td><td>H16—C18</td><td>1.0346</td></tr><tr><td>C2—C6</td><td>1.4926</td><td>H17—C18</td><td>1.0678</td></tr><tr><td>C3—C4</td><td>1.3853</td><td>H18—C12</td><td>0.9973</td></tr><tr><td>C3—H2</td><td>1.0926</td><td>H19—C8</td><td>0.8924</td></tr><tr><td>C4—C5</td><td>1.3824</td><td>H20—C14</td><td>1.0024</td></tr><tr><td>C4—H3</td><td>1.0817</td><td>H21—C15</td><td>0.9291</td></tr><tr><td>C5—N1</td><td>1.3375</td><td>H22—C11</td><td>0.8494</td></tr><tr><td>C5—H4</td><td>1.0778</td><td>H24—C9</td><td>1.0229</td></tr><tr><td>C6—N2</td><td>1.3367</td><td>C7—C8</td><td>1.4947</td></tr><tr><td>C6—O1</td><td>1.23</td><td>C8—C9</td><td>1.5358</td></tr><tr><td>N2—H5</td><td>1.0005</td><td>C8—C10</td><td>1.5195</td></tr><tr><td>N2—H6</td><td>1.0141</td><td>C10—C11</td><td>1.3836</td></tr><tr><td>O2—C7</td><td>1.2189</td><td>C10—C15</td><td>1.3762</td></tr><tr><td>O3—H23</td><td>0.931</td><td>C11—C12</td><td>1.3852</td></tr><tr><td>O3—C7</td><td>1.3025</td><td>C12—C13</td><td>1.3768</td></tr><tr><td>H7—C19</td><td>1.0989</td><td>C13—C14</td><td>1.3749</td></tr><tr><td>H8—C18</td><td>1.0254</td><td>C13—C16</td><td>1.5152</td></tr><tr><td>H9—C19</td><td>0.9924</td><td>C14—C15</td><td>1.375</td></tr><tr><td>H10—C19</td><td>1.1216</td><td>C16—C17</td><td>1.5169</td></tr><tr><td>H11—C9</td><td>1.0407</td><td>C17—C18</td><td>1.5068</td></tr><tr><td>H12—C17</td><td>0.9546</td><td>C17—C19</td><td>1.5192</td></tr><tr><td>C2—C1—N1</td><td>123.09</td><td>C11—C10—C15</td><td>116.98</td></tr><tr><td>C2—C1—H1</td><td>121.53</td><td>H22—C11—C10</td><td>112.72</td></tr><tr><td>N1—C1—H1</td><td>115.35</td><td>H22—C11—C12</td><td>126.16</td></tr><tr><td>C1—C2—C3</td><td>118.04</td><td>C10—C11—C12</td><td>120.87</td></tr><tr><td>C1—C2—C6</td><td>124.07</td><td>H18—C12—C11</td><td>119.07</td></tr><tr><td>C3—C2—C6</td><td>117.87</td><td>H18—C12—C13</td><td>119.18</td></tr><tr><td>C2—C3—C4</td><td>119.52</td><td>C11—C12—C13</td><td>121.74</td></tr><tr><td>C2—C3—H2</td><td>118.46</td><td>C12—C13—C14</td><td>117.06</td></tr><tr><td>C4—C3—H2</td><td>122.01</td><td>C12—C13—C16</td><td>120.72</td></tr><tr><td>C3—C4—C5</td><td>118.26</td><td>C14—C13—C16</td><td>122.17</td></tr><tr><td>C3—C4—H3</td><td>121.47</td><td>H20—C14—C13</td><td>120.59</td></tr><tr><td>C5—C4—H3</td><td>120.26</td><td>H20—C14—C15</td><td>117.86</td></tr><tr><td>C4—C5—N1</td><td>123.12</td><td>C13—C14—C15</td><td>121.44</td></tr><tr><td>C4—C5—H4</td><td>120.33</td><td>H21—C15—C10</td><td>118.14</td></tr><tr><td>N1—C5—H4</td><td>116.56</td><td>H21—C15—C14</td><td>119.94</td></tr><tr><td>C2—C6—N2</td><td>117.82</td><td>C10—C15—C14</td><td>121.9</td></tr><tr><td>C2—C6—O1</td><td>119.71</td><td>H13—C16—H15</td><td>110.18</td></tr><tr><td>N2—C6—O1</td><td>122.47</td><td>H13—C16—C13</td><td>112.11</td></tr><tr><td>C1—N1—C5</td><td>117.95</td><td>H13—C16—C17</td><td>106.34</td></tr><tr><td>C6—N2—H5</td><td>121.28</td><td>H15—C16—C13</td><td>109.01</td></tr><tr><td>C6—N2—H6</td><td>118.44</td><td>H15—C16—C17</td><td>104.77</td></tr></table>
<table><caption>Hydrogen-bond geometry (Å, °)</caption><tr><td>H5—N2—H6</td><td>119.05</td><td>C13—C16—C17</td><td>114.15</td></tr><tr><td>H23—O3—C7</td><td>108.46</td><td>H12—C17—C16</td><td>106.83</td></tr><tr><td>O2—C7—O3</td><td>121.88</td><td>H12—C17—C18</td><td>117.2</td></tr><tr><td>O2—C7—C8</td><td>122.55</td><td>H12—C17—C19</td><td>99.09</td></tr><tr><td>O3—C7—C8</td><td>115.51</td><td>C16—C17—C18</td><td>111.46</td></tr><tr><td>H19—C8—C7</td><td>104.72</td><td>C16—C17—C19</td><td>111.68</td></tr><tr><td>H19—C8—C9</td><td>110.39</td><td>C18—C17—C19</td><td>109.99</td></tr><tr><td>H19—C8—C10</td><td>108.12</td><td>H8—C18—H16</td><td>102.77</td></tr><tr><td>C7—C8—C9</td><td>111.27</td><td>H8—C18—H17</td><td>114.98</td></tr><tr><td>C7—C8—C10</td><td>108.4</td><td>H8—C18—C17</td><td>111.39</td></tr><tr><td>C9—C8—C10</td><td>113.52</td><td>H16—C18—H17</td><td>113.18</td></tr><tr><td>H11—C9—H14</td><td>107.37</td><td>H16—C18—C17</td><td>109.66</td></tr><tr><td>H11—C9—H24</td><td>112.67</td><td>H17—C18—C17</td><td>104.96</td></tr><tr><td>H11—C9—C8</td><td>108.96</td><td>H7—C19—H9</td><td>110.07</td></tr><tr><td>H14—C9—H24</td><td>102.06</td><td>H7—C19—H10</td><td>113.29</td></tr><tr><td>H14—C9—C8</td><td>111.6</td><td>H7—C19—C17</td><td>110.17</td></tr><tr><td>H24—C9—C8</td><td>113.87</td><td>H9—C19—H10</td><td>112.29</td></tr><tr><td>C8—C10—C11</td><td>120.4</td><td>H9—C19—C17</td><td>104.44</td></tr><tr><td>C8—C10—C15</td><td>122.56</td><td>H10—C19—C17</td><td>106.12</td></tr></table>

<table><thead><tr><th>D—H···A</th><th>D—H</th><th>H···A</th><th>D···A</th><th>D—H···A</th></tr></thead><tbody><tr><td>C1—H1···O2<sup>i</sup></td><td>1.07</td><td>1.81</td><td>2.5933</td><td>126.42</td></tr><tr><td>N2—H5···O1<sup>ii</sup></td><td>1.00</td><td>2.07</td><td>2.6637</td><td>115.75</td></tr><tr><td>N2—H6···C1<sup>iii</sup></td><td>1.01</td><td>2.49</td><td>3.2916</td><td>135.09</td></tr><tr><td>N2—H6···C2<sup>iii</sup></td><td>1.01</td><td>2.44</td><td>3.3031</td><td>142.51</td></tr><tr><td>C18—H16···C14</td><td>1.03</td><td>2.07</td><td>2.8104</td><td>126.30</td></tr><tr><td>C12—H18···C14<sup>iv</sup></td><td>1.00</td><td>2.37</td><td>3.3464</td><td>166.97</td></tr><tr><td>C12—H18···C15<sup>iv</sup></td><td>1.00</td><td>2.19</td><td>3.0067</td><td>138.27</td></tr><tr><td>C14—H20···C18</td><td>1.00</td><td>2.26</td><td>2.8104</td><td>112.99</td></tr><tr><td>C15—H21···C11<sup>v</sup></td><td>0.93</td><td>2.43</td><td>3.3463</td><td>168.62</td></tr><tr><td>C15—H21···C12<sup>v</sup></td><td>0.93</td><td>2.24</td><td>3.0067</td><td>139.17</td></tr><tr><td>C11—H22···C9</td><td>0.85</td><td>2.45</td><td>2.8733</td><td>111.23</td></tr><tr><td>O3—H23···N1<sup>vi</sup></td><td>0.93</td><td>1.81</td><td>2.6890</td><td>155.66</td></tr></tbody></table>

Symmetry codes: (i) x, y, z+1; (ii) -x, y-1/2, -z+2; (iii) -x, y+1/2, -z+2; (iv) x, y+1, z; (v) x, y-1, z; (vi) x, y, z-1.