Pharmaceutical Dosage Forms-1 PDF

TEXT BOOKS:  Martin's Physical Pharmacy and Pharmaceutical Sciences Classification of dispersed systems on the :Physical Chemical and Biopharmaceutical Principles in the Pharmaceutical Sciences by Martin, Alfred N. Sinko, Patrick J....

TEXT BOOKS:  Martin's Physical Pharmacy and Pharmaceutical Sciences Classification of dispersed systems on the :Physical Chemical and Biopharmaceutical Principles in the Pharmaceutical Sciences by Martin, Alfred N. Sinko, Patrick J. basis of particle size:  Aulton's Pharmaceutics : the Design and Manufacture of 1. Molecular dispersions Medicines by Michael E. Aulton (Editor); Kevin M. G. Taylor 2. Colloidal dispersions  Introduction to Pharmaceutical Dosage Forms “by Howard Ansel” 3. Coarse dispersions.  Pharmaceutical Calculations; The Pharmacist s Handbook  Pharmaceutical Dosage forms and Drug Delivery Systems  Pharmaceutical Dosage Forms; Disperse System  Comprehensive Pharmacy Review Disperse Systems Pharmaceutical Dosage Forms-1 The term "Disperse System" Course Title Course Lecture Practical Total Periodic Practical Final Oral Total Exam code Exam Time refers to a system in which one Pharmaceutical PT 303 2 1 3 20 40 75 15 150 2 substance (the dispersed phase) Dosage Forms - 1 is distributed, in discrete units, throughout a second substance (the continuous phase or 1-colloids vehicle). 2-Suspensions Each phase can exist in solid, liquid, or gaseous state. 3-Emulsions  B- Colloidal dispersion (Sol): TABLE 1. Classification of Dispersed Systems on the Basis of Particle Size 1- 1 mµ to 0.5 µ (I mµ to 500 mµ). Class Range of Particle Size Characteristics of System Examples 2- Particles are not resolved by ordinary microscope Molecular Less than 1.0 nm 1 nm (nanometer) = 10-9 m 1. Particles invisible in electron Oxygen molecules, dispersion microscope ordinary ions, although they may be detected under the 2. pass through ultra filter and glucose ultramicroscope; visible in the electron microscope; semi permeable membrane; 3. undergo rapid diffusion. 3- Pass through filter paper but do not pass through Colloidal dispersion 1 nm to 0.5 µm 1. Particles are not resolved by ordinary microscope Colloidal silver sols, natural and synthetic 1µm (micrometer) = 10-6 m semipermeable membrane; 2. they may be detected under polymers the ultra-microscope 4-Particles made to settle by centrifugation 3. visible in the electron microscope 5- Diffuse very slowly. 4. pass through filter paper but do not pass semi permeable membrane; diffuse very slowly. Example: colloidal silver sols, natural and synthetic Coarse Greater than 0.5 µm 1. Particles visible under micro- Grains of sand, most polymers. Dispersion scope; 2. do not pass through normal pharmaceutical emulsions and filter paper or dialyze through suspensions, red semi permeable membrane blood cells 3. particles do not diffuse. A- Molecular dispersions: C- Coarse dispersion: 1- Less than I mµ (nm). 1-Greater than 0.5 µ (500 mµ). 2- Particles invisible in electron microscope; 2-Particles visible under microscope 3-Pass through ultrafilter and semipermeable membrane. 3-Do not pass through normal filter paper or dialyze 4-Particles do not settle down on standing through semipermeable membrane 5- Undergo rapid diffusion. 4-Particles settle down under gravity Examples; Oxygen molecules, ordinary ions, glucose 5-Particles do not diffuse. Examples, grains of sand, red blood cells, most pharmaceutical emulsions and suspensions.  Size and shape of colloidal particles: COLLOIDS Particles lying in the colloidal size range The first colloids studied were gelatins and glues, possess a surface area that is enormous and so Thomas Graham (British chemist often compared with the surface area of an equal volume of large particles. referred to as “The father of colloid chemistry) used the Greek word kolla, meaning glue, as the Thus, a cube having a 1-cm edge and a volume of 1 cm3 has a total surface area of 6 cm2. root for his newly coined term. If the same cube is subdivided into smaller cubes each having an edge of 100 mμ, the  Colloid is short synonym for colloidal system. total volume remains the same, but the total  The heterogeneous biphasic system surface area increases to 600,000 cm2. This represents a 105-fold increase in surface area.  The color of colloidal dispersions is related to the size of the The shape of colloidal particles in dispersion is particles present. Thus, the colour of finest gold sol is red. Increasing the size of particles of gold, it becomes purple, important: then colour becomes blue and finally the colour we observed  The more extended the particle the greater its for gold is golden yellow. specific surface the greater the attractive force Antimony and arsenic trisulphides change from red to yellow as the particle size is reduced from that of a coarse powder to between the particles of the dispersed phase that within the colloidal size range. and the dispersion medium.  Flow, sedimentation and osmotic pressure of the colloidal system affected by the shape of colloidal particles. Shape of colloidal systems The possession of a large specific surface area Many colloidal systems, including emulsions, liquid aerosols and results in many of the unique properties of most dilute micellar solutions, contain spherical particles, colloidal dispersions. Small deviations from sphericity are often treated using ellipsoidal models. For example: High molecular weight polymers and naturally occurring Platinum is effective as a catalyst when in the macromolecules often form random coils in aqueous solution. colloidal form as platinum black. This is Clay suspensions are examples of systems containing plate-like particles because catalyst acts by adsorbing the reactants onto their surface. Pharmaceutical Applications of Colloids: I-Certain medicinal have been found to possess  Other synthetic polymers are applied as unusual or increased therapeutic properties coating to solid dosage forms to protect drugs when formulated in the colloidal state. that are susceptible to atmospheric moisture  Colloidal silver chloride, silver iodide and silver or degradation under the acid condition of the protein are effective germicides and donot cause stomach. irritation that is characteristic of ionic silver salts.  Coarsely powdered sulfur is poorly absorbed  Colloidal electrolytes (surface active agents) when administered orally, yet the same dose of are sometimes used to increase the solubility, colloidal sulfur may be absorbed so completely as stability and taste of certain compounds in to cause a toxic reaction and even death. aqueous and oily pharmaceutical preparations.  Colloidal copper has been used in treatment of cancer, colloidal gold as a diagnostic agent for paresis and colloidal mercury for syphilis. II- Many natural and synthetic polymers are  Particle shape may also influence the important in contemporary pharmaceutical pharmacologic action. practice.  Cromoglycic acid, an agent by inhalation to  Proteins are important natural colloids and are control asthmatic attacks was found to be found in the body as components of muscle, suitably deposited in the respiratory tract bone and skin. when prepared as well formed rod-shaped  Naturally occurring plant macromolecules such crystals as starch and cellulose that are used as pharmaceutical adjuncts are capable of existing in the colloidal state.  Hydroxyethyl starch is a macromolecule used as plasma substitute. Types of Colloidal Systems:  Viscosity of the dispersion medium ordinarily is Based on the nature of the interaction between the increased greatly by the presence of the dispersed dispersion medium and the dispersed phase phase. The dispersed phase of a colloidal dispersion may be  At sufficiently high concentrations, the sol may classified as being either lyophilic (solvent-loving) or become a gel. lyophobic (solvent-hating) and association.  Viscosity and gel formation are related to  Lyophilic colloids solvation effect and to the shape of the molecules which are usually highly asymmetric.  Association (amphiphilic) colloids  Dispersions are stable generally in presence of  Lyophobic colloids electrolytes. They may be salted out by high If the solvent is water, these classifications are concentrations of very soluble electrolytes. Effect termed as hydrophilic and hydrophobic, respectively. is due primarily to desolvation of lyophilic molecules. Absorption--- As colloidal dimensions are LYOPHILIC COLLOIDS small enough, they have a huge surface area.  Dispersed phase consists generally of large Hence, the drug constituted colloidal form is organic molecules lying with colloidal size released in large amount. e.g- sulphur colloid range. gives a large quantity of sulphur and this often leads to sulphur toxicity  Molecules of the dispersed phase are solvated i.e; they are associated with the molecules Targeted Drug Delivery--- Liposomes are of comprising the dispersion medium. colloidal dimensions and are preferentially taken up by the liver and spleen.  Molecules dispersed spontaneously to form colloidal solution.  Viscosity of the system increases as the LYOPHOBIC COLLOIDS: concentration of the amphiphile increases as micelles increase in number and become  Dispersed phase ordinarily consists of asymmetric inorganic particles such as gold or silver.  In aqueous solutions, the critical micelle  Little, if any, interaction (solvation) occurs concentration is reduced by the addition of between particles and dispersion medium. electrolyte. Salting out may occur at higher  Material does not disperse spontaneously and salt concentrations special procedures therefore must be adopted to produce colloidal dispersion. ASSOCIATION (AMPHIPHILIC) COLLOIDS  Dispersed phases consist of aggregates (micelles) of small organic molecules or ions whose size individually is below the colloidal range.  Hydrophilic or lipophilic portion of the molecule is solvated, depending on whether the dispersion medium is aqueous or nonaqueous.  Colloidal aggregates are formed spontaneously when the concentration of amphiphile exceeds the critical micelle concentration (cmc).  Comparison of Properties of Colloidal Sols Lyophilic Association (Amphiphillc) Lyophobic Types of colloidal dispersion Dispersed phase consists Dispersed phase consists Dispersed phase Colloids can be made from almost any generally of large organic of aggregates (micelles) consists of inorganic molecules lying within colloidal size range. of small molecules or organic particles such, as gold or silver. combination of gas, liquid, and solid. The ions whose size individually is below the particles of which the colloid is made are colloidal range, Molecules of the dispersed Hydrophilic or lipophific Very little called the dispersed material. phase are solvated, i-e., they are portion of the molecule is associated with the molecules comprising the dispersion medium solvated, depending on whether, the dispersion Colloids are classified on the basis of medium is aqueous or non-aqueous. the dispersed phase and the dispersion medium Molecules disperse spontaneously Colloidal aggregates are Material does not to form Colloidal solution formed spontaneously disperse, when concentration of spontaneously, and, amphiphlie exceeds the therefore, special critical micelle procedures must be concentration (c m c) adopted to produce colloidal dispersion. Lyophilic Association Lyophobic (Amphiphillc) Viscosity of the dispersion Viscosity of the system Viscosity, of the,  Viscosity of the dispersion medium is not medium is increased greatly by the presence of the increases as the concentration dispersion medium is not greatly greatly increased by the presence of dispersed phase. At sufficiently high of the amphiphile increases; as micelles increased ,by the presence of hydrophobic colloidal particles which tend to concentrations, the sol may becomes a gel. Viscosity and increase in number. lyophobic colloidal particles, which tend be unsolvated and symmetric. gel formation are related to solvation effects and to the to, be unsolvated and symmetrical. shape of the molecules,  Lyophobic dispersions are unstable in the which are usually highly asymmetric. presence of even small concentration of Dispersions are stable In aqueous solutions, Lyophobic electrolytes. Effect is due to neutralization of generally in the presence of electrolytes. They may be CMC is reduced' by the addition of electrolytes. dispersions are unstable in the the charge on the particles. Lyophilic colloids salted out by high concentrations of very Salting-out may occur at higher salt presence of even small exert a protective effect. soluble electrolytes. The effect is due primarily to de- concentrations, concentrations of electrolytes. Effect salvation of Iyophilic is due to molecules, neutralization of the charge on the particles. Physical Properties of Colloids Colligative properties Heterogeneous nature The properties of a solution are determined Colloidal solutions are inherently by the number of solute particles present, heterogeneous. It is made up of a dispersed regardless of the identity or nature of the phase and a dispersion medium. solute particle, i.e., shape, size, charge, and so Visibility on. Colloidal particles are too small to be seen Colloidal particles are more substantial with the naked eye, but when viewed through aggregates. In comparison to a true solution, an ultramicroscope, they appear as dark spots the number of particles per unit volume in a against a dark background due to light colloidal solution is small. scattering caused by them. Filterbility Because the size of the solute particles is smaller than the pores of the filter paper, they pass through easily. Colloidal particles, on the other hand, cannot pass through the animal membrane, parchment paper, or ultrafilters. Surface tension and Viscosity Surface tension and viscosity of lyophobic sols are similar to those of the dispersion medium. Lyophilic sols, on the other hand, have higher viscosity and lower surface tension than the dispersion medium. Preparation of Colloids I- Lyophilic Colloids The affinity of lyophilic colloids for the dispersion medium leads to the spontaneous formation of colloidal dispersion. Lyophilic colloidal sols are usually obtained simply by dissolving the material in the solvent being used. For example, acacia, tragacanth, methylcellulose and certain other cellulose derivatives disperse in water. This simple method of dispersion is a general one for the formation of colloids. As with lyopliilic sols, formation of association colloids is spontaneous, provided that the concentration of the amphiphile in solution exceeds the CMC. Because colloidal particles are typically associated, the number of particles in the II-Lyophobic colloids solution decreases as a result of association, as In contrast to lyophilic colloids, it is necessary does the colligative property. As a result, given to employ special methods to prepare an equal concentration of the true solution and lyophobic colloids. colloidal solution, the latter's colligative values These are will be less than the former's. (a) Dispersion methods, in which coarse particle are reduced in size. (b) Condensation methods, in which materials of subcolloidal dimensions are caused to aggregate into particles lying within the colloidal size range. 3-Colloid mill: Chemical reaction Milling and grinding processes may be used although the efficiency is low. Colloidal silver iodide may be obtained by So-called colloid mills, in which the material is reacting dilute solutions of silver nitrate and sheared between two rapidly rotating plates set potassium iodide close together, reduce only a small proportion of the total particles to the colloidal size range. Colloidal sulphur is produced from sodium thiosulphate and hydrochloric acid solutions Colloidal hydrated ferric oxide is produced from boiling ferric chloride with an excess of water. (a) Dispersion methods: (b) Condensation methods: 1-Ultrasonic generator: Change in solvent: Dispersion may be achieved by the use of high, intensity ultrasonic generators operating at frequencies in excess of The required conditions for the formation of 20,000 cycles per second. lyophobic colloids by condensation or 2-Electric arc: (Bridge‘s arc method) aggregation involve a high degree of initial A second dispersion method involves the production of an supersaturation followed by the formation electric arc within, a liquid. Owing to the intense heat generated by the arc, some of the metal of the electrodes and growth of nuclei. is dispersed as vapor, which condenses to form colloidal particles. Supersaturation may be brought about by change in solvent or reduction in temperature. For example, if saturated solution of sulphur in acetone is poured slowly into hot water, the acetone vaporizes leaving a colloidal dispersion of sulphur.  The most important use of dialysis is the purification At equilibrium, the colloidal material is retained in compartment A, whereas the sub-colloidal material is of blood in artificial kidney machines. distributed equally on both sides of the membrane.. Thus, ions and small molecules pass readily from By continually removing the liquid in compartment-B, it is the blood, through a natural semipermeable possible to obtain colloidal material in compartment-A which membrane, to the tissue fluids; the colloidal is free from sub-colloidal contaminants components of the blood remain within the capillary system. Purification of colloidal dispersions Because of their size, colloidal particles can be The process of dialysis may be hastened by: separated from molecular particles with 1. Stirring: relative ease. to maintain a high concentration gradient of diffusible The technique of separation, known as molecules across the membrane and dialysis, uses a semipermeable membrane of 2. By renewing the outer liquid from time to time. collodion or cellophane, the pore size of which 3. Ultrafiltration: By applying pressure (or suction) will prevent the passage of colloidal particles, the solvent and small particles may be forced across a yet permit small molecules and ions, such as membrane but the larger colloidal particles are retained. urea, glucose, and sodium chloride, to pass 4.Electrodialysis: Movement of ions across the through. membrane can be speeded up by applying an electric current through the electrodes induced in the solution.  1. Brownian motion ; Properties of colloids: - is the random zigzag motion of particles that A- Kinetic properties. can be seen under a microscope. The motion is caused by the collision of molecules with B- Optical properties. colloid particles in the dispersing medium. C- Electrical properties. Electrodialysis is the applied potential between A) Kinetic properties the metal screens supporting the membranes speeds up the migration of small ions to the Several properties of colloidal systems that membrane surface prior to their diffusion to the relate to the motion of particles with respect outer liquid. to the dispersion medium. The motion may be thermally induced (Brownian movement, diffusion, osmosis), gravitationally induced (sedimentation), or applied externally (viscosity). Electrodialysis  According to Fick's first law, the amount, dq, of substance diffusing in time, dt, across a plane of It is unaffected by the nature of the colliding area, S, is directly proportional to the change of particles but is affected by their size and the concentration, dc, with distance traveled, dx. viscosity of the solution. The smaller the particle size, the lower the viscosity and the faster the particle movement. Where dq/dt is diffusion rate Increasing the viscosity of dispersion medium D is the diffusion coefficient decreases and then stop Brownian motion. S is the area of diffusion At higher temperatures, the motion becomes dc/dx is the concentration gradient more intense. The minus sign denotes that diffusion takes place in the direction of decreasing concentration. The Brownian movement was named after Robert Brown, who first observed this type of motion. 2. Diffusion: The erratic motion, which may be observed Particles diffuse spontaneously from a region with particles as large as about 5 μm of higher concentration to one of lower The unbalanced bombardment of particles by concentration until the concentration of the the molecules of the dispersion medium system is uniform throughout. causes the Brownian movement. Diffusion is a direct result of Brownian The Brownian movement has a stirring effect movement. that keeps particles from settling and is thus responsible for sol stability.  Replacing c with cg/M in equation, in which cg is At small particle size (less than 0.5 um) the grams of solute per liter of solution and M is Brownian motion is significant & tend to the molecular weight, we obtain prevent sedimentation due to gravity & promote mixing in stead The equation is valid for very dilute solutions in so, we use an ultracentrifuge which provide which the molecules do not interact mutually. stronger force so promote sedimentation in Osmotic pressure is inversely proportional to a measurable manner. molecular weight; so that the pressures observed for say, proteins of molecular weight 5000 will be very low. 3. Sedimentation 4- Osmotic pressure: The method is based on van't Hoff's law, according to This is influenced by gravitational force, applicable for which the osmotic pressure p depends on molar particle size > 0.5 μm. concentration of the solute and on temperature. This The velocity V of sedimentation of spherical particles is shown following equation, where: is given by Π = CRT Π = osmotic pressure Stoke’s law; C = molarity = moles ÷ volume(L) – V = 2r2 g ( ρ - ρo) / 9 ηo R = ideal gas constant – v : velocity of sedimentation of spherical particles. T = temperature (K) – r : the radius of particle – ρ : density of the spherical particles. – ρo : density of the medium. – ηo: viscosity of the medium. – g : acceleration due to gravity.  B- Optical properties: 1- Light scattering (Tyndall effect): When a beam of light passed through the colloidal sol, the path of light is illuminated (a visible cone formed) due to the scattering of the light by the colloidal particles, this phenomenon is known as Faraday- Tyndall effect. Light scattering measurements are of great value for estimating of Particle size, Shape and Molecular weight of colloidal particles 5. Viscosity Viscosity is an expression of the resistance to flow of a system under an applied stress. The more viscous a liquid is, the greater is the applied force required to make it flow at a particular rate. The shapes of particles of the disperse phase affect the viscosity of colloidal dispersions. Spherocolloids form dispersions of relatively low viscosity, whereas systems containing linear particles are more viscous.  For particles less than 0.1 m in diameter which are too small to be truly resolved by the light microscope, Electron Microscope under the ultramicroscope, they look like stars in the dark sky. Their differences in size are indicated by differences in brightness. Electron microscope: 2- Ultramicroscope: - Ultra-microscope has declined in recent years as it Colloidal particles are too small to be seen with an does not able to resolve lyophilic colloids. optical microscope. - Electron microscope is capable of yielding pictures Light scattering is made use of in the ultramicroscope of actual particles size, shape and structure of first developed by Zsigmondy, in which cell colloidal particles. containing the colloid is viewed against a dark background at right angles to an intense beam of - Electron microscope has high resolving power, as its incident light. radiation source is a beam of high energy electrons, The particles, which exhibit Brownian motion, while that of optical microscope is visible light. appear as spots of light against the dark background. The ultramicroscope is used in the technicque of microelectrophoresis for measuring particle charge. Nernst and Zeta Potentials. The movement of a charged surface with The potential at the solid surface, due to the potential- respect to the adjacent liquid phase is the basic determining ion, is the electrothermodynamic (Nernst) potential, E, principle underlying four electrokinetic phenomena : Nernst potential, is defined as the difference in potential between the actual surface and the electroneutral region of Electrophoresis the solution. Electroosmosis The potential located at the shear plane is known as the Sedimentation Potential electrokinetic, or zeta, potential, ζ. Streaming Potential The zeta potential is defined as the difference in potential between the surface of the tightly bound layer (shear plane) and the electroneutral region of the solution. Electric Properties Of Colloids: Zeta potential has practical application in the The particles of a colloidal solution are electrically stability of systems containing dispersed particles charged and carry the same type of charge, either since this potential, rather than the Nernst potential, negative or positive. governs the degree of repulsion between adjacent, The colloidal particles therefore repel each other and similarly charged, dispersed particles. If the zeta do not cluster together to settle down. The charge potential is reduced below a certain value (which on colloidal particles arises because of the depends on the particular system being used), the dissociation of the molecular electrolyte on the attractive forces exceeds the repulsive forces and the surface. particles comes together. This phenomenon is known as flocculation  Electro-osmosis Two main mechanisms for colloid This is essentially the opposite of stabilization: electrophoresis. 1-Steric stabilization i.e. surrounding each In electro-osmosis, the dispersion medium particle with a protective solvent sheath (either a liquid or a gas) moves under the which prevent adherence due to Brownian influence of an electric field, while the movement colloidal particles remain stationary. 2-electrostatic stabilization i.e. providing the This phenomenon can be utilized to measure particles with electric charge the zeta potential, a parameter related to the stability and size of the particle. Electrophoresis Stability of colloids If an electric potential is applied to a colloid, Stabilization serves to prevent colloids from the charged colloidal particles move toward aggregation. the oppositely charged electrode. The presence and magnitude, or absence of a This is known as electrophoresis and may be charge on a colloidal particle is an important used to separate a mixture of colloidal factor in the stability of colloids. substances such as proteins. The charge of the particles can be determined by observing the buildup near the electrodes. If the particles are gathered near a positive electrode, their charge is negative, and vice versa.  2- addition of less polar solvent - e.g. alcohol, acetone - Coagulation also result from mixing of - The addition of less polar solvent renders the oppositely charged colloids. solvent mixture unfavourable for the colloids B- Lyophilic sols and association colloids: solubility - Stable ** Coacervation: - Present as true solution Definition: the process of mixing negatively and - Addition of moderate amounts of electrolytes positively charged hydrophilic colloids, and not cause coagulation (opposite lyophobic) hence the particles separate from the dispersion to form a layer rich in the colloidal aggregates (coacervate) A- Lyophobic sols: Salting out: - Unstable. Definition: agglomeration and precipitation of lyophilic - The particles stabilized only by the presence of colloids. electrical charges on their surfaces through the This is obtained by: addition of small amount of electrolytes. 1- Addition of large amounts of electrolytes - The like charges produce repulsion which prevent - Anions arranged in a decreasing order of coagulation of the particles and subsequent settling. precipitating power: citrate > tartrate > sulfate > - Addition of electrolytes beyond necessary for acetate > chloride> nitrate > bromide > iodide maximum stability results in accumulation of - The precipitation power is directly related to the opposite ions and decrease zeta potential hydration of the ion and its ability to separate water coagulation precipitation of colloids. molecules from colloidal particles  The hydrophilic colloid shields the hydrophobic system from the destabilizing effects of electrolytes; thus the hydrophilic substance is called a "protective colloid". Stability of such a system is enhanced, because in order to precipitate the hydrophobic colloid, both the protective solvent sheath surrounding it and the electric charge must be removed. Gelatin and methylcellulose derivatives are commonly used as protective colloids. Protection: When we need to remove colloids to from The addition of large amount of hydrophilic dispersing media. This accomplished by: colloid (protective colloid) to a hydrophobic colloid tend to stabilize the system. Heating – increased molecular motion leads The addition of a hydrophilic colloid to a to increased collisions and adhesion of particles, leading to coagulation and settling. hydrophobic one causes the hydrophilic colloid to adsorb onto and completely Adding electrolytes – the colloid particle charge is neutralized by the addition of surround the hydrophobic particles which soluble ionic compounds. then take on some of the properties of the Using semi-permeable membranes – ions pass hydrophilic colloid. through, particles do not. (dialysis) n-gl.com