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_1574450
_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, C6 H6 N2 O, C H4 O'
_chemical_formula_sum            'C14 H16 N2 O6'
_chemical_formula_weight         308.29
_chemical_name_systematic        'nicotinamide_2,4-dihydroxybenzoic acid_MeOH'
_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.cc2kmbj2
_audit_creation_date             2024-07-16
_audit_creation_method
;
Olex2 1.5
(compiled 2024.02.16 svn.r378c4104 for OlexSys, GUI svn.r6928)
;
_audit_update_record
;
2024-07-18 deposited with the CCDC.	2025-04-22 downloaded from the CCDC.
;
_cell_angle_alpha                77.229(2)
_cell_angle_beta                 80.117(2)
_cell_angle_gamma                65.746(3)
_cell_formula_units_Z            2
_cell_length_a                   7.2390(2)
_cell_length_b                   7.5083(2)
_cell_length_c                   15.0443(4)
_cell_measurement_reflns_used    8009
_cell_measurement_temperature    149.99(10)
_cell_measurement_theta_max      76.3250
_cell_measurement_theta_min      3.0000
_cell_volume                     724.07(4)
_computing_cell_refinement       'CrysAlisPro 1.171.42.90a (Rigaku OD, 2023)'
_computing_data_collection       'CrysAlisPro 1.171.42.90a (Rigaku OD, 2023)'
_computing_data_reduction        'CrysAlisPro 1.171.42.90a (Rigaku OD, 2023)'
_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      149.99(10)
_diffrn_detector                 'Hybrid Pixel Array Detector'
_diffrn_detector_area_resol_mean 10.0000
_diffrn_detector_type            'HyPix-Arc 100'
_diffrn_measured_fraction_theta_full 0.993
_diffrn_measured_fraction_theta_max 0.939
_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     52.00  77.00   0.50    0.13    --   44.69-140.00-113.00   50
  2  \w     77.00 102.00   0.50    0.13    --  100.88-140.00-113.00   50
  3  \w     53.00  78.00   0.50    0.13    --  109.87-140.00-113.00   50
  4  \w     68.00  93.00   0.50    0.13    --  109.87 -95.00-150.00   50
  5  \w     35.00  97.00   0.50    0.13    --  109.87-125.00 -30.00  124
  6  \w     30.00  93.00   0.50    0.13    --  100.88 -95.00-120.00  126
  7  \w     68.00  93.00   0.50    0.13    --  109.87 -95.00 -30.00   50
  8  \w     68.00  93.00   0.50    0.13    --  109.87 -95.00   0.00   50
  9  \w     59.00  92.00   0.50    0.13    --  109.87 -95.00  30.00   66
 10  \w     64.00  93.00   0.50    0.13    --  109.87 -95.00  60.00   58
 11  \w     58.00  85.00   0.50    0.13    --  109.87-131.00  60.00   54
 12  \w     38.00  92.00   0.50    0.13    --  109.87 -95.00 150.00  108
 13  \w     58.00  85.00   0.50    0.13    --   44.69-131.00  60.00   54
 14  \w     52.00  93.00   0.50    0.13    --  109.87 -95.00-180.00   82
 15  \w     26.00  55.00   0.50    0.13    --  100.88 -61.00 -60.00   58
 16  \w     25.00  50.00   0.50    0.13    --  100.88 -61.00-120.00   50
 17  \w     37.00  63.00   0.50    0.13    --  100.88 -77.00  60.00   52
 18  \w     42.00  68.00   0.50    0.13    --  109.87 -77.00  90.00   52
 19  \w    104.00 130.00   0.50    0.13    --  109.87  30.00  90.00   52
 20  \w    141.00 170.00   0.50    0.13    --  100.88  77.00 120.00   58
 21  \w    129.00 166.00   0.50    0.13    --  100.88  77.00   0.00   74
 22  \w    109.00 168.00   0.50    0.13    --  109.87  61.00-120.00  118
 23  \w    121.00 176.00   0.50    0.13    --  100.88  61.00 -60.00  110
 24  \w    130.00 159.00   0.50    0.13    --  109.87  30.00   0.00   58
 25  \w     94.00 119.00   0.50    0.13    --  109.87  30.00   0.00   50
 26  \w    138.00 169.00   0.50    0.13    --  109.87  30.00  90.00   62
 27  \w    116.00 160.00   0.50    0.13    --  100.88 131.00 131.00   88
 28  \w    123.00 175.00   0.50    0.13    --  100.88 125.00-120.00  104
 29  \w    -16.00  14.00   0.50    0.13    --   44.69 -38.00  90.00   60
 30  \w    -33.00  14.00   0.50    0.13    --   44.69 -38.00  60.00   94
 31  \w     -4.00  36.00   0.50    0.13    --  -43.56  38.00 -30.00   80
 32  \w    -12.00  35.00   0.50    0.13    --  -43.56  38.00 -90.00   94
 33  \w     -6.00  20.00   0.50    0.13    --  -43.56  38.00-120.00   52
 34  \w    -14.00  35.00   0.50    0.13    --  -43.56  38.00-150.00   98
 35  \w    -71.00 -25.00   0.50    0.13    --  -43.56 140.00 -54.00   92
 36  \w    -63.00 -37.00   0.50    0.13    --  -88.13 140.00 -54.00   52
 37  \w    -57.00 -18.00   0.50    0.13    --  -43.56 131.00 131.00   78
 38  \w    -76.00 -45.00   0.50    0.13    --  -88.13 131.00 131.00   62
 39  \w    -44.00 -12.00   0.50    0.13    --  -88.13  61.00  60.00   64
 40  \w    -43.00 -12.00   0.50    0.13    --  -88.13  61.00 -30.00   62
 41  \w    -43.00 -17.00   0.50    0.13    --  -88.13  61.00 -60.00   52
 42  \w   -123.00 -69.00   0.50    0.13    --  -43.56 -38.00-120.00  108
 43  \w   -151.00 -86.00   0.50    0.13    --  -88.13 -30.00   0.00  130
 44  \w   -118.00 -41.00   0.50    0.13    --  -88.13 -15.00  60.00  154
 45  \w   -157.00-104.00   0.50    0.13    --  -88.13 -77.00  90.00  106
 46  \w   -142.00-117.00   0.50    0.13    --  -88.13-131.00  60.00   50
 47  \w      4.00  30.00   0.50    0.13    --   44.81 -57.00 -90.00   52
 48  \w      0.00  25.00   0.50    0.13    --   18.00  73.00 -73.56   50
 49  \w     -4.00  21.00   0.50    0.13    --   18.00  74.00  88.83   50
 50  \w     -5.00  20.00   0.50    0.13    --   18.00  76.00  43.15   50
 51  \w      6.00  32.00   0.50    0.13    --   22.00  68.00 110.42   52
 52  \w    -56.00 -30.00   0.50    0.13    --  -42.00 -51.00 -75.74   52
 53  \w   -117.00 -91.00   0.50    0.13    --  -42.00 -50.00 -46.39   52
 54  \w    -56.00 -30.00   0.50    0.13    --  -42.00 -50.00 -46.39   52
 55  \w    -54.00 -29.00   0.50    0.13    --  -43.81 -50.00 -25.84   50
 56  \w    -56.00 -30.00   0.50    0.13    --  -43.81 -52.00  81.61   52
 57  \w     28.00  53.00   0.50    0.13    --   44.81  61.00-126.55   50
 58  \w     28.00  53.00   0.50    0.13    --   44.81  61.00 -29.65   50
 59  \w     28.00  53.00   0.50    0.13    --   44.81  60.00-148.89   50
 60  \w     28.00  53.00   0.50    0.13    --   44.81  61.00 124.35   50
 61  \w    -59.00 -32.00   0.50    0.13    --  -46.00 -47.00 126.60   54
 62  \w    -62.00 -36.00   0.50    0.13    --  -50.00 -52.00-135.33   52
 63  \w    -68.00 -42.00   0.50    0.13    --  -54.00 -50.00  24.77   52
 64  \w    -74.00 -41.00   0.50    0.13    --  -54.00 -51.00  79.34   66
 65  \w    -70.00 -44.00   0.50    0.13    --  -58.00 -49.00 -66.48   52
 66  \w    -69.00 -44.00   0.50    0.13    --  -58.00 -48.00 -45.39   50
 67  \w    -93.00 -48.00   0.50    0.13    --  -62.00 -51.00-145.81   90
 68  \w   -140.00-114.00   0.50    0.13    --  -62.00 -51.00-145.81   52
 69  \w    -77.00 -52.00   0.50    0.13    --  -66.00 -52.00 128.32   50
 70  \w    -79.00 -52.00   0.50    0.13    --  -66.00 -52.00 169.49   54
 71  \w    -77.00 -51.00   0.50    0.13    --  -66.00 -52.00 -65.84   52
 72  \w    -77.00 -51.00   0.50    0.13    --  -66.00 -52.00-105.49   52
 73  \w    -79.00 -53.00   0.50    0.13    --  -66.00 -52.00   1.35   52
 74  \w   -133.00-107.00   0.50    0.13    --  -66.00 -52.00-105.49   52
 75  \w    -80.00 -53.00   0.50    0.13    --  -66.00 -51.00  64.94   54
 76  \w   -149.00-124.00   0.50    0.13    --  -74.00 -51.00-167.39   50
 77  \w    -94.00 -60.00   0.50    0.13    --  -74.00 -50.00 -73.66   68
 78  \w    -87.00 -61.00   0.50    0.13    --  -74.00 -48.00  26.16   52
 79  \w    -88.00 -62.00   0.50    0.13    --  -74.00 -51.00-117.59   52
 80  \w    -86.00 -60.00   0.50    0.13    --  -74.00 -52.00  96.16   52
 81  \w   -106.00 -60.00   0.50    0.13    --  -74.00 -51.00-167.39   92
 82  \w    -91.00 -65.00   0.50    0.13    --  -78.00 -45.00 147.61   52
 83  \w    -95.00 -70.00   0.50    0.13    --  -82.00 -50.00-153.04   50
 84  \w    -95.00 -69.00   0.50    0.13    --  -82.00 -51.00  62.07   52
 85  \w    -98.00 -72.00   0.50    0.13    --  -86.00 -48.00 119.50   52
 86  \w    -99.00 -73.00   0.50    0.13    --  -86.00 -52.00-101.92   52
 87  \w   -102.00 -76.00   0.50    0.13    --  -90.00 -49.00  -0.53   52
 88  \w   -103.00 -76.00   0.50    0.13    --  -90.00 -51.00  25.61   54
 89  \w   -102.00 -76.00   0.50    0.13    --  -90.00 -49.00  -9.74   52
 90  \w   -158.00-132.00   0.50    0.13    --  -90.00 -49.00  -9.74   52
 91  \w   -111.00 -82.00   0.50    0.13    --  -94.50 -48.00-122.74   58
 92  \w   -171.00-126.00   0.50    0.13    --  -94.50 -48.00-122.74   90
 93  \w   -138.00 -84.00   0.50    0.13    --  -94.50 -55.00 -72.60  108
 94  \w   -171.00-141.00   0.50    0.13    --  -94.50 -55.00 -72.60   60
 95  \w   -123.00 -85.00   0.50    0.13    --  -94.50 -58.00-178.19   76
 96  \w   -107.00 -81.00   0.50    0.13    --  -94.50 -46.00 -33.95   52
 97  \w   -166.00-128.00   0.50    0.13    --  -94.50 -46.00 -33.95   76
 98  \w   -110.00 -84.00   0.50    0.13    --  -94.50 -57.00  64.35   52
 99  \w   -109.00 -83.00   0.50    0.13    --  -94.50 -56.00 -47.99   52
100  \w   -109.00 -84.00   0.50    0.13    --  -94.50 -59.00 -27.12   50
101  \w   -117.00 -80.00   0.50    0.13    --  -94.50 -52.00 152.01   74
102  \w   -113.00 -84.00   0.50    0.13    --  -94.50 -59.00  97.48   58
103  \w   -150.00-123.00   0.50    0.13    --  -94.50 -52.00 152.01   54
104  \w   -110.00 -85.00   0.50    0.13    --  -94.50 -57.00-160.76   50
105  \w   -103.00 -78.00   0.50    0.13    --  -94.50 -36.00-174.79   50
106  \w   -158.00-131.00   0.50    0.13    --  -94.50 -36.00-174.79   54
107  \w   -110.00 -84.00   0.50    0.13    --  -94.50 -59.00 129.36   52
108  \w   -110.00 -85.00   0.50    0.13    --  -94.50 -55.00 110.24   50
109  \w    -77.00 -52.00   0.50    0.13    --  -43.81 140.00 -54.00   50
;
_diffrn_measurement_device       'four-circle diffractometer'
_diffrn_measurement_device_type  'XtaLAB Synergy, Dualflex, HyPix-Arc 100'
_diffrn_measurement_method       '\w scans'
_diffrn_orient_matrix_type
'CrysAlisPro convention (1999,Acta A55,543-557)'
_diffrn_orient_matrix_UB_11      0.0718643000
_diffrn_orient_matrix_UB_12      0.1711308000
_diffrn_orient_matrix_UB_13      -0.0112071000
_diffrn_orient_matrix_UB_21      -0.0060944000
_diffrn_orient_matrix_UB_22      -0.0253110000
_diffrn_orient_matrix_UB_23      0.1047764000
_diffrn_orient_matrix_UB_31      0.2230138000
_diffrn_orient_matrix_UB_32      -0.1489353000
_diffrn_orient_matrix_UB_33      -0.0035986000
_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  0.0267
_diffrn_reflns_av_unetI/netI     0.0189
_diffrn_reflns_Laue_measured_fraction_full 0.993
_diffrn_reflns_Laue_measured_fraction_max 0.939
_diffrn_reflns_limit_h_max       9
_diffrn_reflns_limit_h_min       -8
_diffrn_reflns_limit_k_max       9
_diffrn_reflns_limit_k_min       -9
_diffrn_reflns_limit_l_max       18
_diffrn_reflns_limit_l_min       -18
_diffrn_reflns_number            14600
_diffrn_reflns_point_group_measured_fraction_full 0.993
_diffrn_reflns_point_group_measured_fraction_max 0.939
_diffrn_reflns_theta_full        67.684
_diffrn_reflns_theta_max         76.404
_diffrn_reflns_theta_min         3.024
_diffrn_source                   'micro-focus sealed X-ray tube'
_diffrn_source_target            Cu
_diffrn_source_type              'PhotonJet (Cu) X-ray Source'
_exptl_absorpt_coefficient_mu    0.950
_exptl_absorpt_correction_T_max  1.00000
_exptl_absorpt_correction_T_min  0.79617
_exptl_absorpt_correction_type   multi-scan
_exptl_absorpt_process_details
;
CrysAlisPro 1.171.42.90a (Rigaku Oxford Diffraction, 2023)
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    1.414
_exptl_crystal_description       block
_exptl_crystal_F_000             324
_exptl_crystal_preparation
;
Crystallised from a saturated solution of nicotinamide 
and 2,4-dihydroxybenzoic acid (1:1) in MeOH.
;
_exptl_crystal_recrystallization_method
'High-throughput screening via the ENaCt protocol using SPT Labtech mosquito.'
_exptl_crystal_size_max          0.21
_exptl_crystal_size_mid          0.12
_exptl_crystal_size_min          0.023
_refine_diff_density_max         0.334
_refine_diff_density_min         -0.275
_refine_diff_density_rms         0.047
_refine_ls_extinction_method     none
_refine_ls_goodness_of_fit_ref   1.045
_refine_ls_hydrogen_treatment    mixed
_refine_ls_matrix_type           full
_refine_ls_number_parameters     218
_refine_ls_number_reflns         2852
_refine_ls_number_restraints     141
_refine_ls_restrained_S_all      1.019
_refine_ls_R_factor_all          0.0429
_refine_ls_R_factor_gt           0.0393
_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^)+(0.0605P)^2^+0.2974P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.1112
_refine_ls_wR_factor_ref         0.1139
_reflns_Friedel_coverage         0.000
_reflns_number_gt                2551
_reflns_number_total             2852
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            d4sc07556k2.cif
_cod_data_source_block           nicotinamide_24-dihydroxybenzoic_acid_meoh
_cod_depositor_comments
'Adding full bibliography for 1574434--1574463.cif.'
_cod_database_code               1574450
_shelx_shelxl_version_number     2018/3
_chemical_oxdiff_formula         'C H N O'
_shelx_estimated_absorpt_t_max   0.978
_shelx_estimated_absorpt_t_min   0.825
_olex2_refinement_description
;
1. Fixed Uiso
 At 1.2 times of:
  All C(H) groups, All N(H,H) groups, All O(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:
 C2A(H2A), C6B(H6B), C5A(H5A), C3A(H3A), C3B(H3B), C5B(H5B), C4A(H4A)
3.b Idealised Me refined as rotating group:
 C1S(H1SA,H1SB,H1SC)
;
_shelx_res_checksum              75581
_shelx_hkl_checksum              66775
_olex2_exptl_crystal_mounting_method
;
Crystal mounted using inert oil from the encapsulation 
crystallisation technique onto a MiTeGen Kapton 
micromount.
;
_olex2_submission_original_sample_id
'nicotinamide_2,4-dihydroxybenzoic acid_MeOH'
_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 1.291
_oxdiff_exptl_absorpt_empirical_full_min 0.762