Lec.1 -5 Physical Pharmacy - Thamar University

B1101243 Physical Pharmacy Mohammed Amran, Ph.D. Department Pharmacy, Faculty of medical sciences Thamar University 2 INTRODUCTION TO Physical pharmacy Reference Martins : physical pharmacy and pharmaceutical sciences 3 6 7 8 What is a DRUG How does...

B1101243 Physical Pharmacy Mohammed Amran, Ph.D. Department Pharmacy, Faculty of medical sciences Thamar University 2 INTRODUCTION TO Physical pharmacy Reference Martins : physical pharmacy and pharmaceutical sciences 3 6 7 8 What is a DRUG How does the law define a drug? The Federal Food, Drug, and Cosmetic Act (FD&C Act) defines drugs, in part, by their intended use, as articles intended for use in the diagnosis, cure, mitigation( alleviation, modification), treatment, or prevention of disease“ and "articles (other than food) intended to affect the structure or any function of the body of man or other animals" [FD&C Act, 1938 sec. 201(g)(1)] DRUG This is pharmacologically active ingredient in the medicine, also called Medicinal agent Active ingredient Active pharmaceutical ingredient (API) Pharmaceutical preparation (Medicine) pharmaceutical preparations must be: Elegant Safe Stable Palatable Therapeutically effective Pharmacopei a The term comes from the Greek Pharmakon meaning drug Poiein meaning to make Pharmacopeia , is a book containing directions for the identification of compound medicines, and published by the authority of a government or a medical or pharmaceutical society. Descriptions of preparations are called monographs. In a broader sense it is a reference work for pharmaceutical drug specifications. British Pharmacopeia BP The British Pharmacopeia is the official collection of standards for UK medicinal products and pharmaceutical substances The standards are established by the British Pharmacopeia Commission. Canada and Australia also use the BP as their official standard The United States Pharmacopeia USP The United States Pharmacopeia (USP), established in 1820, contains legally recognized standards of identity, strength, quality, purity, packaging, and labeling for drug substances, dosage forms, and other therapeutic products, including nutritionals and dietary supplements. An official publication, issued first by the American Pharmaceutical Association and now yearly by the United States Pharmacopeial Convention, (a non profit organization) that sets the standards for the quality, purity, identity, and strengths of medicine, food ingredients, and dietary supplements manufactured, distributed, and consumed world wide The book contains two separate official compendia -- the USP and the NF. National FormularyNF The National Formulary (NF), established in 1888 by the American Pharmaceutical Association, includes standards for excipients and other similar products, gives the composition, description, method of preparation, and dosage for drugs. USP purchased the NF in 1975, combining the two publications under one cover, creating the USP-NF United States Pharmacopeia and National Formulary (USP-NF). Monograph USP-NF monographs contain specifications (tests, procedures, and acceptance criteria) that helps ensure the strength, quality, and purity of named items. USP-NF monographs, which are recognized worldwide, may be enforceable by the US Food and Drug Administration (FDA) and also by state agencies in the US.  Overall aim of the course Physical pharmacy course introduces the physico-chemical principles of drugs and formulations and their importance in designing efficient dosage forms. Solubility & Dissolution Objectives 1.To define solubility, saturated and unsaturated solution, polar, non polar and semipolar solvents. 2.To describe and understand the factors controlling the solubility of strong and weak electrolytes such as solvent, pH and surfactants. 3.To describe what a partition 1-Solubility Solution :is the concentration of solute in a saturated solution at a certain temperature True solution = solute +solvent (homogenous dispersion)  Solution unsaturated saturated supersaturated in which dissolved solute concentration is < = > that necessary for complete saturation  Definition Term It is a mixture of two or more components that form single Solution phase forming homogenous molecular dispersion Solution consists of two substances, one called solute Binary solution (present in small amount) and the other called solvent (present in large amount). When solid dissolved in liquid, the solid considered as solute and the liquid considered as solvent irrespective of the relative amount of the constituents Substances that form ions in solution, conduct the electric Electrolyte solute current such as sodium chloride, hydrochloric acid and ephedrine. Substances that do not form ions in solution, do not Nonelectrolyte solute conduct the electric current such as glycerin, sucrose and urea It contains the maximum amount of solute that solvent can Saturated Solution dissolve at a particular temperature. Alternatively, the excess undissolved and dissolved solute is in equilibrium at a definite temperature in the solution. 08:16 PM 8/25/24 It is solution containing the dissolved solute in a concentration Unsaturated Solution below that necessary for complete saturation at a definite temperature The solution contains more solute in the dissolved state than Supersaturated would normally be dissolved at a definite temperature. This solution solution deposits its excess solute by: - Seeding the solution with a small crystal of solute - Scratching the wall of the container in contact with the solution - Vigorous agitation or shaking - Cooling Is the concentration of the substance in a saturated solution at Solubility a certain temperature. Or, the amount of substances that pass into solution in order to establish the equilibrium at constant temperature and pressure and so produced saturated solution. It is the interaction between solvents and solute Solvation The transfer of molecules or ions from solid state into solution Dissolution 08:16 PM 8/25/24 Importance of Solubility Solubility is important to the pharmacist because it helps him to: - Assess the purity of the drug. - Determine the possible dosage form. - Qualitatively analyze the drug in the dosage form. - Expect bioavailability of drugs from solid dosage forms since the most important stage is the dissolution of solid drug particles to form a solution in the gastrointestinal tract. Solubility Expression Percentage: (i): % w/w : No. of grams of solute per 100 gram of solution Mass of solute x 100 = % w/w ------------------------ Mass of solution (ii) % w/v: No. of grams of solute per 100 milliliters of solution Mass of solute x 100 = % w/v --------------------- Volume of solution (iii) %v/v: No. of milliliters of solute per 100 milliliters of solution Volume of solute ---------------------------- Volume of solution x 100 = % v/v (liquid in liquid) Molarity: number of moles (gram molecular weight) of solute dissolved in 1 liter of solution and its unit is mol L -1. Molality: number of moles (gram molecular weight) of solute dissolved in 1000 gram of solvent. Mole Fraction: No. of mole of “A” ------------------------------------------------------- Sum of No. of moles of all components. b.In most pharmacopea as parts of solvent required for One part of solute Term Parts of solvent required for One part of solute Very soluble Less than 1 part Freely soluble 1 to 10 parts Soluble 10 to 30 parts Sparingly soluble 30 to 100 parts Slightly soluble 100 to 1000 parts Very slightly soluble 1000 to 10000 parts Practically insoluble More than 10000 Determination of Solubility 1.Excess drug is added to the solvent in stoppered conical flask.. 2.Shaking in a constant temperature for a specified period. 3.Leave for equilibrium, filter and determine drug concentration with suitable method. We will study 1-THE SOLUBILITY OF GASES IN LIQUIDS 2-THE SOLUBILITY OF LIQUIDS IN LIQUIDS 3-THE SOLUBILITY OF SOLIDS IN LIQUIDS 1-THE SOLUBILITY OF GASES IN LIQUIDS EX: hydrochloric acid, ammonia water, and effervescent preparations containing carbon dioxide. is the concentration of the dissolved gas when it is in.equilibrium with the pure gas above the solution Factors affecting solubility of gas in liquid:  Comment Effect Factor C2 = k p (Henry’s Law ) concentration of a. Pressure dissolved gas(C2) is proportional to the partial pressure of the gas above the solution(p ) -owing to the greater tendency of the gas to b.Temperature expand. - caution :ethyl nitrate (of high vapor pressure) in hot climate. due to the attraction of the salt ions to water c.Salting Out molecules, which reduces the density of the By addition of aqueous environment adjacent to the gas electrolyte such as sodium chloride or non- electrolytes such as sucrose hydrogen chloride, ammonia, and carbon d.Chemical reaction dioxide THE SOLUBILITY OF LIQUIDS IN LIQUIDS-2 Ex: , alcohol +water =hydro alcoholic solutions ;volatile oils +water =aromatic waters.volatile oils +alcohol =spirits and elixirs Solubility of liquid in liquid Non-ideal or real solutions Ideal solution *There are change in the * No change in the properties of properties of the components, the components, other than dilution, * Evolution or absorption of heat * No heat is evolved or absorbed when they are mixed. when they are mixed to form solution. * An example is the addition of * Formed by mixing substances 100 ml of sulfuric acid to 100 with similar properties such as ml of water, the volume of 100 ml of methanol added to solution formed is 180 ml with 100 ml of ethanol. evolution of heat. * Do not obey Raoult's law even * Obey Raoult's law over the when the two components are whole range of composition miscible in all proportions  Liquid-liquid systems. Complete Partial Miscibility Miscibility They mix in all proportions When they are mixed, 2 layers are (one layer) formed each containg some of the.other liquid Ex: water and alcohol Ex: water and ether benzene and carbon tetrachloride. water and phenol. Factors affecting solubility of liquid in liquid:  Comment Effect Factor 1-closed: shows both an upper and a lower a. Temperature CST. For example, Nicotine and Water. 2-upper: upper consolute temperature above which the 2liquids are soluble. For example phenol and water. 3-lower: lower consolute temperature, below which the two members are soluble. For example, triethanol amine and water. 4- no critical solution temperature: For example, ethyl ether and water If the added material is soluble in only 1 of the b. Foreign 2 components or if the solubility in the 2 Substances(ternary liquids are markedly different. system ) When the third substance is soluble in both of the liquids to roughly the same extent. 3-THE SOLUBILITY OF SOLIDS IN LIQUIDS Factors affecting solubility of solid in liquid : a-Solvent related factors b-Solute related factors c-others.  Comment Factor like dissolves like." So, water is a good solvent for salts, sugars," a-Solvent while mineral oil and benzene are often solvents for slightly soluble related substances factors Mechanisms: a-Polar 1) High dielectric constant: reduce the force of attraction between oppositely charged ions in Ex: water crystals such as sodium chloride. 2) Acid-base reactions: for example, water causes the ionization of HC1 as follows: HCl + H2O ------ H30+ + Cl- 3) Dipole interaction forces: the positive end of one molecule attracts the negative end of the other and vice-versa. 4)Hydrogen bond: For example, to dissolve phenols, alcohols , aldehydes and other oxygen and nitrogen containing compounds, which can form hydrogen bonds with water.  Comment Factor Mechanisms: b-Non-Polar Ex: carbon weak van der Waals-London type of forces. tetrachloride, benzene Mechanisms: b-Semi- 1)Semi polar solvents can induce, a certain degree of polarity in Polar non-polar solvent molecule. For example, benzene is soluble in alcohol. Ex: ketones and alcohols 2)They act as intermediate solvent: to bring about miscibility of polar and no polar liquids. For example, acetone increases the solubility of ether in water  Comment Effect Factor b-Solute related factors: 1-Molecular structure of solute: A-hydrophilic hydroxyl the solubility of phenol is higher than that of group : benzene. Branching of the carbon chain reduces the non- B-Branching of carbon polar effect.the solubility of tertiary butyl alcohol chain: is higher than n-butyl alcohol. As the length of a non- polar chain of an aliphatic C-Length of carbon chain alcohol for example increases, the solubility of the compound in water decreases. leads to a much greater degree of ionic dissociation. D-The conversion of a weak acid to its sodium salt: For example, the solubility of sodium salt of. salicylic acid is higher than that of salicylic acid  Comment Effect Factor due to increasing its surface area. 2-Particle size of the solid: *Decrease in particle size: * Further decrease in due to the presence of an electrical charge on particle size (Ultra fine). the particles Crystalline solids have lower solubility than 3-Crystallinity of the amorphous solids due to high intermolecular solid: forces within solute molecules. due to high intermolecular forces within solute 4-Melting point: molecules.  Comment Effect Factor c-Others: solid that absorbs heat when it dissolves 1-temperature: (salts) (endothermic process) as potassium nitrate.. solid that absorbs heat when it dissolves (exothermic process) as sodium sulphate due to formation of water-soluble salts. At low 2-pH: (weak pH, solubility decreases as they are mainly electrolytes) unionized. For example, phenol. C6H5OH + NaOH --------- C6H5O- + Na+ + H2O A-For Weak acids as they are mainly unionized. For example, B-Weak bases: atropine. At low pH, solubility increases due to formation of water-soluble salts. EX: atropine sulfate.  Comment Effect Factor AgCL solid -------- Ag+ + Cl- 3-Common ion effect (slightly soluble electrolytes) The addition of sodium chloride, for example, increases the concentration of chloride ions so that [Ag+] [Cl-] > Ksp so, some of the AgCl precipitates from the solution until the equilibrium [Ag+] [Cl-] = Ksp is reestablished. Some times, The addition of the common ion increases solubility due to formation of water soluble complex with the salt  Comment Effect Factor Solubility may be increased or decreased due to Complex-4 formation of intermolecular complex with the solute. formation For example , KI increases solubility of HgI2 because of formation of a water soluble complex, K2(HgI4) -are capable of forming large aggregates or micelles in 5-Solubilizing solution when their concentrations >(CMC). agent by taking up organic solutes in their center which resembles a separate organic phase This phenomenon is known as solubilization. Using of more than one solvent to increase poorly water 6-Cosolvency: soluble drugs by decreasing the interfacial tension between water and solute and by altering dielectric constant. For example ethanol addition increases solubility of weak electrolyte in water DISTRIBUTION OF SOLUTES BETWEEN IMMISCIBLE SOLVENTS Ifan excess of solute is added to a mixture of two immiscible liquids, it will distribute itself between the two phases so that each becomes saturated.. Co / Cw = P (P is known as the distribution ratio, distribution coefficient or partition coefficient.) As P (or log P) increases ,lipid solubility increases. Application of partition coefficient: 1-Preservative action of weak acids in oil-water systems: The distribution of benzoic acid between the 2 immiscible liquids in this system, might decreases its concentration in the aqueous phase below the effective level. 2-Extraction: solvent can extract a compound from a second solvent depending on its partition coefficient between the 2 solvents. 3-Distribution of drug throughout the body: GIT fluids are aqueous, while GIT membranes are lipid in nature. Drug should first dissolve in GIT fluids, then pass GIT membranes to reach blood.(P)indicates the lipophilic or hydrophilic nature of drug. 4-Dissolution rate: is the amount of solute that goes into solution per unit time. Solute diffuses from aqueous diffusion layer(stagnant liquid film of thickness h at solute surface) which is saturated with drug i.e its concentration is Cs to the bulk, where the concentration is C. Dissolution apparatus Surface and interfacial phenomena Objectives *To study the physical, chemical and electrical properties of molecules situated at interfaces. *To understand how problems arising during preparation of dosage forms (e.g.; emulsions, suspensions..) & involving interfaces can be resolved by the use of surface active agents  Spreading Coefficient When a substance is placed on the surface of water, it will show one of two behaviors: 1. Spread as a film if the force of adhesion between the substance molecules and the water molecules is greater than the cohesive force between the substance molecules themselves such as oleic acid on water. 2. Do not spread and form separate spots if the cohesive force between the substance molecules is greater than the adhesion force between the substance molecules and the water molecules such as mineral oil on water. Surface-active agents  Adsorption at Liquid Interfaces: Surface–active agents (SAA): Certain molecules and ions, when dispersed in the liquid, move to the interface. First, They concentrated at the interface then exceeds their concentration in the bulk of the liquid. The adsorption of the molecules at the interface reduces the surface free energy and the surface tension of the system. Such a phenomenon, where the added molecules are partitioned in favor of the interface, is termed positive adsorption. Other materials such as inorganic electrolytes are partitioned in favor to the bulk, leading to negative adsorption. Adsorption differ from absorption in that , the former is solely surface effect while the second is penetration of the absorbent into the capillary space of the absorbing medium. Molecules and ions that are adsorbed at interfaces are termed surface– active agents (SAA) or surfactants. They are also known as amphiphiles or amphipathic, which suggests that the molecules or ions have certain affinity for both polar and nonpolar solvents. Depending on the number and nature of the polar and nonpolar groups present in their molecules, the amphiphile may be:  a. Predominantly hydrophilic (water–loving) b. Lipophilic (oil–loving) c. Well balanced between these two extremes For example the straight–chain alcohols, amines and acids are amphiphiles which are: Example: *Ethyl alcohol: is miscible with water in all proportions. *Amyl alcohol: The aqueous solubility is much reduced *Cetyl alcohol may be said to be strongly lipophilic and insoluble in water. The Amphiphile Nature: The amphiphile nature of the surface–active agents is the character that cause them to be adsorbed at the interfaces (liquid/gas or liquid/liquid). Their should be a suitable balance between the hydrophilic and lipophilic groups to ensure surface activity. In an aqueous dispersion of SAA: a. The polar groups are able to associate with water molecules. b. The non-polar portion is rejected because the adhesive force it can develop with water molecules is smaller than the cohesive force between the adjacent water molecules. c. As a result the amphiphile molecule is adsorbed at the interface. *In order for the amphiphile to be concentrated at the interface, it must be balanced with the proper amount of water–soluble and oil–soluble groups (e.g. Glyceryl monostearate). *If the molecule is too hydrophilic, it will remain within the body of the aqueous phase and exerts no effect at the interface (e.g. Glycerin). *Likewise, if it is too lipophilic, it will dissolve completely in the oil phase and little appears at the interface (e.g. Glyceryl tristearate). Classification of surface active agent Systems of Hydrophile – Lipophile Classification: Griffin devised an arbitrary scale of values to serve as a measure of the hydrophilic – Lipophilic balance (HLB) of surface-active agents. *This system establishes an HLB range of optimum efficiency for each class of surfactant. *The higher the HLB of an Hydrophilic agent, the more hydrophilic it is. *The spans, sorbitan esters, are Lipophilic and have low HLB values of 1.8 to 8.6. *The tweens, polyoxyethylene Lipophilic derivatives of the spans are hydrophilic and have HLB values of 9.6 to 16.7.  Structural Classification of SAA A. Ionic Surface Active Agents: I. Anionic Surfactants: They are ionized in water with a negative charge and posses the active part of their molecule in the anion II- Cationic Surfactants : They ionized in water bearing a positive charge and posses the surface active portion of their molecule in the cations. B. Non-ionic Surfactants: *Do not ionize in solution. *They are generally compatible with both anionic and cationic additives in a formula. III- Amphoteric Surfactants (zwitterionic): They are the least common of the ionic group. The performance or behavior of this group is pH dependent and they can function as anionic or cationic SAA. Applications of Surface Active Agents: I. Solubilizing agent and Micelle Formation: 1.At low concentration, SAA migrate at the interface between water and air so that the hydrophilic portion is directed towards water and the hydrophobic portion is directed towards air. 2. Further addition of the surfactant leads to the saturation of the surface and molecules are go to the bulk of the solution. 3. After saturation of the bulk and at a specific concentration known as the Critical Micelle Concentration (CMC), SAA molecules aggregate to form micelles of spherical shapes so that the hydrophilic portions of the molecules are directed outward (facing water) and the hydrophobic portions are directed inward (away from water). II- Foaming Agents: Foaming agents are surfactants, which facilitate the formation of air globules inside water film and stabilize them. They are important for toothpaste and fire extinguishing products. III- Antifoam Effect: Antifoams are surface-active agents have low HLB (1 – 3). They destroy air pockets. Antifoaming agents are important for manufacturing of most pharmaceutical liquid preparations containing SAA for wetting or flocculating effect. They reduce the foam formation during the manufacturing process. IV- Wetting agent A wetting agent is a surfactant that, when dissolved in water, lowers the advancing contact angle (the angle between the liquid droplet and the surface over which it spreads), aids in displacing an air phase at the surface and replaces it with a liquid phase. They decrease the contact angle by adsorbing at the interface between the solid and liquid. Under this condition, liquids can spread on the solid and wet its surface. As shown in the Figure outlined later, the contact angle between a liquid and a solid may be 0° signifying complete wetting, or may approach 180°, at which wetting is insignificant, between which the contact angle may have any values. V- Emulsifying Agents: Emulsifying agents are the surfactants that form an interfacial film at the interface of O/W or W/O droplets. Such films significantly alter the rates of coalescence by acting as physical and chemical barriers to coalescence. In general, the phase in which the surfactant is more soluble being the continuous phase. The foregoing helps, the ionized surfactants (possess strong polar group) favor O/W emulsion, while, little dissociated surfactants favor W/O emulsion. Similarly, non-ionic surfactants possess polyoxyethylene moieties favor O/W and that not contain polyoxyethylene moieties favor W/O emulsion. In addition, the type of emulsions formed, depends on the polar/non-polar characteristics (HLB value) of the surfactants. Because of the stabilizing mechanism involved, polar groups are far better barriers to coalescence than their non-polar counterparts. It is thus possible to see why O/W emulsions can be made with greater than 50% disperse phase, and W/O emulsions are limited in this respect and invert (change type) if the amount of water present is significant. VI- Detergents These are surfactants used to remove the dirt. The process of detergency is complex. It includes many of the action of surfactants: 1- Initial wetting of the dirt and of the surface to be cleaned. 2- Deflocculation and Suspension of dirt materials. 3- Emulsification or solubilization of the dirt particles. VII- Antibacterial Activity: SAA can exert antimicrobial activity by two mechanisms: 1.They may have antimicrobial activity by themselves. Quaternary ammonium compounds are adsorbed on the cell surface and increase the permeability or leakiness of the lipid cell membrane leading to cell lyses death due to loss of essential materials from the cell. 2.Surfactants may increase the activity of other Antibacterial compounds by increasing their penetration through the cell membrane. SAA reduces the interfacial tension between the liquid phase containing the antibacterial compounds and the cell wall of the organism. Application of adsorption in pharmacy and allied fields The adsorption phenomena at a solid interface deals with many applications such as: 1- Decolorizing agents Using charcoal to remove traces coloured impurities from solutions 2- Desiccants and drying agents Using of alumina and silica gel to remove a trace of moisture from organic solvents or compounds. 3- Adsorption chromatography A separation technique depends on the difference in affinity of an adsorbent for various solutes. 4- Ion exchangers A removal of ions from some solutions depending on the affinity of some adsorbents to some ions, such as removal of Mg and Ca from hard water. 5- Medical adsorbents Antidotes in oral intoxication by oral administration of charcoal for adsorption & removal of toxins e. g. atropine and strychnine. 6. Fixation of volatile oils on the surface of a solid of large surface area for keeping permanent smell of product. 7- Measurement of powder particle size through measuring the surface area per fixed volume. 8- Wetting agents  ‫الحمد لله‬ First slide heading Point 1 ‫رب‬ Point Point Point 2 3 4 ‫العالمين‬