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190 Cards in this Set
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Pharmaceutics II Focus |
On the design and development of various safe and stable dosage forms or drug delivery systems (tablets, capsules, solutions, suppository, modified release dosage form, etc.) - When a patient receives a medication, it is always administered through a dosage form or a drug delivery system |
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Principles used in Pharmaceutics II |
Physical pharmacy, various properties of solids and liquids, pre-formulation, zero and first order processes, pH, pKa and ionization, equilibrium solubility - Zero and First order processes - Physical-chemical stability of drugs and determination of expiration date - Surface phenomenon such as adsorption, hygroscopicity, surface tension and interfacial tension and their role in many dosage forms - Colligative properties (vapor pressure, freezing point, and osmotic pressure) and their role in dosage form and preparation of isotonic solutions, calculation of osmolarity, and mEq - Viscosity, various types of flow, and their importance in liquid dosage forms
-Emulsion: 2 phase system (water phase and oil phase) – surface tension and interface tension (we need active ingredient, like surface active agent, to reduce surface and interfacial tension) -Suspension: solubility is very important(if we have a drug that is too soluble, it cannot be made into a suspension) -pH, pKa,ionization: we relate it to solubility and absorption of drug (weak acidic drug or weak basic drug)-Linear kinetics: based on principles of first order process, and nonlinear kinetics is based on principles of zero order process -Stability can be predicted by Arrhenius equation based on temperature, and activation energy (activation energy vs.stability) – if activation energy of a drug is low, then we must refrigerate some products to help with stability -Expiration date is generally 2 years –all drugs have an expiration date -Hygroscopicity:ability of a compound to adsorb moisture (that’s why some bottles have desiccator to reduce amount of moisture adsorbed)
-0.9% NS has same freezing point and vapor pressure as body fluid (used when administered drug directly to blood) -Viscosity is important because the physical property of liquids such as emulsions, suspensions, and some ophthalmic products (viscosity is not very important for solutions, since they are clear liquids)
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Dosage Forms/Delivery Systems |
- Solid dosage forms - Liquid dosage forms - Semi-solid dosage forms - Transdermal drug delivery systems - Modified release dosage forms or controlled release dosage forms - Aerosol or Metered dose inhaler (MDI) - Parenteral or injectable dosage form -Transdermal systems: applied topically(not orally) – it’s a modified release dosage form -Physical chemical properties influencethe type of dosage forms that can be made from a particular therapeutic agent -Parenteral or injectable: sterilizationis important since they are administered directly to bloodstream |
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Solid Dosage Forms Categories |
- Conventional solid dosage forms ==> Powder ==> Conventional tablet (IR) ==> Hard and soft gelatin capsules - Modified release or controlled release dosage forms
-Modified release or controlled release: pt takes it less frequently, drug stays in therapeutic range for a longer period of time(ex. Wellbutrin XL and Wellbutrin SR are not interchangeable although they are both modified release forms of a drug but they possess different properties) -Particle size is important for: solid dosage forms, suspensions, topical dosage forms -- If we reduce the particle size, which properties will change? Angle of repose, flow, porosity, bulk density,compressibility (Carr’s index and Haussner’s index) -Oral disintegrating tablet needs special excipients that are different than regular tablet excipients -We made capsule dosage forms because of compressibility properties of a powder --If a powder doesn’t have sufficient compressibility, then we must make it as a capsule dosage form (it’s beneficial because there’s no disintegration – it’s already in powder form) -Soft gelatin capsules are used for oily materials (so whenever we use non-aqueous liquid, we can use soft gelatin capsule) (we cannot used soft gelatin capsules for aqueous liquid materials)
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Liquid Dosage Forms Categories |
- Solution (one phase): clear/transparent liquids - Suspension (two phases): powders are dispersed uniformly into a liquid medium - Emulsion (two phases): oil and aqueous phases are dispersed uniformly - Ophthalmic solution and suspension, elixir, tinctures, and lotions
-Preservatives are necessary to conserve the integrity of a liquid (or microbes will grow, especially in multiple dose vials) ---If we have an acidic product, then microbes will be unlikely to grow (they will start to grow in the pH range of 6,7 or higher) -Lotions are liquid dosage forms but are considered semi-solid dosage form because of the nature of it’s use
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Semi-Solid Dosage Forms |
- These dosage forms are between solid and liquid states - They are generally applied topically for their local or systemic effects - They include products like lotions, ointments, creams, gels, foams, and pastes - Suppository (rectal, vaginal, and urethral) - Transdermal products - Injectable - Inhalers or aerosols
-Pastes are most viscous of semi-solid dosage forms -We need suppository because of therapeutic agent (if made into oral dosage form, most of it will become metabolite once it passes the liver) -Bioavailability: extent (AUC) and rate(peak time and peak concentration) of absorption -Transdermal products: application of zero-order process (xmg per 24 hrs) –constant amount per unit time (drug is released from product at a constantrate)
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Additional Course Studies |
- Additives and/or excipients used in formulating a dosage form - Tests performed on these dosage forms assess their physical and chemical stability - When applicable, we will study the compendial (USP/NF) requirements for some dosage forms - Examine drug properties that preclude its formulation into certain type of dosage forms |
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Pharmaceutics II Lab |
Lab exercises in preparing: solutions, suspensions, emulsions, lotions, suppositories, powders, capsules, ointments, tablets, etc. Phenomenons: diffusion, adsorption, eutectic mixtures, viscosity, etc. Additionally: chemical stability of aspirin |
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Recap from Pharmaceutics I |
- Zero and First order processes - Properties of powders (particle size, true and bulk density, hydrophobicity, porosity, tortuosity, surface area and specific surface) - Partition coefficient - Pre-formulation - pH, pKa, ionization - Equilibrium solubility and methods of improving solubility - Stability and methods of improving stability - Drug dissolution and its factors, and importance of drug dissolution in bioavailability - Diffusion and Fick's law of diffusion -The smaller the powder the more irregularthey became, the higher the porosity, the lower the flow -Lipophilicity of atherapeutic agent is influenced by: molecular weight, substituent groups -Approaches utilized to improve aqueoussolubility of drug: co-solvent, suitable salt, pH of solution -Weak acidic drug: available in sodium orpotassium salt, and are more soluble at higher pH -Weak acidic drug: more unionized at lowpH, and better absorbed at lower pH |
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Disperse Systems |
Encompass a variety of heterogeneous, multiphase systems in which one homogeneous phase (dispersed or discontinuous or internal) is intimately distributed, in discrete units, within the second phase (dispersing or continuous or external)
Homogeneous:glycerin, water, alcohol (when each and every unit of a bigger system is looked under microscope and they are all the same) Heterogeneous:salad dressing, blood (one mL of suspension and analyze under microscope, it’s not the same as another 1 mL of the same suspension) Calcium carbonate is a homogenous system, water is the dispension medium (another homogenous system) => they’re available as discrete units in suspension -Same with acetaminophen -Solid phase that is dispersed is the discontinuous phase Suspension: solid insoluble in liquid vehicle Emulsion: liquid immiscible in liquid vehicle |
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Solutions |
Liquid preparations when the drug or AI is in a molecular form dissolved in the solvent system
- Solutions are NOT dispersions (solutions are homogenous systems - AI is dissolved and soluble in liquid medium - AI is in molecular form) |
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Two-Phase Systems (Dispersions) |
Liquid preparations when the drug or AI is undissolved, insoluble or immiscible and is distributed throughout the vehicle - Dispersed phase: AI or drug - Dispersing phase or medium: the vehicle - Dispersion: the above two phases together Dispersions are heterogenous systems (AI is NOT dissolved and/or NOT in molecular form) - Suspension: AI is insoluble - Emulsion: AI is immiscible ** Distributed throughout: if it's not distributed uniformly throughout, then the dispersion is not stable (distributed throughout is KEY to stability of suspension - it must be physically & chemically stable to act in patient's body) |
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Dispersion Classification Table |
Dispersed(internal) + dispersing(external) = type Gas + Gas = none Liquid + Gas = liquid aerosol Solid + Gas = solid aerosol Gas + Liquid = foam Liquid + Liquid = emulsion Solid + Liquid = suspension Gas + Solid = solid foam Liquid + Solid = solid emulsion Solid + Solid = solid suspension What would the dispersion look like when you mix different states of matter? |
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Dispersion Classification |
Based on particle size of the dispersed phase: Varied particle size-large visible particles to colloidal dimension
Successful and proper dispersions upon moderate agitation must result in a uniform and complete redistribution of the dispersed phase throughout the dispersion
Most popular method of classification used in pharmaceuticals: particle size of internal phase |
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Particle Size Classification: Coarse dispersions |
10-50µm, suspensions & emulsions - Greater tendency to separate from the dispensing medium - Suspensions: Denser than water, solids tend to settle down (caking) - Emulsions: Less dense than water, oils tend to float or cream (sign of instability) on top |
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Particle Size Classification: Fine dispersions |
0.5-10µm, magmas & gels |
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Particle Size Classification: Colloidal dispersions |
1nm-0.5µm |
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Other Classifications |
Lyophobic dispersions (solvent fearing) and lyophilic dispersions (solvent loving) - Lyophilic dispersions exhibit much greater stability than lyophobic systems (Lyophilic is more stable because it's solvent loving, so it disperses easier than lyophobic) (Lyophilic dispersions coexist and don't settle down or break into 2 phases - greater stability) Molecular dispersions and micellar dispersions - Units of dispersed phase composed of single macromolecules vs. micelles or association of several molecules (When you add surfactant in a higher concentration, the molecules of the surfactant gather together and form micelles (molecules)) Molecular dispersions are not dispersions, they are actually solutions. Micellar dispersions are not actually dispersions because they're present in molecular form |
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Principles of Surface Phenomena |
- Surface and interface - Surface tension and interfacial tension - Electrical properties at the interface - Surfactants - Wetting and contact angle |
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Surface and Interface |
The boundary between two homogenous phases is NOT to be regarded as a simple geometric plane, but as a film of a characteristic thickness -- vacuum/liquid ----- air/liquid A surface or an interface, which is defined as the boundary of separation of two phases, where a phase is a mass of substance (solid, liquid, or gas) that possesses a well-defined boundary When you have two phase systems, the two phases could be liquid-liquid, gas-liquid, gas-solid. The boundary is not a simple boundary. The molecules in the boundary are different than molecules on top layer of one of the states of matter - How do you define a boundary between one state of matter and another state of matter? In a suspension, the boundary between each solid particle and liquid medium is a interface In an emulsion, the boundary between the liquid phases is the interface |
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Interfaces Table |
Phases ------- Types of interfaces Gas-gas ---- no interface possible Gas-liquid --- liquid surface (e.g., water exposed to atmosphere) Gas-solid --- solid surface (e.g., table top) Liquid-liquid --- liquid-liquid interface (e.g., emulsion) Liquid-solid --- liquid-solid interface (e.g., suspensions) Solid-solid --- solid-solid interface (e.g., powder particles in contact with each other) |
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Surface and Interfacial Tension |
Molecules forming the surface behave differently from those in the bulk of each phase - Manifested in capillary action, wetting, adsorption, etc. The molecules on the surface are being pulled towards the inside of the liquid, so net force of molecules is towards the bulk. The molecules in the bulk are being pulled toward all directions, so net force is zero. But the molecules in the surface have force, so surface molecules possess some energy. Why do droplets of any liquid want to occupy a spherical shape? Because of surface tension But why a sphere? Because geometrically, a sphere has the lowest (minimum) surface area - The tension on the outside is called surface tension (word surface is used when a gas phase is present) -Word interface is used when liquid and solid phases are present (interfacial tension occurs between liquid-liquid(form droplets) or liquid-solid (caking)) – Molecules of AI stick together in the aqueous medium and form clump Surface are is larger when particle size decreases (when AI settles down and form aggregates). In order to reduce this,we need to decrease interfacial tension (surfactant). The surfactant binds to insoluble particles and also interacts with solvent medium If you have 3 phases and one of them is gas, it’s still interface |
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Surface Tension |
- Describes interface between liquid and gas - In the bulk of the phase, the binding forces between molecules are equivalent in all directions - On the surface, the molecules are subjected to intermolecular forces in the direction of the interface and towards the bulk - These above forces tend to decrease the surface (Water has highest surface are) Surface:liquid-gas or solid-gas The reason they’re being pulled towards the bulk is because the AI wants to occupy a spherical shape, so it decreases the surface area (decreasing the surface that is being exposed to another phase) |
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Surface Tension: Work |
- Work is required to bring molecules from the bulk to the surface - Surface tension or surface free energy per unit area is the amount of this work required to bring the molecules from the interior to the surface to expand by unit area -- W = γ*ΔA -- W: work in erg -- γ: surface tension in dyne/cm -- ΔA: increase in area in sq.cm When we bring molecules from bulk to surface (we decrease the particle size), we need work (energy) – we do this in suspensions When we reduce the particle size of AI, we increase the surface are (we are providing work) – This is expressed as: surface tension, surface free energy, interfacial tension, interfacial free energy |
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Interface vs. Surface Tension |
- Interface is used for all boundaries between any different states of matter (ex. emulsions) - Surface is used for boundaries between gas and other states of matter So what are we doing to the solid phase in the suspension? You reduce the particle size which increases surface area which brings the molecules from the bulk to the surface. That’s why you’re incorporating energy (with pestle, spatula – to reduce particle size) that work per unit area is your interfacial or surface tension. If it’s a suspension you reduce the particle sie and if it’s a emulsion you reduce the droplet size. |
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Cohesion Forces |
Forces of attraction between like molecules
- Water molecules stay intact as water because of cohesion forces between water molecules (same with air molecules, or CaCO3 molecules) Ex. - 2 liquid molecules - 2 solid molecules |
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Adhesion Forces |
Forces of attraction between unlike molecules - CaCO3 and H20 in suspension Ex. - Solid and liquid molecules (coexist in a suspension) |
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Interfacial Tension |
- Describes interface between two liquids or a solid and a liquid - Tension or excess energy is present at the interface between two condensed matters, e.g. liquid-liquid interface - Invariably interfacial tensions between two liquids are less than surface tensions and interfacial tensions between a solid and a liquid because the adhesive forces between the two liquid phases forming the interface are greater than when a liquid and a gas phase or a solid and a liquid exist together |
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Examples: Liquid A & B, and Solid A & Liquid B |
Ex 1. Liquid A (oil) is in contact (coexisting) with Liquid B (water). One liquid is immiscible (ex. emulsion) - Liquid A forces (by itself): cohesion forces - Liquid B forces (by itself): cohesion forces - But Liquid A is immiscible in Liquid B (they coexist), so forces are: adhesion forces Ex 2. Solid A and Liquid B (ex. suspension): 2 different states of matter - Unlike molecules True: Adhesive forces between a liquid in a liquid (emulsion) are stronger than the adhesive forces with a solid in a liquid (suspension). (greater forces: like molecules) - When adhesive forces are stronger, the tension is weaker. (In an emulsion, the adhesive forces are stronger than in a suspension so the adhesive forces cause the tension to be weaker in an emulsion.) True: Interfacial tension in a suspension is higher than interfacial tension in emulsion. (greater tension: unlike molecules) Why is there tension? Because 2 different liquids don’t want to coexist so in emulsions,the adhesive forces are stronger than a suspension. Adhesive forces are forces of attraction! So this lowers the tension in emulsions. When you add oil to water, the oil floats as one layer on top. When you reduce the droplet size of oil to tiny drops so that’s when you can make an emulsion.Providing energy(work)to a system so that’s when you’re making your dispersion to make states of matter coexist. Forces of adhesion are stronger within the same state of matter than compared with 2 different states of matter so that’s why forces of adhesion are stronger in an emulsion than in a suspension and interfacial tension is higher in a suspension than in an emulsion. |
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Interfacial Tension (Mathematically) |
- Interfacial tension is the force per unit length existing at the interface between two liquid immiscible phases or between solid and a liquid phase - Has the same units of surface tension; dyne/cm Mathematically: energy/sq.area OR force/unit length |
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Electrical Properties at the Interface |
- Influence of electrical charges on a surface is very important to the surface's physical chemistry - E.g. Aqueous suspensions are not only influenced by the interfacial properties but also by attraction and repulsion caused by electrostatic charges Interfacial tension is one of the important concepts we must understand to understand physical stability of dispersions. Internal face droplets in emulsions or particles floating in suspensions (uniformly dispersion). What makes them not aggregate in the first few mins? It’s because of the droplet or particles electrical properties. In addition to interfacial tension, the electrical properties of each particle in a susp or droplet in an emulsion from aggregating in the first few minutes. To understand physical stability of dispersions we need to understand interfacial tension and electrical properties because these keep particles and droplets away form each other. |
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Origin of Charge |
When a particle is dispersed in a surrounding liquid environment, as is the case with suspensions, the dispersed particles in the liquid may become charged - Ion adsorption - Ionization - Ion dissolution The net charge at the particle surface affects the ion distribution in the nearby region, increasing the concentration of counter-ions close to the surface An electrical double layer is formed in the region of the particle-liquid interface |
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Origin of Charge Example |
If we add a neutral molecule to water or any liquid, it can obtain a charge based on ion adsorption, ionization, or ion dissolution If we look at CaCO3 particle under a microscope and we assume that the particle is positively charged, CaCO3 can adsorb ions from water/liquid medium; or undergo ionization and get a charge (in this case a negative charge) - When a (+) charged drug particle is added to water (which contains both cations and anions), they will combine with the anions (-) of the water. (if you add a (-) charged drug, then it combines with cation of water) Counter-ions: the oppositely charged particles of the drug particles |
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The Electrical Double Layer |
The potential in the electrical double layer decreases with increasing distance from the surface until at sufficient distance, it reaches the bulk solution value (usually electro-neutrality) - This decrease is given that the zeta potential is the value at the surface of shear.
Stern Layer: layer that is tightly bound to the surface of the drug particle or the droplet - If you have a positive or a negative drug particle and add it to a liquid medium with both anions and cations, the counter-ions will be attracted and gather around the drug particle or droplet of the internal phase. - This layer of counter-ions is tightly bound to the surface of the drug particle and is called the stern layer. - The median of this layer is called the stern plane. - Whenever this drug particle is moving in the dispersion, it is not moving by itself because the layer of counter-ions is tightly bound, so it moves as one unit. So what is the new surface now? When you had your drug particles, that was the surface. As soon as you put it in the liquid medium, the new surface is the outside surface of the stern layer – also know as, the surface of shear or the new effective surface. - The new effective surface is what we want to learn about in a suspension – what keeps the particles in a suspension from aggregating together? This layer of counter ions (stern layer!) - The same type of stern layer is repelled (electrostatic repulsion). If the stern layer is positive, it will be repelled from another positive stern layer.
Let’s say you have 100 positive charges on the drug particle surface. In the stern layer, you can get maybe 90 negative charges (NEVER 100) – the number of counter ions is usually NEVER equal to the co-ions on the surface. In this case, the resulting charge would be +10 (100 positive, 90negative) - Because of your deficiency of counter-ions and the anions in the stern layer, you have the co-ions that are positively charged attracted to the stern layer. ALWAYS want to reach neutrality, so this is why this happens. - The diffuse layer is a layer of both counter-ions and co-ions. - Difference between diffuse and stern layer: stern layer is composed of ONLY counter ions; diffuse layer is BOTH counter and co-ions. Another big difference is the stern layer is tightly bound to the particle surface and the diffuse layer is loose and NOT bound to the particle surface so it doesn't move with the particle. Whenever the particle moves, it takes the stern layer along with it.
Electrical double layer theory: any time you put a solid in an external phase, the particle or droplet will obtain a charge by adsorption,dissolution, or ionization. - As soon as the droplet or particle is emerged in the liquid medium, a layer of counter ions is tightly bound to the surface (stern layer). The outside of the layer is called the sheet plane or surface of shear or new effective surface. - New effective surface: whenever the droplet or particle moves, it takes the tightly bound layer of counter ions. - As the distance is increasing away from the particle, it reaches the electro-neutralregion. |
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How do we get current? |
- Whenever there is a potential difference between the electro-neutral region and the actual particle surface - 100 co-ions/90 counter ions = +10 = potential difference = zeta potential |
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Why is zeta potential important? |
- Whenever the particles move, they don’t move by themselves – they move by counter ions. - The new surface is the surface of shear and the potential at the surface of shear is the zeta potential. - The potential on the surface of shear has the same sign (+ or -) as the particle on the particle surface. (positive particle = positive zeta potential) - The potential difference is at its max on the PARTICLE SURFACE (never greater than +100) - As you move away from the particle surface, the potential difference is decreasing and reaches 0 at the electro-neutral region. - The drop in potential is really fast when it's closer towards the particle and then it gradually slows down as you move away from the particle. |
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Potential Difference |
- The potential difference between the actual particle surface and the electro-neutral region is the electro-thermodynamic potential or Nernst potential - The difference between the shear plane and the electro-neutral region is the zeta potential or electro-kinetic potential - The potential difference drops rapidly adjacent to the particle surface and more gradually as the distance from the particle surface increases Zeta potential is the work required to bring a unit charge from infinity to the surface of the fixed layer |
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Zeta Potential |
- Zeta potential is the charge that develops at the interface between a solid surface and its liquid medium - This potential, which is measured in millivolts, is a.k.a. electro-kinetic potential - Controls the degree of repulsion between adjacent, similarly charged, dispersed particles - When attractive forces overcome the repulsive forces for adjacent molecules, the solid particles come together, resulting in aggregation (an indication of physical instability)
- In an electric field, each particle and its most closely associated ions move through the solution as a unit, and the potential at the surface of shear between this unit and the surrounding medium is known as the zeta potential. When a layer of macromolecules is adsorbed on the particle's surface, it shifts the shear plane further from the surface and alters the zeta potential.
- Zeta potential is therefore a function of the surface charge of the particle, any adsorbed layer at the interface, and the nature and composition of the surrounding suspension medium.It reflects the effective charge on the particles and is therefore related to the electrostatic repulsion between them, the zeta potential is extremely relevant to the practical study and control of stability and flocculation processes in suspensions. The higher the zeta potential, the stronger the electrostatic repulsive forces. When we want to enhance physical stability of dispersions must make sure zeta potential is optimal. Zeta potential = reason why there’s electrostatic repulsive forces Different particles or droplets – you have forces of BOTH attraction and repulsion. The dominant force is what determines the net force of interaction. Aggregates = surface area decreases.
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Surfactant |
- Surface active agents are commonly known as surfactants - They are a group of substances that, when present in low concentration in a system, adsorb onto the surfaces or interfaces of the system and alter to a marked degree the surface or interface free energies
How do we make sure the stability of dispersion is enhanced? The first excipient in dispersion is a surfactant (a surface active agent) Essential in any disperse system. (cleaning agents, used as solvents/co-solvents, in variety of dosage forms including tablets and capsules) their structure is the reason why they play this role. “Active on the surface – active at the interface.” Low concentration is key because we talked about micelles – at higher concentrations, the surface active agent gathers together and forms micelles. Lower concentrations – surface active agent each is adsorbed at interface.
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Surfactant Structure |
- They have two regions in their chemical structure: ==> Hydrophilic: can be an ion, polar or water soluble ==> Hydrophobic or lipophilic: hydrocarbon chain - They are amphiphilic, have an attraction to both aqueous and oil phases - Structural features are responsible for their action at the interface - The hydrophilic part (head group) is oriented towards the relatively hydrophilic phase and the lipophilic part (tail) will towards the relatively lipophilic phase
Hydrophilic– head group. Whatever the surfactant is, the hydrophilic group is ALWAYS the head group. Internal phase – insoluble in external phase (suspension). If it is soluble, it is a solution. Internal phase is hydrophobic in a suspension. To enhance stability, decrease tension so they don’t form aggregates. Adding a surface active agent in lower conc are adsorbed.
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Surfactant Classification |
Surfactants are classified with respect to their chemical composition (based on polar or hydrophilic group attached to it) BASED ON THE CHARGE OF THE POLAR GROUP (HEAD GROUP) |
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Surfactant Classification: Anionic |
- Head group is anionic. - Most commonly used, contain carboxylate, sulfonate and sulfate ions, surfactants with carboxylate ions are soaps. Are electrolytes; used as detergents, shampoos, body cleansers; have high foaming power |
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Surfactant Classification: Cationic |
- Head group has a positive ionic charge - Most of these detergents are derivatives of alkyl amines - Use is limited as antimicrobial preservative Are electrolytes; used as hair conditioners, fabric softeners, etc Not biodegradable (cationic/anionic) => not ionic is usually used because of this (Much safer) |
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Surfactant Classification: Nonjonic |
- Do not have any ionic groups (uncharged) - Nonionic surfactant commonly used have polyoxyethylene chains as the hydrophilic group NOT electrolytes, hydrophilic group does not dissociate |
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Contact Angle |
- The tendency of a liquid to spread is estimated from the magnitude of the contact angle formed, which is defined as the angle formed between the tangent drawn from the drop at the three phase interface and the solid surface over which is spreads
When solid drug particle is immersed (fully wet) in the liquid medium, this is when contact angle is low. If drug particle is floating, the contact angle is 180. Partially immersed, contact angle is 90. Completely immersed = contact angle is 0. Lower contact angle = more wetted solid drug particle is by liquid medium = more liquid is spread on surface. Oil and water – oil spreads evenly and water bubbles up. Contact angle of oil is lower than that of water. Surface active agents are adsorbed into interface (has both hydrophobic/philic properties) this is how the contact angle is lowered
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Wetting |
- Wetting of a solid particle in a liquid results from displacement of the air around the particle with the liquid it comes in contact with - For hydrophobic solids, a surfactant reduces the contact angle of the solid in water and increases wetting - The surfactant molecule is adsorbed on the surface of the solid, thereby losing the solid/water interfacial tension |
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Applications of Surfactants |
Surface active agents are used as co-solvents, the concentrations of surfactants is higher than when used as wetting agents.
Act as preservatives – able to disrupt the membrane of the bacteria or the fungus. Whenever anything is used in eye preparations- the conc of surfactants is much lower. |
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Why does a water droplet assume a spherical shape when places in oil? |
Spherical shape occupies least surface area. Particles are pulled towards the bulk. |
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The surface tension of oil is lower than that of water. Which of the two liquids will be easier to spread on a solid surface? |
The work that needs to be put in to bring a molecule from the bulk to the surface. Surface tension of oil is lower which means you need to put in less work to bring the molecules of oil from the bulk to the surface. Spreading = increasing surface are = bringing molecules from bulk to the surface So, it's easier to spread oil because of lower interfacial tension - Higher interfacial tension = harder to spread |
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What phase would the head group of a cationic surfactant be aligned towards, when added to an oil-in-water emulsion? |
Attracted to water - head group is hydrophilic regardless of charge |
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According to the electrical double layer theory, if negatively charged solid particles are formulated as a suspension dosage form, what charged ions would the stern layer be composed of? |
Stern layer: Counter-ions are cations (positive)
- Zeta potential would be negative |
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Rheology |
Rheology is the science describing the flow properties of liquids or the study of flow and viscosity affected by rate of flow - Rheology has been used extensively in the study of liquid and semisolids dosage forms, including cosmetics - Pharmaceutical applications: It is involved with mixing and flowing of product materials, their packaging into containers, and their removal prior to use that includes pouring from the bottle (solutions and suspensions), extrusion from the tube (paste), and passage through a syringe (solutions and suspension)
Any liquid preparation, be it solutions or dispersion or oral liquids or parenteral liquids, we need to understand the flow of these liquid preparations. In order for you to tell patients to shake or not shake something. VISCOSITY IS OPPOSITE TO FLOW (resistance to flow). If we have a liquid preparation that is viscous, we need to employ more energy to mix. What size containers to use for a liquid container? A narrow, a wide mouthed? Should we invert the molecule or incline it? (don’t pay attention to these questions) How much force should we put to extrude the paste or a gel from a tube?
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Newton's Law of Flow |
- Relates to parallel layers of liquids with the bottom layer fixed - Force on the top layer moves at constant velocity - Each layer below moves at a velocity, v directly proportional to its distance, r from the stationary layer below - Rate of flow or shear, G is the velocity gradient which is the difference of velocity, dv between two planes of liquid separated by distance, dr ------ G = dv/dr
Stress: force you apply perpendicularly. When you’re applying force in the direction of flow (force is applied towards the direction of flow) Two types of stress: - Sheer stress: force applied towards the direction of flow (when you want to pour something out of container, you tip it towards the direction of flow) – what is relevant here is shear stress (think of deck of cards) ==> The layer of fluid that is close to shear stress will move faster when compared to the layer of the ointment that is in the bottom (stationary layer) (top most layer will move faster) (the bottommost layer will move the least) ==> Rate of flow (G) is difference in velocity between the two layers ==> Dv is proportional to Dr (the farther the distance, the fastest ==> Velocity is directly proportional to distance. The greater the amount of shear stress,the faster the flow (G is proportional to F where F is shear stress and G is shear rate/rate of flow) - F is directly proportional to G. Normal stress: force applied perpendicular. Top layer takes second layer, which takes third layer, and bottom layer is stationary layer
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Stress: Shear vs. Normal |
Shearing stress, F is defined as a stress which is applied parallel or tangential to a liquid, as opposed to normal stress which is applied perpendicularly - It is the force applied to the top later that is required to result in flow - Newton suggested that the rate of shear (G) is directly proportional to the applied shear stress (F) ---------- F =nG (where n is the coefficient of viscosity) The more shear stress you apply, the fasted the fluid will flow |
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Viscosity (n) |
- The tenacity with which a moving layer of fluid drags adjacent layers of fluid determines its viscosity - Viscosity determines the internal friction of a moving fluid - The reciprocal of viscosity is fluidity ------ ϕ = 1/n A liquid with high viscosity resists motion because its molecular makeup gives it a lot of internal friction - Top layer drags second layer If viscosity increases, fluidity decreases If viscosity decreases, fluidity increases |
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Units of Viscosity |
- Shear Stress, F: dyne/cm2 or g/cm.s2 ==> dyne = g.cm/s2 - Rate of Flow, G: 1/s - Viscosity = F/G = g/cm.s = poise, P - Usually expressed in Centi poise, cP = poise/100 - A liquid has a viscosity of one poise when a shearing stress of 1 dyne/cm2 is needed to maintain a velocity of 1 cm/s between two parallel planes of liquid 1 cm apart |
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Classification: Newtonian Flow |
Follows Newton's law of flow - Characterized by constant viscosity regardless of change in shear rate, e.g., alcohol, water, glycerin, acetone F is proportional to G (linear relationship) - Even if water is flowing 100mm/s, or 1000mm/s (increase in shear rate), viscosity does not change (constant) - viscosity vs. shear stress graph would look the same - If you increase shear stress, rate of flow increases - No shear stress, no rate of flow - Slope of the F vs. G graph will give you viscosity (n - constant) - Any liquid that follows Newton's law of flow, where increase in shear stress will result in increased rate of flow is classified as Newtonian fluid |
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Classification: Non-Newtonial Flow |
- Emulsions, suspensions and semisolids have complex rheological behavior and thus do not obey Newton's law of flow - Thus they are called non-Newtonian liquids - They are further classified as under: ----- 1. Plastic flow - Bingham bodies ----- 2. Pseudo-plastic flow ----- 3. Dilatant flow |
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Non-Newtonial Flow: Plastic Flow |
- The substance initially behaves like an elastic body and fails to flow when less amount of stress is applied - Further increase in the stress leads to a nonlinear increase in the shear rate which then turns to linearity, e.g., suspensions, emulsions, ointments Plastic fluid follows Newton's law partially: - Not directly proportional (nonlinear) - You need to apply a minimum amount of shear stress in order for fluid to flow (yield value) (yield value is different for each plastic fluid) - Even after yield value is reached, the relationship is still not directly proportional initially (it will then become linear) - Yield value mathematically is when you extrapolate the linear portion of the curve to the y-axis (when the line becomes linear) Similarly: proportional to shear rate (but NOT directly proportional) Viscosity of plastic fluid is calculated by looking at the slope of the linear portion of the line (F vs. G) (Viscosity decreases initially, then it becomes constant) (Curve does not start from origin - because of yield value) |
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Plastic Viscosity |
The equation describing plastic flow is: ------ U = (F - f) / G - U is plastic viscosity - F is shear stress - f is yield value - G is rate of flow (shear rate) |
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Aplastic material was found to have a yield value of 5200 dyne.cm-2. At shearing stresses above the yieldvalue, f was found to increase linearly with G. If the rate of shear was 150 s-1 when F was 8000 dyne.cm-2, calculate U, the plastic viscosity ofthe sample. |
U = (F - f) / G U = (8000 - 5200) / 150 U = 18.67 poise |
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Non-Newtonian Flow: Pseudo-Plastic Flow |
Here the relationship between shear stress and shear rate is not linear and the curve starts from origin - Thus the viscosity of these liquids cannot be expressed by a single value. E.g., methyl cellulose in water, tragacanth in water - Shear thinners: viscosity decreases with shear rate Pseudo plastic (a.k.a. shear thinning fluid): starts from origin - Relationship between F and G is completely nonlinear - F and G are indirectly proportional to each other - As you apply shear stress, fluid is thinning (viscosity decreases) (rate of flow increases) - A good suspension medium or emulsion medium should be pseudo-plastic (at rest it's highly viscous, shear stress is zero) (as you increase shear stress, viscosity decreases) - Viscosity decreases, slope decreases (cannot calculate absolute viscosity - nonlinear relationship) "shear-thinning": viscosity decreasing |
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Non-Newtonian Flow: Dilatant Flow |
- In this type of liquids resistance to flow (viscosity increases with increase in shear rate) - When shear stress is applied their volume increases and hence they are called dilatant. This property is also known as shear thickening. E.g., >50% solid content suspensions As you apply shear stress, the viscosity increases (shear thickening) - F vs. G graph: starts at origin, relationship is completely nonlinear, viscosity increases with increased shear rate - Any paste or suspension with > 50% solid content behaves as a dilatant fluid (the more you rub, the whiter they become - you increase shear rate and viscosity increases) |
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Difference between Pseudo-plastic and Dilatant |
Both: nonlinear relationship Pseudo-plastic: when you increase shear stress, viscosity decreases (shear thinning) Dilatant: when you increase shear stress, viscosity increases (shear thickening) |
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Thixotropy |
When shear stress is reduced once the desired maximum rate is achieved, the down curve would not be identical/superimposed with the up curve, it will displace to the right of the up curve. Somefluids show a change in viscosity with respect to time, under constant shearrate: Thixotropic and rheopectic. Itwas assumed that if stress stress was reduced once the desired maximum rate wasachieved, the down curve would be identical/superimposed with the up curve.This is true with Newtonian systems. For thixotropic systems, the down curve isdisplaced with regards to the up curve. Thereis evident breakdown of structure which does not reform immediately when stressis removed or reduced. Astime passes by, viscosity will change. Similaritybetween thixotrophic and pseudo-plastic: both are shearthinning (as you increase shear stress, shear rate increases, viscositydecreases)- Both can be used as idealsuspending mediums Difference: thixotrophic down curve is not super imposable (doesnot follow the same number when we are decreasing). Pseudoplastic: As constant shear stress, whetherincreasing or decreasing, (at a given shear stress), the shear rate is the same Thixotrophy: Shear rate value depends on if shearstress is increasing or decreasing (more challenging measuring shear stress inthixotropic – because we cannot calculate the absolute viscosity at any givenshear stress value) Thixotrophy: upward and downward curve are NOT superimposable (they’re ever changing, we cannot calculate it) Ex. Vaccines (small amount of AIreleased at small intervals – prolonged periods of time)It’s time dependent- If you leave fluid sitting for t1amount of time, the curve will be different as opposed to if you leave thefluid sitting for t2 amount of time |
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Thixotrophy Definition |
- "An isothermal and comparatively slow recovery, on standing of a material, of a consistency lost through shearing" Viscosity is ever changing, it does not depend on shear stress, shear rate or time (it's never the same) - that's the challenge when handling this type of fluid Viscosity decreases as you apply shear stress (consistency is lost), at unchanging shear (with respect to time) viscosity will go back up |
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Thixotropy vs. Pseudo Plasty |
- A thixotropic fluid displays a decrease in viscosity over time a a constant shear rate. - A shear thinning/pseudo plastic fluid displays decrease in viscosity with increasing shear rate. - A thixotropic fluid displays decrease in viscosity at a constant shear stress or shear rate depending on whether the shear stress/shear rate is increasing or decreasing - A shear thinning/pseudo plastic fluid displays decrease in viscosity only with increase in shear stress or shear rate You have to change shear stress in order to change viscosity for thixotropic fluids. Pseudo-plastic: superimposable. Thixotropic: we need to know if F is increasing or decreasing because we have two different curves. At constant shear stress, viscosity decreases. |
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Antithixotropy |
- This phenomena is called rheopexy or antithixotropy; defined as "a comparatively slow fall, on standing of a material, of a consistency gained through shearing" No fluids used in healthcare that are antithixotropy - It's completely opposite of thixotropy |
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Effect of Temperature in Viscosity |
- Viscosity of Newtonian fluids decreases with increasing temperature - Relationship analogous to Arrhenius equation --- log n1/n2 = (Ea/2.303R)[(T2-T1)/T2*T1] - n is viscosity in poise or centipoise or stokes - Ea is activation energy in cal/mol or kcal/mol - R is gas constant 1.987cal/mol*K - T is absolute temperature in Kelvin Equation used to calculate viscosity of a fluid at a different temperature when viscosity is known at one temperature. For example, to calculate viscosity of plasma before administration at room temperature when viscosity of plasma is known at body temperature. Difference between this and other Arrhenius eq: viscosity and lack of negative sign. - Application: blood transfusions (it needs to be administered to patient at human temperature, so we need to calculate viscosity at body temperature in order to administer to patient). If you know viscosity at one temperature, you should be able to calculate the viscosity at a different temperature. (ONLY CONCEPTUAL HERE) |
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Erythromycin suspension (pseudo plastic) and Amoxicillin sodium solution (newtonian) for injection are both available in plastic bottles with narrow openings. Inverting these bottles causes both the fluids to flow but a different rates. Why? |
Because one is newtonian (viscosity is constant - linear fashion (even if you tilt the bottle, it's the same)), and the other is pseudo plastic (as you apply shear stress, you increase shear rate and viscosity decreases (non-linear fashion) |
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Dispersions: Suspension |
Insoluble, small to fine particles of solid dispersed phase uniformly suspended in the dispersing medium/phase - Coarse dispersion of finely divided solid particles in a liquid medium |
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Dispersions: Emulsion |
Immiscible, fine droplets of a liquid dispersed phase uniformly emulsified and dispersed in the dispersing phase/medium |
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Suspension Preparations |
Preparations containing finely divided drug particles (suspensoid) distributed somewhat uniformly throughout a vehicle in which the drug exhibits a minimum degree of solubility - Readily available Oral, Parenteral, topical, rectal suppositories - Dry powders "For Oral Suspensions" upon reconstitutions - Sustained release suspensions - Pennkinetic extended release suspension 'Somewhat' uniformly is used because suspensions are heterogeneous. The most common type of suspension for children: Tylenol Oral Suspension |
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Types of Suspensions |
- Oral suspension - Parenteral suspension - External suspension - Rectal suspension Lotions: mostly are suspensions. Creams: mostly are emulsions - Though there are some exceptions |
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Advantages of Suspensions |
- Easy to swallow - Flexible dose range - Higher bioavailability - Sustained release - Enhances stability (Procaine penicillin G) - Improved taste (Chloramphenicol, Erythromycin estolate) Why do we need to make a product which is a suspension? Easy to swallow (if it’s liquid preparation we can change the volume dispensed – so we can change the doses (flexible dose range)). As surface are increases, rate of dissolution increases, rate of absorption increases (bioavailability is higher). Sustained release: active in a longer period of time (pennkinetic extended release) the AI is released in the system at time intervals (so we don’t have to take med as often). Stability may be a concern: because it could undergo hydrolysis – so we make the AI insoluble (thus, it won’t undergo hydrolysis) in water and it can be suspended in water. We can improve taste: the external phase masks the AI (which has bitter taste) |
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Rationale: Why as Suspensions? |
- Drug unstable in solution but stable when suspended - Necessary in a convenient dosage form (infants & elderly) - Disagreeable taste - Rapid onset of action (NO disintegration step, greater bioavailability) E.g., Chloramphenicol synthesized as chloramphenicol palmitate for suspensions (Flavorants, sweeteners used as per patient's preference) There are several reasons for formulating a drug in the form of a suspension dosage form. First, some drugs are unstable in solution phase but stable in suspension. In this case, the suspension can assure stability while delivering drugs. Second, for many patients, liquid formulation is preferred over solid form of the same drug since it is easier to swallow. Also it would be easier to control the range of doses for a liquid dosage form rather than a solid dosage form such as tablets. Furthermore, a suspension helps improve the taste of some poor tasting drugs, because the dispersion medium can be flavored and sweetened. Some materials are required to be present in a finely divided form in the dosage form and their formulation as suspension will provide the desired high surface area.Alumina, Magnesia, Simethicone oral suspensions - Maalox, Mylanta, Sulfamethoxazole oral suspensions-Septra, Bactrim Amoxicillin - Amoxil, Ampicillin - Omnipen etc. Cholera, Diphtheria, Tetanus vaccines-dispersions composed of killed microorganism (toxoids) adsorbed onAl(OH)3. |
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Theory of Suspension |
- Comminution process results in generation of surface free energy that makes the system thermodynamically unstable ----- W or dG = ySL * dA - In order to approach a stable state, the system tends to reduce the surface free energy that may be achieved either by reduction of interfacial tension or by reduction of interfacial area Work is done to reduce a large solid material into small particles and disperse them in a continuous medium. The increase in work or surface free energy, W or dG brought about by dividing the solid into smaller particles and eventually increasing the total surface area, dA is given by the equation. As we decrease particle size, we increase surface area, that’s when we are providing energy to the system and making it unstable (any system wants to go back to Gibbs energy of 0) (for a system to be stable, the energy should be 0) - So in order to reach stability, the system needs to lose energy (it needs to go back to zero), it can do this by decreasing dA - We have to decrease surface tension (by using surfactant) |
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Desired Features: General |
1. Therapeutic efficacy 2. Chemical stability 2. Permanency (Physical stability) 4. Aesthetic appeal Chemical stability: If the drug is insoluble or poorly soluble in a suitable solvent, then formulation as a suspension is usually required. Degradation of drug in the presence of water may also lead to its formulation as a suspension.An insoluble derivative of the same compound is synthesized and is formulated as a suspension. If the AI is not stable in the dispersion medium (antibiotics), prolonged contact between the AI in the form of solid drug particles and the liquid vehicle is reduced by preparing the suspension immediately prior to issuing to the patient (reconstituted antibiotic suspension) |
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Desired Features: Physical Stability - Specific to Suspensions |
1. Small and uniform particle size over time 2. Uniform dispersion of the particles in the liquid vehicle (dispersion medium) 3. Slow rate of sedimentation or settling and easy and rapid re-dispersion upon agitation 4. Pour readily and evenly from the container In pharmaceutical suspension, the internal drug phase will separate upon storage; however the main aim of the formulator is to control the process of separation and in doing so to optimize the stability of the formulation. A suspension would be considered stable if after moderate agitation (shaking), the internal phase is uniformly dispersed for a sufficient amount of time to ensure that accurate dose be administered to the patient. - The dispersion on the internal phase or external phase should be uniform - When we increase viscosity, we need to keep pourability in mind |
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Physical Stability of Suspension: Improved by Controlling Sedimentation |
- Uniform particle size - Controlled flocculation - Altering dispersion medium ==> Viscosity modifying agents ==> Wetting agents As discussed before, suspensions are fundamentally unstable which leads to sedimentation, particle-particle interactions and ultimately caking. There are different ways to improve the physical stability of suspensions. Sedimentation: rate of settling -Particle size needs to be uniform -We would rather the sediment be loose rather than aggregate (so it’s easier to re-disperse) (controlling flocculation agent) -Dispersion medium |
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Causes of Sedimentation |
External forces acting on particles: - Gravity - Brownian Motion When we have solid particles which contain difference in density between liquid and solid, the 'heavier' (more dense) will be pulled to bottom of container due to gravity |
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Sedimentation and Stoke's Equation |
v = [d^2 (pi - pe)g] / 18n - v is rate of sedimentation - d is diameter of the particles - pi is density of the particles - pe is density of the medium - g is gravitational constant - n is viscosity of the medium Which of the parameters are directly proportional? - Rate of sedimentation will increase with increase in diameter of particles and density Which are indirectly proportional? - Rate of sedimentation will increase with decrease in viscosity |
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A powder has a density of 1.3g/mL and an average particle diameter of 2.5µg. What is sedimentation rate of these particles in water? Density of water is 1g/mL. Water viscosity is assumed as 1cP (0.01g/cm*s) |
v = [d^2 (pi - pe)g] / 18n v = [ (2.5*10-4)2(1.3-1.0)*980 ] / [18*0.01] v = 1.02*10^-4 cm/sec |
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Stoke's Law |
v, (dx/dt) = [ d^2 (pi - pe)g ] / 18n “v” is the terminal velocity of settling of the solid particles or rate of sedimentation in cm/s “d” is the diameter of the particle in cm “pi” and “pe” are the densities of the internal (solid) and external (liquid) phases respectively "g” is the acceleration due to gravity, cm/s2 “h” is the viscosity of the liquid phase or dispersion medium in poise Derived for an ideal suspension where, 1. Uniform and spherical particle size and shape 2. No turbulence or colliding of particles 3. No physical or chemical affinity with the medium - Does not apply precisely for pharmaceutical suspensions but indicates adjustments necessary to decrease rate of sedimentation thereby enhancing stability - Adjustments done to dispersed phase rather than dispersing phase It is apparent from the equationthat rate of settling can be reduced by: decreasing the particle size (diameter,d)provided the particles are kept in a deflocculated state, minimizing densitydifference between continuous and discontinuous phase,increasing the viscosity ogf thecontinuous phase. The first factorcan be achieved by communition bymilling, the second factor is not too practical, the third factor of increasingviscosity can be achieved by adding polymers like MC or CMC etc. Too much ortoo high a viscosity is undesirable as it affects the re-dispersibility and pourability ofthe suspension. We don’t have ideal pharmaceutical suspensions: -Particleswill collide with each other (no turbulence isnot possible) -Even if negligible, insoluble particlesdissolve in the liquid medium (so physical or chemical affinity occurs) |
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Controlling Sedimentation: Particle Size |
Uniform or narrow size range is desired - Size reduced prior to suspending in the vehicle (milling, comminution, pulverize, trituration - processes of reducing the particle size of a solid substance to a finer state of subdivisions) ==> Micropulverization: 10-50µm, oral & topical suspensions ==> Fluid energy milling, jet milling or micronization: <10µm, ophthalmic & parenteral suspensions ==> Spray drying: 1-200µm - Rate of sedimentation decreases with decrease in particle size, however very fine particles result in settling down to form a rigid layer at the bottom which resists uniform re-dispersion and forms rigid aggregates - Caking Lower particle size is necessaryfor lower rate of sedimentation and also to increase rate of dissolution andhence bioavailability. Particles of size larger than5microns will impart gritty nature to the suspension and may cause irritation ifinjected or instilled into the eye. Even though the particle size of a drug may be small when the suspension is manufactured or prepared extemporaneously, there is always a degree ofcrystal growth that occurs on storage, particularly if temperature fluctuation occur. This isbecause the solubility of the drug may increase as the temperature rises, but oncooling the drug will crystalize out. This is a problem with slightly soluble drugs such as paracetamol. -Micro:small particles -Fluidmilling: tiny particles -Spraydrying: range of particle size When you decrease particle size, rate of sedimentation decreases (BUT when youdecrease particle size, eventually it will be easier for particles to coagulatewhich will cause caking) – particle size needs to be optimal! Or caking willoccur |
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Particle Size Reduction |
- Pulverizer - Mortar and pestle |
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Controlling Sedimentation: Particle Shape |
Affects caking and hence stability E.g., CaCO3 - Barrel shaped particles more stable - Asymmetrical, needle shaped caked on standing, less stable Asymmetrical or needle shape: will cause caking. Barrel shaped: more stable - spherical |
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The Electric Double Layer |
The net charge at the particle surface affects the ion distribution in the nearby region, increasing the concentration of counter-ions close to the surface. Thus,an electrical double layer is formed in the region of the particle-liquid interface. This double layer consists of two parts: an inner region that includes ions bound relatively tightly to the surface, and an outer region where a balance of electrostatic forces and random thermal motion determines the ion distribution.The potential in this region, decreases with increasing distance from the surface until, at sufficient distance, it reaches the bulk solution value, usually electro-neutrality. This decrease is shown by the lower part of the figure and the indication is given that the zeta potential is the value at the surface of shear. - Zeta potential is more relevant when we talk about suspensions, emulsions. - Zeta potential is lower than Nernst potential (sign (+ or -) is the same) |
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Alternate Scenarios |
Electrical neutrality achieved at surface of shear - Zeta potential may be zero Number of counter-ions exceeds the number of adsorbed ions - Zeta potential may exhibit an opposite charge to that of Nernst potential Molecules (surfactants, electrolytes) may interact with the surface and alter the thickness of the double layer and the zeta potential As the concentration of electrolyte, ionic surfactant increases, the double layer is compressed and the zeta potential is decreased. This approach is used to stabilizesuspension by achieving controlled flocculation. - Ifyou have 100+ charges on surface ofparticles, sometimes the stern layer contains 100- counterions, so zeta will be zero - The number of counterions could be greater than the number ofparticles on the surface (110 counterions for 100 ions), so zeta will be negative(sign or zeta is different than Nernst) - Then we need to add flocculating agents- -If we add surfactant, it will be adsorbedin the stern layer Ex. If particle is 100+ charged, andstern layer is 80-, then zeta potential is +20. If we add surfactant to reduceinterfacial tension we are adding more anions to the liquid.Some of these ions are being adsorbed on stern layer. (so it went from 80- to90- on stern layer), so zeta potential went to +10. - As the potential is decreased, the degreeof repulsion is decreased - If zeta potential increases, therepulsion increases |
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DLVO Theory of Stability |
- The DLVO Theory is the classical explanation of the stability of solid particles in suspension - It looks at the balance between two opposing forces: electrostatic repulsion and van der Waals attraction Electrostatic repulsion becomes significant when two solid particles approach each other and their double layers begin to interfere. Energy is required to overcome this repulsion. An electrostatic repulsion curve is used to indicate the energy that must be overcome if the particles are to be forced together. It has a maximum value when they are almost touching and decreases to zero outside the double layer.The maximum energy is related to the surface potential and the zeta potential. Van der Waals attraction is actually the result of forces between individual molecules in each solid particle. An attractive energy curve is used to indicate the variation in van der Waals force with distance between the particles. Two net forces: attraction and repulsion - Which dominates the other will determine the state of interaction (net) |
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Flocculation |
Net force of attraction and repulsion Which force dominates the other force?At what distance is attraction dominating and where is repulsion dominating? Attraction:because of London forces and Van der Waals forces Repulsion: because of zeta potential Repulsion is + side of y axis Attraction is – side of y axis We are working towards keeping particles separate in a suspension (that’s the goal), that’s why repulsion is on + side(because that’s what we want to do) Green curve: energy of repulsion Red curve: energy of attraction Blue: net of interaction At closer distances, the attraction forces dominate (at distances closer to the drug particle) At median distances, the repulsion forces dominate At farther distances, the state of interaction is attraction -Look at depth, because we need to know degree of interaction (look at peaks)Which one is stronger? The one closer to the drug particle First blue box: attraction forces dominate (closer to drug particle) , this is called energy trap or primary minimum (when the second drug particle falls in this region, it is trapped) Second blue box: repulsive forces dominate , this is called energy barrier, primary maximum, Vmax(in median distances) (called energy barrier, because that region is keeping two particles from getting together) (called primary maximum because the height of this curve is Vmax) Third blue box: father distances,attraction forces dominate . This region is called secondary minimum, Vsec At close distances, attraction forces dominate (energy trap), at intermediate distances, repulsive forces dominate (only stage of repulsion – acts as barrier) (because of zeta potential– electrostatic repulsion), at farther distances, attractive forces dominate primary forces but at a lesser degree. Force of attraction is at a minimum when two particles are together, as you try to pull them away the force of attraction increases. At close distance, repulsive forces are stronger, as the distance increases the repulsive forces become weaker When we combine the two, we get the blue curve -First box, at close proximity,attractive forces dominate repulsive forces -At intermediate distance, repulsive forces dominate attractive forces (Vmax)-At a distance, attraction forces dominate again -Imagine that first particle is stationary and second particle is trying to move toward it. There’s energy in the particles,and the energy is called thermo-kinatic-energy. Each particle of internal phase has energy, that’s why there’s movement. Region 1 is attraction, region 2 is repulsion, and region 3 is attraction and we are putting a drug particle that also possesses some energy. If the thermo-kinetic energy of the drug particle is greater than Vsec and greater than Vmax,it will surpass those two peaks and reach energy trap (primary minimum), so now it’s trapped with drug particle (that’s what happens when caking occurs) 1) VmaxVsec --- Aggregation or coalescence (particle will reach other particle) (not ideal for stability) 2) Vmax=kT>Vsec - deflocculation (it will reside in primary maximum) –they are at intermedial distance but they are repelled to each other (each particle will settle down independently as discrete units, and eventually caking will result – the particles will fall down by themselves) (deflocculation: categorized by absence of floccules –each particle is away from each other but they’re away from each other) (notfavorable for stability of suspensions) 3) Vmax>kT=Vsec – controlled flocculation (easy to re-disperse upon moderate shaking, particles will settle down together) |
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DLVO Theory Explained |
The DLVO theory explains the tendency of solid particles to agglomerate or remain discrete by combining the van der Waals attraction curve with the electrostatic repulsion curve to form the net interaction energy curve. At each distance, the smaller value is subtracted from the larger to get the net energy. The net value is then plotted above if repulsive and below if attractive and a curve is formed. As a result, now you have a primary minimum at small distances followed by primary maximum at intermediate distances. When the double layer repulsion is less than the van der Waals attraction at any intermediate distance, the primary maximum will be small and flat. At the primary minimum, the two interacting particles cannot be escapable and irreversible changes between these two particles occur, like coagulation and caking, Hence it is called energy trap In order for agglomeration to happen, two particles would have to have thermal kinetic energy enough to “jump over” (greater than) the primary maximum. Hence it is called energy barrier. We can alter the environment to either increase or decrease the energy barrier to enhance the stability of suspensions (attain controlled flocculation). |
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Three Regions: Primary Minimum (Energy Trap) |
- Region of high attraction between particles - Results in irreversible coagulation - Formulation produced is physically unstable Irreversible coagulation: when two particles fall in the energy trap, they are in close proximity with each other, it's harder to re-disperse particles upon shaking Ionic surfactants and electrolytes compress the electrical double layer and decreases the zeta potential. This leads to reduction in the magnitude of primary maximum and increases the magnitude of secondary minimum. |
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Three Regions: Primary Maximum (Energy Barrier, Vmax) |
- Region of repulsion between particles - Magnitude controlled by zeta potential at the shear plane - Energy barrier: prevents particles from interacting at close distances (falling into energy trap or primary minimum) - Magnitude affected by presence and concentration of electrolytes and ionic surfactants If you increase zeta potential, the height of primary maximum decreases. If you add electrolytes or surfactants to a liquid, zeta potential decreases because the number of counter-ions increases. |
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Three Regions: Secondary Minimum (Vsec) |
- Attractive forces predominate, magnitude of attraction less than primary minimum - Particles located at this region are termed floccules - This interaction increases the physical stability of suspensions by preventing close approach to primary minimum - This interaction can temporarily be broken by moderate agitation or shaking - This process by which particles are engineered to reside in the secondary minimum is referred to as Controlled Flocculation Attractive forces predominate repulsive forces, but when you compare the magnitude of attraction is less than primary minimum (because of height of curve). Controlled flocculation: forcefully making particles reside in the secondary minimum of each other (when they eventually settle down due to gravity, it’s going to take all other secondary particles surround it, with it – forms a loose aggregate which is easier to re-disperse upon moderate shaking). We control flocculation so the settlement formed is loose. |
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Distance of Separation: No interaction |
Kt <<< Vsec - Particles maintained sufficiently distant from each other - Thermodynamically stable When second particle is away from first particle (greater distance) - when Kt is much lower than Vsec - Realistically not possible (thermodynamically stable) |
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Distance of Separation: Coagulation (agglomeration) |
Kt > Vmax - Particles form an intimate contact with each other - Pharmaceutically unstable due to inability to re-disperse upon shaking |
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Distance of Separation: Loose Aggregation (Controlled Flocculation) |
Vmax > Kt = Vsec - Loose reversible interaction enabling re-dispensability upon shaking |
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Stability |
Vmax >>> kt = Vsec - Weak floccules in secondary minimum (reversible) If the primary maximum is sufficiently high compared to the thermal kinetic energy (kT) of the particles, the two particles will not reach a state of close approach and thus are dispersed. If the secondary minimum is small compared to the thermal kinetic energy, the particles will always repel one another and will not aggregate. Otherwise the secondary minimum can trap particles to give a loose, easily re-dispersible assembly of particles (flocs) Vsec>>>>kT- no interaction between particles, ideal suspension but an ideal suspension does not exist. There is always some degree of interaction between the drug particles, attraction or repulsion. How do you achieve stability of suspension? -Weak floccules |
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Controlled Flocculation |
Vmax increases with zeta potential - Practical rule: zeta potential > 25mV; 6 months stable Vmax decreases with increasing electrolyte concentration - Compresses the double layer and reduces zeta potential - Vmax decreases and Vsec increases - Principle of controlled flocculation The height of the energy barrier depends on the magnitude of VR which in turn depends on the zeta potential to be more precise. When zeta potential is greater than or equal to 25 mV, the repulsive forces between two particles exceed the attractive forces and the particles remain dispersed individually and are said to be deflocculated. Even when brought close together by random thermal kinetic motion, deflocculated particles resist collisions because of their high zeta potential. The height of the energy barrier also depends on the electrolyte concentration.Addition of electrolytes compress the double layer and reduce the zeta potential.This has the effect of lowering the primary maximum and deepening the secondary minimum. This latter effect means that there will be increased tendency for particles to flocculate in the secondary minimum and this is the principle of controlled flocculation. Vmax is because of zeta potential -When you add surfactant, or flocculating agent, or electrolyte etc. zeta potential decreases, and the height of Vmax decreases, Vsec is deepening and widening (the total area under the curve should be same – so when you decrease Vmax you increase Vsec – when repulsion is decreasing then attraction is dominating) |
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Controlled Flocculation: Addition of Electrolytes |
Addition of electrolytes causes: - Compression of double layer => reduction in zeta potential => lowering of Vmax => Deepening of Vsec Addition of an ionic surfactant, which is adsorbed within the stern layer reduces the zeta potential. Now the particles reside in the secondary minimum of each other - easier to re-disperse |
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Controlled Flocculation |
- Flocculation is the formation of light, fluffy groups of particles held together by weak Van der Waals forces (to avoid cake formation) - Intentionally form loose, less rigid, aggregates called floc of floccules where a less rigid, loose lattice is formed between the particles - Flocculation resists complete settling and caking - Floccules settle to form a higher sedimentation volume - Floccules break up easily and result in easy re-dispersion upon agitating Flocculation:In a suspension you have drug particles residing in the secondary minimum region of each other, eventually when they start to settle down (they’re all attracted to each other), and it will take down the other particles, but sediment is loose. Cake: compact Floccule: loose aggregate |
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Deflocculation |
Deflocculation is the absence of association which occurs when repulsive forces between particles predominate. Particles repel each other and remain as discrete, single particles - A deflocculated system with a sufficiently high viscosity to prevent sedimentation would be an ideal formulation but even then caking results. - Controlled deflocculation is desired while formulating a suspension as a compromise for physical stability purposes The supernatant of a deflocculated suspension will continue to remain cloudy for sometime due to the very slow settling rate. The smaller particles remain suspended even though the larger ones have sedimented. The repulsive forces between individual particles allow them to slide past each other as they settle. **Slow settling prevents the entrapment of liquid phase between particles and thus the sediment becomes compressed and is very hard to re-disperse.This phenomenon is called caking or claying and is the most serious physical stability problem encountered with suspensions. Deflocculation: When particles are in primary max region of each other(the particles are away from each other), particles are repelled against each other. Eventually (upon prolonged storage), the first particles (larger) settle down by itself, and second particles (smaller) will settle down by itself but there’s no association (no attraction) and eventually they will form a compact cake. Initially it looks uniform because they’re repelled against each other, but eventually they will settle down and form a compact cake – NOT IDEAL (flocculating suspensions are ideal - forms loose aggregates) |
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Relative Properties of Deflocculated Particles in Suspension |
- Particles exist in suspension as separate entities - Rate of sedimentation is slow - The sediment eventually becomes very closely packed, due to weight of upper layers of sedimenting material. Repulsive forces between particles are overcome and a hard cake is formed which is difficult, if not impossible, to re-disperse - The suspension has a pleasing appearance (because rate of sedimentation is low) Rate of sedimentation is lower in deflocculated suspension |
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Relative Properties of Flocculated Particles in Suspension |
- Particles form loose aggregates or flocs - Rate of sedimentation is high - The sediment is loosely packed and possesses a scaffold-like (support each other) structure. Particles do not bond tightly to each other and a hard, dense cake does not form. The sediment is easy to re-disperse, so as to reform the original suspension. - The suspension is somewhat unsightly (more stable long-term) |
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Flocculating Agents |
Substances that form or aid in formation of a loose lattice-like structure between the drug particles called flocs or floccules which settle on standing and readily re-disperse upon agitation - E.g., Clays like bentonite magma (also assists the dispersion medium in supporting the flocs) - Agents altering pH to minimize solubility in ophthalmic and parenteral suspensions leads to flocculation - Electrolytes act by reducing electrical barrier between drug particles and forming bridges linking the particles together - Surfactants by adsorbing on the surface of the drug particles - Polymers by steric stabilization Electrolytes-E.g. Sodium salts of acetates, phosphates, citrates etc Surfactants-Both ionic and nonionic Polymers-Starch, alginates,cellulose derivatives, tragacanth etc Some flocculating agents swell up and form branches of their molecules and they trap the drug particles in those branches. Onlysurfactants and electrolytes work by reducing zeta potential |
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Altering Dispersion Medium |
Suspending agents or viscosity enhancing agents to deter (discourage) rate of sedimentation by increasing viscosity and help suspend the suspensoid - Polysaccharides - Cellulose derivatives - Hydrated silicas Optimal viscosity for the suspension to pour and agitate At low concentrations of viscosity enhancing agents, the suspensions generally behave as Newtonian fluids. Polymers and other viscosity enhancing agents are usually present at a higher concentrations, hence most of the suspensions exist as plastic and pseudo-plastic fluids (depending on the viscosity enhancing agent added). Pseudo plastic flow is useful property for suspensions where high viscosity is useful under low shear stress(storage in the bottle) which deters sedimentation of AI and low viscosity at high shear stress thereby facilitating proper administration to the patient. BUT when you increase viscosity toomuch, it decreases flow (pourability) –so viscosity has to be optimal |
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Wetting Agents |
- To ensure adequate wetting, the interfacial tension between the solid and the liquid must be reduced so that the adsorbed air can be displaced from the solid surface by the liquid dispersion medium - Lowest concentration of wetting agent that provides adequate wetting is chosen ==> Surfactants ==> Hydrophilic colloids ==> Solvents (alcohol, glycerol and glycols which are water miscible) |
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Preparation of Suspensions |
1. Insoluble solid drug, particle size reduced by comminution, trituration, pulverization, micronization, milling, levigation, etc. - Levigation: Combining the powder material and a small amount of liquid (levigating agent: mineral oil, glycerin, etc) in which the powder is insoluble, then triturating the mixture to reduce the particle size and grittiness of added powders (a paste is produced). Purpose is to reduce friction between particles 2. Wetting agents added if the drug has no affinity for the dispersion medium, e.g., alcohol, glycerin, propylene glycol, surfactants, etc. 3. The soluble additives (colorants, flavorants, preservatives, flocculating agent, suspending agents, etc.) are dissolved in a part of the dispersion medium or vehicle prior to the AI or drug. 4. Heat may be employed to facilitate uniform dispersion of the dispersed phase and then cooled down to room temperature (as long as it doesn't degrade the particles). (Dispersed phase, particle size reduce + Wetting agent (optional) + Dispersion Phase) + (Dispersion phase + Suspending agent + Flocculating agent + Colorant + Flavorant + Preservative) => Suspension |
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Preparation of Different Suspensions |
Particles => Addition of wetting agent and dispersion medium => Uniform dispersion of deflocculated particles => - A. Incorporation of structured vehicle => Deflocculated suspension in structured vehicle as final product - B. Addition of flocculating agent => Flocculated suspension as final product - C. Addition of flocculating agent => Flocculated suspension => Incorporation of structured vehicle => Flocculated suspension in structured vehicle as final product Start with internal phase, then add wetting agent (uniform dispersion of deflocculated suspension) -When you add a suspending agent, you get a structured vehicles (product has just suspending agent) -When you add flocculating agent (product has just flocculated agent) (parenteral suspension) -Optimal suspension should possess both viscosity enhancing agent and flocculating agent. Flocculating agent is added to enhance stability of dispersion. Parenteral suspension (injectable): viscosity agents are not used(lower) (intramuscularly, or sustained release may use it,they’re the exception (thixotropic or pseudo-plastic suspensions)) Oral and topical suspension: viscosity agent should be used with flocculating agent (thixotropic or pseudo-plastic) |
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Extemporaneous Preparation |
- All medication not available in convenient dosage forms for everyone (infants & elderly) - Liquid dosage forms convenient for patients who are not able to swallow solid dosage forms - Pharmacist may have to use a solid dosage form to extemporaneously prepare a suspension - Pharmacist should be aware of solubility and stability of the AI in the vehicle to be used, compatibility and interaction with the patient and concurrent medications ==> E.g., Leucovarin Calcium from tablets is stable in milk or antacids and unstable in acidic pH. Preservatives contraindicated for neonates - Available from the manufacturer, package insert, published and unpublished resources |
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Evaluation of Suspension: Sedimentation Volume (F) |
- Ratio of the equilibrium volume of the sediment (Vu) to the total volume of the suspension (Vo) ------ F = Vu/Vo - F ranges from less than 1 to 1, sometimes greater than 1 - F = 1 for ideal suspensions, suspension is at flocculating equilibrium - Gives only a qualitative account of flocculation After preparation of suspension, evaluate suspension.-First parameter: calculate sedimentation volume -Vu= ultimate volume of sediment (aka volume of the sediment) – actual volume of sediment (when we make suspension – how much of the internal phase was sediment after 30 min) (at any given point in time) - Vo= original volume of suspension at time zero - F= sedimentation volume (parameter to evaluate sedimentation of suspension) - F=1 when the suspension does not settle down (suspension is at flocculating equilibrium (because flocculation is at its maximum) – it’s not settling down) (when whole suspension is uniform) - F>1 when (Vu>Vo) you employ viscosity enhancing agent/flocculating agent that swell up and form a network(loose aggregate) which will trap AI particles - F<1 when internal phase settles down (Vo>Vu) – usually occurs in suspensions - will form a cake over time, unless you add flocculating agent. (Gives only a number, what does it mean? So we have another parameter) Vo: volume of suspension before settling Vu: volume of suspension after settling |
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Evaluation of Suspension: Degree of Flocculation (β) |
- Relates the sedimentation volume, F of a flocculated suspension to the sedimentation volume, F∞ of a deflocculated suspension ---- β = (F/F∞) = [(Vu/Vo) / (V∞/Vo)] = Vu/V∞ - The aim of the formulation is to produce as flocculated a product as possible, so higher degree of flocculation is preferred - As the degree of flocculation decreases, β approaches unity, the theoretical minimum value With two formulations with β values of 4 and 6, the formulation with the higher β value of 6is preferred. We want flocculation to be higher, so degree of flocculation should be higher -We compare our suspension at hand, to a suspension without a flocculating agent (deflocculated suspension – lowest sedimentation volume possible (worst)) Which suspension would have lower sedimentation volume? Deflocculated suspension F∞: sedimentation volume of deflocculated suspension V∞: lowest sedimentation volume of deflocculated suspension (ultimate volume of sedimentation of deflocculating suspension). When I have a suspension at hand, and degree of flocculating (β) A is 1, which is true? A.Suspension A is flocculated suspension B.Suspension A is deflocculated suspension (β=F/F∞ = 1, that tells yout hat F=F∞ that means that sedimentation volume of suspension A=sedimentation volume of deflocculated suspension, so that means the suspension is a deflocculated suspension) -β can’t be less than 1 (unless your suspension is worse than deflocculated suspension) In a suspension that utilizesflocculating agent, the degree of flocculation (β) should be greater than 1, the greater the better |
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Composition: An Ideal Suspension Formulation |
Contains: - Drug substance of API (dispersed phase) - Wetting agent (not always, maybe required) - Dispersion medium - Suspending agent - Sweetening/flavoring agent - Flocculating agent - Preservative - Osmotic agent (optional) AI or drug: ALWAYS internal phase. Wetting agent: employed only when contact angle of internal phase is higher (to reduce contact angle of internal phase) Suspending agent/viscosity enhancing agent: added to topical and oral suspensions only Flocculating agent and preservative: employed by all kinds of suspensions (topical,parenteral, oral) Osmotic agent: used to maintain tonicity Wetting agents can be used, but in limited quantity (increases solubility of internal phase, which defeats the purpose of suspensions) |
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Storage & Directions of Suspensions |
- Air tight, light resistant, wide mouthed containers with space available in containers for agitation - Extra precautions for extemporaneously prepared suspensions, ==> Stored in refrigerator ==> Watched for change in color or consistency indicating stability problems - Shake Well Before Use: properly label and instructed to the patients Wide mouthed for pourability. There must be space available, so patients can shake it before taking suspension. Reconstitutions made in pharmacy: the expiration date should be no longer than 2 weeks |
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How does the increase in viscosity of the suspension medium affect the rate of sedimentation of a suspension? |
If you increase viscosity, you decrease rate of sedimentation |
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Which of the following phenomena is undesirable in suspensions? A. Slow settling of internal phase B. Aggregation of internal phase to dense crystals C. Internal phase readily re-disperse upon agitation D. Suspension is pourable evenly from the container |
B. Aggregation of internal phase to dense crystals |
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If the energy of the particles of the internal phase is greater than Vsec but equal to Vmax, what would the state of the suspension be? A. Flocculated B. Aggregated C. Deflocculated D. Ideal |
C. Deflocculated It has enough energy to pass through sec minimum - it's in repulsion area. When AI particles settle down, they do it independently (absence of floccules), they settle down as single units and forms a cake Other: - If Kt is greater than Vsec and greater than Vmax, then it's in primary minimum region (in energy trap - strong attraction) - leads to caking (aggregated) - Flocculated: AI are all away from each other but are attracted to each other (they will settle down eventually, and they take other AI particles along with them because of attraction, forming a loose aggregate (NOT A CAKE) - Ideal: never going to happen because all suspensions eventually lead to caking, and caking does not happen in ideal suspensions |
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Emulsions Definition |
- A dispersion in which the dispersed phase is composed of small droplets or globules of a liquid distributed uniformly throughout a vehicle in which it is immiscible - A formulation consisting of an emulsifying agent and at least two immiscible liquids, one of which is dispersed throughout the other in the form of small droplets or globules ex. Milk, blood, ice cream ex. Oil as dispersion phase and water as continuous phase ex. Multiple emulsion: each droplet contains droplets within them (w/o/w) - less stable than primary two-phase emulsions (upon storage, the internal phase mixes with continuous phase) |
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Emulsion Phases |
- The dispersed phase is the internal phase - The dispersion medium is the external phase or continuous phase Any emulsion can ONLY be diluted with the continuous phase in order to maintain physical stability. If you try to add internal phase, it will break the emulsion into two phases. |
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Emulsion: o/w |
Oil or oleaginous internal phase and aqueous external phase - >45% aqueous phase - Can be diluted only with water or aqueous liquids |
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Emulsion: w/o |
Aqueous internal phase and oil or oleaginous external phase - < 45% aqueous phase - Can be diluted only with oils or oil miscible liquids |
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Multiple Emulsions |
- o/w/o - w/o/w Multiple emulsions are more structurally complex with limited pharmaceutical uses. They are easily prone to physical instability when compared with o/w and w/o emulsions. They are prone to reverting back to their parent emulsions (O/w/o emulsions revert back to w/o emulsion) |
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Other Components of Emulsions |
- To prepare a stable emulsion, a third component called emulsifying agent is necessary - A fourth component, which is not a chemical is necessary, energy is infused to make the two phases come together to form a stable emulsion - Stable emulsions exist as liquids (oral, topical and parenteral) and semi-solids (topical) depending on their viscosity Similar to suspensions, emulsions are fundamentally unstable systems which in the absence of the third component, the emulsifying agent will separate into two separate phases. The type of emulsifying agents used and the volume ratio of the two phases determine the type of emulsions formed. dG = gamma * dA - To prepare a stable emulsion: Internal phase should be added in small droplets (reduced droplet size, increasing surface area), and an emulsifying agent is necessary (for any system to be thermodynamically stable dG wants to decrease, the only thing we can do is reduce interfacial tension by using emulsifying agent (purpose: to protect or maintain droplet size of internal phase)) ----Needs4 components: internal and external phase, emulsifying agent, and energy -Classificationof emulsions for topical use: if it’s highly viscous it’s classified as creamsor paste, if it’s decreased viscosity it’s lotion |
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Rationale for Emulsions |
1. Used to deliver drugs that exhibit low aqueous solubility 2. It also allows the liquid drug in the form of minute globules rather than in the form of bulk (increases surface area) 3. If administered orally, o/w emulsion is helpful in dispersing distasteful oil in a sweetened, flavored aqueous phase (palatability) 4. It also helps formulating a drug that is irritating to the skin by dispersing in the internal phase of a topical dosage form (both types) 5. Employed to administer drugs to patients who have difficulty swallowing solid dosage forms (true for any liquid dosage form) 6. Fluids for total parenteral nutrition (TPN) are available as emulsions |
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Clinical Uses: Emulsions |
Oral emulsions: Usually o/w emulsions - Liquid administration of oils e.g., Vitamins A,D and E - Castor Oil Emulsions (Fleet), Cyclosporine Emulsion (Neoral) Parenteral administration: o/w emulsions - IV administration of al oil, Soybean Oil (Liposyn), Safflower Oil (Intralipid) Topical Administration: both o/w and w/o emulsions - o/w for washable formulations, e.g. Bengay - w/o for waterproof, used as emollient purposes, e.g. Moisturizers, Acne creams - Based on viscosity they are classified as ointments, creams, lotions, past |
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Emulsifying Agent |
To promote and maintain the stability of the emulsion Emulsification theories based on how emulsifying agents function - Surface Tension Theory/Interfacial Tension Theory There is no universal theory of emulsification because emulsions can be prepared using several types of emulsifying agents. Unless interfacial tension is zero,particles of internal phase will try to get together and form aggregates,interfacial tension can never be zero, so that’s why we always need emulsifying agent. |
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Surface Tension Theory |
- Liquids tend to exist with minimum surface are exposed to another phase - A drop of a liquid exists as a sphere because a sphere has the minimum surface area - Two or more drops of a liquid join or coalesce to form a single drop to minimize the surface area - Tendency of liquids to attract its own molecules to assume a shape minimizing the area of exposure to another phase is called: ==> Surface Tension when the surrounding phase is air/gas ==> Interfacial Tension when the surrounding phase is another liquid in which it is immiscible ==> This tension resists the break up of liquid into individual droplets or globules Liquids tend to exist with minimum surface area exposed to another phase because of the intermolecular forces between the droplet molecules. It is easier to spread oil rather than water because oil has lower surface tension than water. |
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Ideal Emulsifying Agents |
- Promote and maintain emulsification and stability - Compatible with other ingredients, non-toxic - Not interfere with the therapeutic efficacy of the AI - Stable and not deteriorate - Little or no odor, color and taste Divided into three groups based on their mechanism of emulsification: - 1. Surface active agents; Monomolecular Adsorption - 2. Hydrophilic colloids; Multimolecular Adsorption and Film Formation - 3. Finely divided solid particles; Solid-Particle Adsorption The factor common on all three groups of emulsifying agents is the formation of a film (whether it's monomolecular, multimolecular, or particulate). Mechanisms of emulsification: All adsorb in interface, they all surround droplets to reduce the interfacial tension. |
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Surfactants (aka Surface Active Agents) |
Agents which lower the surface or interfacial tension - By facilitating the break up of liquids into smaller globules or droplets - They are adsorbed as layers of molecules at the interface and hence reduce the tendency to join or coalesce When the droplet size of the internal phase is reduced, the surface area is increased and so is surface free energy. This increase in surface free energy is equal to interfacial tension*increase in area. The increase in area of the dispersed phase is necessary for a stable emulsion, so any reduction in interfacial tension will reduce the surface free energy and hence the tendency to coalesce. - Reduces interfacial tension - Stabilizes emulsion |
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Monomolecular Adsorption |
Emulsifying agent is adsorbed as monomolecular layer around the droplets of the internal phase - E.g. Surfactants have hydrophilic and lipophilic portions - They orient themselves as coherent monomolecular layers at the interface around the droplets of the internal phase according to the nature of the internal and external phase - Impart a charge to the dispersed phase/internal phase (so they repel each other) - Combination of surfactants are used to produce the desired o/w or w/o emulsions Layer of one molecule (layer that is adsorbed around interface is one molecule thick) (ex. Surfactants). Any emulsion you see in the market has two surfactants: one that forms monomolecular layer, and one to impart charge to internal phase (2 mechanisms of action) - Reduces interfacial tension and imparts a charge |
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Multimolecular Adsorption |
- Emulsifying agent is adsorbed on the surface of the droplets (at the interface) as a multi-molecular film ==> E.g. Hydrocolloids form a pliable film around the water droplets in a w/o emulsion - The film prevents contact and coalescence of the droplets - The more and pliable the film the more stable the emulsion Layer of multiple molecules (ex. hydrophilic polymers and hydrocolloids) |
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Hydrocolloids/Hydrophilic Polymers |
Act as emulsifying agents by - Forming a multi-molecular film or a protective sheath around the droplets - Imparting a charge to the dispersed phase (so they repel each other) - Swelling to increase the viscosity of the system (so droplets are less likely to merge) Examples: carbohydrates, proteins, animal derivatives - They do not cause an appreciable lowering of interfacial tension!!! (unlike surfactants) - They form a multi-molecular film rather than a monomolecular film at the interface - Exhibit an auxiliary effect of promoting stability by increasing viscosity of the dispersion medium - Owing to their hydrophilic nature, they tend to promote the formulation of o/w emulsions |
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Finely Divided Solids |
- They are wetted to some degree by both oil and water - Powders wetted preferentially by water form o/w emulsions whereas those wetted more easily by oil form w/o emulsions - Act by: ==> Accumulating at the interface and forming a particulate layer around the dispersed globules ==> Swelling to increase the viscosity of the system (so droplets are less likely to merge) Ex. - o/w emulsions: Bentotine, Magnesium Hydroxide, Aluminum Hydroxide, Magnesiums Trisilicate, Veegum - w/o emulsions: Talc, Carbon black |
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3 Groups of Emulsifying Agents Recap |
Basedon their mechanisms of action): - Surfactants: interfacial tension isreduced, and they impart charge (stabilize both emulsions) - Hydrocolloids or hydrophilic polymers: interfacial tension is not reduced appreciably, they impart a charge, they swell to increase viscosity (stabilize o/w emulsion) - Finely divided solids: they form a pliable, strong, solid film, increase viscosity, do not impart charge (form both emulsions) |
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Surfactant Structure |
- Surfactants have both hydrophilic and lipophilic part in structure - Structural features are responsible for their action at the interface - The hydrophilic part (head) is oriented towards the relatively hydrophilic phase and the lipophilic part (tail) will towards the relatively lipophilic phase |
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HLB System |
- Applications of surfactants can be determined based on their HLB values (hydrophilic-lipophilic balance - a relative ratio of polar and non-polar groups in the surfactant) - The scale runs from 1-40, the water solubility of the surfactant increases with increase in HLB number The lower the number, the more lipophilic. The higher the number, the more hydrophilic. |
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** HLB Value and Activity of Surfactants |
0 - 3 --------- Antifoaming agents 4 - 6 --------- w/o emulsifying agents 7 - 9 --------- Wetting agent 8 - 18 ------- o/w emulsifying agents 13 - 16 ----- Detergents 15 - 20 ----- Solubilizers Emulsifying agents that are more lipophilic will form w/o emulsions (the nature of the emulsifying agent determines the internal and external phases). Emulsifying agents that are more hydrophilic will form o/w emulsions. |
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Surfactants and their HLB Values |
- HLB provides a means to rate a surfactant's balance of hydrophilicity and lipophilicity - The numeral scale of HLB values are ranging from 1 to 40 - Usual range is between: ==> 1 (totally lipophilic) - 20 (totally hydrophilic) ==> Lower HLB value (<10) indicates liphophilicity while >10 shows hydrophilicity |
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Determinants of the Type of Emulsion Produced |
1. Phase volume of the internal phase
2. Chemical properties of the film surrounding the internal phase |
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Phase Volume |
- For o/w emulsions, the tolerable phase volume ratio is 74:26 - For w/o emulsions, the tolerable phase volume ratio is 40:60 - The tolerable phase volume of the internal phase is called the critical value - It is customary to use a phase volume ratio of 50:50 to 45:55 - The higher the phase volume of internal phase, the greater the probability of droplet to coalesce The markedly lower phase volume of dispersed phase in w/o emulsion is due to the greater mechanical properties of the hydrophilic polymers or polar surfactants that are present at the interface of o/w emulsion than the hydrophobic groups that stabilize the w/o emulsions. o/w emulsions: You can make an o/w emulsions by using 74 parts of oil and only 26 mL of water (more than 50% of internal phase) (more stable – it’s easier to breakdown droplet size of oil compared to droplet size of water)But if you want to make a w/o emulsion, it’s only 40:60 -How can you fit more oil (why can we reduce the droplet size of oil as opposed to water as internal phase): it’s because of surface tension or interfacial tension (water has higher surface tension, oil has lower surface tension – can break apart easier) It’s better to make 50:50, we want to make 74:26 when AI only dissolves in 26mL of external phase (it’s better to be 50:50 so the particles don’t separate once emulsion is resting) Maximum amount of internal phase that can be used to make an emulsion: - What is the critical value of water in w/o emulsion? 40 - What is the critical value of oil in o/w emulsion? 74 When an emulsion breaks that means the proportion of the internal phase has exceeded the value (if I have 80mL of oil in 100mL of emulsion, it will eventually break into oil and water – because it’s more than 74) |
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Interfacial Film Properties |
Emulsifying agents that are predominantly: - Hydrophilic will form o/w emulsions - Hydrophobic will form w/o emulsions |
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Interfacial Film Properties: Bancroft's Rule |
Emulsion type depends more on the nature of the emulsifying agent than on the relative proportions of oil or water present or the methodology of preparing emulsions The phase in which an emulsifier is more soluble constitutes the continuous phase In o/w emulsions - emulsifying agents are more soluble in water than in oil (High HLB surfactants). In w/o emulsions - emulsifying agents are more soluble in oil than in water (Low HLB surfactants) The mechanical properties of the robust film formed around the dispersed phase is very important to prevent coalescence of the dispersed phase. The chemical composition of the film dictates the typeof the emulsion formed. Emulsion type depends more on the nature of the emulsifying agent than on the relative proportions of oil or water present or the methodology of preparing emulsion. The nature of the emulsifying agent determines the type of emulsion formed -If oil is the continuous phase, use lipophilic emulsifying agent -Ifwater is the continuous phase, use hydrophilic emulsifying agent |
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HLB of an Emulsifying Agent |
Single or combination of surfactants used as emulsifying agents: - 1. The HLB of an emulsifying agent used should have the same HLB of the oleaginous phase - 2. One surfactant with HLB higher than required HLB and one with HLB lower than RHLB are chosen HLB of a combination of surfactants or oil phases: -- Total HLB = [(HLB1*Q1)+(HLB2*Q2)]/(Q1+Q2) O/W emulsions: RHLB will be high. W/O emulsions: RHLB will be low. The emulsifying agent should be more soluble in the continuous phase. But when it comes to actual numbers, it’s not sensible to assign as HLB value to water because it’s hydrophilic so HLB would be infinity) -If you want to make a cream, it should have oil as continuous phase (w/o) (we want to choose a emulsifying agent which is more lipophilic) (low HLB value) -If you want to make very thin emulsion, it should be o/w emulsion (water is continuous phase – higher HLB value is of oil phase though, not water (because water can’t have HLB value)) These are the SAME oils, the only difference is the type of emulsion (it’s only an arbitrary value). |
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Calculation of Amount of Surfactant |
- RHLB (required HLB) - % higher HLB surfactant = --- % High HLB = [ (RHLB-HLB[low]) / (HLB[high]-HLB[low]) ]*100 - Example: --- Mineral oil (HLB 10.5) 45g --- Span 80 (4.3) + Tween 80 (15) 4.5g --- Water ad 90g |
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Preparation of Emulsions: Fourth Component is Energy |
Energy supplied by: - Trituration in a mortar and pestle - Heating the ingredients - Shaking the ingredients in a bottle - Extruding the ingredients through a small orifice of a homogenizer - Mechanically blending the ingredients in a high speed mixer or blender Energy is needed to reduce droplet size |
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Emulsion: Equipment |
Emulsions are prepared by several methods depending on the ingredients and equipment available - Dry wedgewood or porcelain mortar and pestle - Blender or mixer - Hand homogenizer - Prescription bottle |
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Emulsion: Methods of Preparation |
1. Continental or Dry Gum Method - Oil phase added to the dry emulsifying agent first, white paste formed, water phase then added 2. English or Wet Gum Method - Water phase added to the emulsifying agent, mucilage formed, oil phase added to the mucilage 3. Bottle or Forbes Method - Reserved for volatile oils or less viscous oils - Variation of dry gum method |
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Continental or Dry Gum Method |
Oil:Water:Gum in the ratio of 4:2:1 - 1. Dry gum or emulsifying agent into a mortar and pestle - 2. Add small portion of oil phase and triturate vigorously until a paste is formed - 3. To this oil-gum mixture add all the water at once and triturate the mixture immediately, continuously and vigorously - 4. Primary emulsion formed is creamy white and produces a crackling sound upon the movement of the pestle - 5. Solid ingredients are dissolved in the rest of the external phase and added to the primary emulsion - 6. Liquid ingredients that might interfere with the other ingredients are added at the end - 7. This mixture is transferred to a graduated cylinder or flask and volume adjusted with the external phase that is used to wash the mortar and pestle |
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English or Wet Gum Method |
Same Oil:Water:Gum ratio of 4:2:1 - 1. Dry gum or emulsifying agent into a mortar and pestle - 2. Add water and triturate vigorously until a mucilage is formed - 3. To this water-gum mixture oil is added in small portions and the mixtures is triturated continuously and vigorously - 4. Primary emulsion formed is creamy white and produces a crackling sound upon the movement of the pestle - 5. Solid ingredients are dissolved in the rest of the external phase and added to the primary emulsion - 6. Liquid ingredients that might interfere with the other ingredients are added at the end - 7. This mixture is transferred to a graduated cylinder or flask and volume adjusted with the external phase that is used to wash the mortar and pestle (Method is same as Dry Gum - just order of adding ingredients is different) |
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Bottle or Forbes Method |
- Used for volatile and less viscous oils - Cannot be used for viscous oils as moderate to vigorous shaking would not result in emulsification for viscous oils -- 1. Dry gum or emulsifying agent into a dry bottle -- 2. Two parts oil added and shaken vigorously -- 3. Two parts water added in small portions and shaken vigorously -- 4. Volume made up using water Analogous to dry gum: order of mixing (but proportion is different 2:2:1 (o:w:g) |
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Emulsions: Identification Tests - Electrical Conductivity |
o/w emulsions conduct electricity while w/o emulsions do NOT
Oils do not conduct electricity (they do not carry a charge), when oil is continuous phase it - emulsion does not conduct electricity. If water is continuous phase, then electricity can be transmitted (stable). |
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Emulsions: Identification Tests - Dilution with External Phase |
Emulsions can maintain physical stability only if diluted with continuous phase |
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Emulsions: Identification Tests - Use of Dyes |
Oil soluble dyes will stain the internal phase of a o/w emulsion Water soluble dyes will stain the internal phase of a w/o emulsion ex. If you have w/o emulsion and you add a oil red dye, it will not change its color. If you add a water red dye, the whole emulsion will turn red |
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Instability of Pharmaceutical Emulsions is Classified as: |
1. Flocculation 2. Creaming 3. Phase Separation (Coalescence or Breaking or Caking) 4. Phase Inversion The main goal of the formulator is toformulate a physically stable emulsion where the droplets of the internal phaseremain discrete, retain their droplet size and are uniformly dispersedthroughout the formulation.A stable pharmaceutical emulsion ischaracterized by the absence of coalescence of the internal phase, retention ofinternal phase droplet size, absence of creaming and maintenance of elegancewith respect to color, appearance etc. Flocculation is needed in suspensions butnot in emulsions Phase separation is permanent – you donot want them to separate |
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Flocculation |
- Flocculation may stabilize the formulation - But in the case of emulsions, there is a possibility that the close location of the droplets (in the secondary minimum) would enable droplet coalescence (and form a bigger droplet), if the mechanical properties of the interfacial film are compromised |
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Creaming |
- Occurs primarily as a result of density difference between oil and water phase - Involves either sedimentation or elevation of the internal phase as droplets - Predominantly an aesthetic problem - Reversible process - Related by Stokes law of sedimentation - Methods employed to reduce creaming: ==> Reduce droplet size by employing colloid mill etc ==> Increase viscosity of external phase Most emulsions are o/w emulsions, oil isless dense than water, so eventually upon storage, it will cream on top (Stoke’sequation is used in creaming (and sedimentation)) - Stokes equation will give you negativevalue for creaming, because of density of internal phase) In suspensions: the internal phase ismore dense than external phase, so Stokes Law equation will give you a positivevalue for sedimentation (because density is higher) Flocculation may stabilize suspensions,but it’s not preferable for emulsions. For suspensions, the particles in theinternal phase are more dense than external phase, so stokes law value will bepositive (settles on the bottom) For emulsions, the particles in theinternal phase are less dense than external phase, so stokes law value will benegative (creams on top) Negative value: internal phase is lessthan external value and will cream on top and it’s a reversible process (creamwill be uniform dispersion again upon shaking) Most of w/o emulsions are viscous, that's why you don't see sedimentation in topical emulsions (cream, ointment, etc.) w/o emulsions (generally, oils are less dense than water) - rate of sedimentation is positive o/w emulsions - rate of sedimentation is negative |
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Phase Separation |
Refers to the complete coalescence of the internal phase resulting in separation of internal phase from the external phase resulting in two undispersed phases - Also called 'breaking' or 'cracking' - Irreversible process Not reversible – more permanentinstability (if you agitate strongly, the droplets will not re-disperse) When the droplets of the internal phasejoin together, they coalesce, and phase out (you start with an emulsion, uponstorage, the phases coalesce, which result in two undispersed phases) If you want to make an ointment or cream,the external phase would be oil (topical emulsion – w/o emulsion) - High HLB: o/w emulsion - Low HLB: w/o emulsion |
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Phase Separation Causes |
- Incorrect selection of emulsifying agents - Presence of incompatible excipients - Extreme temperatures - Microbial growth The nature of emulsifying agentsdetermine the type of emulsion - o/w: hydrophilic emulsifying agents - w/o: lipophilic emulsifying agents Microbial growth causes separationbecause the emulsifying agent will get into the cell wall of the bacteria, andlose its function in the emulsion |
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Creaming vs. Cracking: Aggregation |
- Upward creaming or downward creaming - Coalescence is absent - Redispersed upon shaking or agitation - Reversible process - Insufficient agitation might lead to improper dosage Creaming: reversible (could be redispersed) - result of aggregation. Aggregation: droplets coming together, NOT merging |
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Creaming vs. Cracking: Coalescence |
- Globules of internal phase coalesce together and form larger globules - Might lead to phase separation or 'breaking' or 'cracking' - Irreversible process - Addition of the right emulsifying agent and reprocessing through appropriate machinery for reproduction of emulsion Cracking: irreversible Coalescence: droplets coming together and merging |
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Phase Inversion |
- Phase volume ratio: Inversion from o/w to w/o or vice versa if the volume of internal phase is increased or reached beyond the critical value (critical value - of internal phase) - Tolerable phase volume ratios: ==> o/w emulsions : 74:26 ==> w/o emulsions: 40:60 |
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Causes of Instability |
Loss of protective sheath around the internal phase: - Deterioration of emulsifying agent - Extreme heat and cold temperatures - Light, air and microbial contamination - Light resistant containers, antioxidants, preservatives etc. are employed to enhance stability 3 signs of instability: creaming(density difference), phase separation (incompatibility, incorrect choice ofemulsifying agent, etc.), phase inversion (quantity beyond the critical value). Exposing emulsions or suspensionsto extreme heat will cause LOSS of protective sheath around the internal layer |
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An Ideal Emulsion Formula Contains: |
- Drug substance/dissolved in internal phase (dispersed phase) - Dispersion medium/Vehicle - Emulsifying agents - Sweetening/flavoring agent - Viscosity modifying agent - Antioxidants & Preservative |
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Emulsions: Storage & Directions |
- Air tight, light resistant, wide mouthed containers with space available in containers for agitation - Extra precautions for extemporaneously prepared emulsions, ==> Stored in refrigerator ==> Watched for change in color or consistency indicating stability problems - Shake Well Before Use: properly labeled and instructed to the patients |
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Microemulsions |
- Formulations that are thermodynamically stable, optically transparent, isotropic mixtures of o/w or w/o emulsions with surfactants acting as emulsifying agents - Diameter of the dispersed phase or the internal phase ranges from 500-1000A - Consists of large micelles containing the internal phase - Characterized by the presence of high concentration of emulsifying agents mainly surfactants (15-25%) There are many coarse emulsions where you can see the internal phase (bigger droplets). In microemulsions, the droplet size is very small (cannot see with the naked eye) - it is thermodynamically stable (don't need to shake), they're transparent in color (looks like solution) - the diameter is much smaller than coarse emulsions Drugs are more effectively absorbed transdermally if formulated as microemulsion |
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Microemulsions Characteristics |
- Spontaneously formed - Thermodynamically stable - Optically transparent - Small size of the internal phase (500-1000A) - Require relatively large concentration of surfactants as emulsifying agents (15-20%) Mainly topicals (high concentration of surfactants may be harmful to the body) |
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Coarse Emulsions Characteristics |
- Energy needs to be applied to break down the droplet size of the internal phase (ex. Homogenizer, mortar & pestle) - Kinetically stable (not thermodynamically) - Opaque - Relatively larger droplet size of the internal phase (10-50μm) - Relatively lower concentration of surfactants employed as emulsifying agents (≤0.5%) Oral emulsions |
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Suppositories |
- Are solid dosage forms intended for insertion into body orifices where they melt or dissolve - Exert local or systemic effects - Are commonly used rectally and vaginally, occasionally urethrally - Have various shapes and weights Water soluble suppository: dissolve (ex. PEG) Oil suppository: melt (ex. Cocoa Butter) Shape and size depends on size of patient (child, adult, elderly), and depends of AI properties |
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T/F: Pharmaceutical suppositories can only exert local effects |
FALSE It can exert local or systemic effects |
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Types of Suppositories: Rectal |
- Most frequently used to relieve pain, irritation, itching, and inflammation - A popular laxative, glycerin suppositories, promote laxation by the local irritation of the mucous membranes Astringent (ZnO2 - 10% of weight of sup) and protectant (base is CB - 35% of weight of sup) Glycerin sup for adults use: dose of glycerin is 2g/sup, and 1.2g/sup for pediatric dose |
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Types of Suppositories: Vaginal |
- Mainly used as contraceptives, antiseptics in feminine hygiene, and specific agents to combat as invading pathogen Ex. - Nonoxynol-9 for contraception (100mg AI/suppository (base is PEG - water soluble base) - Trichomonacides to combat vaginitis caused by Trichomonas vaginalis, Candida albicans and other microorganisms - Estrogenic substances as diesnestrol are used to restore the vaginal mucosa state Vaginal inserts: other vaginal dosage forms which usually combine suppository & tablet and are inserted vaginally - usually to treat vaginitis |
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T/F: Nonoxynol-9 suppositories are usually used for constipation |
FALSE It is usually used for contraception |
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Advantages to Suppositories |
- Viable administration route in patients with nausea or vomiting, who are unconscious, severely debilitated, or infants/small children - Does not have taste limitations - Avoid gastric acid and hepatic first-pass metabolism |
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Disadvantages of Suppositories |
- Rectal absorption potentially interrupted by defecation - Relatively smaller area for absorption (as compared to entire GI tract) - Less fluid volume may cause problems with drug dissolution or absorption - Oleaginous base: Absorption of most drugs is erratic and unpredictable - Patients do not prefer this route due to administration difficulties Allsuppositories: have relatively smaller area of absorption when we compare toorally-taken medicine (tablet). Orally degradesmore than rectal (because of gastric enzymes and GI tract) |
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T/F: Rectal suppositories have relatively larger area for absorption as compared to the orally taken dosage forms. |
FALSE It has relatively smaller area for absorption |
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Effects of Locations |
Local action Systemic action - For systemic effects, the mucous membranes of the rectum and vagina permit the absorption of many soluble drugs - Although the rectum is used frequently as the site for the systemic absorption of drugs, the vagina is NOT as frequently used for this purpose |
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T/F: The rectal but not the vaginal suppositories are usually used to achieve the systemic effects of the drugs |
TRUE |
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Examples of Drugs Administered Rectally in the Form of Suppositories for their Systemic Effects |
- Prochlorperazine and chlorpromazine - Oxymorphone HCl - Ergotamine tartrate - Indomethacin - Ondansetron |
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Advantages for Achieving Systemic Effects |
- Drugs destroyed or inactivated by the pH or enzymatic activity of the stomach or intestines need not be exposed to this destructive environments - Drugs irritating to the stomach may be given without causing such irritation - Drugs destroyed by portal circulation may bypass the liver after rectal absorption (liver = first pass) - The route is convenient for administration of drugs to adult or pediatric patients who may be unable or unwilling to swallow medication - It is an effective route in the treatment of patients with vomiting episodes |
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Affects in Drug Absorption from Rectal Suppositories |
- Physiologic factors - Physiochemical factors of the drug - Suppository base |
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Physiologic Factors: Colonic Content |
When deemed desirable, an evacuant may be administered and allowed to act before the administration of a suppository (in order for drug to be better absorbed after evacuant action) - Diarrhea and tissue dehydration influence the effect |
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Physiologic Factors: pH and Lack of Buffering |
- Because rectal fluids are essentially neutral in pH and have no effective in buffer capacity, the form in which the drug is administered will generally not be chemically changed by the rectal environment - The suppository base employed has a marked influence on the release of active constituents incorporated into it Which buffer solution can resist pH change more? Lower or higher buffer capacity? Higher buffer capacity |
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T/F: Because rectal fluids have high buffer capacity, the drug there can be effectively ionized and obtain better solubility. |
FALSE Rectal fluids are neutral in pH - drug is not chemically changed by rectal environment |
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Physiologic Factors: Circulation Route |
- The lower hemorrhoidal veins surrounding the colon receive the absorbed drug and initiate its circulation throughout the body, bypassing the liver - Lymphatic circulation also assists in the absorption of rectally administered drugs |
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Physiologic Factors: Lipid-water Solubility |
- A lipophilic drug that is distributed in a fatty suppository base in low concentration has less tendency to escape to the surrounding aqueous fluids than would a hydrophilic substance present in a fatty base to an extent approaching its saturation - Water soluble bases (ex. PEG), which dissolve in anorectal fluids, release for absorption BOTH water-soluble and oil-soluble drugs - Naturally, the more drug a base contains, the more drug will be available for potential absorption If hydrophilic substances are in fatty base, then this drug can be better released than lipophilic (lipophilic in fatty base will want to stay together in surrounding aqueous fluid) |
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T/F: Water-soluble bases can only be used for water-soluble drugs |
FALSE It can be used for both water-soluble and oil-soluble drugs |
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Physiochemical Factors of Drug: Particle Size |
- For drugs present in a suppository in the undissolved state, the size of the drug particle will influence its rate of dissolution and its availability for absorption - The smaller the particle size, the more readily the dissolution of the particle and the greater the chance for rapid absorption Particlesneed to be dissolved and absorbed. When base dissolves, the AI particles dissolve at the same time (thesize of the drug particles will influence the rate of dissolution andabsorption) If you want to increasedissolution, then decrease the particle size |
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Solubility and Particle Size |
Log S/So = (2yV)/(2.303RTr) - S: solubility of particles - So: solubility of solid - y: surface tension - V: molar volume - T: absolute temperature (K) - r: radius of particles - R: gas constant (8.314*10^7) |
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Physiochemical Factors of the Drug: Nature of the Base |
- The possibility of chemical and/or physical interactions between the medicinal agent and the suppository base, which could affect the stability and/or bioavailability of the drug - If the base is irritating to mucous membranes of the rectum, it may initiate a colonic response and prompt a bowel movement, negating the prospect of complete drug release and absorption |
