Supplemental Material:
Computational Screening of Drug Solvates
Christoph Loschen[1] and Andreas Klamt*[2]
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Table S1. Computed and experimentally reported solubilities for some drugs in different solvents all which are able to form solvates. Solubilities are given as common logarithm of the mole fraction. A solubility of log10(x),exp=0 means complete solubility in that solvent. The free energy of fusion has been obtained according to: DGfus= DHfus – T DSfus .drug / solvent/solvate / log10(x),exp / log10(x),CRS / Tm[K] / DHfus[kcal/mol] / comment
carbamazepine / THF(1) / -1.97(2) / -1.74 / 463(3) / 6.1(4) / -
carbamazepine / dioxane(5) / -1.65(6) / -1.60 / 463 / 6.1 / -
carbamazepine / DMSO(5) / -1.74(7) / -1.22 / 463 / 6.1 / -
furosemide / acetone(8) / -3.32(9) / -1.92 / 534(9) / 11.6(9) / solid not characterized
furosemide / DMSO(10) / -1.85(11) / 0.0 / 534 / 11.6 / -
indomethacin / ethanol(12) / -2.38(13) / -2.13 / 431(14) / 8.2(14) / -
lamotrigine / DMF(15) / -2.50(16) / -1.14 / 489(17) / 7.7 / DHfus estimated by QSPR
lamotrigine / ethanol(18) / -3.09(19) / -2.43 / 489 / 7.7 / -
lamotrigine / methanol(20) / -3.08(19) / -2.03 / 489 / 7.7 / -
lamotrigine / acetone(18) / -2.91(19) / -2.19 / 489 / 7.7 / -
paracetamol / dioxane(21) / -1.77(22) / -1.22 / 443(9) / 6.6(9) / -
paracetamol / pyridine(23) / -0.54(24) / 0.0 / 443 / 6.6 / -
sulfapyridine / dioxane(25) / -3.47(26) / -2.30 / 464(27) / 8.2(27) / -
tenoxicam / DMF(28) / -2.38(29) / -2.00 / 484(30) / 9.2 / DHfus estimated by QSPR
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Table S2. Drugs used in this work to model their solvate formation ability and number of respective solvates. Last column shows the source of the reported solvates.drug / solvates / source
paracetamol / 6 / (21,31)
axitinib / 45 / (32)
thiophanate ethyl / 6 / (33)
thiophanate methyl / 2 / (34,35)
nevirapine / 12 / (36–38)
sulfamerazine / 5 / (39)
droperidol / 10 / (40)
carbamazepine / 18 / (1,5)
furosemide / 4 / (10)
phenobarbital / 5 / (41)
ritonavir / 2 / (42)
indomethacin / 10 / (12,14,43,44)
sulfapyridine / 3 / (25)
phenylbutazone / 10 / (45,46)
tenoxicam / 10 / (28,47,48)
CL-20 / 9 / (49–53)
HMX / 7 / (54–56)
ethinylestradiol / 10 / (57,58)
olanzapine / 10 / (59)
felodipine / 9 / (60–63)
succinylsulfathiazol / 6 / (64)
lamotrigine / 10 / (20,65–67)
Table S3. Influence of different descriptor sets. Evaluation via Leave-One-Group-Out cross-validation (<AUC(CV)>). Coefficient for Hex not optimized (c=-1/RT) during fitting.
descriptor set / AUC(train) / <AUC(CV)> / <AUC(test)>
Hmix / 0.72 / 0.75(+/-0.18) / 0.71(+/-019)
Gex / 0.70 / 0.71(+/-0.17) / 0.65(+/-0.34)
Hmix, nring,API / 0.76 / 0.75(+/-0.18) / 0.71(+/-0.19)
Hmix, Vcosmo / 0.77 / 0.78(+/-0.11) / 0.78(+/-0.20)
Hmix, nrot,solvent / 0.77 / 0.78(+/-0.14) / 0.77(+/-0.15)
Hmix, ovality / 0.80 / 0.81(+/-0.12) / 0.81(+/-0.18)
Hmix, nring,API, ovality / 0.82 / 0.81(+/-0.12) / 0.81(+/-0.17)
Hmix, nring,API, nrot,solvent, Vcosmo / 0.81 / 0.80(+/-0.12) / 0.79(+/-0.18)
Hmix, nring,API, nring,solvent, ovality / 0.82 / 0.81(+/-0.12) / 0.81(+/-0.17)
Hmix, nring,API, nrot,solvent, ovality / 0.82 / 0.81(+/-0.12) / 0.81(+/-0.18)
Hmix, nring,API, nring,solvent, Vcosmo / 0.82 / 0.81(+/-0.12) / 0.81(+/-0.16)
Hmix, nring,API, nrb,solvent, Vcosmo, ovality / 0.82 / 0.81(+/-0.12) / 0.81(+/-0.17)
Table S4. List of solvate screening results as evaluated with the area under the ROC curve metric (AUC) for each individual drug using the mixing enthalpy (DHmix) and the final model of equation 7. In addition enrichment factors (EF10%) and maximum enrichment (EF,max) for the virtual screening via eq. 7 are given.
compound / AUC(DHmix) / AUC(eq. 7) / EF10%(eq. 7) / EF,max
paracetamol / 0.95 / 0.95 / 4.29 / 9.43
axitinib / 1.00 / 0.98 / 1.02 / 1.02
thiophanate ethyl / 0.58 / 0.50 / 1.67 / 2.00
thiophanate methyl / 0.57 / 0.55 / 1.38 / 1.38
nevirapine / 0.67 / 0.67 / 1.67 / 5.17
sulfamerazine / 0.95 / 0.95 / 8.00 / 12.00
droperidol / 0.45 / 0.78 / 2.00 / 3.00
carbamazepine / 0.80 / 0.90 / 2.44 / 3.56
furosemide / 0.94 / 0.96 / 7.25 / 14.75
phenobarbital / 0.45 / 0.73 / 1.80 / 11.80
ritonavir / 0.49 / 0.92 / 5.00 / 29.50
indomethacin / 0.57 / 0.77 / 0.83 / 5.08
sulfapyridine / 0.89 / 0.94 / 6.67 / 20.00
phenylbutazone / 0.69 / 0.76 / 2.00 / 2.60
tenoxicam / 0.92 / 0.94 / 4.29 / 8.43
CL-20 / 0.74 / 0.70 / 2.56 / 7.00
HMX / 0.87 / 0.93 / 4.29 / 8.71
ethinylestradiol / 0.63 / 0.75 / 0.00 / 3.80
olanzapine / 0.85 / 0.76 / 2.70 / 2.70
felodipine / 0.88 / 0.86 / 3.33 / 6.89
succinylsulfathiazol / 0.56 / 0.65 / 1.67 / 10.00
lamotrigine / 0.79 / 0.83 / 2.73 / 5.64
meana / 0.74 (0.17) / 0.81 (0.13) / - / -
Table S5. Mixing enthalpy, number of ring atoms and ovality descriptors of the whole dataset.
API / compound / CAS / H_MIX / NRing_drug / ovality / p_solvate / solvate
paracetamol / piperazine / 8017-90-1 / -1.44 / 6 / 1.090 / 0.77 / 1
paracetamol / dimethylsulfoxide / 164071-41-4 / -1.40 / 6 / 1.088 / 0.77 / 0
paracetamol / n,n'-dimethylpiperazine / 106-58-1 / -1.30 / 6 / 1.137 / 0.56 / 1
paracetamol / N,N-dimethylacetamide / 127-19-5 / -1.48 / 6 / 1.118 / 0.70 / 0
paracetamol / N-methylpyrrolidone / 26138-58-9 / -1.39 / 6 / 1.121 / 0.66 / 0
paracetamol / morpholine / 110-91-8 / -1.14 / 6 / 1.085 / 0.69 / 1
paracetamol / 4,4'-bipyridine / 37275-48-2 / -1.86 / 6 / 1.170 / 0.66 / 1
paracetamol / N,N-dimethylformamide / 68-12-2 / -1.49 / 6 / 1.102 / 0.75 / 0
paracetamol / 3-picoline / 82005-08-1 / -1.71 / 6 / 1.108 / 0.80 / 0
paracetamol / N-methylmorpholine / 109-02-4 / -0.99 / 6 / 1.108 / 0.54 / 1
paracetamol / pyridine / 152758-95-7 / -1.63 / 6 / 1.074 / 0.86 / 0
paracetamol / 1,2-dimethoxyethane / 173201-80-4 / -0.62 / 6 / 1.169 / 0.20 / 0
paracetamol / dioxane / 28347-88-8 / -0.82 / 6 / 1.081 / 0.58 / 1
paracetamol / tert-butylmethylether / 1634-04-4 / -0.30 / 6 / 1.109 / 0.27 / 0
paracetamol / acetone / 67-64-1 / -0.72 / 6 / 1.087 / 0.52 / 0
paracetamol / cyclopentanone / 120-92-3 / -0.81 / 6 / 1.096 / 0.52 / 0
paracetamol / methylethylketone / 78-93-3 / -0.70 / 6 / 1.113 / 0.41 / 0
paracetamol / ethylether / 60-29-7 / -0.21 / 6 / 1.152 / 0.14 / 0
paracetamol / formicacid / 15907-03-6 / -0.08 / 6 / 1.048 / 0.40 / 0
paracetamol / 2-ethoxyethanol / 110-80-5 / -0.37 / 6 / 1.162 / 0.15 / 0
paracetamol / 2-methoxyethanol / 109-86-4 / -0.39 / 6 / 1.123 / 0.26 / 0
paracetamol / 2-hexanone / 591-78-6 / -0.66 / 6 / 1.181 / 0.18 / 0
paracetamol / methylisobutylketone / 108-10-1 / -0.68 / 6 / 1.150 / 0.27 / 0
paracetamol / ethylacetate / 141-78-6 / -0.59 / 6 / 1.153 / 0.23 / 0
paracetamol / sulfolane / 126-33-0 / -0.39 / 6 / 1.105 / 0.31 / 0
paracetamol / methylacetate / 79-20-9 / -0.48 / 6 / 1.113 / 0.32 / 0
paracetamol / isopropylacetate / 108-21-4 / -0.45 / 6 / 1.161 / 0.17 / 0
paracetamol / formamide / 23296-41-5 / -0.10 / 6 / 1.059 / 0.37 / 0
paracetamol / propylacetate / 109-60-4 / -0.56 / 6 / 1.185 / 0.15 / 0
paracetamol / aceticacid / 157090-22-7 / 0.00 / 6 / 1.080 / 0.26 / 0
paracetamol / isobutylacetate / 110-19-0 / -0.42 / 6 / 1.192 / 0.11 / 0
paracetamol / butylacetate / 123-86-4 / -0.45 / 6 / 1.216 / 0.08 / 0
paracetamol / methanol / 54841-71-3 / -0.17 / 6 / 1.046 / 0.44 / 0
paracetamol / ethanol / 121182-78-3 / -0.05 / 6 / 1.073 / 0.30 / 0
paracetamol / 2-propanol / 8013-70-5 / 0.04 / 6 / 1.091 / 0.21 / 0
paracetamol / ethylformate / 109-94-4 / -0.42 / 6 / 1.115 / 0.29 / 0
paracetamol / acetonitrile / 54841-72-4 / -0.19 / 6 / 1.061 / 0.39 / 0
paracetamol / ethyleneglycol / 37221-95-7 / -0.21 / 6 / 1.081 / 0.33 / 0
paracetamol / 2-butanol / 4221-99-2 / 0.05 / 6 / 1.111 / 0.16 / 0
paracetamol / 1-propanol / 71-23-8 / -0.07 / 6 / 1.101 / 0.22 / 0
paracetamol / water / 14314-42-2 / 0.11 / 6 / 1.020 / 0.43 / 0
paracetamol / 1-butanol / 107569-51-7 / -0.07 / 6 / 1.133 / 0.15 / 0
paracetamol / chloroform / 67-66-3 / 0.13 / 6 / 1.097 / 0.18 / 0
paracetamol / 3-methyl-1-butanol / 123-51-3 / -0.04 / 6 / 1.135 / 0.14 / 0
paracetamol / 1-pentanol / 71-41-0 / -0.08 / 6 / 1.166 / 0.09 / 0
paracetamol / 2-methyl-1-propanol / 68989-27-5 / -0.01 / 6 / 1.106 / 0.19 / 0
paracetamol / dichloromethane / 1605-72-7 / 0.10 / 6 / 1.078 / 0.23 / 0
paracetamol / trans-1,2-dichloroethene / 156-60-5 / 0.17 / 6 / 1.107 / 0.15 / 0
paracetamol / anisole / 100-66-3 / 0.12 / 6 / 1.130 / 0.11 / 0
paracetamol / benzene / 27271-55-2 / 0.26 / 6 / 1.079 / 0.19 / 0
paracetamol / 1,2-dichloroethane / 107-06-2 / 0.19 / 6 / 1.097 / 0.16 / 0
paracetamol / 1,1-dichloroethene / 9002-85-1 / 0.25 / 6 / 1.094 / 0.16 / 0
paracetamol / trichloroethylene / 52037-46-4 / 0.26 / 6 / 1.116 / 0.11 / 0
paracetamol / chlorobenzene / 68411-45-0 / 0.27 / 6 / 1.112 / 0.12 / 0
paracetamol / toluene / 438873 / 0.33 / 6 / 1.113 / 0.11 / 0
paracetamol / nitromethane / 19527-13-0 / 0.14 / 6 / 1.080 / 0.22 / 0
paracetamol / 1,2-dimethylbenzene / 95-47-6 / 0.36 / 6 / 1.125 / 0.09 / 0
paracetamol / 1,1,1-trichloroethane / 74552-83-3 / 0.29 / 6 / 1.104 / 0.13 / 0
paracetamol / cumene / 51609-83-7 / 0.44 / 6 / 1.150 / 0.05 / 0
paracetamol / tetralin / 119-64-2 / 0.42 / 6 / 1.140 / 0.06 / 0
paracetamol / carbontetrachloride / 56-23-5 / 0.42 / 6 / 1.106 / 0.10 / 0
paracetamol / pentane / 109-66-0 / 0.63 / 6 / 1.146 / 0.04 / 0
paracetamol / cyclohexane / 25012-93-5 / 0.60 / 6 / 1.089 / 0.10 / 0
paracetamol / hexane / 92112-69-1 / 0.68 / 6 / 1.179 / 0.02 / 0
paracetamol / methylcyclohexane / 108-87-2 / 0.64 / 6 / 1.113 / 0.07 / 0
paracetamol / heptane / 142-82-5 / 0.73 / 6 / 1.211 / 0.01 / 0
axitinib / 1-Octanol / 220713-26-8 / 0.27 / 21 / 1.261 / 0.11 / 1
axitinib / Isoamylacetate / 123-92-2 / 0.08 / 21 / 1.210 / 0.28 / 1
axitinib / 1,2,3,4-Tetrahydronaphthalene / 119-64-2 / 0.37 / 21 / 1.140 / 0.42 / 1
axitinib / Methylbenzoate / 93-58-3 / 0.06 / 21 / 1.171 / 0.42 / 1
axitinib / Heptane / 142-82-5 / 0.78 / 21 / 1.211 / 0.10 / 0
axitinib / n-Butylacetate / 123-86-4 / 0.04 / 21 / 1.216 / 0.27 / 1
axitinib / 1,2-Dichlorobenzene / 95-50-1 / 0.13 / 21 / 1.129 / 0.56 / 1
axitinib / p-Xylene / 106-42-3 / 0.35 / 21 / 1.146 / 0.40 / 1
axitinib / methylisobutylketone / 108-10-1 / -0.07 / 21 / 1.150 / 0.56 / 1
axitinib / Methylcyclohexane / 108-87-2 / 0.66 / 21 / 1.113 / 0.40 / 1
axitinib / Benzylalcohol / 1336-27-2 / -0.02 / 21 / 1.129 / 0.62 / 1
axitinib / Isopropylacetate / 108-21-4 / 0.04 / 21 / 1.161 / 0.47 / 1
axitinib / Cyclohexanol / 108-93-0 / 0.21 / 21 / 1.105 / 0.62 / 1
axitinib / 3-Methyl-1-butanol / 123-51-3 / 0.16 / 21 / 1.135 / 0.52 / 1
axitinib / Tetramethylenesulfone / 126-33-0 / 0.17 / 21 / 1.105 / 0.63 / 1
axitinib / 1-Pentanol / 71-41-0 / 0.14 / 21 / 1.166 / 0.41 / 1
axitinib / Cyclohexanone / 11119-77-0 / -0.28 / 21 / 1.101 / 0.79 / 1
axitinib / Toluene / 438873 / 0.29 / 21 / 1.113 / 0.56 / 1
axitinib / N-Methylpyrrolidone / 26138-58-9 / -0.73 / 21 / 1.121 / 0.86 / 1
axitinib / 2-Pentanone / 27154-67-2 / -0.10 / 21 / 1.147 / 0.58 / 1
axitinib / Trichloroethene / 52037-46-4 / 0.05 / 21 / 1.116 / 0.64 / 1
axitinib / Ethylacetate / 141-78-6 / -0.07 / 21 / 1.153 / 0.55 / 1
axitinib / Tert-butanol / 75-65-0 / 0.32 / 21 / 1.095 / 0.61 / 1
axitinib / Isobutanol / 68989-27-5 / 0.17 / 21 / 1.106 / 0.63 / 1
axitinib / 1-Butanol / 107569-51-7 / 0.11 / 21 / 1.133 / 0.55 / 1
axitinib / 2-Butanol / 4221-99-2 / 0.29 / 21 / 1.111 / 0.56 / 1
axitinib / methylethylketone / 78-93-3 / -0.11 / 21 / 1.113 / 0.71 / 1
axitinib / Chloroform / 67-66-3 / -0.16 / 21 / 1.097 / 0.77 / 1
axitinib / Dimethoxymethane / 109-87-5 / 0.06 / 21 / 1.109 / 0.66 / 1
axitinib / Pyridine / 152758-95-7 / -0.89 / 21 / 1.074 / 0.94 / 1
axitinib / 1,2-Dichloroethane / 107-06-2 / 0.15 / 21 / 1.097 / 0.67 / 1
axitinib / DMF / 68-12-2 / -0.69 / 21 / 1.102 / 0.89 / 1
axitinib / THF / 77392-70-2 / -0.42 / 21 / 1.078 / 0.88 / 1
axitinib / DMSO / 164071-41-4 / -0.66 / 21 / 1.088 / 0.90 / 1
axitinib / Methylacetate / 79-20-9 / -0.02 / 21 / 1.113 / 0.68 / 1
axitinib / Propionicacid / 68990-37-4 / -0.26 / 21 / 1.103 / 0.79 / 1
axitinib / isopropylalcohol / 8013-70-5 / 0.27 / 21 / 1.091 / 0.65 / 1
axitinib / Acetone / 67-64-1 / -0.13 / 21 / 1.087 / 0.79 / 1
axitinib / Allylalcohol / 107-18-6 / 0.07 / 21 / 1.094 / 0.71 / 1
axitinib / dichloromethane / 1605-72-7 / -0.02 / 21 / 1.078 / 0.79 / 1
axitinib / Aceticacid / 157090-22-7 / -0.24 / 21 / 1.080 / 0.84 / 1
axitinib / Ethanol / 121182-78-3 / 0.09 / 21 / 1.073 / 0.77 / 1
axitinib / Nitromethane / 19527-13-0 / 0.27 / 21 / 1.080 / 0.68 / 1
axitinib / acetonitrile / 54841-72-4 / 0.27 / 21 / 1.061 / 0.75 / 1
axitinib / Methanol / 54841-71-3 / -0.07 / 21 / 1.046 / 0.87 / 1
axitinib / Water / 14314-42-2 / -0.07 / 21 / 1.020 / 0.91 / 1
thiophanate_ethyl / water / 14314-42-2 / 0.17 / 6 / 1.020 / 0.40 / 0
thiophanate_ethyl / toluene / 438873 / 0.26 / 6 / 1.113 / 0.12 / 1
thiophanate_ethyl / methanol / 54841-71-3 / -0.23 / 6 / 1.046 / 0.47 / 0
thiophanate_ethyl / ethanol / 121182-78-3 / -0.14 / 6 / 1.073 / 0.33 / 0
thiophanate_ethyl / 1,2-dichloroethane / 107-06-2 / 0.08 / 6 / 1.097 / 0.19 / 0
thiophanate_ethyl / chloroform / 67-66-3 / 0.01 / 6 / 1.097 / 0.21 / 1
thiophanate_ethyl / dichloromethane / 1605-72-7 / -0.02 / 6 / 1.078 / 0.27 / 1
thiophanate_ethyl / acetonitrile / 54841-72-4 / -0.43 / 6 / 1.061 / 0.50 / 0
thiophanate_ethyl / acetone / 67-64-1 / -1.19 / 6 / 1.087 / 0.70 / 1
thiophanate_ethyl / dioxane / 28347-88-8 / -1.63 / 6 / 1.081 / 0.84 / 1
thiophanate_ethyl / pyridine / 152758-95-7 / -2.23 / 6 / 1.074 / 0.94 / 1
thiophanate_ethyl / dmso / 164071-41-4 / -2.13 / 6 / 1.088 / 0.92 / 0
thiophanate_methyl / water / 14314-42-2 / 0.12 / 6 / 1.020 / 0.42 / 0