From this we get that the solubility at pH 9.2 is -0.618 logS. 0000005861 00000 n The predictor can provide quantitative results, giving the solubility in logS, mg/mL or mol/L units. | d� ��sJS���\��t1�_�q�.~�^��\%��LY9+����\Vw��~�y�;�&j�S6����Y*u�k;���Ƀ��. Phenol is a weak acid with a pKa value of 10.02, which means that at pH 6 the molecule will be present in its neutral form, and the equilibrium can be measured only between the solid and the dissolved neutral form. ChemAxon's Solubility Predictor is able to calculate two types of solubility: intrinsic and pH-dependent solubility. My understanding of the difference between intrinsic and equilibrium solubility: Intrinsic solubility is by definition measured at a pH where the substance is uncharged. Our predictor uses a fragment-based method that identifies different structural fragments in the molecule and assigns an intrinsic solubility contribution to them. The predicted pH-dependent logS curve of the HCl salt of ticlopidine shows a good correlation with the experimental curve, meaning that the HH-equation quite accurately describes the pH-dependence of the solubility. The intrinsic solubility is the equilibrium solubility of the free acid or base form of an ionizable compound at a pH where it is fully unionized [6]. ��Q��Gr�^�ʗͦȕ���䃬27. 0000005577 00000 n The two plots below show calculated and experimental pH-logS profiles for different acidic, basic and zwitter-ionic compounds: The Solubility Predictor will be developed further in the future. Equation of Beer's Law Plot (attach graph): Calculate the solubility of salicylic acid at the two pHs: 2. H�\��n�0��3�J(R��R�V�� �d�69䐷����VZ$�g��q��mw��\���v&w�c��e��6�C8�1[����7?�s3f��o�)�w�8du��6x���ݭ����=u!����~o��.�_��o8�8��[�\���G3�5���9�a��x?�,�{Ư�\1���i�.\Ʀ ������V�~�k����7�a�c��IY]`�ba��#��D~o����_�K�)��\����\�Kr �d��X�b��#��{?���������&?����Yѭ�[�u+�[)Y��k �:���ga� V�,p� ܄9e�IO���S�)�x 0000013356 00000 n In our logS Predictor we apply the following cut-off (the following solubility values are all expressed in logS unit): if the predicted logS0 > -2, the applied cut-off will be +2, which means that the pH-dependent logS curve will be "cut off" at logS0 + 2. 0000004479 00000 n pH-Solubility table: displays a table containing the predicted pH-solubility values. (�7si(�u��V�����栢����u_�d Example. 0000008395 00000 n In case only an estimation about how well soluble the compound is needed, the plugin can give a solubility category as a qualitative measure. Fig. The predicted isoelectric point of L-tyrosine is 5.5, which means that we can expect better solubility at pH 9.2 than at pH 5.5. 0000075414 00000 n The most important part of your analysis is going to be your 1st 10% released. Völgyi, G.; Baka, E. et al. Solubility can also be a relevant descriptor for property-based computational screening methods in the drug discovery process. The intrinsic solubility of phenol can be measured at pH 6. The logS Predictor gives -0.98 logS as intrinsic solubility. Sci. The solubility of aniline in an acidic environment will be greater than its intrinsic solubility as the protonation of the compound shifts the equilibrium between the pure liquid aniline and its dissolved form to the right. The predicted logS0 is -3.47, while the experimental logS0 is -4.25. Comput. H�\�ݎ�0��y 0000006485 00000 n 0 = dose/250 mL/solubility), which takes projected human dose into consideration in the Biopharmaceutics Classification System (BCS), is frequently used for clas-sifying a drug substance based on solubility (2, 3). Hou, T. J.; Xia, K.; Zhang, W.; Xu, X. J. ADME Evaluation in Drug Discovery. The following image shows the whole pH-logS curve of the tyrosine with the calculated solubility at pH 9.2. 0.00001 0.0001 0.001 0.01 0.1 012345678 91 0 C B (M) pH Figure 1. 0000012325 00000 n This result also comes from that ticlopidine is a monoprotic base, so the HH-equation works well. 0000019676 00000 n =�"d���5�/������;�C�^{�w�}�Z�/ž�n Prediction of Aqueous Solubility Based on Atom Contribuition Approach. Solubility. 0000010426 00000 n Equilibrium solubility measurement of ionizable drugs - consensus recommendations for improving data quality. %PDF-1.4 %���� 7���M�pS�)ܔn This means that the pH-dependent logS values won't increase above logS0 + 2. if the predicted logS0 < -2, the predicted pH-dependent solubility curve will not be allowed to rise above 0, so the cut-off will be at 0. high: if solubility is > 0.06 mg/ml {primary} About qualitative categories. 0000536121 00000 n endstream endobj 487 0 obj <> endobj 488 0 obj <>stream s) is the dissolution rate of a pure solute, normalized to the solute surface area, and actually decreases with 0000095854 00000 n 524 0 obj <>stream The % distribution of the neutral microspecies: Using these we can easily calculate the (mathjax-inline(\log(1 + \alpha))mathjax-inline) correction: 0000000016 00000 n 0000018141 00000 n 0000005973 00000 n The predicted intrinsic solubility (to which value the pH-dependent logS curve converges) is -1.0. 0000095108 00000 n 0000009651 00000 n The reason the 1st 10% is … If you use 100mg in the intrinsic dissolution device, you care most about the 1st 10%. endstream endobj 489 0 obj <>stream The predicted pH-dependent logS curve of the hydrogen fumarate salt of the diprotic base quetiapine shows good correlation with the experimental curve. The contributions then are summed up to get the intrinsic solubility value. ADMET & DMPK 2(1) (2014) 18-32 Indomethacin solubility doi: 10.5599/admet.2.1.33 19 One difficulty associated with the measurement of the solubility of indomethacin is that the measured solubility can change with over time [2,10,11], suggesting that there is conversion from one form to another. trailer 0000169042 00000 n Zwitterionic molecules are the least soluble around their isoelectric point. 0000096194 00000 n ��� The results are summarised on the following two charts: Tests for pH-logS profile were also run. From the image above we can read that the % distribution of the charged microspecies are (with the charges shown): 23.21 (-1), 0.0 (+1), 11.51 (-1, 1), 21.78 (-1, -1, +1). In equations (1) and (2), X 2 sat is the mole fraction solubility of the solid solute at an absolute temperature T, a is the apparent molar enthalpy of solution, b is the apparent molar entropy of solution, and c’ and c” are constants.. Thermodynamic Solubility: Systems Remaining Phase-stable during Performance of a Solubility Study. Intrinsic solubility means that the drug does not contain any impurities, does not dissociate or associate in the solvent, and does not interact with the concentration of the saturated solution formed. �V��Bg��po{+�d����[ߢtV8+��Jg���Y�tV8+��Jg���S�k��x�9֠�>��e��}�n{M��v>*s��R��N�8�΢pg� ��h In intrinsic dissolution test, known amount of each drug was compressed in the matrix of Wood’s apparatus and subjected to dissolution in each media with agitation of 50 rpm at 37 °C. This unit is the 10-based logarithm of the solubility measured in mol/l unit, that is logS = log (solubility measured in mol/l). Its predicted logS0 is-4.27, while the experimental logS0 -2.84. The intrinsic solubility (usually denoted as logS0) of an ionizable compound is the solubility that can be measured after the equilibrium of solvation between the dissolved and the solid state is reached at a pH where the compound is fully neutral. , of 4 and an intrinsic solubility of 0.1 mM, and these values are inserted into Equation 4, the pH-solubility profile for B can be plotted, see Figure 1.

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