Course Contents PDF

Course Contents No Units/Topics Sub Topics List Number of Weeks 1 Introduction Introduction to physical pharmacy , Importance of 1...

Course Contents No Units/Topics Sub Topics List Number of Weeks 1 Introduction Introduction to physical pharmacy , Importance of 1 studying , physicochemical properties in drug formulation, 2 Surface and Definition of Surface and interfacial tension , 2 interfacial Measurements of surface tension , Surfactants , HLB Phenomenon System , Classification of SAAs, Critical micelle concentration(CMC) , Effect of counter ion and temperature on surface tension and temperature on CMC-values , Determination of the maximum additive (MAC( and Pharmaceutical applications of SAA 3 Adsorption Definition , Mechanism of adsorption ,Heat of adsorption 1 Types of adsorption and factors affecting on adsorption Adsorption isotherm and Pharmaceutical applications Dr. Yousef Algaradi Physical pharmacy No Units/Topics Sub Topics List Number of Weeks 4 Rheology Principles of rheology and types of flow.and Measuring 1. methods in the rheology 5 Midterm exam 1 6 State of States of Matter, Properties of solid ,Physical form (crystal & 2 Matter amorphous) polymorphism, Solvation , Gaseous States and Liquid States. 7 Solubility Definition of solubility, Types of solutions ,, Methods to 3 expression of solubility , Solubility of liquid in liquid and solid in liquids , Factors/ parameters affecting solubility , Determination of solubility based on the pH Partition theory and Partition coefficient , Drug dissolution and Pharmaceutical applications 8 Stability 2 studies No. of weeks per semester 13 Dr. Yousef Algaradi Physical pharmacy Physical pharmacy Dr. Yousef Algaradi Physical pharmacy  Introduction  Physical Pharmacy : The area in pharmacy that deals with the quantitative and theoretical principles of physiochemical science as they applied to the practice of pharmacy.  Why We Study Physical Pharmacy? 1) Proper understanding of subsequent courses in Pharmaceutics and pharmaceutical technology. 2) Integrates knowledge of mathematics, physics and chemistry and applies them to the pharmaceutical dosage form development. 3) It focus on the theories behind phenomena needed for dosage form design Dr. Yousef Algaradi Physical pharmacy  Introduction 4) Enable the pharmacist to make rational decisions on scientific basis concerning the art and technology of dosage forms. 5) provides the basis for understanding the chemical and physical phenomena that govern the in vivo and in vitro actions of pharmaceutical products 6) Aids the pharmacist ,pharmaceutical chemist in their attempt to predict the solubility, stability, compatibility, and biologic action of drug products. Dr. Yousef Algaradi Physical pharmacy  Design of dosage forms Principles of dosage form design:  Drugs:  Rarely administered as pure chemical substances alone  Formulated preparations including additives (excipients).  Drug product:(Dosage form)  Simple solution to complex drug delivery systems.  Prepared of pure drug and excipients  Excipients: formulation additives  Solubilizer, Suspending, flavoring, emulsifying agents, preservative , sweeteners etc. Dr. Yousef Algaradi Physical pharmacy  Design of dosage forms Biopharmaceutical of dosage form design:  The physicochemical properties of the drug.  The dosage form in which the drug is given.  The route of administration  Affect the rate and extent of systemic drug bioavailability Dr. Yousef Algaradi Physical pharmacy Design of dosage forms Variation in time of onset of action for different dosage forms Dr. Yousef Algaradi Physical pharmacy Physicochemical properties of the drug  Understanding the physicochemical properties is crucial for:  Drug formulation  Drug development  Optimization of drug delivery systems  Predicting the drug's behavior in the body. 1) Molecular weight:  The molecular weight of a drug affects its pharmacokinetics, including absorption, distribution, metabolism, and excretion.  Smaller molecules tend to have better absorption and distribution. Dr. Yousef Algaradi Physical pharmacy  Physicochemical properties of the drug 2) Particle size and surface area:  Dissolution and absorption :  Particle size reduction of poorly soluble drugs increase surface area which increase dissolution rate and absorption  High absorption of Inhalation aerosols ( optimum 1- 6 µm)  Stability:  Very fine powders → ↑air adsorption → wetting or agglomeration problems.  Size reduction → changes in crystallinity → chemical stability problems Dr. Yousef Algaradi Physical pharmacy Physicochemical properties of the drug 3) Solubility:  Refers to the ability of a drug to dissolve in a particular solvent.  It is an important property as it affects the drug's absorption, distribution, and bioavailability.  Drugs with poor aqueous solubility exhibit incomplete absorption.  Solubilities of weak acidic or basic drugs are pH- dependent:  Solubility enhancement: 1) Size reduction 2) Formation of complex. 3) Solubilization with excipients eg. surface active agents. Dr. Yousef Algaradi Physical pharmacy Physicochemical properties of the drug 4) Partition coefficient(o/w) :  This property describes the distribution of a drug between two immiscible phases, typically oil and water.  Indicative of drug ability to penetrate biological membranes.  The cell membrane → lipid in nature, the higher the lipid solubility of the drug, the greater is the permeability of a drug molecule. Dr. Yousef Algaradi Physical pharmacy Physicochemical properties of the drug 5) Ionization constant (pKa):  This property determines the degree of ionization of a drug at different pH levels.  It influences the drug's solubility, permeability, and binding affinity to receptors or proteins.  The importance of ionization in drug absorption → the unionized form of the drug has a greater K o/w than the ionized form → ↑ absorption. Dr. Yousef Algaradi Physical pharmacy Physicochemical properties of the drug 6) Crystal properties:  Crystalline, (i.e. high order of regular molecular arrangements),  Amorphous (i.e. without regular molecular arrangements),  Anhydrous , hydrate (various degrees of hydration)  Solvated with other entrapped solvent molecules or  Polymorphs: Drug exists in more than one form of crystal which has different physical properties such as dissolution, solid-state stability, powder flowability Dr. Yousef Algaradi Physical pharmacy Physicochemical properties of the drug 7) Melting point/boiling point:  These properties indicate the temperature at which a solid substance melts or a liquid substance boils.  They can influence formulation processes and storage conditions for drugs. Dr. Yousef Algaradi Physical pharmacy Physicochemical properties of the drug 8) Stability:  The stability of a drug is crucial for its shelf life and effectiveness.  It includes factors such as susceptibility to degradation due to light, heat, moisture, or chemical reactions  Chemical decomposition of drugs : I. Hydrolysis: Example: Aspirin II. Oxidation: Example: Ascorbic acid III. Photochemical decomposition Dr. Yousef Algaradi Physical pharmacy Surface and interfacial phenomenon Dr. Yousef Algaradi Physical pharmacy  Interface & Surface  Interface is the boundary between two phases.  Surface is a term used to describe either a solid-gas or a liquid-gas interface.  Interfacial phase is a term used to describe molecules forming the interface between two phases which have different properties from molecules in the bulk of each phase. Dr. Yousef Algaradi Physical pharmacy Why?? Dr. Yousef Algaradi Physical pharmacy  Surface & Interfacial tensions  Molecules in the bulk liquid are surrounded in all directions by other molecules for which they have an equal attraction (only cohesive forces).  Molecules at the surface can only develop cohesive forces with other molecules that are below and adjacent to them; and can develop adhesive forces with molecules of the other phase. Dr. Yousef Algaradi Physical pharmacy  Surface & Interfacial tensions  This imbalance in the molecular attraction will lead to an inward force toward the bulk that pulls the molecules of the interface together and contracts the surface, resulting in a surface tension. Dr. Yousef Algaradi Physical pharmacy  Surface & Interfacial tensions  Surface tension is the force per unit length that must be applied parallel to the surface to counterbalance the net inward pull.  It has the units of dynes/cm or N/m  Interfacial tension is the force per unit length existing at the interface between two immiscible phases (units are dynes/cm or N/m). Dr. Yousef Algaradi Physical pharmacy  Surface & Interfacial tensions  Usually the term surface tension is used when the interface is between a liquid and a gas, or a solid and a gas.  While interfacial tension is used when the interface is between two liquids or two solids or a solid and a liquid.  Interfacial tensions are weaker than surface tensions because the adhesive forces between two liquid phases forming an interface are greater than that between liquid and gas phases.  For example Mercury has surface tension of 476 dynes/cm while its interfacial tension against water is 375 dynes/cm. Dr. Yousef Algaradi Physical pharmacy  Surface free energy  In the bulk of the liquid: each molecule is pulled equally in all directions by neighboring liquid molecules (net force of Zero)  The surface layer of a liquid possesses additional energy as compared to the bulk liquid.  If the surface of the liquid increases (e.g. when water is broken into a fine spray), the energy of the liquid also increases.  Because this energy is proportional to the size of the free surface, it is called a surface free energy. Dr. Yousef Algaradi Physical pharmacy  Measurement of tensions  Methods for measuring surface and interfacial tension 1) Capillary rise method 2) Ring method 3) Drop weight 4) Drop count method  The choice of a particular method depends on: 1) Surface or interfacial tension is to be determined, 2) The accuracy and convenience desired, 3) The size of sample available, Dr. Yousef Algaradi Physical pharmacy  Capillary Rise Method  When a capillary tube is placed in a liquid contained in a beaker, the liquid rises up in the tube to a certain distance.  By measuring this rise in the capillary, it is possible to determine the surface tension of the liquid using the formula: 𝜸 =½𝒓𝒑𝒈𝒉  𝒓: radius of capillary  𝒉: height  𝒑: density of the liquid  𝒈: acceleration of gravity  This method cannot be used to obtain interfacial tensions. Dr. Yousef Algaradi Physical pharmacy Capillary Rise Method Dr. Yousef Algaradi Physical pharmacy  DuNouy Ring Method (Tensiometer)  The DuNouy tensiometer is widely used for measuring surface and interfacial tensions.  The principle of the instrument depends on the fact that the force necessary to detach a platinum–iridium ring immersed at the surface or interface is proportional to the surface or interfacial tension.  The force required to detach the ring in this manner is provided by a torsion wire and is recorded in dynes on a calibrated dial. Dr. Yousef Algaradi Physical pharmacy DuNouy Ring Method (Tensiometer) Dr. Yousef Algaradi Physical pharmacy  DuNouy Ring Method (Tensiometer)  The surface and interface tensions is given by the 𝐷𝑖𝑎𝑙 𝑟𝑒𝑎𝑑𝑖𝑛𝑔 𝑖𝑛 𝑑𝑦𝑛𝑒𝑠 equation γ= 𝑥 β 2 𝑥 𝑟𝑖𝑛𝑔 𝑐𝑖𝑟𝑐𝑢𝑚𝑓𝑒𝑟𝑒𝑛𝑐𝑒  A correction factor (β) is required before accurate results can be obtained.  Dial reading (F) = mass M of liquid (grams) x 980.665 cm / sec2 (gravity constant)  Ring circumference = 2πr Dr. Yousef Algaradi Physical pharmacy Surface active agents (Surfactants) Dr. Yousef Algaradi Physical pharmacy  Surface active agents (SAAs)  Certain molecules and ions, when dispersed in the liquid, move of their own accord to the interface.  The surface free energy and the surface tension of the system are automatically reduced.  Molecules and ions that are adsorbed at interfaces are termed surface-active agents or surfactants. Dr. Yousef Algaradi Physical pharmacy  Surface active agents (SAAs)  Are solutes that are preferentially adsorbed at the surface or interface of liquid and reduce the surface or interfacial tension and therefore termed Surface active agent.  Surface active agents consists of 2 parts: 1) A lipophilic (hydrophobic) group : Consisting of a long carbon chain which has little affinity for aqueous solvents. Dr. Yousef Algaradi Physical pharmacy  Surface active agents (SAAs) 2) A hydrophilic (or lipophobic) group: Consisting of polar group such as COOH, OH,…which has high affinity for polar solvents.  These molecules are referred to as amphiphilic or amphipathic  Thus, in an aqueous dispersion of amphiphile, the polar group is able to associate with the water molecules and nonpolar portion is rejected.  As a result, the amphiphile is adsorbed at the interface. Dr. Yousef Algaradi Physical pharmacy  HLB System  For the amphiphile to be concentrated at the interface, it must be balanced with the proper amount of water- and oil-soluble groups.  If the molecule is too hydrophilic, it remains within the body of the aqueous phase and exerts no effect at the interface.  if it is too lipophilic, it dissolves completely in the oil phase and little appears at the interface Dr. Yousef Algaradi Physical pharmacy  HLB System  The hydrophile-lipophile balance (HLB) system is an arbitrary scale for expressing the hydrophilic and lipophilic characteristics of an emulsifying agent.  In these system, each surfactant is assigned a number between 1 and 20 representing the relative proportions of lipophilic and hydrophilic parts of the molecule. Dr. Yousef Algaradi Physical pharmacy  HLB System  Depending on their HLB values, the surfactants have different uses.  Agents with HLB value of 1-8 are lipophilic and HLB values of 3-6 are suitable for preparation of w/o emulsions.  Agents with HLB value of 8-18 are hydrophilic and good for o/w emulsions. Dr. Yousef Algaradi Physical pharmacy HLB Values of Some Common SAAs Dr. Yousef Algaradi Physical pharmacy  Classification of SAAs A. According to their ionization: 1) Ionic SAA  Anionic SAA  Cationic SA 2) Non-ionic SAA 3) Ampholytic SAA Dr. Yousef Algaradi Physical pharmacy  Classification of SAAs B. According to their functions & uses: a) Wetting agents b) Detergents c) Antifoaming agents d) Emulsifying agents e) Solubilizing agents f) Antibacterial agents. Dr. Yousef Algaradi Physical pharmacy Micelles formation (OR) Micellization  When a surfactant molecules are added to water, then at low concentrations, the molecules will arrange themselves at the surface.  As the concentration of the surfactant increases, the surface becomes saturated with the surfactant molecules & will aggregate together to form is known as the critical micellar concentration ( CMC) Dr. Yousef Algaradi Physical pharmacy  Micelles formation (OR) Micellization  The CMC value is constant for each surfactant at constant temperatures.  CMC detection :  The CMC can be detected by measuring the surface tension of the surfactant solution:  The surface tension of the surfactant solution decreases as the concentration of the surfactant increases.  Because the surfactant molecules arrange themselves at the surface & hence reducing the upward force due to the surface tension.  As the surface becomes saturated with the surfactant molecules , then no further reduction in the surface tension will occur & the surface tension becomes constant. Dr. Yousef Algaradi Physical pharmacy  Micelles formation (OR) Micellization  The surfactant concentration which corresponds to the beginning of the constant reduction in the surface tension will refer to CMC. Dr. Yousef Algaradi Physical pharmacy  Explanation of micelles formation  On explanation of micelles formation is concerned with the structural organization of water molecules in aqueous solutions.  Water molecules usually possess high degree of structural organization , due to the strong hydrogen boding between water molecules.  If molecules containing a non- polar or hydrophobic group, such as surfactant molecules are added to water, then the water molecules will resist such addition (because of the strong hydrogen bonding attracting water molecules) Dr. Yousef Algaradi Physical pharmacy  Explanation of micelles formation  That attraction will push such surfactant molecules away from them in order to maintain the structural organization of the water molecules.  So at first the surfactant molecules will move to the surface & will arrange the molecules with their polar part facing the water molecule& their non-polar part away from water.  Than as the concentration of surfactants increases, the surface becomes saturated with the surfactant molecules & the surfactant molecules will migrate or move to the bulk of the solution. Dr. Yousef Algaradi Physical pharmacy  Explanation of micelles formation  Surfactant will spontaneously arrange themselves as aggregates to form micelles, with polar group to wards water & the non- polar groups directed inward facing each other & away from water molecules  Such organization will cause the minimum disturbance in the structural organization of water molecules. Dr. Yousef Algaradi Physical pharmacy  Factors Affecting Micellisation 1) Structure of the surfactant 2) Addition of electrolytes 3) Type of counterion 4) Effect of temperature Dr. Yousef Algaradi Physical pharmacy  Structure of the surfactant  Increase in length of the hydrocarbon chain results in a decrease in CMC at constant temperature and an increase in micellar size.  Branched of hydrocarbon chain causes an increase in CMC because decrease in free energy  The CMC is increase 3-4 times by the presence of double (unsaturated) bond in the compound compared to analogous saturated compound.  An increase in the ethylene oxide chain length of a nonionic surfactant makes the molecule more hydrophilic and the CMC increases.  The CMC increases as the polar group is moved from the terminal position towards the middle of hydrocarbon chain. Dr. Yousef Algaradi Physical pharmacy  Addition of electrolytes  Electrolyte addition to solutions of ionic surfactants decreases the CMC and increases the micellar size.  This is because the electrolyte reduces the forces of repulsion between the charged head groups at the micelle surface, allowing the micelle to grow.  Micellar size increases for a cationic surfactant as the counterion is changed and vesa versa for a particular anionic surfactant. Dr. Yousef Algaradi Physical pharmacy  Effect of temperature  For nonionic surfactants, Increasing temperature increases micellar size and decrease CMC.  Temperature has a comparatively small effect on the micellar properties of ionic surfactants.  The effect of temperature stops at a characteristic temperature called the cloud point where the solution become turbid due to the separation of the solution into two phases. Dr. Yousef Algaradi Physical pharmacy  Micellar solubilization  Micellar solubilization is the ability of the micelles to increase the solubility of materials that are normally insoluble, or only slightly soluble, in the dispersion medium used.  The process of bringing hydrophobic (or water insoluble) substances into solution by their incorporation (or entrapment) into micelles.  As Micellar solubilization depends on the existence of micelles; it does not take place below the CMC.  So dissolution begins at the CMC. Dr. Yousef Algaradi Physical pharmacy  Micellar solubilization Above the CMC, the amount solubilized is directly proportional to the surfactant concentration. As the number of micelles increases the extent of solubilization increases. The hydrophobic substance (which its solubility is to be increased) is known as the solubilizate & the surfactant is known as the solubilizing agent. Dr. Yousef Algaradi Physical pharmacy  Micellar solubilization  Concentration of solubilizates (MAC) The maximum additive concentration of a solubilizates (MAC) can be defined as the maximum concentration of a solubilizates that can be incorporated into a given solubilizates system at a fixed surfactant concentration above the CMC.  Determination of the MAC:  First the MAC is approximately determined by adding increasing concentrations of the solubilizates to a fixed known concentration of the surfactant above its CMC.  When turbidity starts to appear, this will correspond approximately to the MAC. Dr. Yousef Algaradi Physical pharmacy  Micellar solubilization  In order to exactly determine the MAC then:- Choose three or four solubilizate concentrations just before the concentration, which causes turbidity. Add each of these concentrations to the same fixed concentration of the surfactant. The lightest solubilizates concentration, which shows clear solution, will correspond to the MAC  Examples :  The solubility of phenolic compounds, such as cresol, chlorocresol & chloroxylenol in water can be highly increased by solubilizing them in triethanolamine oleate  Iodine is insoluble in water & its solubility can be increased by solubilizing it in an aqueous solution of tween (non-ionic surfactant) above the CMC Dr. Yousef Algaradi Physical pharmacy  Application of surfactants in pharmaceutics 1) Solid dosage forms:  Surface-active agents have been widely shown to enhance drug dissolution rates.  This may be due to wetting effects, resulting in increased surface area, effects on solubility.  Consequently surfactants have been included in tablet and capsule formulations.  Also The stainless steel molds are lubricated prior to dipping into the gelatin solution using sodium lauryl sulphate as surfactant. (gelatin capsule manufacturing) Dr. Yousef Algaradi Physical pharmacy  Application of surfactants in pharmaceutics 2) liquid dosage forms:  Formulation of Solution:  Surfactants used as solubilizing agent, which increase drug solubility.  It includes Sorbitan mono oleate and PEG.  It used in rang 0.05-0.5% to avoid toxicity.  Formulation of Suspension: (Dispersants)  Surfactants may be used to aid dispersion of the solid particles in the liquid.  This is particularly important if the powder is not readily wetted by the liquid vehicle.  Surfactants can reduce the interfacial tension between the solid particles and the liquid vehicle. Dr. Yousef Algaradi Physical pharmacy  Application of surfactants in pharmaceutics  Formulation of Emulsions:  Water-in-oil emulsions traditionally contain surfactants of low hydrophilic-lipophilic balance (HLB) (indicating high lipophilicity)  Oil in water emulsion contain surfactants of high hydrophilic-lipophilic balance (HLB) (indicating high hydrophilicity) Dr. Yousef Algaradi Physical pharmacy  Application of surfactants in pharmaceutics 3) Semisolid preparations:  Ointment and cream formulation:  Surfactants are useful for the easy removal from the skin by washing with water & also for the consistency by reduction of surface tension.  Surfactants are also used in formulation of cold cream, cleansing cream, vanishing cream, shaving cream  Suppositories:  Used as lubricants for suopsitories stainless steel molds before filing of liquefied bases.  In addition, emulsifying surfactants help to keep insoluble substances suspended in a fatty base suppository. Dr. Yousef Algaradi Physical pharmacy  Application of surfactants in pharmaceutics  Detergency of surfactants:  The displacement of dirt and debris by the use of detergents in the washing of wounds is an application of wetting agents.  The application of medicinal lotions and sprays to the surface of the skin and mucous membranes Dr. Yousef Algaradi Physical pharmacy Dr. Yousef Algaradi Physical pharmacy Adsorption Dr. Yousef Algaradi Physical pharmacy  Adsorption  Adsorption is the adhesion of atoms, ions, biomolecules or molecules of gas, liquid, or dissolved solids to a surface.  Adsorption can be defined as the accumulation or the existence of high concentration of any particular substance at the surface of a solid or a liquid Dr. Yousef Algaradi Physical pharmacy  Adsorption  Adsorption & Absorption:- The difference between adsorption & Absorption is that  Adsorption is a surface phenomena, which mean that substance only remain at the surface.  While in absorption the substance penetrates through the surface & becomes distributed through out the inner parts of the solid or liquid.  The molecular species or substance, which concentrates or accumulates at the surface is termed adsorbate and the material on the surface of which the adsorption takes place is called adsorbent. Dr. Yousef Algaradi Physical pharmacy  Mechanism of adsorption  Inside the adsorbent all the forces acting between the particles are mutually balanced but on the surface the particles are not surrounded by atoms or molecules of their kind on all sides, and hence they possess unbalanced or residual attractive forces.  These forces of the adsorbent are responsible for attracting the adsorbate particles on its surface.  The extent of adsorption increases with the increase of surface area per unit mass of the adsorbent at a given temperature and pressure. Dr. Yousef Algaradi Physical pharmacy  The heat of adsorption  Another important factor featuring adsorption is the heat of adsorption.  During adsorption, there is always a decrease in residual forces of the surface, i.e., there is decrease in surface energy which appears as heat.  Adsorption , therefore, is invariably an exothermic process.  When a gas is adsorbed, the freedom of movement of its molecules become restricted.  This amounts to decrease in the entropy of the gas after adsorption, i.e., ∆S is negative. Dr. Yousef Algaradi Physical pharmacy  The heat of adsorption  Adsorption is thus accompanied by decrease in enthalpy as well as decrease in entropy of the system.  In other words , ∆H of adsorption is always negative.  For a process to be spontaneous, the thermodynamic requirement is that, at constant temperature and pressure, Dr. Yousef Algaradi Physical pharmacy  Factors affecting on adsorption process  Adsorption on a solid is influenced by a number of factors such as, 1) Surface area 2) Nature of the adsorbate 3) Hydrogen ion concentration (pH) of the solution 4) Temperature 5) Mixed solutes 6) Nature of adsorbent Dr. Yousef Algaradi Physical pharmacy  Examples of adsorptions 1) If a gas like O2, H2, CO or SO2 is taken in a closed vessel containing powdered charcoal, it is observed that the pressure of the gas in the enclosed vessel decreases.  The gas molecules concentrate at the surface of the charcoal, i.e., gases are adsorbed at the surface. 2) In a solution of an organic dye, say methylene blue, when animal charcoal is added and the solution is well shaken, it is observed that the filtrate turns colourless.  The molecules of the dye, thus, accumulate on the surface of charcoal,(adsorbed). Dr. Yousef Algaradi Physical pharmacy  Examples of adsorptions 3) Aqueous solution of raw sugar, when passed over beds of animal charcoal, becomes colourless as the colouring substances are adsorbed by the charcoal 4) The air becomes dry in the presence of silica gel because the water molecules get adsorbed on the surface of the gel. Dr. Yousef Algaradi Physical pharmacy  Types of adsorptions  According to the type of forces or bonds which bind adsorbate molecules to the adsorbent molecules at the surface, adsorption can be classified into two types:- A. Physical adsorption B. Chemical adsorption (chemisorptions). Dr. Yousef Algaradi Physical pharmacy  Physical adsorption  In this type the adsorbate molecules are attracted around to the adsorbent molecules at the surface , by weak physical bonds such as dipole – dipole forces (or Van der weals force).  Because such bonds are weak, the powers of physical adsorption is reversible & the process is characterized by low value of heat of adsorption (0.5-1 kcal/mole)  Example of physical adsorption:  The adsorption of most substances (such as acidic carboxylic acid) onto the surface of charcoal (adsorbent) is a physical adsorption. Dr. Yousef Algaradi Physical pharmacy  Chemical adsorption  In this type the adsorbate molecules are attached or bound to the adsorbent molecules at the surface by Chemical bounds or through Chemical reactions, such as hydrogen bonding or ion-exchange reaction.  This type of adsorption is irreversible & shows high heat of adsorption because chemical adsorption involved stronger chemical bonds.  The amount of heat of adsorption is in the rage of (1-10) Kcal/mole. Dr. Yousef Algaradi Physical pharmacy  Chemical adsorption Example of chemisorptions:  Certain adsorbents such as bentonite & attapulgite have certain ion-exchange groups in their structures; consist of sodium silanolate group.  Such as cationic adsorbents can adsorb cationic drugs or basic drugs such as quaternary ammonia compounds & tertiary amines by cation-exchange mechanism. Dr. Yousef Algaradi Physical pharmacy Types of adsorptions Dr. Yousef Algaradi Physical pharmacy  Adsorption isotherm  Langmuir and Freundlich's isotherms are the most commonly used two-parameter models. 1) Freundlich is valid for multilayer adsorption on heterogeneous sites. 2) The Langmuir isotherm is applicable for monolayer adsorption on a homogeneous site. Dr. Yousef Algaradi Physical pharmacy  Adsorption isotherm Freundlich adsorption isotherm:  The variation in the amount of gas adsorbed by the adsorbent with pressure at constant temperature can be expressed by means of a curve termed as adsorption isotherm.  Freundlich adsorption isotherm: Freundlich, in 1909, gave an empirical relationship between the quantity of gas adsorbed by unit mass of solid adsorbent and pressure at a particular temperature. Dr. Yousef Algaradi Physical pharmacy  Adsorption isotherm  The relationship can be expressed by the following equation: log x/m = log k + 1/n log P Where:  x is the mass of the gas adsorbed on mass m of the adsorbent at pressure P  k and n are constants which depend on the nature of the adsorbent and the gas at a particular temperature. Dr. Yousef Algaradi Physical pharmacy  Adsorption isotherm  The relationship is generally represented in the form of a curve where mass of the gas adsorbed per gram of the adsorbent is plotted against pressure.  These curves indicate that at a fixed pressure, there is a decrease in physical adsorption with increase in temperature. These curves always seem to approach saturation at high pressure. Dr. Yousef Algaradi Physical pharmacy  Adsorption isotherm  The validity of Freundlich isotherm can be verified by plotting log x/m on y-axis (ordinate) and log p on x-axis (abscissa).  If it comes to be a straight line, the Freundlich isotherm is valid, otherwise not.  The slope of the straight line gives the value of 1/n.  The intercept on the y- axis gives the value of log k. Dr. Yousef Algaradi Physical pharmacy  Adsorption isotherm  The factor 1 can have values between 0 and 1.  Thus, above equation holds good over a limited range of pressure.  When1/n = 0, x/m = constant, the adsorption is independent of pressure. Nm  When 1/n = 1, the adsorption varies directly with pressure.  Both the conditions are supported by experimental results.  The experimental isotherms always seem to approach saturation at high pressure. Dr. Yousef Algaradi Physical pharmacy  Adsorption isotherm Langmuir adsorption isotherm:  It is a plot or a graph showing the relationship between (the amount of adsorbate which is adsorbed per unit amount of adsorbent) and the equilibrium concentrations of the unabsorbed adsorbate at a constant temperature.  In order to plot the adsorption isotherm, then adsorption experiments should be conducted as follows:- 1) A number or different adsorbate concentrations (in moles) are prepared.  These concentrations are referred to as initial concentrations (Co) Dr. Yousef Algaradi Physical pharmacy  Adsorption isotherm 2) An equal volume from each of the above concentrations is transferred to a flask containing a certain equal weight (in gm) of the adsorbent (m). 3) The flasks are then tightly closed & shaken for (½ -1) hr at constant temperature & then left for another one hour, after shaking, to equilibrate. 4) After equilibration, the content of each flask is filtered to remove the adsorbent. 5) The concentration of the filtrate is determined in each flask using any proper analytical method ( such as U.V. spectrophotometry or titration) & this concentration will be the equilibrium concentration (CE) ( in moles). Dr. Yousef Algaradi Physical pharmacy  Adsorption isotherm 5) The amount of the adsorbed adsorbate (x) ( in gm) can be calculated each time by subtracting (CE ) from (Co) & the obtained values are then multiplied by the molecular weight of the adsorbate to give you the amount ( x) in (gm). 6) Each time (x) is divided by (m) to give x/m values 7) So now we have different (x/m) values at different (CE) values & by plotting (X/M) against CE we can obtain the adsorption isotherm for the adsorbate in a specific adsorbent system. Dr. Yousef Algaradi Physical pharmacy  Adsorption isotherm  Information of Langmuir adsorption isotherms:  The determination of (x/m) mono which corresponds to the maximum amount of adsorbate (x) which can be adsorbed by a given weight of the adsorbent (m),  Where high (x/m) mono value indicate that the adsorbent is efficiency & can hold a large amount of adsorbate, while small values indicate an inefficient or poor adsorbent. Dr. Yousef Algaradi Physical pharmacy  Applications of adsorption 1) Production of high vacuum: The remaining traces of air can be adsorbed by charcoal from a vessel evacuated by a vacuum pump to give a very high vacuum. 2) Gas masks: Gas mask (a device which consists of activated charcoal or mixture of adsorbents) is usually used for breathing in coal mines to adsorb poisonous gases. 3) Control of humidity: Silica and aluminium gels are used as adsorbents for removing moisture and controlling humidity. Dr. Yousef Algaradi Physical pharmacy  Applications of adsorption 4) Removal of colouring matter from solutions: Animal charcoal removes colours of solutions by adsorbing coloured impurities. 5) Heterogeneous catalysis: Adsorption of reactants on the solid surface of the catalysts increases the rate of reaction. There are many gaseous reactions of industrial importance involving solid catalysts. 6) Separation of inert gases: Due to the difference in degree of adsorption of gases by charcoal, a mixture of noble gases can be separated by adsorption on coconut charcoal at different temperatures. Dr. Yousef Algaradi Physical pharmacy  Applications of adsorption 7) In curing diseases: A number of drugs are used to kill germs by getting adsorbed on them. 8) Froth floatation process: A low grade sulphide ore is concentrated by separating it from silica and other earthy matter by this method using pine oil and frothing agent. 9) Adsorption indicators: Surfaces of certain precipitates such as silver halides have the property of adsorbing some dyes like eosin, fluorescein, etc. and thereby producing a characteristic colour at the end point. Dr. Yousef Algaradi Physical pharmacy  Applications of adsorption 10) Chromatographic analysis: Chromatographic analysis based on the phenomenon of adsorption finds a number of applications in analytical and industrial fields. Dr. Yousef Algaradi Physical pharmacy Rheology Dr. Yousef Algaradi Physical pharmacy  Introduction  Rheology is the science concerned with the deformation of matter under the influence of a stress.  Rheo – to flow logos – science ology – the study of  Viscosity is an expression of the resistance of a fluid to flow, the higher the viscosity, the greater the resistance.  Study of flow properties of liquids is important for Pharmacists working in the manufacture of several dosage forms, viz., simple liquids, gels, ointments, creams, and pastes.  These systems change their flow behavior when exposed to different stress conditions Dr. Yousef Algaradi Physical pharmacy  Importance of rheology 1) Manufacturing of dosage forms:  Mixing and flowing of materials through pipes, filling into the containers etc.  Mixing equipment.  Pipes used  Container used 2) Handling of drugs for administration:  Such pouring from a bottle, extrusion from tube and passage through needle.  All that depend on the changes in flow behavior of dosage forms.  Patient acceptance. 3) Biological availability ( absorption rate from GIT , skin etc.) Dr. Yousef Algaradi Physical pharmacy  Newtonian Flow Law  Newton’s Law of Flow states: that the shear stress between adjacent fluid layers is proportional to the velocity gradient between two layers or shear rate.  Shear: is the movement of material relative to parallel layer.  Shear stress(F) : force tending to cause deformation of a material  Shear rate (G) : the rate of change of velocity.  The velocity of an object : the rate of change of its position. Dr. Yousef Algaradi Physical pharmacy  Newtonian Flow Law  The equation  Representation of the shearing force required to produce a definite velocity gradient between the parallel planes of a block of material. Dr. Yousef Algaradi Physical pharmacy  Newtonian Flow Law  According to Newtonian Law, higher the viscosity of a liquid, the greater is the force per unit area (shearing stress )(F) required to produce a certain rate of shear( G).  Newton was the first to study flow properties of liquids in a quantitative way.  He recognized that the higher the viscosity of a liquid, the greater is the force per unit area (shearing stress) required to produce a certain rate of shear. Dr. Yousef Algaradi Physical pharmacy  Rheogram  Rheogram (Rheology diagrams) is a plot of shear rate, G, as a function of shear stress, F.  Rheogram is also known as consistency curve of flow curve.  Rheogramare typically indicated using viscometer.  These instrument measure the flow properties of materials such as viscosity, shear stress, and shear rate, which are then used to create rheology diagrams. Dr. Yousef Algaradi Physical pharmacy  Types of Flow or Fluids  When classifying materials according to types of flow and deformation, it is ordinary to place them in one of two categories: A. Newtonian (Newtonian Law of Flow) B. Non Newtonian  Liquids that comply with Newton’s law of flow are called as Newtonian fluids and visa versa. Dr. Yousef Algaradi Physical pharmacy  Newtonian fluids  A Newtonian fluid's viscosity remains constant, regardless to the amount of shear applied for a constant temperature.  These fluids have a linear relationship between viscosity and shear stress when shown in rheogram.  Examples:  Water.  Chloroform.  Castor oil.  Ethyl Alcohol etc. Dr. Yousef Algaradi Physical pharmacy  Non-Newtonian Fluids  A non-Newtonian fluids are those fluids for which the relationship between F and G is not a constant for there flow.  Non - Newtonian bodies are those substances, which fail to follow Newton's law i.e. liquid & solid ,heterogeneous dispersions.  The viscosity of such fluids will therefore change as the shear rate is varied.  Examples; colloids, emulsions, liquid suspensions and ointments.  They are classified into three types of flow: 1) Plastic. 2) Pseudoplastic. 3) Dilatant. Dr. Yousef Algaradi Physical pharmacy  Plastic Flow  Associated with flocculated particles or concentrated suspension.  A viscoplastic material does not begin to flow until a shearing stress corresponding to the yield value is exceeded.  Yield value (f); is an indication of the force that must be applied to a system to convert it to a Newtonian System. Dr. Yousef Algaradi Physical pharmacy  Plastic Flow  Examples; suspension of zinc oxide (ZnO) in mineral oil, certain paints, ointments.  The slope of the rheogram is analogous to fluidity in Newtonian system, and its reciprocal is known as Plastic viscosity (U )  Where f is the yield value. Dr. Yousef Algaradi Physical pharmacy Plastic Flow Dr. Yousef Algaradi Physical pharmacy  Pseudoplastic Flow  Also call shear-thinning.  The curve begins at the origin (or approach it) and there is no yield value.  As the shearing molecules orient themselves to the direction of flow.  This orientation reduces internal friction and increase rate of shear. Dr. Yousef Algaradi Physical pharmacy  Pseudoplastic Flow  Occurs in for polymers in solution (e.g. syenthetic or natural gum, cellulose derivatives) Pseudoplastic Flow Behaviour Dr. Yousef Algaradi Physical pharmacy  Dilatant Flow  Also call shear-thickening.  Certain suspensions with a high percentage (upto 50%) of deflocculated solids exhibit an increase in resistance to flow with increasing rate of shear.  Such systems actually increase in volume when sheared and hence termed dilatant and phenomenon as rheopexy.  When stress is removed, a dilatent system returns to its original state of fluidity.  E.g. corn starch in water. Dr. Yousef Algaradi Physical pharmacy Dilatant Flow Dilatant Flow Behaviors Dr. Yousef Algaradi Physical pharmacy  Dilatant Flow  Reasons for Dilatency :  Particles are closely packed with amount of vehicle is enough.  Increase shear stress, the bulk of the system expand (dilate), and the particles take an open form of packing.  The vehicle becomes insufficient.  Particles are no longer completely lubricated by the vehicle.  Finally, the suspension will set up as a stiff paste. Dr. Yousef Algaradi Physical pharmacy  Dilatant Flow  Significance of dilatency :  Such behavior suggests that appropriate precautions should be used during processing of dilatent materials.  Mixing (powder + granulating liquid) is usually conducted in high speed mixers, dilatent materials may solidify under these conditions thereby damage the equipment. Dr. Yousef Algaradi Physical pharmacy Non-Newtonian Dr. Yousef Algaradi Physical pharmacy  Thixotropy  The property of becoming less viscous when subjected to an applied stress.  It is the decrease in viscosity as a function of time upon shearing, then recovery of original viscosity as a function of time without shearing.  Non-Newtonian and time dependent behavior.  Example by some gels which become temporarily fluid when shaken or stirred. Dr. Yousef Algaradi Physical pharmacy  Thixotropy  Downcurve displace left to upcurve for shear thinning system.  When agitated and kept aside it is expected to return its original state of fluidity ,but takes longer time to recover compared to the time taken for agitation.  Thixotropic behavior can be shown by plastic and pseudo plastic system. Dr. Yousef Algaradi Physical pharmacy Influence of Temperature on Viscosity  Apart from the shear rate, temperature strongly influences a fluid’s viscosity.  A substance’s viscosity decreases with increasing temperature.  As temperature is raised, the fluidity of a liquid (the reciprocal of viscosity) increases with temperature.  This inversely proportional relation applies to all substances.  Any change in temperature always influences viscosity, but for different fluids, the extent of this influence varies.  Even a 1 °C temperature increase can raise the viscosity. Dr. Yousef Algaradi Physical pharmacy Dr. Yousef Algaradi Physical pharmacy State of matter Dr. Yousef Algaradi Physical pharmacy  States of Matter  Matter exists in one of the three states-solid liquid or gas.  Two factors usually determined the state in which matter exist. 1) The intensity of intermolecular force 2) The temperature.  Solid have the strongest intermolecular force and the gases have the weakest.  Matter classifications: 1) Solid-Ex: tablet , capsule 2) Liquid-Ex: oral syrup 3) Gas- Ex: aerosol Dr. Yousef Algaradi Physical pharmacy  Solid state  Properties of solids: 1) Strong interaction forces between molecules. 2) Have a definite shape and cannot be changed because molecules move in a fixed positions. 3) Show definite melting point, passing from solid to liquid state. 4) Have crystals which differentiate them from liquids or gases  Most active and inactive pharmaceutical ingredients occur in the solid state as crystals powder  The structure of a solid compound can be classifies as Crystal Habit and Internal Structure. Dr. Yousef Algaradi Physical pharmacy  Solid state  Crystal habit: The description of the outer appearance of crystal.  Internal structure : Molecular arrangement within the solid.  Changing the chemical form (e.g. salt formation) alter both the internal structure and crystal habit.  Crystal habit and internal structure of a drug can 1) Affect physicochemical properties such as; bulk density, particle size, flowability and physical and chemical stability 2) important implications in dosage form process functions. Dr. Yousef Algaradi Physical pharmacy  Crystal habit  The description of the outer appearance of a crystal.  A single internal structure for a compound can have several different habits, depending on the environment for growing crystals.  Different habits of crystals are given below. 1)Tabular: moderate expansion of two parallel faces 2)Platy: plates 3)Prismatic: columns 4)Acicular: needle like 5)Bladed: flat acicular Dr. Yousef Algaradi Physical pharmacy  Internal structure  Depending on internal structure, solid compounds are classified as: 1)Crystalline solids: 2)Amorphous solids: 1) Crystalline solids:  High degree of arrangement of atoms or molecules  Repetition of atom or molecule in regular three dimensional arrays (structure) there are sex crystalline systems, 1)Cubic 2)Hexagonal 3)Tetragonal 4)Orthorhombic 5)Monoclinic 6)Triclinic Dr. Yousef Algaradi Physical pharmacy  Crystalline solids  Units of crystalline structure either:- 1) Ions: eg. NaCl crystal 2) Atoms: eg. Diamond (Binding force: covalent bonds). 3) Molecules : eg. Organic compounds (Binding force: Van der Waals forces or hydrogen bonding).  Note:  Ionic and atomic crystals are hard and have higher melting points.  Molecular crystals are soft and have lower melting points  There are two important terms in crystalline solids, Polymorphism and Solvation Dr. Yousef Algaradi Physical pharmacy  Polymorphism  Drug molecules, are able to be arranged in several different crystalline forms, termed polymorphic forms,  This phenomena is called polymorphism.  Polymorphs: Different crystal forms of a solid drug compound.  The particular polymorph formed by a drug depends on the conditions of crystallization.  For example, the solvent used, the rate of crystallization, the temperature and humidity.  The polymorph with lower free energy will be the most stable and has higher melting point.  Other polymorphs (metastable) with higher free energy will be less stable and have lower melting point. Dr. Yousef Algaradi Physical pharmacy  Polymorphism  Metastable forms will tend to transform into the most stable one at rates that depend on the energy differences between the metastable and stable forms.  Polymorphs of the same drug have different properties and this may cause problems in their formulation, analysis and absorption Dr. Yousef Algaradi Physical pharmacy  Polymorphism  Physical properties that differ among various polymorphs A. Density B. Conductivity. C. Hygroscopicity D. Melting point E. Solubility F. Dissolution rate G. Stability H. Surface area I. Interfacial tension J. Habit (i.e., shape) K. Hardness L. Compressibility,tableting M. Flow and blending N. Vapor pressure O. Color P. Bioavailability Dr. Yousef Algaradi Physical pharmacy  Polymorphism  Example: Spironolactone (orthorhombic crystals)  Form 1: acetone (solvent) at a temperature very close to the B.P. and the solution is then cooled within a few hours down to 0°C. -Form 1 has melting point of 205 °C  Form 2: acetone, dioxane or chloroform (solvents) at room temperature and the solvent is allowed to spontaneously evaporate over a period of several weeks. -Form 2 has melting point of 210 °C Dr. Yousef Algaradi Physical pharmacy  Significance of polymorphism  Obviously, the polymorphism can alter the properties of drugs and excipients.  Polymorphism can affect the: a- Functions of dosage form process: 1) Can affect several formulation parameters such as particle size distribution, powder flow, mixing, dissolution, compression, and tablet hardness in powder.  Eg. Drugs in equidimensional crystals have better flow and compaction properties than needle-like crystals, making them more suitable for tableting Dr. Yousef Algaradi Physical pharmacy  Significance of polymorphism 2) Can affect the rheology and filtration in suspensions.  Eg. Drugs, plate-like crystals, are easier to be injected through a fine needle than needle-like crystals. 3) Can cause grittiness in cream.  Crystal growth in creams as a result of phase transformation can cause the cream to become gritty 4) In suppositories ,produce product with different and unacceptable melting characteristic.  Failure to melt after administration or premature melting during storage. Dr. Yousef Algaradi Physical pharmacy  Significance of polymorphism  E.g polymorphic forms of caco butter, -Unstable gamma form → 18 °C -Alpha form → 22 °C - Beta prime form → 28 °C -Stable beta form → 34.5 °C If we heat caco butter to 35 °C (completely liquefied), nuclei of stable beta crystals are destroyed and produce unstable gamma crystals or alpha crystals So proper method to prepare is to melt caco butter at lowest temp. 33 °C, yet nuclei of stable beta form are not lost Dr. Yousef Algaradi Physical pharmacy  Significance of polymorphism b-Drug bioavailability  Different polymorphs show different solubilities  One polymorphic form may be more active therapeutically than the other form of the same drug in case of slight soluble drug, e.g. chloramphenicol palmitate. Dr. Yousef Algaradi Physical pharmacy  Significance of polymorphism C-Chemical and physical stability:  Chemical stability:  Different polymorphs of a drug may have different chemical properties, such as solubility, reactivity, and degradation rates.  This can affect the drug's stability over time.  For example, one polymorph may be more prone to degradation or hydrolysis than another, leading to changes in the drug's potency or efficacy.  Polymorphs with higher solubility may also exhibit increased chemical stability due to improved dissolution rates and reduced exposure to moisture or other degrading factors. Dr. Yousef Algaradi Physical pharmacy  Significance of polymorphism  Physical Stability:  Different polymorphs may have distinct crystal structures, packing arrangements, and intermolecular forces.  These factors can affect properties such as melting point, density, hardness, and hygroscopicity (ability to absorb moisture).  Changes in these physical properties can impact the drug's shelf life, formulation compatibility, and bioavailability. Dr. Yousef Algaradi Physical pharmacy  Solvation  Crystalline solid to which residual amount of a solvent(s) may be entrapped in the crystal structure during crystallization process and this creates co- crystals, described as solvates.  Crystals that contain solvent of crystallisation are called crystal solvates,  When water is the solvent of crystallization it call Crystal hydrates.  Crystals that contain no water or other solvent of crystallization are termed anhydrates. Dr. Yousef Algaradi Physical pharmacy  Solvation  Solvated forms have different solubility and dissolution rate to the anhydrous form:  The dissolution rate of anhydrate crystals is more than that of hydrates.  The dissolution rate of various solvated forms of a drug is more that of the anhydrous form  There may be measurable differences in bioavailabilities of the solvates of a particular drug. Dr. Yousef Algaradi Physical pharmacy Solvation Dr. Yousef Algaradi Physical pharmacy  Amorphous solids  Supercooled liquid in which the molecules are arranged in a random manner  Higher free energy (higher thermodynamic energy) less stable, has lower melting point higher solubility and dissolution rate (and therefore more absorption or bioavailability) than the crystalline form of the drug.  e.g. amorphous form of Novobiocin is well absorbed whereas crystalline form has poor absorption Dr. Yousef Algaradi Physical pharmacy  Crystalline &Amorphous solids Crystalline solids Amorphous solids Definite melting point No definite melting point High degree of order Random order More stable, less soluble → Less stable, more soluble poorly absorbed → readily absorbed Dr. Yousef Algaradi Physical pharmacy  Gaseous state Properties of gases: 1) Motion: vigorous and rapid motion, gas molecules travel in random path. 2) Very weak interactions between the molecules or absent. 3) Completely miscible with each other. 4) Don‟t have definite shape. 5) Don‟t have definite volume. 6) Gas volume is expressed in liters or cubic centimeter (cm3) Dr. Yoused Algaradi Physical pharmacy  Liquefaction of gases  When the gas is cooled (↓ temp.), gas loses some of its kinetic and the velocity of molecules decrease.  If pressure is applied (↑) to the gas, the molecules are brought within the sphere of Van der Waals interaction forces and pass into the liquid state.  Transition from a gas to liquid depend on temp. as well as the pressure to which the gas is subjected.  liquefaction occurs at a certain temperature called critical temp. which is specific for each gas.  If T is elevated above CT, impossible to liquefy gas irrespective of the applied pressure Dr. Yoused Algaradi Physical pharmacy  Liquefaction of gases Importance of liquefaction:  Reversible change from gas to liquid and from liquid to gas is a basic principle involved in the preparation of pharmaceutical aerosols.  In such products, the drug is dissolved or suspended in a propellant, a material that is liquid at the pressure conditions existing inside the container but forms gas under normal atmospheric pressure conditions.  Propellants (liquefied gases): 1) Chloroflurocarbons 2) Hydroflurocarbons. Dr. Yoused Algaradi Physical pharmacy  Liquid state  Properties of liquids: 1) Motion: less and slowly motion than gas molecules. 2) More interactions forces between the molecules than between gas molecules.( higher viscosity and density) 3) Liquids are practically incompressible under pressure (except if very high pressures are used). 4) A much higher tendency to be miscible with each other than solids. 5) Have definite volume. 6) Take the shape of the container. 7) Have definite boiling point. Dr. Yoused Algaradi Physical pharmacy  Liquid state Boiling Point (B.P):  B.P. may be considered temp at which thermal agitation can overcomes attraction forces between liquid molecules.  B.P. provides a rough indication of magnitude of attractive forces. Dr. Yoused Algaradi Physical pharmacy  Change in the state of matter  The following are the main changes that occur in the states of matter 1) Melting:  Melting, or fusion, is a physical process that results in the phase transition of a substance from a solid to a liquid.  This occurs when the internal energy of the solid increases, typically by the application of heat or pressure, which increases the substance's temperature to the melting point. 2) Freezing:  Freezing is a phase transition in which a liquid turn into a solid when its temperature is lowered below its freezing point Dr. Yoused Algaradi Physical pharmacy  Change in the state of matter 3) Vaporization:  Vaporization of an element or compound is a phase transition from the liquid phase to vapor. 4) Condensation:  Condensation is the change of the physical state of matter from gas phase into liquid phase, and is the reverse of vaporization. 5) Sublimation:  Sublimation is the transition of a substance directly from the solid to the gas phase, without passing through the intermediate liquid phase. Dr. Yoused Algaradi Physical pharmacy  Change in the state of matter 6) Deposition:  Deposition is a thermodynamic process, a phase transition in which gas transforms into solid without passing through the liquid phase.  hence sometimes deposition is called de-sublimation.  One example of deposition is the process by which, in sub-freezing air, water vapor changes directly to ice without first becoming a liquid.  This is how snow forms in clouds, as well as how frost and hoarfrost form on the ground or other surfaces.  The reverse of deposition is sublimation Dr. Yoused Algaradi Physical pharmacy Solubility Dr. Yoused Algaradi Physical pharmacy  Solubility Solution :  It is mixture of components which are physically and chemically homogeneous. Solute:  The components which are present in the solution that dissolves in solvent.  Dispersed as molecules or ions throughout the solvent. Solvent :  The medium in which components are dissolved in.  Constitutes the largest proportion of the system (but not necessarily). Dr. Yoused Algaradi Physical pharmacy  Solubility  Solubility: The ability of substance to dissolve in a anther substance to form homogenous dispersion.(Qualitative)  Also this is the dissolution process.  Solubility : Defined as the concentration of the solute in a saturated solution at a certain temperature. (Quantitative)  The maximum amount of drug that dissolves in a specific amount of solvent at a certain temperature.  Solubility = Grams of drug/ 100 ml of water Dr. Yoused Algaradi Physical pharmacy  Solubility determination  The solubility of a material is usually determined by the equilibrium solubility method, which employs a saturated solution of the material, obtained by stirring an excess of material in the solvent for a prolonged period until equilibrium is achieved. Dr. Yoused Algaradi Physical pharmacy  Types of solutions  Saturated solution:  The solution containing maximum number of solute at a constant temperature.  Supersaturated solution:  A solution that contains more of the dissolved material then could be dissolved by the solvent under normal circumstances. Dr. Yoused Algaradi Physical pharmacy  Types of solutions  Unsaturated solution:  solution which contains the less amount of drug than the saturated solution at a particular temperature.  The solvent can dissolve more solute.  Solution where the solute concentration is lower than its equilibrium solubility. Dr. Yoused Algaradi Physical pharmacy  Types Of Solubility 1) Solubility of gases in liquids 2) Solubility of liquids in liquids 3) Solubility of solids in liquids Solubility of gases in liquids:  Pharmaceutical solutions of gases includes hydrochloric acid, ammonia water, and effervescent preparation containing carbon dioxide (Aerosol) that are dissolved and maintained in solution under positive pressure. Dr. Yoused Algaradi Physical pharmacy  Solubility of gases in liquids  The solubility of such system depends primarily on the pressure, temperature, presence of salts, and chemical reaction (salting out).  Effect of pressure : as the pressure increases the solubility of gases are also increased.  So the effect of pressure is important while considering the solubility of dissolved gases in aerosolized products.  Effect of temperature: as the temperature increases the solubility of most of the gases decreases. Dr. Yoused Algaradi Physical pharmacy  Solubility of liquids in liquids  Frequently two or more liquids are mixed together in the preparation of pharmaceutical solutions.  E.g. Alcohol is added to water to form hydroalcoholic solution (elixirs).  Volatile oils are mixed with water to form aromatic water.  Volatile oils are mixed with alcohol to yield spirits.  Nature of solvents play important role of solubility. Dr. Yoused Algaradi Physical pharmacy  Solubility of solids in liquids  It’s the most term which identify solubility.  Steps of solid going into solution.  Step 1: Hole open in the solvent,  Step 2: One molecule of the solid breaks away from the bulk,  Step 3: The solid molecule is enter into the hole in the solvent Dr. Yoused Algaradi Physical pharmacy  Solubility importance  The solubility of drug is an important physicochemical property because of it affects the bioavailability of the drug consequently, the therapeutic efficacy of the pharmaceutical product.  Pharmaceutical importance of solubility testing: 1)To assess the purity of drug. 2)To determine the possible pharmaceutical dosage form. 3)To analyze the drug in the pharmaceutical dosage form qualitatively and quantitatively. 4)To expect bioavailability of drugs from the pharmaceutical dosage forms (dissolution rates). Dr. Yoused Algaradi Physical pharmacy  Expressions of solubility  Expressions of concentration (solubility) can be in different ways: 1) Percentage:  Percentage terms used in solubility:  % W/V = Percent Weight in volume → No. of gram of solute dissolved in 100 ml of solution.  % V/V = Percent volume in volume → No. of ml of solute dissolved in 100 ml of solution  % W/W = Percent Weight in Weight → No. of gram of solute dissolved in 100 gram of solution. 2) Molarity: It is defined as the number of moles (or gram molecular weight) of solute dissolved in 1 litre of solution. Dr. Yoused Algaradi Physical pharmacy  Expressions of solubility 3) Molality: It is defined as the moles of solute dissolved in 1000 g of solvent. 4) Parts: A certain number of parts by weight (g) of solid are contained in a given number of parts by volume (ml) of solution. Dr. Yoused Algaradi Physical pharmacy  Factors Influencing Solubility 1) Particle size of the solid:  As a particle become smaller, the surface area increases.  The larger surface area causes an increase in solubility. 2) Boiling point and melting point: Aqueous solubility decreases with increasing boiling point and melting point. 3) Temperature:  In endothermic dissolution: Increasing the solution temperature→ increase the solubility of a solid drug.  In exothermic dissolution: Increasing the solution temperature→ decrease the solubility of a solid drug.  Determination of temperature effect on solubility helps in predicting storage condition & dosage form designing. Dr. Yoused Algaradi Physical pharmacy  Factors Influencing Solubility 4) Nature of solvent; co-solvent:  Structural features and presence of nonpolar and polar groups in the molecule are important. 1. Polar solutes dissolve in polar solvents. 2. Non-polar solutes dissolve in non-polar solvents.  Solvent polarity (DEC) is important in determining solvent used.  Water and fixed oils are widely used as solvents in the formulation.  In most cases, a mixture of solvents is used for maximum solubility of drugs.  Although the drug may be freely soluble in water, it may be unstable in aqueous solution.  Accordingly, water-miscible solvents (Co-solvents) are used. Dr. Yoused Algaradi Physical pharmacy  Factors Influencing Solubility 5) Crystal characteristics:  Stable form, ↓↓ energy ,↑ melting point → ↓ solubility.  Less stable form (metastable form), ↑ energy, ↓ melting point → ↑ solubility.  Amorphous powder may also lead to an increase in the solubility of a drug when compared with that of its crystalline form.  The order for dissolution of different solid forms of a drug is Amorphous > Meta stable polymorph > Stable Polymorph. Dr. Yoused Algaradi Physical pharmacy  Factors Influencing Solubility 6) Molecular structure of drug:  It should be realized that even a small change in the molecular structure of a compound can have a marked effect on its solubility in a given liquid.  For example: a) Introduction of polar groups such as –OH to the chemical structure → ↑ hydrophilic property and therefore high aqueous solubility. b) Introduction of non-polar groups such as –CH3 to the chemical structure → ↓hydrophilic property and therefore low aqueous solubility.  Dimension of structure and its configurations of molecules affect drug solubility. Dr. Yoused Algaradi Physical pharmacy  Factors Influencing Solubility 7) pH:  The solubility's of weakly acidic or basic compounds ( partly ionized ) or their salts (representing the vast majority of drug substances) are pH-dependent.  Acidic drugs, such as aspirin, are less soluble in acidic solutions than in alkaline (due to ↓ ionized molecules proportion in the acidic solution and ↑ ionized molecules proportion in the alkaline solution).  Basic drugs, such as ranitidine are more soluble in acidic solutions than in basic (due to ↑ ionized molecules proportion in the acidic solution and ↓ ionized molecules proportion in the alkaline solution).  Henderson-hasselbach equation give deeper explanation. Dr. Yoused Algaradi Physical pharmacy Important considerations in solubility  Ionization and pH - Partition Theory.  Partition Coefficient.  Drug Dissolution Dr. Yoused Algaradi Physical pharmacy  Ionization and pH - Partition Theory  Seventy five percent of all drugs are weak bases, 20% are weak acids and only 5% are non-ionic, amphoteric or alcohol.  Determination of the dissociation content (pKa) for a drug capable of ionization within a pH rang of 1 to 10 is important since solubility and consequently absorption, cab be altered by changing pH.  The unionized forms are more lipid soluble & more rapidly absorbed from GIT.  The relative conc. of unionized & ionized form of weakly acidic or basic drug in a solution at a given pH can be calculated using the Henderson-Hasselbalch equations Dr. Yoused Algaradi Physical pharmacy  Ionization and pH - Partition Theory  Henderson-Hasselbalch equations: pH = pKa + log [unionized form] / [ionized form] ---- for weak bases. pH = pKa + log [ionized form] / [unionized form] ---- for weak acids.  Degree of ionization depends up on the pH of medium:  For acidic drugs pKa ranges from 3-7,  For basic drugs pKa ranges from 7-11  pKa of drug;  Amount of drug that exist in unionized form and in ionized form is a function of pKa of drug & pH of the fluid.  The extent to which a weakly acidic or basic drug ionizes in solution in the gastrointestinal fluid may be calculated using Henderson - Hasselbach equation Dr. Yoused Algaradi Physical pharmacy  Ionization and pH - Partition Theory  Limitations of the pH-partition hypothesis: Despite their high degree of ionization, weak acids are highly absorbed from the small intestine and this may be due to: 1) The large surface area that is available for absorption in the small intestine. 2) A longer small intestine residence time. 3) A microclimate pH, that exists on the surface of intestinal mucosa and is lower than that of the luminal pH of the small intestine Dr. Yoused Algaradi Physical pharmacy Ionization and pH - Partition Theory  Uses of Henderson-Hasselbalch equations:- 1) To determine pka. 2) To predict solubility at any pH provided that pKa are known. 3) To facilitate the selection of suitable salt forming compounds. 4) To predict the solubility & pH properties of the salts. Dr. Yoused Algaradi Physical pharmacy  Partition Coefficient  The gastrointestinal (G.I) membranes are largely lipoidal in character hence the lipid solubility of a drug is an important factor in the assessment for drug absorption potential from its dosage form.  Ideally for optimum absorption, a drug should have sufficient aq solubility to dissolve in fluids at absorption site and lipid solubility high enough to facilitate the partitioning of the drug in the lipoidal biomembrane i.e. drug should have perfect HLB for optimum Bioavailability.  Some drugs are poorly absorbed after oral administration even though they are non-ionized in small intestine.  Low lipid solubility of them may be the reason. Dr. Yoused Algaradi Physical pharmacy  Partition Coefficient  The best parameter to correlate between water and lipid solubility is partition coefficient.  Partition Coefficient (P) is defined as the ratio of concentrations of a compound in a mixture of two immiscible phases at equilibrium. (a biphase of liquid phases), specifically for un-ionized solutes.  Po/w = (Co / Cw) equilibrium Co : organic phase concentration C w :aqueous phase concentration  Hence the partition coefficient measures how hydrophilic ("water-loving") or hydrophobic ("water-fearing") as substance is. Dr. Yoused Algaradi Physical pharmacy  Partition Coefficient  Determination of Partition Coefficient(P , Kp )  If an excess mount of liquid or solid is added to a mixture of two immiscible liquids, it will distribute itself between the two phases so that each becomes saturated.  If the substance is added to the immiscible solvents in an amount insufficient to saturate the solutions, at constant temperature , it will still become distributed between the two layers in a definite concentration ratio. Dr. Yoused Algaradi Physical pharmacy  Partition Coefficient  When one of the solvents is water and the other is a nonpolar solvent, then the P value is a measure of lipophilicity or hydrophobicity of the added substance.  Drug has Po/w values much greater than 1 are classified as lipophilic, whereas those with Po/w values much less than 1 are indicative of a hydrophilic drug.  Applications of Partition Coefficient: 1) Measure of lipophilic/ hydrophilic character of molecules. 2) Solubility: both aqueous and in mixed solvents. 3) Extraction of drug from biological fluid for therapeutic monitoring. 4) Study of absorption& distribution of drug through the body. 5) In dosage form formulation. Dr. Yoused Algaradi Physical pharmacy  Drug Dissolution  Dissolution is a process in which a solid particles solubilized in a given solvent into solution under standard conditions of temperature, pH, solvent composition & constant solid surface area.  The transfer of molecules or ions from a solid state into solution is known as dissolution.  The dissolution rate of a drug is only important where it is the rate-limiting step in the absorption process. Dr. Yoused Algaradi Physical pharmacy  Drug Dissolution  The first step in the commencement of dissolution is the wettability of solid particles, there is a direct correlation between wettability and bioavailability.  Mechanisms of dissolution: (Diffusion layer model) Assumption: it is assumed that: An aqueous diffusion layer or stagnant liquid film of thickness h exists at the interface of the solid undergoing dissolution. This thickness represents stationary layer of the solvent in which the drug molecules exist in saturated concentrations from Cs to C. Dr. Yoused Algaradi Physical pharmacy  Drug Dissolution  Beyond diffusion layer, at x > h, mixing occurs in the solution and the drug is formed in uniform concentration C, thought bulk solution. Dr. Yoused Algaradi Physical pharmacy  Drug Dissolution  Rate of dissolution: The amount of drug that goes (mass transport) in to solution per unit time under standard condition of temperature pH, solvent composition & constant solid surface area.  Rate of dissolution is described by Noyes–Whitney equation: Dr. Yoused Algaradi Physical pharmacy  Drug Dissolution  Noyes–Whitney equation: dm K1A(Cs - C)  dt h Where :  dm/dt is the rate of dissolution;  Cs is the saturation solubility of the drug in solution in the diffusion layer,  C is the concentration of drug in the bulk solution,  A is surface area of undissolved solid exposed to the solvent,  h is the thickness of the diffusion layer,  k1 is the diffusion coefficient of the dissolved solute Dr. Yoused Algaradi Physical pharmacy  Drug Dissolution  In-vitro dissolution test:  The most critical parameter that determines the drug activity, is the dissolution rate in the biological milieu.  Importance of dissolution testing: Dissolution testing is useful method for: 1)Establishment correlation between dissolution rate and extent of absorption (bioavailability). 2)Quality control: monitoring the formulation and manufacturing process. Dr. Yoused Algaradi Physical pharmacy Drug Dissolution In-vitro dissolution apparatus Dr. Yoused Algaradi Physical pharmacy  Solubility enhancement 1) Selection of a different solubilizing agent. 2) Selection of a different chemical salt form of the medicinal agent. 3) Alteration of the pH of a solution. 4) Use of co-solvents , eg. Paracetamol Elixir( PW and Alcohol) 5) Increasing the temperature generally increases the solubility 6) Increasing the pressure for gases dissolved in solvent 7) Decreasing the particle size of a solid solute. 8) Agitating or stirring of the solution Dr. Yoused Algaradi Physical pharmacy  Pharmaceutical applications of solubility  Solubility data and Understanding the solubilities of different drugs can help in: 1) Formulation development:  Select appropriate excipients and optimize drug formulations.  Development of formulations design by enhance its solubility, stability, and overall performance. 2) Drug delivery systems:  Different techniques like solid dispersion or nanoemulsion formulation are employed to improve the solubility of poorly soluble drugs. Dr. Yoused Algaradi Physical pharmacy  Pharmaceutical applications of solubility 3) Bioavailability enhancement:  Poorly soluble drugs often have low bioavailability due to limited dissolution and absorption.  Solubilization techniques can be used to enhance their solubility and improve their bioavailability 4) Preformulation studies:  Physical and chemical properties of a drug are evaluated before formulation development.  These studies help determine the most suitable dosage form for a particular drug based on its solubility characteristics. Dr. Yoused Algaradi Physical pharmacy  Pharmaceutical applications of solubility 5) Drug-drug interactions:  Assessing potential drug-drug interactions during combination therapy.  Predict their compatibility or potential precipitation issues when combined. 6) Quality control:  Solubility testing is often performed as part of quality control measures to ensure consistency and reproducibility in pharmaceutical manufacturing.  Verify that the active pharmaceutical ingredient (API) is within acceptable limits of solubility, which can impact drug efficacy and safety. Dr. Yoused Algaradi Physical pharmacy