Elucidating the crystal structure of the antimalarial drug (±)-mefloquine hydrochloride: a tetragonal hydrated species

Albeit widely studied, the structure of the antimalarial drug (±)-mefloquine hydrochloride is still a controversial issue. A combination of X-ray powder diffraction, theoretical calculations and Fourier transform–infrared spectroscopy is used to unambiguously determine the crystal structure of the molecule in its active pharmaceutical ingredient. It is demonstrated that water is incorporated into the structure, leading to a hydrated form and, most importantly, to significant differences in both structure and bonding. Such changes can lead to significant differences in biological activity.

Computing details

Data collection: Win X-POW; cell refinement: Topas Academic v.5; data reduction: Topas Academic v.5; program(s) used to solve structure: ab initio algorithm; program(s) used to refine structure: TOPAS ACADEMIC 5; molecular graphics: Mercury 3.1; software used to prepare material for publication: TOPAS ACADEMIC 5.

R,S erythro-alpha-2-piperidyl 2,8bis(trifluoromethyl)-4quinolinemethanol hydrochloride

Crystal data

2(C17H16F6N2O)·2(Cl)·H2O	Tetragonal
Mr = 845.55	Dx = 1.457 Mg m^−3
Tetragonal, P42/n	Melting point: 456 K
Hall symbol: -P 4bc	Cu Kα1 radiation, λ = 1.54056 Å
a = 24.5663 (3) Å	µ = 2.40 mm^−1
c = 6.38601 (12) Å	T = 298 K
V = 3853.97 (13) Å^3	Particle morphology: powder
Z = 4	white
F(000) = 1728

Data collection

Stoe STADI-P powder diffractometer	Scan method: step
Radiation source: sealed X-ray tube, Stoe STADI-P	Absorption correction: analytical Correction based on shape and thickness
Curved Ge(111) monochromator
Specimen mounting: "Ultraphan" acetate foils	2θmin = 2°, 2θmax = 60°, 2θstep = 0.015°
Data collection mode: transmission

Refinement

Refinement on F	138 parameters
Least-squares matrix: full	0 restraints
Rp = 0.029	42 constraints
Rwp = 0.041	Hydrogen site location: inferred from neighbouring sites
Rexp = 0.019	All H-atom parameters refined
RBragg = 0.014	Weighting scheme based on measured s.u.'s
3850 data points	(Δ/σ)max = 0.0001
Excluded region(s): none	Background function: 20-term Chebyschev polynomial
Profile function: Fundamental parameters approach	Preferred orientation correction: 4 terms spherical harmonics

Special details

Refinement. A Rietveld refinement was performed with the TOPAS package using the fundamental parameters approach as reflection profiles (convolution of appropriate source emission profiles with axial instrument contributions as well as crystallite microstructure effects). In order to describe small peak half width and shape anisotropy effects, the approach of Le Bail and Jouanneaux was implemented into the TOPAS program and the according parameters were allowed to refine freely. Preferred orientation of the crystallites was described with a spherical harmonics function of 4th order.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq	Occ. (<1)
N1	0.3752 (8)	0.4111 (7)	0.334 (3)	0.09870
C2	0.3939 (11)	0.4527 (14)	0.440 (4)	0.09870
C3	0.3833 (10)	0.5075 (11)	0.393 (3)	0.09870
C4	0.3488 (10)	0.5206 (11)	0.235 (4)	0.09870
C5	0.2909 (8)	0.4848 (9)	−0.056 (3)	0.09870
C6	0.2713 (10)	0.4418 (10)	−0.162 (3)	0.09870
C7	0.2839 (9)	0.3881 (10)	−0.109 (3)	0.09870
C8	0.3170 (11)	0.3773 (11)	0.057 (5)	0.09870
C9	0.3410 (12)	0.4218 (15)	0.171 (4)	0.09870
C10	0.3269 (12)	0.4767 (15)	0.114 (4)	0.09870
C11	0.3387 (9)	0.5801 (10)	0.178 (3)	0.09870
C12	0.3769 (9)	0.5992 (9)	0.003 (4)	0.09870
N13	0.3640 (7)	0.6563 (7)	−0.049 (2)	0.09870
C14	0.3968 (8)	0.6777 (9)	−0.226 (3)	0.09870
C15	0.4577 (9)	0.6728 (8)	−0.185 (3)	0.09870
C16	0.4724 (9)	0.6140 (10)	−0.125 (3)	0.09870
C17	0.4369 (7)	0.5947 (9)	0.058 (3)	0.09870
C18	0.3332 (11)	0.3196 (14)	0.105 (3)	0.09870
C19	0.4327 (12)	0.4393 (10)	0.616 (4)	0.09870
O20	0.3458 (5)	0.6160 (5)	0.3495 (18)	0.09870
F21	0.3108 (5)	0.2835 (5)	−0.0261 (17)	0.09870
F22	0.3869 (6)	0.3125 (5)	0.0921 (13)	0.09870
F23	0.3178 (5)	0.3056 (5)	0.2989 (17)	0.09870
F24	0.4834 (5)	0.4392 (5)	0.5565 (17)	0.09870
F25	0.4257 (4)	0.3899 (5)	0.6930 (19)	0.09870
F26	0.4297 (5)	0.4727 (5)	0.7750 (17)	0.09870
Cl27	0.2587 (3)	0.6167 (2)	0.7083 (7)	0.09870
O44	0.2170 (8)	0.7327 (10)	0.726 (3)	0.09870	0.5
H28	0.2858 (8)	0.5208 (9)	−0.112 (3)	0.11845
H29	0.2705 (9)	0.3594 (10)	−0.197 (3)	0.11845
H30	0.3975 (10)	0.5379 (11)	0.469 (3)	0.11845
H31	0.3007 (9)	0.5854 (10)	0.153 (3)	0.11845
H32	0.2534 (10)	0.4497 (10)	−0.292 (3)	0.11845
H33	0.3185 (5)	0.6104 (5)	0.4605 (18)	0.11845
H34	0.3609 (9)	0.5795 (9)	−0.111 (4)	0.11845
H35	0.3297 (7)	0.6621 (7)	−0.069 (2)	0.11845
H36	0.4455 (7)	0.5568 (9)	0.088 (3)	0.11845
H37	0.4447 (7)	0.6160 (9)	0.179 (3)	0.11845
H38	0.3882 (8)	0.7150 (9)	−0.246 (3)	0.11845
H39	0.3883 (8)	0.6573 (9)	−0.350 (3)	0.11845
H40	0.4667 (9)	0.5908 (10)	−0.244 (3)	0.11845
H41	0.5103 (9)	0.6121 (10)	−0.085 (3)	0.11845
H42	0.4676 (9)	0.6964 (8)	−0.070 (3)	0.11845
H43	0.4777 (9)	0.6832 (8)	−0.307 (3)	0.11845
H45	0.2451 (8)	0.7172 (10)	0.631 (3)	0.11845	0.5
H46	0.2109 (8)	0.7076 (10)	0.845 (3)	0.11845	0.5

Geometric parameters (Å, º)

N1—C2	1.31 (4)	C12—H34	0.96 (3)
N1—C9	1.36 (3)	N13—C14	1.48 (2)
C2—C3	1.40 (4)	N13—H35	0.86 (2)
C2—C19	1.51 (4)	C14—C15	1.52 (3)
C3—C4	1.36 (3)	C14—H38	0.95 (3)
C3—H30	0.96 (4)	C14—H39	0.96 (3)
C4—C10	1.43 (4)	C15—C16	1.54 (3)
C4—C11	1.53 (4)	C15—H42	0.97 (3)
C5—C6	1.34 (3)	C15—H43	0.96 (3)
C5—C10	1.41 (3)	C16—C17	1.53 (3)
C5—H28	0.96 (3)	C16—H40	0.96 (3)
C6—C7	1.40 (3)	C16—H41	0.97 (3)
C6—H32	0.96 (3)	C17—H36	0.97 (3)
C7—C8	1.36 (4)	C17—H37	0.95 (3)
C7—H29	0.96 (3)	C18—F21	1.34 (3)
C8—C9	1.44 (4)	C18—F22	1.33 (3)
C8—C18	1.50 (4)	C18—F23	1.34 (2)
C9—C10	1.44 (5)	C19—F24	1.30 (3)
C11—C12	1.53 (3)	C19—F25	1.32 (3)
C11—O20	1.42 (2)	C19—F26	1.31 (3)
C11—H31	0.96 (3)	O20—H33	0.99 (2)
C12—N13	1.48 (3)	O44—H45	0.99 (3)
C12—C17	1.52 (3)	O44—H46	0.99 (3)
C2—N1—C9	117 (2)	C12—N13—H35	114 (2)
N1—C2—C3	125 (3)	C14—N13—H35	111 (2)
N1—C2—C19	116 (2)	N13—C14—C15	112 (2)
C3—C2—C19	119 (2)	N13—C14—H38	109 (2)
C2—C3—C4	120 (2)	N13—C14—H39	109 (2)
C2—C3—H30	125 (3)	C15—C14—H38	109 (2)
C4—C3—H30	115 (3)	C15—C14—H39	108 (2)
C3—C4—C10	117 (2)	H38—C14—H39	110 (3)
C3—C4—C11	120 (2)	C14—C15—C16	110 (2)
C10—C4—C11	122 (2)	C14—C15—H42	109 (2)
C6—C5—C10	120 (2)	C14—C15—H43	110 (2)
C6—C5—H28	119 (2)	C16—C15—H42	108 (2)
C10—C5—H28	120 (2)	C16—C15—H43	109 (2)
C5—C6—C7	123 (2)	H42—C15—H43	109 (3)
C5—C6—H32	116 (3)	C15—C16—C17	110 (2)
C7—C6—H32	120 (3)	C15—C16—H40	109 (2)
C6—C7—C8	120 (2)	C15—C16—H41	110 (2)
C6—C7—H29	118 (2)	C17—C16—H40	110 (2)
C8—C7—H29	121 (3)	C17—C16—H41	109 (2)
C7—C8—C9	119 (3)	H40—C16—H41	109 (3)
C7—C8—C18	120 (2)	C12—C17—C16	111 (2)
C9—C8—C18	120 (3)	C12—C17—H36	109 (2)
N1—C9—C8	119 (3)	C12—C17—H37	110 (2)
N1—C9—C10	121 (3)	C16—C17—H36	109 (2)
C8—C9—C10	119 (3)	C16—C17—H37	110 (2)
C4—C10—C5	123 (3)	H36—C17—H37	109 (2)
C4—C10—C9	119 (3)	C8—C18—F21	113 (2)
C5—C10—C9	118 (3)	C8—C18—F22	112 (2)
C4—C11—C12	112 (2)	C8—C18—F23	111 (2)
C4—C11—O20	113 (2)	F21—C18—F22	106 (2)
C4—C11—H31	109 (2)	F21—C18—F23	107 (2)
C12—C11—O20	107 (2)	F22—C18—F23	108 (2)
C12—C11—H31	116 (2)	C2—C19—F24	113 (2)
O20—C11—H31	99 (2)	C2—C19—F25	113 (2)
C11—C12—N13	109 (2)	C2—C19—F26	114 (2)
C11—C12—C17	114 (2)	F24—C19—F25	103 (2)
C11—C12—H34	99 (2)	F24—C19—F26	106 (2)
N13—C12—C17	109 (2)	F25—C19—F26	106 (2)
N13—C12—H34	103 (2)	C11—O20—H33	113 (2)
C17—C12—H34	122 (3)	H45—O44—H46	110 (3)
C12—N13—C14	113 (2)