Ketoconazole - p-aminobenzoic acid cocrystal: revival of an old drug by crystal engineering.
Martin, Flavia; Pop, Mihaela; Kacso, Irina; Grosu, Ioana Georgeta; Miclaus, Maria; Vodnar, Dan; Lung, Ildiko; Filip, Gabriela Adriana; Olteanu, Elena Diana; Moldovan, Remus; Nagy, Andras; Filip, Xenia; Baldea, Ioana; Molecular pharmaceutics  (2020) –; doi:10.1021/acs.molpharmaceut.9b01178

data_1557268
_publ_section_title
;
 Ketoconazole - p-aminobenzoic acid cocrystal: revival of an old drug by
 crystal engineering.
;
_journal_name_full               'Molecular pharmaceutics'
_journal_paper_doi               10.1021/acs.molpharmaceut.9b01178
_journal_year                    2020
_chemical_formula_moiety         'C26 H23 Cl2 N4 O4, C7 H7 N O2'
_chemical_formula_sum            'C33 H30 Cl2 N5 O6'
_chemical_formula_weight         663.52
_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   mixed
_atom_sites_solution_primary     iterative
_audit_creation_date             2016-05-02
_audit_creation_method
;
Olex2 1.2
(compiled 2016.02.16 svn.r3265 for OlexSys, GUI svn.r5155)
;
_cell_angle_alpha                64.386(5)
_cell_angle_beta                 71.962(4)
_cell_angle_gamma                85.754(4)
_cell_formula_units_Z            2
_cell_length_a                   9.6678(5)
_cell_length_b                   12.9865(6)
_cell_length_c                   14.6942(7)
_cell_measurement_reflns_used    8820
_cell_measurement_temperature    110.5(6)
_cell_measurement_theta_max      71.5050
_cell_measurement_theta_min      3.4980
_cell_volume                     1577.95(16)
_computing_cell_refinement
;
CrysAlisPro, Agilent Technologies,
Version 1.171.36.24 (release 03-12-2012 CrysAlis171 .NET)
(compiled Dec  3 2012,18:21:49)
;
_computing_data_collection
;
CrysAlisPro, Agilent Technologies,
Version 1.171.36.24 (release 03-12-2012 CrysAlis171 .NET)
(compiled Dec  3 2012,18:21:49)
;
_computing_data_reduction
;
CrysAlisPro, Agilent Technologies,
Version 1.171.36.24 (release 03-12-2012 CrysAlis171 .NET)
(compiled Dec  3 2012,18:21:49)
;
_computing_molecular_graphics    'Olex2 (Dolomanov et al., 2009)'
_computing_publication_material  'Olex2 (Dolomanov et al., 2009)'
_computing_structure_refinement  'ShelXL (Sheldrick, 2015)'
_computing_structure_solution
;
Superflip (Palatinus & Chapuis, 2007;Palatinus & van der Lee, 2008;
Palatinus et al., 2012)
;
_diffrn_ambient_temperature      110.5(6)
_diffrn_detector_area_resol_mean 16.4335
_diffrn_measured_fraction_theta_full 0.998
_diffrn_measured_fraction_theta_max 0.982
_diffrn_measurement_details
;
  1 omega   35.00   61.00   1.0000    1.0000
omega____ theta____ kappa____ phi______ frames
    -        0.0000   57.0000 -180.0000 26

  2 omega  -32.00    2.00   1.0000    1.0000
omega____ theta____ kappa____ phi______ frames
    -        0.0000   77.0000   90.0000 34

  3 omega    6.00   70.00   1.0000    1.0000
omega____ theta____ kappa____ phi______ frames
    -        0.0000   77.0000   90.0000 64

  4 omega  -82.00  -46.00   1.0000    1.0000
omega____ theta____ kappa____ phi______ frames
    -        0.0000  178.0000 -180.0000 36

  5 omega -127.00  -99.00   1.0000    1.0000
omega____ theta____ kappa____ phi______ frames
    -      -56.3168 -126.0000    0.0000 28

  6 omega -128.00  -73.00   1.0000    1.0000
omega____ theta____ kappa____ phi______ frames
    -      -56.3168 -126.0000 -120.0000 55

  7 omega   24.00  112.00   1.0000    1.0000
omega____ theta____ kappa____ phi______ frames
    -       56.3168 -126.0000  120.0000 88

  8 omega    7.00   99.00   1.0000    1.0000
omega____ theta____ kappa____ phi______ frames
    -       56.3168  -95.0000  -60.0000 92

  9 omega  -13.00   73.00   1.0000    1.0000
omega____ theta____ kappa____ phi______ frames
    -       56.3168  -61.0000 -180.0000 86

 10 omega  -17.00  128.00   1.0000    1.0000
omega____ theta____ kappa____ phi______ frames
    -       56.3168    0.0000    0.0000 145

 11 omega  -34.00   -8.00   1.0000    1.0000
omega____ theta____ kappa____ phi______ frames
    -      -64.5000   50.0000    0.0000 26

 12 omega  -73.00  -38.00   1.0000    1.0000
omega____ theta____ kappa____ phi______ frames
    -      -64.5000   65.0000 -149.0000 35

 13 omega  -34.00    5.00   1.0000    1.0000
omega____ theta____ kappa____ phi______ frames
    -      -64.5000   25.0000   90.0000 39

 14 omega   47.00   99.00   1.0000    1.0000
omega____ theta____ kappa____ phi______ frames
    -      112.6336 -112.0000   30.0000 52

 15 omega   39.00  114.00   1.0000    1.0000
omega____ theta____ kappa____ phi______ frames
    -      112.6336 -112.0000   60.0000 75

 16 omega  108.00  134.00   1.0000    1.0000
omega____ theta____ kappa____ phi______ frames
    -      112.6336  112.0000  150.0000 26

 17 omega   42.00   92.00   1.0000    1.0000
omega____ theta____ kappa____ phi______ frames
    -      112.6336  -38.0000 -120.0000 50

 18 omega   40.00   93.00   1.0000    1.0000
omega____ theta____ kappa____ phi______ frames
    -      112.6336  -38.0000    0.0000 53

 19 omega   42.00   80.00   1.0000    1.0000
omega____ theta____ kappa____ phi______ frames
    -      112.6336  -38.0000  150.0000 38

 20 omega   40.00  120.00   1.0000    1.0000
omega____ theta____ kappa____ phi______ frames
    -      112.6336  -77.0000 -120.0000 80

 21 omega   55.00   93.00   1.0000    1.0000
omega____ theta____ kappa____ phi______ frames
    -      112.6336  -25.0000  -90.0000 38

 22 omega   48.00   92.00   1.0000    1.0000
omega____ theta____ kappa____ phi______ frames
    -      112.6336 -112.0000 -120.0000 44

 23 omega   88.00  173.00   1.0000    1.0000
omega____ theta____ kappa____ phi______ frames
    -      112.6336   50.0000 -180.0000 85

 24 omega   58.00   91.00   1.0000    1.0000
omega____ theta____ kappa____ phi______ frames
    -      112.6336  -25.0000 -180.0000 33

 25 omega   79.00  105.00   1.0000    1.0000
omega____ theta____ kappa____ phi______ frames
    -      112.6336 -112.0000 -180.0000 26

 26 omega   39.00   92.00   1.0000    1.0000
omega____ theta____ kappa____ phi______ frames
    -      112.6336  -38.0000   60.0000 53

 27 omega   44.00   89.00   1.0000    1.0000
omega____ theta____ kappa____ phi______ frames
    -      112.6336  -25.0000  150.0000 45

 28 omega   85.00  113.00   1.0000    1.0000
omega____ theta____ kappa____ phi______ frames
    -      112.6336 -112.0000  -90.0000 28

 29 omega   49.00  178.00   1.0000    1.0000
omega____ theta____ kappa____ phi______ frames
    -      112.6336  -12.0000  -30.0000 129

 30 omega   42.00  144.00   1.0000    1.0000
omega____ theta____ kappa____ phi______ frames
    -      112.6336  -77.0000   60.0000 102

 31 omega  -82.00  -34.00   1.0000    1.0000
omega____ theta____ kappa____ phi______ frames
    -        0.0000  178.0000 -120.0000 48

 32 omega  -72.00   33.00   1.0000    1.0000
omega____ theta____ kappa____ phi______ frames
    -        0.0000  -77.0000  120.0000 105

 33 omega -129.00  -23.00   1.0000    1.0000
omega____ theta____ kappa____ phi______ frames
    -      -56.3168  -77.0000 -150.0000 106

 34 omega -126.00  -31.00   1.0000    1.0000
omega____ theta____ kappa____ phi______ frames
    -      -56.3168  -61.0000  120.0000 95

 35 omega -129.00  -23.00   1.0000    1.0000
omega____ theta____ kappa____ phi______ frames
    -      -56.3168  -77.0000  -60.0000 106

 36 omega   23.00  129.00   1.0000    1.0000
omega____ theta____ kappa____ phi______ frames
    -       56.3168   77.0000   90.0000 106

 37 omega   29.00  127.00   1.0000    1.0000
omega____ theta____ kappa____ phi______ frames
    -       56.3168   65.0000   30.0000 98

 38 omega   -3.00   99.00   1.0000    1.0000
omega____ theta____ kappa____ phi______ frames
    -       56.3168  -95.0000  -90.0000 102

 39 omega   40.00  138.00   1.0000    1.0000
omega____ theta____ kappa____ phi______ frames
    -      112.6336  -77.0000   60.0000 98

 40 omega   81.00  178.00   1.0000    1.0000
omega____ theta____ kappa____ phi______ frames
    -      112.6336   38.0000  -30.0000 97

 41 omega   68.00  178.00   1.0000    1.0000
omega____ theta____ kappa____ phi______ frames
    -      112.6336   25.0000  -90.0000 110

 42 omega   81.00  178.00   1.0000    1.0000
omega____ theta____ kappa____ phi______ frames
    -      112.6336   38.0000  150.0000 97

 43 omega   40.00  178.00   1.0000    1.0000
omega____ theta____ kappa____ phi______ frames
    -      112.6336   12.0000   90.0000 138
;
_diffrn_measurement_device_type  'SuperNova, Dual, Cu at zero, Eos'
_diffrn_measurement_method       '\w scans'
_diffrn_orient_matrix_UB_11      -0.0677924000
_diffrn_orient_matrix_UB_12      -0.1230894000
_diffrn_orient_matrix_UB_13      0.0731407000
_diffrn_orient_matrix_UB_21      0.1175159000
_diffrn_orient_matrix_UB_22      -0.0229408000
_diffrn_orient_matrix_UB_23      0.0559925000
_diffrn_orient_matrix_UB_31      -0.0990788000
_diffrn_orient_matrix_UB_32      0.0414081000
_diffrn_orient_matrix_UB_33      0.0803605000
_diffrn_radiation_monochromator  mirror
_diffrn_radiation_type           CuK\a
_diffrn_radiation_wavelength     1.54184
_diffrn_reflns_av_R_equivalents  0.0228
_diffrn_reflns_av_unetI/netI     0.0229
_diffrn_reflns_Laue_measured_fraction_full 0.998
_diffrn_reflns_Laue_measured_fraction_max 0.982
_diffrn_reflns_limit_h_max       11
_diffrn_reflns_limit_h_min       -11
_diffrn_reflns_limit_k_max       15
_diffrn_reflns_limit_k_min       -15
_diffrn_reflns_limit_l_max       18
_diffrn_reflns_limit_l_min       -16
_diffrn_reflns_number            17629
_diffrn_reflns_point_group_measured_fraction_full 0.998
_diffrn_reflns_point_group_measured_fraction_max 0.982
_diffrn_reflns_theta_full        67.684
_diffrn_reflns_theta_max         71.734
_diffrn_reflns_theta_min         3.507
_diffrn_source                   'SuperNova (Cu) X-ray Source'
_exptl_absorpt_coefficient_mu    2.301
_exptl_absorpt_correction_T_max  1.00000
_exptl_absorpt_correction_T_min  0.86520
_exptl_absorpt_correction_type   multi-scan
_exptl_absorpt_process_details
;
CrysAlisPro, Agilent Technologies,
Version 1.171.36.24 (release 03-12-2012 CrysAlis171 .NET)
(compiled Dec  3 2012,18:21:49)
Empirical absorption correction using spherical harmonics,
 implemented in SCALE3 ABSPACK scaling algorithm.
;
_exptl_crystal_colour
;
;
_exptl_crystal_density_diffrn    1.396
_exptl_crystal_description
;
;
_exptl_crystal_F_000             690
_refine_diff_density_max         0.762
_refine_diff_density_min         -0.836
_refine_diff_density_rms         0.060
_refine_ls_extinction_method     none
_refine_ls_goodness_of_fit_ref   1.065
_refine_ls_hydrogen_treatment    constr
_refine_ls_matrix_type           full
_refine_ls_number_parameters     430
_refine_ls_number_reflns         6054
_refine_ls_number_restraints     0
_refine_ls_restrained_S_all      1.065
_refine_ls_R_factor_all          0.0626
_refine_ls_R_factor_gt           0.0576
_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^)+(0.0554P)^2^+2.1970P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.1411
_refine_ls_wR_factor_ref         0.1448
_reflns_Friedel_coverage         0.000
_reflns_number_gt                5509
_reflns_number_total             6054
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            mp9b01178_si_002.cif
_cod_data_source_block           keto-paba-lt
_cod_original_cell_volume        1577.95(15)
_cod_database_code               1557268
_chemical_oxdiff_formula         'c26 h28 cl2 n4 o4'
_reflns_odcompleteness_completeness 99.86
_reflns_odcompleteness_iscentric 1
_reflns_odcompleteness_theta     66.97
_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(C13) = Uanis(C13A)
Uanis(C14) = Uanis(C14A)
Uanis(C12) = Uanis(C12A)
3. Others
 Sof(C13A)=1-FVAR(1)
 Sof(C13)=FVAR(1)
 Sof(C14A)=1-FVAR(2)
 Sof(C14)=FVAR(2)
 Sof(C12A)=1-FVAR(3)
 Sof(C12)=FVAR(3)
4.a Rotating group:
 N1B(H1BA,H1BB)
4.b Secondary CH2 refined with riding coordinates:
 C4(H4A,H4B), C23(H23A,H23B), C24(H24A,H24B), C21(H21A,H21B), C22(H22A,H22B)
4.c Aromatic/amide H refined with riding coordinates:
 C2(H2), C3(H3), C16(H16), C1(H1), C3B(H3B), C2B(H2BA), C17(H17), C20(H20),
 C19(H19), C6B(H6B), C7(H7), C5B(H5B), C10(H10), C8(H8)
4.d Idealised Me refined as rotating group:
 C26(H26A,H26B,H26C)
4.e Idealised tetrahedral OH refined as rotating group:
 O2B(H2B)
;