ADME / Tox >> Bioavailability >> Solubility

Avoid being misled by insoluble compounds

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Thanks to modern screening technology, it is now possible to identify more compounds with low aqueous solubility (<10µM) as hits. These compounds often become lead candidates in their drug discovery programs. However, smooth development of these compounds into drugs can often be difficult.

Poorly soluble compounds may precipitate (or "crash out") during serial dilutions in the screening buffer or cell culture medium after aliquots of the compound have been added from a stock solution. This can lead to erroneous and/or irreproducible data, costly setbacks, and false leads. Even when absorbed, compounds with low solubility are almost always highly bound to plasma proteins, leading to slow tissue distribution and can result in drug-drug interactions.

At Eurofins, our research suggests that the target specificity of small organic molecules can diminish as solubility declines, creating a high risk of identifying false leads. With our expertise, we can help you with the frustrations of insoluble compounds by conducting aqueous solubility studies.

Potential complications arising from low aqueous solubility:

  • Compound precipitation during
    • Serial dilutions in buffer
    • Biochemical and cell based assays
  • Reduced target specificity
  • Low bioavailability in animal studies

 

Compound µM Sol Compound µM Sol Compound µM Sol Compound µM Sol
acetaminophen 201.0 desipramine 195.9 hydrocortisone 202.9 progesterone 21.9
acetazolamide 198.1 dexamethasone 179.1 ibuprofen 205.0 propranolol 201.9
ajmaline 201.0 dextromethorphan 197.2 imipramine 180.6 quinidine 198.1
ampicillin 198.5 diclofenac 197.5 ketoconazole 152.3 ranitidine 203.5
atropine 203.3 disopyramide 198.6 lidocaine 188.6 strychnine 203.4
bisoprolol 200.8 estrone 6.2 metoprolol  204.0 sulfaphenazole 199.9
caffeine 197.2 ethacrynic acid  200.2 mexiletine 203.0 sulfisoxazole 201.6
carbamazepine 197.1 flecainide 204.9 mianserin 68.1 terfenadine 152.8
cefotaxime 192.8 flufenamic acid 200.1 nicardipine 7.1 tetracycline 205.1
chloramphenicol 199.0 flunarizine <1 norethindrone 32.9 thalidomide 55.2
chlorpheniramine 192.5 flurbiprofen 199.1 ouabain 203.1 tolbutamide 202.6
chlorpromazine 107.4 fluoxetine 172.4 paclitaxel <1 trifluoperazine 44.7
cimetidine 193.2 furafylline 198.7 phenacetin 202.8 verapamil 199.5
cinnarizine <1 furosemide 200.5 pimozide 2.5 yohimbine 198.4
colchicine 196.4 griseofulvin 66.8 probenecid 197.5    

 

Table 1. Solubilities of various drugs as determined in Eurofins' aqueous solubility (PBS, pH 7.4) assay