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

Guerain, M.; Chevreau, H.; Elkaim, E.; Guinet, Y.; Paccou, L.; Danède, F.; Hedoux, A.; Affouard, F.

doi:10.1107/S2053229625008952

research papers

STRUCTURAL
CHEMISTRY

ISSN: 2053-2296

Volume 81| Part 11| November 2025| Pages 658-665

https://doi.org/10.1107/S2053229625008952

Open

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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 Hedoux ^a and Frederic Affouard ^a

^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: [email protected]

Edited by X. Wang, Oak Ridge National Laboratory, USA (Received 30 June 2025; accepted 14 October 2025; online 21 October 2025)

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.

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

CCDC reference: 2495679

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 synthons. 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, paracetamol–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 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 P2₁) 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 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.

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

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 P2₁/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 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

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 P2₁) 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 improve the grain-sampling statistics. Data were collected at room temperature (∼20 °C) in the 1.2–40° 2θ range in 3 min.

Table 1
Crystallographic data, profile and structural parameters for S-ibuprofen–nicotinamide cocrystal form A obtained after Rietveld refinement

Crystal data
Chemical formula	C₁₉H₂₄N₂O₃
M_r	328.4
Cell setting, space group	Monoclinic, P2₁
Temperature (K)	293
a,b,c (Å)	27.9925 (13), 5.5286 (2), 6.0213 (2)
β (°)	93.112 (2
V (Å³)	930.48 (7)
Z	2
F(000)	352
μ (mm⁻¹)	0.079
Specimen shape, size (mm)	Cylinder, 0.5
2θ range (°)	1.2–40.284°

Data collection
Beamline	CRISTAL (SOLEIL)
Specimen mounting	0.5 mm diameter Lindemann capillary
Data collection mode	Transmission
Scan method	Continuous scan
Radiation type	Synchrotron 17 KeV, λ = 0.728302 Å
Binning size (°2θ)	0.004

Refinement
R factors and goodness-of-fit	R = 0.0694, R_wp(nb) = 0.0847, R_exp = 0.007

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) (Kabekkodu 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 & Rodríquez-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 M₂₀ = 26.7 and F₂₀ = 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 η₀ of the pseudo-Voight function and its 2θ 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 P2₁ (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 (Petrícek 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_wp(nb) = 0.0847, and R_exp = 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 3
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.

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_wp(nb) = 0.1547 for the RS-ibuprofen–nicotinamide cocrystal, and R = 0.0582 and R_wp(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_wp(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 (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⁻¹ is distinctive of N—H⋯O molecular associations, while the temperature dependences of O—H stretching bands located at 3390 and 3400 cm⁻¹ reflect O—H⋯N associations.

Figure 4
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.

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 NH₂ 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 NH₂ 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.

Figure 5
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.

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 P2₁ (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 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°.

Table 2
Lattice unit-cell parameters comparisons between S-ibuprofen–nicotinamide cocrystal form A and S-ibuprofen–nicotinamide cocrystal form B (Berry et al., 2008)

Structure	a (Å)	b (Å)	c (Å)	β (°)	V (Å³)	Symmetry	Reference
S-IBP:N Form A	27.9925	5.5286	6.0213	93.112	930.48	P2₁	This work
S-IBP:N Form B	5.4110	55.883	11.9006	90.004	3598.5	P2₁	Berry et al. (2008)

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

Figure 6
Projection of 4 × 2 cells of S-IBP:N cocrystal form A along the [010] direction.

Figure 7
Projection of 4 × 1 cells of S-IBP:N cocrystal form B (Berry et al., 2008

) along the [100] direction.

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. 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).

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].

Figure 8
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.

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⋯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.

Supporting information

CCDC reference: 2495679

Crystal structure: contains datablocks global, I. DOI: https://doi.org/10.1107/S2053229625008952/vx3017sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2053229625008952/vx3017Isup2.hkl

PXRD patterns, DSC curves and comparison between refined Rietveld values and DFT-optimized coordinates. DOI: https://doi.org/10.1107/S2053229625008952/vx3017sup3.pdf

Supporting information file. DOI: https://doi.org/10.1107/S2053229625008952/vx3017Isup4.cml

Computing details top

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

Crystal data top

C₁₃H₁₈O₂·C₆H₆N₂O	V = 930.48 (7) Å³
M_r = 328.4	Z = 2
Monoclinic, P2₁	F(000) = 352
Hall symbol: P 2yb	D_x = 1.172 Mg m⁻³
a = 27.9925 (13) Å	Synchrotron radiation
b = 5.5286 (2) Å	T = 293 K
c = 6.0213 (2) Å	white
β = 93.112 (2)°

Data collection top

Synchrotron diffractometer	2θ_min = 2°, 2θ_max = 40.284°, 2θ_step = 0.004°
Radiation source: synchrotron, synchrotron

Refinement top

R_p = 0.069	0 restraints
R_wp = 0.085	1 constraint
R_exp = 0.007	H-atom parameters constrained
R(F) = 0.293	Weighting scheme based on measured s.u.'s
9572 data points	(Δ/σ)_max = 0.021
Profile function: Pseudo-Voigt	Background function: 8 Legendre polynoms
19 parameters	Preferred orientation correction: none

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

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

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
?	?	?	?	?	?	?

Geometric parameters (Å, º) top

C1—C2	1.3844	H13—C16	0.9567
C1—N1	1.3412	H14—C9	0.8629
C1—H1	1.0736	H15—C16	0.976
C2—C3	1.388	H16—C18	1.0346
C2—C6	1.4926	H17—C18	1.0678
C3—C4	1.3853	H18—C12	0.9973
C3—H2	1.0926	H19—C8	0.8924
C4—C5	1.3824	H20—C14	1.0024
C4—H3	1.0817	H21—C15	0.9291
C5—N1	1.3375	H22—C11	0.8494
C5—H4	1.0778	H24—C9	1.0229
C6—N2	1.3367	C7—C8	1.4947
C6—O1	1.23	C8—C9	1.5358
N2—H5	1.0005	C8—C10	1.5195
N2—H6	1.0141	C10—C11	1.3836
O2—C7	1.2189	C10—C15	1.3762
O3—H23	0.931	C11—C12	1.3852
O3—C7	1.3025	C12—C13	1.3768
H7—C19	1.0989	C13—C14	1.3749
H8—C18	1.0254	C13—C16	1.5152
H9—C19	0.9924	C14—C15	1.375
H10—C19	1.1216	C16—C17	1.5169
H11—C9	1.0407	C17—C18	1.5068
H12—C17	0.9546	C17—C19	1.5192

C2—C1—N1	123.09	C11—C10—C15	116.98
C2—C1—H1	121.53	H22—C11—C10	112.72
N1—C1—H1	115.35	H22—C11—C12	126.16
C1—C2—C3	118.04	C10—C11—C12	120.87
C1—C2—C6	124.07	H18—C12—C11	119.07
C3—C2—C6	117.87	H18—C12—C13	119.18
C2—C3—C4	119.52	C11—C12—C13	121.74
C2—C3—H2	118.46	C12—C13—C14	117.06
C4—C3—H2	122.01	C12—C13—C16	120.72
C3—C4—C5	118.26	C14—C13—C16	122.17
C3—C4—H3	121.47	H20—C14—C13	120.59
C5—C4—H3	120.26	H20—C14—C15	117.86
C4—C5—N1	123.12	C13—C14—C15	121.44
C4—C5—H4	120.33	H21—C15—C10	118.14
N1—C5—H4	116.56	H21—C15—C14	119.94
C2—C6—N2	117.82	C10—C15—C14	121.9
C2—C6—O1	119.71	H13—C16—H15	110.18
N2—C6—O1	122.47	H13—C16—C13	112.11
C1—N1—C5	117.95	H13—C16—C17	106.34
C6—N2—H5	121.28	H15—C16—C13	109.01
C6—N2—H6	118.44	H15—C16—C17	104.77
H5—N2—H6	119.05	C13—C16—C17	114.15
H23—O3—C7	108.46	H12—C17—C16	106.83
O2—C7—O3	121.88	H12—C17—C18	117.2
O2—C7—C8	122.55	H12—C17—C19	99.09
O3—C7—C8	115.51	C16—C17—C18	111.46
H19—C8—C7	104.72	C16—C17—C19	111.68
H19—C8—C9	110.39	C18—C17—C19	109.99
H19—C8—C10	108.12	H8—C18—H16	102.77
C7—C8—C9	111.27	H8—C18—H17	114.98
C7—C8—C10	108.4	H8—C18—C17	111.39
C9—C8—C10	113.52	H16—C18—H17	113.18
H11—C9—H14	107.37	H16—C18—C17	109.66
H11—C9—H24	112.67	H17—C18—C17	104.96
H11—C9—C8	108.96	H7—C19—H9	110.07
H14—C9—H24	102.06	H7—C19—H10	113.29
H14—C9—C8	111.6	H7—C19—C17	110.17
H24—C9—C8	113.87	H9—C19—H10	112.29
C8—C10—C11	120.4	H9—C19—C17	104.44
C8—C10—C15	122.56	H10—C19—C17	106.12

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
C1—H1···O2ⁱ	1.07	1.81	2.5933	126.42
N2—H5···O1ⁱⁱ	1.00	2.07	2.6637	115.75
N2—H6···C1ⁱⁱⁱ	1.01	2.49	3.2916	135.09
N2—H6···C2ⁱⁱⁱ	1.01	2.44	3.3031	142.51
C18—H16···C14	1.03	2.07	2.8104	126.30
C12—H18···C14^iv	1.00	2.37	3.3464	166.97
C12—H18···C15^iv	1.00	2.19	3.0067	138.27
C14—H20···C18	1.00	2.26	2.8104	112.99
C15—H21···C11^v	0.93	2.43	3.3463	168.62
C15—H21···C12^v	0.93	2.24	3.0067	139.17
C11—H22···C9	0.85	2.45	2.8733	111.23
O3—H23···N1^vi	0.93	1.81	2.6890	155.66

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.

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

Crystal data
Chemical formula	C₁₉H₂₄N₂O₃
M_r	328.4
Cell setting, space group	Monoclinic, P2₁
Temperature (K)	293
a,b,c (Å)	27.9925 (13), 5.5286 (2), 6.0213 (2)
β (°)	93.112 (2
V (Å³)	930.48 (7)
Z	2
F(000)	352
µ (mm^-1)	0.079
Specimen shape, size (mm)	Cylinder, 0.5
2θ range (°)	1.2–40.284°

Data collection
Beamline	CRISTAL (SOLEIL)
Specimen mounting	0.5 mm diameter Lindemann capillary
Data collection mode	Transmission
Scan method	Continuous scan
Radiation type	Synchrotron 17 KeV, λ = 0.728302 Å
Binning size (°2θ)	0.004

Refinement
R factors and goodness-of-fit	R = 0.694, R_wp(nb) = 0.0847, R_exp = 0.007

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

Structure	a (Å)	b (Å)	c (Å)	β (°)	V (Å³)	Symmetry	Reference
S-IBP:N Form A	27.9925	5.5286	6.0213	93.112	930.48	P2₁	This work
S-IBP:N Form B	5.4110	55.883	11.9006	90.004	3598.5	P2₁	Berry et al. (2008)

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).

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