BIOPHARMACEUTICS

ASPECT OF DRUG
DEVELOPMENT
Prof. HENNY LUCIDA, Ph.D, Apt
ANDALAS UNIVERSITY
Limitation

• Biopharmaceutics
• Pharmacokinetic
• Pharmacodynamic
Biopharmaceutics

• Physicochemical properties of drugs

• Physiological condition

DOSAGE FORM DESIGN

Physicochemical properties of drugs
• Solubility (at 3 different pHs; at 4 and 37oC)
- Henderson-Hasselbach equation
(pH – partition hypothesis)
- pKa

Ka 
 H  A 
 

 HA
Physicochemical properties of drugs
• Hydrophobicity
the association of non-polar groups or molecules in an aqueous
environment which arises from the tendency of water to exclude
non-polar molecules
Physicochemical properties of drugs
• Lipophilicity
represents the affinity of a molecule or a moiety for a lipophilic
environment.
It is commonly measured by its distribution behaviour in a biphasic
system:
Partition and distribution coefficient
Lipophilicity

• Partition coefficient (log

P):

 drug  organic
P
 drug  aqueous
Octanol is the most widely used model of a biological membrane.
∆log P :the difference of log Pchex and log Poct
Lipophilicity

• Distribution coefficient

log D  log P  log 1  10  pH  pKa


Log D7,4 values above 0 normally correlate with effective transfer
across the lipid core of the membrane, whilst values below 0
suggest an inability to traverse the hydrophobic barrier
The relationship between
log P and log D and pKa

1
(ionised (unionised
drug) Aqueous
drug)

2
(unionised drug) Lipid

1. Is a function of pKa
2. Is a function of logP
The role of physicochemical properties on drug dosage form
design

Example 1:
Lipophilicity and H-bonding are important parameters for uptake of
drugs in the brain (because both are related to membrane
permeation)
Log P and Log D are used in a decision tree for the development of
non-sedative antihistamines
Negligible Log D< 0 Log D > 3 Hindered BBB
BBB uptake Log D uptake

0 < log D < 3

Interme 2 < ∆log P < 4 ∆log P > 4

∆log P
diate
cases

∆log P < 2

Good brain penetration

Example 2

∆log D determines the activity of 2 GABA uptake

inhibitors with identical IC50, pKa and Log Doct values.
They differ only in their distribution coefficient in
cyclohexane/water (logDchex).
In this case, ∆log D = 2.71 for the in vivo inactive
compounds is too large for CNS uptake. The active
compound has a ∆log D = 1.42 well below the
critical limit of approx 2
Properties of GABA-uptake inhibitors
COO-
COO-

N
H+
N
H+

IC50 0.11 mM 0.1 mM

In vivo active inactive
pKa 3.57/9.23 3.39/9.25
Log Doct 0.99 0.71
Log Dchex -0.43 -2.00
∆log D 1.42 2.71
Physicochemical properties of drugs
• Molecular size and shape
• Dissolution rate and profile
Physiological condition

• Membrane transfer

Dissolution Membrane transfer

Solid drug Drug in Absorbed
drug
solution
Mechanisms of membrane permeation

Transcellular
Passive diffusion
A1
Luminal Ao Paracellular
A2
metabolism
P-gp efflux A3
Epithelial A4
metabolism
A5 Active transport
A6 Transcytosis

The total percentage of % absorbed is the result of a combination of

several of these processes
Biomembranes

• Composed of a lipid bilayer (phospholipids, glycolipids and

cholesterol)
• Compounds can cross biological membrane by two passive
processesses:
- transcellular mech
- paracellular mech
Lipinsky

Poor permeability is produced by:

• > 5 H-bond donors (sum of OHs and NHs)
• > 10 H-bond acceptors (sum of Ns and Os)
• MW over 500
• Poor dissolution by log P > 5
Models for a study of drug permeability

• In vivo
• In situ (rat perfusion)
• In vitro (Caco-2 and other cell lines; using chamber)
• Physicochemical properties
• In silico (in computro)