Gefitinib salts/cocrystals with phenolic acids as a promising solid-state approach to improve solubility
Zou, Yao; Meng, Xin; Zhang, Baoxi; Yu, Hongmei; He, Guorong; Gong, Ningbo; Lu, Yang; Du, Guanhua; CrystEngComm 26 (2024) 2112–2122; doi:10.1039/D4CE00039K

data_7248299
_publ_section_title
;
 Gefitinib salts/cocrystals with phenolic acids as a promising solid-state
 approach to improve solubility
;
_journal_issue                   15
_journal_name_full               CrystEngComm
_journal_page_first              2112
_journal_page_last               2122
_journal_paper_doi               10.1039/D4CE00039K
_journal_volume                  26
_journal_year                    2024
_chemical_formula_moiety         'C22 H24 Cl F N4 O3, 0.5(C7 H6 O3)'
_chemical_formula_sum            'C25.5 H27 Cl F N4 O4.5'
_chemical_formula_weight         515.96
_space_group_crystal_system      triclinic
_space_group_IT_number           2
_space_group_name_Hall           '-P 1'
_space_group_name_H-M_alt        'P -1'
_atom_sites_solution_hydrogens   geom
_audit_creation_date             2023-11-23
_audit_creation_method
;
Olex2 1.5
(compiled 2023.08.24 svn.re1ec1418 for OlexSys, GUI svn.r6817)
;
_audit_update_record
;
2023-12-27 deposited with the CCDC.	2024-03-11 downloaded from the CCDC.
;
_cell_angle_alpha                65.3898(8)
_cell_angle_beta                 84.3011(6)
_cell_angle_gamma                89.3070(6)
_cell_formula_units_Z            2
_cell_length_a                   7.73274(5)
_cell_length_b                   12.20698(10)
_cell_length_c                   14.35665(12)
_cell_measurement_reflns_used    35704
_cell_measurement_temperature    100.00(10)
_cell_measurement_theta_max      76.1790
_cell_measurement_theta_min      3.4170
_cell_volume                     1225.341(18)
_computing_cell_refinement       'CrysAlisPro 1.171.41.81a (Rigaku OD, 2020)'
_computing_data_collection       'CrysAlisPro 1.171.41.81a (Rigaku OD, 2020)'
_computing_data_reduction        'CrysAlisPro 1.171.41.81a (Rigaku OD, 2020)'
_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      100.15
_diffrn_detector_area_resol_mean 10.0000
_diffrn_detector_type            HyPix
_diffrn_measured_fraction_theta_full 0.999
_diffrn_measured_fraction_theta_max 0.959
_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     69.00  95.00   0.50    0.05    --   47.76  59.00 109.00   52
  2  \w    108.00 161.00   0.50    0.10    --  106.68  59.00 109.00  106
  3  \w    136.00 178.00   0.50    0.10    --  106.68  45.00  30.00   84
  4  \w    129.00 177.00   0.50    0.10    --  106.68  61.00   0.00   96
  5  \w    111.00 173.00   0.50    0.10    --  106.68  30.00  90.00  124
  6  \w     65.00  91.00   0.50    0.05    --   47.76  57.00-150.00   52
  7  \w     91.00 117.00   0.50    0.10    --  106.68  61.00-180.00   52
  8  \w    146.00 171.00   0.50    0.10    --  106.68  61.00-180.00   50
  9  \w     36.00 105.00   0.50    0.10    --  106.68 -77.00 -30.00  138
 10  \w     34.00  72.00   0.50    0.10    --  106.68 -59.00 -30.00   76
 11  \w     35.00  61.00   0.50    0.10    --  106.68 -61.00-150.00   52
 12  \w     -5.00  43.00   0.50    0.05    --   47.76 -59.00 -30.00   96
 13  \w    -22.00  27.00   0.50    0.05    --  -47.76  19.00  90.00   98
 14  \w    -59.00   0.00   0.50    0.05    --  -47.76  59.00 109.00  118
 15  \w     37.00  97.00   0.50    0.10    --  106.68-125.00  90.00  120
 16  \w     80.00 105.00   0.50    0.10    --  106.68 -94.00 150.00   50
 17  \w    -23.00  27.00   0.50    0.05    --  -47.76  19.00-150.00  100
 18  \w    -60.00 -28.00   0.50    0.10    -- -101.00  77.00-180.00   64
 19  \w    -96.00 -66.00   0.50    0.10    -- -101.00  77.00-180.00   60
 20  \w    -65.00 -40.00   0.50    0.10    -- -101.00  61.00 -90.00   50
 21  \w    -68.00 -28.00   0.50    0.10    -- -101.00  61.00 -60.00   80
 22  \w    -57.00 -31.00   0.50    0.10    -- -101.00  61.00 -30.00   52
 23  \w    -65.00 -40.00   0.50    0.10    -- -101.00  59.00 109.00   50
 24  \w   -171.00 -78.00   0.50    0.10    -- -101.00 -77.00 -60.00  186
 25  \w   -155.00 -81.00   0.50    0.10    -- -101.00 -77.00-120.00  148
 26  \w   -162.00-135.00   0.50    0.10    -- -101.00 -61.00-150.00   54
 27  \w   -131.00 -92.00   0.50    0.10    -- -101.00 -61.00-150.00   78
 28  \w   -156.00 -85.00   0.50    0.10    -- -101.00 -61.00-120.00  142
 29  \w   -150.00-125.00   0.50    0.10    -- -101.00 -61.00 -90.00   50
 30  \w   -110.00 -80.00   0.50    0.10    -- -101.00 -77.00 -90.00   60
 31  \w   -110.00 -85.00   0.50    0.10    -- -101.00 -61.00 -90.00   50
 32  \w   -153.00-128.00   0.50    0.10    -- -101.00 -59.00 -30.00   50
 33  \w   -173.00 -93.00   0.50    0.10    -- -101.00 -45.00   0.00  160
 34  \w   -173.00 -84.00   0.50    0.10    -- -101.00 -61.00  60.00  178
 35  \w   -122.00 -37.00   0.50    0.05    --  -47.76 -19.00 150.00  170
 36  \w    -91.00 -65.00   0.50    0.05    --  -47.76 -59.00 -30.00   52
 37  \w   -174.00-136.00   0.50    0.10    -- -101.00 -15.00-180.00   76
 38  \w   -111.00 -77.00   0.50    0.05    --  -47.76-125.00 -60.00   68
 39  \w   -116.00 -75.00   0.50    0.05    --  -47.76-125.00   0.00   82
 40  \w   -171.00-134.00   0.50    0.10    -- -101.00 -94.00 -30.00   74
 41  \w   -129.00 -94.00   0.50    0.10    -- -101.00 -94.00 -30.00   70
 42  \w   -118.00 -74.00   0.50    0.05    --  -47.76-125.00 120.00   88
 43  \w   -144.00-118.00   0.50    0.10    -- -101.00-102.00  95.00   52
 44  \w    -43.00 -17.00   0.50    0.05    --    8.00 131.00 119.43   52
 45  \w    -41.00 -16.00   0.50    0.05    --    8.00 127.00  30.61   50
 46  \w    -24.00   1.00   0.50    0.05    --   12.00 104.00-134.00   50
 47  \w    -11.00  15.00   0.50    0.05    --   16.00  98.00 -26.82   52
 48  \w    -14.00  12.00   0.50    0.05    --   20.00 102.00-100.06   52
 49  \w     -4.00  21.00   0.50    0.05    --   28.00  97.00-173.09   50
 50  \w      6.00  31.00   0.50    0.05    --   36.00  92.00-115.53   50
 51  \w     13.00  38.00   0.50    0.05    --   40.00  87.00 -81.76   50
 52  \w     15.00  40.00   0.50    0.05    --   44.00  90.00  68.51   50
 53  \w     16.00  41.00   0.50    0.05    --   44.00  88.00 -48.76   50
 54  \w    -58.00 -28.00   0.50    0.05    --  -47.76 -77.00 -90.00   60
 55  \w    -51.00 -25.00   0.50    0.05    --  -47.76 -77.00 150.00   52
 56  \w     50.00  91.00   0.50    0.05    --   47.76-125.00  30.00   82
 57  \w     32.00  58.00   0.50    0.05    --   52.00  75.00 136.84   52
 58  \w     34.00  65.00   0.50    0.05    --   56.00  76.00  24.16   62
 59  \w     33.00  59.00   0.50    0.05    --   56.00  77.00-175.16   52
 60  \w     35.00  76.00   0.50    0.05    --   56.00  76.00  64.60   82
 61  \w     97.00 123.00   0.50    0.05    --   56.00  77.00-175.16   52
 62  \w     35.00  61.00   0.50    0.05    --   56.00  76.00-132.75   52
 63  \w    -67.00 -41.00   0.50    0.05    --  -60.00 -71.00-158.45   52
 64  \w     38.00  63.00   0.50    0.05    --   60.00  75.00 146.53   50
 65  \w     39.00  73.00   0.50    0.05    --   60.00  73.00  53.21   68
 66  \w     39.00  65.00   0.50    0.05    --   60.00  72.00 -13.00   52
 67  \w    -68.00 -42.00   0.50    0.05    --  -64.00 -74.00 125.38   52
 68  \w    -70.00 -44.00   0.50    0.05    --  -64.00 -72.00-144.01   52
 69  \w    -69.00 -43.00   0.50    0.05    --  -64.00 -74.00 162.32   52
 70  \w   -134.00-108.00   0.50    0.05    --  -68.00 -69.00-178.55   52
 71  \w    -75.00 -49.00   0.50    0.05    --  -68.00 -70.00-103.24   52
 72  \w    -73.00 -48.00   0.50    0.05    --  -68.00 -70.00 -68.98   50
 73  \w    -73.00 -48.00   0.50    0.05    --  -68.00 -69.00-178.55   50
 74  \w    -75.00 -49.00   0.50    0.05    --  -68.00 -67.00 -90.02   52
 75  \w     46.00  72.00   0.50    0.05    --   68.00  75.00   1.67   52
 76  \w     45.00  71.00   0.50    0.05    --   68.00  77.00 -83.55   52
 77  \w     45.00  71.00   0.50    0.05    --   68.00  77.00  81.68   52
 78  \w    -90.00 -50.00   0.50    0.05    --  -72.00 -75.00  83.53   80
 79  \w    -79.00 -49.00   0.50    0.05    --  -72.00 -76.00  43.60   60
 80  \w    -75.00 -50.00   0.50    0.05    --  -72.00 -74.00  -0.70   50
 81  \w   -140.00-114.00   0.50    0.05    --  -72.00 -75.00  83.53   52
 82  \w    -76.00 -50.00   0.50    0.05    --  -72.00 -76.00-110.02   52
 83  \w    -75.00 -49.00   0.50    0.05    --  -72.00 -76.00 -36.49   52
 84  \w    -81.00 -55.00   0.50    0.10    --  -76.00 -73.00 123.27   52
 85  \w    -83.00 -58.00   0.50    0.10    --  -80.00 -75.00 173.84   50
 86  \w    -84.00 -58.00   0.50    0.10    --  -80.00 -74.00  18.91   52
 87  \w    -87.00 -61.00   0.50    0.10    --  -80.00 -67.00 -74.39   52
 88  \w   -155.00-129.00   0.50    0.10    --  -84.00 -70.00-146.32   52
 89  \w    -88.00 -62.00   0.50    0.10    --  -84.00 -75.00-129.88   52
 90  \w    -90.00 -64.00   0.50    0.10    --  -84.00 -70.00-146.32   52
 91  \w    -87.00 -62.00   0.50    0.10    --  -84.00 -75.00 115.38   50
 92  \w   -148.00-122.00   0.50    0.10    --  -84.00 -75.00 115.38   52
 93  \w    -88.00 -62.00   0.50    0.10    --  -84.00 -74.00-166.29   52
 94  \w    -90.00 -64.00   0.50    0.10    --  -84.00 -73.00  42.06   52
 95  \w    -88.00 -62.00   0.50    0.10    --  -84.00 -75.00 157.94   52
 96  \w    -93.00 -67.00   0.50    0.10    --  -84.00 -61.00-168.28   52
 97  \w    -89.00 -63.00   0.50    0.10    --  -84.00 -73.00 -87.93   52
 98  \w    -88.00 -62.00   0.50    0.10    --  -84.00 -74.00-106.72   52
 99  \w   -144.00-118.00   0.50    0.10    --  -88.00 -73.00   9.97   52
100  \w   -130.00-104.00   0.50    0.10    --  -88.00 -64.00 157.74   52
101  \w    -98.00 -72.00   0.50    0.10    --  -88.00 -63.00-129.32   52
102  \w   -161.00-135.00   0.50    0.10    --  -88.00 -64.00 157.74   52
103  \w    -91.00 -65.00   0.50    0.10    --  -88.00 -76.00 -41.19   52
104  \w   -140.00-114.00   0.50    0.10    --  -88.00 -76.00 -41.19   52
105  \w   -103.00 -67.00   0.50    0.10    --  -88.00 -73.00   9.97   72
106  \w   -160.00-109.00   0.50    0.10    --  -88.00 -74.00 -19.13  102
107  \w    -91.00 -65.00   0.50    0.10    --  -88.00 -76.00 -66.91   52
108  \w    -92.00 -66.00   0.50    0.10    --  -88.00 -75.00  89.61   52
109  \w    -91.00 -66.00   0.50    0.10    --  -88.00 -74.00 -19.13   50
110  \w    -97.00 -68.00   0.50    0.10    --  -88.00 -72.00  93.09   58
111  \w    -96.00 -70.00   0.50    0.10    --  -88.00 -64.00 157.74   52
112  \w    -99.00 -70.00   0.50    0.10    --  -92.00 -74.00 138.04   58
113  \w   -165.00-125.00   0.50    0.10    --  -92.00 -74.00 138.04   80
114  \w    -99.00 -69.00   0.50    0.10    --  -92.00 -76.00  41.85   60
115  \w   -163.00-105.00   0.50    0.10    --  -92.00 -76.00  41.85  116
116  \w   -169.00-143.00   0.50    0.10    --  -96.00 -77.00   3.47   52
117  \w   -139.00 -73.00   0.50    0.10    --  -96.00 -77.00   3.47  132
118  \w   -102.00 -76.00   0.50    0.10    --  -96.00 -69.00-157.78   52
119  \w   -125.00 -86.00   0.50    0.10    -- -101.00 -55.00  44.68   78
120  \w   -104.00 -79.00   0.50    0.10    -- -101.00 -79.00-110.33   50
121  \w   -170.00-134.00   0.50    0.10    -- -101.00 -79.00-110.33   72
122  \w    -53.00 -28.00   0.50    0.10    -- -101.00  77.00-150.00   50
123  \w   -100.00 -74.00   0.50    0.10    -- -101.00  77.00-150.00   52
124  \w    -53.00 -28.00   0.50    0.10    -- -101.00 141.00-150.69   50
125  \w   -123.00 -71.00   0.50    0.10    -- -101.00 141.00-150.69  104
126  \w   -132.00 -78.00   0.50    0.10    -- -101.00 -76.00 -96.52  108
127  \w    -63.00 -29.00   0.50    0.10    -- -101.00 111.00 115.99   68
128  \w   -107.00 -81.00   0.50    0.10    -- -101.00 -74.00-166.82   52
129  \w   -170.00-141.00   0.50    0.10    -- -101.00 -74.00-166.82   58
130  \w   -109.00 -81.00   0.50    0.10    -- -101.00 -69.00 157.68   56
131  \w   -111.00 -70.00   0.50    0.10    -- -101.00 125.00 -60.00   82
132  \w    -53.00 -28.00   0.50    0.10    -- -101.00  61.00 120.00   50
133  \w   -108.00 -77.00   0.50    0.10    -- -101.00 111.00 115.99   62
134  \w   -123.00 -82.00   0.50    0.10    -- -101.00 -67.00 123.02   82
135  \w   -116.00 -82.00   0.50    0.10    -- -101.00 -67.00 -28.27   68
136  \w   -173.00-148.00   0.50    0.10    -- -101.00 -67.00 -28.27   50
137  \w   -119.00 -81.00   0.50    0.10    -- -101.00 -77.00  90.00   76
138  \w     60.00 105.00   0.50    0.10    --  106.68-125.00-120.00   90
139  \w     36.00  65.00   0.50    0.10    --  106.68 -61.00 120.00   58
140  \w     84.00 110.00   0.50    0.10    --  106.68-125.00  60.00   52
141  \w     56.00  82.00   0.50    0.10    --  106.68-125.00  60.00   52
142  \w     53.00  99.00   0.50    0.10    --  106.68-102.00  95.00   92
143  \w     37.00 102.00   0.50    0.10    --  106.68 -94.00 -60.00  130
144  \w     70.00  96.00   0.50    0.10    --  106.68 -94.00-150.00   52
;
_diffrn_measurement_device       'four-circle diffractometer'
_diffrn_measurement_device_type  'XtaLAB Synergy R, HyPix'
_diffrn_measurement_method       '\w scans'
_diffrn_radiation_type           CuK\a
_diffrn_radiation_wavelength     1.54184
_diffrn_reflns_av_R_equivalents  0.0236
_diffrn_reflns_av_unetI/netI     0.0106
_diffrn_reflns_Laue_measured_fraction_full 0.999
_diffrn_reflns_Laue_measured_fraction_max 0.959
_diffrn_reflns_limit_h_max       9
_diffrn_reflns_limit_h_min       -9
_diffrn_reflns_limit_k_max       15
_diffrn_reflns_limit_k_min       -15
_diffrn_reflns_limit_l_max       17
_diffrn_reflns_limit_l_min       -17
_diffrn_reflns_number            42096
_diffrn_reflns_point_group_measured_fraction_full 0.999
_diffrn_reflns_point_group_measured_fraction_max 0.959
_diffrn_reflns_theta_full        67.684
_diffrn_reflns_theta_max         77.144
_diffrn_reflns_theta_min         3.404
_exptl_absorpt_coefficient_mu    1.813
_exptl_absorpt_correction_T_max  0.804
_exptl_absorpt_correction_T_min  0.596
_exptl_absorpt_correction_type   multi-scan
_exptl_absorpt_process_details
;
CrysAlisPro 1.171.41.81a (Rigaku Oxford Diffraction, 2020)
Empirical absorption correction using spherical harmonics,
implemented in SCALE3 ABSPACK scaling algorithm.
;
_exptl_crystal_colour            colourless
_exptl_crystal_colour_primary    colourless
_exptl_crystal_density_diffrn    1.398
_exptl_crystal_description       block
_exptl_crystal_F_000             540
_exptl_crystal_size_max          0.39
_exptl_crystal_size_mid          0.26
_exptl_crystal_size_min          0.12
_refine_diff_density_max         0.269
_refine_diff_density_min         -0.206
_refine_diff_density_rms         0.042
_refine_ls_extinction_coef       0.0053(3)
_refine_ls_extinction_expression Fc^*^=kFc[1+0.001xFc^2^\l^3^/sin(2\q)]^-1/4^
_refine_ls_extinction_method     'SHELXL-2018/3 (Sheldrick 2018)'
_refine_ls_goodness_of_fit_ref   1.022
_refine_ls_hydrogen_treatment    constr
_refine_ls_matrix_type           full
_refine_ls_number_parameters     411
_refine_ls_number_reflns         4977
_refine_ls_number_restraints     144
_refine_ls_restrained_S_all      1.009
_refine_ls_R_factor_all          0.0389
_refine_ls_R_factor_gt           0.0386
_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^)+(0.0215P)^2^+1.2280P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.0900
_refine_ls_wR_factor_ref         0.0901
_reflns_Friedel_coverage         0.000
_reflns_number_gt                4905
_reflns_number_total             4977
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            d4ce00039k2.cif
_cod_data_source_block           6331
_cod_depositor_comments
'Adding full bibliography for 7248298--7248302.cif.'
_cod_original_formula_sum        'C25.50 H27 Cl F N4 O4.50'
_cod_database_code               7248299
_shelx_shelxl_version_number     2018/3
_shelx_estimated_absorpt_t_max   1.0
_shelx_estimated_absorpt_t_min   0.806
_olex2_refinement_description
;
1. Fixed Uiso
 At 1.2 times of:
  All C(H) groups, All C(H,H) groups, All N(H,H) groups
 At 1.5 times of:
  All C(H,H,H) groups, All O(H) groups
2. Uiso/Uaniso restraints and constraints
Uanis(C5) \\sim Ueq, Uanis(C6A) \\sim Ueq, Uanis(C6) \\sim Ueq, Uanis(C4) \\sim
Ueq, Uanis(C2A) \\sim Ueq, Uanis(C3A) \\sim Ueq, Uanis(C4A) \\sim Ueq,
Uanis(C5A) \\sim Ueq, Uanis(C1) \\sim Ueq, Uanis(C2) \\sim Ueq, Uanis(C3) \\sim
Ueq: with sigma of 0.01 and sigma for terminal atoms of 0.02
Uanis(C6A) \\sim Ueq, Uanis(C1A) \\sim Ueq, Uanis(C2A) \\sim Ueq, Uanis(C5A)
\\sim Ueq: with sigma of 0.001 and sigma for terminal atoms of 0.002
3. Rigid body (RIGU) restrains
 C5A, C4A, C3A, C2A, C1A, C6A
 with sigma for 1-2 distances of 0.004 and sigma for 1-3 distances of 0.004
 C5, C4, C3, C2, C1, C6
 with sigma for 1-2 distances of 0.004 and sigma for 1-3 distances of 0.004
4. Others
 Sof(H1A)=Sof(Cl1A)=Sof(F1A)=Sof(C6A)=Sof(C1A)=Sof(H1AA)=Sof(C2A)=Sof(C3A)=
 Sof(C4A)=Sof(H4A)=Sof(C5A)=Sof(H5A)=1-FVAR(1)
 Sof(H1B)=Sof(Cl1)=Sof(F1)=Sof(C5)=Sof(H5)=Sof(C4)=Sof(H4)=Sof(C3)=Sof(C2)=
 Sof(C1)=Sof(H1)=Sof(C6)=FVAR(1)
 Fixed Sof: O6(0.5) H6(0.5) O4(0.5) O5(0.5) H5B(0.5) C26(0.5) C27(0.5)
 H27(0.5) C28(0.5) H28(0.5) C23(0.5) C24(0.5) H24(0.5) C25(0.5) H25(0.5)
 C29(0.5)
5.a Secondary CH2 refined with riding coordinates:
 C15(H15A,H15B), C16(H16A,H16B), C17(H17A,H17B), C18(H18A,H18B), C19(H19A,
 H19B), C20(H20A,H20B), C21(H21A,H21B)
5.b Aromatic/amide H refined with riding coordinates:
 N1(H1B), N1(H1A), C8(H8), C11(H11), C14(H14), C1A(H1AA), C4A(H4A), C5A(H5A),
 C5(H5), C4(H4), C1(H1), C27(H27), C28(H28), C24(H24), C25(H25)
5.c Fitted hexagon refined as free rotating group:
 C6A(C1A,C2A,C3A,C4A,C5A), C5(C4,C3,C2,C1,C6), C26(C27,C28,C23,C24,C25)
5.d Idealised Me refined as rotating group:
 C22(H22A,H22B,H22C)
5.e Idealised tetrahedral OH refined as rotating group:
 O6(H6), O5(H5B)
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_shelx_res_checksum              92590
_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
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