1. Solutions and solubility
“Solubility of a substance may be defined as the amount of solute dissolved in 100gms of a solvent to form a saturated solution at a given temperature”.

2. The Solution Formation Process
Therefore, the energy of solution formation, the enthalpy of solution, equals the sum of the three steps:
ΔHsoln = ΔH1 + ΔH2 + ΔH3.
ΔH1 and ΔH2 are both positive because it requires energy to pull molecules away from each other. When the expanded form of the solvent and the solute are combined to form a solution, energy is released, causing ΔH3 to be negative. This makes sense because the solute and solvent can interact through the various types of intermolecular forces.
solutions will form only when the energy of interaction between the solvent and solute is greater than the sum of the solvent-solvent and solute-solute interactions.

3. Factors Affecting solubility
Crystal Characteristics
Molecular structure of Solute
Effect of Temperature on Solubility
Effect of Added Substances on Solubility:
Particle size of Solid

4. The solubility of solutes is dependent on temperature.
CASE I: Decrease in solubility with temperature:
CASE II: Increase in solubility with temperature:
If the heat given off in the dissolving process is greater than the heat required to break apart the solid, the net dissolving reaction is exothermic ΔH1negative value (energy given off). The addition of more heat (increases temperature) inhibits the dissolving reaction since excess heat is already being produced by the reaction.
If the heat given off in the dissolving reaction is less than the heat required to break apart the solid, the net dissolving reaction is endothermic ΔH1positive value (energy required). The addition of more heat facilitates the dissolving reaction by providing energy to break bonds in the solid. This is the most common situation where an increase in temperature produces an increase in solubility for solids.

5. The solubility of solutes is dependent on temperature.
The solubility of a solute in a solvent is dependent on temperature, nature of solute and nature of solvent.
Heat of solution ΔH represents the heat released or absorbed when a mole of solute is dissolved in a large quantity of solvent.
Most of the substances are endothermic, absorbing heat in the process of dissolution. For this substances, an increase in temperature results in an increase in solubility.
Exothermic substances give off heat in the process of dissolution. The solubility of such substances would decrease with increase in temperature.

6. The solubility of solutes is dependent on temperature.
Why does solubility change with temperature? Consider a beaker that contains a saturated solution of table sugar. The bottom of the beaker is covered with sugar crystals. When a tiny amount of sugar dissolves, heat is absorbed. When a tiny amount of sugar crystallizes out of solution, heat is released. We can write:
heat + solid sugar + water = dissolved sugar
The equation represents two processes: dissolution going left to right, and crystallization going right to left. When the sugar crystals are dissolving at exactly the same rate that sugar is crystallizing out of solution, the system is at equilibrium. The balance between dissolution and crystallization can be changed by changing the temperature of the solution. Adding heat will favor dissolution. Cooling the solution will favor crystallization.

7. II Molecular structure of Solute:
Substituents hydrophobic or hydrophilic, depending on their
Salts are usually more soluble than their weak acids or weak bases. High degree of ionic dissociation of the compound when it dissolves in water.
The greater the number of polar groups, the greater is the solubility in water; pyrogallol is more soluble in water than phenol.
For simple molecules solubility decreases with increase of molecular surface area.
In general, aqueous solubility decreases with increasing boiling point and melting point.

8. Molecular structure of Solute:
Substituents hydrophobic or hydrophilic, depending on their polarity:
Polar groups such as –OH capable of hydrogen bonding with water molecules impart high solubility.
Non-polar groups such as –CH3 and –Cl are hydrophobic and impart low solubility.
Ionization of the substituent increases solubility, e.g. –COOH and –NH2 are slightly hydrophilic whereas –COO– and –NH3 are very hydrophilic.

9. III: Crystal Characteristics
Crystal habit is description of outer appearance of crystal.
Internal structure is molecular arrangement within the solid.
Depending on internal structure compounds are classified as
1. Crystalline
2. Amorphous
Crystalline compounds are characterized by repetitious spacing of constituent atom or molecule in three dimensional arrays.
In amorphous form atoms or molecules are randomly placed.
Solubility & dissolution rate are greater for amorphous form than crystalline, as amorphous form has higher thermodynamic energy.
E.g. Amorphous form of Novobiocin is well absorbed where as crystalline form results in poor absorption.

10. Polymorphism
It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice.
Different crystalline forms are called polymorphs.
Polymorphs differ from each other with respect to their physical property such as
Solubility
Melting point
Density
Hardness
Chloromphenicol exist in A,B & C forms, of these B form is more stable & most preferable.
2)Riboflavin has I,II & III forms, the III form shows 20 times more water solubility than form I.

11. Polymorphism
Various polymorphic forms of a drug have identical chemical structure but different crystalline structures & they show different physical properties such as Melting points, Solubility & Dissolution rates, as we know having the same chemical structure doesn’t mean to have the same orientation in 3D shapes in nature.
At a given temperature only one crystalline form of the different polymorphs will show a highly stable organized & strongly bonded crystals form, this is referred as to the stable form, while the other crystal forms exhibit poorly organized & weakly bonded crystal forms which will be referred to the Metastable forms.
So the metastable form of the polymorphic drug as it shows a poorly organized crystal form, which means weakly bonded also, will have a low melting point & thus a higher solubility & high dissolution rate (as less energy is required to break its bonds), While the stable form exhibits high melting point & low solubility & dissolution rate (as being highly organized & strong bonded so more energy is needed to break its bonds), Accordingly, in order to have high dissolution rates & hence high absorption rates, that’s why the metastable form of polymorphic drug might be always required & recommended over the stable form from absorption point of view.

12. Polymorphism
EXAMPLE 1
Chloramphenicol palmitate exists in polymorphs having a stable & metastable forms, the metastable form of the drug if formulated as a suspension was always found to have higher solubility, dissolution rate & absorption compared to the stable form.
EXAMPLE 2
Methylprednisolone exist as a metastable & stable form & if the drug is formulated as a suspension for subcutaneous injection containing the 2 crystalline forms, then that means a sustained release of the drug can be obtained where the metastable form (being highly soluble compared to the stable form) can provide a rapid initial dose (loading dose), while the stable form (being slowly dissolved) will provide the prolonged or sustained action dose called the maintenance dose.

13. AMORPHISM
In addition to different polymorphic forms, a drug may exist in an amorphous form, which is a non-crystalline or poorly crystallized form.
Since amorphous form is usually more soluble & rapidly dissolving (but having shorter duration of action) than the corresponding crystalline form so it will exhibit a higher dissolution rate & absorption rate.
EXAMPLE 1
The amorphous form of novobiocin (antibiotic) when taken orally as a suspension, found to possess high absorption while crystalline form of the same drug was found to be poorly absorbed.
EXAMPLE 2
Similarly the amorphous form of chloramphenicol stearate is found to be highly bioavailable, while the crystalline form is therapeutically ineffective.
EXAMPLE 3
A mixture of amorphous & crystalline forms of insulin taken subcutaneously or by IM route provide an initial rapid action dose due to the fast dissolving amorphous form followed by a prolonged action because of the slowly dissolving crystalline form.

14. SOLVATION & ASOLVATION
During the process of crystallization, the drug crystals may incorporate (include) one or more molecules of the solvent used into their internal structures & the result is referred to as solvates.
The effect of solvate & asolvate form (hydration is used if the solvent was water & salvation if it was any other organic solvent)(asolvate means drug molecule crystals containing no solvent molecules trapped between them) on the dissolution rate or permeation rate is great hence effecting directly the total bioavailability of the drug which will varies (the bioavailability) greatly between different drug forms & crystals forms depending on the type of the solvent trapped.
When the solvent is water, the anhydrated form (the asolvate) generally shows high dissolution rate than their corresponding hydrates (solvates) & hence shows higher bioavailability. This is because the anhydrous forms of the drug reacts more extensively with water compared to the already hydrated form which is considered to have a level of water saturation already. Some examples of the effect of hydrates & unhydrates on the dissolution & hence bioavailability of the drug is shown as the following:

15. SOLVATION & ASOLVATION
EXAMPLE 1
The anhydrous forms of the following drugs exhibits higher dissolution rates compared to their corresponding hydrated form such as caffeine, theophylline & glutethimide
EXAMPLE 2
The anhydrous form of ampicillin, when taken orally in a hard gelatin capsule formulation was found to possess higher dissolution rates & higher absorption rates than ampicillin trihydrate, which is obviously the hydrated form of ampicillin.
On the other hand, when organic solvates are used (other than water), the drug will exhibit higher bioavailability when it is in the solvate form rather than the other asolvate form.This may be due to the fact that organic solvates has higher lipophilicity (partition coefficient) due to their non-aqueous or Lipophilic environment in general surrounding the drug molecule & hence will increase the rate of permeation of the drug via the GIT leading to general enhanced absorption & bioavailability rate.
EXAMPLE 3
The ethanol & acetone solvates of hydrocortisone & prednisolone show higher absorption rates than the non-solvated forms.
EXAMPLE 4
The chloroform solvates of griseofulvin (anti-fungal) is better absorbed than the same drug asolvate.
So in general we see that crystal formation & the trap of any solvent molecule between the drug crystals will highly & directly affect the whole process of absorption & bioavailability in different manners.

16. IV- Particle size of Solid:-
The Solubility of a substance increases with decreasing particle size.
The particle size and surface area of a drug exposed to a medium can affect actual solubility as indicated by equation:
Where
S is the solubility of the small particles,
S0 is the solubility of the large particles,
γ is the surface tension,
V is the molar volume,
R is the gas constant,
T is the absolute temperature, and
r is the radius of the small particles.
The equation can be used to estimate the decrease in particle size required to increase solubility.The size of the solid particle influences the solubility because as particle becomes smaller, the surface area to volume ratio increases the surface area, which allows a greater interaction with the solvent.
This effect may be significant in the storage of pharmaceutical suspensions, as the smaller particles in such a suspension will be more soluble than the large ones. As small particles disappear, the overall solubility of the suspended particles will decrease and the large particles will grow. The occurrence of crystal growth is of importance in the storage of parenteral suspensions.

17. V- Effect of Added Substances on Solubility:
1.Effect of salts on the solubility of nonelectrolyte
2. Effect of common ion
3-Effect of semipolar solvents on the solubility of nonpolar solutes
4-Effect of semipolar solvents on the solubility of sparingly soluble electrolyte
5-Effect of surface active agent
6-Complex formation
7- pH and solubility

18. 1- Effect of salts on the solubility of nonelectrolyte
. Most commonly, the solubility of the nonelectrolyte is decreased, the effect is referred to as" salting - out", less commonly it is increased, and is described as "salting. - in".
"Salting - out" occurs because the ions of the added electrolyte require water for their hydration, thereby reducing the amount of water available for solution of the nonelectrolyte. The greater the degree of hydration of the ions, the more the solubility of the nonelectrolyte is decreased If, for example, one compares the effect of equivalent amount of lithium chloride, sodium chloride, potassium chloride, rubidium chloride and cesium chloride (all of which belong to the family of alkali metals and are of the same valence type), it is observed that, lithium chloride decreases the solubility of a non-electrolyte to the greatest extent and that, the salting out effect decreases in the order given. This is also the order of the degree of hydration of the cations. Lithium ion, being the smallest ion and therefore having the greatest density of positive charge per unit of surface area is the most extensively hydrated of the cation. (Electro negativity value are Li = 1, Na = 0.9, K = 0.8, Rb = 0.8 and Cs = 0.7)( Example of salting out (addition of electrolytes to aromatic water).
"Salting in" commonly occurs when either the salts of various organic acid or organic - substituted ammonium salts are added to aqueous solutions of nonelectrolyte. The solubility increases as the concentration of added salt is increased. The phenomenon is known as "hydrotropy" & the salt is known as "hydrotropic salt".

19. 2. Effect of common ion
The solubility of slightly soluble electrolyte is decreased by the addition of a second electrolyte that possesses a similar ion to the first. This is known as the common ion effect.
In a saturated solution in contact with undissolved solid, the equilibrium may be represented as follows for a compound AB:
AB(s) AB A+ + B-
Undissolved undissociated ions
Solid molecules
KSP = [A+] [B-]
Where KSP is a constant and known as the apparent solubility product of compound AB,
If ksp is exceeded by the product of the concentration of the ions, i.e. [A+][B-] then the equilibrium shown above, moves towards the left in order to restore the equilibrium, and solid AB is precipitated. The product [A+] [B-] will be increased by the addition of more A+ ions produced by the dissociation of another compound, e.g. AX  A+ + X-
Where A+ is the common ion. Solid AB will be precipitated and the solubility of this compound is therefore decreased. This is known as the common ion effect.
The addition of common B- ion would have the same effect.
Note that: The solubility product principle is valid for aqueous solutions of slightly soluble salts, provided the concentration of added salt is not too great.
When the concentrations are high, deviations from the theory occur. Deviations may also occur as the result of the formation of complexes between the two salts. A pharmaceutical example of increased solubility by virtue of complex-ion formation is seen in the effect of solutions of soluble iodide on mercuric iodide. According to the solubility product principle it might be expected that, soluble iodides would decrease the solubility of mercuric iodide, but because of the formation of the more soluble complex salt K2 Hg l4 which dissociate as follow:
K2Hgl K+ + (Hgl4)-
The iodide ions no longer function as a common ion.

20. 3-Effect of semipolar solvents on the solubility of nonpolar solutes
To enhance the solubility of poorly soluble materials, the water miscible solvents are used in which the drug has good solubility. This process of improving solubility is known as co-solvency.Solvents used to increase the solubility is known as co-solvents.
The mechanism for solubility enhancement by co-solvency is not clearly understood. But it is proposed that, solubility is increased may be by reducing the interfacial tension between the solvent and hydrophobic solutes and decreasing dielectric constant of solvent.
The commonly used and acceptable cosolvents in formulation of aqueous liquids for oral solutions are Ethanol, Sorbitol, Glycerin, Several members of PEG series.
Some characteristics of cosolvent, which are used in preparation:
1. It must be non-toxic. Non-irritating.
2. It should be able to solubilize the drug in given solvent.
3. It should be able to cross the membrane.
Apart from increasing solubility, they are also used to improve the solubility of volatile constituents used to impart a desirable flavor and odor to the product.

21. 4-Effect of semipolar solvents on the solubility of sparingly soluble electrolyte
The solubility of electrolytes depends on the dissociation of dissolved molecules into ions. The ease of this dissociation is affected by the dielectric constant of the solvent, which is a measure of the polar nature of the solvent. Liquid with a high dielectric constant (DEC=80) like water is able to reduce the attractive forces that operate between oppositely charged ions produced by dissociation of an electrolyte. To determine the dielectric constant of the solute, dioxane-water blend having known dielectric constants are used and the dielectric constant at which maximum solubility is attained is noted.
If alcohol is added to an aqueous solution of a sparingly soluble electrolyte, the solubility of the latter is decreased because the alcohol (DEC=25) lowers the dielectric constant of the solvents & ionic dissociation of the electrolyte becomes more difficult. The DEC of glycerin is 46 close to the 60% alcohol mixture, therefore, a salt like sodium chloride to have about the same solubility in glycerin as in 60% alcohol.

22. 5-Effect of surface active agent
Oil
Water
Air

23. 5-Effect of surface active agent
Solubilization has been defined as the spontaneous passage of poorly water-soluble solutes into an aqueous solution of a surface active agent (or surfactant) in which a thermodynamically stable solution is formed. When surfactants are added to a liquid at low concentration they tend to orient at the air-liquid interface. As additional surfactant is added, the interface becomes fully occupied and the excess molecules are forced into the bulk of the liquid. At still higher concentrations, the molecules of surfactant in the bulk of the liquid begin to form oriented aggregates or micelles: this change in orientation occurs rather abruptly, and the concentration of surfactant at which micelle is formed is known as the critical micelle concentration or CMC.

24. Solubilization
Solubilization is thought to occur by virtue of the solute dissolving in or being absorbed onto the micelle. Thus, the ability of surfactant solution to dissolve or solubilize water-insoluble materials starts at the critical micelle concentration and increases with the concentration of the micelles. Example, phenol is markedly more soluble in aqueous soaps than in pure water. Cresol in aqueous solution is known as LYSOL. Surfactant based solution of Taxol, that is solubilized in 50% solution of Cremophor.

25. 6-Complex formation
The apparent solubility of a solute in a particular liquid may be increased or decreased by the addition of a third substance which forms an intermolecular complex with the solute. For example, the formation of the complexes between 3-aminobenzoic acid and various dicarboxylic acids has been shown to increase the apparent water solubility of the former compound. Also, p-aminobenzoic acid increases the apparent solubility of caffeine, while gentisic acid decreases the solubility of caffeine.

26. 7- pH and solubility
Many drugs are weak organic acids (for example, acetylsalicylic acid) or weak organic bases (for example, procaine) or their salts (for example, ephedrine hydrochloride). A weak acid or base is only slightly ionized in solution, unlike a strong acid or base, which is completely ionized. The degree to which weak acids and bases are ionized in solution is highly dependent on the pH. The exceptions to this general statement are the nonelectrolyte, such as the steroids, and the quaternary ammonium compounds, which are completely ionized at all pH values and in this respect, behave as strong electrolytes. Acids ionize in alkaline medium, while bases ionize in acidic medium. The ionized drug is more soluble in water, while the neutral drug is more soluble in other organic solvents e.g., alcohol, chloroform, acetone.

27. pH and solubility Example: Phenobarbital (acidic drug)
Increased pH leads to increased ionization leads to increased water solubility and decreased solubility in other organic solvents.
Example: Procaine HCl (basic drug)
Increased pH leads to decreased ionization leads to decreased water solubility and increased solubility in other organic solvents.
Let’s begin with a definition of the term pH. The p comes from the word power. The H, of course, is the symbol for hydrogen. Together, the term pH means the hydrogen ion exponent.
The pH of a substance is a measure of its acidity, just as a degree is a measure of temperature.
Weak electrolytes undergo ionization and are more soluble when in ionized form. The degree of ionization depends on dissociation constant (pKa) and the pH of the medium. The pKa is the pH at which concentration of ionized and non-ionized forms is equal.

28. Henderson Hasselbach equation:
pH = pKa + log S –S0/ S0
S =St= total solubility.
S0 =Ks= molar solubility of the undissociated form.
(A) Solubility of a weak acid:
  pH = PKa + log [salt (ionized) / acid (unionized)
This pH is called precipitation pH and defined as the minimum pH at which a weak acid at a given total concentration will remain in solution without precipitation i.e., solution stable. pKa is defined as pH at which drug is half ionized, that is, the ratio of concentration of ionized Vs unionized is 1 i.e.
pH – pka = log [1]
pH – pKa = 0
or pH = pka
Therefore, drugs like phenobarbital, a weakly acidic drug with pKa 7.4, will be in ionized as well as unionized state in equal concentration in blood plasma (pH 7.4), provided the drug is directly in contact with the blood.
Example: look to book

29. (B) Solubility of a weak base:
pH = PKw -pkb+ log [base (unionized) / salt (ionized)]
Where PHp is the pH above which the drug begins to precipitate from solution as the free base.

30. Prediction of solubility of a solute in specific solvent
The general statement: "Like dissolve like" Likeness may be
Polarity as measured by the dielectric constant. Polar and weak polar solutes will dissolve in polar solvents.
For non-polar and non-interacting substances, solubility can be predicated by solubility parameter.
Solubility Parameter is a measure of the intermolecular forces in the solvent and is commonly expressed in hildebrand units where 1 hildebrand = (calories / cm3)1/2
Chemical structure: Phenol will dissolve in glycerin both having OH group.

31. RATE OF SOLUTION (DISSOLUTION RATE)
By Fick's first law of diffusion:
Where D is the diffusion coefficient, A the surface area, Cs the solubility of the drug, Cb the concentration of drug in the bulk solution, and h the thickness of the stagnant layer. If Cb is much smaller than Cs then we have so-called "Sink Conditions" and the equation reduces to:
According to Fick's Law. The rate of solution is also directly proportional to the area of the solid, A in cm2, exposed to solvent and inversely proportional to the length of the path(h) through which the dissolved solute molecule must diffuse.
Where:
D is the proportionality constant called diffusion coefficient (cm2/sec).
(Cs) saturation solubility.

32. RATE OF SOLUTION (DISSOLUTION RATE)
Small particles go into solution faster than large particles. For a given mass of solute, as we make the particle size smaller, the surface area increases, the rate must proportionally increase. Hence when the pharmacist wishes to increase the rate of solution of a drug, he should decrease its particle size.
Stirring of a solution increases the rate at which a solid dissolves. This is because the thickness of the stagnant layer depends on how fast the bulk solution is stirred; as stirring rate increases, the length of the diffusion path decreases. Since the rate of solution is inversely proportional to the diffusion path, the faster the solution is stirred, a faster the solute will go into solution.
The larger the saturation solubility, the faster the dissolution rate. Different polymorphs of the same drug may have different solubility, the metastable polymorph usually have higher solubility (as riboflavin can exist in three different polymorphic forms, having a solubility in water at 25° of 60 mg., 80 mg., and 1200 mg. per liter respectively). It is evident that the most soluble form of this vitamin can be particularly useful in certain pharmaceutical products, such as powdered parenteral formulations that are constituted before use by addition of water.
Solubility of weak acids or bases can be highly increased; up to-1000 fold, by the use of their respective salts, e.g.Atropine sulfate, sodium phenobarbital and sodium sulfadiazine.
With a viscous liquid, the rate of solution is slowed. This is because the diffusion coefficient is inversely proportional to the viscosity of the medium.

33. Modified Noyes-Whitney equation which is:
DA/dt = K S (Cs - C)
Where A is the amount of the drug in solution, K is the intrinsic dissolution rate constant, S is the surface area, Cs is the concentration of a saturated solution of the drug, and C is the concentration of the solution at time t.

34. RATE OF SOLUTION (DISSOLUTION RATE)
Dissolution is a process in which a solid substance solubilizes in a given solvent i.e. mass transfer from the solid surface to the liquid phase.
Rate of dissolution is the amount of drug substance that goes in solution per unit time under standardized conditions of liquid/solid interface, temperature and solvent composition.
Solubility plays important role in controlling dissolution from dosage form.
From Noyes-Whitney equation it shows that aqueous solubility of drug which determines its dissolution rate.
Particle size and effective surface area of the drug .Particle size and surface area are inversely related to each other.
Greater the effective surface area, more intimate the contact between the solid surface and the aqueous solvent and faster the dissolution. Amorphous form of drug which has no internal crystal structure represents higher energy state and greater aqueous solubility than crystalline forms.
E.g. - amorphous form of novobiocin is 10 times more soluble than the crystalline form.
Thus, the order for dissolution of different solid forms of drug is amorphous > metastable > stable.
Dissolution rate of weak acids and weak bases can be enhancing by converting them into their salt form.
With weakly acidic drugs, a strong base salt is prepared like sodium and potassium salts of barbiturates and sulfonamides.
With weakly basic drugs, a strong acid salt is prepared like the hydrochloride or sulfate salts of alkaloidal drugs.

35. The Distribution of Solutes between Immiscible Liquids:
If a substance, which is soluble in both components of a mixture of immiscible liquids, is dissolved in such a mixture, then, when equilibrium is attained at constant temperature it is found that the solute is distributed between the two liquids in such a way that the ratio of the activities of the substance in each liquid is a constant, which can be expressed by equation:-. This is known as the Nernst distribution law
aA/ab = constant (1)
Where aA and aB are the activities of the solute in solvent A and B, respectively.
As the concentration of the solution is increased, the ratio becomes less than unity . When the solutions are dilute or when the solute behaves ideally, the activities may be replaced by concentrations (CA and CB),
Ca/Cb = K (2)
Where the constant K is known as the distribution or partition coefficient. In the case of sparingly soluble substances, K is approximately equal to the ratio of the solubility (SA and SB) of the solute in each liquid; i.e.
Sa/Sb = K (3)
If the solute exists as monomers in solvent A and as dimers in solvent B, the distribution coefficient is given by Eq. (4), in which the square root of the concentration of the dimeric form is used:
Ca/ Cb = K (4)
If the dissociation into ions occurs in the aqueous layers, B of a mixture of immiscible liquids, then the degree of dissociation (α) should be taken into account as indicated by Eq. (5).
Ca/Cb1-α= K (5)

36. Applications of Distribution Law:
(1) Extraction:
Extraction of substances from one phase into another is often used in analytical and organic chemistry and in the removal of active principles from crude drugs. Application of the distribution law to the process of extraction shows that it is more efficient to divide the extracting solvent into a number of smaller volumes that are used in successive extraction rather than to use the total amount of solvent in one single process.
(2) Release of Drugs from Certain Dosage Forms:
Suppositories and ointments are often formulated in water-immiscible bases. The rate of release of medicaments from these dosage forms into aqueous body fluids will depend mainly on partition coefficient of the medicament between the base and the body fluid.
(3) Passage of Drugs through Membranes:
The cell membrane consists of a bimolecular lipid sheet (hydrophobic) interspersed with protein molecules (hydrophilic), and contains minute aqueous pores which allow passage of small hydrophilic substances.
The partition coefficient of the drug is therefore important in all processes that involve the transport and distribution of drugs throughout the body; e.g. the absorption of drugs from the gastrointestinal tract, and distribution of drugs between various tissues.
(4) Preservation of Emulsions and Creams:
An emulsion consists of two immiscible liquids one of which is uniformly dispersed through the other as droplets of diameter greater than 0.1 m. Preservatives should have a wide spectrum of activity against a range of bacteria, yeasts and moulds. Since micro­organisms usually multiply in the aqueous phase of this type of system, and preservatives must therefore be capable of exerting their activity in this phase. The selective preservative should have high water solubility and a low oil/water partition coefficient.

37. Solubility of gases in liquids
Henry's Law
Liquids and solids exhibit practically no change of solubility with changes in pressure. Gases as might be expected, increase in solubility with an increase in pressure. Henry's Law states that: The solubility of a gas in a liquid is directly proportional to the pressure of that gas above the surface of the solution (at constant temperature). “the partial pressure of the gas in vapour phase (p) is proportional to the mole fraction of the gas (x) in the solution” and is expressed as:
p = KHx
Here KH is the Henry’s law constant.
If the pressure is increased, the gas molecules are "forced" into the solution since this will best relieve the pressure that has been applied. The number of gas molecules is decreased. The number of gas molecules dissolved in solution has increased as shown in the graphic on the left.

38. Solubility of gases in liquids
The solubility of a gas in a liquid depends on temperature, the partial pressure of the gas over the liquid, the nature of the solvent and the nature of the gas. The most common solvent is water. Carbonated beverages are an example of Henry's law in everyday life. The dissolved carbon dioxide stays in solution in a closed pop bottle or can where the partial pressure of carbon dioxide was set at a high value during bottling. When the can or bottle is opened the partial pressure of CO2 is much lower and the dissolved carbon dioxide will gradually escape from the pop. When the cap is removed, the decreased pressure above the solution results in the decreased solubility of the carbon dioxide—the carbon dioxide escapes the solution.
The concentration of dissolved gas depends on the partial pressure of the gas. The partial pressure controls the number of gas molecule collisions with the surface of the solution. If the partial pressure is doubled the number of collisions with the surface will double. The increased numbers of collisions produce more dissolved gas.
Gases are usually more soluble at colder temperatures. For example, oxygen is more soluble in cold water than in hot water. The decrease in oxygen solubility with increased temperature has serious consequences for aquatic life. Power plants that discharge hot water into rivers can kill fish by decreasing the dissolved oxygen concentration.
The same sort of analysis can be applied to solutions of gases. Dissolving oxygen in water releases a small amount of heat:
Gaseous O2 + nearly saturated O2 solution = saturated O2 solution + heat
Le Chatelier's principle predicts that heating the solution shifts the equilibrium to the left- less oxygen dissolves at higher temperature.
A molecular model of gas solubility. The solubility of gases, like other solubility's, can increase or decrease with temperature. A simple model can be used to explain why gases can behave either way, depending on the gas and the solvent. The heat absorbed or released when a gas dissolves in liquid has essentially two contributions:

39. Solubility of gases in liquids
Energy is absorbed to open a pocket in the solvent. Solvent molecules attract each other. Pulling them apart to make a cavity will require energy, and heat is absorbed in this step for most solvents. Water is a special case- it already contains open holes in its network of loose hydrogen bonds around room temperature. For water, very little heat is required to create pockets that can hold gas molecules.
Energy is released when a gas molecule is popped into the pocket. Intermolecular attractions between the gas molecule and the surrounding solvent molecules lower its energy, and heat is released. The stronger the attractions are, the more heat is released. Water is capable of forming hydrogen bonds with some gases, while organic solvents often can't. A larger amount of heat is released when a gas molecule is placed in the pocket in water than in organic solvents.
There is usually net absorption of heat when gases are dissolved in organic solvents, because the pocket-making contribution is bigger. Le Chatelier's principle predicts that when heat is absorbed by the dissolution process, it will be favored at higher temperature. Solubility is expected to increase when temperature rises.
There is usually net release of heat when gases are dissolved in water, because the pocket-filling contribution is biggest. Solubility is expected to decrease when temperature rises.
The reason for this gas solubility relationship with temperature is an increase in kinetic energy. The higher kinetic energy causes more motion in molecules which break intermolecular bonds and escape from solution.

40. Applications
Carbonated beverages provide the best example of this phenomenon. All carbonated beverages are bottled under pressure to increase the carbon dioxide dissolved in solution. When the bottle is opened, the pressure above the solution decreases. As a result, the solution effervesces and some of the carbon dioxide bubbles off.
Deep sea divers may experience a condition called the "bends" if they do not readjust slowly to the lower pressure at the surface. As a result of breathing compressed air and being subjected to high pressures caused by water depth, the amount of nitrogen dissolved in blood and other tissues increases. If the diver returns to the surface too rapidly, the nitrogen forms bubbles in the blood as it becomes less soluble due to a decrease in pressure. The nitrogen bubbles can cause great pain and possibly death.To alleviate this problem somewhat, artificial breathing mixtures of oxygen and helium are used(11.7% helium, 56.2% nitrogen and 32.1% oxygen). Helium is only one-fifth as soluble in blood as nitrogen. As a result, there is less dissolved gas to form bends".
At high altitudes the partial pressure of oxygen is less than that at the ground level. This leads to low concentrations of oxygen in the blood and tissues of people living at high altitudes or climbers. Low blood oxygen causes climbers to become weak and unable to think clearly, symptoms of a condition known as anoxia.

41. Solubility of solids in solids
If two solids are either melted together and then cooled or dissolved in a suitable solvent,which is then removed by evaporation,the solid that is redeposited from the melt or the solution will either be a one-phase solid solution or a two-phase eutectic mixture.
Solid – Dispersion System
Definition:
Solid dispersion is defined as dispersion of one or more active ingredients in an inert carrier or matrix at solid state prepared by the melting, solvent or melting solvent method.
Classification
Simple Eutectic Mixtures
Solid Solutions
Glass Solutions and Glass Suspensions
A. Eutectic Mixtures
When two or more substances are mixed together they liquefy due to the lowering of melting point than their individual melting point. Such substances are called as eutectic substances.
e.g. paracetamol-urea, griseofulvin-urea
Simple binary phase diagram showing eutectic point E.
The eutectic composition at point E of substance A and B represents the melting point.
TA and TB are melting point of pure A and pure B.

42. Solubility of solids in solids
B. Solid Solutions
It is made up of a solid solute dissolved in a solid solvent. It is often called a “mixed crystal” because the two components crystallize together in a homogenous phase system.
It is prepared by fusion method.
A solid solution of poorly soluble drug in a rapidly soluble carrier achieves a faster dissolution because particle size of drug is reduced to molecular size.
Classification
According to extent of miscibility :
Continuous (iso-morphous, unlimited, complete) solid solution.
Discontinuous (limited, restricted, incomplete) solid solution.
According to crystalline structure of solid solutions :
Substitutional solid solutions.
Interstitial solid solutions.
Continuous Solid Solutions :-
The two components are miscible or soluble at solid state in all proportions.
No established solutions of this kind have been shown to exhibit fast release dissolution properties.
The faster dissolution rate would be obtained if the drug is present as a minor compartment.
Discontinuous Solid Solutions :-
There is only limited solubility of a solute in a solid solvent in this group of solid solutions.

43. Solubility of solids in solids
C. Glass Solutions and Glass Suspensions
A glass solution is a homogenous, glassy system in which a solute is usually obtained by abrupt quenching of the melt.
Many compounds have been shown to be able to form glasses readily upon cooling from liquid state.
These compounds include sucrose, glucose, ethanol and 3- methyl hexane.
It is presumably due to their strong hydrogen bonding which may prevent their crystallization.
Polymers possessing linear, flexible chains can freeze into a glass state to transparency and brittleness.
The strength of chemical binding in a glass solution is much less compared to that in a solid solution.
Hence, dissolution rate of drugs in the glass solution is faster than in solid solution.
E.g. Glass solution of citric acid.
The enhancement of poorly soluble drug solubility's through solid solutions and or eutectic mixtures leading to enhancing bioavailability.