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Drug absorption pathway

Absorption Enhancement in the Intestine

Blood stream “sink” enhances permeation
· pH 7.4 creates a “trap” for bases
· blood flow increases concentration gradient Capillary to
Portal Vein

GI Epithelial
Cell Layer

Uptake transport
· against gradient Salt form
· enhances pH GI Lumen
dissolution · increases
Reduced ionization of bases
Drug Solid for solubility
particle size
Particle
· enhances
surface area Bile salts
for dissolution · solubilize
Formulation
· dispersion to Food Effect
smaller particles · stimulates bile release
or solution enhances
solubility 2

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The multiple mechanisms of transport through the intestinal epithelium

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Solubility

solubility product Ksp = [C+]x[A-]

Henry’s Law: Cg = KgPg

solution

Comparison of Kinetic and Equilibrium Solubility

Comparison Kinetic Solubility Thermodynamic Solubility

Initial State DMSO Stock Solid Crystals
Mixing Time Variable Long mixing
Temperature Room Temperature Controlled Temperature
Equilibrium Not Established Established
Crystal Form Meta-Stable Forms Stable Form
Target Solubility 100 g/mL 10 mg/mL
Throughput 150 Compounds/day 20 Compounds/day
Material 1.5 mg for 4 pHs 100 mg for 20 solvents

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Applications of Solubility in Lead Optimization

Solvents Commonly Used for Solubility Determination of Development

Candidates in Late-Stage Drug Discovery

Physiological Buffers Formulary Solvents Lipophilicity

pH 1 Tween 80 Octanol
pH 4.5 PEG 200 Labrasol
pH 6.6 PEG 400 Cyclohexane
pH 7.4 Phosal 53 MCT
pH 9 Phosal PG
SGF Benzyl Alcohol
SIF EtOH
SIBLM Corn Oil
Plasma 2% Tween / 0.5% MC

Correlation between Solubility, Permeability and Dose

Lipinski has classified the solubility ranges (high is > 60 g/mL, moderate is
10-60 g/mL, low is < 10 g/mL) to provide a general guideline for achieving
acceptable human absorption for compounds with average potency and
permeability.
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Solubility, Solubilization and Dissolution in Drug Delivery During Lead

Optimization

Delivering Drug to the Test System

Typical compound solubilization curve in a cosolvent system

such as DMSO /water (solid line).

Drug Delivery
for In vitro
Screening

Example of a lead selection funnel

and the role of both in vitro and in
vivo “drug delivery” in the funnel

Potential ramifications of “drug delivery”

problems in the screening funnel and
the impact on potency readouts

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The importance of water solubility

to treat infestations tend to crystallise

of the GI tract in the kidney

The reactivity of water will also affect the stability of the drug in transit 11

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Salt formation

Examples of the acids and bases used to form the salts of drugs

the water-insoluble
very bitter taste embonate salt is
almost
tasteless
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Examples of the structures of acids and bases

whose structures contain water solubilising groups

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Solubility
• 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

Biopharmaceutics
Classification
System

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High Solubility Low Solubility

High Permeability Class I Class II

Dissolution rate limits Solubility limits
absorption absorption

Diltiazem Flurbiprofen
Labetalol Naproxen
Enalapril
Propranolol

Low Permeability Class III Class IV

Permeability limits Significant problems for oral
absorption drug delivery are expected

Acyclovir Terfenadine
Famotidine Furosemide
Nadolol

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The effect of pH on the solubility of acidic and basic drugs

Henderson–Hasselbalch equation

The pKa of aspirin, a weak acid, is 3.5. Calculate the degree of ionisation of aspirin in the (a)
stomach and (b) intestine if the pH of the contents of the stomach is 1 and the pH of the
contents of the intestine is 6.

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The effect of pH on the solubility of acidic and basic drugs

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Solubility-pH profile

Compound A and B have the same

pKa, but different intrinsic solubility.
Compound A is more soluble than
Compound B through the entire pH
range, due to higher intrinsic
solubility.

Compound C and D have the same

intrinsic solubility, but a different pKa.
Compounds are more soluble in their
ionization state.

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Partition

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Consequences of Chirality on Solubility

Racemate crystals are more stable and dense

Wallach rule
than their chiral counterparts

O CH3 O CH3
OH OH
* *
O O

S-ketoprofen R,S-ketoprofen

72°C 94°C
2.3 mg/mL 1.4 mg/mL

homochiral interactions (S…S) heterochiral interactions (R…S) 21

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Structure Modification Strategies to Improve Solubility

Log S = 0.8−Log Pow −0.01(MP−25)

S = [HA]+ [A−] Acid

S = [B] + [HB+] Base

Add ionizable group

Reduce Log P
Add hydrogen bonding
Add polar group
Reduce molecular weight
Out-of-plane substitution to reduce crystal packing
Construct a prodrug
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The incorporation of water solubilising groups in a structure

• the type of group introduced;

• whether the introduction is reversible
or irreversible;
• the position of incorporation;
• the chemical route of introduction

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Introduction of a side chain with a carboxylic acid or amine

enhances the solubility of artemisinin.

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Carboxylic acid groups by alkylation

Carboxylic acid groups by acylation

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Phosphate groups
Sulphonic acid groups

Polyhydroxy and ether residues

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Incorporation of basic groups

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Indinavir: Improving Solubility

of by Introduction of Basic
Nitrogen

Improving Solubility by
Introduction of Basic Amines
for a Series of Antitumor
Agents Introduction of Basic Nitrogen Improves
Solubility and In Vivo Activity

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Reduce Log P

Add Hydrogen Bonding

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Add Polar Group Reduce Molecular Weight

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Reduction of Crystal Packing Energy

Introduction of Ethyl Group Disrupted -Stacking, Reduced

Crystal Packing Energy and Improved Solubility

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Out-of-Plane Substitution

Construct a Prodrug

Strategies for Improving Dissolution Rate

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Enabling Formulation Strategies for Drug Delivery

Particle Size Reduction

High Energy Solids
Solubility Enhancement
Cosolvents
Ionization and pH Adjustment
Surfactants
Dispersed Lipid Phases
Complexation
Supersaturation
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Dissolution

A representation of the process of dissolution

Solubility is how much of a compound can dissolve in solution. Dissolution rate is

how fast a compound can dissolve into solution. 34

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Acid–Base Salts Cocrystals

Converting a drug from a neutral organic molecule to an ionized salt is the traditional means
of manipulating a drug’s solubility and crystalline properties
Types of molecular recognition commonly observed in
pKas of protonated nitrogenous bases often seen in drugs cocrystals

Beyond forming an ionic compound, protonating nitrogens in a drug can improve a drug’s shelf-life.

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Polymorphs

Representative solubility curves for a compound with two polymorphs

Different polymorphs can have very different properties, including

solubility and rate of dissolving, and therefore can display different
pharmacokinetics

the more stable polymorph does not always precipitate from solution. If crystals for the less
stable polymorph form first, then the less stable polymorph will likely precipitate
preferentially

The drug was precipitating out of solution within

the semi-solid capsules.

batches of ritonavir were seeded with Form I crystals to

encourage precipitation of the desired polymorph

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Stability
Stability after administration

Strategies are for improving a drug’s in situ stability:

modifying its structure;
administering the drug as a more stable prodrug ;
using a suitable dosage form.

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Stability
Schematic representations of the types of inclusion complexes formed by cyclodextrins
and prostaglandins. The type of complex formed is dependent on the cavity size

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Permeability
• Permeability is the velocity of molecule passage through a membrane barrier.
• Permeability is a determinant of intestinal absorption and oral bioavailability.
• Optimizing passive diffusion is productive because it is the predominant
mechanism for absorption of most commercial drugs.
• Permeability is increased by removing ionizable groups, increasing Log P, and
• decreasing size and polarity.

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The Caco-2 permeability assay

human epithelial colorectal

adenocarcinoma cells

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Comparison of PAMPA and Caco-2 Assay

Comparison PAMPA Caco-2

Membrane Phospholipid Cell Monolayer

Mechanisms Passive Passive, Influx,

Efflux, Metabolism

Throughput 500 / week 30 / week

Cost < $1 / sample ~ $30 / sample

Manpower 0.35 FTE 2 FTE

PAMPA=parallel artificial membrane permeability assay

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Passive Diffusion Permeability

Passive diffusion across a membrane is affected by the

solution pH and compound pKa. In this PAMPA Permeability of Ionizable
permeability experiment, acidic, basic, and neutral Compounds is pH-Dependent
compounds have different permeability at different pH
values. 44

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Permeability Structure Modification Strategies

• Ionizable group to non-ionizable group

• Add lipophilicity
• Isosteric replacement of polar groups
• Esterify carboxylic acid
• Reduce hydrogen bonding and polarity
• Reduce size
• Add nonpolar side chain
• Prodrug
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Ionizable Group to Non-ionizable Group

Add Lipophilicity

Effect of Permeability on Oral

Bioavailability for Factor Xa Inhibitor 46

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Effect of lipophilicity
on Caco-2
Permeability of
Phenylalanine
Dipeptide Series

Effects of Different
Substituents of Caco-2
Permeability

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For this Renin Inhibitor, Reduction of

H-bonds Increased Permeability and
Stability, Resulting in Increased Oral
Bioavailability

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Isosteric Replacement of Polar Groups

Esterify Carboxylic Acid

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Reduce Hydrogen Bonding and Polarity

Reduce Size

Examples of Increasing Permeability by

Decreasing H-Bonds and Polarity.
PAMPA Permeability is in Pe x10-6 cm/s

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Add Nonpolar Side Chain

Prodrug

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