Lloyd S.

Arboleda
Prepared by: Lloyd S. Arboleda
BS Pharmacy Where,
College of Pharmacy and Medical Technology P = pressure
V = volume
University of San Agustin, iloilo City n = number of moles of gas.
R = molar gas constant/constant value for PV/T ratio of an
Chapter 2 – States of Matter ideal gas (0.08205)
T = temperature
Intramolecular force – force of attraction that exist w/in a molecule.
Intermolecular force – force of attraction that exist between 2 molecules. Boyles Law Charles Law
P1V1 = P2 V2 V1 = V2
Impt. to Pharmaceutical Sciences: T1 T2
1. Manufacture of various preparations Gay – Lussac Law Combined Gas Law
2. Stability study P1 = P2 P1V1 = P2 V2
3. Design of new products/drugs
T1 T2 T1 T2
Essential to:
1. Predict physicohemical properties of various dosage forms.
Molecular Weight determination of Gas:
2. Interpret drug action at molecular level.
PV = gRT
3. Structure activity correlation.
M
Various types of Forces
Where,
I. Attractive & Repulsive Forces
Number of moles of gas n is replaced by its equivalent g/M, in which
• Operate & exist simultaneously.
g = number of grams of gas
Attraction 2 molecules of opposite charge are brought closer together
M = molecular weight
causing molecules to attract one another.
Attractive forces Necessary in order for molecules to cohere.
Kinetic molecular theory
Repulsion Molecules are brought so close that the outer charge clouds • Capable of explaining various laws of gaseous behavior.
touch, therefore molecules repel. 1. Gases are composed of particles called atoms or molecules, the total volume of
Repulsive forces Necessary in order that molecules do not interpenetrate & which is so small as to be negligible in relation to the volume of the space in
destroy one another. which the molecules are confined. This condition is approximated in actual gases
only at low pressures and high temperatures, in which case the molecules of the
Manifestation of Intermolecular Forces: gas are far apart.
1. Cohesion – attraction of like molecules. 2. The particles of the gas do not attract one another, but instead move with
2. Adhesion – attraction of unline molecules. complete independence (applies only at low pressures).
3. The particles exhibit continuous random motion owing to their kinetic energy.
II. Van der Waals Forces The average kinetic energy, E, is directly proportional to the absolute
• Exist in most of organic compounds w/ covalent compounds wherein electrons temperature of the gas, or E = (3/2)RT.
are being shared. 4. The molecules exhibit perfect elasticity; that is, there is no net loss of speed or
1. Dipole – dipole interaction • “Keesom forces” or “Orientation effect” transfer of energy after they collide with one another and with the molecules in
• Occurs on dipolar molecules the walls of the confining vessel, which latter effect accounts for the gas
• Ex. Alcohol + water, water + acetone pressure. Although the net velocity, and therefore the average kinetic energy,
2. Dipole – induced dipole interaction • “Debye forces” or “Induction effect” does not change on collision, the speed and energy of the individual molecules
• Occurs between polar & non – polar may differ widely at any instant. More simply stated, the net velocity can be an
molecules. average velocity of many molecules; thus, a distribution of individual molecular
• Ex. Oil + water velocities can be present in the system.
3. Induced – dipole – Induced – • “London attraction or Dispersion
dipole interaction Forces/Effect” Van der Waals Equation for Real Gases
• Occurs between 2 atoms of different
molecule.
• Ex. Oil + Benzene
Where,
III. Ion Dipole/Ion Induced Dipole Forces
Ion Dipole Forces Occurs between polar & ionic compounds.
Ex. NaCl
Ion – Induced Dipole Forces Non – polar & ionic compounds. Methods used to determine Molecular Weight of easily Vaporized Liquids
Ex. KI + water 1. Regnault method For subs. that are gaseous at room temp.
2. Victor Meyer Determined at definite temp. & barometric pressure.
IV. Hydrogen Bond method
• Interaction between a molecule containing H+ atom & a strongly 3. Dumas method Used to determined molecular weight in vapor phase of
electronegative atom forming an electrostatic type of union. readily volatile liquid.
May form into:
1. Intermolecular bond Forms dimmers & polymers Types of Adsorption of Gas by Solid
2. Intramolecular bond Predict the physical property of substance by presence 1. Physical/Van der Waals absorption Reversible; the removal of an
of hydrogen bond. adsorbate from adsorbent
“Desorption”.
V. Hydrophobic Interaction Physically adsorbed gas may be
• Association of non – polar groups w/ each other arising due to tendency of desrobed from solid by increasing
water molecule to exclude non – polar molecules. temperature & reducing the pressure.
2. Chemical/Chemosorption Adsorbate is attached to the adsorbent
4 Phases of Matter by primary chemical bonds, is
1. Gaseous phase reversible.
2. Liquid phase
3. Solid & Crystalline phase Degree of Absorption of Gas by a solid depends on the ff:
4. Liquid Crystalline phase a. Chemical nature of adsorbent & adsorbate or substance being absorbed
b. Surface area of adsorbent ( ↑surface area, ↑ adsorption)
1. Gaseous phase c. Temp. (↑temp.,  adsorption)
“Vapor state” d. Partial pressure of adsorbed gas (not yet added)

Ideal Gas Law - formulated by Boyle, Charles, and Gay-Lussac. 2. Liquid phase
PV = nRT • Transition from gas to liquid state.
 Lloyd S. Arboleda

Critical • Temp. above w/c a liquid can no longer exist.

Temperature 2 component system containing solid & liquid phases:
Critical Pressure • Pressure required to liquefy a gas. Eutectic mixture • Solid & liquid mixtures in w/c 2 components are
• The further a gas is cooled below its critical completely miscible in the liquid state & immiscible
temperature, the less pressure is required to as solids.
liquefy it. • Exist when there’s a decrease in melting point of 2
Equilibrium Vapor • Pressure of saturated vapor above the liquid. substances.
Pressure • As the temp. of liquid is elevated, more Amorphous solids • Super – cooled liquid in w/c molecules are arranged
molecules approach velocity for escape & pass in a random manner as in the liquid state.
into gaseous state.
• Vapor pressure increases w/ rising temp. 4. Liquid Crystalline phase
Boiling Point • Temp. at w/c vapor pressure of a liquid equals • Intermediate between the liquid & solid phase.
the external pressure. 3 main types of Liquid Crystal
• Temp. at w/c thermal agitation can overcome 1. Smectic • Soap or grease like.
the attractive forces between the molecules of • Molecules are mobile in 2 direction.
liquid. 2. Nematic • Thread – like.
• Increases when molecular weight increases. • Molecules are mobile in 3 dimension but rotate in
Latent Heat of • Heat taken up when the liquid vaporize & are one axis.
Vaporization liberated when vapor condense to liquid. 3. Cholesteric • Special case of nematic.
Clausius – Clapeyron Equation
• Relationship between vapor pressure & absolute temp. Phase equilibria & Phase Rule
• Useful device for relating effects of least number of dependent variable upon
various phases than can exist in equilibrium containing a given number of
components.
Where, Formulated by: J. Williard Gibbs
p1 and p2 = VPs at absolute temperatures T1 and T2. Eq: F = C – P + 2
ΔHv = molar heat of vaporization; heat absorbed by 1
mole of liquid when it passes into vapor state. Where,
R = molar gas constant (0.08205 liter atm /mol K) F = number of degrees of freedom in a system.
C = number of components.
Methods of achieving liquefaction: P = number of phases.
1. Subject to intense cold w/ use of freezing mixture
2. Depends on cooling effect produced by a gas as it expands. Chapter 3 – Thermodynamics
Adiabatic expansion – does work external.
Joule – Thomson effect – does work internal Thermodynamics
• Quantitative relationships between heat & other forms of energy.
3. Solid & Crystalline phase • Rest upon 3 basic laws.
• Arranged in fixed geometric patterns or lattices. System
• Incompressible, have definite shapes & definite melting points. • Part of universe separated from the surroundings.
6 distinct Crystal System Work
Pattern Samples • Concept of work may be expressed as a product of an intensity factor & capacity
Cubic NaCl factor.
Tetragonal Urea Formula: dW = Fdl
Hexagonal Iodoform Where,
Rhombic Iodine dW = differential work done.
Monoclinic Sucrose F = force (intensity factor).
Triclinic Boric acid dl = differential distance (capacity factors).
Heat
Unit composition of Crystal structure • Flow into a system w/c is taken to be positive quantity & results in an increase in
1. Atoms internal energy of system.
2. Molecules Formula: dE = dq
3. Ions Where,
q = transfer of thermal energy.
Terms: Forms of Energy w/ Factors & accompanying Units
Melting point/Freezing Temp. at w/c pure liquid & solid exist in equilibrium. Energy Form Intensity or Potential Factor Capacity or Quantity Factor
point (Intensive Property) (Extensive Property)
Latent Heat of Fusion Heat absorbed when a gram of solid melts or heat liberated Heat (thermal) Temperature (deg) Entropy change (cal/deg)
when it freezes. Expansion Pressure (dyne/cm2) Volume change (cm3)
Heat of Fusion Heat required to increase the inter atomic or intermolecular Surface Surface tension (dyne/cm) Area change (cm2)
distances in crystals, hence melting occur. Electric Electromotive force or Quantity of electricity
Polymorphism Exist in more than one crystalline form. potential difference (volts) (coulombs)
Polymorhps Having different melting point, x- ray diffraction Chemical Chemical potential (cal/mole) Number of moles
pattern, solubility though they are chemically identical.
Solvates Sometimes called Pseudopolymorphs. 3 types of Systems:
1. Open system – energy and matter can be exchanged with the surrounding.
Impt. properties of Polymorphs 2. Closed system – energy can be exchanged with the surroundings but not
1. Enantiomers Change from one form to the other is reversible. matter.
2. Monotropism Transition takes place in one direction. 3. Isolated – neither matter nor energy can be exchanged with the surroundings.

Le Chateliers Principle 1st Law of Thermodynamics

• System at equilibrium readjust so as to reduce the effect of external • Law of Conservation of Energy.
stress. • States that energy can be transformed from one form into another, but it cannot be
created nor destroyed.
Condensed system E=Q–W
• Vapor phase (gas) is ignored, only solid & liquid phases are considered. Where,
 E = increase in internal energy.
2 component system containing liquid phase: Q = heat absorb.
Critical soln or Upper consolute W = work done by a system.
• Maximum temp. at w/c 2 phases region exist.
 Lloyd S. Arboleda
Heat of combustion Heat involved in the complete oxidation of 1 mole of a
compound at 1atm.

Processes occuring under various conditions

1. Isobaric Process
2. Adiabatic Process
3. Isochoric or Isometric
4. Isothermal Process
5. Isothermal & reversible
Process (Ideal Gas Law)
2nd Law of Thermodynamics
• A spontaneous rxn involving a system & its surroundings proceed in the direction of
increase entrophy; when the system reaches equilibrium net entropy change
undergone by the system & its surroundings is equal to zero.
Terms:
Entropy (S)
Reversible process
Molar Heat Capacity (C)
Enthalpy (H)
• Work at expansion at constant pressure.
a. Work done by the surroundings – heat is absorbed. Chapter 4 – Physical Properties of Drug Molecules
b. Work done on the system – heat is evolved.
Formulas: Important Physical Properties of Molecules:
H = Qp E = H - PV 1. Electromagnetic Radiation
E = Qp – P(V2 – V1) • A wave model & a field vibrating about a point in space.
• When heat is neither lost nor gained during the process. Λv = C
Q=0 E = -W Where,
• At free expansion & constant volume. v (frequency) = no. of waves passing a fix in 1 sec.
W = PV = 0 Λ (wavelength) = distance between 2 successive maxima of wave.
v=v
W = P(V2 – V1) E = Qv
c
• When temp. is kept constant during the process.
Where,
E = 0
c = speed of light.
Q = W V = wave number.
• In state of virtual thermodynamic equilibrium:
PV = nRT W = nRT InV2 Electromagnetic energy – characterized by continuous wave form of radiation.
V1 Electromagnetic spectrum – classified according to its wave length w/ corresponding
number.
P = nRT W = nRT InP1 Quantum theory – radiant energy absorb by a chemical species has discrete values
V P2 corresponding tp the individual energy transition that can occur in an atom
or molecule.
W = FV 2. Atomic Spectra
• Interaction between Electromagnetic radiation of certain wave length & electrons in
orbital of an atom.
E = hcv
Where,
E = energy of photon of electromagnetic radiation.
h = Plank’s constant (6.626 x 10-34 J sec)
• Measure of randomness or disorderliness of a system & is cv = v frequency of radiation.
fundamental for predicting spontaneity of chemical rxn.
S = Q H = Q S = H Ionization potential – energy required resulting in ionization of a nucleus.
T T Significance:
• Troutons Rule 1. Used to identify & quantify specific elements.
S = nCP InP2 2. Pharmaceutical application.
P1
• Heat (Q) required to raise the temp. of 1 mole of a 3. Molecular Spectra
substance by 1 degree. • More complex than those of atoms.
H = nCPT c=q Absorption of Electromagnetic radiation by molecules include:
E = nCvT dt 1. Vibration transition Associated w/ stretching & bending of bond.
• Heat content 2. Rotational transition Rotation of molecules at the center of gravity.
H = E + W 3. Electronic transition Associated w/ movement of electrons from orbital to another.
H = E + PV 4. Translation transition Straight line.

3rd Law of Thermodynamics 4. Ultraviolet & Visible Spectrophotometry

• The entropy of a crystalline substance is zero at absolute zero. • When organic molecules in soln exposed to light in the V & UV region of the spectrum,
G = Gibbs energy they absorb light of particular wavelength depending on type of electronic transition
associated w/ absorption.
2 new Theromodynamic Properties: Chromophores – part of a molecule directly associated w/ absorption of UV & V light.
1. Helmholtz Free Energy (A) Beer’s Law - relates to the amount of light absorb (A), to the concentration of the
A = E – TS absorbing substance (c) & the length of path (b) of radiation passing through the sample.
2. Gibbs Free Energy (G) A = abc a – constant for absorption
G = E + PV – TS
Beer’s Law Plot – absorbance is plotted against the concentration.
Factors for predicting Spontaneity
Isolated system Ds > 0 (+) Impt. applications of Spectrophotometry
Isothermal & Isochoric system dA < 0 1. Useful tool for studying chemical equilibrium.
2. Used to study enzyme reaction & evaluate effects of drugs on enzyme.
Isothermal & Isobaric system dG < 0 (-)
3. Quantitative analysis in pharmaceutical calculation.
Constant volume & entropy dE< 0
5. Fluorescence & Phosphorescence
Summary:
• Are the emission of light depending on the mechanism.
Spontaneous Process S > 0 (+)
G < 0 (-) Photoluminescence – emission of UV & V light upon returning on the ground state.
At equilibrium S = 0
G = 0 6. Dielectric constant & Induced Polarization
Non – spontaneous process S < 0 (-)
G > 0 (+) Terms:
Dielectric Constant Ratio of 2 capacitances; no dimension.
Terms:
Thermochemistry Study of heat changes in chemical rxn.
Hess’s Law When reactants are coverted to products, the changes in
Where,
enthalpy is the same whether the rxn takes in a single step or
Capacitance (C) – in Farads
in a series of steps.
q = quantity of electric charge in coulomb.
Heat of Formation Heat involved in the formation of a compound from its
v = potential difference.
elements.
Induced Polarization Occurs when nonpolar molecules in a suitable solvent are
 Lloyd S. Arboleda
placed between the plates of a charge capacitor. Terms:
Induced Dipole Occurs because of separationof electric charge w/in the Dextrorotatory A clockwise rotation (+) the beam to the right, produces an
molecules when placed in electric field between the plates. angle of rotation.
Polarizability Ease with which an ion or molecule can be polarized by any Levorotatory A counterclockwise rotation (-) rotating the beam to the left.
external force, whether it be an electric field or light energy or Optical rotary dispersion The measurement of the angle of roration as a function of
through interaction with another molecule. Large anions have (ORD) wavelenth.
large polarizabilities because of their loosely held outer
electrons. 12. Circular Dichroism (CD)
Induced Molar Polarizability • An effect w/c causes circlularly polarized light to become elliptically polarized.

Circular Dichroism Spectra

• Plots of molar ellipticity, [θ], which is proportional to the difference in
absorptivities between the two components of circularly polarized light,
7. Permanent Dipole Moment of Polar Molecules
against the wavelength of light.
• Separation of positively and negatively charged regions can be permanent, and the
molecule will possess a permanent dipole moment, µ.
Chapter 5 – Solutions of Non – Electolytes
Terms:
True solutions Mixture of 2/more components to form a homogenous molecular
dispersion or one system.
Where,
System Definite quantity of substance that is under observation &
P = total molar polarization.
experimentation.
P1 = induction
P0 = permanent dipole effect. Phase A distinct homogenous part of system separated by definite
boundaries from other part of system.
8. Infrared Spectroscopy Coarse dispersion Particle size in emulsion & suspension.
• Study of the interaction of electromagnetic radiation with vibrational or rotational Larger than 0.1 m.
resonances (i.e., the harmonic oscillations associated with the stretching or bending Colloidal dispersion Particle size ranges between 10 to 5000 Angstrom.
of the bond) within a molecular structure. Heterogenous 2 – phase system.
Homogenous 1 – phase system.
Significance: Binary soln Composed of 2 substances.
1. Drug identification
2. Qualitative & Quantitaive analysis of Drugs Classifications of Physical properties of Substances
3. to Analyze aqueous sample Colligative properties Depend mainly on number of particles in soln.
Includes:
9. Electron Spin Resonance Spectrosopy osmotic pressure, freezing point depression, vapor pressure
• Applied to the study of free radical processes, including pathways of photosynthesis lowering, boiling point elevation.
& to the structure of metal complexes. Additive properties Depend on total contribution of atoms in the molecules or on the
• Useful only for species that possess unpaired electrons. sum of properties of constituents in soln.
E = hv = gBeH Ex. Molecular weight of a compound.
Where, Constitutive properties Depend on arrangement & to lesser extent on number & kind of
E = energy difference atoms in molecules in a system.
h = Plank’s constant (6.626 x 10-34) Ex. Refraction of light, optical activity, surface & interfacial
v = frequency characteristics.
g = factor for metal complexes
Be = Borh magneton (9.27 x 10-24) Thermodynamically
H = magnetic field 1. Extensive property Depends on quantity of matter in the system.
2. Intensive property Independent of the amount of substance in the system.
Nuclear Magnetic Resonance Spectroscopy
• Study of interaction of electromagnetic radiation from the radioactive region of 2 Classes of Solute
the spectrum w/ the spin of nuclei in the magnetic field. 1. Non – Electrolyte • Substances that do not yield ions when dissolve in water.
E = hv = (1 - )
• Do not conduct electric current.
Where,
• Shows regular colligative property.
 = nuclei w/ magnetic moments.
• Ex. Sucrose, glycerin, naphthalene, urea
 = shielding constant for a particular atom.
2. Electrolyte • Substances that form ions in soln.
• Conducts electric current.
10. Refractive Index & Molar Refraction
Refractive Index • Shows apparent anomalous colligative property.
• Refractive index varies with the wavelength of light and the temperature because both • Ex. NaCl, H2SO4, H3PO4
alter the energy of interaction. Subdivided into:
• Pressure must also be held constant in measuring the refractive index of gases. Strong electrolyte • Completely dissociated into ions.
Weak electrolyte • Not dissociated into ions.
Used to:
• Identify a substance Ideal solution
• Measure its purity • There is no change in the property of the component when they are mized to form a
• Determine the concentration of one substance dissolved in another. soln.
• No heat is evolved or absorbed during the mizing process.
• Final volume represents an additive property of individual constituents.
• There’s escaping tendency of vapor pressure.
Where, • Fomed by mixing substance of similar properties.
sin I = sine of the angle of incident ray of light.
sin r = sine of angle of refracted ray. Psoln = PA + PB + PC

Molar Refraction (Rm) Terms:

• Related to both the refractive index and the molecular properties of a compound Escaping Tendency Happens when one body is heated to a higher temperature
being tested. than the other, heat will flow “downhill” from the hotter to
the colder body until both bodies are again in thermal
equilibrium.
Free energy Quantitative measure of the escaping tendencies of material
Where, substances undergoing physical and chemical
M = molecular weight. transformations.
ρ = density of the compound.
11. Optical Rotation

Molar Free Energy
Partial molar free
energy or Chemical
potential
Ideal Solutions and
Raoult's Law
Non – Ideal or Real Solutions
• Mixtures w/c occur even though the liquid are miscible in all proportion.
• Heat is evolved or absorbed during the mixing process.
• Its only the solvent that has the capacity to escape off its vapor pressure.
• They don’t adhere to Raoult’s Law throughout the entire range of composition.
Henry's Law
• Becomes identical with Raoult's law.
• Law applies to the solute and Raoult's law applies to the solvent in dilute solutions of real
liquid pairs.
1. Vapor Pressure
Lowering
2. Boiling Point Elevation
3. Freezing Point
Depression
4. Osmotic Pressure
Lloyd S. Arboleda
Free energy per mole w/c provides a measure of escaping Morse equation:  = RTm
tendency for pure substance.  = n2RT
Expression of escaping tendency for the constituent of a V
solution.
Osmotic Pressure Osmometer
Partial vapor pressure of each volatile constituent is equal - Apparatus used to determine Osmotic
to the vapor pressure of the pure constituent multiplied by Pressure.
its mole fraction in the solution. Van’t Hoff
- Recognize a proportion between
osmotic pressure, conc. & temp.
rotating to ideal gas equation.
I. Concentration Expressions
• Concentration of a solution can be expressed either in terms of the quantity of
solute in a definite volume of solution or as the quantity of solute in a definite
mass of solvent or solution.
Expression Symbol Definition
Molarity M,c Moles (gram molecular
weights) of solute in 1 liter of
solution
Normality N Gram equivalent weights of
solute in 1 liter of solution
Molality m Moles of solute in 1000 g of
solvent
Different Colligative Properties Mole fraction X,N Ratio of the moles of one
• According to Raoult's law, the vapor pressure, p1, of a constituent (e.g., the solute) of
solvent over a dilute solution is equal to the vapor pressure a solution to the total moles of
of the pure solvent, p1°, times the mole fraction of solvent all constituents (solute and
in the solution, X1. solvent)
VPL: ΔP = P1° - P Mole percent Moles of one constituent in
100 moles of the solution;
mole percent is obtained by
Rel. VPL: multiplying mole fraction by
100
Percent by weight % w/w Grams of solute in 100 g of
• The vapor pressure curve for the solution lies below that of solution
the pure solvent, and the temperature of the solution must Percent by volume % v/v Milliliters of solute in 100 mL of
be elevated to a value above that of the solvent in order to solution
reach the normal boiling point. Percent weight-in-volume % w/v Grams of solute in 100 mL of
solution
BPE: ΔTb = T - To Milligram percent — Milligrams of solute in 100 mL
of solution
Kb = molal elevation constant. II. Equivalent Weights
= ebullioscopic constant.
= ratio of BPE to the molal concentration in dilute soln. = gram
Eq.
Application of Clapeyron Equation
Cottrell Boiling Point apparatus
- Used to determine BP of pure solvent.
• Proportional to the molal concentration of the
solute.
Kf = molal depression constant or
III. Molecular weight
cryoscopic constant.
• 4 colligative properties may be usedto calculate the molecular weight of non –
elctrolyte present as solutes.
V.L.P. B.P.E. F.P.D.
Tf = freezing point of solvent.
T = freezing point of solution.
Methods for Determination:  = RTm
1. Beckmann method
2. Equilibrium method Chapter 6 – Solutions of Electrolytes
- Most accurate procedure for obtaining
freezing point data. Arrhenius (1887)
• Propsed the theory of Ionic soln based on following studies:
• The excess pressure, or pressure greater than that
1. Electric conductance by Kohlrausch
above the pure solvent, that must be applied to the
solution to prevent the passage of the solvent 2. Colligative properties by van't Hoff
3. Chemical properties (heats of neutralization) by Thomsen
through a perfect semipermeable membrane.
Theory of electrolytic dissociation
Osmotic Pressure:  (ATM) = hpgravity accelaretion
• When electrolytes are dissolved in water they split into charged particles (Ions).
Van’t Hoff equation: V = nRT
 = nRT = cRT
Debye-Hückel Theory (1923)
V
 Lloyd S. Arboleda
• Strong electrolytes are completely dissociated into ions in solutions of moderate
concentration and that any deviation from complete dissociation is due to interionic
attractions.
van't Hoff factor
Electrolysis • Can also be expressed as the ratio of any colligative property of a real solution to that of
• Chemical reaction occurs when under a potential of several volts, a direct electric current (dc) an ideal solution of a nonelectrolyte because i represents the number of times greater
flows through an electrolytic cell. that the colligative effect is for a real solution (electrolyte or nonelectrolyte) than for an
Transport or Transference number ideal nonelectrolyte.
• Fraction of total current carried by the cations or by the anions.
Theory of electrolytic dissociation (Arrhenius)
• When electrolytes are dissolved in water, the solute exist in form of ions in the soln.
NaCl + H20 → Na+ + Cl- + H20

Strong electrolytes • Exist almost completely in the ionic form.

• Ex. NaCl, HCl, inorganic acids, inorganic bases
Ohm’s Law Weak electrolytes • Not readily dissociated into ions.
• The strength of an electric current I in amperes flowing through a metallic conductor • Ex. Acetic acid, Organic acids & bases, inorganic
is related to the difference in applied potential or voltageE and the resistance R in ohms. compounds, salts & complex ions
or
Degree of Dissociation
• A strong electrolyte was one that dissociated into ions to a high degree and
a weak electrolyte was one that dissociated into ions to a low degree.

Where,
Faraday’s Law
Λc = number of solute particles present at a concentration.
• 1833 and 1834, Michael Faraday announced his famous laws of electricity. Λ0 = equivalent conductance at infinite dilution.
• Passage of 96,500 coulombs of electricity through a conductivity cell produces a Λc/Λ0 = conductance ratio.
chemical change of 1 g equivalent weight of any substance. The quantity 96,500 is known as
4
the faraday, F. The best estimate of the value today is 9.648456 × 10 coulombs/gram Degree of Dissociation w/ van't Hoff factor, i,
equivalent.

Faraday (F) = qnty. of 96,500 coulombs of electricity

= 9.648456 × 104 coulombs/gram equivalent. Theory of Strong Electrolytes
• Arrhenius used α to express the degree of dissociation of both strong and weak
Avogadro’s number = 6.02 × 1023
of positive or negative charges electrolytes.
= passage of 96,500 coulombs of electricity results in the transport of 6.02
• van't Hoff introduced the factor i to account for the deviation of strong and weak
× 1023 electrons in the cell. electrolytes and nonelectrolytes from the ideal laws of the colligative properties.
= One faraday is an Avogadro's number of electrons, corresponding to the
• Arrhenius theory is now accepted for describing the behavior only of weak electrolytes.
mole, which is an Avogadro's number of molecules.
The degree of dissociation of a weak electrolyte can be calculated satisfactorily from
the conductance ratio Λc/Λ0 or obtained from the van't Hoff i factor.
• Strong electrolytes may be completely ionized but incompletely dissociated into free
ions.

Debye – Huckel Theory

• Equation based on the principles that strong electrolytes are completely ionized in dilute
solution and that the deviations of electrolytic solutions from ideal behavior are due to
Electrolytic conductance
the electrostatic effects of the oppositely charged ions.
• The resistance, R, in ohms of any uniform metallic or electrolytic conductor
• Equation relates the activity coefficient of a particular ion or the mean ionic activity
is directly proportional to its length, l, in cm and inversely proportional to its
coefficient of an electrolyte to the valence of the ions, the ionic strength of the solution,
cross-sectional area, A, in cm2.
and the characteristics of the solvent.
• Equation can be used to calculate the activity coefficients of drugs whose values have not
been obtained experimentally and are not available in the literature.

activity coefficient, γi, of an ion of valence zi is given by the expression

Specific resistance = between faces

of a 1cm cube of the conductor.
yields a satisfactory measure of the activity coefficient of an ion species up to an ionic
C = conductance; the reciprocal of
strength, µ, of about 0.02. For water at 25°C, A, a factor that depends only on the
resistance.
temperature and the dielectric constant of the medium, is approximately equal to 0.51.
K = specific conductance; reciprocal
of specific resistance.
Quivalent conductance Chapter 7 – Ionic Equilibria
• Λ; conductance of a solution of sufficient volume to contain 1 g equivalent of
the solute when measured in a cell in which the electrodes are spaced 1 cm According to Arrhenius theory • Acid – substance w/c liberates H+ ion.
apart. • Base – substance w/c supplies OH- ion.
According to Bronsted – Lowry theory • Acid – substance (charged/uncharged) capable
of donating a proton.
Where, • Base – substance (charged/uncharged) capable
Λc = eq. conductance at a conc. of gram eq./L of accepting a proton.
K = specific conductance per cm3 of soln.
V = volume in cm3 containing 1gm eq. wt. of solute. Relative strengths of acids and bases are measured by:
1. Tendency to donate or accept a proton.
Colligative property of Electrolytic Solution & Concentrated Solution of Non – electrolyte 2. Ability of solvent to accept the proton from acid.
 = RTc
c = concentration in moles/L
i = correction factor Classification of Solvents
Tf = iKfm Protophilic or basic solvent • One that is capable of accepting protons from
= accounts for irrational behavior
Tb = iKfm solute.
of ionic soln.
P = 0.018ip10m = express the departure of concentrated soln of non • Solvents: acetone, ether, and liquid ammonia
– electrolyte from laws of ideal soln. Protogenic solvent • Proton-donating compound.
= plotted against the molal concentration of both
electrolyte & non – electrolyte.
 Lloyd S. Arboleda
• “acidic solvents”: formic acid, acetic acid, • The concentration of either the hydrogen or the hydroxyl ion in acidic, neutral, or basic
sulfuric acid, liquid HCl, and liquid HF. solutions is usually expressed in terms of the hydrogen ion concentration or in pH unit.
Amphiprotic solvents • Act as both proton acceptors and proton
donors.
• Solvents: water and the alcohols.
Aprotic solvents • Hydrocarbons, neither accept nor donate
protons, and, being neutral.
• Useful for studying the reactions of acids and
bases free of solvent effects. Kw = dissociation constant; autoprotolysis constant; ion product of water.

Relationship: Kw = KaKb Ka = Kw Kb = Kw
Kb Kb
Brönsted–Lowry classification for acids and bases
Anions HSO4-, CH3COO-
Cations NH4+, H3O+
Ionization of Polyprotic Electrolytes
Neutral HCl, NH3 • One that is capable of donating two or more protons (polyprotic acid), and a polyprotic
base is capable of accepting two or more protons (polyprotic base).

Protolytic reactions or protolysis - reactions involve a transfer of a proton.

Acid–base pair or conjugate pair – pair of substance w/c has a mutual ability to gain or lose a Ampholytes
proton. • Species that can function either as an acid or as a base.
Lewis Electronic Theory - an acid is a molecule or an ion that accepts an electron pair to form a
• Amphoteric in nature.
covalent bond. A base is a substance that provides the pair of unshared electrons
• Donates or accepts electron.
by which the base coordinates with an acid.
• Ex. Amino acids & protein.
Equilibrium – a balance between two opposing forces or actions.
Chemical equilibrium - maintains the concentrations of the reactants and products constant.
pH
• Power of hydrogen.
Brönsted–Lowry manner of Writing Ionization or Protolysis of a weak electrolyte
• Hydrogen ion potential.
• Number of concentration of hydronium ion in a soln.

According to the law of mass action – velocity or rate of the forward reaction (Rf) is proportional to Sorensen
the concentration of the reactants. • Simplified method of expressing hydrogen ion concentration.
• Established the term pH.
• Defined it as the common logarithm of the reciprocal of the hydrogen ion concentration.

reverse reaction (Rr) - expresses the rate of re-formation of un-ionized acetic acid. pKw = pH + pOH
pKw = pKa + pKb pK = dissociation constant.

Proton Balance Equations (PBE)

k1 & k2 = proportionality constants (specific reaction rates) for the forward and the reverse • Sum of the concentration terms for species that form by proton consumption is equated
reactions, respectively, and the brackets indicate concentrations. to the sum of the concentration terms for species that are formed by the release of a
proton.
Ionization of Weak Acids
Quadratic equation
According to the concept of equilibrium, the rate of the forward reaction decreases with
time as acetic acid is depleted, whereas the rate of the reverse reaction begins at zero and increases
as larger quantities of hydrogen ions and acetate ions are formed.
• Solutions for strong acids & bases
• Solutions containing only a weak acid/base
Note: balance is attained when 2 rates are equal. • Solutions containing only a diprotic acid

solving for the ratio: pK of weak acidic & basic drugs are determined by:
a. UV spectrophotometry
b. Potentiometric titration
Equilibrium expression for c. Solubility analysis
the dissociation of Acdetic d. Partition coefficient method
➔
acid.
Ka = equilibrium constant. Chapter 8 – Buffered and Isotonic Solutions
= ionization constant.
= acidity constant. Buffers
• Compounds or mixtures of compounds that, by their presence in solution, resist changes
c = initial molal concentration of Acetic acid in pH upon the addition of small quantities of acid or alkali.
x = concentration of [H3O+), [CH3COO-] • Combination of a weak acid and its conjugate base (i.e., its salt) or a weak base and its
conjugate acid acts.

Buffer action
Ionization of Weak Bases • Ability of soln to resist a change in pH.
• Non – ionized weak base reacts w/ water.
Buffer Equation
• “Henderson – Hasselbalch equation”
• Used to calculate the pH of a buffer soln & the change in pH upon the addition of an acid
or base.

For weak acid and its salt

Kb = basicity constant; ionization constant.

Ionization of Water For weak base and its salt

• The concentration of hydrogen or hydroxyl ions in solutions of acids or bases may
• be expressed as gram ions/liter or as moles/liter.
 Lloyd S. Arboleda

Biologic Buffer System

Factors Influencing the pH of Buffer Solutions Blood Maintained at a pH of about 7.4 by the primary buffers in the
1. Addition of neutral salts to buffers changes the pH of the solution by altering the ionic plasma and the secondary buffers in the erythrocytes.
strength Plasma proteins Bahaves as acids in blood, combine w/ bases and acts as
2. Dilution - addition of water in moderate amounts, although not changing the pH, may cause a small buffers.
positive or negative deviation because it alters activity coefficients and because water itself can act as Lacrimal fluid/tears pH7.4
a weak acid or base. Urine pH 4.5 – 8.7
3. Temperature - ↑ temp, ↑pH
Pharmaceutical Buffers
Drugs as Buffers
Gifford Two stock solutions, one containing boric acid and the other
• Buffers are weak electrolytes, since drugs are weak electrolytes therefore they are
monohydrated sodium carbonate - pH values from about 5
considered as buffers.
to 9.
• Ex. SA & Na salicylate, Ephedrine & Ephedrine HCl
Sörensen Sodium phosphate & its salt - pH 6 to 8.
Hind and Goyan Boric acid, sodium borate & NaCl – pH 7 to 9
pH indicators
Clark–Lubs mixtures HCl and KCl, pH 1.2 to 2.2
• Weak acids or bases that act like buffers & exhibit color changes as their degree of
HCl and potassium hydrogen phthalate, pH 2.2 to 4.0
dissociation varies w/ pH.
NaOH and potassium hydrogen phthalate, pH 4.2 to 5.8
Ex. Methyl red – yellow at pH6
NaOH and KH2PO4, pH 5.8 to 8.0
- Red at pH 4
H3BO3, NaOH, and KCl, pH 8.0 to 10.0
tris – pH 7 to 9
aminohydroxymethyl commonly used in biologic research
Dissociation of an acid indicator:
propanediol
General Procedures for Preparing Pharmaceutical Buffer Solutions
• Select a weak acid having a pKa approximately equal to the pH at which the buffer is to
be used. This will ensure maximum buffer capacity.
Equilibrium expression/equation: • From the buffer equation, calculate the ratio of salt and weak acid required to obtain the
desired pH. The buffer equation is satisfactory for approximate calculations within the pH
range of 4 to 10.
• Consider the individual concentrations of the buffer salt and acid needed to obtain a
suitable buffer capacity. A concentration of 0.05 to 0.5 M is usually sufficient, and a
buffer capacity of 0.01 to 0.1 is generally adequate.
• Other factors of some importance in the choice of a pharmaceutical buffer include
Kin = indicator constant availability of chemicals, sterility of the final solution, stability of the drug and buffer on
Universal indicator aging, cost of materials, and freedom from toxicity. For example, a borate buffer, because
• Consist of a mixture of methyl yellow, methyl red, bromthymol blue, thymol blue & of its toxic effects, certainly cannot be used to stabilize a solution to be administered
phenolphthalein. orally or parenterally.
Color • Finally, determine the pH and buffer capacity of the completed buffered solution using a
reliable pH meter. In some cases, sufficient accuracy is obtained by the use of pH papers.
Indicator Acid Base
Thymol blue (acid range) Red Yellow Influence of Buffer Capacity and pH on Tissue Irritation
Methyl violet Blue Violet • The lower is the buffer capacity of the solution, the smaller is the volume used for a given
concentration, and the larger are the volume and buffer capacity of the physiologic fluid.
Methyl orange Red Yellow
Bromcresol green Yellow Blue
Stability versus Optimum Therapeutic Response
Methyl red Red Yellow
• Undissociated form of a weakly acidic or basic drug often has a higher therapeutic activity
Bromcresol purple Yellow Purple
than that of dissociated salt form because undissociated forms are lipid soluble and can
Bromthymol blue Yellow Blue penetrate body membranes readily, whereas the ionic form, not being lipid soluble, can
Phenol red Yellow Red penetrate membranes only with greater difficulty.
Cresol red Yellow Red
Thymol blue (alkaline Yellow Blue Measurement of Tonicity
range) 1. Hemolytic method
Phenolphthalein Colorless Red • The effect of various solutions of drug is observed on appearance of red
Alizarin yellow Yellow Lilac blood cells suspended in solutions. Husa and his associates used this method.
Indigo carmine Blue Yellow • Quantitative method developed by Hunter was used based on the fact that a
hypotonic solution liberates oxyhemoglobin in direct proportion to the
Buffer capacity β number of cells hemolyzed. By such means, the van't Hoff i factor can be
• buffer efficiency, buffer index, and buffer value. determined and the value compared with that computed from cryoscopic
• Magnitude of the resistance of a buffer to pH changes. data, osmotic coefficient, and activity coefficient.
• Quantitatively the buffer capacity of a solution has a value of 1 when the addition of 1 g • Husa found that a drug having the proper i value as measured by freezing
Eq of strong base (or acid) to 1 liter of the buffer solution results in a change of 1 pH unit. point depression or computed from theoretical equations nevertheless may
• Ratio of the increment of strong base (or acid) to the small change in pH brought about by hemolyze human red blood cells; it was on this basis that he suggested
this addition. restriction of the term isotonic to solutions having equal osmotic pressures
with respect to a particular membrane.

2. Based on any of the methods that determine colligative properties.

Approximate Calculation of Buffer Capacity
Classification of Tonicity
Isotonic When soln has essentially same salt conc. (0.9%) & hence same
More Exact Equation for Buffer Capacity osmotic pressure, vapor pressure & freezing point depression as
RBC contents.
Hypertonic Conc. greater than isotonic conc.
Ex. 2% NaCl
If RBCs are suspended in soln, water w/in cells passess through
Maximum Buffer Capacity cell membrane in an attemp to dilute the surrounding salt soln
until salt concentrations on both sides of erythrocyte membrane
are identical.
Event leads to shrinking of cells/crenation.
Hypotonic Conc. of NaCl is less than 0.9%.
 Lloyd S. Arboleda
If RBCs are suspendend in hypotenic soln, hemolysis will occur 2. Ability of solute to form hydrogen bond
wherein water will enter blood cells causing them to swell & • Water dissolves phenols, alcohols, aldehydes, ketones, amines, and other
finally burst, w/ liberation of hemoglobin. oxygen- and nitrogen-containing compounds that can form hydrogen bonds
Tonicic substance – substance w/c render the soln isotonic w/ body fluid. with water.

Method of Adjusting Tonicity

Class 1 methods NaCl or some other subs is added to soln of drug to lower
freezing point of soln to – 0.52 degree celcius making it
isotonic w/ body fluids.
1. Cryoscopic Method of adjusting tonicity of soln to conform that of the
method blood & lacrimal fluid based on adjustment of the freezing
point of soln to 0.9 NaCl.
2. NaCl equivalent “Tonicic equivalent” of drug is the amount of NaCl that is
(E) equivalent to 1g of drug.
Class 2 methods Water is added to drug in sufficient amount to form an
isotonic soln then preparation is brought to final volume w/
an isotonic or a buffered isotonic soln.
1. White – Vincent Uses equation: V = w x E x 111.1.
method V = volume in mL of isotonic soln that may be prepared by
mixing drug w/ water.
3. Structural features such as the ratio of the polar to the nonpolar groups of the
w = wt. in grams of drug
molecule.
111.1 = constant representing volume in mL of isotonic soln
obtained by dissolving 1g of NaCl in water.
Polar solvents Such as water acts as solvent accrdng to the
2. Sprowls method Wt. of drug was arbitrarily fixed to 0.3g.
following mechanisms:
1. Owing to their High Dielectric constant
• Mean of dipole moment of a
Chapter 9 - Solubility and Distribution Phenomena
molecule.
2. Break covalent bonds of otentially strong
Solutions Chemically or physically homogenous mixture of 2 or
electrolytes by acid – base reaction since these
more substances.
substances are amphiprotic.
Types:
3. Capable of solvating molecules and ions
Saturated soln One in w/c solute is in equilibrium w/ solid phase. through dipole interaction forces, particlularly
Soln has a solute concentration equivalent to its limit hydrogen bond formation w/c leads to solubility
of solubility w/c would mean that if same solute is of compound.
added to this soln, even in minute amounts, will lead
Nonpolar solvents • Unable to reduce the attraction between
to crystallization, precipitation, or insolubility of that
the ions of strong and weak electrolytes
solute.
because of the solvents' low dielectric
Unsaturated/ One containing dissolved solute in a concentration
constants.
Subsaturated soln below that necessary for complete saturation at a
• Break covalent bonds and ionize weak
definite temp.
electrolytes, because they belong to the
Supersaturated soln One containing more dissolved solute than it would
group known as aprotic solvents.
normally contain at a definite temp., were the
• Cannot form hydrogen bridges with
undissolved solute present.
nonelectrolytes. Hence, ionic and polar
solutes are not soluble or are only
Solubility slightly soluble in nonpolar solvents.
• Concentration of solute in a saturated solution at a certain temperature. • Nonpolar compounds can dissolve
• Spontaneous interaction of two or more substances to form a homogeneous molecular nonpolar solutes with similar internal
dispersion. pressures through induced dipole
interactions.
Phase rule • Solute molecules are kept in solution by
• Formulated by: J. Willard Gibbs the weak van der Waals–London type of
• Useful device for relating the effect of the least number of independent variables upon forces.
various phases that can exist in equilibrium system containing a given number of • Alkaloidal bases and fatty acids also
components. dissolve in nonpolar solvents.
Semipolar solvents • Includes ketones and alcohols.
Where,
• Induce a certain degree of polarity in
F = degrees of freedom (referring to variables)
nonpolar solvent molecules.
C = number of components
• Can act as intermediate solvents to bring
P = number of phases P
about miscibility of polar and nonpolar
liquids.
Different ways of expressing solubilty
1. Number of mL of solvent in w/c 1g of solute will dissolve. • Ex. Castor oil in H2O but add alc.
2. In terms of Molarity, Molality & Percentage.
SOLUBILITY (mL of solvent needed to dissolve 1 gram of Solute) Factors that bring about solubility:
1. Polarity
Term Parts of Solvent required to Dissolve 1
2. Dielectric constant
Part of Solute
3. Association
Very soluble Less than 1 part
4. Solvation
Freely soluble 1 – 10 parts 5. Internal pressure
Soluble 10 – 30 parts 6. Acid – base reaction
Sparingly soluble 30 – 100 parts
Slightly soluble 100 – 1, 000 parts Solubility of Gases in Liquids
Very slightly soluble 1000 – 10, 000 parts • Concentration of dissolved gas when it is in equilibrium w/ pure gas above the soln.
Practically insoluble/insoluble/ More than 10, 000 parts Depends primarily on:
relatively insoluble 1. Temperature
• As the temperature increases, the solubility of most gases decreases owing
Factors that enhance/influence of Solubility of Drugs to the greater tendency of gas to expand.
1. Polarity of the solvent
• Dipole moment. 2. Pressure
• Polar solvents dissolve ionic solutes (presence of metals) and other • Expressed by Henry’s Law
polar(sharing) substances.
 Lloyd S. Arboleda
• The concentration of dissolved gas is proportional to the partial pressure of Dielectric Constant & Solubility
the gas above the solution at equilibrium. • Relationship is exhibited by:
• Solubility of a gas increases directly as the pressure of gas and conversely the 1. Barbiturates, parabens, xanthines & other drugs
solubility of a gas decreases as the gas escapes when the pressure above the 2. Caffeine in a mixture of dioxide & water
solution is released. 3. Methyl salicylate, isopropanol – water

3. Salting out Molecular connectivity

• Due to presence of salts. • Technique used by Kier & Hall
• Gases are liberated from solution by the addition or introduction of an • Used in investigating solubility of liquid HC, ROH, ethers & esters in water.
electrolyte or non – electrolyte.
Molecular Surface Area & Solubility
4. Chemical reaction • Method consist of regression analysis, in w/c In(solubility) of solute is correlated w/ the
• Henry’s Law applies strictly to gases that are only slightly soluble in solution total surface area (TSA) of the solute.
and don’t react w/ the solvent.
Solubility
Solubility Calculation for Gas in Liquid 1. Ideal solutions
• Expressed by the inverse Henry’s Law constant. 2. Regular solutions of polar and non – polar character
• Bunsen Absorption Coefficient 3. Solution of high polarity

Solubility of Liquids in Liquids Solubility of solids in ideal solution depends on:

Negative deviations 1. Temperature
• Lead to increased solubility and frequently associated w/ H – bonding between 2. Melting point of solid
polar compounds. 3. Molar heat of fuaion – heat absorb when solid melts.
Positive deviation Solubility Parameters
• Better accounted for by the difference in the cohesive forces of the molecules of • Expresses the cohesion between like molecules may be calculated from:
each constituent. 1. Heat of vapoorization
2. Internal pressure
3. Surface tension

Extended Hildebrand Solubility approaches (EHS)

Pharmaceutical Solution where 2 or more Liquid Mix Together • Calculate solubility of polar & non – polar solutes in solvents.
1. Hydroalcoholic solutions
2. Spirits and elixirs Heat of Solution
3. Aromatic waters • Used to calculate solubiility as a function of temperarture for non – electrolyte, weak &
4. Collodions strong ellectrolyte in highly non – ideal soln.

2 categories of Liquid – Liquid system:

1. Complete misciibility
• Polar, semi – polar & non – polar
• Solvents are completely miscible since they mix all proportion.

2. Partial miscibility
• Soluble but not in all proportion.
• Ex. Water & ether, water & phenol

Lower Consolute Temperature

• Exhibited by 2 – liquid pair system when solubility increases & the temperature
decreases.

Solvation – interaction of solvent w/ solute.

Internal pressure
• Attractive forces w/c occur in gases, liquids & solids.

Where,
Hv = Heat of vaporization
V = molar volume of liquid
R = Gas constant
Pi = Internal pressure in cal/cm
Polar liquid
• High cohesive forces, large internal pressure.
• Solvents only for compunds of similar nature.

Non – polar substance

• Have low internal pressures.
• “Squeezed out” by the powerful attractive forces existing between the molecules of polar
liquid.

Influence of Foreign substance

• Addition of tertiary system
• If the added material is soluble in only one of the 2 components, the mutual solubility of
liquid pair is decrease.
• When the third substance is soluble in both of liquid, the mutual solubility of the liquid
pair is increase.
Blending
• Increase in mutual solubility of 2 partially miscible solvents by another agent.

Micellar solubilization
• When solubility in water of a nonpolar liquid is increased by a micelle forming surface –
active agent.
 Lloyd S. Arboleda

Chapter 10 - Complexation and Protein Binding

Complexes or coordination compounds
• Result from a donor–acceptor mechanism or Lewis acid–base reaction between two or
more different chemical constituents.

Intermolecular forces involved in the formation of complexes:

1. Van der Waals forces of dispersion
2. Dipolar types
3. Induced dipolar types

Classification of Complexes
Metal Ion Complexes
4 groups:
1. Inorganic complexes
3 classes of Complexes/Coordination compounds
Includes atomic or electrotonic structure & hybridization.
Based on atomic structure & molecular forces.
1st describe by Werner in 1891
Composed of single, inorganic complexes such as hexamminecobalt III chloride

Ligand - donates a pair of electrons to form a coordinate covalent link between itself and the central ion having an incomplete electron
shell.

Outer sphere complexes – compounds in w/c the ligand lie above a partially filled orbital.
Inner sphere complexes – when ligand lies below a partially filled orbital.
Electron spin resonance spectroscopy – can detect presence of unpaired electrons in a metal ion complex.
2. Chelates Special type of complex formed by combination of metal w/ a subs. containing 2/more donor groups may combine w/ a metal ion.
Monodentate – chelate whose attachment to the central ion is provided by one group of ligand.
Bidentate ligand – 2 molecules w/ donor groups.
Tridentate – molcules w/ 3 donor groups.
Hexadentate – has 6 points of attachment to metal ion.

Chelation – places stringent steric requirement on both metal & ligands.

Cis – coordinated ligands – ligands adjacent on a molecule can be replaced by reaction w/ a chelating agent.

2 impt. compounds naturally occuring chelates in plants & animals:

1. Chlorophyll
2. Hemoglobin

Ex. Albumin – main carrier of various metal ions & small molecules inm blood serum.
Calcium – EDTA complex/EDTA
- Ethylenediaminetetraacetic acid
- Synthetic chelating agent
- Used to tie up or sequester iron and copper ions so that they cannot catalyze the oxidative degradation of ascorbic acid in fruit
juices and in drug preparations.
- Used to sequester and remove calcium ions from hard water.
3. Olefin type Unsaturated chemical compund containing at least one carbon to carbon double bond.
4. Aromatic type Aromatic rings are attached to these compounds.
Organic Complexes Consist of constituents held together by weak forces of the donor acceptor type or by hydrogen bond.

Factors in the formation of molecular complexes:

1. Steric requirement
2. Hydrogen bonding

Charge transfer complexes – molecular complexes resulting in an ionic interaction or charge transfer.
1. Quinhydrone complex Formed by mixing alcoholic solution of equimolar quantities of benzoquinone & hydroquinone.
1:1 complex formed between benzoquinone & hydroquinone result from overlap of pi – framework of the electron – rich hydrpquinone
molecule.
Maximum overlap between the pi – framework is expected if the aromatic rings are parallel.
2. Picric acid complexes 2, 4, 6 Trinitrophenol, pKa = 0.38
Reacts w/ strong bases to form salts and weak bases to form molecular complexes.
3. Drug complexes Complexation w/ drug & complexing agent can improve or impair drug absorption & bioavailability.
1. Complexing of caffeine with a number of acidic drugs
2. Complexes formed between esters and amines, phenols, ethers, and ketones
3. Caffeine forms complexes with organic acid
 Lloyd S. Arboleda
4. Salicylates form molecular complexes with benzocaine
4. Polymer complexes Forms complexes w/ various drugs:
1. Polyethylene glycols
2. Polystyrene
3. Carboxymethylcellulose
4. Polymers containing nucleophilic oxygens
Inclusion Compounds Involves entrapment of 1 compound in molecular framework of another.
Resulting from architecture of molecules rather than from their chemical affinity.
4 types:
1. Channel Lattice Type Ex. Choleic acids in combination w/ paraffin, organic acids, esters, ketones, aromatic compounds, urea, thiourea, starch – iodine soln with
solvents like: ether, dioxane, alcohol
2. Layer type Ex. Graphite, claymontmorillonite, attapulgite, kaolin, activated charcoal
3. Clathrates Crystallizes in the form of cage – like lattices in w/c the coordinating compound is entrapped.
Ex. Hydroquinone, Warfarin Na, USP
4. Monomolecular inclusion Involves entrapment of single guest molecule in the cavity of one host molecule.
Ex. Cyclodextrins – solubilizing & stabilizing agent in pharmaceutical dosage forms.Cyclic oligosaccharides.
5. Macromolecular inclusion compound Have pores to separate compounds like:
or Molecular Sieve Zeolites, dextrins, silica gel, related subs., sephadex, sepharose

Methods of Analysis • Hydraulic pressure or centrifugation is used to force solvent &

Method of Continuous Use of an additive property such as the small molecules (unbound drug) through the membrane while
Variation spectrophotometric extinction coefficient (dielectric preventing passage of drug bound to protein.
constant or the square of the refractive index may also • Untrafiltrate is then analyse using spectrophotometry.
be used) for the measurement of complexation. Key concept: drug – protein complex cannot pass through the
pH Titration Method One of the most reliable methods and can be used membrane. Problem that may be encountered is that freee drug
whenever the complexation is attended by a change in binds to the membrane.
pH.
Distribution Method Method of distributing a solute between two immiscible Dynamic dialysis
solvents can be used to determine the stability constant • Kinetic method for determining the concentrations of bound
for certain complexes. drug in a protein solution.
Solubility Method Excess quantities of the drug are placed in well-
stoppered containers, together with a solution of the Hydrophobic bonding/interaction
complexing agent in various concentrations, and the • Attraction of hydrophobic species, resulting from their
bottles are agitated in a constant-temperature bath until unwelcome reception in water.
equilibrium is attained. Aliquot portions of the
supernatant liquid are removed and analyzed. Factors Affecting Complexation and Protein Binding
Spectroscopy and Absorption spectroscopy in the visible and ultraviolet 1. Hydrophobicity
Change Transfer regions of the spectrum is commonly used to investigate 2. Electrostatic forces
Complexation electron donor–acceptor or charge transfer complexation
Other Methods Available for studying the complexation of metal and
organic molecular complexes are as follows:
• NMR (Nuclear Magnetic Resonance) Chapter 11 – Diffusion
• Infrared spectroscopy Terms:
• Polarography Diffusion Process of mass transfer of individual molecules of a substance brought
• Circular dichroism about by random molecular motion and associated with a driving force
• Kinetics such as a concentration gradient.
• X-ray diffraction Dialysis Separation process based on unequal rates of passage of solutes and solvent
• Electron diffraction through microporous membranes, carried out in batch or continuous mode.
Osmosis passage of both solute and solvent across a membrane but now refers to
Drug–Protein Binding an action in which only the solvent is transferred.
• Binding of drugs to proteins includes: Ultrafiltration Used to separate colloidal particles and macromolecules by the use of a
1. Facilitate the distribution of drugs throughout the body membrane.
2. Inactivate the drug by not enabling a sufficient concentration of free Membrane “Film” separating the phases, and material passes by passive, active, or
drug to develop at the receptor site facilitated transport across the film.
3. Retard the excretion of a drug Barrier Applies in a more general sense to the region or regions that offer resistance
to passage of a diffusing material.
Interaction of a drug with proteins may cause: Total barrier Sum of individual resistances of membranes.
1. Displacement of body hormones or a coadministered agent
2. Configurational change in the protein, the structurally altered form of Diffusion Process of mass transfer of individual molecules of substance,
which is capable of binding a coadministered agent, or brought about by random molecular motion & associated w/ a
3. Formation of a drug–protein complex concentration gradient.
Other types of Diffusion & transport mechanisms:
Albumin – most impt. among plasma; high concentration in the plasma; Ionic/electrochemical Dependent on electrical gradient across the membrane in w/c
ability to bind both acidic & basic drugs. diffusion a cationic drug molecule will be repelled from positive charge
Methods used to determine amount of Drug bound to a protein: on membrane.
1. Equilibrium Dialysis (ED) Facilitated diffusion There is a special molecule w/in the membrane, called the
2. Ultrafiltration (UF) carrier, w/ w/c the transported substance combines.
3. Electrophoresis Active transport An energy dependent movement of subsance against a
4. Gel filtration gradient (from a region of low to high concentration).
5. Nuclear Magnetic Resonance Pinocytosis Process where the cell membrane invaginates into a saccular
structure & then it is pinched off the membrane.
Equilibrium Dialysis (ED) Exocytosis Opposite of pinocytosis.
• for studying the complexation between metal ions or small Convective transport Drug molecules dissolved in aqueous medium move along w/
molecules and macromolecules that cannot pass through a the solvent through a pore.
semipermeable membrane.
Steady state diffusion
Ultrafiltration method Fick's first law
• macromolecules such as serum albumin are separated from • Amount material flowing through a unit cross section of a barrier in unit time is
small drug molecules. known as flux. The flux, in turn, is proportional to the concentration gradient.
• Similar to equlibrium dialysis.
 Lloyd S. Arboleda
Transcorneal permeation

Percutaneous Absorption
• Percutaneous penetration involves:
Where, 1. Dissolution of a drug in its vehicle
J = flux 2. Diffusion of solubilized drug (solute) from the vehicle to the surface
D = diffusion coefficient of the skin, and
C = concentration 3. Penetration of the drug through the layers of the skin, principally the
x = distance stratum corneum.

Fick's Second Law Important factors influencing the penetration of a drug into the skin:
• A change in concentration of diffusant with time at any distance. 1. Concentration of dissolved drug - Cs, because penetration rate is
proportional to concentration;
Procedures & Apparatus 2. Partition coefficient - K, between the skin and the vehicle, which is a
1. Cells of simple construction measure of the relative affinity of the drug for skin and vehicle; and
- best for diffusion work 3. Diffusion coefficients - which represent the resistance of drug molecule
Procedure: movement through vehicle,
• Donor chamber is filled w/ drug soln.
• Samples are collected & assayed spectrophotometrically. Buccal Absorption
• Unlike the intestinal membrane, the buccal membrane does not appear to
2. Plexiglas three-compartment diffusion cell possess significant aqueous pore pathways, and the surface pH is essentially
- Used primarily for either synthetic or isolated biologic membranes. the same as the buffered drug solution pH. Buccal absorption is assumed to
Procedure: be a first-order process owing to the nonaccumulation of drug on the blood
• Drug is allowed to diffuse from the two outer donor compartments in side.
a central receptor chamber.
• Results were reproducible and compared favorably with those from Uterine Diffusion
other workers. • A solution of a model drug was perfused through a specially constructed cell
and implanted in the vagina of the doe, and the drug disappearance was
3. Two-chamber glass cells monitored. The drug release followed first-order kinetics, and the results
- Used for permeation though plastic film of water vapor and of aromatic permitted the calculation of apparent permeability coefficient and diffusion
organic compounds from aqueous solution. layer thickness.
Procedure:
• Permeability of water vapor through enteric coating materials, Thermodynamics of Diffusion
using a glass diffusion cell and a McLeod gauge to measure
changes in pressure across the film. Permeation of gases, liquids & solutes through membranes requires an
• Sorption of gases and vapors can be determined by use of a energy of activation for the small molecules to move through the matrix of the
microbalance enclosed in a temperature-controlled and barrier material.
evacuated vessel. Arrhenius equation: P = P0E-Ep/RT In P = In P0 – Ep/RT
• Gas or vapor is introduced at controlled pressures into the glass Where,
chamber containing the polymer or biologic film of known P0 = factor independent of temp. & proportional to the
dimensions suspended on one arm of the balance. number of molecules entering the film.
4. Permeability cell Ep = energy of activation for permeation in calories/mole
- Used to study the diffusion through stratum corneum (stripped from the R = gas constant
human forearm) of various permeants, including gases, liquids, and gels. T = temp.
Procedure:
• Kept at constant temperature and gently shaken in the plane of the
membrane.
• Samples were withdrawn from the receptor chamber at definite times Diffusion in a closed system
and analyzed for the permeant. • A simple apparatus was used by Graham to obtain diffusion
Multilayer diffusion coefficient, D, for solutes in various solvents.
• Diffusion across biologic barriers may involve several layers consisting of
separate membranes, cell contents & fluids for distribution. Diffusion in a system w/ one open boundary
• In pharmaceutics, physiology & biochemistry studies.
2 Important cases of multilayer diffusion: Boundary condition – condition at the interface between soln & water layer.
1. Diffusion under membrane control Secondary boundary condition – states the change in the concentration in
2. Diffusion under aqueous diffusion layer control w/c change in x position is zero.
Diffusion principles on Biologic System
Diffusion & Ecology
Gastrointestinal Absorption of Drugs Diffusion processes have wide application not only in physical & chemical
Two main classes of transport sciences but also in biology, in w/c living systems (animal colonies) are subject:
1. Passive transport • Diffusion & dispersal of pores by wind, distribution of fish egg in sea, ect.
• Passive transfer involves a simple diffusion driven by differences
in drug concentration on the two sides of the membrane. Chapter 12 – Dissolution

2. Active transport Dissolution

• requires an energy source to ferry drug across membrane. • Limiting or rate controlling step in bio – absorption for drugs of low solubility.

Other special mechanisms include: Dissolution rate

1. Convective transport • Rate at w/c solid dissolves in solvent.
• Drug molecules dissolved in aqeuous medium at the absorption
site move along with solvent through the pore.

2. Ion pair transport Where,

• Transport of ion pairs across lipid membranes w/ the lipophilic M = mass of solute dissolved
counter ions acting as carriers for hydrophilic molecules. T = time
dM/dT = mass rate of dissolution (mass/time)
pH-partition hypothesis D = diffusion rate
• Drugs are absorbed from the gastrointestinal tract by passive diffusion S = surface area of the exposed solid
depending on the fraction of undissociated drug at the pH of the intestines. h = thickness of diffusion layer
Cs = solubility of solid
 Lloyd S. Arboleda
Powder dissolution
• Hixson–Crowell Cube-Root Law
• For a drug powder consisting of uniformly sized particles, it is possible to
derive an equation that expresses the rate of dissolution based on the cube
root of the weight of the particles.

Convective diffusion
• The transfer of heat (energy) and the presence of agitation accompanying
the movement of a fluid, can be combined with diffusion to provide a
convective diffusion model for the study of dissolution.

Drug release
• Release from dosage forms and subsequent absorption are controlled by the
physical chemical properties of drug and delivery system and the physiologic
and physical chemical properties of the biologic system.

Factors that exhibits CR/SR characteristics:

1. Drug concentration
2. Aqueous solubility
3. Molecular size
4. Crystal form
5. Protein binding
6. pKa

Drug in Polymer Matrix

• A powder drug is homogenously dispersed throughout the matrix of an
erodible tablet.

Release from Granular Matrices involves:

1. Simultaneous penetration of the surrounding liquid
2. Dissolution of the drug
3. Leaching out of the drug through interstitial channels or pores

Porosity, ε
• Fraction of matrix that exists as pores or channels into which the surrounding
liquid can penetrate.

Tortuosity, τ
• Account for an increase in the path length of diffusion due to branching and
bending of the pores, as compared to the shortest “straight-through” pores.