Chapter 7. Solubility

2013. 10. 25.Chun Jong-Soo

Overview

Solubility is the maximum dissolved concentration under given solution conditions.

Solubility is a determinant of intestinal absorption and oral bioavailability.

Solubility is increased by adding ionizable groups or reducing Log P and

MW.

Salt forms increase dissolution rate.

Many negative effects can occur for low-solubility compounds Poor absorption and bioavailability after oral dosing

Insufficient solubility for IV dosing

Artificially low activity values from bioassays

Erratic assay results (biological and property methods)

Development challenges (expensive formulations and increased development time)

Burden shifted to patient (frequent high-dose administrations)

low-solubility compounds

too high of a reliance on advanced formulation and delivery technologies

lead a discovery project team toward a clinical candidate

wise to solve solubility insufficiencies with structural modifications

Solubility is determined by many factors

Compound structure

Physical state of compound that is introduced into solution Solid: Amorphous, crystalline, polymorphic form Liquid: Predissolved in solvent (e.g., DMSO) Composition and physical conditions of solvent(s) Types of solvents Amount (%) of co-solvents Solution components (e.g., salts, ions, proteins, lipids,

surfactants) pH Temperature Methods of measurement Equilibration time Separation techniques (e.g., filter, centrifuge) Detection (e.g., ultraviolet, mass spectrometry, turbidity)

Structural Properties Affect Solubility

Lipophilicity : Determined by van der Waals, dipolar, hydrogen bonds, ionic interactions

Size : Molecular weight, shape pKa : Determined by functional group ionizability Crystal lattice energy : Determined by crystal stacking,

melting point

Solubility equation of Yalkowsky and Banerjee

- A demonstration of the effect of lipophilicity and crystal lattice energy on solubility

Log S = 0.8−Log Pow−0.01(MP−25)

S; solubilityLog Pow; octanol/water partition coefficientMP; melting point

Log P 1 unit ↑

MP 100°C ↑Solubility 10-fold

↓

Solubility equation at a particular pH

- A mathematical derivation of the Henderson-Hasselbalch equation

S = S0(1+10(pH−pKa)) (Acid)S = S0(1+10(pKa−pH)) (Base)

S0; intrinsic solubility

HA+H2O = H3O+A− (Acid)B+H2O = OH−+HB+ (Base)

S = [HA]+[A−] (Acid)S = [B]+[HB+] (Base)

- Drugs ionize according to the reactions :

- At equilibrium, the solubility :

more acid

x6

x4000

Inflection point(pH=pka)

S = S0(1+10(pH−pKa))

Kinetic and Thermodynamic SolubilityKinetic Thermodynamic

Characteristics

(a) the compound initially is fully dissolved in an organic solvent (e.g., DMSO) then added to the aqueous buffer

(b) equilibrium is not reached between dissolved compound and solid compound metastable ppt (amorphous, mixture)

(a) the addition of aqueous solvent directly to solid crystalline material

(b) establishment of equilibrium between the dissolved and solid material original ppt

Use

Alert teams to potential absorption or bioassay liabilities

Diagnose erratic bioassay results

Develop structure-solubility relationships

Select compounds for NMR-binding and x-ray co-crystallization experiments

Develop generic formulations for animal dosing

Guide formulation development Diagnose in vivo results Plan development strategy File regulatory submissions

drug discovery late discoveryEarly development

Consequences of Chirality on Solubility

- Chirality affects solubility because of the crystal form

- Wallach’ rule : Racemate crystals are more stable and dense than their chiral

counterparts

racemic crystal more stable higher MP

thermodynamic solubility ↓

S-ketoprofen MP 72°CRS-ketoprofen MP

94°C

Thermodynamic solubility2.3mg/mL1.4mg/mL

Effects of Solubility

- Low Solubility Limits Absorption and Causes Low Oral Bioavailability

(Merck; Antiviral)

Effects of Solubility- Good Solubility is Essential for IV Formulation : compounds must have sufficient solubility in the vehicle to deliver the expected dose in a restricted volume

- Acceptance Criteria for Solubility “What is the minimum solubility required for a compound?”

MAD = S∗Ka∗ SIWV∗SITT

MAD ; maximum absorbable dose at a certain doseS ; solubility (mg/mL, pH 6.5)Ka ; intestinal absorption rate constant (min−1; permeability in

rat intestinal perfusion experiment, quantitatively similar to human Ka)

SIWV ; small intestine water volume (∼250 mL)SITT ; small intestine transit time (min; ∼270 min)

- The solubility classification ranges suggested for medicinal chemists

<10 μg/mL Low solubility 10–60 μg/mL Moderate

solubility >60 μg/mL High solubility

human oral absorption

much higher than 60 μg/mL

- Biopharmaceutics Classification System (BCS) used in drug development

Class I : ideal class for oral absorption. Class II : Formulation typically is used to enhance solubility of compounds in this class. Class III : Prodrug strategies typically are used for these compounds. Class IV : Development of this class of compounds can be risky and costly. (No in vitro/in vivo correlations are expected)

- Molecular Properties for Solubility and Permeability Often are Opposed

↑ Perm ↑ , Sol ↓

↑ Sol ↑, Perm ↓

- Physiology of the Gastrointestinal Tract

basic drugs

acidic drugs

- Species Differences in Gastrointestinal Tract

bioavailability

more increases

Chapter 25. Solubility Method

Overview Solubility can be estimated using pKa, pH, Log P, and melting

point.

Commercial software calculates equilibrium solubility for comparing

series analogs.

High-throughput (HT) kinetic solubility is most relevant in discovery

because it mimics discovery conditions.

HT kinetic methods include direct UV, nephelometry, and turbidimetry.

Custom solubility methods are used to mimic a specific project

issue.

Equilibrium solubility is relevant for animal dosing and development

studies.

Literature Solubility Calculation Methods

- The total solubility “the Henderson-Hasselbalch equation”

Stot = SHA(1+10(pH−pKa))

Stot ; total solubilitySHA ; intrinsic solubility of the neutral acid

- The intrinsic solubility “the Yalkowsky equation”

Log S = 0.8−Log Pow−0.01(MP−25)

S; solubilityLog Pow; octanol/water partition coefficientMP; melting point

- Kinetic Solubility Methods ▶ first dissolve the solid compound in DMSO ▶ then add an aliquot of DMSO solution to the aqueous buffer ▶ most appropriate for drug discovery

- Thermodynamic Solubility Methods ▶ add aqueous buffer directly to compound solid ▶ most appropriate for late drug discovery and development

Direct UV Kinetic Solubility Method

The concentration of the compound is proportional to the UV absorbance useful to measure solubility at various pHs to simulate physiological and assay conditions

Nephelometric Kinetic Solubility Method

Well plate

turning point = maximum concentration = solubility sparingly soluble (<10 μg/mL), partially soluble (10–100 μg/mL), and soluble (>100 μg/mL)

Turbidimetric In Vitro Solubility Method

concentration↑ precipitate↑ Light transmission ↓ turning point = solubility

Customized Kinetic Solubility Method- cases where generic solubility method conditions are not adequate to accurately assess the solubility of compounds under specific conditions

- performed using the same buffer composition, dilution procedure, incubation time, and temperature as the biological assay

Compounds are added to the bioassay buffer

under the conditions of the biological assay

incubated according to bioassay time schedules

Precipitate is removed by filtration

analyzed by LC/UV/MS techniques

Equilibrium Shake Flask Thermodynamic Solubility Method

Potentiometric In Vitro Thermodynamic Solubility Method

used to determine the intrinsic solubility (S0) suitable only for compounds with ionization centers