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_2312370
_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, C2 H4 O'
_chemical_formula_sum            'C19 H22 N2 O7'
_chemical_formula_weight         390.38
_chemical_name_common            'nifedipine 1,4-dioxane solvate'
_chemical_name_systematic
;         
dimethyl 2,6-dimethyl-4-(2-nitrophenyl) 
-1,4-dihydropyridine-3,5-dicarboxylate 1,4-dioxane
;
_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                 97.164(3)
_cell_angle_gamma                90
_cell_formula_units_Z            4
_cell_length_a                   14.0927(5)
_cell_length_b                   9.2253(4)
_cell_length_c                   14.5139(5)
_cell_measurement_reflns_used    7391
_cell_measurement_temperature    150.00(10)
_cell_measurement_theta_max      74.0180
_cell_measurement_theta_min      3.1530
_cell_volume                     1872.21(12)
_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 0.952
_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     63.00 103.00   0.50    1.67    --   38.69 152.00 -22.00   80 
  2  \w   -101.00 -76.00   0.50    1.67    --  -39.38 152.00 -22.00   50 
  3  \w    -83.00 -58.00   0.50    1.67    --  -39.38 122.00 176.00   50 
  4  \w   -110.00 -85.00   0.50    1.67    --  -39.38-152.00 -65.00   50 
  5  \w   -130.00 -27.00   0.50    1.67    --  -95.69 152.00 -22.00  206 
  6  \w    103.00 128.00   0.50    1.67    --  102.48 122.00 176.00   50 
  7  \w     68.00 113.00   0.50    1.67    --  102.48-152.00 -65.00   90 
  8  \w     33.00  59.00   0.50    1.67    --  110.26-152.00 -65.00   52 
  9  \w     64.00  90.00   0.50    1.67    --  110.26-122.00  95.00   52 
 10  \w     63.00 130.00   0.50    1.67    --  110.26-152.00 -65.00  134 
 11  \w      6.00  43.00   0.50    1.67    --   38.69 -38.00 -30.00   74 
 12  \w    -50.00  -3.00   0.50    1.67    --   38.69 -38.00 -30.00   94 
 13  \w     42.00 123.00   0.50    1.67    --   38.69 178.00-180.00  162 
 14  \w    -66.00  44.00   0.50    1.67    --  -39.38  57.00-150.00  220 
 15  \w     22.00  47.00   0.50    1.67    --  -39.38  19.00 150.00   50 
 16  \w    -35.00 -10.00   0.50    1.67    --  -95.69  30.00 120.00   50 
 17  \w    -35.00 -10.00   0.50    1.67    --  -95.69  30.00 150.00   50 
 18  \w    -34.00  -9.00   0.50    1.67    --  -95.69  30.00-120.00   50 
 19  \w     18.00  51.00   0.50    1.67    --  102.48 -45.00   0.00   66 
 20  \w     16.00  51.00   0.50    1.67    --  102.48 -45.00 -90.00   70 
 21  \w     28.00  71.00   0.50    1.67    --  102.48 -61.00 150.00   86 
 22  \w     60.00 103.00   0.50    1.67    --  102.48 152.00 -22.00   86 
 23  \w     18.00  51.00   0.50    1.67    --  102.48 -45.00 -30.00   66 
 24  \w     17.00  43.00   0.50    1.67    --  102.48 -45.00-120.00   52 
 25  \w     32.00 104.00   0.50    1.67    --  102.48 -77.00  90.00  144 
 26  \w     23.00  48.00   0.50    1.67    --  110.26 -45.00 120.00   50 
 27  \w     98.00 177.00   0.50    1.67    --  110.26  45.00  90.00  158 
 28  \w     23.00  48.00   0.50    1.67    --  110.26 -45.00-150.00   50 
 29  \w     28.00  58.00   0.50    1.67    --  110.26 -61.00-120.00   60 
 30  \w     60.00  99.00   0.50    1.67    --  110.26 -95.00  90.00   78 
 31  \w     33.00  58.00   0.50    1.67    --  110.26 -61.00  90.00   50 
;
_diffrn_measurement_device       'four-circle diffractometer'
_diffrn_measurement_device_type
'XtaLAB Synergy, Single source at home/near, HyPix-Arc 100'
_diffrn_measurement_method       '\w scans'
_diffrn_orient_matrix_type
'CrysAlisPro convention (1999,Acta A55,543-557)'
_diffrn_orient_matrix_UB_11      -0.0774080000
_diffrn_orient_matrix_UB_12      0.1180340000
_diffrn_orient_matrix_UB_13      -0.0011427000
_diffrn_orient_matrix_UB_21      -0.0750481000
_diffrn_orient_matrix_UB_22      -0.1169262000
_diffrn_orient_matrix_UB_23      0.0137270000
_diffrn_orient_matrix_UB_31      0.0227691000
_diffrn_orient_matrix_UB_32      0.0165089000
_diffrn_orient_matrix_UB_33      0.1060980000
_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  0.0239
_diffrn_reflns_av_unetI/netI     0.0262
_diffrn_reflns_Laue_measured_fraction_full 0.997
_diffrn_reflns_Laue_measured_fraction_max 0.952
_diffrn_reflns_limit_h_max       17
_diffrn_reflns_limit_h_min       -17
_diffrn_reflns_limit_k_max       11
_diffrn_reflns_limit_k_min       -11
_diffrn_reflns_limit_l_max       17
_diffrn_reflns_limit_l_min       -13
_diffrn_reflns_number            11509
_diffrn_reflns_point_group_measured_fraction_full 0.997
_diffrn_reflns_point_group_measured_fraction_max 0.952
_diffrn_reflns_theta_full        67.684
_diffrn_reflns_theta_max         74.634
_diffrn_reflns_theta_min         3.161
_diffrn_source                   'micro-focus sealed X-ray tube'
_diffrn_source_target            Cu
_diffrn_source_type              'PhotonJet (Cu) X-ray Source'
_exptl_absorpt_coefficient_mu    0.897
_exptl_absorpt_correction_T_max  1.00000
_exptl_absorpt_correction_T_min  0.90910
_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    1.385
_exptl_crystal_description       block
_exptl_crystal_F_000             824
_exptl_crystal_preparation
;        
 'Crystallised from a saturated solution of nifedipine in 1,4-dioxane.' 
;
_exptl_crystal_recrystallization_method
; 
 'High-throughput screening via the ENaCt protocol using an SPT Labtech 
mosquito.' 
;
_exptl_crystal_size_max          0.52
_exptl_crystal_size_mid          0.47
_exptl_crystal_size_min          0.33
_refine_diff_density_max         0.232
_refine_diff_density_min         -0.204
_refine_diff_density_rms         0.040
_refine_ls_extinction_method     none
_refine_ls_goodness_of_fit_ref   1.054
_refine_ls_hydrogen_treatment    mixed
_refine_ls_matrix_type           full
_refine_ls_number_parameters     261
_refine_ls_number_reflns         3659
_refine_ls_number_restraints     198
_refine_ls_restrained_S_all      1.026
_refine_ls_R_factor_all          0.0421
_refine_ls_R_factor_gt           0.0352
_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^)+(0.0449P)^2^+0.5706P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.0904
_refine_ls_wR_factor_ref         0.0946
_reflns_Friedel_coverage         0.000
_reflns_number_gt                3110
_reflns_number_total             3659
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            rm5073sup1.cif
_cod_data_source_block           nifedipine-dioxane
_cod_depositor_comments
'Adding full bibliography for 2312368--2312375.cif.'
_cod_database_code               2312370
_cod_database_fobs_code          2312370
_shelx_shelxl_version_number     2018/3
_chemical_oxdiff_formula         'C H N O'
_shelx_estimated_absorpt_t_max   0.756
_shelx_estimated_absorpt_t_min   0.653
_olex2_refinement_description
; 
1. Fixed Uiso 
 At 1.2 times of: 
  All C(H) groups, All C(H,H) groups 
 At 1.5 times of: 
  All C(H,H,H) groups 
2. Rigid body (RIGU) restrains 
 All non-hydrogen atoms 
 with sigma for 1-2 distances of 0.004 and sigma for 1-3 distances of 0.004 
3.a Ternary CH refined with riding coordinates: 
 C9(H9) 
3.b Secondary CH2 refined with riding coordinates: 
 C2S(H2SA,H2SB), C1S(H1SA,H1SB) 
3.c Aromatic/amide H refined with riding coordinates: 
 C15(H15), C14(H14), C12(H12), C13(H13) 
3.d Idealised Me refined as rotating group: 
 C7(H7A,H7B,H7C), C5(H5A,H5B,H5C), C17(H17A,H17B,H17C), C1(H1A,H1B,H1C) 
;
_shelx_res_checksum              64887
_shelx_hkl_checksum              95778
_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 1,4-dioxane solvate'
_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 1.293
_oxdiff_exptl_absorpt_empirical_full_min 0.806