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_2312369
_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_formula_moiety         'C17 H18 N2 O6'
_chemical_formula_sum            'C17 H18 N2 O6'
_chemical_formula_weight         346.33
_chemical_name_common            Nifedipine
_chemical_name_systematic
'dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate'
_space_group_crystal_system      monoclinic
_space_group_IT_number           14
_space_group_name_Hall           '-P 2ybc'
_space_group_name_H-M_alt        'P 1 21/c 1'
_atom_sites_solution_hydrogens   mixed
_atom_sites_solution_primary     dual
_audit_creation_date             2023-05-11
_audit_creation_method
; 
Olex2 1.5 
(compiled 2023.03.06 svn.rbb2c1857 for OlexSys, GUI svn.r6748) 
;
_cell_angle_alpha                90
_cell_angle_beta                 94.545(2)
_cell_angle_gamma                90
_cell_formula_units_Z            4
_cell_length_a                   10.6713(3)
_cell_length_b                   10.3971(3)
_cell_length_c                   14.7824(3)
_cell_measurement_reflns_used    5449
_cell_measurement_temperature    150.00(10)
_cell_measurement_theta_max      76.5080
_cell_measurement_theta_min      4.1030
_cell_volume                     1634.96(7)
_computing_cell_refinement       'CrysAlisPro 1.171.42.73a (Rigaku OD, 2022)'
_computing_data_collection       'CrysAlisPro 1.171.42.73a (Rigaku OD, 2022)'
_computing_data_reduction        'CrysAlisPro 1.171.42.73a (Rigaku OD, 2022)'
_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_environment      N~2~
_diffrn_ambient_temperature      150.00(10)
_diffrn_detector                 'Hybrid Pixel Array Detector'
_diffrn_detector_area_resol_mean 10.0000
_diffrn_detector_type            'HyPix-Arc 100'
_diffrn_measured_fraction_theta_full 0.997
_diffrn_measured_fraction_theta_max 0.940
_diffrn_measurement_details
; 
List of Runs (angles in degrees, time in seconds): 
 
  # Type    Start    End  Width  t~exp~   \w     \q     \k     \f   Frames 
-------------------------------------------------------------------------- 
  1  \w    -36.00  11.00   0.50    0.19    --  -45.34  85.00-149.00   94 
  2  \w    -67.00 -41.00   0.50    0.19    --  -45.34  85.00-149.00   52 
  3  \w     23.00  49.00   0.50    0.19    --   46.34 -85.00  91.00   52 
  4  \w   -149.00-101.00   0.50    0.19    --  -85.06 -85.00  91.00   96 
  5  \w    -66.00 -32.00   0.50    0.19    --  -85.06  85.00-149.00   68 
  6  \w     47.00  93.00   0.50    0.19    --  109.85 -85.00  91.00   92 
  7  \w    128.00 159.00   0.50    0.19    --  109.85  85.00-149.00   62 
  8  \w    -14.00  28.00   0.50    0.19    --  -45.34  38.00  30.00   84 
  9  \w     -3.00  29.00   0.50    0.19    --  -45.34  38.00 -60.00   64 
 10  \w    -12.00  34.00   0.50    0.19    --  -45.34  38.00  90.00   92 
 11  \w    -41.00 -11.00   0.50    0.19    --  -85.06  61.00 150.00   60 
 12  \w   -142.00-104.00   0.50    0.19    --  -85.06 -77.00 120.00   76 
 13  \w    -45.00 -18.00   0.50    0.19    --  -85.06  61.00  90.00   54 
 14  \w    -44.00 -19.00   0.50    0.19    --  -85.06  61.00  30.00   50 
 15  \w    -38.00 -12.00   0.50    0.19    --  -85.06  61.00 120.00   52 
 16  \w    -41.00 -15.00   0.50    0.19    --  -85.06  61.00 -30.00   52 
 17  \w    -45.00 -20.00   0.50    0.19    --  -85.06  61.00   0.00   50 
 18  \w     30.00  56.00   0.50    0.19    --  100.34 -61.00 150.00   52 
 19  \w     66.00 133.00   0.50    0.19    --  100.34  15.00-180.00  134 
 20  \w     33.00  68.00   0.50    0.19    --  100.34 -77.00-120.00   70 
 21  \w     26.00  51.00   0.50    0.19    --  100.34 -61.00 -60.00   50 
 22  \w     28.00  53.00   0.50    0.19    --  100.34 -61.00 120.00   50 
 23  \w     38.00  63.00   0.50    0.19    --  100.34 -85.00  91.00   50 
 24  \w     30.00  55.00   0.50    0.19    --  100.34 -61.00-120.00   50 
 25  \w     28.00  53.00   0.50    0.19    --  100.34 -61.00  30.00   50 
 26  \w     26.00  51.00   0.50    0.19    --  100.34 -61.00   0.00   50 
 27  \w     44.00  71.00   0.50    0.19    --  109.85 -77.00 150.00   54 
 28  \w     54.00  79.00   0.50    0.19    --  109.85 -95.00-180.00   50 
 29  \w     42.00  80.00   0.50    0.19    --  109.85 -77.00 -90.00   76 
 30  \w     46.00  75.00   0.50    0.19    --  109.85 -77.00-180.00   58 
 31  \w     44.00  71.00   0.50    0.19    --  109.85 -77.00 -30.00   54 
 32  \w     52.00  77.00   0.50    0.19    --  109.85 -77.00-150.00   50 
;
_diffrn_measurement_device       'four-circle diffractometer'
_diffrn_measurement_device_type  'XtaLAB Synergy, Dualflex, HyPix-Arc 100'
_diffrn_measurement_method       '\w scans'
_diffrn_orient_matrix_type
'CrysAlisPro convention (1999,Acta A55,543-557)'
_diffrn_orient_matrix_UB_11      0.0868982000
_diffrn_orient_matrix_UB_12      -0.1149612000
_diffrn_orient_matrix_UB_13      -0.0154861000
_diffrn_orient_matrix_UB_21      0.1056629000
_diffrn_orient_matrix_UB_22      0.0635908000
_diffrn_orient_matrix_UB_23      0.0616148000
_diffrn_orient_matrix_UB_31      -0.0477910000
_diffrn_orient_matrix_UB_32      -0.0685980000
_diffrn_orient_matrix_UB_33      0.0829130000
_diffrn_radiation_monochromator  mirror
_diffrn_radiation_probe          x-ray
_diffrn_radiation_type           'Cu K\a'
_diffrn_radiation_wavelength     1.54184
_diffrn_reflns_av_R_equivalents  0.0308
_diffrn_reflns_av_unetI/netI     0.0287
_diffrn_reflns_Laue_measured_fraction_full 0.997
_diffrn_reflns_Laue_measured_fraction_max 0.940
_diffrn_reflns_limit_h_max       12
_diffrn_reflns_limit_h_min       -13
_diffrn_reflns_limit_k_max       10
_diffrn_reflns_limit_k_min       -13
_diffrn_reflns_limit_l_max       18
_diffrn_reflns_limit_l_min       -15
_diffrn_reflns_number            10751
_diffrn_reflns_point_group_measured_fraction_full 0.997
_diffrn_reflns_point_group_measured_fraction_max 0.940
_diffrn_reflns_theta_full        67.684
_diffrn_reflns_theta_max         77.098
_diffrn_reflns_theta_min         4.156
_diffrn_source                   'micro-focus sealed X-ray tube'
_diffrn_source_target            Cu
_diffrn_source_type              'PhotonJet (Cu) X-ray Source'
_exptl_absorpt_coefficient_mu    0.908
_exptl_absorpt_correction_T_max  1.00000
_exptl_absorpt_correction_T_min  0.86861
_exptl_absorpt_correction_type   multi-scan
_exptl_absorpt_process_details
; 
CrysAlisPro 1.171.42.73a (Rigaku Oxford Diffraction, 2022) 
Empirical absorption correction using spherical harmonics, 
implemented in SCALE3 ABSPACK scaling algorithm. 
;
_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    1.407
_exptl_crystal_description       block
_exptl_crystal_F_000             728
_exptl_crystal_preparation
'Crystallised from a saturated solution of nifedipine in 2,2,2-TFE.'
_exptl_crystal_recrystallization_method
'High-throughput screening via the ENaCt protocol using SPT Labtech mosquito.'
_exptl_crystal_size_max          0.51
_exptl_crystal_size_mid          0.45
_exptl_crystal_size_min          0.22
_refine_diff_density_max         0.407
_refine_diff_density_min         -0.182
_refine_diff_density_rms         0.047
_refine_ls_extinction_method     none
_refine_ls_goodness_of_fit_ref   1.063
_refine_ls_hydrogen_treatment    mixed
_refine_ls_matrix_type           full
_refine_ls_number_parameters     234
_refine_ls_number_reflns         3255
_refine_ls_number_restraints     0
_refine_ls_restrained_S_all      1.063
_refine_ls_R_factor_all          0.0459
_refine_ls_R_factor_gt           0.0409
_refine_ls_shift/su_max          0.000
_refine_ls_shift/su_mean         0.000
_refine_ls_structure_factor_coef Fsqd
_refine_ls_weighting_details
'w=1/[\s^2^(Fo^2^)+(0.0646P)^2^+0.4924P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.1146
_refine_ls_wR_factor_ref         0.1191
_reflns_Friedel_coverage         0.000
_reflns_number_gt                2857
_reflns_number_total             3255
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            rm5073sup1.cif
_cod_data_source_block           nifedipine
_cod_depositor_comments
'Adding full bibliography for 2312368--2312375.cif.'
_cod_database_code               2312369
_cod_database_fobs_code          2312369
_shelx_shelxl_version_number     2018/3
_chemical_oxdiff_formula         'C H N O'
_shelx_estimated_absorpt_t_max   0.825
_shelx_estimated_absorpt_t_min   0.655
_olex2_refinement_description
; 
1. Fixed Uiso 
 At 1.2 times of: 
  All C(H) groups 
 At 1.5 times of: 
  All C(H,H,H) groups 
2.a Ternary CH refined with riding coordinates: 
 C9(H9) 
2.b Aromatic/amide H refined with riding coordinates: 
 C15(H15), C13(H13), C14(H14), C12(H12) 
2.c Idealised Me refined as rotating group: 
 C5(H5A,H5B,H5C), C7(H7A,H7B,H7C), C1(H1A,H1B,H1C), C17(H17A,H17B,H17C) 
;
_shelx_res_checksum              19895
_shelx_hkl_checksum              57855
_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 Nifedipine
_olex2_submission_special_instructions 'No special instructions were received'
_oxdiff_exptl_absorpt_empirical_details
; 
Empirical correction (ABSPACK) includes: 
- Absorption correction using spherical harmonics 
- Frame scaling 
;
_oxdiff_exptl_absorpt_empirical_full_max 1.158
_oxdiff_exptl_absorpt_empirical_full_min 0.831