Test 2 Content Flashcards
Buffer systems
-minimize the changes in a solution’s pH
-if there is a sudden addition of acid or base, the buffer will maintain the pH
What are buffers composed of?
-a weak acid and the salt of the acid (i.e. it’s conjugate base)
-a weak base and the salt of the base (i.e. it’s conjugate acid)
Most pharmaceutical buffers are made of….?
a weak acid and the salt of the acid (i.e. conjugate base)
Buffering region works best within how many pH units of pKa?
Buffering region works best within 1 pH unit of pKa
Polyprotic acids
Acids that are capable of losing more than a single proton per molecule (protons lost in stages - one at a time)
When are buffers used?
-When you need to alter the pH or try to keep the pH of a solution or a dosage form in a particular range to prevent drug degradation
-to help minimize irritation of tissues
Types of dosage forms that commonly contain buffers to minimize irritation/stinging
-injection/infusion
-ophthalmic solutions
-nasal solutions
acidifying agents
added to make dosage form more acidic; can be without the addition of buffers
alkalizing agents
added to make dosage form more basic
How to select a buffer:
-consider route of administration
-buffers often prepared to be isotonic solutions
-select a buffer pair with a pKa approx. equal to (+/- 1 pH of the pKa) to the pH you need to use
-calculate from the Henderson Hasselbach equation what ratio of the buffer pair you need to add to get the desired pH
-may need to adjust the pH of the buffer with an acidifying or alkalizing agent in order to arrive at the exact pH desired
Henderon-Hasselbalch
allows for the calculation of the concentration of constituents necessary to make a buffer a certain pH; the pH of the buffer will be determined by the pKa and the ratio of weak acid to conjugate base
Buffer capacity
-a measure of the resistance to a change in pH when an acid or base is added to the solution
-expressed as the amount of strong acid or base, in gram-equivalents, that must be added to 1 liter of the solution to change its pH by one unit
Buffer capacity depends on….?
-ratio of salt to the acid or base (optimal ratio = 1:1)
-total buffer concentration (takes more acid or base to deplete 0.5M buffer than 0.05M)
Buffer capacity requirements
-must be low enough to allow for rapid adjustment upon administration to physiological pH (ophthalmic and parenteral products)
-must be large enough to maintain the product pH during shelf-life
Disintegration time
-the time required for the tablet to break down into particles
-particles can be measured how the particles pass through a sieve while agitated in a specified fluid (defined by the USP)
Factors that affect disintegration
-dosage form formulation (delayed release, extended release)
-tablet hardness
-use of disintegrants within formulation
Disintegrants
-swell upon contact with water
-break solid dosage form into smaller granules
-many are starch and cellulose derivatives
-promotes disintegration
Dissolution
-the transfer of molecules from solid state into solutions
Dissolution rate
-how quickly the solubility limit is reached
-measured in a dissolution apparatus defined by the USP
solution
a homogeneous mixture of the molecules of one substance with another (homogenous down to the molecular level)
Noyes-Whitney equation
-molecules of the dissolving particle move into solution forming a high concentration at the surface of the particle (Cs)
-molecules diffuse from the saturating film (high concentration) to the bulk fluid (low concentration)
D in Noyes-Whitney equation and how it affects dissolution rate
-Diffusion coefficient (how quickly the solute/drug molecule will diffuse through the solvent)
-viscosity of dissolution medium (this can be decreased by drinking water)
(the viscosity of the solvent is inversely proportional to the diffusion coefficient)
A in Noyes-Whitney equation and how it affects dissolution rate
-Surface area of the particle (how large the particle is “macro or micro”)
-particle size (the smaller the particle size, the larger the surface area and the higher the dissolution rate)
Cs in Noyes-Whitney equation and how it affects dissolution rate
-The concentration of drug in the saturating film equal to the solubility of the drug
-Increasing solubility increases dissolution rate
-molecular structure of solute
-pH of dissolution medium
-temperature
h in Noyes-Whitney equation and how it affects dissolution rate
-The thickness of the diffusion layer
-agitation of dissolution medium will change the thickness of this layer by making it smaller, thus increasing the dissolution rate (highly controlled in in vitro strudies)
-h is inversely proportional to the dissolution rate
C in Noyes-Whitney equation and how it affects dissolution rate
-the concentration of drug in bulk solvent
-sink conditions and the volume of the bulk fluid
-increasing the volume of the bulk fluid increases the dissolution rate (can be done by drinking water)
Solubility
The extent to which a drug (solute) dissolve in a given solvent at a given temperature
-aka equilibrium solubility
Apparent solubility
The observed solubility of a solute in a solvent system; might be higher or lower than the equilibrium solubility
Factors that influence apparent solubility
-physiochemical properties: surface area, particle size, crystal form
-properties of the solubility media: pH, polarity, added surfactants/co-solvents, temperature
Supersaturated solutions
Solutions with a concentration of solute greater than that attained under normal circumstances
-these are unstable because they will move back to true solubility resulting in precipitation
Miscibility
When both the solute and the solvent are liquids
Immiscible
liquids that will not produce a homogenous solution in any proportion (e.g. oil and water)
Miscible
liquids that form a homogenous system when mixed in any proportion (e.g. water and ethanol)
Miscible in certain proportions
e.g. water and chloroform
Its miscibility depends on the ratio of solvents
How is solubility expressed?
-as a weight in a specified volume of solvent (aqueous or other solvent) at a specific temperature. e.g. mg/L, g/L, mg/mL
-sometimes expressed as how much solvent it takes to dissolve 1 gram of solute (ratio strength such as 1g in 50mL)
Difference between solubility and concentration?
-solubility: weight in specified volumes of solvent
-concentration: weight in specified volume of solution
What type of drugs don’t need to have as good of solubility?
Drugs with high potency because a small amount can have its intended effect
FDA definition of solubility
-high potency drugs don’t need to have good solubility
-looks at solubility in a glass of water (approx 250mL)
-takes into account pH-dependent solubility (oral drugs must have sufficient solubility over the entire pH range of 1 to 7.5)
High solubility (FDA definition)
highest dose strength is soluble in less than or equal to 250mL of water over the entire pH range of 1 to 7.5
Low solubility (FDA definition)
Highest dose strength is not soluble in less than or equal to 250mL of water over a pH range of 1 to 7.5
Factors that contribute to water solubility
-polar covalent bonds
-hydrogen bond donors and acceptors
-ionizable functional groups
Factors that detract from water solubility
Nonpolar functional groups
How to alter the apparent solubility of a drug
-change the temperature
-alter the solid state properties (crystalline form vs. amorphous form); polymorphisms
-modify the pH of dissolution medium
-make a salt form
-use a solvent with a different polarity
-formulate with solubilizing agents (sufactants, cyclodextrins)
-make a drug derivative (prodrug)
-use of water-immiscible solvents (oils)
Amorphous form vs. crystalline form
Amorphous form of a drug will have better solubility than crystalline form
Polymorphs and what type will have better solubility
-polymorphs of the same drug will have different dissolution rates
-metastable polymorphs will have a better solubility than the ground state polymorph
Hydrates vs. anhydrous drug solubility
-anhydrous form of a drug will often have better solubility and a faster dissolution rate than the hydrate form
-depends on the drug and if the water incorporated into the crystalline structure strengthens or weakens the crystalline lattice
pH-dependent solubility
-a basic drug will be more soluble at an acidic pH
-an acidic drug will be more soluble at a basic pH
a drug will be more soluble in water when it is ionized
Is dissolution usually an endothermic or exothermic process?
Endothermic (heat is absorbed when dissolution occurs); raising temperature will increase solubility
Cosolvents
a second solvent that is added to a solution (usually water) that is water miscible that is used to increase the solubility of poorly water soluble drugs
Examples of cosolvents
-water
-dimethyl sulphoxide (DMSO)
-glycerine
-propylene glycol
-ethanol
-isopropanol
-polyethylene glycol 400 (PEG 400)
When are cosolvents often used?
Often used for neutral drugs where solubility cannot be altered by adjusting pH
Like dissolves like
Increased structural similarity or polarity between solute and solvent leads to increased solubility
High dielectric constants correspond to….?
High polarity
If wanting to dissolve a nonpolar hydrophobic drug, use a solvent with….
low dielectric constant
If wanting to dissolve a polar hydrophilic drug, use a solvent with….
high dielectric constant
Disadvantages of cosolvents
-oral mixtures are not palatable
-not comfortable when injected or applied to mucous membrane
-often very viscous
-may precipitate when mixed with aqueous injectables
-may cause precipitation of drug after administration
-toxicity of cosolvents via certain routes
Dosage forms that always contain cosolvents
-Elixirs
-Tinctures
Elixirs
clear, sweetened/flavored solutions that contain both water and alcohol
-used for oral admin
Tinctures
solutions prepared from vegetable or chemical substances
-made entirely of alcohol or of a water and alcohol mix
-contain high percentages of alcohol (15-80%)
Surfactants
amphipathic molecules that align themselves at surfaces to remove the hydrophobic portion from water. aka surface-active agents
4 types of surfactants
- nonionic
- anionic
- cationic
- zwitterionic
Nonionic surfactant
Have a water-soluble group that is not charged
Anionic surfactant
carries a negative charge
Cationic surfactants
carries a positive charge
Zwitterionic surfactant
carries both a positive and negative charge
Surfactants can act as the following:
-solubilizing agents
-wetting agents
-flocculating agents
-emulsifying agents
-dispersing agents
-skin penetration enhancers
What happens when concentration of the surfactant is above the critical micelle concentration (CMC)?
Surfactants will form micelles
Disadvantages of surfactants
-can disrupt normal cell membranes causing toxicity/irritation
-some can only be used for certain routes of administration
-may cause precipitation of drug due to dilution below CMC
Cyclodextrins
another type of solubilizing agent used to improve drug solubility
-consists of cyclic oligosaccharides that contain a hydrophobic interior/cavity and a hydrophilic outer surface
-contain 6 or more (a-1,4) line a-D-glucopyranose units
-enhances solubility of poorly soluble compounds
Passive Diffusion
Molecules diffuse from a region of high concentration to an area of low concentration until an equilibrium is reached (no energy is needed)
What are the two types of passive diffusion?
Transcellular and paracellular
Transcellular
Passive diffusion into and out of the the cell
Paracellular diffusion
Passive diffusion between cells
How is permeability defined?
The distance traveled by a drug through the membrane per unit time (measured as a velocity - distance/time)
How are blood capillaries affected by permeability?
-very permeable
-permeability is independent of lipophilicity, charge and size
How is nasal mucosa affected by permeability?
affected by lipophilicity, charge, and size but more porous than GI tract
How are buccal mucosa, GI tract and lungs affected by permeability?
affected by lipophilicity, charge, and size
How is blood brain barrier affected by permeability?
highly affected by lipophilicity, charge and size
Arrange the permeability of cell types in order from excellent permeability to poor permeability
simple squamous –> simple columnar —> stratified squamous (non-keratinized) –> stratified squamous (keratinized)
Three types of Cytosis
pinocytosis, phagocytosis, recepter-mediated cytosis
Cytosis
Used by cells to engulf larger macromolecules and particles
Pinocytosis
cells endocytose water/fluids
Phagocytosis
endocytose large particles or macromolecules
Receptor-mediated cytosis
endocytosis that is inititated by binding of a ligand to a cell-surface receptor
Apical side
faces inward towards the lumen
Basolateral side
faces underlying connective tissue
Facilitated diffusion
-does not require energy
-drugs move along a concentration gradient
-allows charged and/or polar molecules to cross plasma membrance
Two types of facilitated diffusion
- channel-mediated diffusion (pores)
- carrier-mediated diffusion (transporters)
Channel-mediated diffusion (pores)
-channel is either open or closed
-allow the diffusion of ions, water, small molecules
Carrier-mediated diffusion (transporters)
-bind specific substrates, undergo conformational change to transport across the membrane
-can be passive or active (if active, no longer considered facilitated diffusion)
Active transport
-require input of energy
-actively move substances across membranes against the concentration gradient
Two types of active transport
- Primary
- Secondary
Primary active transport
active transport is driven by ATP hydrolysis
Secondary active transport
-active transport is driven by ion gradients
-uphill transfer of one solute is coupled to the downhill transfer of a second solute (called co-transporters)
Two types of co-transporters in secondary active transport
- Symporter
- Antiporter
Carrier-mediated diffusion follows which form of kinetics?
-Michaelis-Menten kinetics making it a saturable process
Transporters are most concerned about transporters in….
-intestinal epithelia
-hepatocytes
-kidney proximal tubules
-brain capillary endothelial cells
Transporter types
uptake and efflux
Transporters
essential for the absorption, distribution and elimination of many drugs
Superfamilies of transporters
- Solute carrier (SLC)
- ATP binding cassette (ABC)
Solute Carrier Family
-facilitated transporters, symporters, or antiporters;
-primarily uptake transporters
-OATP (anion transporting polypeptide), OAT (anion transporter), OCT (cation transporter)
ATP Binding Cassette (ABC)
-primary active transport
-efflux transporter
-p-glycoprotein (MDR1), MRP2-6, BCRP
Three physiological properties that affect permeability
size, lipophilicity, charge (degree of ionization)
Lapinski’s Rule of Five
Compounds likely to have good absorption and permeation if they have:
1. </= 5 hydrogen-bond donors
2. </=10 hydrogen-bond acceptors
3. Molecular weight </= 500 g/mol
4. Log P</= 5
rate-limiting step
slowest step in a series of kinetic processes
Dissolution rate limited
drugs with poor water solubility and poor dissolution
permeability rate limited
permeation across cell membrane is rate-limiting
How to improve solubility/absorption in dissolution rate limited drugs
alter pH or add a cosolvent
How to improve absorption in permeability rate limited drugs
form a prodrug
Biopharmaceutics Classification System (BCS)
classifies drugs based on their solubility and membrane permeability
-four different classes
-used to predict drug absorption and potential drug candidates
Biopharmaceutics Drug Disposition Classification System (BDDCS)
classifies drugs based on their solubility and metabolism
-can also be used to predict drug-drug interactions and food effects in vivo
Bioprecursor prodrug
type of drug that does not contain a promoiety
-still considered a prodrug because the structure is modified by enzymatic action to form the active drug
Reasons to make prodrugs
-improve solubility or permeability
-decrease first pass loss
-improve oral absorption
-protect against chemical stability problems
-mask taste/odor of drug
-minimize toxicity or local irritation
-enable site-specific delivery
-provide extended release of drug
