Midodrine hydro­chloride Form A, C12H19N2O4+·Cl−

Jacob K Salazar; James A Kaduk; Anja Dosen; Thomas N Blanton

doi:10.1107/S2056989026004810

. 2026 May 15;82(Pt 6):645–650. doi: 10.1107/S2056989026004810

Midodrine hydrochloride Form A, C₁₂H₁₉N₂O₄⁺·Cl⁻

Jacob K Salazar ^a, James A Kaduk ^b,^c,^*, Anja Dosen ^d, Thomas N Blanton ^d

Editor: S-L Zheng^e

PMCID: PMC13239003 PMID: 42254761

The crystal structure of midodrine hydrochloride Form A has been solved and refined using synchrotron X-ray powder diffraction data, and optimized using density functional theory techniques.

Keywords: powder diffraction, midodrine, ProAmatine®, Rietveld refinement, density functional theory

Abstract

The crystal structure of midodrine hydrochloride Form A (systematic name: {[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]carbamoyl}methanaminium chloride, C₁₂H₁₉N₂O₄⁺·Cl⁻) has been solved and refined using synchrotron X-ray powder diffraction data, and optimized using density functional theory techniques. Midodrine hydrochloride Form A crystallizes in space group P2₁/c (#14). The crystal structure is characterized by layers perpendicular to the c-axis direction. The Cl anions reside in the center of the layer. Hydrogen bonds are prominent in the structure. Each of the three H on the protonated N acts as a donor – one to the carbonyl group and the other two to the Cl ion. The hydroxyl group and the amide also act as donors to Cl. Considering the classical hydrogen bonds, the Cl ion is four-coordinate.

1. Chemical context

Midodrine hydrochloride (marketed as ProAmatine, among others) is used to treat hypotension (low blood pressure) and urinary incontinence. In particular, midodrine HCl treats symptomatic low blood pressure upon standing from a sitting or laying down position. The systematic name (CAS Registry Number 43218-56-0) is 2-amino-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]acetamide hydrochloride.

A process for preparing midodrine hydrochloride has been claimed in US Patent Application US 2022/0144754 A1 (Singh et al., 2022 ▸; Cadila Healthcare Ltd.), and powder diffraction data labeled as Form A are provided but no crystal structure was reported.

This work was carried out as part of a project (Kaduk et al., 2014 ▸) to determine the crystal structures of large-volume commercial pharmaceuticals, and includes high-quality powder diffraction data for them in the Powder Diffraction File (Kabekkodu et al., 2024 ▸).

2. Structural commentary

The synchrotron pattern of midodrine hydrochloride is similar enough to that reported by Singh et al. (2022 ▸) for Form A (Fig. 1 ▸) to conclude that they represent the same material. The patent pattern exhibits small displacement/transparency peak position error, as well as significant preferred orientation.

Comparison of the synchrotron pattern from this study of midodrine hydrochloride (black) to that reported for Form A by Singh *et al.* (2022 ▸; green). The patent pattern (measured using Cu K_α radiation) was digitized using *UN-SCAN-IT* (Silk Scientific, 2013 ▸) and converted to the synchrotron wavelength of 0.4687342 Å using *JADE Pro* (MDI, 2026 ▸). Image generated using *JADE Pro* (MDI, 2026 ▸).

The root-mean-square deviation of the non-H atoms in the Rietveld-refined and VASP-optimized structures of midodrine hydrochloride Form A, calculated using the Mercury CSD-Materials/Search/Crystal Packing Similarity tool (Macrae et al., 2020 ▸) is 0.050 Å (Fig. 2 ▸); the structures are essentially identical. The root-mean-square Cartesian displacement of the non-H atoms in the refined and optimized structures of the cation, calculated using the Mercury Calculate/Molecule Overlay tool, is 0.042 Å (Fig. 3 ▸). The absolute position difference of the Cl is 0.033 Å. The agreements are within the normal range for correct structures (van de Streek & Neumann, 2014 ▸). The asymmetric unit is illustrated in Fig. 4 ▸. The remaining discussion will emphasize the VASP-optimized structure.

Comparison of the Rietveld-refined (colored by atom type) and *VASP*-optimized (pale green) structures of midodrine hydrochloride Form A, calculated using the *Mercury* CSD-Materials/Search/Crystal Packing Similarity tool. The root-mean-square Cartesian displacement is 0.050 Å. Image generated using *Mercury* (Macrae *et al.*, 2020 ▸).

Comparison of the refined structure of the cation in midodrine hydrochloride Form A (red) to the *VASP*-optimized structure (blue). The comparison was generated using the *Mercury* Calculate/Molecule Overlay tool; the r.m.s. deviation is 0.042 Å. Image generated using *Mercury* (Macrae *et al.*, 2020 ▸).

The asymmetric unit of midodrine hydrochloride Form A, with the atom numbering. The atoms are represented by 50% probability spheroids/ellipsoids. Image generated using *Mercury* (Macrae *et al.*, 2020 ▸).

All of the bond distances, bond angles, and torsion angles (Table 1 ▸) fall within the normal ranges indicated by a Mercury Mogul Geometry check (Macrae et al., 2020 ▸). Quantum chemical geometry optimization of the isolated midodrine cation (DFT/B3LYP/6-31G*/water) using Spartan ’24 (Wavefunction, 2025 ▸) indicated that the observed conformation is 4.4 kcal mol⁻¹ higher in energy than a local minimum, which has an essentially identical conformation (r.m.s. deviation = 0.066 Å). The global minimum-energy conformation (MMFF force field) is 98.1 kcal mol⁻¹ lower in energy, but is unreasonably folded on itself to form intramolecular hydrogen bonds. Intermolecular interactions are important in determining the solid-state conformation.

Table 1. Selected geometric parameters (Å, °) for midodrine.

O1—C7	1.437 (2)	C15—O4	1.224 (2)
O1—H26	0.989 (2)	C15—N5	1.329 (2)
O2—C10	1.3741 (17)	C15—C16	1.5115 (19)
O2—C17	1.427 (3)	C16—N6	1.467 (3)
O3—C12	1.3814 (19)	C16—C15	1.5115 (19)
O3—C18	1.425 (3)	C16—H27	1.085 (3)
O4—C15	1.224 (2)	C16—H28	1.125 (3)
N5—C9	1.451 (2)	C17—O2	1.427 (3)
N5—C15	1.329 (2)	C17—H29	1.060 (3)
N5—H23	1.047 (2)	C17—H30	1.115 (3)
N6—C16	1.467 (3)	C17—H31	1.100 (3)
N6—H35	1.072 (3)	C18—O3	1.425 (3)
N6—H36	1.070 (2)	C18—H32	1.142 (3)
N6—H37	1.015 (3)	C18—H33	1.067 (3)
C7—O1	1.437 (2)	C18—H34	1.089 (3)
C7—C8	1.5181 (10)	H19—C7	1.118 (3)
C7—C9	1.519 (3)	H20—C9	1.116 (3)
C7—H19	1.118 (3)	H21—C9	1.121 (3)
C8—C7	1.5181 (10)	H22—C11	1.0811 (19)
C8—C10	1.3914 (18)	H23—N5	1.047 (2)
C8—C11	1.4010 (18)	H24—C13	1.119 (2)
C9—N5	1.451 (2)	H25—C14	1.1036 (19)
C9—C7	1.519 (3)	H26—O1	0.989 (2)
C9—H20	1.116 (3)	H26—Cl38ⁱ	2.1733 (10)
C9—H21	1.121 (3)	H27—C16	1.085 (3)
C10—O2	1.3741 (17)	H28—C16	1.125 (3)
C10—C8	1.3914 (18)	H29—C17	1.060 (3)
C10—C13	1.391 (2)	H30—C17	1.115 (3)
C11—C8	1.4010 (18)	H31—C17	1.100 (3)
C11—C12	1.3917 (18)	H32—C18	1.142 (3)
C11—H22	1.0811 (19)	H33—C18	1.067 (3)
C12—O3	1.3814 (19)	H34—C18	1.089 (3)
C12—C11	1.3917 (18)	H35—N6	1.072 (3)
C12—C14	1.383 (2)	H35—Cl38ⁱⁱ	2.1656 (10)
C13—C10	1.391 (2)	H36—N6	1.070 (2)
C13—C14	1.378 (2)	H36—Cl38ⁱⁱⁱ	2.0529 (10)
C13—H24	1.119 (2)	H37—N6	1.015 (3)
C14—C12	1.383 (2)	Cl38—H26ⁱ	2.1733 (10)
C14—C13	1.378 (2)	Cl38—H35ⁱⁱ	2.1656 (10)
C14—H25	1.1036 (19)	Cl38—H36^iv	2.0529 (10)

C7—O1—H26	104.5 (2)	C12—C11—H22	122.58 (19)
C10—O2—C17	118.16 (15)	O3—C12—C11	123.4 (2)
C12—O3—C18	118.2 (2)	O3—C12—C14	116.5 (2)
C9—N5—C15	123.69 (18)	C11—C12—C14	120.08 (12)
C9—N5—H23	117.7 (2)	C10—C13—C14	120.27 (14)
C15—N5—H23	117.5 (2)	C10—C13—H24	120.83 (18)
C16—N6—H35	108.7 (2)	C14—C13—H24	118.9 (2)
C16—N6—H36	109.0 (2)	C12—C14—C13	120.11 (13)
H35—N6—H36	104.9 (2)	C12—C14—H25	119.3 (2)
C16—N6—H37	111.8 (3)	C13—C14—H25	120.6 (2)
H35—N6—H37	111.9 (2)	O4—C15—N5	124.03 (18)
H36—N6—H37	110.3 (2)	O4—C15—C16	120.44 (17)
O1—C7—C8	111.60 (16)	N5—C15—C16	115.28 (18)
O1—C7—C9	107.8 (2)	N6—C16—C15	110.65 (17)
C8—C7—C9	111.2 (2)	N6—C16—H27	107.5 (3)
O1—C7—H19	113.5 (2)	C15—C16—H27	113.1 (3)
C8—C7—H19	106.94 (18)	N6—C16—H28	109.3 (3)
C9—C7—H19	105.68 (19)	C15—C16—H28	109.6 (3)
C7—C8—C10	120.30 (12)	H27—C16—H28	106.7 (2)
C7—C8—C11	120.84 (13)	O2—C17—H29	112.0 (2)
C10—C8—C11	118.84 (11)	O2—C17—H30	111.8 (3)
N5—C9—C7	112.7 (2)	H29—C17—H30	111.3 (3)
N5—C9—H20	107.4 (2)	O2—C17—H31	112.3 (3)
C7—C9—H20	109.9 (2)	H29—C17—H31	106.1 (3)
N5—C9—H21	109.7 (2)	H30—C17—H31	102.9 (2)
C7—C9—H21	110.8 (2)	O3—C18—H32	109.9 (3)
H20—C9—H21	106.0 (2)	O3—C18—H33	107.7 (3)
O2—C10—C8	115.41 (11)	H32—C18—H33	108.8 (3)
O2—C10—C13	124.17 (13)	O3—C18—H34	111.0 (3)
C8—C10—C13	120.42 (12)	H32—C18—H34	106.7 (2)
C8—C11—C12	120.22 (13)	H33—C18—H34	112.8 (3)
C8—C11—H22	117.19 (18)

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Symmetry codes: (i) Inline graphic ; (ii) ; (iii) ; (iv) .

3. Supramolecular features

The crystal structure (Fig. 5 ▸) is characterized by layers perpendicular to the c-axis direction. The Cl anions reside in the center of the layer. The Mercury Aromatics Analyser indicates three moderate interactions (d = 5.18, 5.18, and 6.08 Å), which include both slipped stacking and end-face interactions. The mean plane of the aromatic rings is approximately (3,4,10).

Crystal structure of midodrine hydrochloride Form A, viewed down the a-axis. Image generated using *DIAMOND* (Crystal Impact, 2025 ▸).

Analysis of the contributions to the total crystal energy of the structure using the Forcite module of Materials Studio (Dassault Systèmes, 2025 ▸) indicated that the intramolecular energy is dominated by angle distortion terms. The intermolecular energy is small and dominated by van der Waals repulsions, which in this force field based analysis include hydrogen bonds. The hydrogen bonds are better discussed using the results of the DFT calculation.

Hydrogen bonds (Table 2 ▸) are prominent in the structure. Each of the three H on the protonated N6 acts as a donor – one to the carbonyl group O4 and the other two to Cl38. The energy of the N—H⋯O hydrogen bond was calculated using the correlation of Wheatley & Kaduk (2019 ▸). The hydroxyl group O1—H26 also acts as a donor to Cl38. The energy of the O—H⋯Cl bond was calculated using the correlation of Kaduk (2002 ▸). The amide N5—H23 also acts as a donor to Cl38. Considering the classical hydrogen bonds, the Cl is four-coordinate. These hydrogen bonds result in rings and chains, with graph sets (Etter, 1990 ▸; Bernstein et al., 1995 ▸; Motherwell et al., 2000 ▸) Inline graphic (10), (7), (10), (20), and larger features. The result is a complex network of hydrogen bonds in the center of the layers (Fig. 6 ▸). C—H⋯Cl and C—H⋯O hydrogen bonds also contribute to the lattice energy.

Table 2. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A	Mulliken overlap	H-bond energy
N6—H37⋯O4	1.043	1.807	2.781	153.7	0.063	5.8
N6—H36⋯Cl38	1.054	2.070	3.094	163.2	0.088
N6—H35⋯Cl38	1.047	2.181	3.159	154.6	0.077
O1—H26⋯Cl38	0.993	2.159	3.146	172.1	0.064	35.6
N5—H23⋯Cl38	1.025	2.545	3.465	149.0	0.036
C16—H28⋯Cl38	1.099	2.485	3.422	142.4	0.032
C11—H22⋯O1	1.090	2.443	2.825	98.9	0.017
C13—H24⋯O3	1.089	2.656	3.592	143.7	0.012
C17—H31⋯O3	1.100	2.642	3.637	150.3	0.010

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The hydrogen bonding pattern in the layers of midodrine hydrochloride Form A. Image generated using *Mercury* (Macrae *et al.*, 2020 ▸).

The volume enclosed by the Hirshfeld surface of midodrine hydrochloride Form A (Fig. 7 ▸, Hirshfeld, 1977 ▸, Spackman et al., 2021 ▸) is 343.78 Å³, 97.74% of 1/4 of the unit-cell volume. The packing density is thus typical. The close contacts (red in Fig. 7 ▸) involve the hydrogen bonds. The volume/non-hydrogen atom is normal, at 18.5 Å³.

The Hirshfeld surface of midodrine hydrochloride Form A. Intermolecular contacts longer than the sums of the van der Waals radii are colored blue, and contacts shorter than the sums of the radii are colored red. Contacts equal to the sums of radii are white. Image generated using *CrystalExplorer* (Spackman *et al.*, 2021 ▸).

The Bravais–Friedel–Donnay–Harker (Bravais, 1866 ▸; Friedel, 1907 ▸; Donnay & Harker, 1937 ▸) algorithm suggests that we might expect platy morphology for midodrine hydrochloride Form A, with {002} as the major faces. A 2nd-order spherical harmonic model for preferred orientation was included. The texture index was 1.003, indicating that the preferred orientation was negligible in this rotated capillary specimen.

4. Database survey

A reduced cell search in the Cambridge Structural Database (CSD 2026.1.0; Groom et al., 2016 ▸) yielded 16 hits, but no structures of midodrine or its derivatives.

5. Synthesis and crystallization

Midodrine hydrochloride was a commercial reagent, purchased from TargetMol (Batch #150940), and was used as-received.

6. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 3 ▸. The white powder was packed into a 1.5 mm diameter Kapton capillary, and rotated during the measurement at ∼50 Hz. The powder pattern was measured at 295 K at beam line 11-BM (Lee et al., 2008 ▸; Wang et al., 2008 ▸; Antao et al., 2008 ▸) of the Advanced Photon Source at Argonne National Laboratory using a wavelength of 0.4687342 Å from 0.5–50° 2θ with a step size of 0.001° and a counting time of 0.1 sec/step. The high-resolution powder diffraction data were collected using twelve silicon crystal analyzers that allow for high angular resolution, high precision, and accurate peak positions. A mixture of silicon (NIST SRM 640c) and alumina (NIST SRM 676a) standards (ratio Al₂O₃:Si = 2:1 by weight) was used to calibrate the instrument and refine the monochromatic wavelength used in the experiment.

Table 3. Experimental details.

	midodrine
Crystal data
Chemical formula	C₁₂H₁₉N₂O₄⁺·Cl⁻
M _r	290.75
Crystal system, space group	Monoclinic, P2₁/c
Temperature (K)	295
a, b, c (Å)	5.17893 (2), 8.25455 (3), 32.95227 (15)
β (°)	87.2465 (3)
V (Å³)	1407.08 (1)
Z	4
Radiation type	Synchrotron, λ = 0.46873 Å
μ (mm⁻¹)	0.03
Specimen shape, size (mm)	Cylinder, 2.0 × 1.5

Data collection
Diffractometer	11-BM, APS
Specimen mounting	Kapton capillary
Data collection mode	Transmission
Scan method	Step
2θ values (°)	2θ_min = 0.510, 2θ_max = 49.995, 2θ_step = 0.001

Refinement
R factors and goodness of fit	R_p = 0.049, R_wp = 0.061, R_exp = 0.044, R(F²) = 0.03133, χ² = 2.008
No. of parameters	96
No. of restraints	42
(Δ/σ)_max	8.514

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Computer programs: GSAS-II (Toby & Von Dreele, 2013 ▸).

The pattern was indexed on a primitive monoclinic unit cell with a = 5.17847, b = 8.25254, c = 32.94869 Å, β = 92.757°, V = 1406.4 Å³, and Z = 4 using N-TREOR as incorporated into EXPO2014 (Altomare et al., 2013 ▸). The suggested space group was P2₁/c, which was confirmed by the successful solution and refinement of the structure.

The molecular structure of midodrine was downloaded from PubChem (Kim et al., 2023 ▸) as Conformer3D_COMPOUND_CID_4195.sdf. It was converted to a *.mol2 file using Mercury (Macrae et al., 2020 ▸), and to a Fenske–Hall Z-matrix using OpenBabel (O’Boyle et al., 2011 ▸). The structure was solved by parallel tempering techniques as implemented in FOX (Favre-Nicolin & Černý, 2002 ▸) using a midodrine molecule and a Cl atom as fragments, and by Monte Carlo simulated annealing techniques as implemented in EXPO2014 (Altomare et al., 2013 ▸) and DASH (David et al., 2006 ▸). All three programs yielded equivalent structures. The FOX structure was selected for refinement. H37 was added to N6 using Mercury.

Rietveld refinement was carried out using GSAS-II (Toby & Von Dreele, 2013 ▸). Only the 1.5–28.0° portion of the pattern was included in the refinements (d_min = 0.969 Å). All non-H bond distances and angles were subjected to restraints, based on a Mercury/Mogul Geometry Check (Sykes et al., 2011 ▸; Bruno et al., 2004 ▸). The Mogul average and standard deviation for each quantity were used as the restraint parameters. The phenyl ring was restrained to be planar. The restraints contributed 1.5% to the overall χ². The hydrogen atoms were included in calculated positions, which were recalculated during the refinement using Materials Studio (Dassault Systèmes, 2025 ▸). The U_iso of the non-H atoms were grouped by chemical similarity. The U_iso of the H atoms were fixed at 1.2 × the U_iso of the heavy atom to which they are attached. The Cl was refined anisotropically. The peak profiles were described using the generalized microstrain model (Stephens, 1999 ▸). The background was modeled using a six-term shifted Chebyshev polynomial, with peaks at 1.58 and 5.56° to model the scattering from the Kapton capillary and any amorphous component of the sample.

The final refinement of 96 variables using 26,501 observations and 42 restraints yielded the residuals R_wp = 0.06154 and GOF = 1.42. The largest peak (0.77 Å from O3) and hole (0.37 Å from O3) in the difference-Fourier map were 0.17 (4) and −0.17 (4) e Å⁻³, respectively. The final Rietveld plot is shown in Fig. 8 ▸. The largest features in the normalized error plot are in the shapes of some of the strong low-angle peaks.

The Rietveld plot for midodrine hydrochloride Form A. The blue crosses represent the observed data points, and the green line is the calculated pattern. The cyan curve is the normalized error plot, and the red line is the background curve. The blue tick marks indicate the peak positions. The vertical scale has been multiplied by a factor of 10× for 2θ > 11.6°.

The crystal structure of midodrine hydrochloride Form A was optimized (fixed experimental unit cell) with density functional theory techniques using VASP (Kresse & Furthmüller, 1996 ▸) through the MedeA graphical interface (Materials Design, 2024 ▸). The calculation was carried out on 32 cores of a 144-core (768 Gb memory) HPE Superdome Flex 280 Linux server at North Central College. The calculation used the GGA-PBE functional, a plane wave cutoff energy of 400.0 eV, and a k-point spacing of 0.5 Å⁻¹ leading to a 3 × 2 × 1 mesh, and took ∼2.6 h. Single-point density functional theory calculations (fixed experimental cell) and population analysis were carried out using CRYSTAL23 (Erba et al., 2023 ▸) and CRYSTAL17 (Dovesi et al., 2018 ▸). The basis sets for the H, C, N and O atoms in the calculation were those of Gatti et al. (1994 ▸), and that for Cl was from Peintinger et al. (2013 ▸). The calculations were run on a 3.5 GHz PC using 8 k-points and the B3LYP functional, and took ∼1.8 hr. The powder pattern has been submitted to ICDD for inclusion in the Powder Diffraction File™ (PDF®).

Supplementary Material

Crystal structure: contains datablock(s) midodrine, midodrine_midodrine_VASP. DOI: 10.1107/S2056989026004810/oi2037sup1.cif

e-82-00645-sup1.cif^{(1.5MB, cif)}

e-82-00645-midodrinesup2.cml^{(5.5KB, cml)}

Supporting information file. DOI: 10.1107/S2056989026004810/oi2037midodrinesup2.cml

CCDC references: 2552708, 2552707

Additional supporting information: crystallographic information; 3D view; checkCIF report

Acknowledgments

Use of the Advanced Photon Source at Argonne National Laboratory was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. DE-AC02–06CH11357. We thank Saul Lapidus for his assistance in the data collection. We also thank the ICDD team – Megan Rost, Steve Trimble, and Dave Bohnenberger – for their contribution to research, sample preparation, and in-house XRD data collection and verification.

supplementary crystallographic information

{[2-(2,5-Dimethoxyphenyl)-2-hydroxyethyl]carbamoyl}methanaminium chloride (midodrine). Crystal data

C₁₂H₁₉N₂O₄⁺·Cl⁻	V = 1407.08 (1) Å³
M_r = 290.75	Z = 4
Monoclinic, P2₁/c	D_x = 1.373 Mg m⁻³
a = 5.17893 (2) Å	Synchrotron radiation, λ = 0.46873 Å
b = 8.25455 (3) Å	µ = 0.03 mm⁻¹
c = 32.95227 (15) Å	T = 295 K
β = 87.2465 (3)°	cylinder, 2.0 × 1.5 mm

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{[2-(2,5-Dimethoxyphenyl)-2-hydroxyethyl]carbamoyl}methanaminium chloride (midodrine). Data collection

11-BM, APS diffractometer	Scan method: step
Specimen mounting: Kapton capillary	2θ_min = 0.510°, 2θ_max = 49.995°, 2θ_step = 0.001°
Data collection mode: transmission

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{[2-(2,5-Dimethoxyphenyl)-2-hydroxyethyl]carbamoyl}methanaminium chloride (midodrine). Refinement

Least-squares matrix: full	96 parameters
R_p = 0.049	42 restraints
R_wp = 0.061	34 constraints
R_exp = 0.044	Weighting scheme based on measured s.u.'s
R(F²) = 0.03133	(Δ/σ)_max = 8.514
49486 data points	Background function: Background function: "chebyschev-1" function with 6 terms: 35.73(7), -4.92(12), -6.39(12), 3.98(12), -3.39(9), -0.15(7), Background peak parameters: pos, int, sig, gam: 1.580(20), 4.39(21)e3, 2.09(13)e3, 0.100, 5.557(6), 4.34(6)e3, 2.74(7)e3, 0.100,
Profile function: Finger-Cox-Jephcoat function parameters U, V, W, X, Y, SH/L: peak variance(Gauss) = Utan(Th)²+Vtan(Th)+W: peak HW(Lorentz) = X/cos(Th)+Ytan(Th); SH/L = S/L+H/L U, V, W in (centideg)², X & Y in centideg 1.163, -0.126, 0.063, 0.000, 0.000, 0.002,	Preferred orientation correction: Simple spherical harmonic correction Order = 2 Coefficients: 0:0:C(2,-2) = -0.0581(18); 0:0:C(2,0) = 0.078(4); 0:0:C(2,2) = -0.0919(24)

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{[2-(2,5-Dimethoxyphenyl)-2-hydroxyethyl]carbamoyl}methanaminium chloride (midodrine). Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²)

	x	y	z	U_iso*/U_eq
O1	1.0970 (4)	0.7465 (3)	0.57295 (6)	0.0323 (4)*
O2	0.6632 (4)	0.9002 (2)	0.67443 (6)	0.0391 (5)*
O3	1.3249 (4)	0.3806 (2)	0.68910 (6)	0.0391 (5)*
O4	1.5002 (4)	1.0459 (3)	0.54902 (6)	0.0323 (4)*
N5	1.0987 (4)	1.0938 (3)	0.57585 (7)	0.0323 (4)*
N6	1.4661 (5)	1.2607 (3)	0.48827 (8)	0.0323 (4)*
C7	0.9770 (5)	0.8305 (3)	0.60708 (6)	0.0323 (4)*
C8	0.9847 (5)	0.7310 (3)	0.64575 (6)	0.0311 (5)*
C9	1.1161 (5)	0.9912 (3)	0.61138 (8)	0.0323 (4)*
C10	0.8228 (5)	0.7694 (3)	0.67930 (6)	0.0311 (5)*
C11	1.1581 (5)	0.6018 (3)	0.64869 (7)	0.0311 (5)*
C12	1.1601 (5)	0.5099 (3)	0.68409 (8)	0.0311 (5)*
C13	0.8299 (6)	0.6787 (3)	0.71481 (7)	0.0311 (5)*
C14	0.9978 (6)	0.5498 (3)	0.71712 (7)	0.0311 (5)*
C15	1.2919 (5)	1.1156 (4)	0.54837 (8)	0.0323 (4)*
C16	1.2304 (5)	1.2225 (4)	0.51286 (9)	0.0323 (4)*
C17	0.4688 (6)	0.9328 (4)	0.70550 (9)	0.0391 (5)*
C18	1.5119 (6)	0.3451 (4)	0.65719 (9)	0.0391 (5)*
H19	0.76985	0.86202	0.60297	0.0388 (5)*
H20	1.32549	0.96936	0.61586	0.0388 (5)*
H21	1.04032	1.05789	0.63909	0.0388 (5)*
H22	1.28492	0.57675	0.62242	0.0373 (6)*
H23	0.93892	1.17104	0.57467	0.0388 (5)*
H24	0.70477	0.71120	0.74223	0.0373 (6)*
H25	1.00097	0.47574	0.74497	0.0373 (6)*
H26	0.98954	0.64869	0.56984	0.0388 (5)*
H27	1.09480	1.16753	0.49287	0.0388 (5)*
H28	1.13894	1.33833	0.52442	0.0388 (5)*
H29	0.35462	1.03463	0.69851	0.0469 (6)*
H30	0.34623	0.82426	0.71243	0.0469 (6)*
H31	0.55160	0.95960	0.73490	0.0469 (6)*
H32	1.41042	0.31642	0.62801	0.0469 (6)*
H33	1.61746	0.24085	0.66595	0.0469 (6)*
H34	1.63568	0.44937	0.65061	0.0469 (6)*
H35	1.60707	1.30873	0.50782	0.0388 (5)*
H36	1.42630	1.35768	0.46795	0.0388 (5)*
H37	1.53415	1.16293	0.47244	0.0388 (5)*
Cl38	0.2652 (2)	0.55463 (11)	0.44075 (3)	0.0394

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{[2-(2,5-Dimethoxyphenyl)-2-hydroxyethyl]carbamoyl}methanaminium chloride (midodrine). Atomic displacement parameters (Å²)

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
Cl38	0.0457 (9)	0.0273 (9)	0.0446 (9)	0.0127 (16)	0.0036 (15)	−0.0002 (15)

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{[2-(2,5-Dimethoxyphenyl)-2-hydroxyethyl]carbamoyl}methanaminium chloride (midodrine). Geometric parameters (Å, º)

O1—C7	1.437 (2)	C15—O4	1.224 (2)
O1—H26	0.989 (2)	C15—N5	1.329 (2)
O2—C10	1.3741 (17)	C15—C16	1.5115 (19)
O2—C17	1.427 (3)	C16—N6	1.467 (3)
O3—C12	1.3814 (19)	C16—C15	1.5115 (19)
O3—C18	1.425 (3)	C16—H27	1.085 (3)
O4—C15	1.224 (2)	C16—H28	1.125 (3)
N5—C9	1.451 (2)	C17—O2	1.427 (3)
N5—C15	1.329 (2)	C17—H29	1.060 (3)
N5—H23	1.047 (2)	C17—H30	1.115 (3)
N6—C16	1.467 (3)	C17—H31	1.100 (3)
N6—H35	1.072 (3)	C18—O3	1.425 (3)
N6—H36	1.070 (2)	C18—H32	1.142 (3)
N6—H37	1.015 (3)	C18—H33	1.067 (3)
C7—O1	1.437 (2)	C18—H34	1.089 (3)
C7—C8	1.5181 (10)	H19—C7	1.118 (3)
C7—C9	1.519 (3)	H20—C9	1.116 (3)
C7—H19	1.118 (3)	H21—C9	1.121 (3)
C8—C7	1.5181 (10)	H22—C11	1.0811 (19)
C8—C10	1.3914 (18)	H23—N5	1.047 (2)
C8—C11	1.4010 (18)	H24—C13	1.119 (2)
C9—N5	1.451 (2)	H25—C14	1.1036 (19)
C9—C7	1.519 (3)	H26—O1	0.989 (2)
C9—H20	1.116 (3)	H26—Cl38ⁱ	2.1733 (10)
C9—H21	1.121 (3)	H27—C16	1.085 (3)
C10—O2	1.3741 (17)	H28—C16	1.125 (3)
C10—C8	1.3914 (18)	H29—C17	1.060 (3)
C10—C13	1.391 (2)	H30—C17	1.115 (3)
C11—C8	1.4010 (18)	H31—C17	1.100 (3)
C11—C12	1.3917 (18)	H32—C18	1.142 (3)
C11—H22	1.0811 (19)	H33—C18	1.067 (3)
C12—O3	1.3814 (19)	H34—C18	1.089 (3)
C12—C11	1.3917 (18)	H35—N6	1.072 (3)
C12—C14	1.383 (2)	H35—Cl38ⁱⁱ	2.1656 (10)
C13—C10	1.391 (2)	H36—N6	1.070 (2)
C13—C14	1.378 (2)	H36—Cl38ⁱⁱⁱ	2.0529 (10)
C13—H24	1.119 (2)	H37—N6	1.015 (3)
C14—C12	1.383 (2)	Cl38—H26ⁱ	2.1733 (10)
C14—C13	1.378 (2)	Cl38—H35ⁱⁱ	2.1656 (10)
C14—H25	1.1036 (19)	Cl38—H36^iv	2.0529 (10)

C7—O1—H26	104.5 (2)	C12—C11—H22	122.58 (19)
C10—O2—C17	118.16 (15)	O3—C12—C11	123.4 (2)
C12—O3—C18	118.2 (2)	O3—C12—C14	116.5 (2)
C9—N5—C15	123.69 (18)	C11—C12—C14	120.08 (12)
C9—N5—H23	117.7 (2)	C10—C13—C14	120.27 (14)
C15—N5—H23	117.5 (2)	C10—C13—H24	120.83 (18)
C16—N6—H35	108.7 (2)	C14—C13—H24	118.9 (2)
C16—N6—H36	109.0 (2)	C12—C14—C13	120.11 (13)
H35—N6—H36	104.9 (2)	C12—C14—H25	119.3 (2)
C16—N6—H37	111.8 (3)	C13—C14—H25	120.6 (2)
H35—N6—H37	111.9 (2)	O4—C15—N5	124.03 (18)
H36—N6—H37	110.3 (2)	O4—C15—C16	120.44 (17)
O1—C7—C8	111.60 (16)	N5—C15—C16	115.28 (18)
O1—C7—C9	107.8 (2)	N6—C16—C15	110.65 (17)
C8—C7—C9	111.2 (2)	N6—C16—H27	107.5 (3)
O1—C7—H19	113.5 (2)	C15—C16—H27	113.1 (3)
C8—C7—H19	106.94 (18)	N6—C16—H28	109.3 (3)
C9—C7—H19	105.68 (19)	C15—C16—H28	109.6 (3)
C7—C8—C10	120.30 (12)	H27—C16—H28	106.7 (2)
C7—C8—C11	120.84 (13)	O2—C17—H29	112.0 (2)
C10—C8—C11	118.84 (11)	O2—C17—H30	111.8 (3)
N5—C9—C7	112.7 (2)	H29—C17—H30	111.3 (3)
N5—C9—H20	107.4 (2)	O2—C17—H31	112.3 (3)
C7—C9—H20	109.9 (2)	H29—C17—H31	106.1 (3)
N5—C9—H21	109.7 (2)	H30—C17—H31	102.9 (2)
C7—C9—H21	110.8 (2)	O3—C18—H32	109.9 (3)
H20—C9—H21	106.0 (2)	O3—C18—H33	107.7 (3)
O2—C10—C8	115.41 (11)	H32—C18—H33	108.8 (3)
O2—C10—C13	124.17 (13)	O3—C18—H34	111.0 (3)
C8—C10—C13	120.42 (12)	H32—C18—H34	106.7 (2)
C8—C11—C12	120.22 (13)	H33—C18—H34	112.8 (3)
C8—C11—H22	117.19 (18)

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

(midodrine_midodrine_VASP). Crystal data

C₁₂H₁₉ClN₂O₄	c = 32.95150 Å
M_r = 290.75	β = 87.25°
Monoclinic, P2₁/c	V = 1406.93 Å³
a = 5.17880 Å	Z = 4
b = 8.25410 Å

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(midodrine_midodrine_VASP). Data collection

h = →	l = →
k = →

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(midodrine_midodrine_VASP). Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²)

	x	y	z	B_iso*/B_eq
O1	1.08609	0.75160	0.57288
O2	0.66329	0.90588	0.67624
O3	1.32010	0.37844	0.68884
O4	1.49956	1.03863	0.54807
N5	1.10117	1.10119	0.57712
N6	1.46798	1.26472	0.48858
C7	0.97486	0.83368	0.60772
C8	0.98777	0.73521	0.64646
C9	1.11992	0.99460	0.61196
C10	0.82320	0.77413	0.68029
C11	1.15908	0.60486	0.64894
C12	1.16333	0.51097	0.68431
C13	0.82942	0.68120	0.71575
C14	0.99768	0.55011	0.71764
C15	1.28930	1.11376	0.54791
C16	1.23005	1.22586	0.51307
C17	0.47051	0.93180	0.70822
C18	1.50565	0.34561	0.65626
H19	0.76985	0.86202	0.60297
H20	1.32549	0.96936	0.61586
H21	1.04032	1.05789	0.63909
H22	1.28492	0.57675	0.62242
H23	0.93892	1.17104	0.57467
H24	0.70477	0.71120	0.74223
H25	1.00097	0.47574	0.74497
H26	0.98954	0.64869	0.56984
H27	1.09480	1.16753	0.49287
H28	1.13894	1.33833	0.52442
H29	0.35462	1.03463	0.69851
H30	0.34623	0.82426	0.71243
H31	0.55766	0.96164	0.73709
H32	1.41042	0.31642	0.62801
H33	1.61746	0.24085	0.66595
H34	1.63568	0.44937	0.65061
H35	1.60707	1.30873	0.50782
H36	1.42630	1.35768	0.46795
H37	1.53415	1.16293	0.47244
Cl38	1.26072	1.55497	0.44040

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(midodrine_midodrine_VASP). Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N6—H37···O4	1.043	1.807	2.781	153.7
N6—H36···Cl38	1.054	2.070	3.094	163.2
N6—H35···Cl38	1.047	2.181	3.159	154.6
O1—H26···Cl38	0.993	2.159	3.146	172.1
N5—H23···Cl38	1.025	2.545	3.465	149.0
C16—H28···Cl38	1.099	2.485	3.422	142.4
C11—H22···O1	1.090	2.443	2.825	98.9
C13—H24···O3	1.089	2.656	3.592	143.7
C17—H31···O3	1.100	2.642	3.637	150.3

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Funding Statement

Funding for this research was provided by: International Centre for Diffraction Data (grant No. 09-03).

References

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Crystal structure: contains datablock(s) midodrine, midodrine_midodrine_VASP. DOI: 10.1107/S2056989026004810/oi2037sup1.cif

e-82-00645-sup1.cif^{(1.5MB, cif)}

e-82-00645-midodrinesup2.cml^{(5.5KB, cml)}

Supporting information file. DOI: 10.1107/S2056989026004810/oi2037midodrinesup2.cml

CCDC references: 2552708, 2552707

Additional supporting information: crystallographic information; 3D view; checkCIF report

[bb1] Altomare, A., Cuocci, C., Giacovazzo, C., Moliterni, A., Rizzi, R., Corriero, N. & Falcicchio, A. (2013). J. Appl. Cryst.46, 1231–1235.

[bb2] Antao, S. M., Hassan, I., Wang, J., Lee, P. L. & Toby, B. H. (2008). Can. Mineral.46, 1501–1509.

[bb3] Bernstein, J., Davis, R. E., Shimoni, L. & Chang, N. L. (1995). Angew. Chem. Int. Ed. Engl.34, 1555–1573.

[bb4] Bravais, A. (1866). Etudes Cristallographiques. Paris: Gauthier Villars.

[bb5] Bruno, I. J., Cole, J. C., Kessler, M., Luo, J., Motherwell, W. D. S., Purkis, L. H., Smith, B. R., Taylor, R., Cooper, R. I., Harris, S. E. & Orpen, A. G. (2004). J. Chem. Inf. Comput. Sci.44, 2133–2144. [DOI] [PubMed]

[bb6] Crystal Impact. (2025). DIAMOND. Crystal Impact GbR, Bonn, Germany.

[bb7] Dassault Systèmes. (2025). BIOVIA Materials Studio 2025. BIOVIA, San Diego, CA, USA.

[bb8] David, W. I. F., Shankland, K., van de Streek, J., Pidcock, E., Motherwell, W. D. S. & Cole, J. C. (2006). J. Appl. Cryst.39, 910–915.

[bb9] Donnay, J. D. H. & Harker, D. (1937). Am. Mineral.22, 446–467.

[bb39] Dovesi, R., Erba, A., Orlando, R., Zicovich-Wilson, C. M., Civalleri, B., Maschio, L., Rérat, M., Casassa, S., Baima, J., Salustro, S. & Kirtman, B. (2018). WIREs Comput. Mol. Sci.8, e1360.

[bb10] Erba, A., Desmarais, J. K., Casassa, S., Civalleri, B., Donà, L., Bush, I. J., Searle, B., Maschio, L., Edith-Daga, L., Cossard, A., Ribaldone, C., Ascrizzi, E., Marana, N. L., Flament, J.-P. & Kirtman, B. (2023). J. Chem. Theory Comput.19, 6891–6932. [DOI] [PMC free article] [PubMed]

[bb11] Etter, M. C. (1990). Acc. Chem. Res.23, 120–126.

[bb38] Favre-Nicolin, V. & Černý, R. (2002). J. Appl. Cryst.35, 734–743.

[bb12] Friedel, G. (1907). Bull. Soc. Française Minéral.30, 326–455.

[bb13] Gatti, C., Saunders, V. R. & Roetti, C. (1994). J. Chem. Phys.101, 10686–10696.

[bb14] Groom, C. R., Bruno, I. J., Lightfoot, M. P. & Ward, S. C. (2016). Acta Cryst. B72, 171–179. [DOI] [PMC free article] [PubMed]

[bb15] Hirshfeld, F. L. (1977). Theor. Chim. Acta44, 129–138.

[bb16] Kabekkodu, S., Dosen, A. & Blanton, T. N. (2024). Powder Diffr.39, 47–59.

[bb17] Kaduk, J. A. (2002). Acta Cryst. B58, 370–379. [DOI] [PubMed]

[bb18] Kaduk, J. A., Crowder, C. E., Zhong, K., Fawcett, T. G. & Suchomel, M. R. (2014). Powder Diffr.29, 269–273.

[bb19] Kim, S., Chen, J., Cheng, T., Gindulyte, A., He, J., He, S., Li, Q., Shoemaker, B. A., Thiessen, P. A., Yu, B., Zaslavsky, L., Zhang, J. & Bolton, E. E. (2023). Nucleic Acids Res.51, D1373–D1380. [DOI] [PMC free article] [PubMed]

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PERMALINK

Midodrine hydro­chloride Form A, C12H19N2O4+·Cl−

Jacob K Salazar

James A Kaduk

Anja Dosen

Thomas N Blanton

Roles

Abstract

1. Chemical context

2. Structural commentary

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Table 1. Selected geometric parameters (Å, °) for midodrine.

3. Supra­molecular features

Figure 5.

Table 2. Hydrogen-bond geometry (Å, °).

Figure 6.

Figure 7.

4. Database survey

5. Synthesis and crystallization

6. Refinement

Table 3. Experimental details.

Figure 8.

Supplementary Material

Acknowledgments

supplementary crystallographic information

{[2-(2,5-Dimethoxyphenyl)-2-hydroxyethyl]carbamoyl}methanaminium chloride (midodrine). Crystal data

{[2-(2,5-Dimethoxyphenyl)-2-hydroxyethyl]carbamoyl}methanaminium chloride (midodrine). Data collection

{[2-(2,5-Dimethoxyphenyl)-2-hydroxyethyl]carbamoyl}methanaminium chloride (midodrine). Refinement

{[2-(2,5-Dimethoxyphenyl)-2-hydroxyethyl]carbamoyl}methanaminium chloride (midodrine). Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2)

{[2-(2,5-Dimethoxyphenyl)-2-hydroxyethyl]carbamoyl}methanaminium chloride (midodrine). Atomic displacement parameters (Å2)

{[2-(2,5-Dimethoxyphenyl)-2-hydroxyethyl]carbamoyl}methanaminium chloride (midodrine). Geometric parameters (Å, º)

(midodrine_midodrine_VASP). Crystal data

(midodrine_midodrine_VASP). Data collection

(midodrine_midodrine_VASP). Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2)

(midodrine_midodrine_VASP). Hydrogen-bond geometry (Å, º)

Funding Statement

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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Links to NCBI Databases

Midodrine hydrochloride Form A, C₁₂H₁₉N₂O₄⁺·Cl⁻

3. Supramolecular features

{[2-(2,5-Dimethoxyphenyl)-2-hydroxyethyl]carbamoyl}methanaminium chloride (midodrine). Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²)

{[2-(2,5-Dimethoxyphenyl)-2-hydroxyethyl]carbamoyl}methanaminium chloride (midodrine). Atomic displacement parameters (Å²)

(midodrine_midodrine_VASP). Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²)