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_7251808
_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 H8 O4, 2(C8 H17 N O2)'
_chemical_formula_sum            'C24 H42 N2 O8'
_chemical_formula_weight         486.59
_chemical_name_systematic        'Pregbalin-Vanillic Acid Cocrystal'
_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             2024-11-14
_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                86.3588(16)
_cell_angle_beta                 88.5344(15)
_cell_angle_gamma                88.8594(16)
_cell_formula_units_Z            1
_cell_length_a                   6.90572(12)
_cell_length_b                   7.69426(16)
_cell_length_c                   12.1634(2)
_cell_measurement_reflns_used    14753
_cell_measurement_temperature    100.00(10)
_cell_measurement_theta_max      75.7180
_cell_measurement_theta_min      3.6090
_cell_volume                     644.67(2)
_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    'SHELXS  (Sheldrick, 2008)'
_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 0.993
_diffrn_measured_fraction_theta_max 0.977
_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    -32.00  -7.00   0.50    0.05    --  -63.73  45.00-180.00   50
  2  \w    -32.00  -7.00   0.50    0.05    --  -63.73  45.00 -60.00   50
  3  \w    -53.00 -25.00   0.50    0.05    --  -77.78  61.00 -30.00   56
  4  \w    -32.00  -7.00   0.50    0.05    --  -63.73  45.00-150.00   50
  5  \w    -31.00  -6.00   0.50    0.05    --  -63.73  45.00 150.00   50
  6  \w    -53.00 -27.00   0.50    0.05    --  -77.78  61.00 150.00   52
  7  \w      3.00  29.00   0.50    0.05    --    2.00  71.00 -12.98   52
  8  \w     19.00  44.00   0.50    0.05    --   18.00  64.00 -65.53   50
  9  \w     19.00  44.00   0.50    0.05    --   18.00  64.00-154.68   50
 10  \w      6.00  31.00   0.50    0.05    --    6.00  69.00 -98.31   50
 11  \w     27.00  52.00   0.50    0.05    --   22.00  61.00 -43.57   50
 12  \w     24.00  49.00   0.50    0.05    --   22.00  60.00-119.66   50
 13  \w     28.00  53.00   0.50    0.05    --   26.00  60.00  36.74   50
 14  \w     28.00  53.00   0.50    0.05    --   26.00  60.00  -0.66   50
 15  \w     19.00  44.00   0.50    0.05    --   18.00  65.00  79.13   50
 16  \w     33.00  58.00   0.50    0.05    --   30.00  54.00 109.84   50
 17  \w     19.00  44.00   0.50    0.05    --   18.00  63.00 160.54   50
 18  \w     11.00  36.00   0.50    0.05    --   10.00  66.00 152.77   50
 19  \w     28.00  53.00   0.50    0.05    --   26.00  59.00  67.70   50
 20  \w     37.00  62.00   0.50    0.05    --   34.00  54.00  24.24   50
 21  \w     33.00  58.00   0.50    0.05    --   30.00  54.00 -60.27   50
 22  \w     49.00  74.00   0.50    0.05    --   46.00  54.00 -93.89   50
 23  \w     46.00  71.00   0.50    0.05    --   38.00  53.00-146.58   50
 24  \w     42.00  67.00   0.50    0.05    --   38.00  52.00-163.59   50
 25  \w     34.00  59.00   0.50    0.05    --   30.00  53.00-101.97   50
 26  \w     46.00  71.00   0.50    0.05    --   42.00  52.00-101.82   50
 27  \w     47.00  72.00   0.50    0.05    --   42.00  54.00 -55.53   50
 28  \w     46.00  71.00   0.50    0.05    --   42.00  51.00   2.34   50
 29  \w     50.00  81.00   0.50    0.05    --   46.00  51.00  76.84   62
 30  \w     34.00  68.00   0.50    0.05    --   30.00  53.00 142.21   68
 31  \w    117.00 143.00   0.50    0.05    --   93.51 111.00  90.00   52
 32  \w    107.00 134.00   0.50    0.05    --   93.51 111.00 120.00   54
 33  \w    115.00 142.00   0.50    0.05    --   93.51 111.00  60.00   54
 34  \w    109.00 135.00   0.50    0.05    --   93.51 111.00   0.00   52
 35  \w    108.00 146.00   0.50    0.05    --   93.51 111.00 -60.00   76
 36  \w    112.00 140.00   0.50    0.05    --   93.51 111.00-120.00   56
 37  \w    117.00 145.00   0.50    0.05    --   93.51 111.00-150.00   56
 38  \w    123.00 148.00   0.50    0.05    --   93.51 111.00-180.00   50
 39  \w    120.00 147.00   0.50    0.05    --   93.51 111.00 -90.00   54
 40  \w    116.00 142.00   0.50    0.05    --   93.51  95.00-170.00   52
 41  \w    119.00 144.00   0.50    0.05    --   93.51 111.00 -30.00   50
 42  \w    111.00 136.00   0.50    0.05    --   93.51 111.00  30.00   50
 43  \w    110.00 138.00   0.50    0.05    --   93.51 111.00 150.00   56
 44  \w     97.00 144.00   0.50    0.05    --   93.51  61.00 -60.00   94
 45  \w     99.00 141.00   0.50    0.05    --   93.51  61.00-120.00   84
 46  \w     95.00 147.00   0.50    0.05    --   93.51  61.00   0.00  104
 47  \w     98.00 136.00   0.50    0.05    --   93.51  61.00 -90.00   76
 48  \w     95.00 120.00   0.50    0.05    --   93.51  61.00  60.00   50
 49  \w     98.00 146.00   0.50    0.05    --   93.51  61.00  90.00   96
 50  \w     95.00 142.00   0.50    0.05    --   93.51  61.00 150.00   94
 51  \w     95.00 142.00   0.50    0.05    --   93.51  61.00 120.00   94
 52  \w     95.00 120.00   0.50    0.05    --   93.51  61.00  30.00   50
 53  \w     65.00  90.00   0.50    0.05    --   62.27  45.00 150.00   50
 54  \w     61.00  86.00   0.50    0.05    --   58.13  54.00  58.59   50
 55  \w     65.00  90.00   0.50    0.05    --   62.27  45.00 120.00   50
 56  \w     65.00  90.00   0.50    0.05    --   62.27  45.00 -60.00   50
 57  \w     57.00  82.00   0.50    0.05    --   54.00  45.00 -30.00   50
 58  \w     57.00  82.00   0.50    0.05    --   54.00  45.00   0.00   50
 59  \w     57.00  82.00   0.50    0.05    --   54.00  45.00  30.00   50
 60  \w     95.00 125.00   0.50    0.05    --   93.51  61.00 -30.00   60
 61  \w    101.00 135.00   0.50    0.05    --   93.51  45.00  90.00   68
 62  \w     65.00  90.00   0.50    0.05    --   62.27  45.00 -90.00   50
 63  \w     99.00 135.00   0.50    0.05    --   93.51  45.00-150.00   72
 64  \w    107.00 147.00   0.50    0.05    --   93.51  61.00-180.00   80
 65  \w     98.00 138.00   0.50    0.05    --   93.51  45.00-180.00   80
 66  \w     98.00 137.00   0.50    0.05    --   93.51  45.00-120.00   78
 67  \w     90.00 116.00   0.50    0.05    --   93.51  30.00 -60.00   52
 68  \w    101.00 140.00   0.50    0.05    --   93.51  45.00   0.00   78
 69  \w    117.00 143.00   0.50    0.05    --   93.51  30.00 -60.00   52
 70  \w     99.00 136.00   0.50    0.05    --   93.51  45.00  30.00   74
 71  \w     96.00 140.00   0.50    0.05    --   93.51  45.00  60.00   88
 72  \w    104.00 138.00   0.50    0.05    --   93.51  45.00 120.00   68
 73  \w     49.00  93.00   0.50    0.05    --   93.51-111.00  90.00   88
 74  \w     40.00  65.00   0.50    0.05    --   93.51-111.00 150.00   50
 75  \w     40.00  89.00   0.50    0.05    --   93.51-111.00  60.00   98
 76  \w     40.00  70.00   0.50    0.05    --   93.51-111.00  30.00   60
 77  \w     48.00  93.00   0.50    0.05    --   93.51-111.00   0.00   90
 78  \w     63.00  89.00   0.50    0.05    --   93.51 -95.00  78.00   52
 79  \w     13.00  38.00   0.50    0.05    --   54.00 -95.00  78.00   50
 80  \w     11.00  47.00   0.50    0.05    --   62.27 -95.00  78.00   72
 81  \w     40.00  65.00   0.50    0.05    --   93.51-111.00 -60.00   50
 82  \w     40.00  92.00   0.50    0.05    --   93.51-111.00 -90.00  104
 83  \w     41.00  67.00   0.50    0.05    --   93.51-111.00-120.00   52
 84  \w     45.00  89.00   0.50    0.05    --   93.51 -94.00 -90.00   88
 85  \w     49.00  89.00   0.50    0.05    --   93.51 -94.00 -60.00   80
 86  \w     45.00  91.00   0.50    0.05    --   93.51 -94.00-150.00   92
 87  \w     44.00  92.00   0.50    0.05    --   93.51 -94.00 -30.00   96
 88  \w     51.00  90.00   0.50    0.05    --   93.51 -94.00-180.00   78
 89  \w     46.00  89.00   0.50    0.05    --   93.51 -94.00   0.00   86
 90  \w     50.00  92.00   0.50    0.05    --   93.51 -94.00  90.00   84
 91  \w     45.00  91.00   0.50    0.05    --   93.51 -94.00 120.00   92
 92  \w     45.00  88.00   0.50    0.05    --   93.51 -94.00 150.00   86
 93  \w     18.00  43.00   0.50    0.05    --   62.27 -77.00 -30.00   50
 94  \w     11.00  47.00   0.50    0.05    --   62.27 -61.00-120.00   72
 95  \w    -36.00 -11.00   0.50    0.05    --  -10.00 -71.00  10.13   50
 96  \w   -131.00 -86.00   0.50    0.05    --  -77.78 -61.00  30.00   90
 97  \w   -127.00-101.00   0.50    0.05    --  -77.78 -61.00 120.00   52
 98  \w   -124.00 -86.00   0.50    0.05    --  -77.78 -61.00 -60.00   76
 99  \w   -126.00 -86.00   0.50    0.05    --  -77.78 -61.00 -90.00   80
100  \w   -131.00 -86.00   0.50    0.05    --  -77.78 -61.00-120.00   90
101  \w   -114.00 -88.00   0.50    0.05    --  -77.78 -61.00-180.00   52
102  \w   -131.00 -88.00   0.50    0.05    --  -77.78 -61.00-150.00   86
103  \w   -129.00 -91.00   0.50    0.05    --  -77.78 -61.00 -30.00   76
104  \w   -129.00 -86.00   0.50    0.05    --  -77.78 -61.00 150.00   86
105  \w   -128.00 -86.00   0.50    0.05    --  -77.78 -61.00  90.00   84
106  \w   -122.00 -86.00   0.50    0.05    --  -77.78 -61.00  60.00   72
107  \w    -87.00 -61.00   0.50    0.05    --  -54.67 -45.00  90.00   52
108  \w    -94.00 -68.00   0.50    0.05    --  -63.73 -45.00 150.00   52
109  \w    -88.00 -63.00   0.50    0.05    --  -54.67 -45.00   0.00   50
110  \w    -93.00 -67.00   0.50    0.05    --  -63.73 -45.00  30.00   52
111  \w   -105.00 -80.00   0.50    0.05    --  -77.78 -45.00 -30.00   50
112  \w   -114.00 -89.00   0.50    0.05    --  -77.78 -45.00 -90.00   50
113  \w   -112.00 -86.00   0.50    0.05    --  -77.78 -45.00-180.00   52
114  \w    -83.00 -57.00   0.50    0.05    --  -54.67 -45.00 120.00   52
115  \w    -86.00 -58.00   0.50    0.05    --  -54.67 -45.00  60.00   56
116  \w    -82.00 -57.00   0.50    0.05    --  -54.67 -45.00 -30.00   50
117  \w    -92.00 -66.00   0.50    0.05    --  -63.73 -45.00-180.00   52
118  \w    -27.00  -2.00   0.50    0.05    --  -14.00  90.00 -57.94   50
119  \w    -89.00 -48.00   0.50    0.05    --  -77.78 111.00-120.00   82
120  \w    -92.00 -39.00   0.50    0.05    --  -77.78 111.00 -30.00  106
121  \w    -57.00 -12.00   0.50    0.05    --  -63.73  95.00-170.00   90
122  \w    -83.00 -58.00   0.50    0.05    --  -77.78  95.00-170.00   50
123  \w    -62.00 -37.00   0.50    0.05    --  -54.67  95.00-170.00   50
124  \w    -92.00 -25.00   0.50    0.05    --  -77.78 111.00  60.00  134
125  \w    -97.00 -54.00   0.50    0.05    --  -82.00 115.00 143.73   86
126  \w    -33.00  -7.00   0.50    0.05    --   -6.00 110.00 126.78   52
;
_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      0.1566009000
_diffrn_orient_matrix_UB_12      0.0724887000
_diffrn_orient_matrix_UB_13      -0.0819888000
_diffrn_orient_matrix_UB_21      0.1569757000
_diffrn_orient_matrix_UB_22      -0.0481547000
_diffrn_orient_matrix_UB_23      0.0849726000
_diffrn_orient_matrix_UB_31      0.0255155000
_diffrn_orient_matrix_UB_32      -0.1808074000
_diffrn_orient_matrix_UB_33      -0.0466211000
_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  0.0175
_diffrn_reflns_av_unetI/netI     0.0149
_diffrn_reflns_Laue_measured_fraction_full 0.993
_diffrn_reflns_Laue_measured_fraction_max 0.977
_diffrn_reflns_limit_h_max       8
_diffrn_reflns_limit_h_min       -8
_diffrn_reflns_limit_k_max       8
_diffrn_reflns_limit_k_min       -9
_diffrn_reflns_limit_l_max       15
_diffrn_reflns_limit_l_min       -15
_diffrn_reflns_number            17929
_diffrn_reflns_point_group_measured_fraction_full 0.910
_diffrn_reflns_point_group_measured_fraction_max 0.879
_diffrn_reflns_theta_full        67.684
_diffrn_reflns_theta_max         76.015
_diffrn_reflns_theta_min         3.642
_diffrn_source                   'Rotating-anode X-ray tube'
_diffrn_source_type              'Rigaku (Cu) X-ray Source'
_exptl_absorpt_coefficient_mu    0.770
_exptl_absorpt_correction_T_max  1.00000
_exptl_absorpt_correction_T_min  0.95288
_exptl_absorpt_correction_type   multi-scan
_exptl_absorpt_process_details
'CrysAlisPro 1.171.43.136a (Rigaku Oxford Diffraction, 2024)'
_exptl_crystal_density_diffrn    1.253
_exptl_crystal_description       block
_exptl_crystal_F_000             264
_exptl_crystal_size_max          0.35
_exptl_crystal_size_mid          0.3
_exptl_crystal_size_min          0.24
_refine_diff_density_max         0.159
_refine_diff_density_min         -0.142
_refine_diff_density_rms         0.027
_refine_ls_abs_structure_details
;
 Flack x determined using 2069 quotients [(I+)-(I-)]/[(I+)+(I-)]
 (Parsons, Flack and Wagner, Acta Cryst. B69 (2013) 249-259).
;
_refine_ls_abs_structure_Flack   0.00(4)
_refine_ls_extinction_coef       0.0119(12)
_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   1.050
_refine_ls_hydrogen_treatment    mixed
_refine_ls_matrix_type           full
_refine_ls_number_parameters     345
_refine_ls_number_reflns         4757
_refine_ls_number_restraints     3
_refine_ls_restrained_S_all      1.050
_refine_ls_R_factor_all          0.0223
_refine_ls_R_factor_gt           0.0221
_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^)+(0.0364P)^2^+0.0750P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.0591
_refine_ls_wR_factor_ref         0.0592
_reflns_Friedel_coverage         0.799
_reflns_Friedel_fraction_full    0.827
_reflns_Friedel_fraction_max     0.781
_reflns_number_gt                4695
_reflns_number_total             4757
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            d6ce00023a2.cif
_cod_data_source_block           37-cr-20241114f_auto
_cod_depositor_comments
'Adding full bibliography for 7251808--7251810.cif.'
_cod_database_code               7251808
_shelx_shelxl_version_number     2018/3
_shelx_estimated_absorpt_t_max   0.837
_shelx_estimated_absorpt_t_min   0.774
_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
2.a Ternary CH refined with riding coordinates:
 C2(H2), C4(H4), C10(H10), C12(H12)
2.b Secondary CH2 refined with riding coordinates:
 C1(H1D,H1E), C3(H3A,H3B), C7(H7A,H7B), C9(H9A,H9B), C11(H11A,H11B), C15(H15A,
 H15B)
2.c Aromatic/amide H refined with riding coordinates:
 C19(H19), C20(H20), C23(H23)
2.d Idealised Me refined as rotating group:
 C24(H24A,H24B,H24C), C5(H5A,H5B,H5C), C6(H6A,H6B,H6C), C13(H13A,H13B,H13C),
 C14(H14A,H14B,H14C)
;
_shelx_res_checksum              17156
_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 1.261
_oxdiff_exptl_absorpt_empirical_full_min 0.751