Transcript Chapter 7. Solubility

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 ↑
MP 100°C ↑
Solubility 10-fold ↓
Solubility equation at a particular pH
- Drugs ionize according to the reactions :
HA+H2O = H3O+A−
B+H2O = OH−+HB+
(Acid)
(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
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)
Thermodynamic
(a) the addition of aqueous solvent directly
to solid crystalline material
(b) establishment of equilibrium between
the dissolved and solid material
 original ppt
 Alert teams to potential absorption or
bioassay liabilities
 Diagnose erratic bioassay results
Use
 Develop structure-solubility relationships
 Select compounds for NMR-binding and
x-ray co-crystallization experiments
 Guide formulation development
 Diagnose in vivo results
 Plan development strategy
 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
RS-ketoprofen MP 94°C
2.3mg/mL
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
>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
↑  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