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; solubility
Log Pow; octanol/water partition coefficient
MP; melting point

Log P 1 unit ↑
Solubility 10-fold ↓
MP 100°C ↑
 Solubility equation at a particular pH

- Drugs ionize according to the reactions :

HA+H2O = H3O+A− (Acid)

B+H2O = OH−+HB+ (Base)

- At equilibrium, the solubility :

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

- 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

 x6

more acid x4000

 Inflection point
(pH=pka)

S = S0(1+10(pH−pKa))
 Kinetic and Thermodynamic Solubility
Kinetic Thermodynamic

(a) the compound initially is

(a) the addition of aqueous solvent directly
fully dissolved in an organic solvent (e.g.,
to solid crystalline material
DMSO) then added to the aqueous buffer
Characteristics (b) establishment of equilibrium between
(b) equilibrium is not reached between
the dissolved and solid material
dissolved compound and solid compound
 original ppt
 metastable ppt (amorphous, mixture)

 Alert teams to potential absorption or

bioassay liabilities
 Guide formulation development
 Diagnose erratic bioassay results
 Diagnose in vivo results
 Develop structure-solubility relationships
Use
 Plan development strategy
 Select compounds for NMR-binding and
x-ray co-crystallization experiments
 File regulatory submissions
 Develop generic formulations for
animal dosing

drug discovery late discovery

Early 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 ↓

Thermodynamic solubility

S-ketoprofen MP 72°C 2.3mg/mL

RS-ketoprofen MP 94°C 1.4mg/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 dose

S ; 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 human oral absorption
>60 μg/mL High solubility

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

↑  Sol ↑, Perm ↓

↑  Perm ↑, Sol ↓
- Physiology of the Gastrointestinal Tract

basic drugs

acidic drugs
- Species Differences in Gastrointestinal Tract

earlier absorption

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 solubility

SHA ; intrinsic solubility of the neutral acid

- The intrinsic solubility

“the Yalkowsky equation”

Log S = 0.8−Log Pow−0.01(MP−25)

S; solubility
Log Pow; octanol/water partition coefficient
MP; 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