Predicting the solubility of boc-serine by modifying the Abraham descriptors of boc-glycine


Researchers

Jean-Claude Bradley and Andrew Lang

Objective

To predict the solubility of boc-serine in organic solvents by modifying the Abraham descriptors of boc-glycine.
boc-serine (N-(tert-Butoxycarbonyl)-L-serine)
SMILES: O=C(OC(C)(C)C)N[C@H](C(=O)O)CO
CSID: 89204
boc-glycine (boc-gly)
SMILES: O=C(OC(C)(C)C)NCC(=O)O
CSID: 70660

Background

Comparing the model001 predicted solubility values of boc-serine with the couple of measured values, we see that model001 underestimates the solubility of boc-serine in THF and methanol. This is not surprising and we expect the other solubility predictions for boc-serine to be unreliable. This is because boc-serine is similar to boc-glycine, and boc-glycine is a known outlier for model001. However, we can better predict the solubility of boc-glycine in various organic solvents using Abraham descriptors obtained by regressing the measured solubility of boc-glycine in various organic solvents against Abraham's general solvation model[Abraham09]. Then by using the Abraham descriptors of boc-glycine we can approximate the Abraham descriptors for boc-serine by noting the fragment-wise difference between the two compounds and using Platts' values of the fragments[Platts99].

Abraham descriptors of boc-serine

To change boc-glycine into boc-serine fragment-wise we replace >CH2 (Platts Table2:2) with >CH- (Platts Table2:3) and then add back a >CH2 and an -OH (Platts Table2:26). The changes also affect the A descriptor -OH (Platts Table5:1) and H-bond 10 OCCC=O (Platts Table5:37). The results are as follows (*V is always predicted from structure):

E
S
A
B
V
boc-glycine
0.402
0.825
0.256
0.789
1.343
modifiers
+0.150
+0.283
-0.256
+0.318
*
boc-serine
0.552
1.108
0.000
1.107
1.522

Conclusion

Using the above as Abraham descriptors for boc-serine, we can predict the solubility of boc-serine in over 70 solvents. Comparing the predicted solubility using the modified Platts fragment method and model001, see the table of molar concentrations below, we see that the modified Platts fragment method is more accurate than, the ab initio method, model001; at least for THF and methanol.

THF
methanol
model001
0.313
0.875
mpfm
4.099
4.708
measured
3.113
3.620
References
[Abraham09] Abraham MH, et al. 2009. Prediction of Solubility of Drugs and Other Compounds in Organic Solvents. Journal of Pharmaceutical Sciences. DOI: 10.1002/jps.21922
[Platts99] Platts JA; Butina D; Abraham MH; and Hersey A. Estimation of Molecular Linear Free Energy Relation Descriptors Using a Group Contribution Approach. J. Chem. Inf. Comput. Sci. 1999, 39, 835-845