Liquid Dosage Forms: Disperse Systems
Unit 7 Module 12: Liquid Dosage Forms - Disperse Systems
Disperse Systems Overview
Definition: A system where particulate matter (the dispersed phase) is distributed in discrete units throughout a second substance (the continuous phase, vehicle, or dispersion medium).
Particle Size Range: Dispersed material can range from atomic/molecular dimensions (less than 1 ext{ nm}) to particles measured in millimeters.
Phase States: Each phase (dispersed and continuous) can exist as a solid, liquid, or gas.
Classification of Disperse Systems Based on Particle Size
Molecular Dispersion:
Range: Less than 1 ext{ nm}.
Characteristics: Invisible in an electron microscope, undergo rapid diffusion.
Examples: Oxygen molecules, ordinary ions, glucose, air (molecular mixture), electrolytes (aqueous solutions of salts), metal alloys.
Colloidal Dispersion:
Range: From 1 ext{ nm} - 0.5 ext{ µm} (or 1 ext{ nm} - 1000 ext{ nm}).
Characteristics: Visible in an electron microscope, diffuse very slowly.
Examples: Colloidal silver solutions, cheese, butter, jelly, milk, shaving cream.
Coarse Dispersion:
Range: Greater than 0.5 ext{ µm} (or 1000 ext{ nm} / 4 imes 10^{-5} ext{ inch}).
Characteristics: Visible under a microscope, do not diffuse.
Examples: Grains of sand, most pharmaceutical emulsions and suspensions, red blood cells.
Measurement Units:
1 ext{ nm (nanometer)} = 10^{-9} ext{ m}
1 ext{ µm (micrometer)} = 10^{-6} ext{ m}
Interfacial Phenomenon
Interface: The boundary between two phases.
Surface: A term frequently applied when one of the phases is a gas or vapor.
Importance in Pharmacy: Interfacial phenomena are crucial in processing various formulations and often govern their subsequent behavior in vivo.
Wetting Phenomenon
Issue: Poorly wetted solid particles may trap air, causing them to float and preventing dispersion.
Encouraging Wetting: Reducing the interfacial tension between the solid and the vehicle helps displace adsorbed air, allowing the liquid to wet the solid surfaces.
Wetting Agents: These agents reduce interfacial tension but can also decrease interparticle forces, affecting flocculation.
Adsorption
Definition: The binding of molecules or particles to a surface.
Distinction: Must be differentiated from absorption, which is the filling of pores within a solid.
Binding Characteristics: Usually weak and reversible.
Strong Binding: Compounds with color, taste, or odor tend to bind strongly.
Surface Active Agents (Surfactants)
Structure: Compounds with two distinct regions:
Hydrophilic region: (Water-liking) confers water solubility.
Hydrophobic region: (Water-hating) renders material soluble in hydrocarbon solvents.
Energetics: These materials preferentially adsorb at interfaces, orienting themselves so that each region associates with its appropriate solvent.
Solubilization in Pharmacy
Application: Used to formulate a wide range of insoluble drugs.
Hydrolysis Rate: Solubilization can modify the rate of drug hydrolysis.
Protection: Non-polar compounds solubilized deep within the hydrocarbon core of a micelle are better protected against hydrolyzing species than more polar compounds located closer to the micellar surface.
Micellar Solubilization
Effect: Can increase the solubility of drugs in the gastrointestinal tract.
Dependence: The ability of bile salts to solubilize drugs largely depends on the drug's lipophilicity.
Coarse Dispersion Systems (Revisited)
Description: Heterogeneous dispersed systems with particles larger than 1000 ext{ nm}.
Sedimentation: Characterized by relatively fast sedimentation of the dispersed phase due to gravity or other forces.
Separation: Dispersed phase can easily be separated from the continuous phase by filtration.
Examples: Emulsions, colloids, and suspensions.
Emulsions
Definition: A biphasic liquid preparation containing two immiscible liquids, where one is dispersed as minute globules into the other.
Phases:
Dispersed phase: The liquid converted into minute globules.
Continuous phase (or dispersion medium): The liquid in which the globules are dispersed.
Emulsifying Agent: Added to stabilize the system, forming a film around globules to scatter them indefinitely in the continuous phase.
Globule Size: Varies from 0.25 to 25 ext{ µm}.
Theory of Emulsification
No Universal Theory: Emulsions can be prepared using different types of emulsifying agents, each operating on a different principle.
Meaningful Theory: Should explain the stability of the product and the type of emulsion formed.
Process: Describes what happens when two immiscible liquids are agitated, and one disperses into the other.
Types of Emulsions
Typically involve oil and water.
Oil-in-Water (O/W) Emulsion: Oil is the dispersed phase, and water is the dispersion medium/continuous phase.
Water-in-Oil (W/O) Emulsion: Water is the dispersed phase, and oil is the dispersion medium/continuous phase.
Determination of Emulsion Type
1. Dilution Test:
O/W: Remains stable when diluted with water.
W/O: Breaks when diluted with water but remains stable when diluted with oil.
2. Dye Test: (Using scarlet red dye)
O/W: Dispersed globules appear red, and the continuous 'ground' appears colorless under the microscope.
W/O: Dispersed globules appear colorless, and the continuous 'ground' appears red.
3. Conductivity Test: (Water is a good conductor, oil is not)
O/W: Bulb glows when electrodes connected through a low-voltage bulb are dipped in the emulsion (water is continuous).
W/O: Bulb does not glow (oil is continuous).
4. Fluorescence Test: (Certain fixed oils fluoresce under UV radiation)
W/O: The whole field fluoresces, indicating oil is in the continuous phase.
O/W: Droplets fluoresce, indicating oil is in the dispersed phase.
Emulsifying Agents
Function: Reduce interfacial tension between the oily and aqueous phases, making them miscible and forming a stable emulsion.
Terminology: Also known as emulgents or emulsifiers.
Examples: Acacia, Glyceryl monostearate, Tragacanth.
Stability of Emulsions
Definition: An emulsion is stable if dispersed globules remain uniformly distributed throughout the dispersion medium during storage.
Requirements: Must be chemically stable and free from bacterial growth throughout its shelf life.
Common Changes During Storage:
Cracking: Irreversible separation of the two phases.
Creaming: Upward or downward movement of the dispersed phase relative to the continuous phase, leading to concentration but usually still redispersible.
Phase Inversion: The emulsion type changes (e.g., O/W becomes W/O).
Colloids (Detailed)
Definition: Dispersions where the size of dispersed particles is between 1 ext{ nm} and 0.5 ext{ µm} (or 1 ext{ nm} to 1000 ext{ nm}).
Characteristics: Very small, finely divided solids that do not dissolve but remain dispersed due to their small size and electrical charge. They have negligible settling velocity due to low gravitational force compared to surface frictional forces.
Nature: Micro-heterogeneous dispersed systems.
Separation: Cannot be separated under gravity, centrifugal, or other forces but can be separated by micro-filtration.
Examples: Milk (emulsion of fat in water), fog (aerosol of water micro-droplets in air), opal (colloidal silica), silica aerogel, alumina aerogel monolith.
Classification/Types of Colloids
1. Lyophilic Colloids: (Solvent-loving)
Systems containing colloidal particles that interact significantly with the dispersion medium.
2. Lyophobic Colloids: (Solvent-hating)
Materials with little to no attraction for the dispersion medium.
3. Association Colloids: (Amphiphilic)
The third group forms associations (e.g., micelles) in solution.
Properties of Colloids
Size and Shape of Colloidal Particles:
Size distribution: Refers to the range of particle sizes present.
Size range: Typically 1 ext{ nm} to 0.5 ext{ µm}.
Shape: Can be varied, e.g., rugby ball-shaped, discus-shaped.
Kinetic Properties: Related to the motion of particles.
Brownian motion: Random movement of particles.
Diffusion: Movement from high to low concentration.
Sedimentation: Settling under gravity.
Osmotic pressure: Pressure caused by differences in solute concentration.
Viscosity: Resistance to flow.
Optical Properties:
Light scattering: Colloidal particles scatter light, visible as the Tyndall effect (path of light observed).
Ultramicroscopy: Used to observe scattered light.
Electron microscopy: Visualizes colloidal particles directly.
Electrical Properties:
Electrical properties of interfaces: Important for stability.
Electrical double layer: Ions accumulate at particle surfaces, creating a potential difference.
Electrokinetic phenomena: Movement of charged particles in an electric field.
Particle Charge: Colloidal particles selectively absorb ions, acquiring an electric charge (all particles of a given colloid take the same charge and repel each other).
Physical Stability of Colloidal Systems:
Stability of lyophobic systems.
Stability of lyophilic systems.
Steric stabilization (protective colloid action): Using polymers or other agents to physically prevent particle aggregation.
Stability of Colloidal Systems
Key Factor: The presence, magnitude, or absence of charge on a colloidal particle significantly impacts stability.
Stabilization Methods:
1. Electric Charge: Providing dispersed particles with an electric charge (repulsion prevents aggregation).
2. Protective Solvent Sheath: Surrounding each particle with a solvent layer that prevents mutual adherence upon collision (due to Brownian movement).
Protective Colloids and Other Agents: Gelatin, Albumin, Acacia, Sodium oleate, Tragacanth.
Application of Colloids
Modifying Drug Properties: Extensively used, especially for affecting drug solubility.
Drug Delivery Systems (CDDS): An important pharmaceutical application.
Examples: Hydrogels, microspheres, microemulsions, liposomes, micelles, nanoparticles, and nanocrystals.
Benefits: Minimize problems of conventional therapy (e.g., poor penetration, drug resistance, systemic toxicity) and improve drug efficacy and therapeutic index.
Colloidal Drug Delivery Systems (CDDS)
Purpose: Formulations or devices that enable a therapeutic substance to selectively reach its site of action without affecting non-target cells, organs, or tissues.
Prime Objectives: Controlled delivery of pharmacological agents at therapeutically optimal rates and dosage regimens, avoiding toxicity, and improving drug efficacy and therapeutic index.
Promising Systems: Liposomes, niosomes, microemulsions, and nanoparticles.
Nature: Particulate or vesicular dosage forms in the nanometer size range.
Colloids and Coagulation
Mechanism: Most particles dissolved in water have a negative charge, causing them to repel each other and remain dispersed (colloidal).
Role of Coagulants: Chemicals (often positively charged) neutralize the negative charges on turbidity particles, preventing repulsion.
Zeta Potential and Coagulation:
Zeta potential: A measurement of the magnitude of electrical charge surrounding colloidal particles, representing the repulsive force.
Effect: A larger zeta potential indicates more repulsive force, thus requiring more coagulant.
Process:
1. Neutralization: Positively charged coagulants are attracted to negatively charged particles, resulting in a neutral charge.
2. Van der Waals Forces: Once particles are neutrally charged and no longer repel, weak attractive van der Waals forces cause them to drift together.
3. Floc Formation: Enough particles joining together form floc.
4. Settling: Flocs settle out of the water.
Colloidal Stability and DVLO Theory
Origin: Developed in the 1940s by Derjaguin, Verwey, Landau, and Overbeek.
Concept: The stability of a particle in solution depends on its total potential energy function (V_T).
Components of Total Potential Energy:
VT = VA + VR + VS
V_S (solvent potential energy): Marginal contribution over the last few nanometers of separation.
V_A (attractive contribution - van der Waals forces):
Formula: V_A = -A / (12 ext{ π} D^2)
Where: A is the Hamaker constant, and D is the particle separation.
V_R (repulsive contribution - electrical double layer):
Formula: V_R = 2 ext{ π} ext{ ε } a ext{ ζ}^2 ext{ ext{exp}}(- ext{κ}D)
Where: a is the particle radius, ext{ε} is the solvent permeability, ext{κ} is a function of the ionic composition, and ext{ζ} is the zeta potential.
Stability Determinant: DVLO theory suggests that colloidal system stability is determined by the balance of these van der Waals attractive (VA) and electrical double layer repulsive (VR) forces between particles as they approach each other due to Brownian motion.
Suspensions
Definition: Biphasic liquid dosage form of medicament where finely divided solid particles (ranging from 0.5 to 5.0 ext{ µm}) are dispersed in a liquid or semisolid vehicle.
Phases:
Disperse phase: Solid particles.
Continuous phase: Liquid vehicle.
Routes of Administration: Generally taken orally, parenterally, or used for external applications.
Classifications/Types of Suspensions
1. Flocculated Suspension: Individual particles are in contact, forming a network-like structure.
2. Non-Flocculated Suspension: Individual particles exist as separate entities.
Properties of Suspensions (General)
Uniform Particle Size: All particles behave alike, producing consistent behavior.
No Particle-Particle Interaction (Ideal): Each particle remains discrete, no aggregation or clumping.
No Sedimentation (Ideal): Drug particles are stationary or move randomly, ensuring uniform distribution.
Stability of Suspensions
Criteria: A stable suspension can be homogeneously redispersed with moderate shaking and can be easily poured throughout its shelf life.
Most Stable: Flocculated suspensions are generally the most stable pharmaceutical suspensions because their sedimented particles are easily redispersed with moderate shaking.
Non-Flocculated Stability: Can be improved by decreasing particle size or increasing the density and viscosity of the vehicle.
Applications of Suspensions
Oral dosage form.
Topical application for skin.
Application to mucous membrane surfaces.
Given parenterally by injection.
Rationale for Using Pharmaceutical Suspensions
Insoluble Compounds: To administer insoluble compounds as a liquid.
Taste Masking:
Formulating in a vehicle where the drug is insoluble.
Using an insoluble form of the drug (e.g., salt form or prodrug).
Adsorbing the drug onto an insoluble carrier.
Drug Release: To modify the release rate of the drug.
Stability: To improve stability by reducing the fraction of the drug in solution.
Industrial Use: Used as in-process materials (e.g., tablet coating suspensions, wet granulation, fluidized bed-drying/granulation).
Properties of an Ideal Suspension
Uniform dispersion.
Palatable, pleasing odor and color.
No grittiness.
Easy to pour yet not watery.
No cap-lock (drug accumulation in the cap).
Temperature insensitive.
Particles should settle slowly.
Easy redispersion of sedimented particles.
A flocculated suspension is desirable over a deflocculated suspension.
Not too viscous to reduce the sedimentation rate while allowing pouring.
Ideal Features of Suspension Dosage Form
Physically, chemically, and microbiologically stable.
Aesthetically pleasing with good odor and taste.
Small, uniformly sized particles resulting in a smooth, grit-free product.
Sufficiently homogenous for the period between shaking and dose removal.
Pourable (from bottle) or flowable (through syringe needle for injectables).
Acceptable uniformity of drug content for multi-dose containers.
Drug substance must not recrystallize or change polymorphic form during storage.
Particles should settle slowly, and sediment/creaming should readily redisperse upon gentle shaking.
Parenteral and ophthalmic suspensions should be sterilizable and syringable (for parenteral).
Parenteral suspensions should be isotonic and non-irritating.
For external lotions: fluid enough to spread easily but not run off; dries quickly; provides an elastic protective film that doesn't rub off easily.
Thixotropic Suspension
Definition: A suspension that is viscous during storage but becomes fluid upon shaking (loses consistency).
Behavior: A well-formulated thixotropic suspension remains fluid long enough for easy dispensing but slowly regains its original viscosity.
Thixotropy: The isothermal (constant temperature) slow reversible conversion of gel to sol.
Benefits: Conversion to gel on standing increases viscosity infinitely, preventing dispersed particles from settling (stability). Conversion to sol on shear stress makes them easy to pour and measure (pourability).
Types of Suspensions (Detailed Classification)
1. Based on Route of Administration:
a. Oral Suspension: Liquid preparations with one or more active ingredients suspended in a sweetened, flavored, usually viscous vehicle. E.g., Mepron (Atovaquone) suspension (750 mg/5 mL). May contain high concentrations of solids (e.g., antacids, radiopaque suspensions).
b. Externally Applied/Topical Suspensions: Designed for dermatological, cosmetic, and protective purposes. Typically colored, may be perfumed, usually lack sweeteners/flavors. Can exceed 20 ext{%} dispersed phase. E.g., Calamine lotion (fluid, leaves light deposit), pastes (semisolid, high powder conc. in paraffin base), zinc cream (powdered drug in emulsion base).
c. Parenteral/Injectable Suspensions: Dispersed, heterogeneous systems of insoluble drug particles in aqueous or vegetable oil vehicles. Designed for intramuscular (IM) or subcutaneous (SC) administration. E.g., Triamcinolone Acetonide Injectable Suspension, insulin zinc suspension. May contain 0.5 to 30 ext{% w/w} solid particles. Viscosity and particle size are critical for syringability and depot therapy. Sterility is paramount (sterile API, aseptic processing; antimicrobial preservatives not recommended for IV suspensions).
d. Rectal Suspensions: Liquid preparations for rectal use, treating local colon disorders. E.g., Mesalamine suspension for Crohn's disease. Formulation and quality similar to oral suspensions.
e. Otic Suspensions: Liquid preparations with micronized particles for instillation in the outer ear. Often antibiotics, corticosteroids, or analgesics. Generally formulated as sterile suspensions.
g. Pulmonary Suspensions/Aerosols: Suspensions of drug particles or drug solution in air for inhalation (lung delivery). Volatile propellants are common vehicles. An aerosol is generally a suspension of liquid droplets or fine solid particles in a gas. Blood is also an example of a suspension.
2. Based on Concentration of Dispersed Phase:
a. Dilute Suspension: Contains 2 - 10 ext{% w/v} solid. E.g., Cortisone acetate, Prednisolone acetate.
b. Concentrated Suspension: Contains 10 - 50 ext{% w/v} solid. E.g., Zinc oxide suspension. Highly concentrated suspensions are termed slurries.
3. Based on Electrokinetic Nature of Solid Particles:
a. Flocculated Suspension: Supernatant quickly clears due to large flocs settling rapidly. Forms loose, easily redispersible sediments. Disadvantages: risk of inaccurate dose, inelegant appearance.
b. Deflocculated Suspension: Dispersed particles remain as discrete, separate units. Supernatant remains cloudy for a long time due due to slow settling of smallest particles. Sediment becomes compacted and difficult to redisperse (forms a solid hard cake).
4. Based on Size of Solid Particles:
Coarse suspension: > 1 ext{ µm} (typically 1 - 100 ext{ µm}).
Colloidal dispersion: < 1 ext{ µm} (typically 1 ext{ nm} - 0.5 ext{ µm}).
Nanosuspension: 10 - 100 ext{ nm}.
Excipients Used in Pharmaceutical Suspensions
1. Solvents/Vehicles: Major components as a base. Purified water is common. Viscous nonaqueous solvents (propylene glycol, polyethylene glycols) impart stability. Choice depends on API properties and intended use.
2. Buffering Agents/pH Modifiers: Control pH changes. Citrates ( ext{pH } 3-5), Phosphates ( ext{pH } 7-8).
3. Preservatives: Protect against microbial contamination in aqueous suspensions. Parabens, alcohol, glycerin, propylene glycol, sorbates.
4. Antioxidants: Enhance chemical stability of therapeutic agents susceptible to oxidation. Thiourea, butyl hydroxy toluene (BHT), tocopherols, ascorbic acid, sodium bisulphate.
5. Wetting Agents/Surfactants: Improve liquid vehicle flow across particle surface, enhancing drug particle homogeneity. Polysorbates, sorbitan esters.
6. Antifoaming Agents: Prevent foam during manufacturing or reconstitution. Simethicone, organic phosphates, alcohols, paraffin oils, stearates, glycols.
7. Flocculation Modifiers: Neutral electrolytes (usually 0.01 - 1.00 ext{%}) that prevent caking. Sodium or potassium chloride, aluminum chloride, calcium salts, citrates.
8. Suspending Agents/Viscosity-Modifiers: Hydrophilic colloids (cellulose derivatives, acacia, xanthan gum) added to increase viscosity, inhibit agglomeration, and decrease sedimentation.
9. Flavoring Agents: For taste-masking. Peppermint, lemon oils, butterscotch, 'tutti-frutti' flavor.
10. Sweeteners: Reduce unpleasant taste and improve palatability. Sorbitol, corn syrup, sucrose, saccharin, acesulfame, aspartame.
11. Colorants: Provide aesthetic appearance. Choice linked to flavor, patient population (age), and therapeutic need (e.g., red with strawberry for pediatrics).
12. Humectants: Retard evaporation of aqueous vehicle. Glycerol, propylene glycol.
13. Chelating Agents: Protect drug substances from catalysts that accelerate oxidative reactions.
Zeta Potential (Factors to be Considered)
Definition: The difference in potential between the surface of the tightly bound layer (shear plane) and the electro-neutral region of the solution. It's a physical property of any particle in suspension, macromolecule, or material surface.
Applications: Optimizes formulations (suspensions, emulsions, protein solutions); predicts surface interactions; aids in film/coating formation; reduces trial formulation time; predicts long-term stability.
Potential Drop: Rapid drop near the surface, followed by a more gradual decrease further away. This is due to counter-ions close to the surface screening the electrostatic attraction between the charged surface and distant counter-ions.
Importance: Governs the degree of repulsion between adjacent, similarly charged, dispersed particles, rather than the Nernst potential (potential difference between actual surface and electroneutral region).
Flocculation Threshold: If the zeta potential is reduced below a critical value (which depends on the system), attractive forces exceed repulsive forces, leading to flocculation.
Flocculation (Factors to be Considered)
Cause: Occurs when the zeta potential falls below a critical value, and attractive forces supersede repulsive forces.
Sedimentation: Loosely packed particles (flocs) settle faster due to their larger sizes.
Redispersibility: The sediment of flocs does not form a solid cake and is easy to redisperse with minimal agitation.
Deflocculation (Factors to be Considered)
Cause: Occurs when the zeta potential is higher than the critical value, and repulsive forces supersede attractive forces.
Sedimentation: Deflocculated particles, when settled, form a close-packed arrangement with smaller particles filling voids between larger ones.
Problem: This often leads to the formation of a SOLID HARD CAKE that is difficult to redisperse.
External Forces Acting on Particles
Gravity
Brownian Movement (random motion of particles)
Sedimentation Equilibrium: Occurs when gravity is neutralized by Brownian movement.
Settling & Aggregation
Desirable Outcome: The suspension should form loose networks of flocs that settle rapidly, do not form cakes, and are easy to resuspend.
Undesirable Outcome: Settling and aggregation can result in the formation of cakes (in suspensions) that are difficult to resuspend, or in phase separation (in emulsions).