Reversible interconversion of pharmaceutical salt polymorphs facilitated by mechanical methods.
Ma, Liulei; Zheng, Qixuan; Unruh, Daniel K.; Hutchins, Kristin M.; Chemical communications (Cambridge, England) 59 (2023) 7779–7782; doi:10.1039/d3cc02188b

data_7131712
_publ_section_title
;
 Reversible interconversion of pharmaceutical salt polymorphs facilitated
 by mechanical methods.
;
_journal_issue                   50
_journal_name_full               'Chemical communications (Cambridge, England)'
_journal_page_first              7779
_journal_page_last               7782
_journal_paper_doi               10.1039/d3cc02188b
_journal_volume                  59
_journal_year                    2023
_chemical_absolute_configuration rm
_chemical_formula_moiety         'C14 H19 N4 O3, C3 H5 O3'
_chemical_formula_sum            'C17 H24 N4 O6'
_chemical_formula_weight         380.40
_space_group_crystal_system      triclinic
_space_group_IT_number           1
_space_group_name_Hall           'P 1'
_space_group_name_H-M_alt        'P 1'
_atom_sites_solution_hydrogens   mixed
_atom_sites_solution_primary     dual
_audit_creation_date             2022-08-01
_audit_creation_method
;
Olex2 1.5
(compiled 2021.12.09 svn.r5202d8cf for OlexSys, GUI svn.r6439)
;
_audit_update_record
;
2023-02-10 deposited with the CCDC.	2023-05-25 downloaded from the CCDC.
;
_cell_angle_alpha                85.388(2)
_cell_angle_beta                 88.8410(10)
_cell_angle_gamma                77.804(2)
_cell_formula_units_Z            2
_cell_length_a                   5.06650(10)
_cell_length_b                   9.7541(2)
_cell_length_c                   19.4423(3)
_cell_measurement_reflns_used    31700
_cell_measurement_temperature    99.96(12)
_cell_measurement_theta_max      74.8220
_cell_measurement_theta_min      2.2470
_cell_volume                     936.09(3)
_computing_cell_refinement       'CrysAlisPro 1.171.41.93a (Rigaku OD, 2020)'
_computing_data_collection       'CrysAlisPro 1.171.41.93a (Rigaku OD, 2020)'
_computing_data_reduction        'CrysAlisPro 1.171.41.93a (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_environment      N~2~
_diffrn_ambient_temperature      99.96(12)
_diffrn_detector                 'Hybrid Pixel Array Detector'
_diffrn_detector_area_resol_mean 10.0000
_diffrn_detector_type            HyPix
_diffrn_measured_fraction_theta_full 0.989
_diffrn_measured_fraction_theta_max 0.917
_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   -118.00 -35.00   0.50    1.26    --  -47.88 170.00  32.00  166
  2  \w    -82.00  -6.00   0.50    1.26    --  -47.88 115.00-109.00  152
  3  \w   -120.00 -45.00   0.50    1.26    --  -47.88-170.00  17.00  150
  4  \w     27.00  91.00   0.50    1.26    --   47.88-115.00 160.00  128
  5  \w     57.00 122.00   0.50    1.26    --   47.88-170.00  17.00  130
  6  \w     67.00 120.00   0.50    1.26    --   47.88 170.00  32.00  106
  7  \w   -118.00 -35.00   0.50    5.06    --  -91.75 170.00  32.00  166
  8  \w   -163.00 -80.00   0.50    5.06    --  -91.75-115.00 160.00  166
  9  \w   -134.00 -45.00   0.50    5.06    --  -91.75-170.00  17.00  178
 10  \w    -83.00 -19.00   0.50    5.06    --  -91.75 115.00-109.00  128
 11  \w     67.00 151.00   0.50    5.06    --  107.81 170.00  32.00  168
 12  \w     57.00 144.00   0.50    5.06    --  107.81-170.00  17.00  174
 13  \w    101.00 178.00   0.50    5.06    --  107.81 115.00-109.00  154
 14  \w     35.00 109.00   0.50    5.06    --  107.81-115.00 160.00  148
 15  \w    -11.00  23.00   0.50    1.26    --   22.00  99.00 127.69   68
 16  \w    -12.00  18.00   0.50    1.26    --   22.00 101.00 169.76   60
 17  \w      4.00  39.00   0.50    1.26    --   34.00  92.00 119.98   70
 18  \w     17.00  43.00   0.50    1.26    --   46.00  90.00-137.47   52
 19  \w   -120.00 -25.00   0.50    1.26    --  -47.88 -77.00  30.00  190
 20  \w   -120.00 -25.00   0.50    1.26    --  -47.88 -77.00-120.00  190
 21  \w   -120.00 -25.00   0.50    1.26    --  -47.88 -77.00  60.00  190
 22  \w     25.00 121.00   0.50    1.26    --   47.88  77.00   0.00  192
 23  \w     25.00 121.00   0.50    1.26    --   47.88  77.00 -30.00  192
 24  \w     36.00 121.00   0.50    1.26    --   47.88  38.00  90.00  170
 25  \w     36.00 121.00   0.50    1.26    --   47.88  38.00 -60.00  170
 26  \w     36.00 121.00   0.50    1.26    --   47.88  38.00   0.00  170
 27  \w     25.00 121.00   0.50    1.26    --   47.88  77.00-180.00  192
 28  \w     35.00 123.00   0.50    1.26    --   47.88  19.00 -90.00  176
 29  \w     33.00 126.00   0.50    1.26    --   54.00  74.00 141.32  186
 30  \w     36.00 131.00   0.50    1.26    --   58.00  75.00 -39.67  190
 31  \w     36.00 131.00   0.50    1.26    --   58.00  76.00 112.13  190
 32  \w     41.00 135.00   0.50    1.26    --   62.00  73.00  98.11  188
 33  \w     41.00 135.00   0.50    1.26    --   62.00  74.00-121.91  188
 34  \w   -139.00 -47.00   0.50    1.26    --  -66.00 -68.00 176.86  184
 35  \w   -139.00 -48.00   0.50    1.26    --  -66.00 -65.00  83.24  182
 36  \w   -139.00 -43.00   0.50    1.26    --  -66.00 -76.00 145.34  192
 37  \w   -139.00 -47.00   0.50    1.26    --  -66.00 -68.00 -75.72  184
 38  \w     43.00 139.00   0.50    1.26    --   66.00  77.00  52.50  192
 39  \w     43.00 139.00   0.50    1.26    --   66.00  77.00 -96.78  192
 40  \w     43.00 139.00   0.50    1.26    --   66.00  77.00-165.55  192
 41  \w   -143.00 -52.00   0.50    5.06    --  -70.00 -66.00  65.71  182
 42  \w   -146.00 -53.00   0.50    5.06    --  -74.00 -73.00  44.60  186
 43  \w   -146.00 -52.00   0.50    5.06    --  -74.00 -74.00 122.66  188
 44  \w   -146.00 -52.00   0.50    5.06    --  -74.00 -74.00  11.31  188
 45  \w   -146.00 -55.00   0.50    5.06    --  -74.00 -67.00 125.29  182
 46  \w   -146.00 -55.00   0.50    5.06    --  -74.00 -67.00 119.96  182
 47  \w   -146.00 -56.00   0.50    5.06    --  -74.00 -65.00-157.02  180
 48  \w   -146.00 -56.00   0.50    5.06    --  -74.00 -64.00 178.60  180
 49  \w   -151.00 -60.00   0.50    5.06    --  -78.00 -64.00 160.69  182
 50  \w   -151.00 -57.00   0.50    5.06    --  -78.00 -73.00-106.88  188
 51  \w   -151.00 -56.00   0.50    5.06    --  -78.00 -74.00  -7.97  190
 52  \w   -154.00 -65.00   0.50    5.06    --  -82.00 -62.00 -85.51  178
 53  \w   -154.00 -64.00   0.50    5.06    --  -82.00 -66.00  60.08  180
 54  \w   -154.00 -62.00   0.50    5.06    --  -82.00 -70.00 145.97  184
 55  \w   -154.00 -60.00   0.50    5.06    --  -82.00 -74.00 -29.24  188
 56  \w   -159.00 -64.00   0.50    5.06    --  -86.00 -74.00  48.26  190
 57  \w   -162.00 -67.00   0.50    5.06    --  -90.00 -76.00 116.35  190
 58  \w   -162.00 -73.00   0.50    5.06    --  -90.00 -63.00-164.51  178
 59  \w   -163.00 -70.00   0.50    5.06    --  -91.75 -74.00 134.69  186
 60  \w   -163.00 -70.00   0.50    5.06    --  -91.75 -74.00  12.30  186
 61  \w   -163.00 -73.00   0.50    5.06    --  -91.75 -67.00 -11.89  180
 62  \w   -163.00 -72.00   0.50    5.06    --  -91.75 -69.00-173.47  182
 63  \w   -163.00 -69.00   0.50    5.06    --  -91.75 -76.00-100.58  188
 64  \w   -163.00 -69.00   0.50    5.06    --  -91.75 -76.00 132.41  188
 65  \w   -163.00 -69.00   0.50    5.06    --  -91.75 -77.00  30.00  188
 66  \w   -163.00 -69.00   0.50    5.06    --  -91.75 -77.00 -11.29  188
 67  \w   -163.00 -70.00   0.50    5.06    --  -91.75 -74.00 -46.15  186
 68  \w   -163.00 -71.00   0.50    5.06    --  -91.75 -71.00  89.43  184
 69  \w   -163.00 -71.00   0.50    5.06    --  -91.75 -72.00  36.54  184
 70  \w   -163.00 -73.00   0.50    5.06    --  -91.75 -66.00-123.87  180
 71  \w   -163.00 -71.00   0.50    5.06    --  -91.75 -72.00  69.41  184
 72  \w   -163.00 -74.00   0.50    5.06    --  -91.75 -63.00 -42.80  178
 73  \w    -85.00 -19.00   0.50    5.06    --  -91.75 125.00 -30.00  132
 74  \w   -163.00 -75.00   0.50    5.06    --  -91.75 -61.00 -95.64  176
 75  \w   -163.00 -69.00   0.50    5.06    --  -91.75 -77.00 -60.00  188
 76  \w   -163.00 -74.00   0.50    5.06    --  -91.75 -64.00-144.75  178
 77  \w   -163.00 -69.00   0.50    5.06    --  -91.75 -77.00-120.00  188
 78  \w   -163.00 -72.00   0.50    5.06    --  -91.75 -70.00 161.95  182
 79  \w    -64.00 -19.00   0.50    5.06    --  -91.75  57.00  90.00   90
 80  \w   -163.00 -74.00   0.50    5.06    --  -91.75 -65.00  91.99  178
 81  \w     35.00 112.00   0.50    5.06    --  107.81-125.00-120.00  154
 82  \w     35.00  68.00   0.50    5.06    --  107.81 -57.00-150.00   66
 83  \w     35.00 106.00   0.50    5.06    --  107.81 -99.00 -30.00  142
 84  \w     35.00 107.00   0.50    5.06    --  107.81-104.00 -53.90  144
 85  \w     35.00 106.00   0.50    5.06    --  107.81 -99.00  30.00  142
 86  \w     35.00 106.00   0.50    5.06    --  107.81 -99.00  90.00  142
 87  \w     35.00 107.00   0.50    5.06    --  107.81 -77.00 150.00  144
 88  \w     35.00 106.00   0.50    5.06    --  107.81 -99.00-120.00  142
 89  \w     35.00  68.00   0.50    5.06    --  107.81 -57.00  30.00   66
 90  \w   -120.00 -25.00   0.50    1.26    --  -47.88 -77.00 -90.00  190
 91  \w    -24.00 120.00   0.50    1.26    --   47.88   0.00 -30.00  288
 92  \w    -24.00 120.00   0.50    1.26    --   47.88   0.00  60.00  288
 93  \w    -24.00 120.00   0.50    1.26    --   47.88   0.00 -60.00  288
 94  \w    -24.00 120.00   0.50    1.26    --   47.88   0.00  90.00  288
 95  \w    -24.00 120.00   0.50    1.26    --   47.88   0.00 -90.00  288
 96  \w    -24.00 120.00   0.50    1.26    --   47.88   0.00   0.00  288
 97  \w    -24.00 120.00   0.50    1.26    --   47.88   0.00 120.00  288
 98  \w    -24.00 120.00   0.50    1.26    --   47.88   0.00  30.00  288
 99  \w    -24.00 120.00   0.50    1.26    --   47.88   0.00-180.00  288
100  \w    -24.00 120.00   0.50    1.26    --   47.88   0.00-150.00  288
101  \w    -24.00 120.00   0.50    1.26    --   47.88   0.00-120.00  288
102  \w   -131.00 -35.00   0.50    1.26    --  -58.00 -76.00 -50.93  192
103  \w   -131.00 -35.00   0.50    1.26    --  -58.00 -77.00 -52.77  192
104  \w   -135.00 -45.00   0.50    1.26    --  -62.00 -61.00 140.41  180
105  \w   -135.00 -43.00   0.50    1.26    --  -62.00 -67.00 -91.50  184
106  \w     39.00 135.00   0.50    1.26    --   62.00  77.00  50.72  192
107  \w     40.00 135.00   0.50    1.26    --   62.00  75.00  25.42  190
108  \w   -139.00 -47.00   0.50    1.26    --  -66.00 -68.00 -68.45  184
109  \w   -139.00 -48.00   0.50    1.26    --  -66.00 -64.00-114.04  182
110  \w     43.00 139.00   0.50    1.26    --   66.00  77.00  20.12  192
;
_diffrn_measurement_device       'four-circle diffractometer'
_diffrn_measurement_device_type  'XtaLAB Synergy, Dualflex, HyPix'
_diffrn_measurement_method       '\w scans'
_diffrn_orient_matrix_type
'CrysAlisPro convention (1999,Acta A55,543-557)'
_diffrn_orient_matrix_UB_11      0.1296234000
_diffrn_orient_matrix_UB_12      -0.0004282000
_diffrn_orient_matrix_UB_13      0.0710351000
_diffrn_orient_matrix_UB_21      -0.2827043000
_diffrn_orient_matrix_UB_22      0.0332713000
_diffrn_orient_matrix_UB_23      0.0331953000
_diffrn_orient_matrix_UB_31      0.0072179000
_diffrn_orient_matrix_UB_32      -0.1586279000
_diffrn_orient_matrix_UB_33      0.0130990000
_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  0.0681
_diffrn_reflns_av_unetI/netI     0.0360
_diffrn_reflns_Laue_measured_fraction_full 0.989
_diffrn_reflns_Laue_measured_fraction_max 0.917
_diffrn_reflns_limit_h_max       6
_diffrn_reflns_limit_h_min       -6
_diffrn_reflns_limit_k_max       10
_diffrn_reflns_limit_k_min       -12
_diffrn_reflns_limit_l_max       23
_diffrn_reflns_limit_l_min       -24
_diffrn_reflns_number            54448
_diffrn_reflns_point_group_measured_fraction_full 0.946
_diffrn_reflns_point_group_measured_fraction_max 0.852
_diffrn_reflns_theta_full        67.684
_diffrn_reflns_theta_max         76.908
_diffrn_reflns_theta_min         2.280
_diffrn_source                   'micro-focus sealed X-ray tube'
_diffrn_source_type              'PhotonJet (Cu) X-ray Source'
_exptl_absorpt_coefficient_mu    0.867
_exptl_absorpt_correction_T_max  1.000
_exptl_absorpt_correction_T_min  0.715
_exptl_absorpt_correction_type   gaussian
_exptl_absorpt_process_details
;
CrysAlisPro 1.171.41.93a (Rigaku Oxford Diffraction, 2020)
Numerical absorption correction based on gaussian integration over
a multifaceted crystal model
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    1.350
_exptl_crystal_description       irregular
_exptl_crystal_F_000             404
_exptl_crystal_recrystallization_method 'Re-crystallisation from solvent'
_exptl_crystal_size_max          0.151
_exptl_crystal_size_mid          0.128
_exptl_crystal_size_min          0.063
_refine_diff_density_max         0.251
_refine_diff_density_min         -0.229
_refine_diff_density_rms         0.047
_refine_ls_abs_structure_details
;
 Refined as an inversion twin.
;
_refine_ls_abs_structure_Flack   -0.1(2)
_refine_ls_extinction_method     none
_refine_ls_goodness_of_fit_ref   1.037
_refine_ls_hydrogen_treatment    constr
_refine_ls_matrix_type           full
_refine_ls_number_parameters     556
_refine_ls_number_reflns         6761
_refine_ls_number_restraints     231
_refine_ls_restrained_S_all      1.021
_refine_ls_R_factor_all          0.0507
_refine_ls_R_factor_gt           0.0443
_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^)+(0.0874P)^2^+0.0831P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.1177
_refine_ls_wR_factor_ref         0.1243
_reflns_Friedel_coverage         0.857
_reflns_Friedel_fraction_full    0.902
_reflns_Friedel_fraction_max     0.786
_reflns_number_gt                6060
_reflns_number_total             6761
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            d3cc02188b2.cif
_cod_data_source_block           TMP_LLA_b
_cod_depositor_comments
'Adding full bibliography for 7131709--7131712.cif.'
_cod_database_code               7131712
_shelx_shelxl_version_number     2018/3
_chemical_oxdiff_formula         'C H O N'
_chemical_oxdiff_usercomment     TMP+LLA2
_shelx_estimated_absorpt_t_max   0.947
_shelx_estimated_absorpt_t_min   0.880
_olex2_refinement_description
;
1. Twinned data refinement
 Scales: 1.1(2)
 -0.1(2)
2. Fixed Uiso
 At 1.2 times of:
  All C(H) groups, All C(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
3. Uiso/Uaniso restraints and constraints
O10B \\sim O12A \\sim O10A \\sim C33A \\sim C34A \\sim C32A \\sim O11B \\sim
O12B \\sim C33B \\sim C32B \\sim C34B: within 2A with sigma of 0.01 and sigma
for terminal atoms of 0.02 within 2A
O10B \\sim O12A \\sim O10A \\sim C33A \\sim C34A \\sim C32A \\sim O11B \\sim
O12B \\sim C33B \\sim C32B \\sim C34B \\sim O11A: within 2A with sigma of 0.01
and sigma for terminal atoms of 0.02 within 2A
4. Rigid body (RIGU) restrains
 O10B, O12A, O10A, C33A, C34A, C32A, O11B, O12B, C33B, C32B, C34B
 with sigma for 1-2 distances of 0.004 and sigma for 1-3 distances of 0.004
 O10B, O12A, O10A, C33A, C34A, C32A, O11B, O12B, C33B, C32B, C34B, O11A
 with sigma for 1-2 distances of 0.004 and sigma for 1-3 distances of 0.004
5. Others
 Sof(O10B)=Sof(O11B)=Sof(O12B)=Sof(H12B)=Sof(C33B)=Sof(H33B)=Sof(C32B)=
 Sof(C34B)=Sof(H34A)=Sof(H34B)=Sof(H34C)=1-FVAR(1)
 Sof(O12A)=Sof(H12A)=Sof(O10A)=Sof(C33A)=Sof(H33A)=Sof(C34A)=Sof(H34D)=
 Sof(H34E)=Sof(H34F)=Sof(C32A)=Sof(O11A)=FVAR(1)
6.a Rotating group:
 N8(H8A,H8B)
6.b Ternary CH refined with riding coordinates:
 C30(H30), C33A(H33A), C33B(H33B)
6.c Secondary CH2 refined with riding coordinates:
 C24(H24A,H24B), C10(H10A,H10B)
6.d Aromatic/amide H refined with riding coordinates:
 N5(H5), C18(H18), N1(H1), C20(H20), C28(H28), C14(H14), C4(H4), C2(H2)
6.e X=CH2 refined with riding coordinates:
 N6(H6A,H6B), N4(H4A,H4B), N2(H2A,H2B)
6.f Idealised Me refined as rotating group:
 C23(H23A,H23B,H23C), C21(H21A,H21B,H21C), C7(H7A,H7B,H7C), C9(H9A,H9B,H9C),
 C8(H8C,H8D,H8E), C31(H31A,H31B,H31C), C22(H22A,H22B,H22C), C34A(H34D,H34E,
 H34F), C34B(H34A,H34B,H34C)
6.g Idealised tetrahedral OH refined as rotating group:
 O9(H9), O12A(H12A), O12B(H12B)
;
_shelx_res_checksum              3771
_shelx_hkl_checksum              52932
_olex2_exptl_crystal_mounting_method 'Crystal was mounted on a 20 um nylon loop'
_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
- Detector area scaling
;
_oxdiff_exptl_absorpt_empirical_full_max 2.742
_oxdiff_exptl_absorpt_empirical_full_min 0.495