SKKU Physical Pharmacy Laboratoryphysicalpharm.skku.edu/erp/erpmenus/lesson_pds/upLoadFiles/9.Solubility.pdfSKKU Physical Pharmacy Laboratory 성균관대학교물리약학연구실

SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실


Solution : a liquid in which a solid substance has been

dissolved.

• Solute : a solid substance that is dissolved in a liquid.

• Solvent : a liquid that can dissolve other substances.

Solubility :

• the concentration of solute in a saturated solution at

equilibrium at a given temperature

• given as per weight or volume of solvent

g (solute) / 100g (solvent)

1g (solute) / volume (ml) of solvent


Solubility (continue)

• Unbuffered solubility

• Water solubility

• Buffered solubility

• Intrinsic solubility (cf. dissolution - extrinsic property)

• solubility of an ionizable compound in its neutral form

(the molar solubility of the undissociated acid S0)

• Thermodynamic solubility


Saturated Solutionthe solute is in equilibrium with the solid phase

Unsaturated or Subsaturated Solutionone containing the dissolved solute in a concentration

that necessary for complete saturation at a definite

temperature

Supersaturated Solution one that contains more of the dissolved solute than it

would normally contain at a definite temperature


Miscible

when a solute is a liquid and will form a solution with a

solvent over any concentration range

The Phase RuleF = C – P + 2


Description Forms

(Solubility Definition)

Parts of Solvent

Required

for One Part of Solute

Solubility Range

(mg/mL)

Solubility Assigned

(mg/mL)

Very soluble(VS) <1 >1,000 1,000

Freely soluble(FS) From 1 to 10 100 - 1000 100

Soluble From 10 to 30 33 - 100 33

Sparingly soluble(SPS) From 30 to 100 10 - 33 10

Slightly soluble(SS) From 100 to 1,000 1 - 10 1

Very slightly soluble(VSS) From 1,000 to 10,000 0.1 - 1 0.1

Practically insoluble(PI) >10,000 <0.1 0.01


USP Chart of Descriptive terms

TermParts solvent to 1 part

solute

Very soluble Less than 1

Freely soluble 1-10 (3-10%)

Soluble 10-30

Sparingly soluble 30-100

Slightly soluble 100-1000

Very slightly soluble 1000-10,000

Practically insoluble, insoluble

More than 10,000

용어

썩 잘 녹는다

잘 녹는다

녹는다

조금 녹는다

녹이 어렵다

매우 녹기 어렵다

거의 녹지 않는다

대한약전 제 11개정


Temperature

Pressure

pH

Common Ion Effects

Chemical Structures- Dipole moment

- Dielectric properties

- Hydrogen bonding


“Like Dissolves Like”


Polar Solvents

Nonpolar Solvents

Semipolar Solvents

Hydrogen bondingcapability

Yes No No

Dielectric constant High Low

InteractionDipole interaction

Induced dipole interaction(London type)

Induce polarity in non-polar solvent

Example Water HydrocarbonsKetones, alcohols

Amphiprotic Cosolvents


Influential Factors• Dipole moment

• Hydrogen bonds

• Acidic and basic character of constituents

• Structural features

Mechanism • High dielectric constant

• Amphiprotic

• Dipole interaction force

Water

(dissolve ionic solutes and other polar substances)


Influential Factors• Induced dipole interactions

• Weak van der Waals-London type forces

• Low dielectric constant, No hydrogen bond

Hydrocarbons

(dissolve nonpolar solutes)


Influential Factors• Induce a certain degree of polarity in non-polar solvent molecules

• No hydrogen bond

• Cosolvent

Ketones and alcohols

(Intermediate solvents)


Solubility of Gases in Liquids


Henry’s Law

C2 = σp

C2 = concentration of the dissolve gas (g/l)

p = partial pressure (mm of the undissolved gas)

σ = inverse of the Henry’s law constant, K

in a dilute solution at constant temperature, the

concentration of dissolved gas is proportional to the

partial pressure of the gas above the solution at

equilibrium


As the temperature increases, the solubility of most gases

decreases, owing to the greater tendency of the gas to expand


Gases are often liberated from solutions in which they are

dissolved by the introduction of an electrolytes and

sometimes by a nonelectrolyte

NaCl or

sucrosegases

carbonated solution


Gases (HCl, NH3, CO2) + Solvent

→ Chemical reaction

→ Increase solubility


Inverse Henry’s law constant,

C2 = P

Bunsen absorption coefficient,

: 일정온도, gas의 partial pressure 1 기압하에 solvent 1L에녹는 gas의 volume (L)

Saturated condition : 0℃, 760mmHg

Vgas. STP

Vsoln.

= P


Solubility of Liquids in Liquids


Complete Miscibility

Solvents are said to be completely miscible when they are

mix in all proportions

Partial Miscibility

When certain amounts of two liquids are mixed, two liquid

layers are formed, each containing some of the other liquid in

the dissolved state


Mixture of polar and semipolar solvents ▪ Water-Alcohol

▪ Glycerin-Alcohol

Mixture of nonpolar solvents▪ Benzene-Carbon tetrachloride

“Completely miscible liquid mixtures in generalcreate no solubility problems”


Phenol-Water System Triethylamine-Water System Nicotine-Water System

Consolute temperature※ mixture of water-ether mixture – no consolute temp.


The solubility of peppermint oil in various

portions of water and polyethylene glycol.

Triangular phase diagram for the three-

component system.


If the added material is soluble in only one of the two components /

if the solubilities in the two liquids are markedly different

When the third substance is soluble in both of the liquids roughly

the same extent

✓ The mutual solubility of the liquid pair is decreased

✓ The mutual solubility of the liquid pair is increased

Blending

“The increase in mutual solubility of two partially miscible solvents by another agent”

Micellar Solubilization

”Solubility in water of a non-polar liquid is increased by a micelle-forming surfactant”

BinaryAdded

materialTernary


Solubility of Solids in Liquids




Acidic

Basic

Amphoteric

Indomethacin

Chlorpromazine

Oxytetracycline

Figure 25. Alexander T. Florence and David Attwood. 『Physicochemical Principles of Pharmacy』, Pharmaceutical Press(2016) p.165


Weak Acids

−+ +=+ AOHOHHA 32

][

]][[ 3

HA

AOHK a

−+

=

분자형 이온형 −+= AHAS

)][

1]([][

][][

33++

+=+=OH

KHA

OH

HAKHAS a

a

약전해질 포화용해도 𝑆0 ≈ [𝐻𝐴] )][

1(3

0 ++=

OH

KSS a

apKpHa

a OHKOH

K −+

+=→=−→= 10log]log[log

][3

3

S0, pKa를 알면 주어진 pH에서의 S 계산𝑆 = 𝑆0(1 + 10𝒑𝑯−𝒑𝑲𝒂)


Weak Acids

0

0logS

SSpKpH ap

−+=

][ 3

00 ++=

OH

KSSS a

][ 3

00 +=−

OH

KSSS a

]log[loglog)log( 300+−+=− OHSKSS a


Weak Bases−+ + OHBHB

][

][][

B

OHBHKb

−+ +=

0

0logSS

SpKpH ap

−+=

𝑆 = 𝑆0(1 + 10𝒑𝑲𝒂−𝒑𝑯)


Strong Electrolytes :strong acids and bases and all salts are soluble in water

Weak Electrolytes :weak acids and bases with high molecular weight are not soluble in water

Nonelectrolytes :high-molecular-weight organic drugs that do not dissociate or associate in water are generally soluble in organic solvents and have little or no solubility in water

Cosolvency :a solute is more soluble in a mixture of solvents than in one solvent alone


The solubility of phenobarbital in a mixture

of water, alcohol, and glycerin at 25℃

Cosolvencya solute is more soluble in a mixture

of solvents than in one solvent alone

“cosolvents”


The influence of alcohol concentration on the

dissociation constant (ka) of phenobarbital. Example 9-3.

Weak electrolyte buffered aqueous solution + Alcohol

→ 𝑖𝑛𝑐𝑟𝑒𝑎𝑠𝑒𝑠 the solubility ofthe un − ionized species ∶ 𝑆0 ↑

→ 𝑑𝑒𝑐𝑟𝑒𝑎𝑠𝑒𝑠 the dissociation ofa weak electrolyte ∶ 𝐾𝑎 ↓ (≡ 𝑝𝐾𝑎 ↑)





Solubility product, :the real solution solubility of poorly soluble strong electrolytes in

water is calculated by using the solubility product constant

obtained from thermodynamics

Common ion :

adding a common ion is to reduce the solubility of a slightly

soluble electrolyte

spK


Solubility determination:

1. Drug is added in a specific amount of solvent.

2. After equilibrium is achieved, excess drug is removed

(usually by filtering).

3. The concentration of the dissolved drug is measured

using standard analysis techniques such as HPLC.

“Saturation Shake Flask” Method

Limitations (p.196)


𝐹 = 𝐶 − 𝑃 + 2temperature, pressure and concentration, etc.

F = 1 (concentration)F = 0 (temp., pressure, conc. are constant)

solid state drug, P=2

“valid only for pure drug substance”saturate concentration


System having one impurity

solution saturated with the first component

solution saturated with two components


“measure a precipitation rate rather than solubility”

Using highthroughput kinetic measurement of antisolvent precipitation commonly referred to“kinetic solubility”

Use of Dimethyl sulfoxide(DMSO) stock solutions

Advantages but limitations

“small amount of stock solution is added to the aqueous buffer incrementally until the limit of solubility is achieved.”

“Speed up the process, limit compound consumption, reduce the occurrence of manual errors, and increase data consistency.”


Solubility product, :the real solution solubility of poorly soluble strong electrolytes in

water is calculated by using the solubility product constant

obtained from thermodynamics

Common ion :

adding a common ion is to reduce the solubility of a slightly

soluble electrolyte

spK


Partition Phenomena


The partition law :a solute will distribute itself between two immiscible

solvents so that the ratio of its conc. in each solvent is

equal to the ratio of its solubility in each one

Co = molar conc. in organic layer

Cw = molar conc. in aqueous layer

Kd = partition coefficient or distribution constant

w

dC

CK 0=


Strong Electrolyte

Strong electrolytes are completely

dissociated in aqueous solution

→ cations & anions in aqueous layer

→ water soluble

Without ion pairing, do not partition

into the organic layer

Nonelectrolyte

OKd →w

dC

CK 0=


The partition law : depends on pH

pH different from pKa

(pH < pKa for weak acid ; pH > pKa for weak base)

For a weak organic acid,

For a weak organic base, w

dC

CK 0=

w

dHA

HAK

][

][ 0=

w

dC

CK 0=

w

dB

BK

][

][ 0=


Effect of Ionic Dissociation and Molecular Association on Partitioning

SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실

Schematic representation of the distribution of benzoic acid between water and an oil phase.

SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실SKKU Physical Pharmacy Laboratory 성균관대학교 물리약학연구실51


Peanut Butter Oil & Water Solution

Benzoic acid


In Peanut Butter Oil In Water

𝐾 ∶ 𝑡𝑟𝑢𝑒 𝑑𝑖𝑠𝑡𝑟𝑖𝑏𝑢𝑡𝑖𝑜𝑛 𝑐𝑜𝑒𝑓𝑓𝑖𝑐𝑖𝑒𝑛𝑡

𝐾′ ∶ 𝑎𝑝𝑝𝑎𝑟𝑒𝑛𝑡 𝑑𝑖𝑠𝑡𝑟𝑖𝑏𝑢𝑡𝑖𝑜𝑛 𝑐𝑜𝑒𝑓𝑓𝑖𝑐𝑖𝑒𝑛𝑡

[𝐻𝐴]0: 𝑐𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑏𝑒𝑛𝑧𝑜𝑖𝑐 𝑎𝑐𝑖𝑑 𝑖𝑛 𝑜𝑖𝑙

[𝐻𝐴]𝑤: 𝑐𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑏𝑒𝑛𝑧𝑜𝑖𝑐 𝑎𝑐𝑖𝑑 𝑖𝑛 𝑤𝑎𝑡𝑒𝑟

𝐶𝑤: 𝑡𝑜𝑡𝑎𝑙 𝑐𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑏𝑒𝑛𝑧𝑜𝑖𝑐 𝑎𝑐𝑖𝑑 𝑖𝑛 𝑤𝑎𝑡𝑒𝑟

𝐶𝑜: 𝑡𝑜𝑡𝑎𝑙 𝑐𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑏𝑒𝑛𝑧𝑜𝑖𝑐 𝑎𝑐𝑖𝑑 𝑖𝑛 𝑜𝑖𝑙


In Peanut Butter Oil In Water




𝐶: 𝑐𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑏𝑒𝑛𝑧𝑜𝑖𝑐 𝑎𝑐𝑖𝑑 𝑖𝑛 𝑤𝑎𝑡𝑒𝑟 𝑏𝑒𝑓𝑜𝑟𝑒 𝑑𝑖𝑠𝑡𝑟𝑖𝑏𝑢𝑡𝑖𝑜𝑛


Benzene & Acidic Water Solution

Benzoic acid


In Water In Oil (Benzene)


𝐾𝑑: 𝑑𝑖𝑠𝑠𝑜𝑐𝑖𝑎𝑡𝑖𝑜𝑛 𝑐𝑜𝑛𝑠𝑡𝑎𝑛𝑡

[𝐻𝐴]𝑜: 𝑐𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑏𝑒𝑛𝑧𝑜𝑖𝑐 𝑎𝑐𝑖𝑑 𝑖𝑛 𝑜𝑖𝑙

[𝐻𝐴]𝑤: 𝑐𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑏𝑒𝑛𝑧𝑜𝑖𝑐 𝑎𝑐𝑖𝑑 𝑖𝑛 𝑤𝑎𝑡𝑒𝑟




Distribution of Solutes between Immiscible Solvents


𝐾 =𝐶𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑠𝑜𝑙𝑢𝑡𝑒 𝑖𝑛 𝑜𝑟𝑖𝑔𝑖𝑛𝑎𝑙 𝑠𝑜𝑙𝑣𝑒𝑛𝑡

𝐶𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑠𝑜𝑙𝑢𝑡𝑒 𝑖𝑛 𝑒𝑥𝑡𝑟𝑎𝑐𝑡𝑖𝑛𝑔 𝑠𝑜𝑙𝑣𝑒𝑛𝑡=

𝑤1/𝑣1(𝑤 − 𝑤1)/𝑣2

𝑤1 ∶ 𝑤𝑡. 𝑜𝑓 𝑡ℎ𝑒 𝑠𝑜𝑙𝑢𝑡𝑒 𝑟𝑒𝑚𝑎𝑖𝑛𝑖𝑛𝑔 𝑖𝑛 𝑡ℎ𝑒 𝑜𝑟𝑖𝑔𝑖𝑛𝑎𝑙 𝑠𝑜𝑙𝑣𝑒𝑛𝑡𝑎𝑓𝑡𝑒𝑟 𝑒𝑥𝑡𝑟𝑎𝑐𝑡𝑖𝑛𝑔 𝑤𝑖𝑡ℎ 𝑡ℎ𝑒 𝑓𝑖𝑟𝑠𝑡 𝑝𝑜𝑟𝑡𝑖𝑜𝑛 𝑜𝑓 𝑡ℎ𝑒 𝑜𝑡ℎ𝑒𝑟 𝑠𝑜𝑙𝑣𝑒𝑛𝑡

Example 9-7


K: distribution coefficient

The most efficient extraction results when a larger number (𝑛) of extractions are carried out with small portions (𝑣) of extracting liquid

𝒗𝟐 𝒏 𝒘𝟏Amount extracted

10 1 0.005660 0.094339623

5 2 0.001148 0.098852041

2 5 6.54E-05 0.099934553

1 10 5.50E-06 0.099994501

0.5 20 5.43E-07 0.099999457

Total vol. of extracting liq. is fixed.


𝑻𝒐𝒕𝒂𝒍 𝑷𝒓𝒆𝒔𝒆𝒓𝒗𝒂𝒕𝒊𝒗𝒆 𝒂𝒅𝒅𝒆𝒅 = 𝑪 = 𝑪𝒐 + 𝑪𝒘

ww AHAHAC ][][][ 0

−++=

w

dHA

HAK

][

][ 0= wd HAKHA ][][ 0 =

][

][][

][

]][[

3

3

+

−−+

=→=OH

HAKA

HA

AOHK wa

w

w

wa

][

][][][

3

+++=

OH

HAKHAHAKC w

awwd

)][

1(][3

+++=

OH

KKHA a

dw

][1

][

3

+++

=

OH

KK

CHA

ad

w

Conc. of undissociated acid in the aqueous phase

Documents

SKKU Physical Pharmacy Laboratoryphysicalpharm.skku.edu/erp/erpmenus/lesson_pds/upLoadFiles/9.Solubility.pdfSKKU Physical Pharmacy Laboratory 성균관대학교물리약학연구실