Dosage II Exam 1 Flashcards
Liquid Dosage Forms: Solutions, Emulsions, and Suspensions
What are the different types of liquid dosage forms?
- Solution: Homogenous molecular dispersion
- Emulsion: oil in water or water in oil
- Suspension: Solid in water or oil
What are common solvents?
Water or oils
What are common co-solvents?
ethanol, glycerin, propylene glycol
What are common flavors and sweeteners?
- Sucrose
- Sorbitol
How can you tell if something is an emulsion?
- Liquid drops suspending
A solution looks milky. What is it?
Milk is an emulsion and suspension.
What are the advantages of solutions?
- Homogenous: no problems of content uniformity
- Easy to manufacture
- Good bioavailability–> already dissolved
What are different types of liquid dosage forms?
- Solution (homogenous molecular dispersion)
- Emulsion (oil in water, water in oil)
- Suspension (solid in water OR oil)
What are the advantages of solutions?
- Homogenous- content uniformity
- Easy to manufacture
- Good bioavaliability
What is a buffer?
A solution of a weak acid and a salt of its conjugate base
* Weak acid removes added base
* Salt removes added acid
What is the H-H equation?
pH = pKa + log [A-]/[HA]
What is the buffering capacity equation?
β = 2.3 C (Ka*[H3O+]/(Ka + [H3O+])2)
C = total buffer concentration = [HA] + [A-]
What are common buffers?
- Acetic acid
- Glycine
- Citric acid
- Phsophoric acid
Why to we normally select a weak acid with a pKa close to the desired pH?
- Provides the max stability for the drug
- Keeps the pH around the optimal pH for the drug so it’s not broken down too quickly
How can we minimize the effects of the pH of a solution not matching the pH of the body fluid?
- Minimize buffering capacity
- Minimize volume
- Administer slowly
What is the purpose of antimicrobial preservatives?
- To protect pts from pathogens
- Maintain potency and stability of DF
What is the mechanism of action for antimicrobial preservatives?
- absorb bacterial membrane and disrupt the membrane
- the membrane is lipophilic and has negative surface charge
How does absorption work?
* Absorption due to lipid solubility (alcohols, acids, and esters)
Absorption due to electrostatic attraction (quaternary ammonium cmpd)
What are ampules?
Single dose, no preservative needed (PF)
My enemy bc you can never get all of the drug out with the stupid filter needle.
What are multiple dose vials?
Needs preservative to kill microorganisms that are introduced during use
List out all the preservatives
- Alcohols
- Acids (only in unionized form)
- Esters of p-hydroxybenzoic acid (parabens)
- Quaternary ammonium compounds (benzalkonium chloride, cetyltrimethylammonium chloride)
Describe key preservatives in the alcohol class.
- Ethanol: requires >15%, limited to oral products, may be lost due to volatility
- Benzyl alcohol: local anesthetic action, burning taste (not used orally), water soluble, stable over wide pH range, widely used in parenterals
- Chlorobutanol: campor-like odor (not used orally), used in parenterals and opthalamics, volatile, lost through rubber stoppers and plastic containers
Describe key preservatives in the acids class.
- Benzoic acid (pKa = 4.2): used in oral products
- Sorbic acid (pKa = 4.8): used in oral products, excellent for molds and yeast
Describe key preservatives in the esters of p-hydroxybenzoic acid (parabens) class.
Widely used orally, not ionized but hydrolyze rapidly at pH >7, anesthetize tongue, low solubility, skin sensitization
* Lipophilic: propyl paraben, butyl paraben, best against mold and yeast
* Less lipophilic: methyl paraben, ethyl paraben, best against bacteria
Describe key preservatives in quaternary ammonium compounds class.
benzalkonium chloride, cetyltrimethylammonium chloride
* Widely used in ophthalmics, water soluble and fast killing, incompatibility issues due to positive charge
* REMEMBER: positive charge means it does NOT cross the BBB
What are antioxidants?
Antioxidants are molecules that help protect your cells from damage caused by free radicals—unstable molecules that can lead to oxidative stress.
Why are antioxidants important when it comes to liquid dosage forms?
Drug substances are less stable in aqueous media than solid
* Meaning, that damage from free radicals may be more common
Describe oxidation as a degradation pathway.
- Auto oxidation: automatic reaction with oxygen without drastic external interference
- Initiated by heat, light, peroxides, metals -> free radicals -> react with oxygen -> more free radicals
- Result: oxidative stress (linked to aging and various diseases, including cancer, heart disease, and neurodegenerative disorders.)
What are examples of antioxidants?
- Free radical scavengers
- Reducing agents
- Chelating agents
What are free radical scavengers?
Agents that retard and delay oxidation by reacting with free radicals (propyl, octyl, dodecyl esters of gallic acid, BHA, BHT, tocopherols, vitamin E)
What are reducing agents?
- Agents that have a lower redox potential than drugs, so they are more readily oxidized (sodium bisulfate, ascorbic acid, thiols).
What are chlelating agents?
They are antioxidant synergists with little antioxidant effect themselves. They work to reduce trace metals.
* Citric acid
* EDTA
What is an emulsion?
A system of two immisible liquids in which one is dispersed as droplets (water phase and oil phase)
* Dispersed phase
* Continous phase (external phase)–> determines organoleptic properties (taste, smell, feel)
What are the two types of emulsion?
Oil in water (O/W)
* oil is dispersed, water is continous
Water in oil (W/O)
* water is dispersed, oil is continous
What are the clinical applications of oral emulsions?
- O/W to mask taste of an oil (ex. mineral oil emulsion as a laxative)
- O/W to enhance absorption of an oil (vit A and D, cod liver oil)
What are the clinical applications of external emulsions applied topically?
- O/W: water washable, vanishing cream
- W/O: for cleansing skin, cold cream
What are the clinical applications of IV lipid emulsions (O/W)?
- For parenteral nutrition
- 100 mL of 20% emulsion provides 200 kcal, while 100 mL of 5% dextrose only provides 20 kcal
- Smallest capillaries are 5 μm: critical that droplet size is <1 μm to avoid embolisms
How does the boundary between phases come into play in molecular interactions?
- Unequal Forces at the Interface
* Molecules in the bulk of a phase (e.g., deep inside a liquid) experience uniform attractive forces in all directions because they are surrounded by similar molecules.
* However, molecules at the boundary (interface) are in contact with molecules from a different phase, which may exert different types or strengths of attractive forces. - Different Interaction Forces
At the interface, molecules experience asymmetric forces:
* For example, a water molecule at the surface of a glass of water feels strong attraction from other water molecules below but weaker attraction from air molecules above.
* This imbalance creates surface tension and affects molecular movement. - Movement from Interface to Bulk
* Due to this imbalance, molecules at the interface may tend to move toward the bulk phase where they can achieve a more stable energetic state.
* This spontaneous movement helps reduce the system’s overall energy, making it more thermodynamically favorable.
Example
Consider an oil-water interface: water molecules at the boundary are exposed to both water and oil molecules, experiencing different intermolecular forces. Some water molecules may migrate back into the bulk water phase to reduce the energy imbalance.
What is interfacial tension?
Interfacial tension is the force per unit length acting at the boundary between two immiscible phases (such as oil and water), making the interface behave as if it is under tension. This occurs because molecules at the interface experience unequal attractive forces from each phase, creating a tendency to minimize the interface area. It is similar to surface tension but applies specifically to interfaces between two different liquids or a liquid and a solid.
What are surfactants?
Surfactants are molecules with both hydrophilic (water-attracting) and hydrophobic (water-repelling) regions. Due to this dual nature, they position themselves at interfaces (liquid-liquid or liquid-air), aligning so that their hydrophilic part interacts with water and their hydrophobic part interacts with oil or air. This arrangement reduces interfacial tension, making it easier for the two phases to mix, which is essential in emulsification, detergency, and foaming processes.
What are examples of surfactants?
Alkyl sulfate, alkylbenzene sulfonate, alkyltrimethylammonium bromide, alkylpyridinium chloride, alkyl betaine, alkyldimethylamine oxide, alcohol ethoxylate, polyethylene-polyoxypropylene-polyoxyethylene block copolymer
What is HLB?
The measure of relative contributions of the hydrophilic and lipophilic regions of a surfactant
* Low = greater lipid solubility
Explain how interfacial tension impacts the stability of an emulsion.
- Stronger intermolecular force in bulk phase = higher interfacial tension
- Greater tendency to interact = less interfacial tension
- Higher temperature = lower interfacial tension (intermolecular forces are reduced at high temp)
What are the emulsifying agents?
Emulsifying agents
* Surface active agents (surfactants)
* Hydrophilic colloids (polymers)
* Finely divided solid particles
How do surfactants affect the formation of micelles in solutions?
When the concentration of surfactants exceeds a certain level, known as the critical micelle concentration (CMC), surfactant molecules self-assemble into micelles. In water, these micelles have their hydrophobic (water-repelling) tails oriented inward, forming a lipid-like core, while their hydrophilic (water-attracting) heads face outward, interacting with water. This structure allows micelles to encapsulate water-insoluble substances, such as hydrophobic drugs, aiding in their solubility and delivery.
How do hydrophilic colloids act as emulsifying agents?
Hydrophilic colloids, such as hydrophilic polymers, act as emulsifying agents in oil-in-water (O/W) emulsions by forming a protective multimolecular film around dispersed oil droplets. This stabilizes the emulsion by preventing droplets from coalescing. Additionally, they increase the viscosity of the water phase, further improving stability. Unlike surfactants, they do not significantly lower interfacial tension but instead stabilize emulsions through steric and viscosity effects.
What are examples of hydrophilic colloids?
acacia, tragacanth, gelatin
How do finely divided solid molecules act as emulsifying agents?
Finely divided solid particles stabilize emulsions by adsorbing at the interface and forming a protective film around dispersed droplets. This barrier prevents coalescence, enhancing emulsion stability. These particles are typically less than a micron in size and can stabilize either oil-in-water (O/W) or water-in-oil (W/O) emulsions.
What are examples of O/W finely divided solid particles?
Must be hydrophilic:
* bentonite, magnesium aluminum silicate, aluminum hydroxide
What are examples of W/O finely divided solid particles?
Must be hydrophobic:
* Charcoal
What law describes creaming?
Causes physical INSTABILITY of emulsions
Stokes Law
What mathematical equation describes stokes law?
V = (d2(pi – pe)980)/18n
* V: velocity of sedimentation
* d: diameter of droplets
* pi: density of internal phase
* pe: density of external phase
* n: viscosity of external phase
* 980 cm/sec2: gravity constant
What is creaming? Is it reversible?
Causes physical INSTABILITY of emulsions
Creaming refers to the upward or downward movement of dispersed droplets in an emulsion due to density differences between the internal and external phases. According to Stokes’ Law, the velocity (V) of this movement depends on factors like droplet size (d), density difference (pi - pe), viscosity (n), and gravity.
Trends:
* Larger droplets and greater density differences lead to faster creaming.
* Higher viscosity of the external phase slows down creaming.
* Creaming is reversible as long as the interfacial film around droplets remains intact, preventing coalescence and phase separation.
What is viscosity?
Viscosity is a measure of a fluid’s resistance to flow. It describes how thick or sticky a liquid is and how easily it deforms under an applied force.
* High viscosity: Fluids like honey or syrup flow slowly.
* Low viscosity: Fluids like water or alcohol flow quickly.
Viscosity is influenced by temperature (higher temperatures usually lower viscosity) and molecular interactions within the fluid. It plays a crucial role in emulsions, suspensions, and many industrial applications.
What is coalescence? Is it reversible?
Causes physical INSTABILITY of emulsions
- Droplet size increases because interfacial film is unable to maintain integrity of individual droplets
- Irreversible, ultimately leads to layer of oil and layer of water (broken emulsion), can’t be fixed by shaking and must be reformulated
What is phase inversion?
Causes physical INSTABILITY of emulsions
Phase inversion occurs when an oil-in-water (O/W) emulsion changes into a water-in-oil (W/O) emulsion or vice versa. This can happen when the phase volume ratio exceeds 74% (ideally kept below 50%) or due to chemical changes.
For example, an O/W emulsion stabilized with sodium stearate can invert to a W/O emulsion when exposed to hard water containing calcium. This is because sodium stearate reacts with calcium, forming calcium stearate, which has different emulsifying properties, leading to phase inversion.
How do we predict the type of emulsion by inspecting the formula?
To predict the type of emulsion, consider the solubility of the emulsifier and the phase volume ratio:
* Emulsifier solubility: The phase in which the emulsifier dissolves best will become the external phase.
Surface-active agents (based on HLB value):
* HLB < 10 → Forms W/O emulsions
* HLB > 10 → Forms O/W emulsions
Hydrophilic colloids → Always form O/W emulsions
Finely divided solids:
* Hydrophilic (contact angle <90°) → O/W
* Hydrophobic (contact angle >90°) → W/O
Phase volume ratio (oil phase volume/total emulsion volume):
* 0-26% oil → O/W only
* 26-74% oil → Either O/W or W/O
* 74-100% oil → W/O only
What are the typical components of an emulsion?
Dispersed Phase (Internal Phase)
* The phase that is broken into small droplets and dispersed in the continuous phase.
* In oil-in-water (O/W) emulsions, the oil is the dispersed phase.
* In water-in-oil (W/O) emulsions, the water is the dispersed phase.
Continuous Phase (External Phase)
* The phase in which the dispersed droplets are suspended.
* In O/W emulsions, water is the external phase, while in W/O emulsions, oil is the external phase.
Emulsifying Agent (Surfactant or Stabilizer)
* Reduces interfacial tension and stabilizes the emulsion by preventing droplet coalescence.
Can be:
* Surfactant (e.g., Tween, Span)
* Hydrophilic colloids (e.g., acacia, gelatin)
* Finely divided solids (e.g., bentonite, magnesium hydroxide)
Additional Ingredients (Optional but Common)
* Preservatives: Prevent microbial growth (e.g., parabens, benzoic acid).
* Viscosity Modifiers: Enhance stability (e.g., xanthan gum, carbomers).
* Antioxidants: Prevent oxidation of oils (e.g., tocopherol, BHT).
* Flavoring/Coloring Agents: For oral and cosmetic emulsions.
How are emulsions manufactured?
Selection of Emulsifier
* Choose based on solubility and HLB value for desired emulsion type.
Phase Preparation
* Heat both the oil phase (containing oil-soluble ingredients) and aqueous phase (containing water-soluble ingredients) separately.
Emulsification (Mixing and Homogenization)
* Mix the two phases under agitation while adding the emulsifier to create small droplets.
* Use high-speed homogenization or sonication for fine droplet dispersion.
Cooling & Final Adjustments
* Cool the emulsion while stirring to prevent phase separation.
* Adjust pH, viscosity, or add preservatives if needed.
Storage & Stability Testing
* Store under controlled conditions and test for creaming, coalescence, or phase separation to ensure long-term stability.
Why would we rather select a suspension dosage form rather than a solution?
- Solubility (less soluble)
- Chemical stability: zero order (constant degradation rate, longer shelf life at higher concentrations, predictable stability)
- Palatability (taste)–> masks flavor
When would a suspension be preferred to a tablet dosage form?
- Flexibility of dose (more flexible)
- Ease of swallowing (easier to swallow)
- Dissolution rate (dissolves faster)
What properties are desirable for a suspension?
Suspended material shouldn’t settle rapidly
Particles that settle must not form a hard cake, should be readily redispersed into uniform mix when container is shaken
Easy to administer
* Not too viscous to pour freely form orifice or through syringe
* External lotion: fluid enough to spread over affected area but not so mobile that it runs off
Particle size is constant during storage
Based on Stokes Law, what factors affect the velocity of sedimentation of a suspension dosage form?
According to Stokes’ Law, the velocity of sedimentation (V) in a suspension is influenced by:
* Particle Diameter (d): Smaller particles (smaller d) settle more slowly, reducing V, which improves suspension stability.
* Viscosity of the External Phase (n): Higher viscosity (larger n) slows down sedimentation, also reducing V, which helps keep particles suspended longer.
Thus, reducing particle size and increasing viscosity are key strategies to enhance the stability of suspension dosage forms.
List common methods of particle size reduction.
- Micropulverization (10-50 µm) – Uses mechanical impact to reduce particle size; commonly used for oral and topical formulations.
- Fluid Energy Grinding (<10 µm) – High-velocity gas streams break down particles; suitable for parenteral and ophthalmic formulations requiring ultra-fine particles.
- Spray Drying (<5 µm) – Liquid is atomized into fine droplets and dried rapidly, producing very small particles, often used for inhalable drugs and dry powders.
What processes occur during aging of a suspension to bring ΔG toward zero?
During the aging of a suspension, the system tends to reduce its free energy (ΔG) to reach a more stable state by minimizing surface area. This leads to:
* Aggregation – Small particles clump together, reducing the overall surface area and lowering energy.
* Crystal Growth – Smaller particles dissolve and recrystallize onto larger particles, increasing their size and reducing surface energy.
Both are a result of ΔA (particle size) being larger
How do Van der Waals forces affect suspensions?
Operates at moderate distance from the surface but becomes strong close to surface, formulation factors don’t affect (all molecules are affected by van der waals)
How does hydration repulsion affect suspensions?
Due to absorbed water molecules at surface of a particle, the formulation factors don’t affect
How does electrostatic repulsion affect suspensions?
Due to surface charge on particles, we can control with formulation.
How does steric repulsion affect suspensions?
Due to an adsorbed layer of neutral polymer at the surface of a particle, we can control with formulation.
What is dispersion?
When individual molecules separate, but cake when they settle.
What is flocculation?
When molecules have certain forces between them that keep them a certain distance apart from each other. This results in a higher suspension volume when the molecules settle.
What is newtonian flow?
- constant fluid viscosity
What is non-newtonion flow?
Not constant fluid viscosity
* Plastic: typical for flocculated suspensions, shear-thinning
* Pseudoplastic: typical for polymer solutions (methyl cellulose, polyvinyl alcohol, sodium carboxymethylcellulose, xanthan), shear-thinning
* Dilatant: exhibited by suspension having high solids content, shear-thickening
How can shear-thinning rheology be used to prepare suspensions?
Facilitating Mixing and Dispersion:
* Shear-thinning fluids exhibit a high viscosity at rest, which helps keep particles suspended and prevents settling.
* Under shear (e.g., during mixing or processing), the viscosity decreases, reducing resistance and allowing for easier dispersion of solid particles in the liquid medium.
Controlling Flow and Stability:
* Since a certain shear stress is needed to initiate flow, the suspension remains stable when undisturbed.
* When subjected to shear (e.g., during pumping or application), the lower viscosity ensures smooth and uniform flow.
What is the the dispersed (Stokes law) approach to suspensions?
- Aim to achieve slow rate of sedimentation
- Cloudy suspension, dense sediment
- May form non-suspendable sediment
What is the the controlled flocculation approach to suspensions?
- Rapid rate of sedimentation
- Clear supernatant, large sediment volume
- Easily redispersed by shaking
What is the the structured vehicle approach to suspensions?
- May appear as a semi-solid when undisturbed but is fluid when shaken
- No sedimentation
- Thixotropic
What does thixotropic mean?
A material’s viscosity decreases under shear stress but gradually recovers when the shear is removed
What are the usual components of suspension dosage forms?
- Active ingredient (solid particles)
- Vehicle
- Buffer
- Preservative
- Flocculating agent
- Structured vehicle system
- Wetting agent
- Antifoaming agent
- Flavor and sweetener
What does parenteral mean?
Taken into the body or administered in a manner other than through the digestive tract (IV or IM)
What are examples of parenterals?
- Solutions ready for injection
- Dry, soluble preparations ready to be combined with solvent before use
- Suspensions ready for injection
- Dry, insoluble preparations ready to be combined with a vehicle before use
- Emulsions
- Liquid concentrates ready for dilution prior to administration
What are some considerations with parenteral products?
You must meet stringent requirements, such as sterile, endotoxin-free, particle-free (particles have to be really small if going directly to the bloodstream).
What was the New England Compound Center tragedy?
Triggered the passage of Drug Quality and Security Act
* Section 503B: higher production standards
What happened?
* Inadequate controls increase risk of incidence of medication errors: incorrect ingredients and strengths of ingredients, contamination with pathogens or pyrogens
* Several deaths and increased illness occurred as a result
What USP chapters are enforcable by the FDA?
USP chapters <1000
What is USP 797?
Standards for sterile compounding:
* Microbial contamination (non-sterility)
* Excessive bacterial endotoxins)
* Variability from intended strength of ingredients
* Physical and chemical incompatibilities
* Chemical and physical contaminants
* Use of ingredients of inappropriate quality
What are the standards of sterility for parenteral products?
- Parenteral formulations must be free of microbial organisms
- Achieved by sterilization: steam, filtration, dry heat, gas, irradiation
What does it mean when parenteral products are endotoxin free?
- Pathogenic contaminants that produce fever and septic shock
- Remnants of microorganisms
- Not removed by sterilization: sterilization kills, and these are already dead
Foreign particles can…
- Trigger immune response
- Produce damage to lungs/kidneys
- Kill people
