Solubility - Physical Pharmaceutics-I Colored Notes B.Pharmacy 3rd Semester 2021 (2020-2021) Previous Year's Question Papers/Notes Download - HK Technical PGIMS

BP302T (Physical Pharmaceutics-I) Colored Notes 3rd Sem B.Pharm

BP302T Notes on Solubility

1
Solubility helps the pharmacist to:
1. Select the best solvent for a drug or a mixture of drugs.
2. Overcome problems arising during preparation of pharmaceutical solutions.
3. Have information about the structure and intermolecular forces of the drug.
4. Many drugs are formulated as solutions, or added as powder or solution forms to liquids.
5. Drugs with low aqueous solubility often present problems related to their formulation and
bioavailability.
Solvent-Solute interactions
In pre or early formulation, the selection of the most suitable solvent is based on the principle of
“Like dissolve like”
 Solute dissolves best in solvent with similar chemical properties.
 Two substances with similar intermolecular forces are likely to be soluble in each others.
 Polar solutes dissolve in polar solvents.
 E.g. salts and sugar dissolves in water
 Ammonia dissolves in water
 Polar ammonia molecules dissolve in polar water molecules
 This is because both molecules engages in hydrogen bonding
 Alcohol dissolves in water because –OH in group in alcohol is polar and mixes
with polar water through formation of hydrogen bond.
 Acetic acid and hydrochloric acid also dissolve in water.
 Non-polar solutes dissolve in non-polar solvents.
 E.g. Naphthalene dissolves in benzene
If the solvent is A and the solute is B, and the force attraction are represented by A-A, B-B and
A-B.
One of the following conditions will occur:
1. If The solvent molecules will be attracted to each other and the solute
will be excluded.
 Example: Benzene and water, where benzene molecules are unable to penetrate
the closely bound water aggregates.
2. If The solvent will not able to break the binding forces between
solute molecules.
 Example: NaCl in benzene, where the NaCl crystal is held by strong electrovalent
force which cannot be broken by benzene.
Downloaded from HK Technical PGIMS (pgims.hktechnical.com)
BP302T Notes on Solubility
2
3. If or the three forces are equal The solute will form a
solution.
 Example: NaCl in water.
Solvents can be:
i. Polar: Water (Strong Di Electric constant – containing N or O)
 Polarity increases with Di-electric constant
 Functional Group: Ketones , Ca. Acid and amides.
ii. Non-Polar : Hexane
 Di-electric constant – 15 = Non Polar
iii. Semi Polar : Alcohols
Dielectric constant (relative permittivity of the material)
 The dielectric constant (k) of a material is the ratio of its permittivity ε to the permittivity
of vacuum .




 The dielectric constant is therefore also known as the relative permittivity of the
material.
 Since the dielectric constant is just a ratio of two similar quantities, it is dimensionless
(Unit less).
 Dielectric constant of water is high nearly 80.
 Dielectric constant of vacuum is 1
 Dielectric constant of ether, mineral oil and fixed vegetable oil is 0
Downloaded from HK Technical PGIMS (pgims.hktechnical.com)
BP302T Notes on Solubility
3
Ideal Solubility Parameters
 Ability of liquid to act as solvent.
 Described by: Hildebrand and Scott
 Expresses cohesiveness between like molecules
 It is used to estimate whether substance will dissolve in other substance or not.
 Can be calculate by this equation:
(

)

WHERE,
 ∆𝑯𝒗 = 𝐇𝐞𝐚𝐭 𝐨𝐟 𝐯𝐚𝐩𝐨𝐫𝐢𝐳𝐚𝐭𝐢𝐨𝐧
 Vt = molar volume
 R = gas constant
 T = absolute temp.
Example:

o
o
o
 So, Phenanthrene is more soluble in carbon disulfide than hexane.
 This shows if value to solubility parameter is the same or nearly the same the
solubility will be good.
 Hansen parameter divided the total Hildebrand parameter value into three parts:
1. dispersion force components
2. A hydrogen bonding components
3. A polar components















1) More similarity in the structure of solute and solvent enhances the solubility of solute in
that solvent
2) Polar solutes dissolve in polar solvents while nonpolar solutes dissolve in non-polar
solvents.
3) Addition of polar groups like-OH,-CHO, -CHOH, -CH, OH,-COOH, -NH2 etc, tend to
increase the solubility of organic compounds in water.
Downloaded from HK Technical PGIMS (pgims.hktechnical.com)
BP302T Notes on Solubility
4
4) Addition of non-polar groups tends to decrease the solubility of compounds in
water.
5) Introduction of halogen groups tend to decrease the solubility while branching of
chain increase the solubility in water.
6) Solid compounds of high molecular weights are generally more difficult to dissolve in
water.
Solvation
 Solvation is the process in which molecules of a solvent attract the particles of a solute.
 The main forces in solvation are ion-dipole and hydrogen bonding attractions. It is the
main reason why solutes dissolve in solvents.
 Ionic compounds like NaCl dissolve in polar solvents like water.
 The Na⁺ ions attract the negative oxygen atoms of water.
 The Cl⁻ ions attract the positive hydrogen atoms of water.
 The ions become surrounded by a solvation shell of water molecules.
 The closer the opposite charges can get to each other, the more stable the system.
 That's why solvation stabilizes the ions.

Diffusion
 It may be defined as the process of mass transfer of individual molecule of a
substance.
 The movement of molecules from an area in which they are highly concentrated to an
area in which they are less concentrated is called as DIFFUSION.
 Diffusion causes net movement of particles until an equilibrium is reached.
 It is a spontaneous process.
 Diffusion can affect a variety of different quantities such as: Concentration, Heat and
Momentum.
 Diffusion increases entropy, decreasing Gibb’s free energy and therefore it is
thermodynamically favorable.
 Diffusion can be described mathematically by Diffusion Equation.
Downloaded from HK Technical PGIMS (pgims.hktechnical.com)
BP302T Notes on Solubility
5
Passive Diffusion:
 The transport of drug from a higher concentration gradient to a lower
concentration gradient is called as Passive Transport or Passive Diffusion.
 Generally, the lipid soluble drugs gets easily diffused or transported through the GI
barrier.
 Example : Propranol, Testosterone, Cisapride, Naproxen.
Active Diffusion:
 It occurs when cells have to move particles against the concentration.
 Henceforth moving from a lower Concentration to a higher Concentration.
 Energy in the form of ATP is required for such a movement.
 Since the energy is required in such type of diffusion, it is differentiated from passive
diffusion.
 Most often, active diffusion happens with the help of protein pump or poton port.
 EXAMPLES: Levodopa, Captopril, Cephalexin
Fick’s First Law Of Diffusion:
 The amount M of a material flowing trough a unit cross section S, of a barrier in a unit
time, t, is known as the flux.
J = dM/S.dt
 This equation is derived from Fick's law, which states that “The net movement of
diffusing substance per unit area of section (the flux) is proportional to the concentration
gradient and is towards lower concentration”.
J = - D dC/dx.
 Where D is the diffusion coefficient of penetrant in cm2
/sec,
 C is the concentration in g/cm3
and
 x is the distances in cm of movement perpendicular to the surface of the barrier
the time t in second
 The unit of J is gm/cm2
.
 The negative sign indicate that diffusion occur in direction opposite to that of increasing
concentration.
 D is affected by solvent, temperature, pressure, and that of the chemical nature of the
formulation.
 Thus if the concentration is uniform there will be no net motion.
 The constant of proportionality is the diffusion coefficient D, which depends on the
diffusing species and the material through which diffusion occurs.
Downloaded from HK Technical PGIMS (pgims.hktechnical.com)
BP302T Notes on Solubility
6
Fick’s Second Law Of Diffusion :
 Fick's second law is used in non-steady or continually changing state diffusion. This
means when the concentration within the diffusion volume changes with respect to time
at a definite location with respect to x, y and z axes.
 “It states that the change in concentration with respect to time in a particular region
is proportional to change in the concentration gradient at that point of time.”
 In particular volume element, the concentration C changes as a result of net flow of
molecule in and outside the region.
This is as a result of amount of diffusing molecules or flux changed with distances

dC/dt = dJ/dx
This relationship can be expressed as;
 dC/dt = dJ/dx --------- (1)
 Concentration and flux are both function of t and x.
 Considering ficks first law of expression
 J = -D dC/dx. --------- (2)
 Differentiating it with respect to x gives:
 dJ/dx = -D d2C/d2x ---------(3)
 Substituting, dC/dt in (3) for dJ/dx, we get,
 dC/dt = D d2C/d2x ---------(4)
 Extending equation in three coordination ,
 dC/dt = D [ d2C/d2x + d2C/d2y + d2C/d2z ]
Downloaded from HK Technical PGIMS (pgims.hktechnical.com)
BP302T Notes on Solubility
7
Solubility of gas in liquid
 The amount of gas dissolved in liquid which is in equilibrium with the pure gas above the
solution.
 A very good example is the solution of carbon dioxide in an aqueous solution of
sugar, coloring agent and flavoring agent.
 Other examples are preparation containing dissolved ammonia and hydrochloride
gas.
 The solubility of gas depends on:
 Temperature
 Pressure
 Salt Present
 Chemical Reaction
 Micellar Solubilization
i. Temperature
 Increase in temperature decreases the solubility of the gases.
 This is due to Ability of the gas to expand at higher temperatures
 Increase in pressure at the elevated temperatures
 Therefore lower temperature is preferred for storage of these solutions.
• 10 – 3.25 ml of oxygen per 100 ml
• 20 – 2.85 ml of oxygen per 100 ml
 Usually water is heated at 90 for removal of gases
 Decrease in solubility of gases at higher temperature can be explained by increase in
higher kinetic energy of gas molecule which tends to `break intermolecular bond and get
to escape.
ii. Pressure and Solubility
 When two or more gases are present above the liquid, each gas dissolves in the liquid
independently of the other, and the solubility of each at constant temperature is directly
proportional to its own partial pressure.
 Alternately, It can be said that the weight of the gas dissolved in a given mass of a liquid
at constant temperature is directly proportional to the pressure exerted upon the gas.
 This is the Henry's law which states that at constant temperature a given quantity of
liquid dissolves the same volume of the gas at all pressures.
 Henry's law is an ideal law and is obeyed by gases such as hydrogen, nitrogen and
oxygen that have low solubilities and do not interact with the solvent.
 The gases with high solubilities at room temperature such as HCI and ammonia show
large deviation from the Henry's law.
 To illustrate Henry's law let us assume that carbon dioxide obeys
 Henry's law and Boyle's law at room temperature.
Downloaded from HK Technical PGIMS (pgims.hktechnical.com)
BP302T Notes on Solubility
8
 At 20°C and at one atmosphere pressure, the mass of carbon dioxide
dissolved by one liter of water is 1.7 gram.
 This mass of carbon dioxide occupies a volume of 943 ml. If the pressure of carbon
dioxide is double at 20 the mass of carbon dioxide gas dissolved by same volume of
water is also doubled i.e., it becomes 3.4 grams; this mass of the gas will occupy the
same volume i.e. 943 ml, occupied by 1.7 grams of carbon dioxide at one atmosphere
pressure.
iii. Presence of Salt
 Effect of the Presence of Salt Gases are released from a liquid by an introduction of a
salt. (Salting out)
 This is due to greater affinity of the electrolytes towards the water molecules resulting in
weakening of the gas solvent interactions.
 Therefore if a salt is added then the solubility of the gas decreases.
iv. Effect of Chemical Reaction
 The solubility of a gas will increase if the gas reacts with the solvent.
 For these solutions Henry’s law is not applicable.
E.g. Ammonia and Carbon dioxide solutions.
 Application: Preparation of reagents such as Hydrochloric acid, sulphuric acid and nitric
acid.
v. Effect of Micellar Solubilization
 Putting the gas molecules inside micelles increases the solubility of
the gas.
 Micelles are used to increase the solubility of a non-polar solute (gas) in a polar
solvent.
 An example of this in the body is the lungs.
 The lungs allow the non-polar air to be transported through the polar water to the tissues.
 This is accomplished by a micellar transport system
Downloaded from HK Technical PGIMS (pgims.hktechnical.com)
BP302T Notes on Solubility
9
Ideal solution
 Ideal solution is defined as the one in which there is no change in the properties of the
components other than dilution, when they are mixed to form a soln. AND Ideal soln
is the one in which each component of soln obeys Raoult’s law at all temperature and
concentration)
 Heat is neither evolved nor absorbed during mixing.
 In other words, No shrinkage or expansion occurs when the liquids are mixed.
 Ideal soln are formed by mixing substances with similar properties.
Examples of Ideal Solution
 Ideal soln are formed by mixing substances with similar properties.
Example: When 100 ml of Methanol is mixed with 100 ml of Ethanol, the
final volume of the soln is 200 ml and no heat is evolved or absorbed.
 The solution is nearly ideal.
Escaping Tendency
 Two bodies are in thermal equilibrium when their temperature are same.
 If 1 body is heated to a higher temperature than the other, heat will flow “downhill” from
the hotter to the colder body until both bodies are again in thermal equilibrium.
 We can describe this process in another way by using the concept of escaping tendency
and say that the heat in the hotter body has a greater escaping tendency than that in
the colder one.
 Finally, when both the bodies have the same temperature, the escaping tendency of each body is same
in all parts of the system.
Downloaded from HK Technical PGIMS (pgims.hktechnical.com)
BP302T Notes on Solubility
10
Raoult’s Law
 In 1887, Raoult recognized that, in an ideal soln, the partial vapor pressure of each
volatile constituent (liquid) is equal to the vapor pressure of the pure constituent
(liquid) multiplied by its mole fraction in the soln.
 Raoult’s law can be mathematically expressed as:
𝒗

Thus for 2 constituents A and B in a mixture,
 pA = pAo XA ------------ Eq 1
 pB = pBo XB ------------ Eq 2
Where,
pA = Partial Vapor Pressure exerted by liquid A, Kilopascal (kPa)
pB = Partial Vapor Pressure exerted by liquid B, Kilopascal (kPa)
pAo
=Vapor Pressure exerted by Pure Liquid A, kPa
pBo
=Vapor Pressure exerted by Pure Liquid B, kPa
XA = Mole Fraction Concentration of A in liquid
XB = Mole Fraction Concentration of B in liquid
 When 2 liquids are mixed, the vapor pressure of each liquid is reduced by the presence of
other liquid by the extent of dilution of each phase.
 Ideal soln obey Raoult’s Law.
Raoult’s law is obeyed by a few soln of liquid in liquid.
The components of these soln have similar structures i.e. Benzene and Toluene, Ethyl
Bromide and Ethyl Iodide.
Finally complete uniformity of Attractive forces is observed in the individual components
of Ideal Soln.
Dalton’s law
 Dalton’s law of partial pressure states that “The total pressure exerted by a mixture of
ideal gases may be considered as sum of the partial vapor pressures exerted by each
gas.”
 Dalton’s law is mathematically expressed as:
𝒗 𝒗
P = pA + pB ----------- Eq 3
Substituting Eq 1 and Eq 2 in Eq 3 gives
P = pA
o XA + pB
o XB ----------- Eq 4
 These properties are additive i.e. Total Vapor pressure of the mixture is the weighted
average of the individual vapor pressures.
Downloaded from HK Technical PGIMS (pgims.hktechnical.com)
BP302T Notes on Solubility
11
Real Solution
 When 100 ml of H2SO4 is mixed with 100 ml of H2O, the total volume of the soln is
about 180 ml at room temp. Slight heat is evolved.
 The soln is said to be non – ideal or real soln.
 Most of the liquid mixtures show varying degree of deviation from Raoult’s law
depending on the nature of the liquids and the temp.
 In many soln, the “Cohesive” attraction of A for A exceeds the “Adhesive” attraction
existing between A and B.
Downloaded from HK Technical PGIMS (pgims.hktechnical.com)
BP302T Notes on Solubility
12
 The attractive forces between A and B may be greater than those between A and A or B
and B.
 This may occur even if the liquids are miscible in all proportions.
 Such mixtures are known as Real or Non ideal i.e. they do not obey Raoult’s law.
In this case, Raoult’s law is modified by replacing the term, “Concentration‟ by the term,
“Effective Concentration” indicating Activity (Thermodynamic Activity)
Eq 1 and Eq 2 are modified to:
pA = pAo aA -----------Eq 5
pB = pBo aB -----------Eq 6
Where, aA & aB are activities of components A & B respectively.
Eq 5 & Eq 6 are applicable for both ideal & non – ideal solution.
Ideal Solution: a = X -----------Eq 7
Non – Ideal Solution: a ≠ X -----------Eq 8
The ratio of activity to concentration is known as Activity Coefficient and it provides a
measure of deviations from Ideality (Ratio = 1).
2 types of deviation from Raoult’s law are recognized i.e.
Negative and Positive Deviation.
Positive Deviation from Raoult’s Law
 When the vapor pressure is greater than the sum of the partial pressures of the individual
components, the system is said to show Positive Deviation from Raoult’s Law.
 Example: CCl4 and Cyclohexane, Benzene and Ethanol, Water and Ethanol.
 This type of behaviour occurs when the components differ in their Polarity, Length of
Hydrocarbon Chain and Degree of Association.
 The degree of deviation from Raoult’s law ↓ with ↑ in Temp., since the differences are
reduced at higher temp.
 Conversely, a decrease in temp. reduces the miscibility of two components, resulting
in phase separation.
Downloaded from HK Technical PGIMS (pgims.hktechnical.com)
BP302T Notes on Solubility
13
Negative Deviation from Raoult’s Law
 When the vapor pressure is less than the sum of the partial pressures of the individual
components, the system is said to show Negative Deviation from Raoult’s Law.
 Example: CHCl3 and CH3COCH3, Pyridine and Acetic Acid, H2O and HNO3.
 Negative deviation occurs when interactions such as Hydrogen bonding, salt formation
and hydration occur between components.
 The adhesive attractions are greater than the cohesive attractions resulting in ↓
vapor pressure of each component.
 When the “adhesive” attractions between unlike molecules exceeds the “cohesive”
attractions between like molecules, the vapor pressure of the solution is less than that
expected from Raoult‟s ideal solution law and negative deviation occurs.
 When the “cohesive” attractions between like molecules exceeds the “adhesive”
attractions between unlike molecules, vapor pressure of the solution is more than that
expected from Raoult’s ideal solution law and positive deviation occurs
Downloaded from HK Technical PGIMS (pgims.hktechnical.com)
BP302T Notes on Solubility
14
Distribution law or the Partition law
 When a solid is added into two non-miscible liquids, it is distributed between them an a
manner similar to the distribution of a gas between a liquid and a gas phase.
 Sometimes it is required to remove certain substances from and aqueous solution which
are soluble in organic solvents like ether, chloroform, or some other solvent immiscible
in water.
 In the alkaloidal assays, it is common practice to extract organic substances by
chloroform or ether from aqueous solutions.
 This is done by shaking the solution together with some solvent say ether in a separating
funnel, removing the ether solution, and repeating the treatment with ether until
practically all of the substance has been extracted
 The substance can be recovered from the rather solution by the ether.
If we were to shake the aqueous solution with ether until equilibrium was reached, and if
the water and ether solutions were dilute, the distribution of the solute in the two
solvents.
 Let ether and water, would follow a very simple law, known as the Distribution law or
the Partition law.
 If C is the molar concentration in the ether layer and Cr is the molar concentration in
the water layer, then,
 C / C1 =K, where K is the partition coefficient
 The value of K will be constant provided the solute has the same molecular weight in the
two solvents.
 Suppose iodine (1) is added in the mixture of water and chloroform, it will distribute in
water and the chloroform according to the solubility in the solvents.
 It can be represented by the following expression:
 I2 (aq) -------------- I2 (in chloroform)
 Iodine is slightly soluble in water but very soluble in organic solvent. If we want extract
iodine from its aqueous solution, we will have to shake it with organs solvent like
chloroform or carbon tetrachloride.
• The equilibrium equation for above is:
K = I2 in Chloroform / I2 in water
 The ratio of the concentration of 1; in the two solvents at constant temperature constant,
as is shown by the above expression for equilibrium. This constant is partition
coefficient or distribution coefficient.
 If K>1 solute prefers organic solvent
 if K<1 solute prefers the aqueous solvent.
 Thus, Distribution Law can be defined as when a solute distributes itself two
immiscible solvents, the ratio of the concentration of the solute in the two solvents.
Downloaded from HK Technical PGIMS (pgims.hktechnical.com)
BP302T Notes on Solubility
15
Appilcations of Distribution law
 The distribution law commonly called Nernst's distribution law is applicable in
pharmacy in following important phenomenon:
 Solubility of drugs in water and other solvents and in mixture of solvents can be
predicted.
 Extraction process: The drugs from biological fluids such as blood, urine and tissues can
be extracted efficiently by the principle of multiple extraction.
 This can be used in partition chromatography to separate organic substance from
mixtures.
 In vivo drug absorption can be predicted by the value of partition coefficient
 Passage of drug through membranes specially to evaluate semisolids
 Preservation of emulsions and creams These biphasic systems contain
Mobile phase : Oil and aqueous phase therefore preservatives added
may distribute in both the
 Characteristics of Drug molecules : The oil-water partition coefficients
can predict the hydrophilic or hydrophobic nature of the drug This may
help in structure activity relationship (SAR) study of the series of drugs.
 Chemical modification :Chemical changes related to lipid solubility and its af options
are best exemplified by the barbiturates.
Limitations of Distribution (Partition) law
1. Dilute solutions: The concentrtion of solute must be low in two solvents. This law does
not holds good when the concentrations are high.
2. Constant temperature: Temperature should be kept constant throughout the experiment,
since solubilty is depend on temperature.
3. Same molecular state: Solute must be in the same molecular state in both the solvent.
This law does not hold, if there is association or dissociation of solute molecules in one
of the solvents.
4. Equilibrium concentration: This achieved by shaking mixures for longer time.
5. Non-miscibility of solvents: So, the solvents are to be allowed for separation for a
sufficient time.
Downloaded from HK Technical PGIMS (pgims.hktechnical.com)