Flufenamic Acid

(Last updated 1 March 2023)

Embedded image

Figure . The molecular diagram of Flufenamic Acid.

CSP studies

REFCODE	FPAMCA
Formula	C14 H10 F3 N1 O2
Common Name	Flufenamic Acid
IUPAC Systematic Name	2-[3-(trifluoromethyl)anilino]benzoic acid
CSD Refcodes	FPAMCA18, FPAMCA17, FPAMCA19, FPAMCA15, FPAMCA16, FPAMCA14, FPAMCA20, FPAMCA13
Search Identifier	A
Scientist	Dave Case
Date	2018
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	10
Programs	Flexible CrystalPredictor (1.8), CrystalOptimizer (2.4.5), DMACRYS (2.2.1.0)
Location on S Drive	/CHEMISTRY_CPOSS/Fenamates/FlufenamicAcid/FPAMCA_CO
Potential Description	CrystalOptimizer with GDMA2.2(PBE1PBE/6-31+G(d)) + FIT
Energy Model	2
Study_ID	30 (published)
Programs	Study_ID=10, DMACRYS (2.2.0.1)
Location on S Drive	/CHEMISTRY_CPOSS/Fenamates/FlufenamicAcid/FPAMCA_PCM
Potential Description	GDMA2.2(PCMdielectric3(PBE1PBE/6-31+G(d))) + FIT
Scientist	Louise Price
Date	2024
Publication	Database updating paper
Energy Model	3
Study_ID	11 (includes pDFT-D)
Programs	Study_ID=10, CrystalOptimizer (2.4.7), DMACRYS (2.3.1.1)
Location on S Drive	/CHEMISTRY_CPOSS/Fenamates/FlufenamicAcid/FPAMCA_DFT
Potential Description	CrystalOptimizer with GDMA2.2(PBE1PBE/6-31+G(d)) + FIT

Embedded image

Figure . Crystal energy landscape of Flufenamic Acid from (top left) CrystalOptimizer refinement, (top right) PCM refinement, (bottom left) reoptimization with CrystalOptimizer and (bottom right) comparisons across the different energy models.

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

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

REFCODE	space group	Z’	a / Å	b / Å	c / Å	α / °	β / °	γ / °	density / g cm^-3	Form
FPAMCA	C2/c	1	39.848	5.107	12.24	90	92.47	90	1.501	III
FPAMCA01	P21/c	1	12.53	7.86	12.87	90	95.1	90	1.48	I
FPAMCA02	P*/a	0	12.87	7.85	12.52	90	95.5	90	1.484	I
FPAMCA03	P*/a	0	11.85	10.425	11.22	90	112.83	90	1.462	II
FPAMCA04	C*/c	0	39.76	5.104	12.24	90	92.5	90	1.505	III
FPAMCA11	P21/c	1	12.523	7.868	12.874	90	95.2	90	1.479	I
FPAMCA12	P21/c	2	14.9687	20.641	7.9486	90	98.316	90	1.537	VII
FPAMCA13	P-1	9.5	17.0047	17.887	19.1941	81.321	89.58	78.56	1.569	VIII
FPAMCA14	P-1	6	8.6485	11.5115	38.895	87.914	85.91	72.26	1.524	VI
FPAMCA15	P-1	3	8.7589	11.6629	20.0229	80.632	81.041	73.532	1.458	IV
FPAMCA16	P21/c	4	26.6592	7.9007	23.243	90	94.084	90	1.53	V
FPAMCA17	P21/c	1	10.8813	10.2374	11.7487	90	111.318	90	1.532	II
FPAMCA18	P21/c	1	12.4157	7.7528	12.6469	90	94.688	90	1.54	I
FPAMCA19	C2/c	1	39.683	5.0556	11.963	90	91.91	90	1.557	III
FPAMCA20	P21/c	2	15.004	20.749	7.965	90	98.31	90	1.523	VII
FPAMCA21	C2/c	1	39.6616	5.0561	11.9613	90	91.962	90	1.558	III
FPAMCA22	C2/c	1	39.6836	5.055	11.9667	90	91.939	90	1.557	III

Table . Experimental information for CSD entries for Flufenamic Acid.

REFCODE	space group	R factor	T / K	Year	Comments
FPAMCA	C2/c	4.9	RT	1973	Cryst.Struct.Commun. 2 459 (1973)
FPAMCA01	P21/c	11	RT	1978	Acta Cryst A. 34 S80 (1978)
FPAMCA02	P*/a	0	RT	1977	Microscope 25 31 (1977)
FPAMCA03	P*/a	0	RT	1977	Microscope 25 31 (1977)
FPAMCA04	C*/c	0	RT	1977	Microscope 25 31 (1977)
FPAMCA11	P21/c	7.4	RT	1982	Slow evaporation of a solution of 95% ethanol.¹
FPAMCA12	P21/c	10.11	85	2012	Grown from ethanol solution using polymers as heteronuclei.²
FPAMCA13	P-1	19.67	85	2012	Grown from ethanol solution using polymers as heteronuclei.² One additional independent flufenamic acid molecule was severely disordered and the disordered density was taken into account using the SQUEEZE/PLATON procedure. The unit cell was found to contain a void of 271 A3 holding 126 electrons.
FPAMCA14	P-1	16.13	85	2012	Low temperature (-130 °C) transformation from form IV, by submerging a vial in liquid nitrogen for 10-15 minutes.²
FPAMCA15	P-1	5.42	273	2012	Grown from ethanol solution using polymers as heteronuclei.² F1,F2,F3 and F1A,F2A,F3A disordered over two sites with occupancies 0.508:0.492; F4,F5,F6 and F4A,F5A,F6A disordered over two sites with occupancies 0.67:0.33; F7,F8,F9 and F7A,F8A,F9A disordered over two sites with occupancies 0.618:0.382.
FPAMCA16	P21/c	7.27	95	2012	Grown from ethanol solution using polymers as heteronuclei.²
FPAMCA17	P21/c	7.36	95	2012	Grown from ethanol solution using polymers as heteronuclei.²
FPAMCA18	P21/c	3.74	90	2014	Recrystallization from mixed xylenes above 130 °C.³
FPAMCA19	C2/c	3.59	90	2014	Recrystallization from methanol at room temperature.³
FPAMCA20	P21/c	6.14	100	2020	Encapsulated nanodroplet crystallization. 200 nL PDMSO, 50 nL of 50 mg/mL flufenamic acid in DMF, 50 nL H₂O.⁴ Synchrotron data
FPAMCA21	C2/c	3.75	106	2022	Slow evaporation from methanol or toluene under ambient conditions.⁵ A plastic and bendable crystal.
FPAMCA22	C2/c	11.64	106	2022	Slow evaporation from methanol or toluene under ambient conditions.⁵ A plastic and bendable crystal.

Other notes

There is also a Form IX, but this doesn’t have full structural characterization yet.²

Structure matches in the search (anything nine molecules or more out of a 25 molecule coordination sphere)

FPAMCA18 (Form I, Z’=1)=A560 (RMSD25=0.205 Å), E1 (RMSD₂₅=0.283 Å)

FPAMCA17 (Form II, Z’=1)=A748 (RMSD25 = 0.124 Å), E2 (RMSD₂₅=0.142 Å)
\nFPAMCA17~A826 (11/25)

FPAMCA19 (Form III, Z’=1)=E3 (RMSD₂₅=0.161 Å)
\nFPAMCA19~A1094 (20/25); A928 (20/25); A1767 (18/25); A1098 (12/25); A1508 (10/25); A1511 (10/25); A354 (9/25)
\nA1098 is the same sheet. A1094 and A1767 are double sheets on the hydrogen bonding side and A928 is a double sheet on the opposite side.

FPAMCA15 (Form IV, Z’=3)=E6 (RMSD₂₅=0.391 Å)
\nFPAMCA15~E4 (17/25)

FPAMCA16 (Form V, Z’=4)=E5 (RMSD₂₅=0.378 Å)
\nFPAMCA16~A799 (11/25); 833 (11/25); A1439 (10/25);

FPAMCA14 (Form VI, Z’=6)=E6 (RMSD₂₅=0.38 Å)
\nFPAMCA14~E4 (21/25)

FPAMCA20 (Form VII, Z’=2)=E7 (RMSD₂₅=0.235 Å)

FPAMCA13 (Form VIII, Z’=9.5)~A1782 (11/25)

(a) (Form I from search)	(b) (Form I experimental minimized)
(c) (Form II from search)	(d) (Form II experimental minimized)
(e) (Form III experimental minimized)	(f) (Form IV overlaid with experimental Form VI minimized)
(g) (Form V experimental minimized)	(h) (Form VI experimental minimized)
(i) (Form VII experimental minimized)

Figure . Overlays of (a) FPAMCA18 (by element) with A560 (green) (RMSD₂₅=0.205 Å), (b) FPAMCA18 (by element) with E1 (green) (RMSD₂₅=0.283 Å), (c) FPAMCA17 (by element) with A748 (green) (RMSD25=0.124 Å), (d) FPAMCA17 (by element) with E2 (green) (RMSD₂₅=0.142 Å), (e) FPAMCA19 (by element) with E3 (green) (RMSD₂₅=0.161 Å), (f) FPAMCA15 (by element) with E6 (green) (RMSD₂₅=0.391 Å), (g) FPAMCA16 (by element) with E5 (green) (RMSD₂₅=0.378 Å), (h) FPAMCA14 (by element) with E6 (green) (RMSD₂₅=0.380 Å), (i) FPAMCA20 (by element) with E7 (green) (RMSD₂₅=0.235 Å),

Previous CASTEP calculations

ffa1129				An optimization
	D02			A single point energy
	MBDstar			A single point energy
ffa1173				An optimization
ffa1248				An optimization
	D02			A single point energy
	MBDstar			A single point energy
ffa1956				An optimization
	MBDstar			A single point energy
	wrong			Not sure, but some optimizations
ffa882				An optimization
	D02			A single point energy
	MBDstar			A single point energy
ffa_kaxxai				An optimization
	D02			A single point energy
	MBDstar			A single point energy
ffa_kaxxai01				An optimization
	D02			A single point energy
	MBDstar			A single point energy
ffax (ffa_f3)				An optimization
	D02sp			A single point energy
	MBDsp			A single point energy
fpamca (this is also called f3)				An optimization
	D02sp			A single point energy
	mag			Magnetic Susceptibility
	MBDstar			A single point energy
	ncp			An optimization (same as above?)
		redo		An optimization (continued from above?)
	opt2			An optimization (continued from first optimization?)
		D02		A single point energy
		MBDstar		A single point energy
		phonon
			121	A phonon calculation
	TSsp			A single point energy
fpamca11				An optimization
	D02sp			A single point energy
	MBDstar			A single point energy
	ncp			An optimization (same as above?)
		phonon
			111	A phonon calculation
			222	A phonon calculation
			222/path	A phonon calculation
	phonon
		121		A phonon calculation
			path	A phonon calculation
		222		A phonon calculation
			path	A phonon calculation
fpamca12				An optimization
	D02sp			A single point energy
	mag			Magnetic Susceptibility
	MBDstar			A single point energy
fpamca15				An optimization
	D02sp			A single point energy
	mag			Magnetic Susceptibility
	MBDstar			A single point energy
fpamca17				An optimization
	D02sp			A single point energy
	mag			Magnetic Susceptibility
	MBDstar			A single point energy
	TSsp			A single point energy

1. H. M. Krishna Murthy, T. N. Bhat and M. Vijayan, Acta Crystallographica Section B, 1982, 38, 315-317.

2. V. Lopez-Mejias, J. W. Kampf and A. J. Matzger, Journal of the American Chemical Society, 2012, 134, 9872-9875.

3. S. P. Delaney, T. M. Smith and T. M. Korter, Journal of Molecular Structure, 2014, 1078, 83-89.

4. A. R. Tyler, R. Ragbirsingh, C. J. McMonagle, P. G. Waddell, S. E. Heaps, J. W. Steed, P. Thaw, M. J. Hall and M. R. Probert, Chem, 2020, 6, 1755-1765.

5. Y. Liu, P. Yang, K. Zhang, J. Xu, S. Wu and J. Gong, Crystal Growth & Design, 2022, 22, 1312-1318.