FARMASI FISIKA I

Penetuan sifat fisik molekul obat

 Physical properties of drug molecules
Why physical properties are
important in drug delivery?
• before the drug reaches its active site,
there are many hurdles to overcome
• many complicated biological processes
can be modelled using simple physical
chemistry models or properties
• Ex: oral therapy
Physical properties of drug molecules
Molecular structure, energy, and resulting physical properties:
• The atomic mass is derived from counting the number of protons
(positively charged) and neutrons (neutral in charge) in a nucleus.
• Electrons (negatively charged) exist in atomic orbits surrounding the
nucleus
• An imbalance in the number of protons and electrons can lead to
ionic interaction
• Atomic structure and molecular bonding order affect the physical
property of the molecule, such as reactivity , dipole moment, optical
rotation, molar refraction
• Ex: bonding of two carbon atoms
Physical properties of drug molecules
two carbon atoms not bound

6P+6n 6P+6n
Similar in charge
distribution, but
6e 6e different in shape

6P+6n 2e 6P+6n behave differently

5e 5e
when exposed to
external energy fields
two carbons form a covalent bond
Additive and constitutive properties
The physical properties come from molecular bonding order in the atom can
be either additive or constitutive.
• Additive: sum of the properties of the individual atoms or functional groups
• Constitutive: dependent on the structural arrangement of the atoms within
the molecule
Ex:
 2-Butanone and 2-Buten-1-ol have exactly the same number and type of
atoms (C, H, O – constitutive), resulting in the different of molar refractive
index (additive)
 many drugs show differing activity or efficacy when the molar refractive index
different
Dielectric constant and induced polarization
• Polarization is the process of separating
opposite charges within an object.
• Induced polarization is inducing the
movement of electrons within an object
(parallel-plate condenser), one side of
the object is left with an excess of
positive charge and the other side of
the object is left with an excess of
negative charge  the positive charge
becomes separated from the negative
charge.
Voltage source
r
+ -
- +
+ -
+ -
+ -
+ -
+ -
+ - + -
polarized molecule
 Dielectric constant and induced polarization
• Polarizability is the ease with which an
ion or molecule can be polarized by any
external field
• A molecule maintain a separation of
electric charge through:
1. induction by an external electric
field, or
2. by a permanent charge separation
within a polar molecule
Voltage source
r
+ -
- +
+ -
+ -
+ -
+ -
+ -
+ - + -
polarized molecule
 Dielectric constant and induced polarization
• Dielectric constant or relative permittivity (ε) is the ratio of the
amount of electrical energy stored in a material (medium) by an
applied voltage, relative to that stored in a vacuum. It reflects the
extent of electrostatic flux of a material in a given electric potential
• Dielectric constant reflects the ability of molecule to resist charge
separation
• Note: field strength and temperature play a role
Dielectric constant and induced polarization
The capacitance of the condenser:
C = q/V
C = the capacitance (in farads),
q = the quantity of electric charge (in coulombs),
V = potential difference (in volts) between the plates

When a vacuum fills the space between the plates, the capacitance
is Co. This value is used as a reference to compare capacitances
when other substances fill the space.
The dielectric constant :
ε = Cx / Co
Cx = the capacitance of the condenser filled with some material
Dielectric constant and induced polarization
The dielectric constant of solvent mixture can be
related to drug solubility and drug plasma
concentration.
Dielectric constant and induced polarization
Induced molar polarization
The Clausius-Mosotti equation:
ε −1 𝑀 4 π 𝑛 𝑀 αρ 4
= = π N αρ = Pi
ε+2 ρ 3 ρ 3

ε = dielectric constant
M = molecular weight of the substance
ρ = solvent density
𝑛 = number of molecules per unit volume
𝜌 = induced polarizability
N = Avogadro’s number 6.023 x 1023 mole-1
Pi = Induced molar polarization
 Exercise
Induced molar polarization
Use the Clausius-Mosotti equation:
ε −1 𝑀 4 π 𝑛 𝑀 αρ 4
= = π N αρ = Pi
ε+2 ρ 3 ρ 3

1. What is the induced molar polarization of ethyl acetate with a molecular

weight of 88.10 g/mole)and a density of 0.897 g/cm³ at 25C?
2. What is the induced molar polarization of HCl if its polarizabilities is 3.01 x
1024 cm3 ?
 Permanent dipole moment of polar
molecule
• In a polar molecule, the separation of positively and negatively
charged regions can be permanent  a permanent dipole
moment, µ
• the permanent dipole of a solvent can strongly interact with the
solute molecules  solvent effect
• Solvent: water  the hydration of ions and molecules
• If a molecule has a permanent dipole  the resistance to charge
separation is minimal  charge will easily migrate in the field
• Ex: water, carbon dioxide, peptide
Ex: dipolar nature of a peptide bond

α
 Ex: dipolar nature of a peptide bond

amino acid
• The formation of partial double bond carbon-oxygen in the carbonyl
groups causes a partial positive charge of nitrogen yielding a net
dipole.
• The trans-isomer of a peptide is energetically favored due to steric
hindrance of the amino acid
The importance of dipole interactions
• Ion-induced dipole interactions have an essential role in
solubility phenomena for ionic solutes and nonpolar solvents
• Permanent dipole moments can be correlated with biologic
activities. Ex: the insecticidal activity of the three isomers of
DDT
• The dipole interactions of solids composed of molecules with
permanent dipole moment contributed to the crystalline
arrangement and structural nature of the solid. Ex. ice
crystals are organized through their dipole forces
The importance of dipole interactions
Dipole-dipole interactions are essential non covalent forces
that contributes to enhance pharmacological activity
The importance of dipole interactions
The symmetry of the molecule can also be associated
with its dipole moment

Benzene and p-dichlorobenzene  simmetric plannar  dipole moment = 0

m and o-dichlorobenzene  assymmetric  dipole moments = 1.5 and 2.3
Dielectric constants (25C) and dipole
moments of some compounds
Substance Dielectric Constant, Dipole Moment
ε (Debye Units)
Water 78.5 1.84
Methanol 32.6 1.70
Ethanol 24.5 1.69
Acetone 20.7 2.88
N-Propanol 20.1 1.68
Chloroform 4.80 1.86
Acetonitrile 3.92 3.92
Testosterone and methyl testosterone
Increased oral
bioavailability

Molecular Formula C19H28O2 C20H30O2

Average mass 288.424408 Da 302.450989 Da
Molar Refractivity: 83.113 cm3 87.774 cm3
Polarizability: 32.949 10-24cm3 34.796 10-24cm3
Dipole moment: 4.32 DU 4.17 DU
 Latihan (1 jam studi literatur)
A. Berikan contoh dari 1 reserch article mengenai
hubungan antara konstanta dielektrik dan bioavailabilitas
senyawa obat berbasis peptida

B. Berikan contoh dari 1 reserch article mengenai

penentuan sifat fisik molekul obat berbasis protein
(dielectric constant, dipole moment, molar refractive, etc)
Dibahas minggu depan,
isi spread sheet yang dapat diakses di farmasifisika1@gmail.com password farfis2012:
https://docs.google.com/spreadsheet/ccc?key=0Alwsm5ctM7iJdFBuLTdzMnNDWXBJcUt
ub0NoV05VQUE
Contoh pengisian spread sheet