Relationships between Lipophilicity and Solubility

1 Relationships between Lipophilicity and SolubilityKarl J. Box Physical Chemistry Symposium Nov 29th 2006 Sirius Analytical Instruments Limited/ 342 Copyright Sirius Analytical Instruments Ltd. 2006 LogS vs CLogP-7-6-5-4-3-2-1-1012345 CLogPLogSSolubility versus calculated lipophilicityPresented by James Blake, Array BioPharma Finding Drugs within Chemistry Space / 343 Copyright Sirius Analytical Instruments Ltd. 2006 Log(Intrinsic Solubility ) vs LogPy = - = PLog SMeasured Solubility versus Measured Lipophilicity40 out of 78 compounds within 1 log unit of best fit line = 51%/ 344 Copyright Sirius Analytical Instruments Ltd. 2006 Log(Intrinsic Solubility ) vs LogPy = - = PLog SMeasured Solubility versus Measured Lipophilicity59 out of 78 compounds within log units of best fit line = 76%LogS = - 345 Copyright Sirius Analytical Instruments Ltd.

2 2006 Log(Intrinsic Solubility ) vs LogPy = - = PLog SHigh and Low Solubility RegionsHigh Solubility region for a given lipophilicityWhat often happens ! Poor Solubility region for a given Lipophilicity / 346 Copyright Sirius Analytical Instruments Ltd. 2006 Log(Intrinsic Solubility ) vs LogPy = - = PLog SCompounds in High Solubility RegionPoor Solubility region for a given lipophilicityOHIOHCH3CH3CH34-lodophenolT hymol/ 347 Copyright Sirius Analytical Instruments Ltd. 2006 Log(Intrinsic Solubility ) vs LogP-10-8-6-4-202-20246810 Log PLog SLow Solubility Regiontetracycline and floxacinsfolic acidpiroxicam, flumequine, nitrofurantoin and many sulphonamidesloperamide and terfenadineOONOHOOHOHOHNH2CH3 OHCH3CH3 HNNONHOFOHNNHNNNHOOONH2 NHOOHOH folic acidciprofloxacintetracyclineNNOOHClCH3C H3 SNHNOONNHOONHCH3glipizideloperamide/ 348 Copyright Sirius Analytical Instruments Ltd.

3 2006 Low Solubility Compounds with High Melting Points-10-8-6-4-202-20246810 Log PLog SCompounds with MPts > 200oC/ 349 Copyright Sirius Analytical Instruments Ltd. 2006 All Compounds with High Melting PointsAll Compounds with MPts > 200oC-10-8-6-4-202-20246810 Log PLog S/ 3410 Copyright Sirius Analytical Instruments Ltd. 2006 relationship with Melting PointsCompounds with MPts > 145oC-10-8-6-4-202-20246810 Log PLog S/ 3411 Copyright Sirius Analytical Instruments Ltd. 2006-10-8-6-4-202-20246810 Log PLog SCompounds in High Solubility Region with low Melting PointsOHIOHCH3CH3CH34-lodophenol MPt = 93oCThymol MPt = 51oC/ 3412 Copyright Sirius Analytical Instruments Ltd. 2006 All Compounds with low Melting Points-10-8-6-4-202-20246810 Log PLog SCompounds with MPts < 100oC/ 3413 Copyright Sirius Analytical Instruments Ltd.

4 2006 relationship with Melting PointsCompounds with MPts < 135oC-10-8-6-4-202-20246810 Log PLog SBut what is left? Do compounds shown as have MPts between 135 145oC?Light Blue circles have melting points < 135oCRed circles have melting points > 145oC/ 3414 Copyright Sirius Analytical Instruments Ltd. 20061234 HIGH PERMEABILITYLOW PERMEABILITYHIGH Solubility LOW SOLUBILITYaRATE OF DISSOLUTION limits in vivoabsorptionbSOLUBILITY limits absorption fluxcPERMEABILITY is rate determiningCLASS 1 aCLASS 3 cCLASS 2 bCLASS 4 Amidon, G L. Lennernas, H. Shah, V P. Crison, J R. Pharm. Res. 1995, (12(3)) pp 413-420* *Drug considered HIGHLY SOLUBLE if the highest dose remains in aqueous solution between pH 1 - 8*Drug considered HIGHLY PERMEABLE if human absorption >90%Biopharmaceutics Classification System (BCS)/ 3415 Copyright Sirius Analytical Instruments Ltd.

5 2006 LOW PERMEABILITYHIGH PERMEABILITYHIGH Solubility LOW SOLUBILITYCLASS 1 CLASS 3 CLASS 2 CLASS 4 Biopharmaceutics Classification System (BCS)/ 3416 Copyright Sirius Analytical Instruments Ltd. 2006-10-8-6-4-202-20246810 Log PLog SClass 1 HighSolubility, Highfraction absorbedClass 2 LowSolubility, Highfraction absorbedClass 3 HighSolubility, Lowfraction absorbedClass 4 LowSolubility, Lowfraction absorbedNot known (includes topical anesthetics)LogP vs LogS and the BCS/ 3417 Copyright Sirius Analytical Instruments Ltd. 2006-10-8-6-4-202-20246810 Log PLog S12 Class 1 HighSolubility, Highfraction absorbedClass 2 LowSolubility, Highfraction absorbedClass 3 HighSolubility, Lowfraction absorbedClass 4 LowSolubility, Lowfraction absorbed34?111333222444 LogP vs LogS and the BCS/ 3418 Copyright Sirius Analytical Instruments Ltd.

6 2006-10-8-6-4-202-20246810 Log PLog SClass 1 HighSolubility, Highfraction absorbedClass 2 LowSolubility, Highfraction absorbedClass 3 HighSolubility, Lowfraction absorbedClass 4 LowSolubility, Lowfraction absorbedActive transport or paracellular transportSulfasalazineFa < 20%Marketed drugs. All compounds >20% fraction absorbed except transported and paracellularly transported compounds/ 3419 Copyright Sirius Analytical Instruments Ltd. 2006-10-8-6-4-202-20246810 Log PLog SClass 1 HighSolubility, Highfraction absorbedClass 2 LowSolubility, Highfraction absorbedClass 3 HighSolubility, Lowfraction absorbedClass 4 LowSolubility, Lowfraction absorbedNot known (includes topical anesthetics)Problems with reported literature valuesLoperamidemeasured at Sirius/ 3420 Copyright Sirius Analytical Instruments Ltd.

7 2006 Class 1 HighSolubility, Highfraction absorbedClass 2 LowSolubility, Highfraction absorbedClass 3 HighSolubility, Lowfraction absorbedClass 4 LowSolubility, Lowfraction absorbedNot known (includes topical anesthetics)Problems with reported literature values-10-8-6-4-202-20246810 Log PLog SLoperamide becomes Class 3 three orders of magnitude difference between measured and literature Solubility values/ 3421 Copyright Sirius Analytical Instruments Ltd. 2006 Now let s return to the compounds with missing melting points-10-8-6-4-202-20246810 Log PLog SBut what is left? Do compounds shown as have MPts between 135 145oC?Same slide as slide 13. Red circles have melting points > 145oCLight Blue circles have melting points < 135oC/ 3422 Copyright Sirius Analytical Instruments Ltd. 2006 These compounds cannot form supersaturated solutions.

8 When the pH is right, they fall out of solution immediately the Solubility limit is exceeded. We call these compounds Non-Chasers. The kinetic Solubility and Intrinsic Solubility of non-chasers is equal. The missing compounds can not form supersaturated solutions-10-8-6-4-202-20246810 Log PLog SAll other compounds not marked in green have the ability to form supersaturated solutions. We call these compounds have kinetic solubilitiesgreater than their intrinsic 3423 Copyright Sirius Analytical Instruments Ltd. 2006 Can we predict whether a sample is a non-chaser?NNCH3CH3 ImipramineNon-chaser NCH3CH3 AmitryptylineNon-chaserChlorpromazineNSN ClCH3CH3 Non-chaserNNHCH3 DesipramineNon-chaser NHCH3 NortriptylineNon-chaserNHCH3 MaprotilineChaserSecondary and tertiary amines with logP > 4. SNClCH3CH3 ChlorprothixeneNon-chaser converts to chaserNNCH3CH3CH3 Similar structures, but maprotiline contains a -CH2-CH2- bridge.

9 Non-chaser Trimipramine/ 3424 Copyright Sirius Analytical Instruments Ltd. 2006 Other 3425 Copyright Sirius Analytical Instruments Ltd. 2006 NNOOOOCH3CH3CH3CH3CH3CH3CH3 More 3426 Copyright Sirius Analytical Instruments Ltd. and some chasers TerfenadineNadololLoperamideNOHOHCH3CH3C H3 ONHNH2 ClONCH3CH3CH3 MetoclopramideNHNNClOHCH3CH3 AmodiaquinNNNH2NH2 ClCH3 Pyrimethamine/ 3427 Copyright Sirius Analytical Instruments Ltd. 2006 References chasers and non-chasers First paper, introducing the concept of chasing equilibrium Stuart, M. Box, K. Chasing equilibrium: measuring the intrinsic Solubility of weak acids and bases. Anal. Chem. 2005, 77(4), 983-990 Second paper, collaborative research to validate method and introduce concept of non-chasers Box, K J. V lgyi, G. Baka, E. Stuart, M. Tak cs-Nov k, K. Comer, J E A.

10 Equilibrium vs. kinetic measurements of aqueous Solubility , and the ability of compounds to supersaturate in solution - a validation study. J. Pharm. Sci. 2006, 95, 3428 Copyright Sirius Analytical Instruments Ltd. 2006 Non-chasers While the similarities between some non-chasing structures are obvious, we don t yet have strict rules for predicting non-chasing from structure. Since introducing CheqSol in March 2004, we have found only a few non-chasing acids, but about 20% of bases have been non-chasers. Supersaturation impacts on drug bioavailability and must be considered during formulation and manufacturing. Some attempts at predicting non-chasing compounds are shown in the following 3429 Copyright Sirius Analytical Instruments Ltd. 2006 Possible implications of chasing vs. non-chasing The propensity of a compound to supersaturate and remain so for a reasonable time might have implications in drug adsorption For example, a weak base might dissolve fully in the stomach butprecipitate on entering the high pH environment of the upper intestinal tract.