221 PHT

1. 221 PHT Nahla S. Barakat, Ph.D King Saud University Dept. of Pharmaceutics First Term 1432-2011 1

2. Course Syllapus • Liquid dosage forms • Colloid • Disperse system: suspension, emulsion • Liposome and nanoparticles • Aerosols • Drug stability

3. References:Remington’s pharmaceutical Sciences, Mack Publishing Co.,The design and manufacture of medicines; Aulton, Third edition, 2007

4. Solution is a homogenousmixturecomposed of two or more substances. In such a mixture, asoluteis dissolved in another substance, known as asolvent.A common example is asolid, such assaltorsugar, dissolved inwater, aliquid. • Gasesmaydissolvein liquids, for example:carbon dioxideoroxygenin water. • Liquids may dissolve in other liquids. Gases can combine with other gases to form mixtures, rather than solutions. 4

5. 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. 5

6. Advantage of solutions • Liquids are easier to swallow • A drug must be in solution before it can be absorbed • A solution is an homogenous system, the drug will be uniformly distributed throughout the preparation • Some drugs can irritate the gastric mucosa if localized in one area. Irritation is reduced by administration of a solution of the drug 6

7. Problem associated with the manufacturing of solutions • 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 7

8. Aqueous solutions and non-aqueous solutions • Aqueous solutionsSolutions that contain water as the solvent are called aqueous solutions.For example, sugar in water, carbon dioxide in water, etc.  • Non-aqueous solutionsSolutions 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.  8

9. 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.  9

10. Saturated and unsaturated solutions • 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. 10

11. Solubility and Miscibility • Different substances have different solubilities. • Solubilityrefers 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 beinsoluble. 11

12. 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.

13. Relative terms of solubility 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

14. Soluble Group I and ammonium (NH4+) compounds Nitrates Acetates (Ethanoates) Chlorides, bromides and iodides except: Silver (Ag+), Lead(II) (Pb2+), Mercury(I) (Hg22+), Copper (Cu+) Sulfates except: Silver (Ag+), Lead (Pb2+), Barium (II) (Ba2+), Strontium(II) (Sr2+) and Calcium(II) (Ca2+) Insoluble Carbonates 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

15. Miscibilityrefers to the ability of a liquid to dissolve in another in all proportions. • Alcohols like methanol and ethanol aremisciblewith 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 beimmiscible. Oil and water are immiscible. 15

16. Electrolytes and Non-Electrolytes • One way to distinguish between solutions that contain ions and those that contain molecules is an electrical conductivity test. 16

17. A solution that conducts electrical current is said to beelectrolyticand the solute is called anelectrolyte. The sodium chloride solution is an electrolytic solution. • The solute in a solution that does not conduct electrical current is anon-electrolyte. Examples include:sugar, urea, glycerol, andmethylsulfonylmethane (MSM. • Generally, dissociated ionic compounds are electrolytes whereas dissolved molecular compounds are non-electrolytes. 17

18. Units of Measure in Solutions • 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. • AMolar Solutionis an aqueous solution consisting of one mole of a substance plus enough water to make one Liter of solution. • AMolal Solutionis 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 inEquivalents (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 ofCHARGEconcentration. 18

19. Mass per unit volume. This unit is typically milligrams per milliliter (mg/mL) or milligrams per cubic centimeter (mg/cm3 ) A useful note is that 1 mL = 1 cm3 and that cm3 is sometimes referred to as a "cc" (cubiccentimeter. 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

20. 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.

21. Terms of expression the strength of pharmaceutical preparations • 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)

23. Solubility and TemperatureDependence 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.

25. 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.

26. 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

27. 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.

29. Nature of Solute and Solvent • 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

30. Nature of Solute and Solvent

31. Molecular size The 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.

32. 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. Stirring Agitation 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.

34. 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

35. 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.

36. 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.

37. 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.

38. 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.

39. 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)

40. 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) Vh Where, 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

41. 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.

42. 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: • Size of solid particles • – A1/Particle size. • Particle size will change during dissolution process, because large particle will become smaller and small particles will disappear. • ) 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. • Porosity of solid particle. • - Pores must be large enough to allow access of dissolution medium and outward diffusion of dissolved solute molecules.

43. 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 -

44. 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.

45. 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.

46. 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

47. 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

48. 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

49. 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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