Tolfenamic Acid

(Last updated 13 March 2023)

Embedded image

Figure . The molecular diagram of Tolfenamic Acid.

CSP studies

Ogaga Uzoh did a limited search on tolfenamic acid as part of his work on whether the fenamate group was a polymorphophore. Unfortunately, this was too limited to find many experimentally observed crystal structures, and so it was repeated by Louise at a later date.

REFCODE	KAXXAI
Formula	C14 H12 Cl1 N1 O2
Common Name	Tolfenamic Acid
IUPAC Systematic Name	2-((3-Chloro-2-methylphenyl)amino)benzoic acid
Other Names	N-(2-Methyl-3-chlorophenyl)anthranilic acid
CSD Refcodes	KAXXAI, KAXXAI01, KAXXAI02, KAXXAI03, KAXXAI04, KAXXAI05, KAXXAI06, KAXXAI07, KAXXAI11

Search Identifier	A
Scientist	Ogaga Uzoh
Date	2011
Publication	Uzoh OG, Cruz-Cabeza AJ, Price SL 2012. Cryst Growth Des 12, 4230-4239. DOI: Open paper (10.1021/cg3007348)
Energy Model	1
Study_ID	10
Programs	CrystalPredictor (1.8), CrystalOptimizer (2.1), DMACRYS (2.0.4)
Location on S Drive	/CHEMISTRY_CPOSS/Fenamates/TolfenamicAcid/KAXXAI_CO
Potential Description	CrystalOptimizer PBE1PBE/6-31+G(d) intramolecular energy with PBE1PBE/6-31+G(d) charge density and FIT potential
Energy Model	2
Study_ID	30 (published)
Programs	Study_ID=10, DMACRYS (2.0.4)
Location on S Drive	/CHEMISTRY_CPOSS/Fenamates/TolfenamicAcid/KAXXAI_PCM
Potential Description	GDMA2.2(PCMdielectric3(PBE1PBE/6-31+G(d))) + FIT

Search Identifier	B
Scientist	Louise Price
Date	2016
Publication	Case, D. H.; Srirambhatla, V. K.; Guo, R.; Watson, R. E.; Price, L. S.; Polyzois, H.; Cockcroft, J. K.; Florence, A. J.; Tocher, D. A.; Price, S. L., Successful Computationally Directed Templating of Metastable Pharmaceutical Polymorphs. Crystal Growth & Design 2018, 18, (9), 5322-5331. DOI: Open paper (10.1021/acs.cgd.8b00765)
Energy Model	1
Study_ID	21
Programs	CrystalPredictor (1.8), dmaflex-Quick, DMACRYS (2.2.0.1)
Location on S Drive	/CHEMISTRY_CPOSS/Fenamates/TolfenamicAcid/KAXXAI_CP
Potential Description	CrystalPredictor + DMAflex-Quick, rotated charge densities from B3LYP/6-31G(d,p) + FIT
Energy Model	2
Study_ID	11
Programs	Study_ID=21, CrystalOptimizer (2.4.m), DMACRYS (2.2.0.1)
Location on S Drive	/CHEMISTRY_CPOSS/Fenamates/TolfenamicAcid/KAXXAI_CO2
Potential Description	CrystalOptimizer PBE1PBE/6-31+G(d) intramolecular energy with PBE1PBE/6-31+G(d) charge density and FIT potential
Energy Model	3
Study_ID	31 (published)
Programs	Study_ID=11, DMACRYS (2.2.0.1)
Location on S Drive	/CHEMISTRY_CPOSS/Fenamates/TolfenamicAcid/KAXXAI_PCM2
Potential Description	GDMA2.2(PCMdielectric3(PBE1PBE/6-31+G(d))) + FIT
Energy Model	4
Date	2024
Publication	Database updating paper
Study_ID	12 (includes pDFT-D)
Programs	Study_ID=11, CrystalOptimizer (2.4.7), DMACRYS (2.3.1.1)
Location on S Drive	/CHEMISTRY_CPOSS/Fenamates/TolfenamicAcid/KAXXAI_DFT
Potential Description	CrystalOptimizer PBE1PBE/6-31+G(d) intramolecular energy with PBE1PBE/6-31+G(d) charge density and FIT potential

Embedded image

Figure . Crystal energy landscapes of Tolfenamic Acid from previous work. (Top) the original work by Ogaga Uzoh with (left) CrystalOptimizer refinement and (right) PCM refinement. (Middle, bottom) the repeated work by Louise Price with (middle left) the CrystalPredictor search, (middle right) CrystalOptimizer refinement and (bottom) PCM refinement.

CSD structures (CSD version 5.43 with Mar, Jun, Sep and Nov 2022 updates)

Table . Crystallographic information for CSD entries for Tolfenamic Acid. Different polymorphs are coloured differently.

REFCODE	space group	Z’	a / Å	b / Å	c / Å	α / °	β / °	γ / °	density / g cm^-3	Form
KAXXAI	P21/n	1	3.836	21.997	14.205	90	94.11	90	1.454	yellow II
KAXXAI01	P21/c	1	4.826	32.128	8.041	90	104.88	90	1.443	white I
KAXXAI02	P21/c	2	7.6356	11.305	28.065	90	93.03	90	1.437	III
KAXXAI03	P-1	3	7.5237	14.3308	17.592	103.68	98.253	93.038	1.435	IV
KAXXAI04	P-1	1	7.6488	9.016	9.4184	107.385	92.062	101.662	1.439	V
KAXXAI05	P21/n	1	6.748	29.153	7.1	90	112.829	90	1.35	VII
KAXXAI06	P-1	1	8.0025	16.4742	4.8422	95.735	105.222	94.752	1.427	VIII
KAXXAI07	P-1	1	6.7482	7.2034	14.3406	77.497	78.947	65.963	1.408	VI
KAXXAI08	P-1	1	6.7049	7.2778	14.163	77.167	79.908	65.487	1.424	VI
KAXXAI09	P21/c	1	4.8283	32.0832	8.0221	90	104.936	90	1.448	I
KAXXAI10	P21/n	1	3.84618	21.9502	14.1764	90	94.235	90	1.456	II
KAXXAI11	P21/c	1	10.5841	7.8503	14.9718	90	101.399	90	1.425	IX

Table . Experimental information for CSD entries for Tolfenamic Acid.

REFCODE	space group	R factor	T / K	Year	Comments
KAXXAI	P21/n	2.9	110	1989	Rapid cooling of a boiling 96% ethanol solution using an ice bath¹
KAXXAI01	P21/c	5.2	110	1989	Recrystallization from absolute ethanol¹
KAXXAI02	P21/c	4.48	85	2009	Grown from an ethanol solution using nonpolar aromatic polymers as heteronuclei²
KAXXAI03	P-1	7.23	85	2009	Grown from an ethanol solution using nonpolar aromatic polymers as heteronuclei²
KAXXAI04	P-1	6.58	85	2009	Grown from an ethanol solution using nonpolar aromatic polymers as heteronuclei²
KAXXAI05	P21/n	7.04	293	2018	Sublimation onto tolfenamic/flufenamic acid solid solution.³
KAXXAI06	P-1	16.1	120	2018	Sublimation onto a metal surface.³
KAXXAI07	P-1	5.03	151	2018	Sublimation onto isomorphous mefenamic acid form I.³
KAXXAI08	P-1	7.92	100	2020	50 mg of TFA was dissolved in 10 ml of acetone:methanol (1:1) solvent mixture at 50 to 55°C to produce clear solution which was then allowed to cool without stirring. After cooling to 30°C, a couple of single crystals of MFA form I were added to the solution. Upon evaporation of the solvent, crystals of TFA form VI were obtained.⁴
KAXXAI09	P21/c	6.41	100	2020	Slow evaporation at room temperature from ethyl acetate.⁵
KAXXAI10	P21/n	4.56	150	2020	Attempted salt crystallization experiment. A 1:1 molar ratio of tolfenamic acid and N-(2-hydroxyethyl)pyrrolidine were dissolved in ethyl acetate. This was left to slowly evaporate giving yellow needle crystals of pure form II.⁵
KAXXAI11	P21/c	5.77	293	2021	A suspension of tolfenamic acid form I in 2-propanol was heated to 50°C. After dissolution and filtering into a crystallizing dish, the dish was covered with parafilm and put in a fridge at 5°C. After two hours a few blocky crystals of form IX were discovered concomitantly with forms I and II.⁶

Other notes

REFCODES for solid solutions are SIMDOK (60TFA:04FFA), SIMDOK01 (53TFA:47FFA), SIMFUS (25MFA:75TFA), SIMGAZ (57MFA:42TFA), SIMGED (42MFA:58TFA).

TFA-VII is isomorphous with a TFA/FFA solid solution

TFA-VI is isomorphous with MFA-I

Matches in the CO2 search (with 10 or more molecules out of 25)

KAXXAI01 (Form I, Z’=1)=A4121 (RMSD₂₅=0.350 Å)=E1 (RMSD₂₅=0.349 Å)
\nKAXXAI01~A211 (19/25); A2 (19/25); A41 (19/25); A495 (19/25); A4136 (19/25); E7 (19/25); A2497 (13/25)

KAXXAI (Form II, Z’=1)=A283 (RMSD₂₅=0.284 Å)=E2 (RMSD₂₅=0.286 Å)
\nKAXXAI~A147 (16/26); A269 (14/25); A133 (13/25); A221 (13/25); A35 (13/25); A628 (13/25); A22 (12/25); A31 (12/25); A61 (12/25); A96 (12/25); A1516 (12/25); A188 (11/25); A292 (11/25); A34 (11/25); A216 (10/25); A1040 (10/25)

KAXXAI02 (Form III, Z’=2)=A93 (RMSD₂₅=0.313 Å)=E3 (RMSD₂₅=0.303 Å)
\nKAXXAI02~A4420 (20/25); A917 (19/25); A983 (19/25); A2741 (19/25); A4809 (19/25); E61 (19/25); E4 (18/25); E62 (18/25); A3724 (17/25); A2859 (14/25); A1731 (11/25)

KAXXAI03 (Form IV, Z’=3)
\nKAXXAI03~A93 (16/25); A983 (16/25); E61 (22/25); E3 (19/25); E4 (19/25); E62 (19/25); A2741 (16/25); A2859 (16/25); A3724 (16/25);A4420 (16/25); A1646 (11/25); A4809 (10/25)

KAXXAI04 (Form V, Z’=1)

KAXXAI07 (Form VI, Z’=1)=A917 (RMSD₂₅=0.497 Å)=E4 (RMSD₂₅=0.345 Å)=E61 (RMSD₂₅=0.484 Å)
\nKAXXAI07~A93 (19/25); A983 (19/25); A2859 (19/25); E3 (19/25); E62 (19/25); A3724 (17/25); A1731 (15/25); A1803 (12/25); A4420 (12/25); A2741 (10/25)

KAXXAI05 (Form VII, Z’=1)=A4809 (RMSD₂₅=0.977 Å)
\nKAXXAI05~A4420 (20/25); A93 (19/25); A917 (19/25); A983 (19/25); A2741 (19/25); A2859 (19/25); A3724 (19/25); E3 (19/25); E4 (19/25); E61 (19/25); E62 (19/25); A1731 (15/25)

KAXXAI06 (Form VIII, Z’=1)=A495 (RMSD₂₅=0.730 Å)=A2 (RMSD₂₅=0.745 Å)=E7 (RMSD₂₅=0.723 Å)
\nKAXXAI06~A211 (19/25); A4121 (19/25); A4136 (19/25); E1 (19/25); A41 (18/25); A2497 (14/25); A1046 (13/25); A2488 (13/25); A333 (12/25); A404 (12/25); A40 (12/25); A497 (12/25); A1613 (12/25); A5242 (12/25); A1324 (11/25); A113 (10/25); A535 (10/25)

KAXXAI11 (Form IX, Z’=1)=A5102 (RMSD₂₅=0.2 Å)
\nKAXXAI11~A1646 (17/25)

(a) (Form I from search)	(b) (Form I experimental minimized)
(c) (Form II from search)	(d) (Form II experimental minimized)
(e) (Form III from search)	(f) (Form III experimental minimized)
(g) (Form VI from search)	(h) (Form VI overlaid with experimental form IV minimized)
(i) (Form VI experimental major component)	(j) (Form VII from search)
(k) (Form VIII from search)	(l) (Form VIII from search)
(m) (Form VIII experimental minimized)	(n) (Form IX from search)

Figure . Overlays of (a) KAXXAI01 (by element) with A4121 (green) (RMSD₂₅=0.350 Å), (b) KAXXAI01 (by element) with E1 (green) (RMSD₂₅=0.349 Å), (c) KAXXAI (by element) with A283 (green) (RMSD₂₅=0.284 Å), (d) KAXXAI (by element) with E2 (green) (RMSD₂₅=0.286 Å),
\n(e) KAXXAI02 (by element) with A93 (green) (RMSD₂₅=0.313 Å), (f) KAXXAI02 (by element) with E3 (green) (RMSD₂₅=0.303 Å), (g) KAXXAI07 (by element) with A917 (green) (RMSD₂₅= 0.497 Å), (h) KAXXAI07 (by element) with E4 (green) (RMSD₂₅=0.345 Å), (i) KAXXAI07 (by element) with E61 (green) (RMSD₂₅=0.484 Å), (j) KAXXAI05 (by element) with A4809 (green) (RMSD₂₅=0.977 Å), (k) KAXXAI06 (by element) with A495 (green) (RMSD₂₅=0.730 Å), (l) KAXXAI06 (by element) with A2 (green) (RMSD₂₅=0.745 Å), (m) KAXAI06 (by element) with E7 (green) (RMSD₂₅=0.723 Å), (n) KAXXAI11 (by element) with A5102 (green) (RMSD₂₅=0.2 Å).

Matches in Ogaga’s search

KAXXAI01 (Form I, Z’=1)=A8 (RMSD₂₅=0.363 Å)=A2144 (RMSD₂₅=0.377 Å)
\nKAXXAI01~A15 (19/25)

KAXXAI (Form II, Z’=1)=A38 (RMSD25=0.289 Å)
\nKAXXAI~A45 (12/25); A82 (12/25); A95 (12/25); A42 (11/25); A975 (11/25); A80 (10/25); A4, (9/25); A526 (9/25); A73 (9/25)

KAXXAI03 (Form IV, Z’=3)~A470 (9/25)

KAXXAI07 (Form VI, Z’=1)~A470 (9/25)

KAXXAI06 (Form VIII, Z’=1)=A15 (RMSD₂₅=0.728 Å)
\nKAXXAI06~A2144 (19/25); A8 (19/25)

(a)	(b)
(c)	(d)

Figure . Overlays of (a) KAXXAI01 (by element) with A8 (green) (RMSD₂₅=0.363 Å), (b) KAXXAI01 (by element) with A2144 (green) (RMSD₂₅=0.377 Å), (c) KAXXAI (by element) with A38 (green) (RMSD₂₅=0.289 Å), and (d) KAXXAI06 (be element) with A15 (green) (RMSD₂₅=0.728 Å).

Previous CASTEP calculations

a4809			An optimization
	G06sp		A single point energy
kaxxai			An optimization
	newopt (Jul 25 2017)		An optimization
		D02	A single point energy
		MBDstar	A single point energy
	opt2 (Jun 14 2015)		An optimization
		G06sp	A single point energy
		MBDstar	A single point energy
		phonon	A phonon calculation
	opt3 (Jun 14 2016)		An optimization
	opt4 (Jun 18 2016)		An optimization
		fgs4	An optimization
kaxxai01			An optimization
	newopt (Jul 26 2017)		An optimization
		D02	A single point energy
		MBDstar	A single point energy
	opt2 (Jun 14 2015)		An optimization
		G06sp	A single point energy
		MBDstar	A single point energy
		phonon	A phonon calculation
	opt3 (Jun 14 2016)		An optimization
	opt4 (Jun 19 2016)		An optimization
		fgs4	A single point energy
kaxxai02			An optimization
	opt2		An optimization
		G06sp	A single point energy
		MBDstar	A single point energy
		phonon	A phonon calculation
kaxxai03			An optimization
	opt2		An optimization
		D02opt	An optimization
		G06sp	A single point energy
		MBDstar	A single point energy
		phonon	A phonon calculation
kaxxai04mi			An optimization
	opt2		An optimization
		G06sp	A single point energy
		MBDstar	A single point energy
		phonon	A phonon calculation
kaxxai04mj			An optimization
	opt2		An optimization
		G06sp	A single point energy
		MBDstar	A single point energy
		phonon	A phonon calculation
ta_158			An optimization
ta_1666_ma			An optimization
	opt2		An optimization
		G06sp	A single point energy
		phonon	A phonon calculation
ta_237_ma			An optimization
	opt2		An optimization
		G06sp	A single point energy
		phonon	A phonon calculation
ta_288_ma			An optimization
	opt2		An optimization
		G06sp	A single point energy
		phonon	A phonon calculation
ta_497_ma			An optimization
	opt2		An optimization
		G06sp	A single point energy
		phonon	A phonon calculation
ta_510_ma			An optimization
	opt2		An optimization
		G06sp	A single point energy
		phonon	A phonon calculation
ta_889_ma			An optimization
	opt2		An optimization
		G06sp	A single point energy
		phonon	A phonon calculation
ta_978_ma			An optimization
	opt2		An optimization
		G06sp	A single point energy
		phonon
ta_fpamca			An optimization
	D02		A single point energy
	MBDstar		A single point energy
ta_fpamca11			An optimization
	D02		A single point energy
	MBDstar		A single point energy
	TSsp		A single point energy
ta_ss_ffa			An optimization
	D02		A single point energy
	MBDstar		A single point energy
ta_vii			An optimization
	G06sp		A single point energy
	MBDstar		A single point energy
	phonon		A phonon calculation
ta_vi_mi			An optimization
	D02opt		An optimization
	G06sp		A single point energy
	MBDstar		A single point energy
	phonon		A phonon calculation
ta_vi_mj			An optimization
	D02opt		An optimization
	G06sp		A single point energy
	MBDstar		A single point energy
	phonon		A phonon calculation
ta_xyanac			An optimization
	opt2		An optimization
		G06sp	A single point energy
		phonon	A phonon calculation
ta_xyanac02mi			An optimization
	opt2		An optimization
		G06sp	A single point energy
		phonon	A phonon calculation
ta_xyanac02mj			An optimization
	opt2		An optimization
		G06sp	A single point energy
		phonon	A phonon calculation
ta_xyanac03			An optimization
	opt2		An optimization
		G06sp	A single point energy
		MBDstar	A single point energy
		phonon	A phonon calculation

1. K. V. Andersen, S. Larsen, B. Alhede, N. Gelting and O. Buchardt, Journal of the Chemical Society, Perkin Transactions 2, 1989, 1443-1447.

2. V. Lopez-Mejias, J. W. Kampf and A. J. Matzger, Journal of the American Chemical Society, 2009, 131, 4554-4555.

3. D. H. Case, V. K. Srirambhatla, R. Guo, R. E. Watson, L. S. Price, H. Polyzois, J. K. Cockcroft, A. J. Florence, D. A. Tocher and S. L. Price, Crystal Growth & Design, 2018, 18, 5322-5331.

4. S. Ranjan, R. Devarapalli, S. Kundu, S. Saha, S. Deolka, V. R. Vangala and C. M. Reddy, IUCrJ, 2020, 7, 173-183.

5. H. Blade, C. D. Blundell and I. J. Vitorica-Yrezabal, Acta Crystallographica Section E, 2020, 76, 1421-1426.

6. P. Sacchi, S. M. Reutzel-Edens and A. J. Cruz-Cabeza, CrystEngComm, 2021, 23, 3636-3647.