Experimental and Hirshfeld Surface Investigations for Unexpected Aminophenazone Cocrystal Formation under Thiourea Reaction Conditions via Possible Enamine Assisted Rearrangement

Abstract

Considering the astounding biomedicine properties of pharmaceutically active drug, 4-aminophenazone, also known as 4-aminoantipyrine, the work reported in this manuscript details the formation of novel cocrystals of rearranged 4-aminophenazone and 4-nitro-N-(4-nitrobenzoyl) benzamide in 1:1 stoichiometry under employed conditions for thiourea synthesis by exploiting the use of its active amino component. However, detailed analysis via various characterization techniques such as FT-IR, nuclear magnetic resonance spectroscopy and single crystal XRD, for this unforeseen, but useful cocrystalline synthetic adduct (4 and 5) prompted us to delve into its mechanistic pathway under provided reaction conditions. The coformer 4-nitro-N-(4-nitrobenzoyl) benzamide originates via nucleophilic addition reaction following tetrahedral mechanism between para-nitro substituted benzoyl amide and its acid halide (1). While the enamine nucleophilic addition reaction by 4-aminophenazone on 4-nitrosubstituted aroyl isothiocyanates under reflux temperature suggests the emergence of rearranged counterpart of cocrystal named N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carbonothioyl)-4-nitrobenzamide. Crystallographic studies reveal triclinic system P-1 space group for cocrystal (4 and 5) and depicts two different crystallographically independent molecules with prominent C–H···O and N–H···O hydrogen bonding effective for structure stabilization. Hirshfeld surface analysis also displays hydrogen bonding and van der Waals interactions as dominant interactions in crystal packing. Further insight into the cocrystal synthetic methodologies supported the occurrence of solution-based evaporation/cocrystallization methodology in our case during purification step, promoting the synthesis of this first-ever reported novel cocrystal of 4-aminophenazone with promising future application in medicinal industry.

1. Introduction

Neutral crystalline single-phase materials composed of two or more different molecular and/or ionic compounds, which are neither solvates nor simple salts, nevertheless, maintain a stoichiometric ratio which are termed as ‘‘Cocrystals’’ [1]. In order to improve the performance of pharmaceuticals such as solubility, pharmacokinetics and stability, cocrystallization of drug substance with coformer is considered as a promising and emerging approach [2]. Cocrystalline materials possess non-covalent interactions such as: ionic interactions, hydrogen bonding and van der Waals interactions between the active pharmaceutical ingredient (API), i.e., the active cocrystal component and its conformer [3,4]. They can have varying stoichiometry, as documented in the case of carbamazepine: 4-aminobenzoic acid cocrystal system [5]. Such compounds (pharmaceutical cocrystals) are eye-catching not only to chemical and pharma industries but also to drug regulatory agencies because of their superior physical properties to either of pure starting molecules.

Cocrystal synthetic methodologies include both solid and solution phase strategies. The solid state methods include contact formation [6], solid-state grinding and [7] extrusion [8] while evaporation/cocrystallization [9,10], cooling crystallization and [11] reaction crystallization [12] highlight the solution-based strategies. Additional methods include laser, mechanochemical [13,14], freeze drying [15], spray drying [16] and resonant acoustic mixing [17].

The first cocrystal reported in 1958 was for quinone and hydroquinone in a ratio of 1:1 [18]. With the advancement in this field, various reports [17,19,20,21,22,23] on design and growth of cocrystals with potent pharmaceutical aspects have been reported in literature and some imperative examples are displayed in Figure 1.

The pyrazolone nucleus is important in pharmaceutical industry and a variety of synthetic drugs contain this core entity [24]. A potent example of pyrazolone ring containing drug is 4-aminophenazone that belongs to the family of non-steroidal anti-inflammatory drugs (NSAIDs). The drug is used for treatment of anti-inflammatory [25], analgesic and antipyretic conditions and is considered a prophylactic against oxidative stress [26,27]. In addition, it is used for treatment of soft tissue disorders, neuralgia, arthritis and lung inflammation [28]. Moreover, it has been shown to cause agranulocytosis in various cases besides other degrading effects [29]. In order to reduce the associated side effects with the non-steroidal anti-inflammatory (NSAID) drugs, specifically 4-aminophenazone, efforts have been directed in developing the cocrystals of this unique pharmacophore with ultimate enhanced effect on its biophysical properties. So far, to the best of our knowledge, only eleven molecular salts of 4-aminoantipyrine (4-AAP) have yet been reported [30,31,32,33,34,35], two of which are simple salts with halide counter-ions. Some representative examples of 4-aminophenazone salts are highlighted in Figure 2 [35].

Organosulfur compounds with SC(NH₂)₂ formula are termed as ‘‘thioureas or thiocarbamide’’. Derivatives of this class of compounds are associated with a broad-spectrum application [36,37,38] in comparison to other organic compounds. They depict an exceptional role in almost every branch of chemistry and have attracted huge significance on academic, industrial and commercial scale. The presence of hard and soft sites in these compounds offer huge potential for generation of new functionalities [39,40]. Various methodologies have been documented to access this privileged functionality including: chemical, microwave, photochemical, organocatalytic and mechanochemical methods [37,41,42,43,44,45,46].

In order to meet the demand of medicinal and pharma industries of today’s world to cope with the growing number of vulnerable diseases and to address the side effects of drugs in practice, either in form of thermodynamic stability, purity, solubility or bioavailability, there is a dire need for the synthesis as well as performance optimization of active pharmaceutical drug targets.

Considering these aspects, herein, we report the unexpected cocrystal formation of active 4-aminophenazone drug (as shown in Figure 3) under conditions for thiourea synthesis along with details on its likely mechanistic route. Enamine nucleophilic addition pathway has been proposed that facilitates the unusual rearrangement in the 4-aminophenaznoe molecule. Further investigations on the molecular structural features and crystal packing via single crystal X-ray diffraction (XRD) and Hirshfeld surface analysis have also been documented.

2. Materials and Methods

2.1. Materials

All chemicals, as well as solvents such as potassium thiocyanate, 4-nitrobenzoic acid, thionyl chloride, 4-aminophenazone, acetone and ethanol, were purchased from Merck-Sigma Aldrich and used as received.

2.2. Instrumentation

Melting points were determined using Gallenkamp melting point apparatus (MP-D) and are uncorrected. Infrared spectra were recorded using a Bruker Tensor 27 FTIR spectrometer in ATR mode as neat samples.¹H-NMR (300 MHz) and ¹³C-NMR (75 MHz) spectra were obtained using a Bruker 300 NMR MHz spectrometer in CDCl₃ solution using TMS as an internal reference. Elemental analysis was conducted using a LECO CHNS 932 instrument.

2.3. Single Crystal X-ray Crystallography

The crystallographic data of the title compound, (4 and 5), were collected on Xcalibur, Eos, Gemini diffractometer using MoK_α radiation (λ = 0.71073 Å) at 173(2) K. The multi-scan absorption correction (CrysAlisPro) [47] applied data were processed by SHELX program packages (SHELXS97 and SHELXL97) [48] for solving and refining the structure, and ORTEP-3 and PLATON [49,50] programs were used in drawings. The NH hydrogen atoms are located in a difference Fourier map and refined freely. The remaining hydrogen atom positions were calculated geometrically at distances of 0.95 Å (for aromatic CH) and 0.98 Å (for CH₃) and refined using a riding model by applying the constraints of U_iso(H) = k X U_eq (C), where k = 1.2 (for aromatic CH H atoms) and k = 1.5 (for CH₃ H atoms). Crystallographic data for the structure reported herein have been deposited with the Cambridge Crystallographic Data Centre as Supporting Information, CCDC Deposition Number 1998556. Copies of the data can be obtained through application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK. (fax: +44 1223 336033 or e-mail: [email protected] or at http://www.ccdc.cam.ac.uk).

2.4. Synthesis

General procedure for synthesis in favor of N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carbonothioyl)-4-nitrobenzamide; 4-nitro-N-(4-nitrobenzoyl) benzamide (4 and 5).

Freshly synthesized 4-nitrobenzoyl chloride formed via reaction between equimolar quantities of 4-nitrobenzoic acid (0.5 g, 2.99 mmol) and thionyl chloride (0.20 mL, 2.99 mmol) under reflux conditions was added to the flask containing clear solution of potassium thiocyanate (4) (0.56 g, 5.8 mmol) in dry acetone under inert atmosphere of nitrogen. The reaction mixture was stirred for two hours with mild heating while tracking the formation of corresponding isothiocyanate intermediate (2) with TLC. This was followed by the addition of 4-aminophenazone solution (0.56 g, 2.99 mmol) in dry acetone with visual color change indication to orange. The reaction mixture was set to reflux for four hours under inert conditions to attain the expected product 6 (which, though, ended up as cocrystal 4 and 5 formation) on aqueous work-up followed by recrystallization from aqueous ethanol.

N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carbonothioyl)-4-nitrobenzamide; 4-nitro-N-(4-nitrobenzoyl) benzamide (4 and 5).

White and orange crystalline compound; Yield: 85%; R_f: 0.42 (n-Hexane: CHCl₃, 4:1); m.p.: 67–68 °C; FTIR (ATR, cm⁻¹): 3460, 3445 (N–H), 1690 (NHC=O), 1234 (NHC=S); ¹H-NMR ((CH₃)₂SO, 300 MHz): δ 14.48 (s, 1H, NH-coformer), 11.96 (s, 1H, NH-aminophenazone), 8.35 (d, 2H, J = 9 Hz, Ar-H-conformer), 8.13 (d, 2H, J = 9 Hz, Ar-H-Aminophenazone), 7.62–7.48 (m, 5H, Ar-H-aminophenazone), 3.43 (s, 3H, -NCH₃ aminophenazone), 2.88 (s, 3H, Csp²-CH₃ aminophenazone); ¹³C-NMR ((CH₃)₂SO, 75 MHz): δ 188.9 (NHC=S), 165.9 (NHC=O), 158.0, 144.5, 143.4, 129.4, 126.4, 125.1, 124.0. 121.5, 35.3, 13.7. Anal. Calc. for C₃₃H₂₅N₇S: C 56.63, H 3.74, N 13.18, S 4.21; Found: C 56.60, H 3.78, N 13.13, S 4.25.

3. Results and Discussion

3.1. Chemistry

The synthetic strategy employed to prepare the expected product 6 is illustrated in Scheme 1. Consequently, the freshly synthesized para-nitro substituted benzoyl chloride (1) was added to the solution of potassium thiocyanate in dry acetone at 35–40 °C for 2 h to form the corresponding isothiocyanate intermediate (2). It was followed by addition of an acetone solution of 4-aminophenazone (3) to intermediate (2) under reflux condition for 4 h. Completion of reaction on tracking with TLC was followed by aqueous work-up of reaction mixture with subsequent filtration, drying and recrystallization of crude expected product.

However, to our surprise, detailed spectroscopic and single crystal XRD analysis revealed the formation of the rearrangement product of 4-aminophenazone (4) along with its side product (5) (as coformer), both cocrystallized as orange and white crystals (4 and 5) rather than the expected thiourea product (6).

The structure of 4-aminophenazone cocrystal has been fully characterized by FT-IR, ¹H-NMR, ¹³C-NMR (see Supplementary Materials) and detailed single crystal XRD analysis. In FT-IR, a characteristic symmetric stretching signal for N–H bond of the cocrystal appears at 3460 cm⁻¹ with a shoulder peak at 3445 cm⁻¹, respectively. A very sharp stretching at 1690 cm⁻¹, indicative of amide bonds with additional signal at around 1234 cm⁻¹ corresponding to thioamide functionality, confirmed the structure of cocrystal. Medium-intensity peaks appearing in the range of 1000–600 cm⁻¹ as overtones confirm the aromatic skeleton of the structure (4 and 5). In ¹H-NMR, two singlets, each integrating to one proton, confirms the presence of N–H bonds in the cocrystal (4 and 5) with the deshielded signal at 14.48 ppm corresponding to N–H of 4-nitro-N-(4-nitrobenzoyl) benzamide while the shielded one at 11.96 ppm highlights the presence of N–H bond of API cocrystal unit, i.e., N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carbonothioyl)-4-nitrobenzamide. The resonances for para disubstituted benzene rings for both cocrystallized structures appear with specific para substitution pattern as clean doublets with coupling constant J = 9 Hz in the range of 8.37–8.12 ppm, while the mono substitution aromatic pattern appears as multiplets in range 7.62–7.48 ppm, respectively. Resonances in the aliphatic region in form of singlets further confirms the methyl protons of the aminophenazone ring with the N-substituted methyl resonance slightly in deshielded region at 3.43 ppm than the Csp²-CH₃ at 2.88 ppm, fully justifies the structure of unexpected cocrystal formation of 4-aminophenazone. The typical resonances for thioamide thiocarbonyl (NHC=S) along with the thioamide carbonyl carbon (NHC=O) appear at their specific ppm values, i.e., 188.9 ppm and 165.9 ppm, respectively in ¹³C-NMR, supporting the structural features in cocrystal (4 and 5). Other characteristic signals approving the remaining structural components include the signals for 4-aminophenazone skeleton at 158.01, 144.50, 143.4 ppm while the methyl resonates at 58.0 and 13.7 ppm, respectively. The signals in the range from 129.4–121.5 ppm feature the para and mono substitution aromatic signals which fully justify the cocrystal structure (4 and 5).

3.2. Plausible Reaction Mechanism

The possible mechanism favoring the formation of cocrystal 4 and 5 is shown in Figure 4 below.

The conceivable mechanistic route for the synthesis of cocrystal 4 and 5 has been proposed in Figure 4. The pyrazolone ring of 4-aminophenazone (3) serves as active enamine species which reacts in nucleophilic addition manner [51] with para nitro substituted benzoyl isothiocyanate (2) to form the rearranged aminophenazone-based cocrystal unit over two steps. The potassium thiocyanate (that exists in equilibrium with thiocyanic acid) used in first step of synthesis, acts as a source of ammonia that facilitates the synthesis of p-nitro substituted benzoyl amide via nucleophilic addition reaction with freshly synthesized 4-nitrosubstituted benzoyl chloride (1) following tetrahedral mechanism which was accompanied by elimination of HCl. The p-nitro substituted benzoyl amide then reacts with another molecule of (1) following the same mechanistic steps giving rise to the coformer (5) (Figure 4).

3.3. X-ray Structure

The experimental details are given in

Table 1. Experimental details.

Crystal Data
Chemical Formula	C19H16N4O4S·C14H9N3O6
Mr	711.66
Crystal system, space group	Triclinic, P-1
Temperature (K)	173
a, b, c (Å)	8.1153 (12), 11.8550 (12), 17.5835 (13)
α, β, γ (°)	106.482 (8), 93.949 (9), 92.558 (10)
V (Å3)	1614.6 (3)
Z	2
Radiation type	Mo Kα
µ (mm−1)	0.17
Crystal size (mm)	0.32 × 0.25 × 0.20
Data collection
Diffractometer	Xcalibur, Eos, Gemini
Absorption correction	Multi-scan CrysAlisPro, Agilent Technologies, 2010.
Tmin, Tmax	0.947, 0.966
No. of measured, independent and observed [I > 2σ(I)] reflections	15,990, 8300, 6486
Rint	0.035
(sin θ/λ)max (Å−1)	0.676
Refinement
R[F2 > 2σ(F2)], wR(F2), S	0.050, 0.134, 1.02
No. of reflections	8300
No. of parameters	468
No. of restraints	2
H-atom treatment	H atoms treated by a mixture of independent and constrained refinement
Δρmax, Δρmin (e Å−3)	0.31, −0.25

For (as-1a)Computer programs: CrysAlisPro (Oxford Diffraction, 2010), CrysAlis RED (Oxford Diffraction, 2010), SHELXS97 (Sheldrick, 2008), SHELXL97 (Sheldrick, 2008).

. The asymmetric unit of the title compound (4 and 5) contains two different crystallographically independent molecules, where the cocrystals are linked through the trifurcated, one C–H···O and two N–H···O, hydrogen bonds (

Table 2. Hydrogen-bond geometry (Å, º). for (as-1a).

D—H···A	D—H	H···A	D···A	D—H···A
N2—H2N···O4	0.87 (2)	1.88 (2)	2.6758 (17)	150 (2)
N6—H6N···O4	0.86 (2)	2.36 (2)	3.096 (2)	145 (2)
C1—H1A···O5 ii	0.95	2.45	3.168 (2)	133
C5—H5A···O10 vi	0.95	2.39	3.238 (2)	149
C15—H15A···O2 xiii	0.95	2.47	3.411 (2)	170
C20—H20A···O4	0.95	2.29	3.210 (2)	164
C23—H23A···O2 xi	0.95	2.56	3.498 (2)	169
C33—H33A···O3 xii	0.95	2.55	3.325 (2)	139
	(1)

Symmetry codes: ⁱⁱ −x + 2, −y + 1, −z; ^vi −x + 1, −y + 1, −z + 1; ^xi −x + 2, −y, −z; ^xii x + 1, y, z; ^xiii x, y + 1, z.

and Figure 5). These hydrogen bonds as well as the close contacts between the atoms in the asymmetric unit (

Table 3. Selected interatomic distances (Å). for (as-1a).

S1···H12C	2.84	O6···H17A vii	2.80
S1···H19A i	2.90	O7···H24A	2.43
S1···H33A i	3.09	H13C···O7 xiii	2.83
O1···C16 ii	3.343 (3)	H13B···O7 xiii	2.52
O1···O1 iii	3.196 (2)	H13A···O8 xiii	2.39
O1···N1 iii	3.217 (2)	H13B···O8 xiii	2.87
O2···C17 iv	3.266 (2)	O8···H29A	2.59
O2···C15 v	3.411 (2)	O9···H32A	2.46
O3···C30 vi	3.302 (2)	O9···H12B	2.76
O4···C20	3.210 (2)	O9···H13C ix	2.82
O4···N2	2.6758 (17)	O9···H13A ix	2.86
O4···C1	3.389 (2)	O10···H30A	2.47
O4···C33	3.142 (2)	O10···H5A vi	2.39
O4···C19	3.321 (2)	O10···H12C x	2.84
O4···N6	3.096 (2)	O10···H13C ix	2.78
O5···N5 vii	3.179 (2)	N2···H1A	2.58
O5···C2 ii	3.389 (3)	N6···H33A	2.62
O5···C1 ii	3.168 (2)	N6···H20A	2.58
O6···C17 vii	3.387 (2)	N7···H13C ix	2.87
O6···C11 ii	3.320 (2)	C2···C26	3.388 (2)
O6···C18 vii	3.366 (3)	C8···C31	3.493 (2)
O7···O8	2.791 (2)	C8···C30	3.534 (2)
O8···C31 viii	3.285 (2)	C9···C32	3.431 (2)
O8···O7	2.791 (2)	C9···C31	3.591 (2)
O9···C13 ix	3.205 (3)	C11···C33	3.365 (2)
O10···C12 x	3.297 (3)	C11···C32	3.429 (2)
O10···C5 vi	3.238 (2)	C13···C15	3.235 (3)
O1···H16A ii	2.6348	C15···C23 ii	3.454 (3)
O1···H2A	2.44	C16···C23 ii	3.571 (3)
O2···H23A xi	2.56	C28···C29 viii	3.593 (2)
O2···H13B v	2.88	C29···C33 viii	3.595 (3)
O2···H15A v	2.47	C1···H2N	2.46 (2)
O2···H17A iv	2.61	C8···H18A i	2.98
O2···H4A	2.44	C9···H18A i	2.92
O3···H30A vi	2.69	C11···H2N	2.24 (2)
H33A···O3 xii	2.55	C12···H13A	2.70
O3···H5A	2.54	C13···H12A	2.59
O4···H20A	2.29	C14···H13C	2.60
O4···H2N	1.884 (17)	C15···H13C	2.95
O4···H6N	2.355 (17)	C20···H6N	2.49 (2)
O4···H1A	2.70	C33···H6N	2.50 (2)
O5···H2A ii	2.91	H1A···H2N	2.03
O5···H21A	2.39	H6N···H20A	1.97
O5···H1A ii	2.45	H6N···H33A	2.14
O6···H23A	2.43	H12A···H13A	2.15
O6···H18A vii	2.75	H15A···H23A ii	2.52

Symmetry codes: ⁱ x−1, y, z; ⁱⁱ −x + 2, −y + 1, −z; ⁱⁱⁱ −x + 1, −y, −z; ^iv x−1, y−1, z; ^v x, y−1, z; ^vi −x + 1, −y + 1, −z + 1; ^vii −x + 3, −y + 1, −z; ^viii −x + 2, −y + 1, −z + 1; ^ix −x + 2, −y + 2, −z + 1; ^x −x + 1, −y + 2, −z + 1; ^xi −x + 2, −y, −z; ^xii x + 1, y, z; ^xiii x, y + 1, z.

) seem to be effective in the stabilization of the structure as clarified by the detailed Hirshfeld surface analysis in Section 3.4. The planar rings: A (C1—C6), B (N3/N4/C9—C11), C (C14—C19) (for molecule I) and D (C20—C25), E (C28—C33) (for molecule II) are oriented at dihedral angles of A/B = 23.99(4)°, A/C = 66.51(6)°, B/C = 69.90(6)° and D/E = 30.88(6)°. On the other hand, the dihedral angles between the rings of the two different crystallographically independent molecules in the asymmetric unit are A/D = 10.62(6)°, A/E = 22.75(6)°, B/D = 28.12(6)°, B/E = 11.92(6)°, C/D = 56.04(6)° and C/E = 80.06(6)°. In the crystal structure, the intermolecular C–H···O and N–H···O hydrogen bonds (Table 2) link the molecules into a three-dimensional architecture (Figure 6a), in which they may be effective in the stabilization of the structure. On the other hand, the rings of the two molecules are stacked along the a-axis (Figure 6b). There is neither π··· π nor C–H··· π interactions in the structure as mentioned in Section 3.4. The S···H interatomic distances (Table 3) are nearly on the border of the van der Waals interactions (where r_S = 1.80 Å, r_H = 1.20 Å and r_S + r_H = 3.00 Å). Thus, they are very weak.

3.4. Hirshfeld Surface Analysis

To visualize the intermolecular interactions in the crystal of the title compound, a Hirshfeld surface (HS) analysis [52,53] was carried out by using Crystal Explorer 17.5 [54]. In the HS plotted over d_norm (Figure 7), the white surface indicates contacts with distances equal to the sum of van der Waals radii, and the red and blue colors indicate distances shorter (in close contact) or longer (distinct contact) than the van der Waals radii, respectively [55]. The bright-red spots appearing near O2, O10 and hydrogen atoms H5A, H15A, H23A, H33A indicate their roles as the respective donors and/or acceptors. The shape-index of the HS is a tool to visualize the π … π stacking by the presence of adjacent red and blue triangles; if there are no adjacent red and/or blue triangles, then there are no π … π interactions. Figure 8 clearly suggests that there are no π … π interactions in 4 and 5. The overall two-dimensional fingerprint plot, Figure 9a, and those delineated into H … O/O … H, H … H, H … C/C … H, H … S/S … H, C … C, O … C/C … O, O … O, O … N/N … O, H … N/N … H and C … N/N … C contacts [52,53] are illustrated in Figs. 9b—k, respectively, together with their relative contributions to the Hirshfeld surface. The most important interaction is H … O/O … H (Table 3), contributing 43.3% to the overall crystal packing, which is reflected in Figure 9b as the pair of characteristic wings and is viewed as pair of spikes with the tips at de + d_i = 2.25 Å. The widely scattered points of high density due to the large hydrogen content of the molecule, the H … H contacts (Table 3), Figure 6, with 22.0% contribution to the HS are viewed with the tips at d_e + d_i = 2.37 Å and 2.17 Å, for big and small wings, respectively. In the absence of C—H … π interactions, the pair of characteristic wings resulting in the fingerprint plot delineated into H … C/C … H contacts, Figure 9d; the 12.4% contribution to the HS are viewed as pair of spikes with the tips at d_e + d_i = 2.78 Å, arising from the H … C/C … H contacts (Table 3). The pair of characteristic wings resulting in the fingerprint plot delineated into H … S/S … H, Figure 9e, contacts with 6.0% contribution to the HS arises from the H … S/S … H contacts (Table 3) and is viewed as pair of spikes with the tips at d_e + d_i = 2.75 Å. The C … C contacts (Table 3), Figure 9f, with 5.0% contribution to the HS have a split arrow-shaped distribution of points with the tips at d_e + d_i = 3.43 Å.

The Hirshfeld surface analysis confirms the importance of H-atom contacts in establishing the packing. The large number of H … H, H … O/O … H and H … C/C … H interactions suggest that van der Waals interactions and hydrogen bonding play the major roles in the crystal packing [56].

4. Conclusions

Taking into account the reactivity of active amino group of non-steroidal anti-inflammatory drug 4-aminophenazone under employed reaction conditions for thiourea synthesis, we encountered an unanticipated formation of cocrystal of rearranged aminophenazone, i.e., N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carbonothioyl)-4-nitrobenzamide), along with its coformer 4-nitro-N-(4-nitrobenzoyl)benzamide. Spectroscopic (FT-IR, ¹H-NMR, ¹³C-NMR) and single crystal XRD analysis fully corroborates the entire structural units of cocrystal hence authenticating their favored formation under used reaction conditions. Plausible mechanistic justification highlighting the enamine nucleophilic addition reaction by aminophenazone has also been provided. Solution-based evaporation/cocrystallization methodology has been suggested based on its formation. Detailed crystal analysis explains the triclinic lattice arrangement for the cocrystal while the Hirshfeld surface analysis penlights the prevalence of hydrogen bonding together with van der Waals interaction as a promising feature responsible for cocrystal stabilization. This unexpected formation of novel cocrystal will prove to be a useful addition to the increasing demand of drug and pharmaceutical industries for active cocrystal pharmacophores. In future, more detailed studies will be supportive in determining drug candidacy of cocrystal form with its coformer.