Nahla S. Barakat, Ph.DKing Saud University

Dept. of Pharmaceutics

First Term

1432-2011

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Liquid dosage forms Colloid Disperse system: suspension, emulsion Liposome and nanoparticles Aerosols Drug stability

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Solution is a homogenous mixture composed of two or

more substances. In such a mixture, a solute is dissolved in

another substance, known as a solvent. A common

example is a solid, such as salt or sugar, dissolved in water

, a liquid.

Gases may dissolve in liquids, for example:carbon dioxide

or oxygen in water.

Liquids may dissolve in other liquids. Gases can combine

with other gases to form mixtures, rather than solutions.

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Possible Types of Solutions solid in solid e.g. brass solid in liquid e.g. sugar in water solid in gas e.g. mothball in air liquid in solid e.g. dental amalgam liquid in liquid e.g. ethanol in water liquid in gas e.g. water in air gas in solid e.g. hydrogen in palladium gas in liquid e.g. O2 in water gas in gas e.g. oxygen in nitrogen

Of the nine possible types of solutions, you are probably most familiar with those in which the solvent is a liquid, especially those in which the solvent is water.

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1. Liquids are easier to swallow2. A drug must be in solution before it can be absorbed3. A solution is an homogenous system, the drug will be

uniformly distributed throughout the preparation4. Some drugs can irritate the gastric mucosa if localized in

one area. Irritation is reduced by administration of a solution of the drug

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Liquids are bulky and inconvenient to transport and store The stability of ingredients in aqueous solution is often poor

than in solid dosage form Solution provide suitable media for the growth of micro-

organisms and may require the addition of preservative Accurate dose measuring depends on the ability of patient to

measure the dose The taste of a drug is always pronounced when it in solution

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Aqueous solutions Solutions that contain water as the solvent

are called aqueous solutions. For example, sugar in water,

carbon dioxide in water, etc. 

Non-aqueous solutions Solutions that contain a solvent

other than water are called non-aqueous solutions. Ether,

benzene, petrol, carbon tetrachloride etc., are some common

solvents.or example, sulphur in carbon disulphide,

naphthalene in benzene, etc. 

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Concentrated solutions and dilute solutions

Between two solutions, the solute quantity may be relatively

more or less.

The solution that has a greater proportion of solute is said to

be more concentrated than the other that has a lesser

proportion. If the proportion of solute is less, the solution is

said to be dilute. 

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• Saturated Solution 

A solution in which no more solute can be dissolved at a given

temperature is called a saturated solution

• Unsaturated solution 

A solution in which more solute can be dissolved at a given

temperature is called an unsaturated solution. 

A given solution that is saturated at a particular temperature

may become unsaturated when the temperature is increased.

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Solubility and Miscibility

Different substances have different solubilities.

Solubility refers to the maximum amount of a solute that

can be dissolved in an amount of solvent under specific

temperature and pressure conditions.

A substance that cannot be dissolved in another (or does so

to a very limited extent) is said to be insoluble.

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Solubility The solubility of a solute is the maximum quantity of solute

that can dissolve in a certain quantity of solvent or quantity of solution at a specified temperature

How do substances dissolve? Solvation - there is an interaction between the solute and the solvent.

The solute particles are usually surrounded by the solvent particles. This process is called solvation.

parts of solvent required

for 1 part of solute

Very soluble 1 Freely soluble 1-10 Soluble 10-30 Sparingly soluble 30-100 Slightly soluble 100-1000 Very slightly soluble 1000-10,000 Practically insoluble 10,000

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SolubleGroup I and ammonium (NH4

+) compounds Nitrates Acetates (Ethanoates) Chlorides, bromides and iodides except: Silver (Ag+), Lead(II) (Pb2+), Mercury(I) (Hg2

2+), Copper (Cu+) Sulfates except: Silver (Ag+), Lead (Pb2+), Barium (II) (Ba2+), Strontium(II) (Sr2+) and Calcium(II) (Ca2+) InsolubleCarbonates except Group I, ammonium (NH4

+)Sulfites except Group I and NH4

+ compounds Phosphates except Group I and NH4

+ compounds Hydroxides and Oxides except Group I, NH4

+, Barium (Ba2+), Strontium (Sr2+) and Thallium (Tl+) Sulfides except Group I, Group II and NH4

+ compoun

Miscibility refers to the ability of a liquid to dissolve in another in all proportions.

Alcohols like methanol and ethanol are miscible with water. There is no limit to the amount of these alcohols that can be dissolved in water - they dissolve in all proportions. When the amount of one liquid exceeds the other, their roles reverse. For example if you add alcohol to water, alcohol is said to be dissolved in water; however, if you add alcohol to the point where its volume is greater than the volume of water, then water becomes the solute and alcohol the solvent. When a liquid does not dissolve in another to any extent, the liquids are said to be immiscible. Oil and water are immiscible.

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Electrolytes and Non-Electrolytes One way to distinguish between solutions that contain ions

and those that contain molecules is an electrical conductivity test.

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A solution that conducts electrical current is said to be

electrolytic and the solute is called an electrolyte.

The sodium chloride solution is an electrolytic solution.

The solute in a solution that does not conduct electrical

current is a non-electrolyte.

Examples include: sugar, urea, glycerol, and

methylsulfonylmethane (MSM.

Generally, dissociated ionic compounds are electrolytes

whereas dissolved molecular compounds are non-electrolytes.

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Concentrations are often given in terms of weight/volume.  For example, mg/L, or mg/100 mL (common clinical units), are used.  These units do not depend on knowledge of the molecular structure of the measured substance.

A Molar Solution is an aqueous solution consisting of one mole of a substance plus enough water to make one Liter of solution.

A Molal Solution is an aqueous solution consisting of one mole of a substance plus 1 kg of water (usually very close to 1 L water).  The total volume may thus be more than 1 L.

Concentrations of ions are often given in Equivalents (or milliequivalents, mEq) per Liter.  The equivalents of an ion is equal to the molarity times the number of charges per molecule.  Thus Equivalents is the measure of CHARGE concentration.

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Mass per unit volume. This unit is typically milligrams per milliliter (mg/mL) or milligrams per cubic centimeter (mg/cm 3 )

A useful note is that 1 mL = 1 cm3 and that cm 3 is sometimes referred to as a "cc" (cubic centimeter.Mass per unit volume is handy when discussing how soluble a material is in water or a particular solvent. For example, "the solubility of Substance X is 3 grams per liter".

Percent by Mass. Also called weight percent or percent by weight, this is simply the mass of the solute divided by the total mass of the solution and multiplied by 100%:

Percent by mass= mass of component x 100

mass of solution

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Parts per million (PPM). Parts per million works like percent by mass, but is more convenient when there is only a small amount of solute present. PPM is defined as the mass of the component in solution divided by the total mass of the solution multiplied by 106 (one million)A solution with a concentration of 1 ppm has 1 gram of substance for every million grams of solution. Therefore, in general, one ppm implies one mg of solute per liter of solution.

Percentage (%) % w/v 1g in 100 mL preparation %v/v 1mL in 100 mL preparation % w/w 1 g in 100 g preparation Ratio strength: weight in volume (1:1000 w/v= 1g constituent in 1000 mL

preparation) volume in volume (1:1000 v/v = 1ml constituent in 1000 mL

preparation) weight in weight (1:1000 w/w = 1 g constituent in 1000 g

preparation)

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FACTORS AFFECTING SOLUBILITY   There are three main factors that control solubility of a solute.   (1) Temperature   (2) Nature of solute or solvent   (3) Pressure (4) Particle size (5) Stirring

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Solubility and Temperature Dependence

Electrostatic attractions between water and solid ions/molecules play an important role in the solubility of solids in aqueous solutions. However, there are other factors that also play an important role. One of these factors is temperature. Temperature is a direct result of the kinetic movement of the solution molecules/ions. The higher the temperature the greater the kinetic energy of the solution molecules.

The higher the kinetic energy of water molecules, the better the chance they have of dislodging solid molecules and thereby getting them into solution. This is so because the water molecules collide with the solid and higher collision energies lead to more effective dislodgment and thus solubility. In a few instances (e.g., Ce2SO4) the solubility of the salt will decrease with temperature.

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CASE I: Decrease 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 (energy given off). The addition of more heat (increases temperature) inhibits the dissolving reaction since excess heat is already being produced by the reaction. This situation is not very common where an increase in temperature produces a decrease in solubility.

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CASE II: Increase in solubility with temperature: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 (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

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Solubility of Gases vs. Temperature:The variation of solubility for a gas with temperature can be determined by examining the graphic on the left.As the temperature increases, the solubility of a gas decrease as shown by the downward trend in the graph .More gas is present in a solution with a lower temperature compared to a solution with a higher temperature.The reason for this gas solubility relationship with temperature is very similar to the reason that vapor pressure increases with temperature. Increased temperature causes an increase in kinetic energy. The higher kinetic energy causes more motion in molecules which break intermolecular bonds and escape from solution.

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• Nature of both the solute and the solvent affect the solubility.

Substances with similar intermolecular attractive forces tend to be soluble in one another. This generalization is stated as "like dissolves like."

• Non polar solutes are soluble in non polar solvents; Polar or ionic solutes are soluble in polar solvents

Liquids that are attracted by charged objects are composed of polar molecules; those that are not attracted by a charged body are non polar

Nature of Solute and Solvent

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SolutePolar SolventNon-polar solvent

PolarSolubleInsoluble

Non-PolarInsolubleSoluble

IonicSolubleInsoluble

Nature of Solute and Solvent

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Molecular sizeThe larger the molecules of the solute are, the larger is their molecular weight and their size. It is more difficult for solvent molecules to surround bigger molecules. The larger particles are generally less soluble. In the case of organic compounds the amount of carbon "BRANCHING" will increase the solubility since more branching will reduce the size (or volume) of the molecule and make it easier to solvate the molecules with solvent.

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Pressure The effect of pressure is observed only in the case of gases.    An increase in pressure increases of solubility of a gas in a liquid.   For example carbon di oxide is filled in cold drink bottles (such as coca cola, Pepsi 7up etc.)under    pressure.

StirringAgitation makes the solute dissolves more rapidly because it brings fresh solvent into contact with the surface of the solute. However, agitation affects only the rate at which a solute dissolves. It cannot influence the amount of solute that dissolves. An insoluble substance will remain undissolved no matter how much the system is agitated.

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Diffusion layer model:

Simplest and most common theory for dissolution The process of dissolution of solid particle in a liquid, in the absence of reactive or chemical force Consists of two consecutive stages: STAGE 1:First is an interfacial reaction that results in the liberation of solute molecules from the solid phase. This involves a phase change so that molecules of solid become molecules of solute in the solvent in which the crystal is dissolving. The solution in contact with the solute will be saturated(because it is in direct contact with undissolved solid. Its concentration will be Cs , a saturated solution. In short solution of the solute form a thin film or layer at the solid/liquid interface called as stagnant layer or diffusion layer or boundary layer This step is usually rapid. DIFFUSION LAYER MODEL

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STAGE 2: After this , the solute molecules must migrate through the boundary layers surrounding the crystal to the bulk of the solution,at which time its concentration will be Cb. This step involves the transfer of these molecules away from the solid liquid interface into the bulk of the liquid phase under the influence of diffusion or convection. This step is slow step.

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BOUNDARY LAYERS Boundary layers are static or slow moving layers of liquid that surround all wetted solid surfaces. The rate of flow of fluid over an even surface will be dependant upon the distance from the surface. The velocity, which will be almost zero at the surface , increases with the increasing distance from the surface until the bulk of the fluid is reached and the velocity becomes constant. In short, the region over which differences in velocity are observed is referred to as boundary layers. Its depth is dependant upon the viscosity of the fluid and the rate of flow in the bulk fluid. If high viscosity and low flow rate then thick boundary. If low viscosity and high flow rate then thin boundary. Boundary layers arises because of the intermolecular forces between the liquid molecules and solid surface. They are important barrier for heat and mass transfer.

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Now, Mass transfer takes place more slowly trough these static or slow moving layers ,which inhibit the movement of solute molecules from the surface of the solid to the bulk of the solution. The concentration of the solution in the boundary layers changes therefore from being saturated (Cs) at the crystal surface to being equal to that of the bulk of the solution (Cb) at its outmost limit.

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RATE LIMITING STEP Like any reaction that involves consecutive stages, the overall rate of dissolution will depend on whichever of this steps is the slowest. Here the interfacial step-1 is rapid and step-2 is slower and so the rate of dissolution will be determined by the rate of slower step-2, of diffusion of dissolved solute across the static boundary layers of liquid that exists at a solid liquid interface.

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FICK’S SECOND LOW OF DIFFUSION Whitney equation based on Fick’s second low of diffusion. The rate of diffusion will obey fick’s law of diffusion, i.e the rate of change in concentration of dissolved material with time it directly proportional to the concentration difference between the two sides of diffusion layer. i.e, dc/dt ∆ C----------(1) dc/dt = k x ∆C--------------(2) where the constant k is the rate constant(sec-1) and ∆ C is the difference in concentration of solution at solid surface(Cs) and the bulk of the solution(Cb). So, dc/dt = k(Cs-Cb)--------------(3)

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MODIFIED NOYES WHITNEY EQATION It was developed to defined the dissolution from a single spherical particle. It is based on the Fick’s fist law of diffusion. The rate of mass transfer of solute molecules or ions through a static diffusion layer (dm/dt) is directly proportional to the surface area available for molecule or ionic migration (A) , the concentration difference (Cs-Cb) across the boundary layer, is inversely proportional to the thickness of the boundary layer (h).Dm/dt= DAK (Cs-Cb) VhWhere, dm/dt =Rate of mass transfer, D=diffusion coefficient(m2/s) A=surface area, Kw/o=water/oil partition coefficient of the drug, (Cs-Cb)=concentration gradient, V=volume of dissolution media, h=Thickness of boundary layer

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Non Sink condition Above Equation represents first order dissolution process ,the driving force for which is the concentration gradient (Cs-Cb). Under such a situation , dissolution is said to be under non sink conditions. This is true in case of in vitro dissolution in a limited dissolution medium. Dissolution in such a situation slow down after sometime due to build up in the concentration of drug in the bulk of solution . Sink condition The in vivo dissolution is always rapid than in vitro dissolution because the moment the drug dissolves, it is absorbed into the systemic circulation. As a result Cb=0 and dissolution is at its maximum. Thus, under in vivo conditions, there is no concentration build up in the bulk of the drug i.e Cs>>Cb and sink condition are maintained.

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Factor affecting in-vitro dissolution rate of solid in liquid

1] Diffusion Co-efficient - greater the value faster the dissolution - Affected by viscosity of dissolution medium and size of diffusing molecules. - Diffusion decreases as the viscosity of the dissolution medium increases. 2] Surface area - Greater the surface area faster the dissolution Affected by: 1)Size of solid particles – A1/Particle size. Particle size will change during dissolution process, because large particle will become smaller and small particles will disappear. 1)) Dispersibility of powdered solid in dissolution medium. - If particles tend to form coherent mass in the dissolution medium then the surface area available for dissolution is reduced.This effect may be overcome by addition of wetting agent. 1)Porosity of solid particle. - Pores must be large enough to allow access of dissolution medium and outward diffusion of dissolved solute molecules.

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3] Water oil partition co-efficient Higher the value , more the hydrophiliciity and faster the dissolution in aqueous fluid. 4] Concentration gradient Greater the concentration gradient, faster the diffusion and drug dissolution. Can be increased by increasing drug solubility and volume of dissolution media. This is affected by: 4.1) Volume of dissolution media -If volume is small Cb will approach Cs, if volume is large Cb may be negligible WRT Cs i.e apparent sink condition. 4.2) Temperature -Dissolution may be an exothermic or endothermic process. According to thermodynamic equation, G= H- T S

The change in the Gibbs free energy of the system that occurs during a reaction is therefore equal to the change in the enthalpy of the system minus the change in the product of the temperature times the entropy of the system.

∆G = ∆H - ∆(TS)If the reaction is run at constant temperature, this equation can be written as follows.

∆G = ∆H - T∆S

-

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When ∆H is positive, the dissolution process is endothermic i.e heat is absorbed when dissolution occurs.In endothermic process, a rise in temperature will lead to an increase in the solubility of the solid with positive heat of solution. -In exothermic dissolution, an increase in temp will lead to decrease in solubility. Solubility curve are often used to describe the effect of temperature. For e.g. sodium Sulphate exist as the decahydrate form up to 32.5°C, and its dissolution in water is endothermic process. Its solubility therefore increases with rise in temp up to 32.5°C. Above this temp it is converted in to anhydrous form and the dissolution of this is an Exothermic process. The solubility therefore exhibits a change from +ve to –ve slope as the temp exceed the transition value.

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4.3) Nature of dissolution media A- Co solvents -Some mixtures are used to increase the solubility of solid. This is achieved by using co solvents such as ethanol or propylene glycol, which are miscible with water and which act as better solvent for solute. -For e.g..the aqueous solubility of metronidazole is about 100mg in 10 ml. The solubility of this drug can be increased by the incorporation of water miscible co solvent to the 500mg in 10 ml. B- pH -If the pH of the solution of either weakly acidic drug or a salt of a drug is reduced then the proportion of unionized molecules in the solution increases. -Precipitation may occur because the solubility of the unionized species is less than that of ionized form. In case of solution of weakly basic drugs or their salts, precipitation is favoured by an increase in pH.

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4.4) Molecular structure of solid. -A small change in the molecular structure of the compound can have a marked effect on its solubility in a given liquid For e.g.. The introduction of hydrophilic hydroxyl group can produce a large improvement in water solubility as evidenced by more than 100 fold difference in the solubility of phenol and benzene. -The conversion of weak acid to its sodium salt led to a much greater degree of ionic dissociation of the compound.A specific e.g. of this effect is provided by comparison of aqueous solubility of salicylic acid and its sodium salt,which are 1:550 and 1:1 respectively.

5] Thickness of stagnant layer more the thickness , lesser the diffusion and drug dissolution. Can be decreased by increasing agitation. Affected by degree of agitation , which depends on speed of stirring and shaking , shape , size , and position of stirrer , volume of dissolution medium , shape and size of container, viscosity of dissolution medium

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To obtained good in vitro in vivo dissolution rate correlation, the in vitro dissolution must be carried under sink condition, this can be achieved by: Bathing the dissolving solid in fresh solvent from time to time. Increasing the volume of dissolution. Removing the drug by partitioning it from the aqueous phase of the dissolution fluid into an organic phase placed either above or below the dissolution fluid –for example ,hexane or chloroform. Adding a water miscible solvent such as alcohol to the dissolution fluid,or By adding selected adsorbents to remove the dissolved drug. The in vitro sink conditions are so maintained that Cb is always less than 10% of CS

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Problem 1:

Calculate the dissolution rate of a hydrophobic drug having the following physicochemical characteristics: surface area = 2.5 x 103 cm2

saturated solubility = 0.35 mg/mL (at room temperature) diffusion coefficient = 1.75 x 10-7 cm2/s thickness of diffusion layer = 1.25 µm [Note: need to convert to cm, so 1 µm = 1 x 10-4 cm and 1.25 x 10-4 cm] conc of drug in bulk = 2.1 x 10-4 mg/mL

dM/dt = DS(CS-Cb) / h

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What is surface tension? 

Surface tension is a property of the surface of a liquid that allows it to resist an external force

Surface tension is a measurement of the cohesive energy present at an interface .

The cohesive forces among the liquid molecules are responsible for this phenomenon of surface tension. In the bulk of the liquid, each molecule is pulled equally in every direction by neighboring liquid molecules, resulting in a net force of zero. The molecules at the surface do not have other molecules on all sides of them and therefore are pulled inwards. This creates some internal pressure

and forces liquid surfaces to contract to the minima

Surface tension is typically measured in dynes/cm, the force in dynes required to break a film of length 1 cm. Equivalently, it can be stated as surface energy in ergs per square centimeter. Water at 20°C has a surface tension of 72.8 dynes/cm compared to 22.3

for ethyl alcohol and 465 for mercury .

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• Walking on water

• Small insects such as the water strider can walk on water because their weight is not enough to penetrate the surface.

• Soaps and detergents

• help the cleaning of clothes by lowering the surface tension of the water so that it more readily soaks into pores and soiled areas.

• Floating a needle

• If carefully placed on the surface, a small needle can be made to float on the surface of water even though it is several times as dense as water. If the surface is agitated to break up the surface tension, then needle will quickly sink.

• Surface tension disinfectants

• Disinfectants are usually solutions of low surface tension. This allow them to spread out on the cell walls of bacteria and disrupt them. One such disinfectant, S.T.37, has a name which points to its low surface tension compared to the 72 dynes/cm for water.

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• Surface tension is responsible for the shape of liquid droplets. Although easily deformed, droplets of water tend to be pulled into a spherical shape by the cohesive forces of the surface layer

• Cohesion and Surface Tension

• The cohesive forces between molecules down into a liquid are shared with all neighboring atoms. Those on the surface have no neighboring atoms above, and exhibit stronger attractive forces upon their nearest neighbors on the surface. This enhancement of the intermolecular attractive forces at the surface is called surface tension.

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Adhesive ForcesForces of attraction between a liquid and a solid surface are called adhesive forces. The difference in strength between cohesive forces and adhesive forces determine the behavior of a liquid in contact with a solid surface. Water does not wet waxed surfaces because the cohesive forces within the drops are stronger than the adhesive forces between the drops and the wax. Water wets glass and spreads out on it because the adhesive forces between the liquid and the glass are stronger than the cohesive forces within the water.

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Surface tension is the energy required to stretch a unit change of a surface area. Surface tension will form a drop of liquid to a sphere since the sphere offers the smallest area for a definite volume.Surface tension can be defined as σ = Fs / l          (1)

where σ = surface tension (N/m)Fs =  stretching force (N)

l = unit length (m)

Alternative UnitsAlternatively, surface tension is typically measured in dynes/cm, which is the force in dynes required to break a film of length 1 cmor as surface energy J/m2 or alternatively ergs per square centimeter.

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When liquid water is confined in a tube, its surface (meniscus) has a concave shape because water wets the surface and creeps

up the side.

Mercury does not wet glass - the cohesive forces within the drops are stronger than the adhesive forces between the drops and glass. When liquid mercury is

confined in a tube, its surface (meniscus) has a convex shape because the cohesive forces in liquid mercury

tend to draw it into a drop.

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Capillary ActionCapillary action is the rise of a liquid that wets a tube up the inside of a small diameter tube (i.e., a capillary) immersed in the liquid. The liquid creeps up the inside of the tube (as a result of adhesive forces between the liquid and the inner walls of the tube) until the adhesive and cohesive forces of the liquid are balanced by the weight of the liquid. The smaller the diameter of the tube, the higher the liquid rises.

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• Surface Tension of Water • The surface tension of water is 72 dynes/cm at 25°C . It

would take a force of 72 dynes to break a surface film of water 1 cm long. The surface tension of water decreases significantly with temperature as shown in the graph. The surface tension arises from the polar nature of the water molecule. Hot water is a better cleaning agent because the lower surface tension makes it a better "wetting agent" to get into pores and fissures rather than bridging them with surface tension. Soaps and detergents further lower the surface tension.

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• The polar nature of water molecules allows them to bond to each other in groups and is associated with the high surface tension of water.

• The polar nature of the water molecule has many implications. It causes water vapor at sufficient vapor pressure to depart from the ideal gas law because of dipole-dipole attractions. This can lead to condensation and phenomena like cloud formation, fog, the dewpoint, etc. It also has a great deal to do with the function of water as the solvent of life in biological systems

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• Surface Tension and Bubbles• The surface tension of water provides the necessary wall

tension for the formation of bubbles with water. The tendency to minimize that wall tension pulls the bubbles into spherical shapes (LaPlace's law).

• The pressure difference between the inside and outside of a bubble depends upon the surface tension and the radius of the bubble. The relationship can be obtained by visualizing the bubble as two hemispheres and noting that the internal pressure which tends to push the hemispheres apart is counteracted by the surface tension acting around the cirumference of the circle.

• For a bubble with two surfaces providing tension tension, the pressure relationship is:

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• Capillary Action• Capillary action is the result of adhesion and

surface tension. Adhesion of water to the walls of a vessel will cause an upward force on the liquid at the edges and result in a meniscus which turns upward. The surface tension acts to hold the surface intact, so instead of just the edges moving upward, the whole liquid surface is dragged upward.

•

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The smaller the diameter of the tube, the higher the liquid rises

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Influence of solute concentrationSolutes can have different effects on surface tension depending on their structure:Little or no effect, for example sugarIncrease surface tension, inorganic saltsDecrease surface tension progressively, alcoholsDecrease surface tension and, once a minimum is reached, no more effect: surfactants

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Effect of Temperature

The surface tension of a liquid in contact with air or its own vapour depends only on temperature and nature of liquid. Surface tension decreases with raise of temperature. It represents the variation of surface tension and surface energy of water with temperature. Clearly the Surface tension decreases with raise of high temperature. and becomes zero at 374⁰C which is the critical temperature of water.

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• Effects of Solute

• If the solute is less soluble in liquid, the factors affecting surface tension of liquid decreases. For example by  mixing soap, detergent powder or phenol in water, the surface tension of water decreases but if the solute is very soluble in liquid, the surface tension of liquid increases. For example if salt is mixed in water, the surface tension of water increases.

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• Effect of Contamination

• The presence of dust, oil or grease on the surface of water, reduces the surface tension of water.

• Factors affecting surface tension decreases with rise of temperature and becomes zero at critical temperature. Critical temperature of water is 374 C.⁰

• The surface of a liquid acts like a stretched membrane and tends to occupy the minimum surface area. This property of the liquid is called the surface tension.

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Surfactants Surface tension is visible in other common phenomena,

especially when surfactants are used to decrease it: Soap bubbles have very large surface areas with very little

mass. Bubbles in pure water are unstable. The addition of surfactants, however, can have a stabilizing effect on the bubbles (see Marangoni effect). Notice that surfactants actually reduce the surface tension of water by a factor of three or more.

Emulsions are a type of solution in which surface tension plays a role. Tiny fragments of oil suspended in pure water will spontaneously assemble themselves into much larger masses. But the presence of a surfactant provides a decrease in surface tension, which permits stability of minute droplets of oil in the bulk of water (or vice versa

An aqueous solution is a solution in which the solvent is

water. As water is an excellent solvent as well as naturally abundant. Substances that do not dissolve well in water are called

hydrophobic )'water fearing') whereas those that do are

known as hydrophilic (Water-loving'). An example of a hydrophilic substance would be the

sodium chloride , ordinary table salt.

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Factors affecting solution stability:Temperature− Arrhenius equation:

k = Ae−Ea / RT

− Underlying assumption• Reaction mechanism does not change as a function oftemperature, i.e., Ea is independent of T• May not be valid for some reactions, especially the complex reactions Factors

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Solvent− pH of aqueous solvents• Acid, base, and water catalyzed reactions, mostly hydrolysis• Leading to various kinetic profiles: L, V, U• More complex shapes of kinetic profiles if the compound has(multiple)ionizable functionality− Composition: medium effect on chemical reactions• Non-traditional dosage forms: e.g. co-solvents, soft gel, lipidbased systemsFactors

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Light •Oxygen

•Co-solutes −Buffer salts: catalysis

−Surfactants: different environment in the micelles −Complexation agents: different environment, e.g.

cyclodextrin −Antioxidants and/or chelating agents

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Common Degradation Routes •Solvolysis/hydrolysis

−Most frequently encountered hydrolysis – ester −Typically pseudofirst order

−Intramolecular catalysis and steric factors •Photolysis/oxidation

•Racemization −May cause substantial decrease in biological activities: e.g.

Pilocarpine, tetracycline •Others

−e.g. decarboxylation

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Aqueous solutionsTypes of pharmaceutical water Purified water, USP Water for injection Aromatic water Physiological compatibility Lack of toxicity Possesses a high dielectric constant ensuring the dissolution of a wide range of ionizable

materials Lack of selectivity

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I- Some solvents for liquid preparations Alcohol The most useful solvent in pharmacy (orally and parenterally) It form hydroalcoholic mixture with water that dissolves both

alcohol-soluble and water-soluble substances It is miscible with water and can dissolve many water-

insoluble ingredients, including drug substances, flavorants, preservatives.

It is used as antimicrobial preservative (15%) Toxicity of ingested alcohol particularly for children.

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• Diluted alcohol• Is prepared by mixing equal volumes of alcohol and purified

water (50%)• Alcohol, Rubbing• Alcohol rubbing compound• It contains about 70% ethyl alcohol by volume• It is employed as a rubefacient externally and as

soothing rub for bedridden patients, a germicide for instruments

• As vehicle for topical preparation• As skin cleanser before injection

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Glycerol It is a clear syrup liquid with sweet taste It is miscible with water and alcohol As solvent it is compatible with alcohol It is used as a stabilizer and as auxiliary solvent It has preservative qualities It is used in internal preparations Isopropyl rubbing alcohol Is about 70% by volume isopropyl alcohol, with or without colour

additives, stabilizers and perfume oils It is used externally as a rubefacient and soothing rub and for topical

products It is less likely to be abused

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Propylene glycol A viscous liquid, miscible with water, glycerol and alcohol It is substituted for glycerol in modern pharmaceutical

preparations It is used for formulation of digoxin, diazepam, phenobarbital

injection As diluent for ear drops PEG 400 Is used as a solvent in topical solution Used as co-solvent with alcohol and water Can be used for extraction processes In the formulation of veterinary solutions

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Ethyl ether Used for extraction of crude drugs It is used as a co-solvent with alcohol in some

collodions It is not used for internal use

Liquid paraffin It is unpleasant to use externally It is used as a solvent for topical application of

drugs in emulsion formulations

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Dimethylsulfoxide It is used as a solvent for veterinary drugs It is used for application to human skin

Miscellaneous solvents Isopropyl myristate, isopropyl palmitate are solvent for

external use, cosmetics Low viscous, lack of greasiness Xylene is used in ear drops for human use to dissolve ear wax

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• BuffersInjection, eye drops and nasal drops should be buffered at pH 7.4

Ex: carbonates, citrates, phosphate, lactates, gluconates, tartarates, borates (external)

• Density modifierEx: dextrose

• Isotonicity modifierEx: dextrose and sodium chloride

• Viscosity enhancementLow conc., of gelling agents can be used to increase the apparent viscosity of

the product

Ex: Povidone, Carbomer, Hydroxyethylcellulose

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• PreservativesEx: parahydroxybenzoic acid esters (Parabens)

• Reducing agent and antioxidantsEx: sodium metabisulphite, butylated hydroxyanisole or butylated

hydroxytoluene

• Sweetening agentEx: sucrose, polyhydric alcohols: sorbitol, mannitol,

artificial sweeteners: sodium or calcium salt of saccharin• Flavours and perfumes

To mask the unpalatable taste, ex: fruit juices, aromatic oils, herps

• ColoursTo improve the attractiveness of the product and to enable ease of

identification

Ex: carotenoids, chlorophyll, riboflavines, coal tar dyes

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According to particular pharmaceutical solution’s use may be classified as: • Oral• Otic• Ophthalmic• Nasal• Topical

According to the composition or use, solutions may be classified as :• Aqueous solution containing sugar are termed syrups• Sweetened hydroalcoholic solutions are termed elixirs• Solution of aromatic materials are termed spirits• Solutions prepared by extracting active constituents from crude drugs are

termed tinctures

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Dry mixtures for solutionCertain antibiotics have insufficient stability in aqueous

solution to meet extended shelf life periodsThey are provided in dry powders or granules for reconstitution

before use Once reconstituted, the solution remain stable for 7-14 days

depending on the condition of storageExamples: Penicillin V Potasium for oral solution, USP Cloxacillin Sodium for oral solution, USP

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Oral rehydration solutions

Are usually effective in treatment of diarrhea and mild volume depletion (5-10% of body weight). These are available OTC

Oral solution contains: 45mEq Na+, 20 mEq K+, 35 mEq CL-, 30 mEq citrate,

25 g dextrose / 1 Liter

These formulations are available in liquid or powder packets form for reconstitution

These products should not be mixed with milk or fruit juice

Oral colonic lavage solution

Used for preparation of the bowel for colonoscopy

Composed of oral solution of electrolytes with PEG-3350.

Before dispensing it to the patient, the solution is reconstituted with water, creating an iso-osmotic solution. PEG is an osmotic agent in the GIT

The formulation is as follows: PEG-3350; Sodium sulfate; sodium bicarbonate; sodium

chloride; potassium chloride 240 ml every 10 min (total 4 L).

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In cooking, a syrup (from Arabic شراب sharab, beverage, via Latin

siropus) is a thick, viscous liquid, containing a large amount of

dissolved sugars, or sugar substitute with or without flavoring agents

and medicinal substances.

Syrup containing flavoring agents but not medicinal substances are

called nonmedicated or flavored vehicles (syrup):

Cherry syrup

Orange syrup

Raspberry syrup

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The syrup are intended to serve as pleasant-tasting vehicles for medicinal

substances, consists of a concentrated or saturated solution of refined sugar

in distilled water.

The "simple syrup" of the British Pharmacopoeia is prepared by dissolving

85 g of refined sugar in purified water to make 100 mL of syrup. The

specific gravity of the syrup should be 1.313.

Flavoured syrups are made by adding flavouring matter to a simple syrup.

For instance, syrupus aromaticus is prepared by adding certain quantities

of orange flavouring and cinnamon water to simple syrup. Similarly,

medicated syrups are prepared by adding medicaments to, or dissolving

them in, the simple syrup.

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• As syrups can contain up to 85% of sugars, they are capable of resisting bacterial growth by virtue of their osmotic effect.

• Syrup, NF, also called simple syrup.• The amount of preservative required to protect a syrup against microbial

growth varies with the proportion of water available for growth• Preservative commonly used in syrups : benzoic acid 0.1-0.2%, sodium

benzoate 0.1-0.2%, parabens (0.1%)• To enhance the appeal of the syrup, a coloring agent that correlates with

the flavorant employed (green with mint, brown with chocolate).• Most syrups are flavored with synthetic flavorants or with naturally

occurring materials, such as volatile oils (orange oil), vanilin• Colorant to enhance the appeal of the syrup may be added• Sucrose-based syrup may be substituted by a polyol, such as sorbitol

solution USP, 64% •

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Examples of medicated syrup: Analgesic Anticholenergic Antiemetics Anticonvulsant Antihistamine Antiviral Antitussives Expectrorant Bronchodilators Fecal softener

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An elixir (From Arabic,اإلكسير ) are clear, sweetened

hydroalcoholic solutions intended for oral use and usually

flavored to enhance their palatability.

Non-medicated elixirs are employed as vehicles.

Elixirs are usually less sweet and less viscous than syrup.

In addition to alcohol and water, other solvents, such as

glycerol and propylene glycol are frequently employed in

elixirs as adjunctive solvents.

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Elixirs are sweetened with sucrose, sorbitol, glycerol, and/or artificial sweeteners

Most elixirs have coloring agents to enhance their appearance Elixirs containing more than 10-12% alcohol are usually self-

preserving Because of their usual content of volatile oils and alcohol,

elixirs should be stored in tight, light-resistant containers and protected from excessive heat

Antihistamine Elixir: Diphenhydramine HCl Analgesic Elixir: acetominophen Cardiotonic Elixir: digoxin Antispasmodic Elixir: hyoscyamine sulfate Sedative Elixir: phenobarbital

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• In medicine, a tincture is an alcoholic extract

(e.g. of leaves or other plant material) or solution

of a non-volatile substance; e.g. of iodine,

mercurochrome). • Tinctures contain alcohol in amounts ranging

from approx. 15-80%. The alcohol content protects against microbial growth

• Other solvent, such as glycerol, may be employed• Tincture must be tightly stopered and not

exposed to excessive temperature

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Many tinctures must be stored in light-resistant containers and protect from sunlight.

Some examples that were formerly common in medicine include:

Tincture of Cannabis sativa Tincture of Benzoin Tincture of cantharides Tincture of green soap ( (which also contains lavender) Tincture of guaiac Tincture of iodine Tincture of opium (laudanum) Camphorated opium tincture (paregoric)

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Tincture of iodine is often found in emergency survival kits, used both to disinfect wounds and to sanitize surface water for drinking.

When an alcohol solution is not desirable, Lugol's iodine, an aqueous solution of iodine in potassium iodide solution, or povidone iodine (Betadine), a PVP solution, can be used.

Other names for Lugol's solution are I2KI (Iodine-Potassium Iodide); Markodine, Strong solution (Systemic); Aqueous Iodine Solution BP.

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A viscous preparation, usually for the relief of cough It consists of a simple solution of the active agent in a high

concentration of sucrose The syrup content has a demulcent action on the mucous

membranes of the throat For diabetic use, the sucrose is replaced by sorbitol or

synthetic sweeteners This type of product, should be sipped slowly and not be

diluted beforehand It is administered in multiple of 5 mL

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Sodium Salicylate – 15 gr.Sodium Bicarbonate – 30 gr.Aromatic Spirit of Ammonia – 20 min.Camphor water, up to – 1 oz.For use in acute rheumatism and other febrile conditions

Sodium Salicylate – 15 gr.Sodium Bicarbonate – 30 gr.Strong Solution of Ammonium Acetate – 30 min.Compound Tincture of Cinchona – 20 min.Syrup of Tolu – 1 dr.Camphor water, up to – 1 oz.Useful in Influenza.

Topical solutions• Aluminum acetate (Burow’s solution)• Is colourless and has a faint acetous odor, is applied topically as an

astringent wash or wet dressing after dilution with 10 to 40 parts of water.• Used in various types of dermatological lotions, cream and pastes• Commercial tablets are available for preparation of this solution

• Calcium hydroxide• It is called Limewater, contain not less than 140 mg of Ca(OH)2 in each

100 mL of solution• Cool purified water is the solvent • The solution is intended to be saturated with solute• The solution should be stored in well-filled tightly stopered containers and

kept in a cool place to maintain an adequate conc., of dissolved solute.• The solution is astringent and is employed in dermatological solutions and

lotions

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Hydrogen peroxide Synonym: Peroxide It contains 2.5-3% w/v hydrogen peroxide H2O2, suitable preservative may

be added (0.05%) Is a clear, colorless liquid. It deteriorates upon long standing also by the effect of light and heat The solution should be preserved in tight, light-resistant containers, at

temp. not exceeding 35 C It is categorized as a local anti-infective for use topically on the skin or

mucous membranes. Its germicidal activity is based on the release of nascent oxygen on contact

with the tissues and its ability to cleanse wounds

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Povidone iodine Commercial product: Betadine Solution It is a chemical complex of iodine with PVP It contains approx. 10% available iodine and slowly released when applied

to the skin It is employed as surgical scrub and nonirritating antiseptic solution

Thimerosal topical Is a water-soluble organic mercurial antibacterial agent used topically for

its bacteriostatic and mild fungistatic properties It is used to disinfect skin and as an application to wounds and abrasions It has been also applied to the eye, nose, throat in dilution 1:5000 It is also used as a preservative for various preparations The solution is affected by light and must be maintained in light resistant

containers

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Iodine Tincture It is a reddish-brown colour tincture It is prepared from 2% iodine crystal and 2.4% sodium iodide in a vehicle

alcohol/water (44-50% alcohol) It is a popular local anti-infective agent applied to the skin in general

household first aid Compound Benzoin tincture It is prepared from 10% benzoin and lesser amounts of aloe, storax and

tolu balsam The mixture is macerated in alcohol It is used to protect and toughen skin in the treatment of bedsores, ulcers,

cracked nipples, and fissures of the anus Also used in treatment of venereal warts It is also used as an inhalent for bronchitis and other respiratory conditions It is best stored in tight, light-resistant containers

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Thimerosal Tincture The vehicle is water, acetone and 50% alcohol It must be manufactured and stored in glass or suitably resistant containers Ethylenediamine is used as stabilizer in the official solution and tincture The commercial preparation is colored orange red, the colour defines the

area of application It is a commonly used household antiseptic for application to the skin

abrasions and cuts and in preparation of patients for surgery Green Soap tincture 65% of active constituent in alcohol Also contains 2% lavender oil as perfume Used as detergent

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Vaginal douches • Solution for irrigation cleansing of the vagina, used for hygienic effect Solutions may be prepared from powders or liquid concentrates. The resultant solution contains the appropriate amount of

chemical agents in proper strength Boric acid – astringents - antimicrobial – quaternary ammonium

compound – detergents – oxidizing agents – salts – aromatics Evacuation Enemas Rectal enemas are used to cleanse the bowel. The enema solution are solutions of; sodium phosphate, sodium

biphosphate, glycerin, docusate sodium, light mineral oil The product will work within 5-10 min They are available in disposable plastic squeeze bottles Typical example: Soft soap 25 g / 500 mL water as an emollient

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Simple EnemaTake of:Soft Soap – 1 oz.Warm water, up to – 1 pint.Dissolve and mix. For use in constipation. To be given at body temperature.

Also known as otic products, these are simple solutions of drugs in water, glycerol, propylene glycol or alcohol/water mixture for local use

Hydrogen peroxide (5-volume), Phenol (6% w/w) ear drops Ear drops are a form of medicine used to treat or prevent ear infections,

especially infections of the outer ear and ear canal (Otitis externa). Bacterial infections are sometimes treated with antibiotics. Examples are:- Gentisone HCL ear drops (containing Gentamicin and hydrocortisone). Ciproxin HCL ear drops (containing ciprofloxacin and hydrocortisone). Kenacomb ear drops, containing triamcinolone acetonide, neomycin and

gramicidin (antibiotics) and nystatin (antifungal). Over the counter ear drops are also available, including spirit drops

(alcohol solution), which dries out the ear, and drops such as Aqua Ear (used for swimmer's ear) containing a mixture of substances such as alcohol and acetic acid, to dry the ear and make it difficult for microbes to grow.

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Eye drops are sterile aqueous or oily solutions or suspensions intended for instillation into the eye.

Depending on the condition being treated, they may contain steroids (e.g. mydriatics, dexamethasone), antihistamines, sterile sympathomimetics, beta receptor blockers, parasympathomimetics (e.g. pilocarpine), parasympatholytics (e.g. tropicamide or atropine), prostaglandins, non-steroidal anti-inflammatory drugs (NSAIDs) or topical anesthetics.

Eye drops sometimes do not have medications in them and are only lubricating and tear-replacing solutions,

and they can also contain anti-redness and similar chemicals.

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These are formulated as small-volume solutions is an aqueous vehicle for instillation into the nostrils

Formulation are isotonic with nasal secretions using sodium chloride.

Viscosity can be modified using cellulose derivatives Nasal administration can be used to deliver drugs for either

local or systemic effect. Locally acting drugs are for example decongestants and

allergy treatments. Examples of systemically active drugs available as nasal

sprays are migraine drugs, nicotine replacement and hormone treatments, anti-convulsant.

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Are sterile, large volume aqueous–based solutions for the cleansing of body cavities (peritoneal dialysis solution) and cleansing wounds.

They should be made isotonic with tissue fluid

They are not for oral or parenteral use For external use only

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Spray An aqueous or oleaginous solutions in the form of

coarse droplets or as finely divided solids to be applied topically, most usually to the nasopharyngeal tract or to the skin by means of an atomizer

The type of atomizer used depends on the viscosity of the spray solution

Drugs used for relief of asthma are commonly dispensed as spray

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Oromucosal preparations: are designed for application to the throat or oral cavity and can includes solids and semi-solids as well as solutions

Mouthwashes and gargles These aqueous solutions are for the prevention and treatment of mouth and

throat infections and can contain antiseptics, analgesics and / or astringents They are intended to bring the medication into contact with mucous

surface of the throat They are usually diluted with warm water before use Gargles may have some analgesic effect and provide symptomatic relief Mouthwash are intended to wash out the mouth , they may be of value for

local hygiene of the mouth

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Alkaline Gargle and Mouth WashTake of:

Bicarbonateof Soda 1 oz.

Boric Acid 1 oz Chloride of Sodium 2 oz.

Directions- Add a teaspoonful to 8 ounces of warm water and use as a gargle, mouth wash or nasal douche.

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Compound Potassium Chlorate GargleTake of:Potassium Chlorate – 6 gr.Borax – 3 gr.Tincture of Myrrh – 5 min.Water, up to – 1 oz.

Useful in stomatitis

Gingival and sublingual preparations These are in the form of drops or sprays for application to

specific areas of the oral mucosa such as the gums for the prevention and treatment of periodontal disease or under the tongue to enable fast absorption of active agents into systemic circulation

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Liniments Are liquid preparation for external use only and may be applied with or

without friction.

They should not be applied to unbroken skin

They are alcoholic or oleaginous solutions or emulsions of various medicinal substances

For oleaginous liniments, the solvent may be a fixed or volatile oil

(almond, sesame, peanut, wintergreen, turpentine oil)

Alcoholic or hydroalcoholic vehicle are useful when rubefacient or counterirritant action is desired

For relief of pain, they may be applied on warmed flannel or lint or may be painted with a soft brush

Liniment may be alcoholic solutions They should be dispensed in colored bottle

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Menthol Camphor Compound Liniment Menthol – 2 gr. Camphor – 5 gr. Oil of Turpentine – 2 dr. Soft Soap- 2 dr. Olive Oil, up to – 1 oz. Useful in chronic inflammation of joints.

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Aconite Belladonna and Camphor Liniment (ABC Liniment)

Take of:Liniment AconiteLiniment of Belladonna Each equal parts.Liniment of CamphorFor use in Rheumatism, etc.

PaintsLiquids for application to the skin or mucous membranes in small amounts

using a small brush

The solvent is water, alcohol, ether or acetone

Glycerol is often added to ensure prolonged contact with the skin (viscocity modifier)

CollodionsIs a clear viscous liquid prepared by dissolving pyroxylin in a 3:1 mixture of

ether and alcohol or acetone/alcohol

Pyroxylin obtained by the action of a mixture of nitric and sulfuric acids on cotton, consists of cellulose tetranitrate

The resulting solution is highly volatile and flammable

The product is capable of forming a protective film on application to the skin

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Castor oil may be applied to collodion to render the film flexible, permitting its comfortable use

After evaporation of the solvent leaves a tough , flexible film hold the drug in intimate contact with the skin

Salicylic acid Collodion It is 10% solution of salicylic acid in flexible collodion Has keratolytic effect especially in the removal of corns from the toes The product is applied as one drop on the corn or wart, allowing time to

dry As salicylic acid is irritant to normal skin, it should be applied directly on

the corn or wart

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