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_7248302
_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 H25 Cl F N4 O3, C22 H26 Cl F N4 O3, 3(C7 H5 O3), C7 H6 O3'
_chemical_formula_sum            'C72 H72 Cl2 F2 N8 O18'
_chemical_formula_weight         1446.28
_space_group_crystal_system      orthorhombic
_space_group_IT_number           19
_space_group_name_Hall           'P 2ac 2ab'
_space_group_name_H-M_alt        'P 21 21 21'
_atom_sites_solution_hydrogens   geom
_audit_creation_date             2023-12-12
_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                90
_cell_angle_beta                 90
_cell_angle_gamma                90
_cell_formula_units_Z            4
_cell_length_a                   14.45160(10)
_cell_length_b                   18.00040(10)
_cell_length_c                   26.7026(2)
_cell_measurement_reflns_used    63909
_cell_measurement_temperature    301.92(14)
_cell_measurement_theta_max      75.9190
_cell_measurement_theta_min      2.9240
_cell_volume                     6946.27(8)
_computing_cell_refinement       'CrysAlisPro 1.171.42.92a (Rigaku OD, 2023)'
_computing_data_collection       'CrysAlisPro 1.171.42.92a (Rigaku OD, 2023)'
_computing_data_reduction        'CrysAlisPro 1.171.42.92a (Rigaku OD, 2023)'
_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 2014/5 (Sheldrick, 2014)'
_diffrn_ambient_environment      air
_diffrn_ambient_temperature      301.92(14)
_diffrn_detector                 'Hybrid Pixel Array Detector'
_diffrn_detector_area_resol_mean 10.0000
_diffrn_detector_type            HyPix
_diffrn_measured_fraction_theta_full 1.000
_diffrn_measured_fraction_theta_max 0.990
_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    -23.00  29.00   0.50    0.16    --  -46.87  19.00  60.00  104
  2  \w    -40.00  26.00   0.50    0.16    --  -46.87  38.00 -60.00  132
  3  \w    -23.00  29.00   0.50    0.16    --  -46.87  19.00 -90.00  104
  4  \w    -23.00  29.00   0.50    0.16    --  -46.87  19.00-180.00  104
  5  \w     74.00 100.00   0.50    0.62    --  104.56 -95.00-120.00   52
  6  \w     35.00 115.00   0.50    0.16    --   46.87-157.00-146.00  160
  7  \w     35.00 134.00   0.50    0.62    --  104.56-157.00-146.00  198
  8  \w     37.00 103.00   0.50    0.62    --  104.56-125.00-150.00  132
  9  \w     52.00 110.00   0.50    0.62    --  104.56-125.00-120.00  116
 10  \w     16.00  90.00   0.50    0.16    --   46.87-120.00   8.00  148
 11  \w     35.00 111.00   0.50    0.62    --  104.56-125.00 -90.00  152
 12  \w     37.00 111.00   0.50    0.62    --  104.56-125.00 -30.00  148
 13  \w     35.00 110.00   0.50    0.62    --  104.56-120.00   8.00  150
 14  \w     48.00 102.00   0.50    0.62    --  104.56 -95.00  30.00  108
 15  \w     34.00  63.00   0.50    0.62    --  104.56 -77.00   0.00   58
 16  \w     33.00  70.00   0.50    0.62    --  104.56 -61.00  30.00   74
 17  \w     39.00  73.00   0.50    0.62    --  104.56 -61.00  60.00   68
 18  \w     73.00  98.00   0.50    0.62    --  104.56 -77.00   0.00   50
 19  \w     32.00  57.00   0.50    0.62    --  104.56 -61.00 -30.00   50
 20  \w     33.00  71.00   0.50    0.62    --  104.56 -61.00-180.00   76
 21  \w     95.00 176.00   0.50    0.62    --  104.56  30.00 -90.00  162
 22  \w     92.00 169.00   0.50    0.62    --  104.56  45.00-180.00  154
 23  \w     35.00 120.00   0.50    0.16    --   46.87  38.00-150.00  170
 24  \w     24.00 118.00   0.50    0.16    --   46.87  77.00  90.00  188
 25  \w     89.00 175.00   0.50    0.62    --  104.56  61.00 120.00  172
 26  \w     83.00 174.00   0.50    0.62    --  104.56 120.00  92.00  182
 27  \w     82.00 108.00   0.50    0.62    --  104.56 125.00  30.00   52
 28  \w    117.00 151.00   0.50    0.62    --  104.56 125.00  30.00   68
 29  \w     58.00 160.00   0.50    0.62    --  104.56 157.00-112.00  204
 30  \w     58.00 120.00   0.50    0.16    --   46.87 157.00-112.00  124
 31  \w   -114.00 -29.00   0.50    0.16    --  -46.87 157.00-112.00  170
 32  \w   -133.00 -30.00   0.50    0.62    -- -103.00 157.00-112.00  206
 33  \w    -90.00  -9.00   0.50    0.16    --  -46.87 120.00  92.00  162
 34  \w   -109.00 -33.00   0.50    0.62    -- -103.00 120.00  92.00  152
 35  \w   -102.00 -45.00   0.50    0.62    -- -103.00  77.00  90.00  114
 36  \w    -67.00 -41.00   0.50    0.62    -- -103.00  61.00 -60.00   52
 37  \w    -74.00 -34.00   0.50    0.62    -- -103.00  77.00-120.00   80
 38  \w   -155.00 -91.00   0.50    0.62    -- -103.00 -15.00  60.00  128
 39  \w   -111.00 -86.00   0.50    0.62    -- -103.00 -61.00  90.00   50
 40  \w   -174.00 -90.00   0.50    0.62    -- -103.00 -45.00  30.00  168
 41  \w   -171.00-133.00   0.50    0.62    -- -103.00 -61.00  90.00   76
 42  \w   -173.00 -77.00   0.50    0.62    -- -103.00-120.00   8.00  192
 43  \w   -119.00 -51.00   0.50    0.16    --  -46.87-157.00-146.00  136
 44  \w   -160.00 -51.00   0.50    0.62    -- -103.00-157.00-146.00  218
;
_diffrn_measurement_device       'four-circle diffractometer'
_diffrn_measurement_device_type  'XtaLAB Synergy R, DW system, HyPix'
_diffrn_measurement_method       '\w scans'
_diffrn_orient_matrix_type
'CrysAlisPro convention (1999,Acta A55,543-557)'
_diffrn_orient_matrix_UB_11      0.0151971000
_diffrn_orient_matrix_UB_12      -0.0653107000
_diffrn_orient_matrix_UB_13      -0.0363854000
_diffrn_orient_matrix_UB_21      0.0053587000
_diffrn_orient_matrix_UB_22      0.0549299000
_diffrn_orient_matrix_UB_23      -0.0441502000
_diffrn_orient_matrix_UB_31      0.1053480000
_diffrn_orient_matrix_UB_32      0.0066497000
_diffrn_orient_matrix_UB_33      0.0074925000
_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  0.0730
_diffrn_reflns_av_unetI/netI     0.0263
_diffrn_reflns_Laue_measured_fraction_full 1.000
_diffrn_reflns_Laue_measured_fraction_max 0.990
_diffrn_reflns_limit_h_max       17
_diffrn_reflns_limit_h_min       -13
_diffrn_reflns_limit_k_max       22
_diffrn_reflns_limit_k_min       -22
_diffrn_reflns_limit_l_max       33
_diffrn_reflns_limit_l_min       -33
_diffrn_reflns_number            130656
_diffrn_reflns_point_group_measured_fraction_full 1.000
_diffrn_reflns_point_group_measured_fraction_max 0.980
_diffrn_reflns_theta_full        67.684
_diffrn_reflns_theta_max         76.462
_diffrn_reflns_theta_min         2.961
_diffrn_source                   'Rotating-anode X-ray tube'
_diffrn_source_type              'Rigaku (Cu) X-ray Source'
_exptl_absorpt_coefficient_mu    1.546
_exptl_absorpt_correction_T_max  0.805
_exptl_absorpt_correction_T_min  0.752
_exptl_absorpt_correction_type   multi-scan
_exptl_absorpt_process_details
;
CrysAlisPro 1.171.42.92a (Rigaku Oxford Diffraction, 2023)
Empirical absorption correction using spherical harmonics,
implemented in SCALE3 ABSPACK scaling algorithm.
;
_exptl_crystal_density_diffrn    1.383
_exptl_crystal_description       block
_exptl_crystal_F_000             3024
_exptl_crystal_size_max          0.25
_exptl_crystal_size_mid          0.18
_exptl_crystal_size_min          0.14
_refine_diff_density_max         0.374
_refine_diff_density_min         -0.243
_refine_diff_density_rms         0.039
_refine_ls_abs_structure_details
;
 Flack x determined using 5067 quotients [(I+)-(I-)]/[(I+)+(I-)]
 (Parsons, Flack and Wagner, Acta Cryst. B69 (2013) 249-259).
;
_refine_ls_abs_structure_Flack   0.005(5)
_refine_ls_extinction_coef       0.00064(10)
_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   1.016
_refine_ls_hydrogen_treatment    constr
_refine_ls_matrix_type           full
_refine_ls_number_parameters     1129
_refine_ls_number_reflns         14320
_refine_ls_number_restraints     286
_refine_ls_restrained_S_all      1.021
_refine_ls_R_factor_all          0.0566
_refine_ls_R_factor_gt           0.0518
_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^)+(0.0905P)^2^+1.1201P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.1452
_refine_ls_wR_factor_ref         0.1499
_reflns_Friedel_coverage         0.810
_reflns_Friedel_fraction_full    1.000
_reflns_Friedel_fraction_max     0.968
_reflns_number_gt                12776
_reflns_number_total             14320
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            d4ce00039k2.cif
_cod_data_source_block           samp7416
_cod_depositor_comments
'Adding full bibliography for 7248298--7248302.cif.'
_cod_database_code               7248302
_shelx_shelxl_version_number     2018/3
_shelx_estimated_absorpt_t_max   0.805
_shelx_estimated_absorpt_t_min   0.752
_olex2_refinement_description
;
1. Fixed Uiso
 At 1.2 times of:
  All C(H) groups, All C(H,H) groups, All C(H,H,H,H) groups, All N(H) groups,
  All N(H,H) groups
 At 1.5 times of:
  All C(H,H,H) groups, All O(H) groups
2. Restrained distances
 Cl1C-C2A \\sim Cl1A-C4C
 with sigma of 0.02
 C6A-C5A \\sim C6A-C1C
 with sigma of 0.02
 C6A-C1A \\sim C6A-C5C
 with sigma of 0.02
 F1C-C3A \\sim F1A-C3C
 with sigma of 0.02
 C5A-C4A \\sim C1C-C2C
 with sigma of 0.02
 C1A-C2A \\sim C5C-C4C
 with sigma of 0.02
 C4A-C3A \\sim C2C-C3C
 with sigma of 0.02
 C2A-C3A \\sim C4C-C3C
 with sigma of 0.02
 Cl1C-C1A \\sim Cl1A-C5C
 with sigma of 0.04
 Cl1C-C3A \\sim Cl1A-C3C
 with sigma of 0.04
 C6A-C4A \\sim C6A-C2C
 with sigma of 0.04
 C6A-C2A \\sim C6A-C4C
 with sigma of 0.04
 F1C-C4A \\sim F1A-C2C
 with sigma of 0.04
 F1C-C2A \\sim F1A-C4C
 with sigma of 0.04
 C5A-C3A \\sim C1C-C3C
 with sigma of 0.04
 C1A-C3A \\sim C5C-C3C
 with sigma of 0.04
 C4A-C2A \\sim C2C-C4C
 with sigma of 0.04
 O4B-C29B \\sim O4F-C29F
 with sigma of 0.02
 C23B-C28B \\sim C23F-C28F
 with sigma of 0.02
 C23B-C29B \\sim C23F-C29F
 with sigma of 0.02
 C23B-C24B \\sim C23F-C24F
 with sigma of 0.02
 C28B-C27B \\sim C28F-C27F
 with sigma of 0.02
 C29B-O5B \\sim C29F-O5F
 with sigma of 0.02
 C25B-C24B \\sim C25F-C24F
 with sigma of 0.02
 C25B-C26B \\sim C25F-C26F
 with sigma of 0.02
 O6B-C24B \\sim O6F-C24F
 with sigma of 0.02
 C27B-C26B \\sim C27F-C26F
 with sigma of 0.02
 O4B-C23B \\sim O4F-C23F
 with sigma of 0.04
 O4B-O5B \\sim O4F-O5F
 with sigma of 0.04
 C23B-C25B \\sim C23F-C25F
 with sigma of 0.04
 C23B-O6B \\sim C23F-O6F
 with sigma of 0.04
 C23B-O5B \\sim C23F-O5F
 with sigma of 0.04
 C23B-C27B \\sim C23F-C27F
 with sigma of 0.04
 C28B-C29B \\sim C28F-C29F
 with sigma of 0.04
 C28B-C24B \\sim C28F-C24F
 with sigma of 0.04
 C28B-C26B \\sim C28F-C26F
 with sigma of 0.04
 C29B-C24B \\sim C29F-C24F
 with sigma of 0.04
 C25B-O6B \\sim C25F-O6F
 with sigma of 0.04
 C25B-C27B \\sim C25F-C27F
 with sigma of 0.04
 C24B-C26B \\sim C24F-C26F
 with sigma of 0.04
3. Rigid body (RIGU) restrains
 O4F, O5F, O6F, C23F, C24F, C25F, C26F, C27F, C28F, C29F
 with sigma for 1-2 distances of 0.0001 and sigma for 1-3 distances of 0.0001
 O4B, O5B, O6B, C23B, C24B, C25B, C26B, C27B, C28B, C29B
 with sigma for 1-2 distances of 0.0001 and sigma for 1-3 distances of 0.0001
 N2A, N3A, C7A, C8A, C9A, C10A
 with sigma for 1-2 distances of 0.001 and sigma for 1-3 distances of 0.001
 C6A, C1A, C2A, C3A, C4A, C5A
 with sigma for 1-2 distances of 0.001 and sigma for 1-3 distances of 0.001
 C6A, C1C, C2C, C3C, C4C, C5C
 with sigma for 1-2 distances of 0.001 and sigma for 1-3 distances of 0.001
4. Others
 Sof(Cl1A)=Sof(F1A)=Sof(C1C)=Sof(H1C)=Sof(C2C)=Sof(H2C)=Sof(C3C)=Sof(C4C)=
 Sof(C5C)=Sof(H5C)=1-FVAR(1)
 Sof(Cl1C)=Sof(F1C)=Sof(C1A)=Sof(H1AA)=Sof(C2A)=Sof(C3A)=Sof(C4A)=Sof(H4AA)=
 Sof(C5A)=Sof(H5A)=FVAR(1)
 Sof(O4F)=Sof(O5F)=Sof(O6F)=Sof(H6F)=Sof(C23F)=Sof(C24F)=Sof(C25F)=Sof(H25F)=
 Sof(C26F)=Sof(H26F)=Sof(C27F)=Sof(H27F)=Sof(C28F)=Sof(H28F)=Sof(C29F)=1-FVAR(2)
 Sof(O4B)=Sof(O5B)=Sof(O6B)=Sof(H6B)=Sof(C23B)=Sof(C24B)=Sof(C25B)=Sof(H25B)=
 Sof(C26B)=Sof(H26B)=Sof(C27B)=Sof(H27B)=Sof(C28B)=Sof(H28B)=Sof(C29B)=FVAR(2)
 Sof(H4BA)=Sof(H16C)=Sof(H16D)=Sof(C17B)=Sof(H17C)=Sof(H17D)=Sof(C18B)=
 Sof(H18C)=Sof(H18D)=Sof(C19B)=Sof(H19C)=Sof(H19D)=Sof(C20C)=Sof(H20C)=
 Sof(H20D)=Sof(C21C)=Sof(H21C)=Sof(H21D)=1-FVAR(3)
 Sof(H4B)=Sof(H16A)=Sof(H16B)=Sof(C17C)=Sof(H17A)=Sof(H17B)=Sof(C18C)=
 Sof(H18A)=Sof(H18B)=Sof(C19C)=Sof(H19A)=Sof(H19B)=Sof(C20B)=Sof(H20A)=
 Sof(H20B)=Sof(C21B)=Sof(H21A)=Sof(H21B)=FVAR(3)
5.a Ternary CH refined with riding coordinates:
 N4B(H4B), N4B(H4BA), N4A(H4A)
5.b Secondary CH2 refined with riding coordinates:
 C15B(H15A,H15B), C16B(H16A,H16B), C16B(H16C,H16D), C17C(H17A,H17B), C18C(H18A,
 H18B), C19C(H19A,H19B), C20B(H20A,H20B), C21B(H21A,H21B), C17B(H17C,H17D),
 C18B(H18C,H18D), C19B(H19C,H19D), C20C(H20C,H20D), C21C(H21C,H21D), C15A(H15C,
 H15D), C16A(H16E,H16F), C17A(H17E,H17F), C18A(H18E,H18F), C19A(H19E,H19F),
 C20A(H20E,H20F), C21A(H21E,H21F)
5.c Aromatic/amide H refined with riding coordinates:
 N1B(H1B), N3B(H3B), C1B(H1BA), C2B(H2B), C5B(H5B), C8B(H8B), C11B(H11B),
 C14B(H14B), N1A(H1A), C8A(H8A), C11A(H11A), C14A(H14A), C1A(H1AA), C4A(H4AA),
 C5A(H5A), C1C(H1C), C2C(H2C), C5C(H5C), C25A(H25A), C26A(H26A), C27A(H27A),
 C28A(H28A), C25C(H25C), C26C(H26C), C27C(H27C), C28C(H28C), C25D(H25D),
 C26D(H26D), C27D(H27D), C28D(H28D), C25B(H25B), C26B(H26B), C27B(H27B),
 C28B(H28B), C25F(H25F), C26F(H26F), C27F(H27F), C28F(H28F)
5.d Idealised Me refined as rotating group:
 C22B(H22A,H22B,H22C), C22A(H22D,H22E,H22F)
5.e Idealised tetrahedral OH refined as rotating group:
 O6A(H6A), O6C(H6C), O5D(H5D), O6D(H6D), O6B(H6B), O6F(H6F)
;
_shelx_res_checksum              720
_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 3.210
_oxdiff_exptl_absorpt_empirical_full_min 0.427