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CSLogWS

...Dataset  and pH Solubility Profiles

CSLogWS Compound Profile

General Compound Profile Information for the CSLogWS Training Set:


Since the type of substituents and major structural elements (e.g., a N-heterocyclic ring) in a compound determine its intrinsic solubility, the following table gives a breakdown of such groups contained within the WS dataset. Also given are the average FW (formula weight in g/mol) and the percentage of drug-like compounds, based on the permeability matrix from Lipinski's "rule of fives".


(see CSpKa Dataset Profile for an explanation of the Rule of Fives)


Analysis of various ring types in compounds within the training set gave the following: 47% were aromatic, 36% contained a fused ring system (i.e., arom-arom, arom-saturated), 28% contained N, and 8% had a phenolic ring.


The primary substituent groups were amides and amines, followed by halogens and hydroxyl groups.


Twenty percent of all compounds were straight and branched hydrocarbons plus substituents with aliphatic ring systems.


Date sources for intrinsic water solubilities came from PHYPROP (Syracuse Research Corp (www.syrres.com), Aquasol (www.pharmacy.arizona.edu/outreach/aquasol), and journal publications.


Temperature end-points in the WS dataset were 25°C ± 5°C with 85% at 25°C.  The small temperature spread of 5°C was found to have little effect (<1%) on the difference in MAE values.

CSLogWS  Solubility - pH Profiles

Intrinsic aqueous solubility (WSo) is a measure of the solubility of a neutral compound in an aqueous environment.  The solubility pH-profile gives the solubility as function of pH, which reflects either an increase or decrease in solubility as a function of the fractional ionization of acidic or basic groups at various pH values.


CSLogWS simulated solubility-pH profile is based on predicted pKas.  However, this leads to unrealistically high solubility values in light of ion-pairing leading to salt precipitation.  CSLogWS employs cut-off points as a “rule of thumb“ for ion-pairing (salt formation) for acids and bases (1) in 0.15M NaCl( or KCl).


The solubility pH-profiles for two drugs, Ibuprofen and Desipramine, are given below, showing two different profiles.

Ibuprofen pH Solubility Profile

Ibuprofen, as shown below, is a monoprotic acid with logWSo(exp) = - 3.42 mol/l.  CSLogWS computed LogWS = - 3.3 with pKa = 4.4.  Its pH-solubility plot describes its behavior with pH, predicting a minimum solubility of 78 ug/ml to 291 mg/ml just prior to salt precipitation (see CSLogWS Introduction).  With ion-pairing resulting in salt precipitation, a constant equilibrium solubility is established via the carboxylate group pairing with positive counter ion ( e.g. RCO2- + Na+ = RCO2- : Na+ ) to form a solid in equilibrium with the dissolved acid.

Lomefloxacin pH Solubility Profile

Lomefloxacin

LogWSo = -2.53 (Mol/L)

Lomefloxacin is an ampholyte with pKa1, pKa2, and pKa3 calculated at 3.6, 5.7,and 8.5 respectively within CSLogWS.  Itís predicted intrinsic solubility is -3.08 via CSLogWS in good agreement with the measured value of -2.53. At higher pH values (i.e., > 6), it exits as a zwitterion, which accounts for the flatting of the pH-profile in the pH range between 6 to 8. Solubility start to increase rapidly at higher pH values as the amine group (pKa3) becomes fully deprotonated, leaving the carboxylate group as the only ionized center.

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