Synthesis, Characterization and structure-activity relationship of a novel pregabalin cocrystals with sustained-release performance
Ren, Jiaxuan; Wu, Di; Feng, Yaoguang; Zhang, Man; Yuan, Jiahui; Wang, Na; Wang, Ting; Huang, Xin; Hao, Hongxun; CrystEngComm  (2026) –; doi:10.1039/D6CE00023A

data_7251810
_publ_section_title
;
 Synthesis, characterization and structure--activity relationship of novel
 pregabalin cocrystals with sustained-release performance
;
_journal_issue                   17
_journal_name_full               CrystEngComm
_journal_page_first              2815
_journal_page_last               2834
_journal_paper_doi               10.1039/D6CE00023A
_journal_volume                  28
_journal_year                    2026
_chemical_absolute_configuration ad
_chemical_formula_moiety         'C8 H17 N O2, C8 H8 O2'
_chemical_formula_sum            'C16 H25 N O4'
_chemical_formula_weight         295.37
_chemical_name_systematic        'Pregbalin-p-Methylbenzoic Acid Cocrystal'
_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
_atom_sites_solution_primary     dual
_audit_creation_date             2024-11-23
_audit_creation_method
;
Olex2 1.5
(compiled 2024.02.16 svn.r378c4104 for OlexSys, GUI svn.r6928)
;
_audit_update_record
;
2025-05-21 deposited with the CCDC.	2026-03-13 downloaded from the CCDC.
;
_cell_angle_alpha                90
_cell_angle_beta                 90
_cell_angle_gamma                90
_cell_formula_units_Z            4
_cell_length_a                   6.54204(4)
_cell_length_b                   7.72068(6)
_cell_length_c                   31.8964(2)
_cell_measurement_reflns_used    28975
_cell_measurement_temperature    100.00(10)
_cell_measurement_theta_max      74.1940
_cell_measurement_theta_min      4.1480
_cell_volume                     1611.055(19)
_computing_cell_refinement       'CrysAlisPro 1.171.43.136a (Rigaku OD, 2024)'
_computing_data_collection       'CrysAlisPro 1.171.43.136a (Rigaku OD, 2024)'
_computing_data_reduction        'CrysAlisPro 1.171.43.136a (Rigaku OD, 2024)'
_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  (Sheldrick, 2015)'
_diffrn_ambient_environment      N~2~
_diffrn_ambient_temperature      100.00(10)
_diffrn_detector                 'Hybrid Pixel Array Detector'
_diffrn_detector_area_resol_mean 10.0000
_diffrn_detector_type            'HyPix-Arc 150'
_diffrn_measured_fraction_theta_full 0.995
_diffrn_measured_fraction_theta_max 0.986
_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     53.00  82.00   0.50    0.05    --   79.02  15.00 -30.00   58
  2  \w     88.00 127.00   0.50    0.05    --   79.02  15.00 -30.00   78
  3  \w     85.00 110.00   0.50    0.05    --   66.00  60.00 -22.38   50
  4  \w     98.00 125.00   0.50    0.05    --   79.02  15.00-180.00   54
  5  \w     80.00 127.00   0.50    0.05    --   79.02  15.00  30.00   94
  6  \w     89.00 127.00   0.50    0.05    --   79.02  15.00  90.00   76
  7  \w     79.00 104.00   0.50    0.05    --   62.00  55.00 133.20   50
  8  \w     59.00  86.00   0.50    0.05    --   42.00  54.00 125.90   54
  9  \w     54.00  79.00   0.50    0.05    --   38.00  52.00   5.85   50
 10  \w     58.00  83.00   0.50    0.05    --   42.00  53.00 -98.67   50
 11  \w     57.00  83.00   0.50    0.05    --   38.00  52.00 171.08   52
 12  \w     18.00  64.00   0.50    0.05    --   59.33-108.00  61.00   92
 13  \w     34.00  59.00   0.50    0.05    --   72.67-108.00  61.00   50
 14  \w     52.00 101.00   0.50    0.05    --   79.02-125.00  60.00   98
 15  \w     64.00  93.00   0.50    0.05    --   79.02-108.00  61.00   58
 16  \w     75.00 101.00   0.50    0.05    --   79.02-125.00-120.00   52
 17  \w     69.00 101.00   0.50    0.05    --   79.02-125.00-180.00   64
 18  \w     28.00  95.00   0.50    0.05    --   72.67-125.00 -30.00  134
 19  \w   -119.00 -94.00   0.50    0.05    --  -78.00 -65.00 120.58   50
 20  \w   -127.00-102.00   0.50    0.05    --  -82.00 -56.00 163.37   50
 21  \w   -122.00 -97.00   0.50    0.05    --  -82.00 -61.00 141.89   50
 22  \w   -125.00-100.00   0.50    0.05    --  -82.00 -64.00  63.88   50
 23  \w   -125.00-100.00   0.50    0.05    --  -82.00 -60.00  41.12   50
 24  \w   -127.00 -98.00   0.50    0.05    --  -82.00 -50.00  21.81   58
 25  \w   -125.00 -97.00   0.50    0.05    --  -82.00 -55.00 -84.72   56
 26  \w   -129.00-104.00   0.50    0.05    --  -82.00 -50.00-172.93   50
 27  \w   -128.00-103.00   0.50    0.05    --  -82.00 -51.00-130.28   50
 28  \w   -124.00 -99.00   0.50    0.05    --  -82.00 -49.00 -69.07   50
 29  \w   -130.00-100.00   0.50    0.05    --  -82.00 -43.00 -56.53   60
 30  \w   -122.00 -96.00   0.50    0.05    --  -82.00 -40.00-126.31   52
 31  \w   -127.00-101.00   0.50    0.05    --  -82.00 -47.00 -33.60   52
 32  \w   -130.00-105.00   0.50    0.05    --  -82.00 -44.00  60.78   50
 33  \w   -128.00-102.00   0.50    0.05    --  -82.00 -47.00  83.32   52
 34  \w   -116.00 -91.00   0.50    0.05    --  -67.25 -38.00  61.91   50
 35  \w   -129.00-104.00   0.50    0.05    --  -82.00 -32.00  82.89   50
 36  \w   -132.00 -95.00   0.50    0.05    --  -82.00 -32.00  75.65   74
 37  \w   -109.00 -58.00   0.50    0.05    --  -78.06 -15.00  90.00  102
 38  \w    -68.00 -42.00   0.50    0.05    --  -60.24 -15.00  90.00   52
 39  \w   -119.00 -54.00   0.50    0.05    --  -74.26 -15.00-150.00  130
 40  \w   -126.00 -98.00   0.50    0.05    --  -78.06 -15.00-180.00   56
 41  \w   -115.00 -85.00   0.50    0.05    --  -78.06 -15.00 -30.00   60
 42  \w    -80.00 -55.00   0.50    0.05    --  -82.00  93.00 155.77   50
 43  \w   -101.00 -75.00   0.50    0.05    --  -82.00 131.00 161.53   52
 44  \w    -63.00 -37.00   0.50    0.05    --  -82.00 131.00 161.53   52
 45  \w    -73.00 -36.00   0.50    0.05    --  -82.00 126.00 100.70   74
 46  \w    -62.00 -37.00   0.50    0.05    --  -82.00 131.00 -55.73   50
 47  \w   -100.00 -60.00   0.50    0.05    --  -82.00 129.00-102.09   80
 48  \w    -99.00 -67.00   0.50    0.05    --  -82.00 126.00-122.14   64
 49  \w    -72.00 -44.00   0.50    0.05    --  -78.06 125.00 -90.00   56
 50  \w    -99.00 -73.00   0.50    0.05    --  -82.00 131.00 -55.73   52
 51  \w   -100.00 -74.00   0.50    0.05    --  -78.06 125.00 -90.00   52
 52  \w    -94.00 -44.00   0.50    0.05    --  -82.00 125.00-146.08  100
 53  \w    -70.00 -33.00   0.50    0.05    --  -78.06 125.00-150.00   74
 54  \w    -85.00 -59.00   0.50    0.05    --  -78.06 125.00   0.00   52
 55  \w    -68.00 -39.00   0.50    0.05    --  -82.00 125.00  14.72   58
 56  \w    -94.00 -67.00   0.50    0.05    --  -82.00 126.00  64.20   54
 57  \w   -101.00 -33.00   0.50    0.05    --  -78.06 125.00  60.00  136
 58  \w    -68.00 -34.00   0.50    0.05    --  -78.06 125.00 120.00   68
 59  \w    -71.00 -37.00   0.50    0.05    --  -82.00 125.00  81.81   68
 60  \w    -67.00 -37.00   0.50    0.05    --  -82.00 124.00  30.44   60
 61  \w    -98.00 -73.00   0.50    0.05    --  -82.00 124.00  30.44   50
 62  \w    -99.00 -71.00   0.50    0.05    --  -82.00 125.00 -33.40   56
 63  \w    -64.00 -39.00   0.50    0.05    --  -82.00 125.00 -59.47   50
 64  \w    -95.00 -69.00   0.50    0.05    --  -82.00 117.00-140.69   52
 65  \w    -98.00 -57.00   0.50    0.05    --  -82.00 116.00-154.70   82
 66  \w    -97.00 -52.00   0.50    0.05    --  -82.00 115.00-166.54   90
 67  \w    -93.00 -67.00   0.50    0.05    --  -82.00 113.00 -42.97   52
 68  \w    -73.00 -47.00   0.50    0.05    --  -82.00 123.00 -47.26   52
 69  \w    -92.00 -67.00   0.50    0.05    --  -82.00 109.00 -92.14   50
 70  \w    -76.00 -49.00   0.50    0.05    --  -82.00 109.00  23.42   54
 71  \w    -86.00 -38.00   0.50    0.05    --  -82.00 124.00  41.11   96
 72  \w    -81.00 -44.00   0.50    0.05    --  -82.00 108.00 -16.71   74
 73  \w    -85.00 -60.00   0.50    0.05    --  -82.00 108.00 116.48   50
 74  \w    -65.00 -39.00   0.50    0.05    --  -82.00 124.00 128.62   52
 75  \w    -80.00 -55.00   0.50    0.05    --  -74.26 108.00 158.00   50
 76  \w    -87.00 -62.00   0.50    0.05    --  -78.06 108.00 158.00   50
 77  \w    -53.00 -27.00   0.50    0.05    --  -60.24 108.00 158.00   52
 78  \w    -86.00 -61.00   0.50    0.05    --  -82.00  95.00 -28.70   50
 79  \w    -89.00 -42.00   0.50    0.05    --  -82.00 100.00 -48.89   94
 80  \w    -85.00 -42.00   0.50    0.05    --  -82.00  94.00-166.71   86
;
_diffrn_measurement_device       'four-circle diffractometer'
_diffrn_measurement_device_type  'ROD, Synergy Custom DW system, HyPix-Arc 150'
_diffrn_measurement_method       '\w scans'
_diffrn_orient_matrix_type
'CrysAlisPro convention (1999,Acta A55,543-557)'
_diffrn_orient_matrix_UB_11      -0.0327416000
_diffrn_orient_matrix_UB_12      -0.1863442000
_diffrn_orient_matrix_UB_13      0.0159326000
_diffrn_orient_matrix_UB_21      0.0448582000
_diffrn_orient_matrix_UB_22      -0.0701928000
_diffrn_orient_matrix_UB_23      -0.0442613000
_diffrn_orient_matrix_UB_31      0.2288266000
_diffrn_orient_matrix_UB_32      -0.0129048000
_diffrn_orient_matrix_UB_33      0.0109570000
_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  0.0149
_diffrn_reflns_av_unetI/netI     0.0052
_diffrn_reflns_Laue_measured_fraction_full 0.995
_diffrn_reflns_Laue_measured_fraction_max 0.986
_diffrn_reflns_limit_h_max       7
_diffrn_reflns_limit_h_min       -6
_diffrn_reflns_limit_k_max       9
_diffrn_reflns_limit_k_min       -9
_diffrn_reflns_limit_l_max       38
_diffrn_reflns_limit_l_min       -39
_diffrn_reflns_number            34170
_diffrn_reflns_point_group_measured_fraction_full 0.996
_diffrn_reflns_point_group_measured_fraction_max 0.987
_diffrn_reflns_theta_full        67.684
_diffrn_reflns_theta_max         74.359
_diffrn_reflns_theta_min         5.548
_diffrn_source                   'Rotating-anode X-ray tube'
_diffrn_source_type              'Rigaku (Cu) X-ray Source'
_exptl_absorpt_coefficient_mu    0.706
_exptl_absorpt_correction_T_max  1.00000
_exptl_absorpt_correction_T_min  0.88466
_exptl_absorpt_correction_type   multi-scan
_exptl_absorpt_process_details
'CrysAlisPro 1.171.43.136a (Rigaku Oxford Diffraction, 2024)'
_exptl_crystal_density_diffrn    1.218
_exptl_crystal_description       block
_exptl_crystal_F_000             640
_exptl_crystal_size_max          0.24
_exptl_crystal_size_mid          0.2
_exptl_crystal_size_min          0.14
_refine_diff_density_max         0.177
_refine_diff_density_min         -0.157
_refine_diff_density_rms         0.029
_refine_ls_abs_structure_details
;
 Flack x determined using 1323 quotients [(I+)-(I-)]/[(I+)+(I-)]
 (Parsons, Flack and Wagner, Acta Cryst. B69 (2013) 249-259).
;
_refine_ls_abs_structure_Flack   0.026(17)
_refine_ls_extinction_coef       0.0076(9)
_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   1.078
_refine_ls_hydrogen_treatment    constr
_refine_ls_matrix_type           full
_refine_ls_number_parameters     196
_refine_ls_number_reflns         3232
_refine_ls_number_restraints     0
_refine_ls_restrained_S_all      1.078
_refine_ls_R_factor_all          0.0238
_refine_ls_R_factor_gt           0.0238
_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^)+(0.0341P)^2^+0.2976P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.0630
_refine_ls_wR_factor_ref         0.0631
_reflns_Friedel_coverage         0.697
_reflns_Friedel_fraction_full    0.998
_reflns_Friedel_fraction_max     0.990
_reflns_number_gt                3227
_reflns_number_total             3232
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            d6ce00023a2.cif
_cod_data_source_block           37-cr-20241122d_auto
_cod_depositor_comments
'Adding full bibliography for 7251808--7251810.cif.'
_cod_database_code               7251810
_shelx_shelxl_version_number     2018/3
_shelx_estimated_absorpt_t_max   0.908
_shelx_estimated_absorpt_t_min   0.849
_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, All N(H,H,H) groups, All O(H) groups
2.a Ternary CH refined with riding coordinates:
 C3(H3), C6(H6)
2.b Secondary CH2 refined with riding coordinates:
 C2(H2A,H2B), C4(H4A,H4B), C5(H5A,H5B)
2.c Aromatic/amide H refined with riding coordinates:
 C11(H11), C12(H12), C14(H14), C15(H15)
2.d Idealised Me refined as rotating group:
 N1(H1A,H1B,H1C), C7(H7A,H7B,H7C), C8(H8A,H8B,H8C), C16(H16A,H16B,H16C)
2.e Idealised tetrahedral OH refined as rotating group:
 O4(H4)
;
_shelx_res_checksum              47573
_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 1.182
_oxdiff_exptl_absorpt_empirical_full_min 0.824