High-throughput nanoscale crystallization of dihydropyridine active pharmaceutical ingredients.
Metherall, Jessica P.; Corner, Philip A.; McCabe, James F.; Hall, Michael J.; Probert, Michael R.; Acta crystallographica Section B, Structural science, crystal engineering and materials 80 (2024) 4–12; doi:10.1107/S2052520623010053

data_2312373
_publ_section_title
;
 High-throughput nanoscale crystallization of dihydropyridine active
 pharmaceutical ingredients.
;
_journal_coeditor_code           RM5073SUP1
_journal_issue                   1
_journal_name_full
'Acta crystallographica Section B, Structural science, crystal engineering and materials'
_journal_page_first              4
_journal_page_last               12
_journal_paper_doi               10.1107/S2052520623010053
_journal_volume                  80
_journal_year                    2024
_chemical_absolute_configuration unk
_chemical_formula_moiety         'C27 H28 N2 O7'
_chemical_formula_sum            'C27 H28 N2 O7'
_chemical_formula_weight         492.51
_chemical_name_common            cilnidipine
_chemical_name_systematic
;         
(rac)-3-cinnamyl 5-(2-methoxyethyl) 2,6-dimethyl-4-(3-nitrophenyl) 
-1,4-dihydropyridine-3,5-dicarboxylate
;
_space_group_crystal_system      orthorhombic
_space_group_IT_number           43
_space_group_name_Hall           'F 2 -2d'
_space_group_name_H-M_alt        'F d d 2'
_atom_sites_solution_hydrogens   mixed
_atom_sites_solution_primary     dual
_audit_creation_date             2023-09-27
_audit_creation_method
; 
Olex2 1.5 
(compiled 2023.08.24 svn.re1ec1418 for OlexSys, GUI svn.r6817) 
;
_cell_angle_alpha                90
_cell_angle_beta                 90
_cell_angle_gamma                90
_cell_formula_units_Z            16
_cell_length_a                   15.0989(17)
_cell_length_b                   59.567(7)
_cell_length_c                   10.9540(12)
_cell_measurement_reflns_used    9164
_cell_measurement_temperature    100
_cell_measurement_theta_max      25.092
_cell_measurement_theta_min      3.17
_cell_volume                     9852.0(19)
_computing_cell_refinement       'SAINT V8.40B (?, 2016)'
_computing_data_collection       'Bruker Instrument Service v6.2.6'
_computing_data_reduction        'SAINT V8.40B (?, 2016)'
_computing_molecular_graphics    'Olex2 1.5 (Dolomanov et al., 2009)'
_computing_publication_material  'Olex2 1.5 (Dolomanov et al., 2009)'
_computing_structure_refinement  'SHELXL 2018/3 (Sheldrick, 2015)'
_computing_structure_solution    'SHELXT 2018/2 (Sheldrick, 2018)'
_diffrn_ambient_temperature      100
_diffrn_detector                 'Photon counting pixel array'
_diffrn_detector_area_resol_mean 7.3910
_diffrn_detector_type            'Dectris Pilatus 2M'
_diffrn_measured_fraction_theta_full 0.996
_diffrn_measured_fraction_theta_max 0.996
_diffrn_measurement_device       'Fixed \c 3-circle diffractometer'
_diffrn_measurement_device_type  'Fluid Film Devices'
_diffrn_measurement_method       '\f and \w rotation with 0.1 degree frames'
_diffrn_measurement_specimen_support 'MiTeGen MicroMount'
_diffrn_orient_matrix_type       'Bruker AXS Inc. convention APEX3'
_diffrn_radiation_collimation    'focussed source'
_diffrn_radiation_monochromator  'Silicon 111'
_diffrn_radiation_probe          x-ray
_diffrn_radiation_type           Synchrotron
_diffrn_radiation_wavelength     0.6889
_diffrn_reflns_av_R_equivalents  0.0565
_diffrn_reflns_av_unetI/netI     0.0564
_diffrn_reflns_Laue_measured_fraction_full 0.996
_diffrn_reflns_Laue_measured_fraction_max 0.996
_diffrn_reflns_limit_h_max       17
_diffrn_reflns_limit_h_min       -16
_diffrn_reflns_limit_k_max       70
_diffrn_reflns_limit_k_min       -70
_diffrn_reflns_limit_l_max       12
_diffrn_reflns_limit_l_min       -13
_diffrn_reflns_number            15527
_diffrn_reflns_point_group_measured_fraction_full 0.968
_diffrn_reflns_point_group_measured_fraction_max 0.967
_diffrn_reflns_theta_full        24.271
_diffrn_reflns_theta_max         24.271
_diffrn_reflns_theta_min         1.325
_diffrn_source                   Synchrotron
_diffrn_source_current           0.0
_diffrn_source_power             0.0
_diffrn_source_type              'Undulator, I19, DLS, RAL'
_diffrn_source_voltage           0.0
_diffrn_standards_number         0
_exptl_absorpt_coefficient_mu    0.091
_exptl_absorpt_correction_T_max  0.7450
_exptl_absorpt_correction_T_min  0.4565
_exptl_absorpt_correction_type   multi-scan
_exptl_absorpt_process_details
; 
SADABS-2016/2 (Bruker,2016/2) was used for absorption correction. 
wR2(int) was 0.1842 before and 0.0893 after correction. 
The Ratio of minimum to maximum transmission is 0.6128. 
The \l/2 correction factor is Not present. 
;
_exptl_crystal_colour            'clear light colourless'
_exptl_crystal_colour_lustre     clear
_exptl_crystal_colour_modifier   light
_exptl_crystal_colour_primary    colourless
_exptl_crystal_density_diffrn    1.328
_exptl_crystal_description       needle
_exptl_crystal_F_000             4160
_exptl_crystal_preparation
'Crystallised from a saturated solution of cilnidipine in toluene.'
_exptl_crystal_recrystallization_method
'High-throughput screening via the ENaCt protocol using SPT Labtech mosquito.'
_exptl_crystal_size_max          0.56
_exptl_crystal_size_mid          0.14
_exptl_crystal_size_min          0.032
_refine_diff_density_max         0.187
_refine_diff_density_min         -0.170
_refine_diff_density_rms         0.039
_refine_ls_abs_structure_details
; 
 Flack x determined using 1451 quotients [(I+)-(I-)]/[(I+)+(I-)] 
 (Parsons, Flack and Wagner, Acta Cryst. B69 (2013) 249-259). 
;
_refine_ls_abs_structure_Flack   -0.6(7)
_refine_ls_extinction_method     none
_refine_ls_goodness_of_fit_ref   0.986
_refine_ls_hydrogen_treatment    mixed
_refine_ls_matrix_type           full
_refine_ls_number_parameters     339
_refine_ls_number_reflns         4234
_refine_ls_number_restraints     1
_refine_ls_restrained_S_all      0.986
_refine_ls_R_factor_all          0.0458
_refine_ls_R_factor_gt           0.0398
_refine_ls_shift/su_max          0.001
_refine_ls_shift/su_mean         0.000
_refine_ls_structure_factor_coef Fsqd
_refine_ls_weighting_details
'w=1/[\s^2^(Fo^2^)+(0.0504P)^2^] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.0915
_refine_ls_wR_factor_ref         0.0936
_reflns_Friedel_coverage         0.838
_reflns_Friedel_fraction_full    0.936
_reflns_Friedel_fraction_max     0.935
_reflns_number_gt                3656
_reflns_number_total             4234
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            rm5073sup1.cif
_cod_data_source_block           cilnidipine
_cod_depositor_comments
'Adding full bibliography for 2312368--2312375.cif.'
_cod_database_code               2312373
_cod_database_fobs_code          2312373
_shelx_shelxl_version_number     2018/3
_shelx_estimated_absorpt_t_max   0.997
_shelx_estimated_absorpt_t_min   0.951
_olex2_refinement_description
; 
1. Fixed Uiso 
 At 1.2 times of: 
  All C(H) groups, All C(H,H) groups, All N(H) groups 
 At 1.5 times of: 
  All C(H,H,H) groups 
2.a Ternary CH refined with riding coordinates: 
 C11(H11) 
2.b Secondary CH2 refined with riding coordinates: 
 C2(H2A,H2B), C3(H3A,H3B), C19(H19A,H19B) 
2.c Aromatic/amide H refined with riding coordinates: 
 N1(H1), C17(H17), C16(H16), C15(H15), C13(H13), C26(H26), C27(H27), C25(H25), 
 C21(H21), C23(H23), C24(H24), C20(H20) 
2.d Idealised Me refined as rotating group: 
 C1(H1A,H1B,H1C), C9(H9A,H9B,H9C) 
;
_shelx_res_checksum              57461
_shelx_hkl_checksum              56785
_olex2_exptl_crystal_mounting_method
; 
 'Crystal mounted using inert oil from the encapsulation  
crystallisation technique onto a MiTeGen Kapton micromount.' 
;
_olex2_submission_original_sample_id Cilnidipine
_olex2_submission_special_instructions 'No special instructions were received'