High-throughput encapsulated nanodroplet screening for accelerated co-crystal discovery
Metherall, Jessica P.; Corner, Philip A.; McCabe, James F.; Probert, Michael R.; Hall, Michael J.; Chemical Science 16 (2025) 9843–9853; doi:10.1039/D4SC07556K

data_1574443
_publ_section_title
;
 High-throughput encapsulated nanodroplet screening for accelerated
 co-crystal discovery
;
_journal_issue                   22
_journal_name_full               'Chemical Science'
_journal_page_first              9843
_journal_page_last               9853
_journal_paper_doi               10.1039/D4SC07556K
_journal_volume                  16
_journal_year                    2025
_chemical_formula_moiety         'C7 H6 O4, C8 H10 N4 O2, H2 O'
_chemical_formula_sum            'C15 H18 N4 O7'
_chemical_formula_weight         366.33
_chemical_name_systematic        'caffeine_2,4-dihydroxybenzoic acid_H2O'
_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     dual
_audit_block_doi                 10.5517/ccdc.csd.cc2kmbdy
_audit_creation_date             2025-03-31
_audit_creation_method
;
Olex2 1.5
(compiled 2025.03.04 svn.red2d20d0 for OlexSys, GUI svn.r7188)
;
_audit_update_record
;
2025-04-01 deposited with the CCDC.	2025-04-22 downloaded from the CCDC.
;
_cell_angle_alpha                90.289(4)
_cell_angle_beta                 100.961(4)
_cell_angle_gamma                106.499(5)
_cell_formula_units_Z            2
_cell_length_a                   7.1718(4)
_cell_length_b                   8.5853(5)
_cell_length_c                   13.7480(6)
_cell_measurement_reflns_used    1841
_cell_measurement_temperature    150
_cell_measurement_theta_max      70.0910
_cell_measurement_theta_min      3.2540
_cell_volume                     795.26(8)
_computing_cell_refinement       'CrysAlisPro 1.171.42.63a (Rigaku OD, 2022)'
_computing_data_collection       'CrysAlisPro 1.171.42.63a (Rigaku OD, 2022)'
_computing_data_reduction        'CrysAlisPro 1.171.42.63a (Rigaku OD, 2022)'
_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_temperature      150.00
_diffrn_detector                 'Hybrid Pixel Array Detector'
_diffrn_detector_area_resol_mean 10.0000
_diffrn_detector_type            'HyPix-Arc 100'
_diffrn_measured_fraction_theta_full 0.986
_diffrn_measured_fraction_theta_max 0.954
_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     -1.00  24.00   0.50    4.99    --   28.59 -73.00 -45.00   50
  2  \w    -67.00 -26.00   0.50    4.99    --  -30.47  73.00  83.00   82
  3  \w    -16.00  21.00   0.50    4.99    --  -30.47  73.00  83.00   74
  4  \w     20.00  46.00   0.50   19.98    --   68.15 -73.00 -45.00   52
  5  \w   -158.00-133.00   0.50   19.98    --  -68.90 -73.00 -45.00   50
  6  \w     23.00  58.00   0.50   19.98    --   73.41 -73.00 -45.00   70
  7  \w    -61.00 -18.00   0.50   19.98    --  -74.54  73.00  83.00   86
  8  \w   -137.00-112.00   0.50   19.98    --  -74.54 -73.00 -45.00   50
  9  \w   -146.00-105.00   0.50   19.98    --  -99.50 -73.00 -45.00   82
 10  \w    -65.00 -40.00   0.50   19.98    --  -99.50  73.00  83.00   50
 11  \w    127.00 152.00   0.50   19.98    --  110.67  73.00  83.00   50
 12  \w    143.00 169.00   0.50   19.98    --  115.27  73.00  83.00   52
 13  \w     20.00  45.00   0.50   19.98    --  115.27 -73.00 -45.00   50
 14  \w      2.00  52.00   0.50    4.99    --   28.59  57.00 -30.00  100
 15  \w     -9.00  36.00   0.50    4.99    --   28.59  57.00-150.00   90
 16  \w    -70.00 -24.00   0.50    4.99    --   28.59 -19.00 -60.00   92
 17  \w     19.00  48.00   0.50    4.99    --  -30.47  19.00-150.00   58
 18  \w    -27.00   5.00   0.50    4.99    --  -30.47 -57.00-180.00   64
 19  \w     21.00  55.00   0.50    4.99    --  -30.47  19.00 -60.00   68
 20  \w     22.00  47.00   0.50    4.99    --  -30.47  19.00-120.00   50
 21  \w    -21.00   4.00   0.50   19.98    --   68.15 -30.00  30.00   50
 22  \w    -28.00   4.00   0.50   19.98    --   68.15 -30.00-180.00   64
 23  \w    -26.00   6.00   0.50   19.98    --   68.15 -30.00 -30.00   64
 24  \w    -29.00   4.00   0.50   19.98    --   68.15 -30.00 120.00   66
 25  \w     27.00  88.00   0.50   19.98    --   68.15-112.00 150.00  122
 26  \w    114.00 154.00   0.50   19.98    --   68.15  61.00  90.00   80
 27  \w   -162.00-112.00   0.50   19.98    --  -68.90 -95.00 150.00  100
 28  \w    -23.00   5.00   0.50   19.98    --   73.41 -30.00-120.00   56
 29  \w     29.00  86.00   0.50   19.98    --   73.41-112.00 -60.00  114
 30  \w     17.00  72.00   0.50   19.98    --   73.41 -77.00 150.00  110
 31  \w    111.00 148.00   0.50   19.98    --   73.41  61.00-180.00   74
 32  \w    -23.00   3.00   0.50   19.98    --   73.41 -30.00-150.00   52
 33  \w    -25.00   0.00   0.50   19.98    --   73.41 -30.00 -90.00   50
 34  \w    -22.00   3.00   0.50   19.98    --   73.41 -30.00 120.00   50
 35  \w    -24.00   6.00   0.50   19.98    --   73.41 -30.00  60.00   60
 36  \w    -25.00   0.00   0.50   19.98    --   73.41 -30.00-180.00   50
 37  \w    -25.00   5.00   0.50   19.98    --   73.41 -30.00 150.00   60
 38  \w    -25.00   0.00   0.50   19.98    --  -74.54  45.00 150.00   50
 39  \w    -83.00 -46.00   0.50   19.98    --  -99.50 139.00 -60.00   74
 40  \w    -40.00 -14.00   0.50   19.98    --  -99.50  77.00  30.00   52
 41  \w    -65.00 -36.00   0.50   19.98    --  -99.50  77.00 -90.00   58
 42  \w   -154.00-101.00   0.50   19.98    --  -99.50 -92.00  30.00  106
 43  \w    -73.00 -30.00   0.50   19.98    --  -99.50 139.00 150.00   86
 44  \w   -171.00 -69.00   0.50   19.98    --  -99.50 -50.00-120.00  204
 45  \w     57.00  92.00   0.50   19.98    --  110.67-104.00 150.00   70
 46  \w    115.00 166.00   0.50   19.98    --  110.67  64.00-120.00  102
 47  \w     42.00  88.00   0.50   19.98    --  110.67-104.00-120.00   92
 48  \w     25.00  92.00   0.50   19.98    --  110.67-104.00  90.00  134
 49  \w     53.00  89.00   0.50   19.98    --  110.67 -92.00 -60.00   72
 50  \w     23.00  48.00   0.50   19.98    --  110.67 -92.00 -60.00   50
 51  \w    115.00 162.00   0.50   19.98    --  110.67  64.00 120.00   94
 52  \w    126.00 158.00   0.50   19.98    --  110.67  77.00 -90.00   64
 53  \w     47.00  73.00   0.50   19.98    --  110.67 -92.00 120.00   52
 54  \w     66.00  91.00   0.50   19.98    --  110.67-104.00-180.00   50
 55  \w     22.00  90.00   0.50   19.98    --  110.67-104.00  60.00  136
 56  \w     24.00  61.00   0.50   19.98    --  110.67-104.00-180.00   74
 57  \w     18.00  43.00   0.50   19.98    --  110.67 -73.00 -45.00   50
 58  \w     67.00  92.00   0.50   19.98    --  115.27-104.00  30.00   50
 59  \w     67.00  92.00   0.50   19.98    --  115.27-104.00 -60.00   50
 60  \w     25.00  60.00   0.50   19.98    --  115.27-104.00  30.00   70
 61  \w    106.00 151.00   0.50   19.98    --  115.27 139.00-120.00   90
 62  \w     66.00  92.00   0.50   19.98    --  115.27-104.00 -90.00   52
 63  \w     21.00  91.00   0.50   19.98    --  115.27-104.00-150.00  140
 64  \w     21.00  61.00   0.50   19.98    --  115.27-104.00 -90.00   80
 65  \w    137.00 166.00   0.50   19.98    --  115.27  12.00 -90.00   58
 66  \w     65.00 112.00   0.50   19.98    --  115.27  12.00 -90.00   94
 67  \w     33.00  74.00   0.50   19.98    --  115.27 -77.00 -90.00   82
 68  \w     28.00  91.00   0.50   19.98    --  115.27-104.00   0.00  126
 69  \w    124.00 150.00   0.50   19.98    --  115.27  77.00 -30.00   52
 70  \w    125.00 178.00   0.50   19.98    --  115.27  77.00-150.00  106
;
_diffrn_measurement_device       'four-circle diffractometer'
_diffrn_measurement_device_type  'XtaLAB Synergy, Dualflex, HyPix-Arc 100'
_diffrn_measurement_method       '\w scans'
_diffrn_radiation_monochromator  mirror
_diffrn_radiation_probe          x-ray
_diffrn_radiation_type           CuK\a
_diffrn_radiation_wavelength     1.54184
_diffrn_reflns_av_R_equivalents  0.0318
_diffrn_reflns_av_unetI/netI     0.0497
_diffrn_reflns_Laue_measured_fraction_full 0.986
_diffrn_reflns_Laue_measured_fraction_max 0.954
_diffrn_reflns_limit_h_max       6
_diffrn_reflns_limit_h_min       -8
_diffrn_reflns_limit_k_max       10
_diffrn_reflns_limit_k_min       -10
_diffrn_reflns_limit_l_max       16
_diffrn_reflns_limit_l_min       -16
_diffrn_reflns_number            6338
_diffrn_reflns_point_group_measured_fraction_full 0.986
_diffrn_reflns_point_group_measured_fraction_max 0.954
_diffrn_reflns_theta_full        67.684
_diffrn_reflns_theta_max         71.340
_diffrn_reflns_theta_min         3.281
_diffrn_source                   'micro-focus sealed X-ray tube'
_diffrn_source_target            Cu
_diffrn_source_type              'PhotonJet (Cu) X-ray Source'
_exptl_absorpt_coefficient_mu    1.051
_exptl_absorpt_correction_T_max  1.00000
_exptl_absorpt_correction_T_min  0.78851
_exptl_absorpt_correction_type   multi-scan
_exptl_absorpt_process_details
;
CrysAlisPro 1.171.42.63a (Rigaku Oxford Diffraction, 2022)
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    1.530
_exptl_crystal_description       needle
_exptl_crystal_F_000             384
_exptl_crystal_preparation
;
Crystallised from a saturated solution of caffeine
and 2,4-dihydroxybenzoic acid (1:2) in MeOH.
;
_exptl_crystal_recrystallization_method
;
High-throughput screening via the ENaCt co-
crystallisation protocol using SPT Labtech mosquito.
;
_exptl_crystal_size_max          0.17
_exptl_crystal_size_mid          0.012
_exptl_crystal_size_min          0.007
_refine_diff_density_max         0.345
_refine_diff_density_min         -0.233
_refine_diff_density_rms         0.053
_refine_ls_extinction_method     none
_refine_ls_goodness_of_fit_ref   1.050
_refine_ls_hydrogen_treatment    mixed
_refine_ls_matrix_type           full
_refine_ls_number_parameters     253
_refine_ls_number_reflns         2949
_refine_ls_number_restraints     192
_refine_ls_restrained_S_all      1.015
_refine_ls_R_factor_all          0.0620
_refine_ls_R_factor_gt           0.0480
_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^)+(0.0695P)^2^+0.1880P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.1219
_refine_ls_wR_factor_ref         0.1290
_reflns_Friedel_coverage         0.000
_reflns_number_gt                2371
_reflns_number_total             2949
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            d4sc07556k2.cif
_cod_data_source_block           caffeine_24-dihydroxybenzoicacid_h2o
_cod_depositor_comments
'Adding full bibliography for 1574434--1574463.cif.'
_cod_database_code               1574443
_shelx_shelxl_version_number     2018/3
_shelx_estimated_absorpt_t_max   0.993
_shelx_estimated_absorpt_t_min   0.842
_diffrn_oxdiff_digest_hkl
;
01519685a147138f9264b86b41e5da347ee448
;
_olex2_refinement_description
;
1. Fixed Uiso
 At 1.2 times of:
  All C(H) groups, All O(H) groups, All O(H,H) groups
 At 1.5 times of:
  All C(H,H,H) groups
2. Rigid body (RIGU) restrains
 All non-hydrogen atoms
 with sigma for 1-2 distances of 0.004 and sigma for 1-3 distances of 0.004
3.a Aromatic/amide H refined with riding coordinates:
 C3A(H3AA), C5A(H5A), C6A(H6A), C6B(H6B)
3.b Idealised Me refined as rotating group:
 C2B(H2BA,H2BB,H2BC), C5B(H5BA,H5BB,H5BC), C8B(H8BA,H8BB,H8BC)
;
_shelx_res_checksum              34249
_shelx_hkl_checksum              40129
_olex2_exptl_crystal_mounting_method
'Crystal mounted using inert oil from the encapsulation crystallisation technique onto a MiTeGen Kapton micromount.'
_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 1.691
_oxdiff_exptl_absorpt_empirical_full_min 0.403