FARMAS ARMASI I FISIK FISIKA A I
Penetuan sifat fisik molekul obat
Physical Ph ysical properties of drug molecules Why physical properties are important in drug delivery? •
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before the drug reaches its active site, before there are many hurdles to overc overcome ome many complicated biological processes can be modelled using simple physical chemistry models or properties Ex: oral therapy
Physical Ph ysical properties of drug molecules Molecular structure, energy, and resulting physical properties: •
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The atomic mass is derived from counting the number of protons (positively charged) and neutrons (neutral in charge) in a nucleus. Electrons (negatively (negatively charged) charged) exist exist in atomic orbits surrounding the nucleus An imbalance in the number of protons and electrons can lead to ionic inter interaction action 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 Ph ysical properties of drug molecules two carbon atoms not bound
6P+6n
6P+6n
6e
6e
6P+6n 5e
2e
6P+6n 5e
Similar in charge distribution, but different in shape
behave differently when exposed to external energy fields
Additive and constitutiv constitutive e 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 th e 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), constitutive), resulting in the differ di fferent ent of molar refractive index (additive) many drugs show differing activity or efficacy when the molar refractive index different
Dielectric constant and induced polarization •
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Polarization is the process of separating opposite charges within an object. Induced polarization is inducing the movement of electrons within an object (parallel-plate (parallel-pla te 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 negativ
Voltage source
r + + + + + + +
-
-
+
-
+
Dielectric constant and induced polarization •
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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. in indu duct ctio ion n by an ext xter erna nall el elec ectr tric ic field, or 2. by a pe perm rman anen entt cha charg rge e se sepa parrati tion on within a polar molecule
Voltage source
r + + + + + + +
-
-
+
-
+
Dielectric constant and induced polarization •
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Dielectric constant 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 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 = the capacitance (in farads), C = q = the quantity of electric charge (in coulombs),
= potential difference (in volts) between the plates V =
When a vacuum fills the space between the plates, the capacitance is C o. This value is used as a reference to compare capacitances when other substances fill the space. The dielectric constant : ε = C x / C o
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
ε+2
ρ
=
4 π αρ 3
constant ε = dielectric constant M = molecular weight of the substance ρ = solvent density = number of molecules per unit volume = induced polarizability
N = Avogadro’s number 6.023 x 1023 mole-1
ρ
=
4 3
π N α ρ = Pi
Exercise Induced molar polarization Use the Clausius-Mosotti equation: ε −1
ε+2
ρ
=
4 π αρ 3
ρ
=
4 3
π N α ρ = Pi
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 g /cm³ at 25C? 2. What is the induced molar molar polarization polarization of HCl if its polarizabilities polarizabilities is 3.01 x 1024 cm3 ?
Permanent dipole moment of polar molecule •
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In a polar molecule, the separation of positively and negatively negatively charged regions can be permanent a permanent dipole moment, µ the permanent dipole of a solvent can strongly interact 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
α
Ex: dipolar nature of a peptide bond
amino acid •
The formation of partial double bond carbon-oxygen carbon-oxygen in the carbonyl groups causes a partial positive charge of nitrogen yielding a net dipole. The trans-isomer of a peptide is ally favored favored due to
The importance of dipole di pole interactions interactions •
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Ion-induced dipole interactions have an essential role in solubility phenomena for ionic solutes and nonpolar solvents Permanent dipole moments can be correlat correlated ed 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 contributed to to the crystalline crystalline arrangement and structural nature nature of the solid. Ex. ice crystals are organized organized through their dipole forc forces es
The importance of dipole di pole interactions interactions Dipole-dipole Dipole-d ipole interactions interactions are essential non covalent forces that contributes contributes to enhance pharmacological activity
The importance of dipole di pole interactions 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 (25C) and dipole moments of some compounds Substance
Dielectric Constan Constant, t, Dipole Moment (Debye Units) ε
Water
78.5
1.84
Methanol
32.6
1.70
Ethanol
24.5
1.69
Acetone
20.7
2.88
N-Propanol N-Propanol
20.1
1.68
Chloroform Chloroform
4.80
1.86
Acetonitrile Acetonitrile
3.92
3.92
Testosterone and methyl testosterone Increased oral bioavailability
Molecular Formula
C19H28O2
C20H30O2
Average Average mass
288.424408 Da
302.450989 Da
Molar Refractivity: Refractivity:
83.113 cm3
87.774 cm3
Polarizability: Polarizability:
32.949 10-24
3
34.796 10-24
3
Latihan (1 jam studi literatur) A. Berikan contoh contoh dari 1 reserch article mengenai hubungan antara konstant onstanta a dielektrik dan bioavailabilitas bioavai labilitas senyawa obat berbasis peptida
B. Berikan contoh dari 1 reserch article mengenai penentuan sifat fisik molekul molekul obat berbasis protein (dielectric constant, dipole moment, molar refractive, etc) Dibahas minggu depan, isi spread sheet yang dapat diakses di
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Contoh pengisian spread sheet
