A new polymorph of the gastrokinetic drug cisapride monohydrate

Cisapride monohydrate (systematic name: 4-amino-5-chloro-N-{(3RS,4SR)-1-[3-(4-fluoro­phen­oxy)prop­yl]-3-meth­oxy­piperidin-4-yl}-2-meth­oxy­benzamide monohydrate), C₂₃H₂₉ClFN₃O₄·H₂O, is a nondopamine-blocking gastrokinetic drug. A new polymorph of cisapride monohydrate has been reported nearly three decades after the report of its first known crystal structure [Collin et al. (1989). J. Mol. Struct. 214, 159–175]. The second polymorph is also monoclinic, but with different unit-cell parameters. A comparison of both polymorphic forms shows that the difference is thus not in the mol­ecular conformation but in the arrangements of mol­ecules in the crystal packing. The crystal morphology of two forms was predicted with the BFDH model in Materials Studio and inferred that the powder of the new polymorph has better flowability than the original polymorph. The results of DSC (differential scanning calorimetry) analysis and slurry experiments show that both polymorphs are stable at room temperature.

Computing details

Data collection: PROCESS-AUTO (Rigaku, 2006); cell refinement: PROCESS-AUTO (Rigaku, 2006); data reduction: CrystalStructure (Rigaku, 2007); program(s) used to solve structure: SHELXT (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2018 (Sheldrick, 2015b); molecular graphics: ORTEP-3 (Farrugia, 2012); software used to prepare material for publication: OLEX2 (Dolomanov et al., 2009).

4-Amino-5-chloro-N-{(3RS,4SR)-1-[3-(4-fluorophenoxy)propyl]-3-methoxypiperidin-4-yl}-2-methoxybenzamide monohydrate

Crystal data

C23H29ClFN3O4·H2O	F(000) = 1024
Mr = 483.96	Dx = 1.315 Mg m^−3
Monoclinic, P21/n	Mo Kα radiation, λ = 0.71073 Å
a = 12.3225 (9) Å	Cell parameters from 11147 reflections
b = 14.5183 (8) Å	θ = 3.2–27.5°
c = 13.8141 (8) Å	µ = 0.20 mm^−1
β = 98.361 (2)°	T = 296 K
V = 2445.1 (3) Å^3	Chunk, colorless
Z = 4	0.53 × 0.48 × 0.4 mm

Data collection

Rigaku R-AXIS RAPID diffractometer	2637 reflections with I > 2σ(I)
ω scans	Rint = 0.052
Absorption correction: multi-scan (ABSCOR; Higashi, 1995)	θmax = 25.1°, θmin = 3.2°
Tmin = 0.901, Tmax = 0.924	h = −14→14
19055 measured reflections	k = −17→17
4348 independent reflections	l = −16→16

Refinement

Refinement on F^2	Hydrogen site location: mixed
Least-squares matrix: full	H-atom parameters constrained
R[F^2 > 2σ(F^2)] = 0.090	w = 1/[σ^2(Fo^2) + (0.1051P)^2 + 4.5913P] where P = (Fo^2 + 2Fc^2)/3
wR(F^2) = 0.253	(Δ/σ)max = 0.002
S = 1.00	Δρmax = 1.05 e Å^−3
4348 reflections	Δρmin = −0.40 e Å^−3
301 parameters	Extinction correction: SHELXL2018 (Sheldrick, 2015b), Fc^*=kFc[1+0.001xFc^2λ^3/sin(2θ)]^-1/4
0 restraints	Extinction coefficient: 0.0041 (14)

Special details

Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.

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

	x	y	z	Uiso*/Ueq
C1	0.4204 (3)	0.2612 (3)	−0.0518 (3)	0.0450 (10)
C2	0.4981 (3)	0.3266 (3)	−0.0726 (3)	0.0462 (10)
C3	0.5244 (4)	0.3354 (3)	−0.1664 (3)	0.0502 (11)
H3	0.575694	0.379382	−0.178535	0.060*
C4	0.4757 (4)	0.2798 (3)	−0.2432 (3)	0.0481 (11)
C5	0.4001 (4)	0.2146 (3)	−0.2214 (3)	0.0525 (11)
C6	0.3742 (4)	0.2057 (3)	−0.1289 (3)	0.0522 (11)
H6	0.323756	0.160916	−0.117158	0.063*
C7	0.6330 (4)	0.4410 (4)	−0.0126 (4)	0.0728 (15)
H7A	0.692127	0.406579	−0.033222	0.109*
H7B	0.659091	0.472967	0.047110	0.109*
H7C	0.605782	0.484757	−0.062330	0.109*
C8	0.3783 (4)	0.2478 (3)	0.0429 (3)	0.0500 (11)
C9	0.3665 (4)	0.3025 (3)	0.2090 (3)	0.0539 (12)
H9	0.349898	0.238174	0.222715	0.065*
C10	0.2618 (4)	0.3571 (4)	0.2051 (3)	0.0586 (13)
H10A	0.207087	0.333192	0.153636	0.070*
H10B	0.275416	0.421035	0.190438	0.070*
C11	0.2193 (4)	0.3506 (4)	0.3030 (3)	0.0619 (13)
H11A	0.151644	0.385323	0.299896	0.074*
H11B	0.203447	0.286780	0.316341	0.074*
C12	0.4033 (4)	0.3359 (4)	0.3875 (3)	0.0618 (13)
H12A	0.391151	0.272511	0.405532	0.074*
H12B	0.456561	0.362438	0.438508	0.074*
C13	0.4505 (4)	0.3368 (3)	0.2918 (3)	0.0551 (12)
H13	0.514764	0.296246	0.298025	0.066*
C14	0.5809 (5)	0.4596 (5)	0.3175 (5)	0.102 (2)
H14A	0.573519	0.463728	0.385592	0.154*
H14B	0.596996	0.519388	0.293625	0.154*
H14C	0.639420	0.417926	0.309413	0.154*
C15	0.2584 (5)	0.3771 (4)	0.4777 (3)	0.0758 (16)
H15A	0.230074	0.315205	0.482562	0.091*
H15B	0.319074	0.385034	0.530237	0.091*
C16	0.1723 (6)	0.4431 (7)	0.4908 (5)	0.114 (3)
H16A	0.122584	0.445981	0.429638	0.137*
H16B	0.206579	0.503191	0.500696	0.137*
C17	0.1020 (7)	0.4287 (8)	0.5733 (6)	0.140 (3)
H17A	0.052082	0.480078	0.575118	0.168*
H17B	0.059017	0.372786	0.561479	0.168*
C18	0.1157 (5)	0.4117 (4)	0.7409 (4)	0.0697 (15)
C19	0.0074 (6)	0.4256 (4)	0.7456 (4)	0.0838 (18)
H19	−0.039845	0.439471	0.688672	0.101*
C20	−0.0347 (5)	0.4195 (4)	0.8349 (5)	0.0827 (17)
H20	−0.108341	0.430685	0.838382	0.099*
C21	0.0366 (5)	0.3968 (4)	0.9157 (4)	0.0696 (15)
C22	0.1429 (6)	0.3800 (4)	0.9108 (4)	0.0817 (17)
H22	0.189916	0.363008	0.966827	0.098*
C23	0.1818 (6)	0.3880 (4)	0.8231 (4)	0.0839 (18)
H23	0.255616	0.376737	0.820473	0.101*
Cl1	0.33694 (15)	0.14458 (11)	−0.31512 (10)	0.0905 (6)
F1	−0.0006 (4)	0.3878 (3)	1.0038 (2)	0.1087 (13)
N1	0.5026 (3)	0.2899 (3)	−0.3347 (3)	0.0668 (12)
H1A	0.472504	0.255336	−0.381597	0.080*
H1B	0.549698	0.330941	−0.345663	0.080*
N2	0.4117 (3)	0.3047 (3)	0.1171 (3)	0.0574 (10)
H2	0.462014	0.344305	0.110529	0.069*
N3	0.3000 (3)	0.3867 (3)	0.3827 (2)	0.0523 (10)
O1	0.5470 (3)	0.3796 (2)	0.0033 (2)	0.0608 (9)
O2	0.3121 (3)	0.1858 (2)	0.0507 (2)	0.0728 (11)
O3	0.4820 (3)	0.4267 (2)	0.2644 (2)	0.0611 (9)
O4	0.1677 (4)	0.4224 (4)	0.6572 (3)	0.1035 (15)
O5	0.1856 (4)	0.0853 (3)	0.1649 (3)	0.1034 (16)
H5A	0.220616	0.095952	0.119960	0.155*
H5B	0.189336	0.029332	0.156210	0.155*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
C1	0.049 (3)	0.045 (2)	0.042 (2)	−0.0014 (19)	0.0103 (19)	0.0020 (19)
C2	0.046 (3)	0.049 (2)	0.044 (2)	0.003 (2)	0.0081 (19)	−0.0021 (19)
C3	0.048 (3)	0.056 (3)	0.048 (2)	0.000 (2)	0.014 (2)	0.002 (2)
C4	0.049 (3)	0.058 (3)	0.039 (2)	0.011 (2)	0.0121 (19)	0.002 (2)
C5	0.063 (3)	0.053 (3)	0.042 (2)	−0.005 (2)	0.009 (2)	−0.010 (2)
C6	0.062 (3)	0.051 (3)	0.045 (2)	−0.008 (2)	0.012 (2)	−0.005 (2)
C7	0.071 (4)	0.071 (3)	0.075 (3)	−0.026 (3)	0.008 (3)	−0.002 (3)
C8	0.058 (3)	0.052 (3)	0.041 (2)	−0.005 (2)	0.010 (2)	−0.002 (2)
C9	0.074 (3)	0.052 (3)	0.038 (2)	−0.008 (2)	0.015 (2)	−0.002 (2)
C10	0.056 (3)	0.079 (3)	0.040 (2)	−0.018 (3)	0.007 (2)	−0.005 (2)
C11	0.059 (3)	0.086 (4)	0.042 (2)	−0.020 (3)	0.013 (2)	−0.007 (2)
C12	0.079 (4)	0.064 (3)	0.040 (2)	0.002 (3)	0.001 (2)	−0.001 (2)
C13	0.061 (3)	0.056 (3)	0.048 (3)	0.007 (2)	0.009 (2)	0.001 (2)
C14	0.065 (4)	0.105 (5)	0.130 (6)	−0.021 (4)	−0.010 (4)	−0.014 (4)
C15	0.097 (4)	0.093 (4)	0.038 (3)	−0.018 (3)	0.014 (3)	−0.008 (3)
C16	0.097 (5)	0.189 (8)	0.064 (4)	0.016 (5)	0.039 (4)	−0.013 (4)
C17	0.109 (6)	0.200 (10)	0.107 (6)	0.012 (6)	0.003 (5)	−0.018 (6)
C18	0.098 (4)	0.071 (3)	0.044 (3)	0.006 (3)	0.025 (3)	0.002 (2)
C19	0.113 (5)	0.088 (4)	0.047 (3)	−0.015 (4)	−0.001 (3)	0.012 (3)
C20	0.079 (4)	0.086 (4)	0.085 (4)	−0.005 (3)	0.017 (3)	0.006 (3)
C21	0.100 (5)	0.067 (3)	0.046 (3)	−0.008 (3)	0.024 (3)	−0.002 (2)
C22	0.107 (5)	0.092 (4)	0.046 (3)	0.011 (4)	0.011 (3)	0.014 (3)
C23	0.106 (5)	0.092 (4)	0.059 (3)	0.026 (4)	0.030 (3)	0.017 (3)
Cl1	0.1271 (14)	0.0933 (11)	0.0532 (8)	−0.0378 (10)	0.0199 (8)	−0.0224 (7)
F1	0.158 (4)	0.116 (3)	0.065 (2)	−0.012 (3)	0.060 (2)	−0.0002 (19)
N1	0.078 (3)	0.081 (3)	0.044 (2)	−0.007 (2)	0.021 (2)	−0.004 (2)
N2	0.075 (3)	0.056 (2)	0.045 (2)	−0.015 (2)	0.0221 (19)	−0.0073 (18)
N3	0.059 (2)	0.063 (2)	0.0365 (19)	−0.0063 (19)	0.0121 (17)	−0.0054 (17)
O1	0.070 (2)	0.064 (2)	0.0493 (18)	−0.0210 (17)	0.0132 (16)	−0.0080 (15)
O2	0.098 (3)	0.073 (2)	0.0527 (19)	−0.035 (2)	0.0291 (18)	−0.0111 (17)
O3	0.0510 (19)	0.063 (2)	0.069 (2)	−0.0085 (15)	0.0067 (16)	−0.0076 (17)
O4	0.120 (4)	0.137 (4)	0.056 (2)	−0.005 (3)	0.019 (2)	0.021 (2)
O5	0.121 (4)	0.071 (2)	0.139 (4)	0.004 (2)	0.088 (3)	0.008 (2)

Geometric parameters (Å, º)

C1—C2	1.408 (6)	C13—O3	1.429 (6)
C1—C6	1.389 (6)	C14—H14A	0.9600
C1—C8	1.488 (6)	C14—H14B	0.9600
C2—C3	1.387 (6)	C14—H14C	0.9600
C2—O1	1.368 (5)	C14—O3	1.410 (6)
C3—H3	0.9300	C15—H15A	0.9700
C3—C4	1.397 (6)	C15—H15B	0.9700
C4—C5	1.392 (6)	C15—C16	1.461 (9)
C4—N1	1.361 (5)	C15—N3	1.482 (6)
C5—C6	1.367 (6)	C16—H16A	0.9700
C5—Cl1	1.739 (4)	C16—H16B	0.9700
C6—H6	0.9300	C16—C17	1.542 (10)
C7—H7A	0.9600	C17—H17A	0.9700
C7—H7B	0.9600	C17—H17B	0.9700
C7—H7C	0.9600	C17—O4	1.317 (9)
C7—O1	1.426 (6)	C18—C19	1.360 (8)
C8—N2	1.335 (5)	C18—C23	1.343 (8)
C8—O2	1.230 (5)	C18—O4	1.409 (6)
C9—H9	0.9800	C19—H19	0.9300
C9—C10	1.509 (7)	C19—C20	1.409 (8)
C9—C13	1.511 (6)	C20—H20	0.9300
C9—N2	1.459 (5)	C20—C21	1.357 (8)
C10—H10A	0.9700	C21—C22	1.343 (8)
C10—H10B	0.9700	C21—F1	1.368 (6)
C10—C11	1.523 (6)	C22—H22	0.9300
C11—H11A	0.9700	C22—C23	1.372 (7)
C11—H11B	0.9700	C23—H23	0.9300
C11—N3	1.469 (6)	N1—H1A	0.8600
C12—H12A	0.9700	N1—H1B	0.8600
C12—H12B	0.9700	N2—H2	0.8600
C12—C13	1.521 (6)	O5—H5A	0.8200
C12—N3	1.464 (6)	O5—H5B	0.8231
C13—H13	0.9800
C2—C1—C8	127.0 (4)	O3—C13—H13	108.9
C6—C1—C2	116.7 (4)	H14A—C14—H14B	109.5
C6—C1—C8	116.2 (4)	H14A—C14—H14C	109.5
C3—C2—C1	120.8 (4)	H14B—C14—H14C	109.5
O1—C2—C1	117.4 (4)	O3—C14—H14A	109.5
O1—C2—C3	121.8 (4)	O3—C14—H14B	109.5
C2—C3—H3	119.2	O3—C14—H14C	109.5
C2—C3—C4	121.5 (4)	H15A—C15—H15B	107.7
C4—C3—H3	119.2	C16—C15—H15A	108.9
C5—C4—C3	117.1 (4)	C16—C15—H15B	108.9
N1—C4—C3	120.5 (4)	C16—C15—N3	113.5 (5)
N1—C4—C5	122.4 (4)	N3—C15—H15A	108.9
C4—C5—Cl1	118.5 (3)	N3—C15—H15B	108.9
C6—C5—C4	121.4 (4)	C15—C16—H16A	107.3
C6—C5—Cl1	120.1 (4)	C15—C16—H16B	107.3
C1—C6—H6	118.8	C15—C16—C17	119.9 (7)
C5—C6—C1	122.4 (4)	H16A—C16—H16B	106.9
C5—C6—H6	118.8	C17—C16—H16A	107.3
H7A—C7—H7B	109.5	C17—C16—H16B	107.3
H7A—C7—H7C	109.5	C16—C17—H17A	110.0
H7B—C7—H7C	109.5	C16—C17—H17B	110.0
O1—C7—H7A	109.5	H17A—C17—H17B	108.3
O1—C7—H7B	109.5	O4—C17—C16	108.7 (7)
O1—C7—H7C	109.5	O4—C17—H17A	110.0
N2—C8—C1	119.1 (4)	O4—C17—H17B	110.0
O2—C8—C1	119.6 (4)	C19—C18—O4	126.1 (5)
O2—C8—N2	121.3 (4)	C23—C18—C19	118.4 (5)
C10—C9—H9	107.8	C23—C18—O4	115.4 (6)
C10—C9—C13	110.0 (4)	C18—C19—H19	119.3
C13—C9—H9	107.8	C18—C19—C20	121.4 (5)
N2—C9—H9	107.8	C20—C19—H19	119.3
N2—C9—C10	113.0 (4)	C19—C20—H20	121.4
N2—C9—C13	110.2 (4)	C21—C20—C19	117.3 (6)
C9—C10—H10A	109.7	C21—C20—H20	121.4
C9—C10—H10B	109.7	C20—C21—F1	119.6 (6)
C9—C10—C11	109.8 (4)	C22—C21—C20	121.5 (5)
H10A—C10—H10B	108.2	C22—C21—F1	118.8 (5)
C11—C10—H10A	109.7	C21—C22—H22	120.1
C11—C10—H10B	109.7	C21—C22—C23	119.8 (6)
C10—C11—H11A	109.4	C23—C22—H22	120.1
C10—C11—H11B	109.4	C18—C23—C22	121.5 (6)
H11A—C11—H11B	108.0	C18—C23—H23	119.3
N3—C11—C10	111.2 (4)	C22—C23—H23	119.3
N3—C11—H11A	109.4	C4—N1—H1A	120.0
N3—C11—H11B	109.4	C4—N1—H1B	120.0
H12A—C12—H12B	107.7	H1A—N1—H1B	120.0
C13—C12—H12A	108.9	C8—N2—C9	122.7 (4)
C13—C12—H12B	108.9	C8—N2—H2	118.6
N3—C12—H12A	108.9	C9—N2—H2	118.6
N3—C12—H12B	108.9	C11—N3—C15	110.2 (4)
N3—C12—C13	113.3 (4)	C12—N3—C11	110.1 (4)
C9—C13—C12	110.4 (4)	C12—N3—C15	108.8 (4)
C9—C13—H13	108.9	C2—O1—C7	119.2 (4)
C12—C13—H13	108.9	C14—O3—C13	114.8 (4)
O3—C13—C9	106.5 (4)	C17—O4—C18	115.8 (6)
O3—C13—C12	113.0 (4)	H5A—O5—H5B	91.7
C1—C2—C3—C4	−0.4 (7)	C13—C12—N3—C11	56.0 (5)
C1—C2—O1—C7	174.5 (4)	C13—C12—N3—C15	176.9 (4)
C1—C8—N2—C9	173.6 (4)	C15—C16—C17—O4	55.9 (11)
C2—C1—C6—C5	−1.4 (7)	C16—C15—N3—C11	−74.1 (6)
C2—C1—C8—N2	3.2 (7)	C16—C15—N3—C12	165.1 (5)
C2—C1—C8—O2	−178.2 (4)	C16—C17—O4—C18	178.2 (6)
C2—C3—C4—C5	−0.4 (6)	C18—C19—C20—C21	−1.8 (9)
C2—C3—C4—N1	179.7 (4)	C19—C18—C23—C22	−1.7 (10)
C3—C2—O1—C7	−4.5 (6)	C19—C18—O4—C17	−14.0 (10)
C3—C4—C5—C6	0.3 (7)	C19—C20—C21—C22	−0.5 (9)
C3—C4—C5—Cl1	179.5 (3)	C19—C20—C21—F1	−178.5 (5)
C4—C5—C6—C1	0.6 (7)	C20—C21—C22—C23	1.6 (9)
C6—C1—C2—C3	1.3 (6)	C21—C22—C23—C18	−0.5 (10)
C6—C1—C2—O1	−177.8 (4)	C23—C18—C19—C20	2.8 (9)
C6—C1—C8—N2	−173.8 (4)	C23—C18—O4—C17	167.9 (7)
C6—C1—C8—O2	4.8 (6)	Cl1—C5—C6—C1	−178.5 (4)
C8—C1—C2—C3	−175.7 (4)	F1—C21—C22—C23	179.6 (5)
C8—C1—C2—O1	5.2 (7)	N1—C4—C5—C6	−179.8 (4)
C8—C1—C6—C5	175.9 (4)	N1—C4—C5—Cl1	−0.7 (6)
C9—C10—C11—N3	59.6 (5)	N2—C9—C10—C11	179.4 (4)
C9—C13—O3—C14	−162.6 (4)	N2—C9—C13—C12	179.2 (4)
C10—C9—C13—C12	54.0 (5)	N2—C9—C13—O3	56.2 (5)
C10—C9—C13—O3	−69.0 (4)	N3—C12—C13—C9	−54.3 (5)
C10—C9—N2—C8	−84.1 (5)	N3—C12—C13—O3	64.8 (5)
C10—C11—N3—C12	−58.2 (5)	N3—C15—C16—C17	165.9 (6)
C10—C11—N3—C15	−178.3 (4)	O1—C2—C3—C4	178.7 (4)
C12—C13—O3—C14	76.0 (6)	O2—C8—N2—C9	−4.9 (7)
C13—C9—C10—C11	−57.0 (5)	O4—C18—C19—C20	−175.2 (5)
C13—C9—N2—C8	152.4 (4)	O4—C18—C23—C22	176.6 (6)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1B···O5^i	0.86	2.06	2.894 (6)	164
N2—H2···O1	0.86	2.00	2.683 (5)	135
O5—H5A···O2	0.82	2.05	2.785 (5)	149
O5—H5B···N3^ii	0.82	2.15	2.968 (6)	174

Symmetry codes: (i) x+1/2, −y+1/2, z−1/2; (ii) −x+1/2, y−1/2, −z+1/2.