Drug Delivery Systems: A Comprehensive Guide to Pharmaceutical Formulations
Colloids and Gels
Disperse Systems
- Molecular (<1mm): Oxygen molecules, ions, glucose
- Colloidal (1nm-500nm): Polymers, cheese, butter
- Coarse (>500nm): Sand in water, red blood cells
DLVO Theory
- Attractive Forces: Result from van der Waals forces, which are caused by dipole-dipole interactions.
- Electrostatic Repulsion: Results from electrical double layers on each particle.
Colloidal Drug Delivery Systems
- Micelles: Solubilize poorly water-soluble compounds.
- Microemulsions: Deliver oil-soluble drugs via percutaneous, oral, or parenteral routes.
- Liposomes: Encapsulate synthetic drugs and peptides.
- Microspheres/Nanoparticles:
Gels
Colloidal dispersions made of small inorganic particles or large organic molecules.
Gel Classification
- Inorganic: Two-phase system (e.g., aluminum hydroxide gel).
- Organic: Single-phase system (e.g., carbopol, plastibase).
Gelling Agents
- Acacia
- Carboxymethylcellulose
- Xanthan Gum
- Polyvinyl alcohol
- Gelatin
Physicochemical Considerations
- Imbibition: Taking up a certain amount of liquid without a measurable increase in volume.
- Swelling: Taking up liquid with an increase in volume.
- Syneresis: Contraction of gel caused by interaction between particles of the dispersed phase. If osmotic pressure decreases, such as on cooling, water is squeezed out.
Stability of Gels
Observe for:
- Shrinkage
- Separation of liquid from gel
- Discoloration
- Microbial contamination (avoided by preservatives)
Suspensions
Reasons for Formulating Suspensions
- Drug may be unstable in solution.
- Drug is poorly soluble in water.
- Drug has a displeasing taste (less bitter taste in suspension).
- Prolonged release is desired.
- Flexible dosing is required.
Desirable Features of a Suspension
- Particles should not settle rapidly. If they do settle, they should re-disperse easily.
- Suspension should flow freely from the bottle.
- A uniform dose should be obtained when the bottle is shaken, and this uniformity should remain for a sufficient time.
- Particle size should remain constant over time.
Solid Particle-Liquid Vehicle Interactions
Interactions between solid particles and the liquid vehicle determine the behavior of the suspension.
Factors Affecting Electrical Double Layer
- Surfactants added at concentrations below the Critical Micelle Concentration (CMC) will localize on the particle surface.
- If the concentration is above the CMC, the drug may be dissolved.
DLVO Theory
- Primary Minimum: Higher attraction energy than repulsion; particles will aggregate irreversibly.
- Primary Maximum: High energy of repulsion; particles will remain separate or deflocculated.
- Secondary Minimum: Particles have an overall limited attraction to each other and behave as floccules.
Factors Affecting Sedimentation Rate
- Particle size
- Difference in density between particles and liquid
- Gravity
- Viscosity
Deflocculation & Flocculation
- Deflocculated: Separate particles, slow rate of sedimentation, sediment formed slowly.
- Flocculated: Loose aggregates, high rate of sedimentation, sediment formed rapidly, loosely packed, easy to redisperse.
Importance of Particle Size
Influences:
- Rate of sedimentation
- Bioavailability
- Rate of dissolution and absorption
- Physical stability
Ostwald Ripening and Crystal Growth
- While most of the drug is suspended, a small amount will be in solution.
- Fluctuations in temperature can lead to Ostwald ripening, where dissolved drug deposits on larger particles, causing them to grow in size. This changes the size distribution of suspended particles.
- May produce changes in sedimentation, caking, and altered bioavailability.
Pharmaceutical Suspension Excipients
- Flavors
- Antimicrobial preservatives
- Buffers
- Chemical stabilizers
- Wetting agents
- Flocculation modifiers
Emulsions
Advantages & Disadvantages
Advantages:
- Easier administration to patients with swallowing difficulties.
- Improve absorption of poorly soluble drugs.
- Controlled release of drug from parenteral formulations.
- Protect drug from oxidation or hydrolysis.
Disadvantages:
- Thermodynamically unstable.
- Difficult to formulate.
- Difficult to manufacture.
Emulsion Tests
- Dilution Test: Oil-in-water (o/w) emulsions can be diluted with water and will wash off fingers easily.
- Conductivity Test: Oil has no conductivity, so o/w emulsions will conduct electricity.
- Dye Solubility Test: Water-soluble dyes will dissolve in the water phase of an o/w emulsion.
Emulsifiers
- Natural Products: Polysaccharides, sterols, phospholipids, proteins.
- Surface Active Agents: Anionic surfactants, soaps.
- Finely Divided Solids:
Required HLB (Hydrophilic-Lipophilic Balance) for Emulsion
(See example)
Stability and Stability Testing
Visual inspection of:
- Cracking: Separation of emulsion into oil and water layers.
- Flocculation:
- Coalescence: Fusion of agglomerates into larger drops.
- Changes in consistency, grittiness, drying.
Excipients in Emulsions
- Vehicle
- Buffers
- Antioxidants
- Flavors
- Viscosity modifiers
- Emulsifying agents
Preparing Emulsions
- Dispersion
- Agitation
- Wet & Dry Gum Method
Different Cream Bases
- Aqueous Creams: Oil-in-water (o/w) emulsions.
- Oil-Miscible Creams: Water-in-oil (w/o) emulsions; protective and emollient.
Compatibility of Bases
- Do not use anionic surfactants with cationic surfactants (vice versa).
- Always safer to use nonionic surfactants.
Preservation of Emulsions and Creams
- Bacteriostatic agents are used to reduce the growth of microorganisms.
- Bacteria have also been shown to degrade nonionic and anionic emulsifying agents.
- Antimicrobial agents are added to an emulsion to partition into the oil phase, reducing the concentration available to the aqueous phase.
Ointments and Pastes
Ointment, Cream, Paste, Gel
- Ointment: Contains very little water.
- Cream: Semi-solid preparations that contain medication and a large percentage of water.
- Paste: Larger proportion of solid material (25%); stiffer compared to other semi-solid counterparts.
- Gel: Semi-solid systems containing gelling agents.
Ointment Bases
- Hydrocarbon (Oleaginous): Emollient effect (trap in moisture), difficult to wash off, small amount of water can be incorporated. Contains hard paraffin, white/yellow soft paraffin, liquid paraffin.
- Absorption Base: Not as occlusive as oleaginous bases, still not easily removed from the skin, better skin penetration. Contains one or more paraffins and a sterol-based emulsifying agent.
- Water-Miscible/Removable: Oil-in-water (o/w) emulsion, can accommodate large volumes of water (aqueous solutions of drugs or excess fluid (exudate from wounds)), not occlusive, easily washed from skin and clothing. Contains 20% w/w liquid paraffin, 50% white soft paraffin, 30% anionic, cationic, nonionic emulsifying wax.
- Water-Soluble: Contain water-soluble components, hydrophilic. Polyethylene glycol (PEG) is included at different molecular weights to produce the required consistency. Inability to incorporate large volumes of aqueous solutions; reserved for incorporation of solid material.
Preparing Ointment Bases
- Incorporation: Components are mixed until a uniform preparation is obtained. Small scale. Reduce particle size of powder or crystalline material before incorporation. Liquids should only be incorporated after consideration of the base’s ability to accept volumes of liquid. Alcoholic solutions of small volumes can be easily added to oleaginous vehicles.
- Fusion: All or some components of an ointment are combined by being melted together and stirred while cooling. Ointments that contain beeswax, paraffins, stearyl alcohol, and high molecular weight PEGs are prepared by fusion.
Factors to Select Appropriate Ointment Base
- Desired release rate of drug substance from the ointment base.
- Desired topical or percutaneous absorption of the drug.
- Stability of the drug in the ointment base.
- Desirability of occlusion of moisture from the skin.
- Desire for the base to be easily removed by washing with water.
- Effect, if any, of the drug on the consistency or other features of the ointment base.
Other Excipients in Ointments
- Antioxidants
- Water repellants
- Preservatives
- Organic esters
Use of Dermatological Semi-Solid Dosage Forms
- The drug in a medicated application should penetrate and be retained in the skin for a period of time.
- Oleaginous bases provide greater occlusion and emollient effects.
- Pastes offer greater occlusion.
- Creams (o/w) spread more easily than ointments.
- Water-soluble bases are not greasy and are applied and removed easily.
Emerging Technologies in Development of Semi-Solid Dosage Forms
- In-Situ Gel System: Solution form that changes forms outside of the container at application under different physiological conditions (pH & ions), thus improving contact time and drug retention. Reduced frequency of administration for the client.
- Thermostat Gel Systems: Thermo-sensitive and muco-adhesive properties. Liquid at ambient temperature, which facilitates preparation and spreading in the rectal cavity. Muco-adhesive properties help maintain the gel for a prolonged period of time.
Sterilization and Sterility
Importance
- Sterility: If a product is not sterile, microorganisms can deteriorate the product itself. Sterile products should also be free from pyrogens (fragments of dead bacteria).
Sterile Dosage Forms
- Injections
- Topical ophthalmic & nasal medications
- Irrigation solutions
- Dialysis fluids
- Topical wound healing ointments
- Sterile devices
Sterile Production Methods
- Terminal Sterilization: Holistic sterilization of the container, drug, and excipients.
- Aseptic Processing: Refers to the sterilization of each individual excipient before final product assembly (drug, container, excipient separately). Terminal sterilization is preferred.
Sterilization Methods and Applications
- Heat Sterilization:
- Steam Heat Sterilization (Autoclave): Increased pressure to raise temperature >100°C, non-toxic, not suitable for anhydrous preparations or those not penetrated by moisture, does not destroy all pathogens.
- Dry-Heat Sterilization: Carried out in ovens or through tunnels, used for sterilization of glassware and containers, can be used to destroy pathogens, less efficient, cannot be used for aqueous solutions.
- Gas Sterilization: Uses ethylene oxide gas to sterilize, very potent and high penetrating gas, flammable if mixed with air (usually mixed with an inert gas like CO2 or N2), denatures proteins by replacing functional groups with alkyl groups. Should not be used when steam sterilization is practicable.
- Radiation Sterilization: Exposure to radiation, gamma rays (most effective and penetrative), beta particles, ultraviolet light (low energy, surface sterilization). Directly damages essential molecules (DNA or enzymes) through ionization or electron excitation.
- Filtration Sterilization: Physically removes microbes by passage of a liquid or gas through a filter.
Sterility Testing
- Sterility Assurance Level (SAL) is a graph that indicates the changes in microorganisms in a product after a duration of exposure and heat.
- Parenteral: 1 in 1,000,000 (SAL of 10-6)
- Topicals: 1 in 1,000 (SAL of 10-2)
Key Components of Injectable Products
- Drug
- Solvent
- Solubilizer
- Preservative
- Buffer
- Antioxidant
- Toxicity adjuster
- Diluent
Preparation of Sterile Products
- Freeze-Dry Method: Product is aseptically filtered and filled as a solution. Stabilizing process where the substance is first frozen and then the quantity of solvent is reduced, first by sublimation and then desorption, to a value that no longer supports biological activity or chemical reactions.
- Sterile Crystallization: Dissolve the drug in a non-sterile solvent. Sterilize the solution by filtration and collect in a crystallizer. Aseptic isolation of the sterile substance by centrifuging or filtration. Aseptic sampling and packaging of the drug substance.
Packaging Requirements: Single vs. Multiple Dose
- Common Packaging: Small glass sealed ampules, rubber-closed vials, pre-filled syringes, cartridges, small and large volume bottles made either of glass or plastic, etc.
- Single-Dose Container: Opened aseptically and should be used once.
- Multiple-Dose Container: Increased risk of contamination. An antimicrobial preservative must be included. Once opened, it needs to be disposed of after a certain period of time.
Parenteral Incompatibilities
- Physical changes in the appearance of the drug product.
- Leaking of packaging.
- Acceleration of chemical components into drug solutions and/or loss of drug onto packaging material.
Dosage Form Design
Considerations for Dosage Forms
- Protect the drug substance from the destructive environment of the body.
- Conceal unpleasant flavors.
- Provide rate-controlled drug action.
- Enhance drug action and reduce side effects.
- Consideration of desired product type, therapeutic matters, age, and anticipated condition of the patient.
- Consideration of drug substances: physical, chemical, and biological characteristics, compatibility with excipients.
Common Pharmaceutical Ingredients and Excipients
- Solvents
- Flavors and sweeteners
- Colorants
- Stabilizers
- Preservatives
- Diluents/fillers
- Binders
- Anti-adherents or lubricants
Preformulation Studies
- Physical description
- Chemical properties
- Particle size
- Crystalline structure
- Melting point
- Solubility
- Dissolution rate
- Membrane permeability
- Stability
Stability Testing
Must always test:
- pH
- Expected color
- Odor
- Consistency
- Sterility
Storage
- Must be stored under proper conditions.
- Labeling of each product with desired conditions of storage.
Mechanics of Drug Absorption
Absorption is the rate and extent at which drugs reach the systemic circulation from the site of drug administration.
- Passive Diffusion: Absorption process is driven by the concentration gradient of the drug across the membrane (high to low concentration).
- Active Transport: A process using a “carrier” to move the drug across the membrane against a concentration gradient (lower to higher). Energy is required.
- Facilitated Diffusion: Specialized transport using a “carrier,” but the drug is not moved against the concentration gradient.
Bioavailability
The fraction of the drug dose of unchanged drug that reaches the systemic circulation.
Effect of Food
- Delay gastric emptying.
- Change in pH of the GI tract.
- Physical or chemical interaction of drug and meal.
Pharmaceutical Stability
Stability Factors that Affect Shelf Life
- Chemical Degradation of Drug or Excipients: Hydrolysis, oxidation, isomerization, polymerization.
- Microbial Contamination: Introduction of microbes.
- Physical Changes: In cracked coated tablets, precipitation resulting in microbial growth.