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_2312368
_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         'C18 H19 Cl2 N O4'
_chemical_formula_sum            'C18 H19 Cl2 N O4'
_chemical_formula_weight         384.24
_chemical_name_common            felodipine
_chemical_name_systematic
;          
 (rac)-3-ethyl 5-methyl 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4- 
dihydropyridine-3,5-dicarboxylate
;
_space_group_crystal_system      monoclinic
_space_group_IT_number           14
_space_group_name_Hall           '-P 2yn'
_space_group_name_H-M_alt        'P 1 21/n 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                 107.056(6)
_cell_angle_gamma                90
_cell_formula_units_Z            4
_cell_length_a                   11.1017(7)
_cell_length_b                   12.5717(7)
_cell_length_c                   13.5023(8)
_cell_measurement_reflns_used    5521
_cell_measurement_temperature    150.00(10)
_cell_measurement_theta_max      74.0320
_cell_measurement_theta_min      4.5390
_cell_volume                     1801.60(19)
_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 0.993
_diffrn_measured_fraction_theta_max 0.947
_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    -32.00  -7.00   0.50    0.52    --  -39.19  38.00  60.00   50 
  2  \w     11.00  47.00   0.50    0.52    --  -39.19  19.00  30.00   72 
  3  \w     13.00  39.00   0.50    0.52    --  -39.19  38.00  60.00   52 
  4  \w    -53.00  -9.00   0.50    0.52    --   38.32 -19.00  90.00   88 
  5  \w      5.00  43.00   0.50    0.52    --   38.32 -38.00  60.00   76 
  6  \w      0.00  27.00   0.50    0.52    --   38.32 -19.00  90.00   54 
  7  \w    -36.00 -11.00   0.50    0.52    --   38.32 -38.00  60.00   50 
  8  \w     34.00 108.00   0.50    0.52    --  110.26-111.00 120.00  148 
  9  \w     65.00 103.00   0.50    0.52    --  102.48-126.00  57.00   76 
 10  \w     45.00  70.00   0.50    0.52    --  110.26-126.00  57.00   50 
 11  \w     51.00  76.00   0.50    0.52    --   38.32-145.00-110.00   50 
 12  \w     79.00 116.00   0.50    0.52    --  102.48-145.00-110.00   74 
 13  \w     36.00  61.00   0.50    0.52    --   38.32-126.00  57.00   50 
 14  \w     39.00 104.00   0.50    0.52    --  102.48 -77.00  60.00  130 
 15  \w     38.00  69.00   0.50    0.52    --  110.26 -61.00 120.00   62 
 16  \w     22.00  48.00   0.50    0.52    --  102.48 -45.00 150.00   52 
 17  \w     23.00  48.00   0.50    0.52    --  110.26 -45.00 120.00   50 
 18  \w     16.00  51.00   0.50    0.52    --  102.48 -45.00  90.00   70 
 19  \w    130.00 172.00   0.50    0.52    --  110.26  45.00  60.00   84 
 20  \w     75.00 121.00   0.50    0.52    --  110.26 126.00 134.00   92 
 21  \w     74.00  99.00   0.50    0.52    --   38.32 126.00 134.00   50 
 22  \w     76.00 117.00   0.50    0.52    --   38.32 145.00 -57.00   82 
 23  \w     87.00 165.00   0.50    0.52    --  110.26 111.00-180.00  156 
 24  \w    -38.00 -12.00   0.50    0.52    --  -95.69  45.00 -90.00   52 
 25  \w    -48.00 -14.00   0.50    0.52    --  -95.69  45.00 -30.00   68 
 26  \w    -50.00  -9.00   0.50    0.52    --  -95.69  45.00   0.00   82 
 27  \w    -35.00 -10.00   0.50    0.52    --  -95.69  30.00 -60.00   50 
 28  \w    -35.00 -10.00   0.50    0.52    --  -95.69  30.00 -90.00   50 
 29  \w    -35.00  -9.00   0.50    0.52    --  -95.69  30.00-120.00   52 
 30  \w    -34.00  -9.00   0.50    0.52    --  -95.69  30.00-180.00   50 
 31  \w   -149.00-124.00   0.50    0.52    --  -95.69-126.00  57.00   50 
 32  \w   -128.00 -44.00   0.50    0.52    --  -39.19-178.00-150.00  168 
 33  \w   -115.00 -73.00   0.50    0.52    --  -95.69-145.00-110.00   84 
 34  \w   -127.00 -74.00   0.50    0.52    --  -95.69 145.00 -57.00  106 
;
_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      -0.0898813000
_diffrn_orient_matrix_UB_12      -0.0133831000
_diffrn_orient_matrix_UB_13      0.0668389000
_diffrn_orient_matrix_UB_21      -0.0171166000
_diffrn_orient_matrix_UB_22      0.1215977000
_diffrn_orient_matrix_UB_23      0.0012143000
_diffrn_orient_matrix_UB_31      -0.1126781000
_diffrn_orient_matrix_UB_32      -0.0077246000
_diffrn_orient_matrix_UB_33      -0.0989254000
_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  0.0311
_diffrn_reflns_av_unetI/netI     0.0346
_diffrn_reflns_Laue_measured_fraction_full 0.993
_diffrn_reflns_Laue_measured_fraction_max 0.947
_diffrn_reflns_limit_h_max       10
_diffrn_reflns_limit_h_min       -13
_diffrn_reflns_limit_k_max       15
_diffrn_reflns_limit_k_min       -15
_diffrn_reflns_limit_l_max       16
_diffrn_reflns_limit_l_min       -16
_diffrn_reflns_number            10365
_diffrn_reflns_point_group_measured_fraction_full 0.993
_diffrn_reflns_point_group_measured_fraction_max 0.947
_diffrn_reflns_theta_full        67.684
_diffrn_reflns_theta_max         74.760
_diffrn_reflns_theta_min         4.552
_diffrn_source                   'micro-focus sealed X-ray tube'
_diffrn_source_target            Cu
_diffrn_source_type              'PhotonJet (Cu) X-ray Source'
_exptl_absorpt_coefficient_mu    3.441
_exptl_absorpt_correction_T_max  1.00000
_exptl_absorpt_correction_T_min  0.73839
_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    1.417
_exptl_crystal_description       block
_exptl_crystal_F_000             800
_exptl_crystal_preparation
'Crystallised from a saturated solution of felodipine in toluene.'
_exptl_crystal_recrystallization_method
'High-throughput screening via the ENaCt protocol using SPT Labtech mosquito.'
_exptl_crystal_size_max          0.45
_exptl_crystal_size_mid          0.32
_exptl_crystal_size_min          0.29
_refine_diff_density_max         0.409
_refine_diff_density_min         -0.476
_refine_diff_density_rms         0.059
_refine_ls_extinction_method     none
_refine_ls_goodness_of_fit_ref   1.053
_refine_ls_hydrogen_treatment    mixed
_refine_ls_matrix_type           full
_refine_ls_number_parameters     262
_refine_ls_number_reflns         3494
_refine_ls_number_restraints     204
_refine_ls_restrained_S_all      1.027
_refine_ls_R_factor_all          0.0660
_refine_ls_R_factor_gt           0.0561
_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^)+(0.0693P)^2^+1.9737P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.1525
_refine_ls_wR_factor_ref         0.1599
_reflns_Friedel_coverage         0.000
_reflns_number_gt                2903
_reflns_number_total             3494
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            rm5073sup1.cif
_cod_data_source_block           felodipine
_cod_depositor_comments
'Adding full bibliography for 2312368--2312375.cif.'
_cod_database_code               2312368
_cod_database_fobs_code          2312368
_shelx_shelxl_version_number     2018/3
_chemical_oxdiff_formula         'C H N O Cl'
_shelx_estimated_absorpt_t_max   0.435
_shelx_estimated_absorpt_t_min   0.307
_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. Others 
 Fixed Sof: O5(0.65077) C20(0.65077) H20A(0.65077) H20B(0.65077) H20C(0.65077) 
 C19(0.65077) H19A(0.65077) H19B(0.65077) O4(0.34923) C17(0.34923) 
 H17A(0.34923) H17B(0.34923) C18(0.34923) H18A(0.34923) H18B(0.34923) 
 H18C(0.34923) 
4.a Ternary CH refined with riding coordinates: 
 C9(H9) 
4.b Secondary CH2 refined with riding coordinates: 
 C19(H19A,H19B), C17(H17A,H17B) 
4.c Aromatic/amide H refined with riding coordinates: 
 C11(H11), C13(H13), C12(H12) 
4.d Idealised Me refined as rotating group: 
 C7(H7A,H7B,H7C), C5(H5A,H5B,H5C), C1(H1A,H1B,H1C), C20(H20A,H20B,H20C), 
 C18(H18A,H18B,H18C) 
;
_shelx_res_checksum              34217
_shelx_hkl_checksum              35354
_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 Felodipine
_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 1.252
_oxdiff_exptl_absorpt_empirical_full_min 0.696