Multicomponent Solids of Niflumic and Mefenamic Acids Based on Acid-Pyridine Synthon

Abstract

The present study discusses comparative structural features of fourteen multicomponent solids of two non-steroidal anti-inflammatory drugs, Niflumic and Mefenamic acids, with amine and pyridine-based coformers. All the solids were structurally characterized through PXRD, SCXRD, DSC, and the monophasic nature of some of the solids was established through Rietveld refinement. The solid forms include salt, cocrystal, hydrate, and solvate. Except for two, all the solids reported here showed relatively higher solubility compared to the acids. The difference in pKa and similarity in structural features of both the molecules enabled us to study the effect of ΔpKa on crystallization outcome systematically. The structures of all the solids are described through acid-pyridine synthon perspective.

Keywords: acid-pyridine synthon; cocrystallization; hirshfeld surface analysis; intermolecular interactions; ΔpKa rule.

SCHEME 1

The anthranilic acid derivatives (fenamates) surveyed in this study. The five NSAIDs within the circle have a common anthranilic acid moiety with different substitutions. In case of Flufenamic and Niflumic acids, the difference is the presence of nitrogen instead of carbon in the anthranilic acid ring.

SCHEME 2

Polymorphic forms of fenamate derivatives. The substitutions on the phenyl ring are critical in governing the relative orientation of the two aromatic rings which in turn impacts the number of polymorphic forms as well as how it interacts with a coformer under given conditions. Here, Ffa = Flufenamic Acid, Ta = Tolfenamic Acid, 2-Pna = 2-(phenylamino)nicotinic acid, 2-(2-M3ca) = 2-(2-Methyl-3-chloroanilino)nicotinic acid, 2-Mana = 2-(Mesitylamino)nicotinic acid, Tna = 2-(phynylamino)nicotinic acid, and Mef = Mefenamic Acid.

SCHEME 3

Molecular structure of APIs Niflumic (Nif) and Mefenamic (Mef) acid as well as coformers (bpe, bpee, bpp,2ap,3ap, and 4ap) used in this study.

SCHEME 4

Different types of synthons as observed in the solids 1-12.

FIGURE 1

Nif─bpe─Nif trimers are interacted via C─H∙∙∙N (synthon VII) and C─H∙∙∙F interaction, forming a planar sheet.

FIGURE 2

In 2 and 2a, Nif─bpee─Nif trimers are interconnected via C─H∙∙∙N and C─H∙∙∙F interactions, forming a planar sheet.

FIGURE 3

(A) In 3, Nif─bpp─Nif trimers are connected with other trimers forming a planar sheet via C─H∙∙∙F interaction. (B) Different sheets further connect via other C─H∙∙∙F interactions to form a 3D structure.

FIGURE 4

(A) Mef─bpe─Mef trimers are connected with other trimers via C─H∙∙∙π interaction in 7. (B) Isostructural 8 shows the same types of Mef─bpee─Mef trimers interactions.

FIGURE 5

(A) Nif─bpp dimers interconnected via C─H∙∙∙N forming a planar sheet in 9. (B) Planar sheets via C─H∙∙∙π and C─H∙∙∙N interaction are stacked one over the other, forming a 3D structure.

FIGURE 6

(A) Nif─2ap dimers interacted with other dimers via N─H∙∙∙O to form a 1D Chain in 4. (B) The chains are connected through C─H∙∙∙F in the other two planes forming a 3D network.

FIGURE 7

(A) Interaction of Nif─2ap dimers via N─H∙∙∙O with other dimers to form a tetramer, in 4a. (B) Stacking of tetramer through C−H∙∙∙π interaction one over the other and cross-sects each other via C−H∙∙∙F interaction to form a 3D structure.

FIGURE 8

(A) In 6, Nif─4ap dimers interacted with other dimers via N─H∙∙∙O, forming a 1D Chain. (B) The chains are interconnected via C─H∙∙∙F and C─H∙∙∙O interaction in a perpendicular fashion.

FIGURE 9

In 10, The dimers of Mef─2ap are connected with other dimers through N─H∙∙∙O forming columns. These columns further connect with other columns via C─H∙∙∙π to form a 3D network.

FIGURE 10

(A) In 12, tetramers of Mef─H₂O─Mef are formed via synthon II which further connected through N─H∙∙∙O with other tetramers forming columns. (B) These columns, interacting with others via C─H∙∙∙π and π∙∙∙π interactions, form a 3D network.

FIGURE 11

(A,E,H) Hirshfeld surface analysis and structural environment of Nif, Mef I, and Mef II. (B–D) O∙∙∙H/H∙∙∙O, C∙∙∙H/H∙∙∙C, and F∙∙∙H/H∙∙∙F interactions resolved fingerprint plots of Nif. (F,G) and (I,J) O∙∙∙H/H∙∙∙O and C∙∙∙H/H∙∙∙C interactions resolved fingerprint plots of both forms of Mef. The two spikes present in the solids are characteristic of the carboxylic acid dimer.

FIGURE 12

(A–D) O∙∙∙H/H∙∙∙O N∙∙∙H/H∙∙∙N, C∙∙∙H/H∙∙∙C, and F∙∙∙H/H∙∙∙F interactions Resolved fingerprint plots of Nif in solid 1, respectively. (E–L) O∙∙∙H/ H∙∙∙O and N∙∙∙H/H∙∙∙N interactions resolved fingerprint plots of Nif of solid 2 and 2a, respectively.

FIGURE 13

(A–F) Resolved fingerprint plots of Mef of 7 and 8 in O∙∙∙H/ H∙∙∙O, N∙∙∙H/H∙∙∙N, and C∙∙∙H/ H∙∙∙C interactions, respectively.

FIGURE 14

(A–D) Resolved fingerprint plots of Nif of solid 3 in O∙∙∙H/ H∙∙∙O, N∙∙∙H/H∙∙∙N, C∙∙∙H/ H∙∙∙C, and F∙∙∙H/ H∙∙∙F interactions, respectively. (E–G) Resolved fingerprint plots of Mef of solid 9 in O∙∙∙H/ H∙∙∙O, N∙∙∙H/H∙∙∙N, and C∙∙∙H/H∙∙∙C interactions, respectively.

FIGURE 15

(A–L) Resolved fingerprint plots of Nif in 4 and Nif I &Nif II in 4a in O∙∙∙H/ H∙∙∙O, N∙∙∙H/H∙∙∙N, C∙∙∙H/H∙∙∙C, and F∙∙∙H/H∙∙∙F interactions, respectively. (M–O) Resolved fingerprint plots of Mef of 10 in O∙∙∙H/H∙∙∙O, N∙∙∙H/H∙∙∙N, and C∙∙∙H/H∙∙∙C interactions, respectively.

FIGURE 16

(A–D) Resolved fingerprint plots of Nif in 5 in O∙∙∙H/H∙∙∙O, N∙∙∙H/H∙∙∙N, C∙∙∙H/H∙∙∙C, and F∙∙∙H/H∙∙∙F interactions, respectively. (E–G) Resolved fingerprint plots of Mef in 11 in O∙∙∙H/ H∙∙∙O, N∙∙∙H/H∙∙∙N, and C∙∙∙H/ H∙∙∙C interactions, respectively.

FIGURE 17

(A–D) Resolved fingerprint plots of Nif in 6 in O∙∙∙H/H∙∙∙O, N∙∙∙H/H∙∙∙N, C∙∙∙H/H∙∙∙C, and F∙∙∙H/H∙∙∙F interactions, respectively. (E–G) Resolved fingerprint plots of Mef in 12 in O∙∙∙H/ H∙∙∙O, N∙∙∙H/H∙∙∙N, and C∙∙∙H/ H∙∙∙C interactions, respectively.

FIGURE 18

(A) Molecular overlay diagrams of Nif in salts/cocrystals. Color codes: Light blue‒Nif, Red‒1, Orange‒2, Yellow‒2a, Green‒3, Cyan‒4, Blue‒4a, Purple‒5, Magenta‒6. (B) Molecular overlay diagrams of Mef molecule in salts/cocrystals. Color codes: Light blue‒Mef I, Green‒Mef II, Red‒7, Orange‒8, Yellow‒9, Cyan‒10, Blue‒11, Purple‒12.