Physical Properties of Drug Molecules

Physical Properties of Drug Molecules

Contents of This Chapter

• The liquid crystalline state, its properties and significance

• Determination and applications of refractive index

• Determination and applications of dipole moment

• Determination and application of dissociation constant

• Determination and applications of optical rotation

• Determination and application of dielectric constant

Learning Objectives

• At the end of this lecture, student will be able to

- Explain the concept of liquid crystalline state and describe its properties and significance

- Explain   the   fundamental   principles   of   refraction   of electrons and neutrons

- Explain the relationships between atomic and molecular forces and their response to electromagnetic energy

- Describe the fundamental principle of dissociation constant

-  Describe the polarization of light beams and use of polarized light to study chiral molecules

- Discuss the relationships between atomic and molecular forces and their response to electromagnetic energy

Liquid Crystalline State- Structure

• Liquid crystals (mesophase) are intermediate between the liquid and solid state

• The two main types of liquid crystals are termed as:

- Sematic (soap like or grease like)

- Nematic (threadlike)

• In the sematic state molecules are mobile in two directions and can rotate about one axis

• In the nematic state, the molecules again rotate only about one axis but are mobile in three dimensions

• The sematic mesophase is of pharmaceutical significance

• This phase usually forms internary mixtures containing a surfactant, water and a weakly amphiphilic or nonpolar additive

• Molecules that form mesophases are –

- Organic

- Elongated and rectilinear in shape

- Rigid

- Possesses strong dipoles and easily polarizable groups

Liquid Crystalline State- Properties and Significance

• Because of their intermediate nature, liquid crystals have some properties of liquids and some properties of solids

• Liquid crystals are mobile and can be considered to have flow properties of liquids

• They exhibit birefringence where, the light passing through a material is divided into two components with different velocities and refractive index

• The sematic mesophase has application in the solubilization of water insoluble materials

• Liquid crystalline phases are present in emulsions and responsible for physical stability owing to their highly viscous nature

• The lipoidal forms of liquid crystalline state is found in nerves, brain tissue and blood vessels

• Three components of bile (cholesterol, bile acid salt and water) can form a sematic mesophase

• The principle of liquid crystal formation can be applied to the solubilisation and dissolution of cholesterol

• Liquid crystals have structures that are similar to those in cell membranes

Refractive Index

• Light passes more slowly through a substance than through vacuum

• When a ray passes from one medium to another it shows refraction

• If light enters a denser substance at an angle, one part of the wave slows down more quickly as it passes the interface

• This produces bending of the wave toward the interface, this phenomenon is called refraction

• If the light enters a less dense substance, it is refracted away from the interface

• As light enters a denser substance, the advancing waves interact with the atoms in the substance at the interface and throughout the thickness of the substance

• These interactions modify the light waves by absorbing energy, resulting in the waves being closer together by reducing the speed and shortening the wavelength

• The relative value of the effect of the refraction between two substances is given by Snell’s law

• Snell’s law states that the refractive index (n) of the liquid as a constant ratio of the sine of the angle of incidence to that of the refraction

sin I          velocity of light in the first substance            c₁

n =------= ----------------------------------------------------------- = -------

sin r    velocity of the light in the second substance    c₂

Where, sin i is the angle of the incident ray of light, sin r is the sine  of  the  angle  of  the  refracted  ray  and  c1   and  c2   are  the speeds of the light in the respective media

Refractive Index- Factors Affecting

•   Refractive index varies with the wavelength of light and the temperature

• The refractive index decreases with increase in the wavelength of light

• Refractive index of liquid decreases as the temperature increases

• For measuring the refractive index of gases, pressure should be held constant

Molar Refraction

• Molar refraction Rm, is related to both the refractive index and the molecular properties of a compound being tested

• Molar refraction is expressed by

Where, M is the molecular weight and ρ is the density of the compound

Refractive Index- Applications

• To identify a substance

• Measurement of purity of a substance

• Determination of concentration

• Determination of dielectric constant

• Determination of molar polarizability

• Determination of molar refraction

Refractive Index- Determination

• Abbe’s refractometer is used to determine the refractive index

Dipole Moment

• Dipolar molecule is defined as the one in which the regions of positive and negative charges are well separated

• The separation is due to uneven distribution of electrons in the molecule

• The regions of positive and negative charges are balanced

• Examples of dipolar molecules are water, hydrochloric acid etc.

• In water molecules, oxygen is an electronegative atom and have a greater tendency   draw the shared pair of electrons towards it

• As a result hydrogen atom assumes positive charge

• Positive and negative centers are developed in the molecule

• In a polar molecule, the separation of positively and negatively charged regions are permanent and the molecule will possess a permanent dipole moment, (μ)

Dipole Moment- Mathematical treatment

• Dipole moment is defined as the vector equal in magnitude to the product of electric charge and distance, having the direction of the line joining the positive and negative centers

• Mathematically, dipole moment (μ) can be expressed as:

Dipole moment = distance X charge

μ           =              r     X    e

SI units:   cm                         meter X coulomb

• In CGS system the unit is debye

• 1 debye is equal to 10^-18 electrostatic unit (esu) cm or 3.34X 10^-30 coulomb meter

• In an electric field, the molecules with permanent dipole moments can also have induced dipole

• The total molar polarization, P, is the sum of induction and permanent dipole effects:

Where P₀ is the orientation polarization of the permanent dipoles

Dipole Moment- Applications

• Solubilisation of drugs

• Crystalline nature of solids

• Drug receptor interactions

• Therapeutic activity of the drugs

• Chemical structure of compounds

Dissociation Constant

• About 75% of all drugs are weak bases and 20% are weak acids

• As drugs are weak electrolytes they undergo dissociation

• The degree to which drugs are ionized depends on the pH of the solution

• The relationship between pH and drug ionization is useful in predicting the following:

- Absorption of the drug from the site of application

- Distribution of drugs from blood into tissue and brain

- Elimination of drugs by liver and kidneys

- Estimation of solubility of drugs

- Attainment of optimum bioavailability

• The ionic equations of weak acids and bases exist in equilibrium

• Equilibrium is defined as a balance between two opposing forces or actions

• At equilibrium, concentrations of products and reactants remain equal

• Equilibrium is a dynamic process indicating the quality between velocities of the forward and backward reactions

Dissociation Constant- Ionization Constant of a Weak Acid

• The ionization of acetic acid is a reversible chemical reaction and can be written as:

HAc + H₂O  <-------------> H₃O+ +Ac- ........... (1)

•  The equilibrium rate constant K may be written as :

 

                K=  [H₃O+ ]  [Ac −]   …………..(2)

[HAc] [H₂O]

• The square brackets represent the stoichiometric molar concentration

• In dilute solution, water is considered regarded as constant

              [H₃O+]  [Ac −]

Ka = K x constant = ----------------------- ……….(3)

                  [HAc]

• The new constant, K is denoted as ionization constant or dissociation constant at a particular temperature

• Ka denotes the acid ionization constant

• The greater the dissociation constant of the acid, the stronger is the acid

pKa = - log [Ka]………(4)

• The pKa is defined as the negative logarithm of acid ionization constant

Dissociation Constant- Ionization Constant of a Weak Base

• The ionization of ammonia (weak base) is a reversible chemical reaction and is written as:

NH₃ + H₂O   <----------->   NH₄⁺ + OH^- …….. (5)

• Applying the law of mass action to equation (5) gives base ionization constant (Kb) as:

[NH₄⁺]  [OH⁻]

K_b = -------------------- …… (6)

[NH₃]

• The general expression for ionization of base B may be written as:

[BH⁺]  [OH⁻]

              K_b = ----------------- …………. (7)

[B⁻]

• The greater the dissociation constant of the base, the stronger is the base

• pKb is defined as the negative logarithm of base ionization constant and it is expressed by

pk_b = -log [K_b]…………..(8)

 

Dissociation Constant- Applications

• It is important in Hendersen-Hasselbalch equation to calculate the extent of ionization

• The absorption of drug in GIT can be predicted

• The concentration of preservative required can be predicted

• The pH of the solution can be calculated

• It can be used to obtain the maximal yields in the extraction of drugs

Dissociation Constant- Methods of Determination

• Ionization or dissociation constant can be determined by the following methods:

- Conductivity method

- Solubility method

- Potentiometric method

- Spectrophotometric method

Optical Rotation

• Ordinary light transmits its rays in all directions (all planes)

• When light is allowed to pass through a polarizing prism (Nicol prism), light vibrations in only one plane are transmitted

• Such a light beam is known as plane polarized light

• When certain substances are placed in the path of the plane polarized light, its velocity may decrease or increase

• The change in velocity results in a corresponding change in the rotation of plane polarized light through a certain angle called as angle of rotation, α

• Optical activity is the ability of certain substances to rotate the plane polarized light

• Optically active substances are the substances which can rotate the plane polarized light either to right- side or to left- side

• When viewed through the path of beam, if the rotation of plane polarized light takes place in clock-wise direction (towards right) it is called Dextrorotatory

• If  the  rotation  of  plane  polarized  light  takes  place  in  anti- clockwise direction (towards left), then the rotation is called as Levorotatory

• A dextrorotatory substance produces an angle of rotation, α, that is defined as positive

• The levorotatory substance, which rotates the beam to the left, has an α, that is defined as negative

• Molecules that have an asymmetric center (chiral) and therefore lack symmetry about a single plane are optically active

• Symmetric molecules (achiral) are optically inactive and do not rotate the plane of polarized light

• Optical rotation, α, depends on density of an optically active substance

• The specific rotation, at a specified temperature t and wavelength λ is given by the equation

• Where l is the length in decimeters (dm) of the light path through the sample

• g is the number of grams of optically active substance in ν millilitre volume

Optical Rotation- Applications

• For identification of substance

• Purity of a substance can be measured

• Concentration of a substance dissolved in a substance can be determined

Optical Rotation- Determination

• A polarimetry is used to measure optical activity

Dielectric Constant

• Dielectric constant is a physical property that is influenced by interatomic and intermolecular attractions

• It is a measure of efficiency of a substance to induce dipoles in another molecule

• Condenser is one that can store electricity

• Condenser consists of two parallel plates separated by an insulating medium

• Electricity that a condenser store is directly proportional to the potential difference in volts applied across the plate

• Electricity in a condenser (coulombs) ∝potential difference (volts)

Electricity in a condenser, q = constant x potential difference, ν

• The constant is designated as capacitance and given as:

      q

C =  ------

        ν

• Dielectric constant can be given as:

     C_x

ε = -------

      C₀

Where, ε is dielectric constant of liquid, C_x  is capacitance of condenser in liquid and C₀is capacitance of condenser in vacuum

• Dielectric constant is a physicochemical property of a solvent relating to the amount of energy required to separate two oppositely charged regions in the solvent as compared to the energy required to separate the same in vacuum

• Dielectric constant is dimensionless because it is the ratio of two capacitances

Dielectric Constant in Nonpolar Compounds

• When nonpolar compounds are kept between the plates, an induced polarization of the molecule occurs

• The induced dipole moment is proportional to the field strength of the capacitor and the induced polarizability, α_p

• The relationship can be represented as

n is the number of molecules per unit volume

Dielectric Constant- Applications

• Measurement of polarity of a solvent

• Solubilisation of drugs

• Selection of solvents for the solubility of drugs

Summary

• Liquid crystals (mesophase) - These are intermediate between the liquid and solid state

• The two main types of liquid crystals are termed as:

- Smectic (soap like or grease like)

- Nematic (threadlike)

• Because of their intermediate nature, liquid crystals have some properties of liquids and some properties of solids

• Snell’s law -Itstates that the refractive index (n) of the liquid as a constant ratio of the sine of the angle of incidence to that of the refraction. It is given by

     sin i

n =  ---------

    sin r

• Molar refraction R_m- Itis related to both the refractive index and the molecular properties of a compound being tested. It is given by

• Dipolar molecule -It is defined as the one in which the regions of positive and negative charges are well separated

• Dipole moment-It is defined as the vector equal in magnitude to the product of electric charge and distance, having the direction of the line joining the positive and negative centers

• In a polar molecule, the separation of positively and negatively charged regions are permanent and the molecule will possess a permanent dipole moment, μ

• Dipole moment is defined as the vector equal in magnitude to the product of electric charge and distance, having the direction of the line joining the positive and negative centers

• The greater the dissociation constant of the acid, the stronger is the acid

pK_a = - log [K_a]

• pKb is defined as the negative logarithm of   base ionization constant and it is expressed by

pk_b = -log [K_b]

• Plane polarised light- When light is allowed to pass through a polarizing prism (Nicol prism), light vibrations in only one plane are transmitted, and such a light beam is known as plane polarized light

• Optical activity -It is the ability of certain substances to rotate the plane polarized light

• Optically active substances - These are the substances which can rotate the plane polarized light either to right- side or to left- side

• Dextrorotatory substances rotate the plane polarised light towards the right, has an α, that is defined as positive

• Levorotatory substances rotate the plane polarised light towards left, has an α, that is defined as negative

• Specific rotation -The specific rotation, at a specified temperature t and wavelength λ is given by the equation

• A polarimeter is used to measure optical rotation

• Dielectric constant – It is a physicochemical property of a solvent relating to the amount of energy required to separate two oppositely charged regions in the solvent as compared to the energy required to separate the same in vacuum

• Dielectric constant can be given as:

      C_x

ε =  -------

        C₀

• Dielectric constant is dimensionless

For PDF Notes Click on Download Button