SOLUBILITY OF DRUGS Sele£ted Dellnltlons •
Soludon: It is mixture of two or more components to form homogenous system.
•
Solute: It is dissolved substance in solution.
•
Solvent: It is the component which have ability to dissolve solute.
•
Molarity: It is number of moles of a solute per liter of solution.
•
Molality: It is Moles of solute in 1000 gm of solvent.
•
Nonnality: It is number of Gram equivalent weights of solute in I !iter of solution at any given temperature.
•
Mole fraction ot solute : It is the ratio of the number of moles of solute and the total number of moles of solute and solvent.
•
Percentage by Weight(% w/w): It is defined as gm of solute in lOOgm of solution
•
Percentage by Volume(%v/v): It is expressed as ml of solute in 100 ml of solution
•
Percentage Weight 10 Volume (% w/v): It is expressed as gm of solute in 100 ml of solution
•
Electrolyte: These substances when dissolved in water they undergo physical and chemical changes and generate ions in the solution.
•
Non electrolyte: Substances that do not yield ions when dissolved.
•
Saturated soludon : It is defined as a solution in which the solvent is in equilibrium with the solid phase or solute.
•
Unsaturated soludon are those having the dissolved solute in a concentration below that necessary for complete saturation at a definite temperature.
•
Supersaturated soludon : The solution which contains more of the dissolved solute than it would normally contain at a definite temperature.
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1. 1 INTRODUCTION In quantitative terms, Solubility is "At a specified temperature, maximal amount of solute that can dissolve in an amount of solvent ". In a qualitative way, it can be defined as the when solute (may be solid, liquid or gaseous) is to be dissolved in solvent (may be solid, liquid or gaseous), it form a homogeneous solution of the solute in the solvent. IUPAC (The International Union of' Pure and Applied Chemistry) defines the solubility as an analytical composition of a saturated solution expressed as a proportion of a designated solute in a designated solvent. Additional or Extra solute will not dissolve in a saturated solution. The solubility may be indicated in units of concentration, molar, molar fraction, molar ratio and other units. The solubility of a substance depends on the solvent used, the temperature and pressure. The thermodynamic solubility of a drug in a solvent is "Under equilibrium conditions, at a given temperature and pressure, the maximum amount of the most stable crystalline form that stay in solution in a given volume of the solvent". Thermodynamic equilibrium is obtained when the lowest overall energy state of the system is obtained. The solubility of a drug can be expressed in several ways. Solubility is expressed as ppm( parts per Million) according to BP (British Pharmacopoeia) and in mg/mL and in moles/litre (MlL) etc. The United States Pharmacopeia (USP) describes the solubility of the drugs as parts of the solvent required for a part of the solute. The USP describes the solubility using the seven groups listed in Table 1.1 Table 1.1 Solubility description in the United States Pharmacopeia Definition
Parts of solvent reqnired for one part of solute
Very Soluble Freely soluble Soluble Sparingly soluble Slightly soluble Very slightly soluble Practically Insoluble
<I 1-10 10- 30 30- 100 100 - 1000 1000 - 10,000 > 10,000
Solubility Range (mg/mL) >1000 100-1000 33-100 10-33 1-10 0.1-1 <0.1
Solved Problems Exercise 1.1: Calculate the molarity of a solution that contains 1.524 moles of H2S04 in 2.50 L . of solution. Solution: Molarity = 1.524 = 0'.609 M H2S04 2.50 Ans 0.609 M H2S04
Solubility of Drugs
3
Exercise 1.2 Calculate molality of a solution containing 4.0 g NaCl dissolved in 20.0 g :vater. Solution: (i)
mole of solute= mass / molar mass molar mass = 22.99 + 35.45 = 58.44 g mol"
4
So moles(solute) (ii)
mass(water)
= -= 0.068 mol 58.44 = 20.0 g -;. 1000 g/kg = 20.0 x 10"3= 0.0200 kg
Molality = moles(solute) ¡ = --0.068 or Mola 1ity 0.0200
/ mass(solvent
in kg)
= 34. m
Ans 3.4m Exercise 1.3 What will be the normality of 5 molar solution of calcium hydroxide? Solution: Molarity of calcium hydroxide = 5 M. Since calcium hydroxide releases 2 electrons in its solution, equivalent. So, its normality would be: 5/2= 2.5 normal. So, the solution of 5M calcium hydroxide would be 2.SN.
1 mole would be equal to 112
Ans 2.SN Exercise 1.4 Calculate the mole fraction of HCl in a solution of hydrochloric containing 34% HCl by weight. Solution: The solution contains 34 grams of Hydrochloric Molecular mass of HCl is 36.5 grams/mole. Molar mass of water is 18 grams/mole.
acid and 66 grams of water. Also,
Moles ofHCl = 34 grams of HClxl mole ofHCI 36.5 grams of HCI Moles of water =
66 grams of H20xl
mole of H20
18 grams of H20
= 0.93 mole ofHCl.
= 3.7 moles of H20.
MolesofHCl 0.93 Mole fraction of HCl = ----------= Moles of HCl + Moles of water 34+0.93 ns 0.027
:: 0.027
acid in water,
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1.2 DETERMINATION OF SOLUBILITY A simple method used for the determination of solubility at laboratory scale and particularly at room temperature. Saturated solution of excess of solid substance with solvent is prepared by shaking in a vessel placed in a constant temperature bath. Then filtered the solution. During filtration, solid may be deposited on the filter paper or in the stem of the funnel. A known volume of saturated solution is evaporated in china dish. And from the weight of the residue, the solubility can easily be calculated. On vigorous shaking
Excess of solid in fixed volume of solvent
â&#x20AC;˘
Saturated solution is prepared ,
Filtration
,
A fixed volume of saturated solution evaporated
Estimated solubility
â&#x20AC;˘
Weight of residue
Figure 1.1 Flow chart for solubility determination
Evaporation of a liquid is a highly undesirable operation. This difficulty can be overcome whenever a chemical analysis method is used. Another defect of this method is that it takes a long time to maintain the equilibrium between the solid with the solution. This difficulty can be overcome by first preparing the saturated solution at a higher temperature and then cooling it to the desired temperature at which the solubility is to be determined.
1.2.1 Solubility Curve A curve drawn between solubility and temperature is termed Solubility Curve. (1) Any point on a line represents a saturated solution. In a saturated solution, the solvent contains the maximum amount of solute.
5
Solubility of Drugs
50g
••••••••••••••••••••••
solute (g) per lOOg water (I)
temperature
lOO·C
Figure 1.2: solubility curve showing saturated solution (2) Any point below a line represents an unsaturated solution. In an unsaturated solvent contains less than the maximum amount of solute.
solution, the
,"
40g
••••••••••••••
solute (g) per lOOg water (I)
temperature
90·C
Figure 1.3: solubility curve showing unsaturated (3)
solution
Any point above a line represents a supersaturated solution. In a supersaturated solution, the solvent contains more than the maximum amount of solute. A supersaturated solution is very unstable and the amount in excess can precipitate or crystallize.
;pJ
6 60g
----------
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_
solute (g) per lOOg water (I)
tempera t ure
90¡C
Figure 1.4: solubility curve showing supersaturated
1.3 MECHANISMS
solution
OF SOLUTE SOLVENT INTERACTIONS
Most suitable solvent is selected on the basis of principle of "like dissolves like". The solubility of the solute in the solvent depends on the nature of the solvent (Whether it is polar or non-polar). The solubility also depends on the chemical, electrical and structural properties that cause mutual interactions between the solute and the solvent. The solubility of a drug is due to the polarity of the 01 ent (i.e. its dipole moment). For example water is a good solvent for salts, sugars and similar compounds. While mineral oil is often a solvent for substances that are normally slightly luble in water. Nonpolar compounds can dissolve nonpolar solutes with similar internal pressures through induced dipole interactions. Cleavage of solute-solute intermolecular bonds
f
Cleavage of solvent-solvent intermolecular bonds
~ Formation of cavity in solvent phase to accommodate solute molecule Movement of solute into the cavity of solvent phase
Formation of solute-solvent intermolecular bonds Figure 1.5 Flow chart of mechanism of solute solvent interaction For example: If X is solvent & Y is solute, the forces of attraction are represented and X -Y. In this case, one of the following condition may occur
by X -X, Y -Y
-:,
Solubility of Drugs
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1. If X-X ÂťX-Y The solvent molecules will be attracted to each other & the solute will be eliminated. Example: Benzene & water 2. If Y-Y ÂťX-X The solvent will not be able to break binding forces between solute molecules. Example: NaCI in Benzene 3. If X -Y Âť X-X or Y-Y, or three forces are equal- The solute will disperse and form a solution. Example: NaCl in water
1.3.1 Polar solvent Water, glycols, methyl & ethyl alcohol. Polar solvent is used to dissolve ionic solutes & other polar substances. The mechanism of the polar solvents mainly depends on the high dielectric constant (which reduces the attraction between the oppositely charged particles) and by hydrogen bond formation and also by dipole interaction.
1.3.2 Non'1)olar solvents The mechanism of the non-polar solvents are based on the weak van der Waal's forces.
1.3.3 Semi polar solvent They can act as intermediate solvents to induce the miscibility of polar and nonpolar liquids. Semipolar solvents (ketones) can induce a certain degree of polarity in non-polar solvent molecules.
1.4 SOLUBILITY PARAMETERS In 1936, Joel H. Hildebrand proposed the solubility parameter (0) is the square root of the cohesive energy density: (eq 1.1) Where LlHv= the heat of vaporization = the molar volume of the liquid at the desired temperature R = gas constant T = Temperature
VI
The value indicate the solvency behavior of a specific solvent. The cohesive energy density is the amount of energy required to completely eliminate the unit volume of neighboring molecules at infinite separation (an ideal gas). This is equal to the heat of vaporization of the compound divided by its molar volume in the condensed phase
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Solubility parameter provides a numerical estimate of the degree of interaction between materials . The conventional units for the solubility parameter are (calories per cm3)If2, or cal1f2 cm-312. The SI units are J1/2m-3/2 ,equivalent to the pascal'f Another solubility parameter is Hansen solubility parameter. This was developed by Charles M. Hansen in 1966. The Hansen parameters consist of three parts: a dispersion force component, hydrogen bond component and dipole-dipole component. So, Hansen parameters is shown as (eq 1.2) where 0(2
= Total Hildebrand parameter
ol = o = p
2
dispersion component polar component
Oh2= hydrogen bonding component
1.5 SOLVATION & ASSOCIATION 1.5.1 Solvation , Commonly known as dissolution. It is the process of attracting and associating the molecules of a solvent with molecules or ions of a solute. When solute or ions dissolve in a solvent, then solute get surrounded by solvent molecules. This process is known as a solvation complex. The larger the ion, the more solvent molecules can surround it and the more they are solvated .
•• ••• •• Solute
+
.:., ••• •
Solvent
Solution
Figure 1.6: solvation of solute with solvent
Solvation depends on factors such as hydrogen bonding and van der Waals forces. For solvation to occur, energy is release. from crystal lattices in which they are present. The solvation energy is the amount of energy related with the dissolution of a solvent. If it is a positive number, the dissolution process is endothermic; If it is negative, it is exothermic.
1.5.2. Association The association of ions is a chemical reaction in which the opposite electric charge ions come together in solution and form a distinct chemical entity. The extent of the ionic association depends on the dielectric constant of the solvent. The ions of opposite charge are naturally attracted to one another by electrostatic force. This is described by Coulomb's law:
9
(eq 1.3) where F is the force of attraction, ql and q2 are the magnitudes of the electrical charges, s is the dielectric constant of the medium and r is the distance between the ions. Ion association will increase if 1. the magnitude of the electrical charge q, and q2 increase, 2. the size of the ions decreases so that the distance r between cation and anion decreases. 3. the magnitude of the dielectric constant e decreases.
1.6 FACTORS INFLUENCING SOLUBILITYOF DRUGS There are mainly following factors which affect solubility. 1. Temperature: Solubility is directly proportional to temperature; This means that if the temperature increases, the solubility also increases. But in some cases, the solubility decreases as the temperature increases. In the exothermic process (energy given off), solubility decreases with increasing temperature. But in case of the endothermic process (energy required) solubility increases with increasing temperature and vice versa. For example: The solubility of potassium nitrate increases with increasing temperature (as shown in figure)
..
~01 ~
120
100
0= 0= ...
80
C :3
60
=
40
~
~ Q
V'J
20 0 0
20
40
60
80
Temperature,°C
Figure 1.7 : Effect of temperature on solubility of potassium nitrate
2. Nature of the solvent: The solubility of a solute in a solvent depends solely on the nature of the solute and the solvent. The polarity of the solute and the polarity of the solvent affect the solubility. For example, polar solvents dissolve polar solutes. Nonpolar solvents dissolve non-polar solutes. 3. Effect of pressure: The solubility of the gases is increased by the increase in pressure. There is direct relationship between them. For example, gaseous carbon dioxide dis 01 . in liquids for effervescent preparations under pressure. Henry's law dictates that
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Physical Pharmaceutics-I
temperature is constant, the solubility of the gas corresponds to its partial pressure. Consider the following formula of Henry's law: P = Kh.c (eq 1.4) Where: P is the partial pressure of the gas above the liquid, K, is Henry's law constant, and c is the concentrate of the gas in the liquid. This formula indicates that (at a constant temperature) when the partial pressure decreases, the concentration of gas in the liquid decreases as well, and consequently the solubility also decreases. Conversely, when the partial pressure increases in such a situation, the concentration of gas in the liquid will increase as well as the solubility also increases. 4. pH: For non-ionizing substances solubility can be enhanced by change of dipole moment. pH has little effect on non-ionizable substances. In the case of ionizable substances, the pH depends on the HENDERSON-HASSELBALCH equation. For Acidic drug pH = pKa
+
For basic drug pH = pKa +
log[ (S;,S,) ] log[
So ] (S -So)
(eq 1.5)
(eq 1.6)
Where S= solubility of substance So=solubility of unionized species S-So=solubility of ionized species pH of a substance is related to its pKa and the concentration of the ionized and unionized forms of the substance.
pH
FIgure 1.8: The effect
pH
or pH
on a weak acid (A) and a weak base (8)
5. Particle Size : As the particle size decreases, the solubility increases due to the increase in surface area. However, after some time decrease in the particle size decreases the solubility due to the formation of agglomerates.
6. CrystalStructure: Amorphous form of drugs is more soluble than Crystalline form. Solubility: SOLVATES >ANHYDROUS > HYDRATES
Solubility of Drugs
7.
11
Molecular Structure: The change in molecular structure strongly affects the solubility of the compound. For example, the introduction of the hydrophilic group into a hydrophobic substance may improve the solubility.
8. Solute-Solvent Interactions Affect Solubility: The relation between the solute and solvent is very important in determining solubility. Strong solute-solvent attractions equate to greater solubility while weak solute-solvent attractions equate to lesser solubility.
Solved problem Exerci e 1.5 If 7.68 mg/rnl procaine solution stable at pH 7.4 given that 1 gm dissolves in 200 rnl water and pka = 8.0S.
Solution: pH
=
pKa +
IOg[
So ] (S-So)
S =7.68 mg/rnl pka = 8.0S So
=
Igm 200rnl
=
lOOOmg= Smg 200rnl rnl
pH = 8.0S + log (S/7.68-S) pH = 8.0S + log 1.86 pH= 8.0S + 0.27 Ans
pH= 8.32, therefore solution is stable and no ppt. occurs.
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1.7 SOLUBILITY OF GAS IN GAS 1.7.1 Dalton's law of partial pressure
r
This law is related to the ideal gas laws. It indicates that total pressure exerted by the mixture of non-reactive gases is the sum of the partial pressures of the individual gases. Mathematically, Dalton's law of partial pressure shown as: Ptotal
= PI + Pl + P3 + P.â&#x20AC;˘ + ... (at constant
T, V)
(eq 1.7)
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= total pressure exerted by the mixture of gases.
P2,
P3
are the partial pressures of the gases.
E erd!le 1.6 If The Total pressure of a mixture of Hyrogen, carbon dioxide and oxygen is 170 kPa. What is the partial pressure of oxygen if the partial pressures of the Hydrogen and carbon dioxide are 80 kPA and 30 kPa, respectively?
SoIudon: According to Dalton's law of partial pressure P
=
Phydrogen
+
Pcarbondioxide
+
Poxygen
170 kPa = 80 kPa + 30 kPa +
A
P oxygen
P oxygen
= 170 kPa - 80 kPa - 30 kPa
P oxygen
= 60 kPa
60kPa
1.8 SOLUBILITY OF GASES IN LIQUIDS The solubility of a gas in a liquid depends on the following factors such as temperature, partial pre ure of the gas on the liquid, the nature of the solvent and the nature of the gas. Henry' law tates that the solubility (S) of a gas in a liquid is directly proportional to the partial pres ure (P) of that gas at a constant temperature. It was formulated by William Henry in 1803. Sa P S KP (eq 1.8) Where K = Henry's constant
=
If solubility measurement is based on the molar fraction of a gas in the solution then Henry's law state that "the partial pressure of the vapor phase (p) is proportional to the molar fraction of the gas (x ) in the olution "and is expressed as follows: p = KHx Where KH is Henry's law constant.
Solubility of Drugs
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Partial pressure of the gas in vapour phase (P)
Mole fraction of the gas (x) in the solution Fi&Ore1.9: Graph between partial pressure of gas In vapor phase and mole fraction
or gas
The concentration of dissolved gas depends on the partial pressure of the gas. If partial pressure is low then concentration of gas will also less (as shown in figure a). If the partial pressure is doubled, the number of collisions with the surface will also double and eventually it will produce more dissolved gas (as shown in figure b). Low pressure equillibrium show low cone.
.
Double the pressure equillibrium show double cone.
I
• ••• • • • • • • • • •• •• • • • •• • • • • .: :.- •. - :.- .-.: ..
............ . . . .. . (a)
.... . -. .. . -
_••
.. .. .....
e••
:
: •••••••••
• ••
_
(b)
Figure 1.10: (a) ngure showlnalow pressure equilibrium at low concentration (b) ngure showlna double pressure equilibrium when concentration aet double
Henry's law applied to increase the solubility of CO2 in carbonated drinks and soda water, the bottle is sealed under high pressure. But there are still limitations of Henry's law. Because Henry's law is applicable only under the following conditions when: 1. There is no chemical reaction between gas and solvent. 2. The gas should not undergo dissociation in the solvent. 3. Pressure of the gas in not too high. 4. Temperature is not too low
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Solved problem Exercise 1.7 Calculate the quantity of CO2 dissolved in a lL bottle of carbonated water if the pressure of 2.7 ann is applied in the bottling process at 25° C? Given that KH of CO2 in water is 29.76 atml(mollL) at 25° C Solution: We know the equation p = KH x Therefore, x= P/KH 2.7 x = --= 29.76
/ 0.09 mol L of CO2
To convert into grams, 1 mole of CO2 = 12 + (16 x 2) = 44g Mass of CO2 in grams
= mol of CO2 x 44 g/mol
Mass of CO2 in grams
= 9.0 x 10.2 x 44= 3.96
Therefore 3.96 g of C02 is dissolved in 1 L of carbonated
water.
Ans 3.96 g
1.9 RAOULTS LAW The partial vapor pressure (Pi) of each component in a solution is directly related to the mole fraction (Xi) of the component in the liquid and the vapor pressure of the pure component (P,") Pi = Xi P," (eq 1.10) For a solution of two liquids, A and B, then the total vapor pressure P of the solution is equal to the weighted sum of the "pure" vapor pressures of the two components, PA and PB. Thus the total pressure will be (eq1.11) Where XA
is mole fraction of component A
XB
is mole fraction of component B
Limitation of Raoult's Law: I. 2. 3.
This applies only to very dilute solutions. This applies to solutions containing only a non-volatile solute. This does not apply to solutes that dissociate or associate within the particular solution.
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Solved problem Exercise 1.8 Determine mole fraction of solvent that produces a solution 23.476 tOIT.The vapor pressure of water at this temperature is 42.362 tOIT.
vapor pressure
of
Solution: =
P solution
(Xsolvenl)
23.476 tOIT
(PO solvenl)
= (x) (42.362
tOIT)
x·0.5541 Ans 0.5541 Exercise 1.9 What is the vapor pressure of an aqueous solution that has a solute mole fraction of 0.1000? The vapor pressure of water is 25.467 rrunHg at 25°C.
Solution: Molvenl
= 1.0000 - 0.1000 = 0.9000
Use Raoult's Law:
Psolution
PIO/ullon
= (0.900) (25.467) • 22.9 mmHg
Ans 22.9 mmHg
1.9.1 Binary solution It is a combination or mixture of two completely miscible liquids. The boiling point of the binary solution based on the composition of the solution.
1.9.2 Ideal solution The solutions which obey the Raoult's law in all the solute compositions in a solvent at any temperature are called ideal solutions. Two liquids A and B form an ideal solution when the molecular attraction between A-A and B-B are identical and therefore the molecular attraction AB will be almost identical to the molecular attraction A-A and B-B.
Ideal solution
Mole fraction
XA = 0 X8=1
Figure 1.11: phase diagram for Ideal solution
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Characteristics of Ideal solution 1. Ideal solution obey Raoult's law i.e., PA = XA and PB = XB 2. No heat absorbed or evolved during mixing ( Hmixing = 0) 3. No expansion or contraction on mixing ( V mixing 0)
=
1.9.3 Real solution or Non ideal solution: The solution which do not obey Raoult's law over entire range of composition. are called non ideal solution or real solutions . These solution deviate from their ideal behaviour. (A)When (i) PA < XA pOA (ii) D.Hmix < 0 and (iii) D.Vmix < O. In this case Solutions of this type show negative deviation from Raoult's law Negative deviation P'; â&#x20AC;˘:O.t:I.~a~~~r pressurel
e¡
.... '. P';
='
.
~ g.
=
"" Q g.
~ Mole fraction
XA = 0 XB= 1
Figure 1.12 : phase diagram of Solutions showing negative deviation from Raoult's law
When the adhesive forces between the molecules of A and B are greater than the cohesive forces between A & A or B & B, the vapor pressure of the solution is less than the expected vapor pressure from the Raoult's law. This is called the negative deviation from Raoult's law. (B) When i) P A> XA P?A (ii) D.Hmix > 0 and (iii) show positive deviation from Raoult's law
O. In this case solutions of this type
D.V mix>
Positive deviation Total Vapour pressure p,. A
.
Ideal '. XA = 1
XB=O
Mole fraction
XA
=0
XB=l
Figure 1.13 : phase diagram of Solutions showing positive deviation from Raoult's law
Solubility of Drugs
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When the cohesive forces between similar molecules are greater than the adhesion forces, differences in polarity or internal pressure will cause the two components to escape more easily from the solution. Consequently, the vapor pressure will be higher than that provided by Raoult's law, showing positive deviation.
1.10 AZEOTROPES When liquid in solution up to a certain composition continues to boil at constant temperature without modification in the composition of the solution is called an Azeotrope or constant boiling mixture. Their mixture may have a higher boiling point than one of the components or they may have a lower boiling point. Types of azeotropes
Azeotropes with Minimum boiling point
Azeotropes with Maximum boiling point
1.10.1 Azeotropes with minimum boiling point: Minimum boiling Azeotrope
Vapor T
Liquid X 0% y 100%
:
Composition
100% 0%
Figure 1.14: Curves for Minimum boDing azeotropes
When the liquids in a solution have a positive deviation, they do not have a great chemical association for each other and their higher escape capacity rise the vapor pressure much more than expected on the basis of the Raoult's law. The point of maximu~ vapor pressure means that the boiling point at this composition will be minimum and constant. This type of solution is called a minimum boiling azeotrope.
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1.10.2 Azeotropes with maximum boiling point: Maximum boiling Azeotrope Vapor
T Liquid
X 0% y 100%
Composition
100% 0%
Figure 1.15: Curves for Maximum boiling azeotropes
When liquids in solution have a negative deviation from ideality, their escape patterns and therefore the vapor pressure decreases compared with the predictions based on Raoult's law. The point of minimum vapor pressure in the curve means that the boiling point of this composition will be maximum and constant. This type of solution is called maximum boiling azeotrope
1. 11 SOLUBILITY OF COMPLETEL V MISCIBLE LIQUIDS Miscible liquids are liquids that dissolve in each other. Fractional distillation is best for separating a solution of two miscible liquids. This method only works if all the liquids in the mixture are miscible (e.g. alcohol & water). This method also work with liquids with different boiling points but it can be quite close together. Thermometer Water out
I.~:==m Alcohol and water Heat Figure 1.16: Fractional distillation
The liquid or solution mixture is poured into the round bottom flask, heated and boiled to vaporize. The vapor passes through a fractionation column. The fractionation column is packed
Solubility of Drugs
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with glass beads which provide a large surface area for evaporation and condensation. The higher boiling liquids, condense and separate, return to the mixture of the flask, while the vapor of the low-boiling liquid passes through the condenser. The (alcohol) vapor is cooled by cold water to condense it to a liquid that is collected in the flask (known as distillate). Here, each liquid distils, with an increasing boiling point, on top of the column. The boiling point of each fraction can be read on the thermometer.
1.12 SOLUBILITY OF PARTIALLY MISCIBLE LIQUIDS 1.12.1 Phenol water system A large number of liquids (phenol and water) dissolve only to a limited extent. They are known as partially miscible liquids. When equal volumes of phenol and water is agitated together, two layers are formed, one of a saturated solution of phenol in water and another is saturated solution of water in phenol. These two solutions are called conjugate solutions.
Tuc
t
Temperature
o
% by weight of phenol
100
Figure 1.17: Temperature-composition curves (in case oCPhenol-water system)
When two partially miscible liquids are mixed and shaken together, we get solutions of different compositions. e.g. on shaking phenol and water, we get 2 layers : the one layer (layer 1) is a solution of water in phenol, and the second layer (layer 2) is a solution of phenol in water. With a rise in temperature, the water concentration in the phenol layer and also the phenol in the water layer increases, the compositions of the two conjugated solutions become nearly same. At a fixed temp, the composition of each solution is fixed, and both the solutions are in equilibrium. Above a particular temperature, such solutions are completely miscible in all proportions. Such a temperature is known as the Critical Solution Temperature (CST) or Consolute Temperature. The upper critical solution temperature, T is the highest temperature at which phase eparation occur. U~
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1.12.2 Triethylamine-water system For triethylamine and water, the system is partially miscible above TIc, and single phase below.
The lower critical solution temperature, Tie. is the lowest temperature at which phase separation occur.
Composition of one phase
P=2 Composition of second phase
T 10
- - - - - - -.~-::-. â&#x20AC;˘â&#x20AC;˘ -.-.,:
P=1
o
1 Mole fraction of triethylamine FI&Ure 1.18: Triethylamine-Water
ay
Unlike the phenol-water system, solubilities decrease with increasing temperature in this system. The two conjugated solutions mix completely at or below Tic. This temperature is also referred to as the critical solution temperature or the lower consolation temperature. The determination of the critical solution temperature can therefore be used for the test the purity of phenol and other such substances.
1.13 DISTRIBUnON LAW According to this law "If a solute A distributes between two immiscible solvents x and y at a constant temperature and the solute A distributes itself between the two liquids in such a way then the ratio of its concentrations in two solvents is a constant value" i.e.
Si C2
= K (constant)
(eq 1.12)
Where Cl =Concentration of "A" in solvent x C2 = Concentration of "A" in solvent y K (constant) is called the partition coefficient and also denoted by KD( distribution constant)
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1.13.1 Explanation of distribution law This is a equillibrium law. When the distribution of the equilibrium, the rate (RI) at which molecules of A pass from concentration (Cl) in X. The rate (R2) at which the molecules is proportional to its concentration (C2) in Y. Moreover, migration from one solvent to the other is equal. So RI aCI or RI = k, x Cl And R2 a C2 or R2 = k2 X C2 At equilibrium RI =R2 So k, X Cl = k2 X C2 C k Or _I =_2 =Ko C2 k,
solute A has reached a dynamic solvent X to Y is proportional to its of A pass from the solvent Y to X at equilibrium, the rate of solute
This is the Nernst's Distribution law equation and the distribution constant if temperature
(where k, is constant) (where k2 is constant)
(eq 1.13) coefficient
Ko is also
is fixed.
1.13.2 Deflation (rom distribution law Several complications may arise, which would influence the constancy of the partition eoefficient. In few cases, deviation from Distribution Law has been attributed If (I) There is Alteration in the mutual solubility of two liquids as a result of increasing concentration. (2) If Molecular state of the solute get Change in the two solvents. The change in molecular state include: a. When solute undergoes association in one of the solvents (eq 1.14) K - Cl D Or
n,J"C;
nJE:
(eq 1.15)
=-Where D C2 Cl and C2 are the concentrations of the solute in two phases. KD is called distribution coefficient or partition coefficient. and n =order of association K
b. When the solute undergoes a dissociation
=
K D
Cl
C2(1-a)
in one of the solvent (eq 1.16)
Or (eq 1.17) Where a i degree of dissociation
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Physical Pharmaceutics-I
Limitations There are following limitations of this law 1. The solute should not react with any of the solvents. 2. The solute must not undergo any change in its molecular state in the solvents, i.e. it must not be dissociated or associate. 3. The temperature should be constant throughout the experiment 4. Solute concentrations are noted after equilibrium is established. 5. The solute concentration in both solvents is low. The law does not hold when concentrations are high.
Applications 1.
The process is used for the separation of organic substances from aqueous solutions
2. The principle of distribution law is very useful in metallurgical example is Desilverization of Lead (Parke Process). 3.
4.
The distribution The distribution
operations.
A popular
law is also useful in the study of complexions, hydrolysis of salts law is also useful in determination of association and dissociation.
Solved problem Exercise 1.10 When a solid A is added to a mixture of toulene and water. After shaking and standing, 20 ml of the toluene layer was found to contain 0.10 g of A and 90 ml of water layer contained 0.20 g of A. Calculate the value of distribution coefficient. Solution: Concentration
of A in benzene (Cb) 0.10 =0.005 g ml-l 20
Concentration
of A in water (Cw) 0.20 = 0.0022 g ml-l 90
. to Distributi 0.005 According istn ution Iaw: -Cb or --Cw 0.0022
Ans 2.27
= 2.27
Solubility of Drugs
23
REVIEW QUESTIONS SUBJECTIVE PART VERY SHORT ANSWER QUESTIONS 1. 2. 3.
4.
5.
Define Molality. Answer- It is Moles of solute in 1000 gm of solvent Define Molarity. Answer- It is number of moles of a solute per liter of solution. Define supersaturated solution. Answer- The solution contains more of the dissolved solute than it would normally contain at a definite temperature Define ideal solution. Answer- The solutions which obey the Raoult's law in all the solute compositions in a solvent at any temperature are called ideal solutions Define association. Answer- The association of ions is a chemical reaction in which the opposite electric charge ions come together in solution and form a distinct chemical entity.
SHORT ANSWER QUESTIONS 1.
2. 3.
4.
5.
6.
7. 8.
Why solute dissolved faster in its amorphous state? Answer- In an amorphous state, their molecules are arranged randomly. Their structure is also less stable, which gives them a greater solubility than crystalline structures Why solute dissolved faster at high temperature? Answer- At higher temperature the molecules move faster with heat, increasing the speed of the reaction How are the solvation energy related with the dissolution of a solvent? An wer- If solvation energy value is a positive number, the dissolution process is endothermic; If it is negative, it is exothermic Why solubility of gas decrease with increase in the temperature? Answer- For all gases, as the temperature increases, the solubility decreases. Kinetic molecular theory can be used to explain this phenomenon. As the temperature increases, the gas molecules move faster and can then escape from the liquid. The solubility of the gas then decreases. How Solute-Solvent Interactions Affect Solubility? Answer- A general rule to remember is, "Like dissolves like." Strong solute-solvent attractions equate to greater solubility while weak solute-solvent attractions equate to lesser solubility. In turn, polar solutes tend to dissolve best in polar solvents while non-polar solutes tend to dissolve best in non-polar solvents How the solubility of carbon dioxide affects as pressure increases? Answer- An increase in pressure results in more gas particles entering the liquid in order to decrease the partial pressure. So, the solubility would increase. What is the molarity of the 0.3181 N HCl Answer-O.3181 M What is the normality orthe 0.0521 M H~.? Answer- O.156N
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Physical Pharmaceutics-I
LONG ANSWER QUESTIONS I. 2. 3. 4.
5. 6. 7.
Define solubility. Describe solubility parameters. Write the factors influencing solubility of drug. Refer article 1.1, 1.4, 1.6 Explain Dalton's Law of Partial pressure. Refer article 1.7.1 State and explain Henry's Law. Rerer article 1.8 Write notes on the following a. Theory of fractional distillation Rerer article 1.11 b. Raoult's Law Refer article 1.9 Define Azeotropes. Draw with diagram to distinguish between a maximum and minimum boiling azeotrope. Refer article 1.10, 1.10.1, 1.10.2 Draw and explain phase diagram of Phenol-water system Refer article 1.12.1 State the Distribution Law. Discuss the limitations and applications. Rerer article 1.13
OBJECTIVE PART MULTIPLE CHOICE QUESTIONS 1.
2.
3.
4.
Number of moles of a solute per llter of solution a. Molarity b. Molality c. Normality d. Equivalency Mole fraction of solute is the ratio of a. the number of moles of solute b. the total number of moles of solute and solvent c. the number of moles of solute and the total number of moles of solute and solvent. d. None of these Which of the roUowlng is not a system of measure or solubility, a. Mass per volume b. Molarity c. Milliequivalent d. Enthaply Description: Enthalpy is a measure of the heat content of a thermodynamic system. AccordJng to USP, Sparingly soluble means the Parts or solvent required for one part of solute Is a. 3D-lOO b. 10-30 c. 100-1000 d. Less than 1
Solubility of Drugs
S.
6.
7.
8.
9.
10.
11.
U.
13.
14.
15.
25
The solubility of a substance depends on the a. solvent used b. temperature c. pressure. d· All of the above At a specified temperature, maximal amount of solute that can dissolve in an amount of solvent is known as a. Solubility b. Dissolution c. Diffusion d. Capacity Additional or Extra solute wUl not dissolve in a a. saturated solution b. dilute solution c. concentrated solution d. non aqueous solution Solubility Curve is a curve drawn between a. solubility and temperature b. solubility and pressure c. solubility and mole fraction d. None of the above The solubility of gas with rising temperature a. Increase b. Decrease b. Remain constant d. None of the above The mechanism of the polar solvents mainly depends on a. High dielectric constant b. hydrogen bond formation b. Dipole interaction. d. All of the above The Hansen parameten consist of a. dispersion force component b. hydrogen bond component b. dipole-dipole component d. All of the above The chemical reaction in which the opposite electric charge ions come together in solution and fono a distinct chemical entity is caUed a. Association b. Solvation b. Combination d. Capacitance The solutions which obey the Raoult's law is known as a. Ideal solution b. Real solution b· Binary solution d- Supersaturated solution The solubility of drug wUl be high when it is in its a. Stable form b. Metastable form b. Unstable form d. None of the above pH of the solution depends on a. Henderson-Hasselbalch equation b. Henry's Law b. Charle's law d. Dalton's Law
ANSWERS la
2c
3d
4a 5d
6a
t«
Sa 9a
1Oct"
ua
12a
13a
14a
15a