Exam 3 First Set of Lecture Slides Flashcards
Why are small molecules needed?
Proteins naturally do not get into cells (but are starting to level off at around 32%)
What are some challenges to the pharmacy field?
- Move towards automation and mail order reduces need for retail positions
- More diseases and dosage forms increases the background knowledge needed
What is drug product performance?
The ability of the drug to elicit a therapeutic response and to stay in a safe therapeutic range during dosing regimens
What is the importance of drug product performance?
- If there is too little of a drug = not efficacious
- If too much of a drug = toxic effects
Drug product performance is…
a function of the drug, the formulation, and the body
What is the main goal of formulations?
Transfer new, promising therapeutic compound and develop a reproducible dosage form
The dosage form will go through different stages of what?
Formulation scale (from small batches on a bench to large batches in facilities)
What does reproducible mean?
Each dosage form contains the same amount of drug and has the same performance in the body
What has to be balanced?
The release of the dosage form and the way the body processes the medicine
What are some components of a typical blood level versus time curve?
Cmax: highest concentration of the drug in the blood
Tmax: the time it takes to get to Cmax
AUC: area under the curve
What can we not control?
disposition phase
What occurs during disposition?
distribution, metabolism, excretion
What primarily controls the removal of the drug from the body during the elimination phase?
metabolism and excretion
Where do we normally measure the blood/plasma levels?
in the arm
What is enterohepatic recycling?
Drugs that get secreted in the liver can get reabsorbed
What can we and cannot control?
We can control the dosage form but not what the body does to the drug
What is the absorption rate (kabs) defined by?
- the drug properties
- the excipient/drug composition of the formulation
- the physiological barriers between the GI tract and systemic circulation
When does absorption begin declining?
As disposition begins to increase
What are we trying to achieve with the dosage form design?
The margin of safety (don’t want to cause unwanted effects)
What is druggability?
the binding as well as the drug like properties that are favorable for product translation such as solubility
What is the difference between druggability and developability?
- discovery stage
- assesses the ability of NCEs to bind to the drug target
- in vivo models are used to assess
What is the difference between developability and druggability?
- refers drug product performance
- incorporates factors like biorelevant solubility and dissolution
- formulation factors related to ADME/T incorporated
What does the druggable genome refer to?
Genes that encode disease related proteins that can be modulated by drug like molecules → compare the genome of a healthy individual to a person that might have a disease
What is a druggable protein?
proteins that can bind drug like compounds with binding affinity below 10 mM (have to modulate the protein)
What is the process of druggability?
druggable genes are identified by pharmacogenomic methods → genes that encode disease related proteins and are modulated by drug like molecules are identified → druggable genes are converted to proteins with in silico methods so that binding cavities can be identified
What is a pharmaceutically tractable genome?
Genes that encode proteins which can be targeted by small molecular weight compounds, antibodies, and recombinant therapeutic proteins for pharmaceutical use
What is the goal when finding a drug candidate to a gene and the protein associated with the disease?
Want something to bind to the pocket and also mitigate the disease
What does druggability not infer?
That a compound will elicit a therapeutic response in a patient
What are the main indices of safe and efficacious use?
pharmacokinetics (what the body does to the drug) and pharmacodynamics (drug effect on the body)
What goes into consideration for the drug itself?
physicochemical properties and pharmacological efficacy
What goes into consideration when selecting a vehicle?
Properties are selected based on the ability to overcome physiological barriers and enable therapeutically relevant drug delivery from the site of administration
What is the trinity of formulation design?
- physicochemical properties of the drug
- physicochemical properties and composition of the formulation
- biological factors that influence performance (ADMET)
What are the 3 factors that govern drug performance in the clinic (need to be balanced)?
- physicochemical properties of the API
- physicochemical properties and composition of the formulation
- physiological barriers that influence the “targeted bioavailability” of the drug
What are some physicochemical properties of the drug that can affect absorption?
- solubility
- drug stability in solution (aka esters so if break down too fast = bad)
- lipophilicity (need some to get across the cell)
- molecular size and shape (big, long and extended = bad)
- pKa of ionizable groups (ionized has harder time)
- physical state of the drug
4.
What are the subsections of the physical state of the drug which is a physicochemical property that can affect a drug’s absorption?
- amorphous vs crystalline
- polymorphism
- hydrates/solvates
- liquid/gaseous
What are the 4 things that solubility depends on?
- molecular structure
- physical state
- composition of solvent
- measurement methods
What are the 2 physical states that solubility can depend on?
solid: amorphous (cotton candy is amorphous with sugar), crystalline, polymorphic form
liquid: predissolved in a solvent
What goes into consideration of the solvent composition?
- types of solvents
- co-solvent percentages
- solution components like salts and ions
- pH, temperature
What are the 2 measurement methods of solubility?
equilibration time and detection method
What is the partition coefficient?
The ratio of concentrations in 2 immiscible solvents (octanol and water) given as K = Coctanol/Cwater
What is the pH-partition hypothesis?
For drugs that are absorbed passively (transcellular mechanism), the permeability transport depends on the fraction of unionized drug at the intestinal pH.
What is the relationship between solubility and the partition coefficient?
As the partition coefficient (Ko/w) increases, the solubility decreases.
As we move down the stomach and the small intestine where the pH is different, how do the absorption of different molecules change?
The absorption of weak acids in the beginning of the duodenum and as we travel to the ileum, weak bases are absorbed
What is the difference in solubility of octanol and water?
The solubility of water in octanol is 4% but the solubility of octanol in water is 0.4%
Why is octanol:water partitioning not an accurate predictor of physiological conditions?
The protein to lipid ratio in the GI tract is 1.7:1
What is the importance of the mucus layer in the GI tract?
Mainly used for protection → if not present, the intestines could digest themselves
What can affect drug transport?
different extracellular and the intracellular pHs
Organelle pH can result in what?
the trapping of a molecule in a cell
What is the trend in pH of the GI tract?
Starting from the stomach at 8.0, it decreases to 6 in the proximal jejunum and then increases to 6.9 in the distal colon
What is the trend of most acidic to least acidic of intracellular organelles?
lysosomes → secretory granules → endosomes → golgi → ER → cytosol → mitochondria
Polyprotic molecules have multiple what?
Charged sites (so multiple charged states at different pH environments)
How are cells held together?
With tight junctions that act like a Ziploc bag with small pores
How can we overcome the effect of the pH partition hypothesis?
- functionalize the compound change pKa
- prodrug strategy
- salt selection
- drug delivery system
What does the prodrug strategy involve?
Can modify the charged moiety or modify the molecule to be recognized by a transporter
What does salt selection entail?
ion pairing can be effective in improving permeation (with transdermal to pair a fatty acid and an amine) and the salt form can alter the unionized fraction
What is the rule of 5 when there is poor absorption/permeation is likely?
- More than 5 H bond donors
- More than 10 H bond acceptors
- MW over 500
- MlogP is over 4.15 and ClogP is over 5
What is polar surface area (PSA)?
Is the solvent accessible surface area (SASA) provided by O, N, and H attached to them → good estimate of H bonding potential but does not account for charges
What percent of drugs are transporter substrates?
30%
What is performance?
The ability of the drug to elicit a therapeutic response and to stay in a therapeutic range → has a lack of a toxic/non-efficacious response (balance)
What are the formulation factors that affect absorption?
- dosage form design
- rates of drug release from the dosage form
- residence time at absorption site
What goes into the dosage form design?
- size, excipient compositions (want good size everyone can swallow)
- manufacturing parameters
What goes into the rates of drug release from the dosage form?
disintegration, dissolution, deaggregation, erosion of coating, osmotic pumps
What goes into the residence times at the absorption site?
mucoadhesives and coatings (ex. at low pH ciprofloxacin could stick to the stomach wall and mucus to increase residence time)
What are the types of solid dosage forms?
tablets, capsules, film strips, powders (fine), granules, beads, minitabs, osmotic pumps, gelcaps
What is the mechanism of an osmotic pump?
Have a water and salt chamber and when water comes in, salt swells up and squeezes the drug out of tiny holes into the GI tract
What is the anatomy of a tablet?
an outer coating and the ingredients: active, diluent, binder, disintegrant, glidant, lubricant
What happens if the release of a tablet is not correct?
Too fast = can risk toxicity
Too slow = may never get to the target site
What happens when the release of the drug is incorrect?
Too fast = can risk toxicity
Too slow = may never get to the target site and get efficacious response
What is the role of a disintegrant?
The tablet can swell and break up into smaller parts to have a larger amount of surface area and could better dissolve
What is an excipient?
Usually an inert substance (like gum arabic or starch) that forms a vehicle for the drug to control the release → low toxicity
Pharmaceutical products may comprise of what percentage of excipients?
> 10% to <99%
Excipients are…
NOT INERT
(ex. amprenavir (Agenerase) that had a large amount of propylene glycol in solution to achieve adequate solubility which caused patients discomfort)
What are the 13 functional classes of excipients?
binders, disintegrants, fillers (diluents), lubricants, gildants, compression aids, colors, sweeteners, preservatives, dispersing agents, film formers, flavors, printing inks
What are examples of binders?
starches, sugars, cellulose, lactose, sugar alcohols
What are some examples of disintegrants?
starches, sugars
What are some examples of fillers (diluents)?
starches, sugars, cellulose
What are some examples of lubricants?
magnesium stearate, talc
What are some examples of gildants (flow enhancers)?
silicon dioxide, cellulose, titanium dioxide, talc
What are some examples of compression aids?
starches, sugars, lactose, cellulose
What is an example of colors?
titanium dioxide
What are examples of sweeteners?
sucrose, fructose, dextrose
What are examples of preservatives?
citric acid, sodium citrate, methyl paraben, propyl paraben
What are examples of dispersing agents?
gelatins, starches, gums, cellulose
What are some examples of film formers?
polymers
What are some examples of flavors?
sodium chloride, citric acid
What are some cellulose based excipients?
microcrystalline cellulose (MCC), SMCC, HPMC, HPC, ethylcellulose (usually bulking agents)
What are some sugars as common excipients?
sucrose, lactose, mannitol
What are some starches as common excipients?
pregelatinized starch, sodium starch glycolate
What are some synthetic polymers as common excipients?
polyvinyl pyrrolidone (PVP), polyethylene oxide (PEO)
What are some common inorganic excipients?
dicalcium phosphate, silicon dioxide
What are some common organic excipients?
magnesium stearate, stearic acid, crospovidone, talc, shellac, titanium dioxide, gelatin
What does compendial status mean?
That it is approved for pharmaceutical use (GRAS status only applies to food additives)
What are critical factors in excipient selection?
- origin, source, availability
- functional category
- quality and purity
- impurity levels and extent of characterization
- batch to batch consistency (different suppliers have to be interchangeable)
- stability in the pure form and in formulation (don’t want it to break down)
- compatibility with active and packaging material
- toxicological considerations
- cost, regulatory, or compendial status
- biological activity
- patent status
What are the ingredients that affect bioavailability, stability, and marketing considerations?
- disintegrants → enhance rate of disintegration/dissolution
- coatings → control release
- flavors/sweeteners → mask drug taste
- colors → recognition
What are some common methods for excipient compatibility testing?
- binary or formulation blends (with or without 10-20% w/w water)
- suspension or solution of excipients and drug
- mechanical stress by milling or co-milling drug
- using amorphous drug (want to see if it stays amorphous or crystallizes)
- compacts of prototype formulation by direct compression
- tablets processed by wet granulation
- calorimetry (measuring heat)
Excipients can be used to control what?
Flow (glidants) → better flow means better mixing and filling of tablet machines → increases the ability to keep the dose the same
What is the angle of repose?
A characteristic of how well a powder flows → smaller angles mean increased flow
What is small scale blending?
Like a mortar and pestle where you take 10 mg AI and 10 mg excipient and mix it well and continue to add/mix
What is larger scale blending?
Like a Kitchen Aid mixer that results in a lighter, fluffy product
What is content uniformity?
Assures that all capsules and tablets contain the same weight and content of powder with no variations (all have same concentration of AI) → important so we know patients will get a reproducible performance
What happens when you overcompress that tablet?
It becomes plastic like/brittle and will fall apart (want same plastic to elastic ratio)
What are some ingredients that can affect compaction properties?
- diluents/fillers → add mass
- binders/adhesives → hold tablets/formulation together
- lubricants → reduce friction in tablet presses
- anti-adherents → keeps powders/particles from sticking to surfaces
- gildants → enhance inter-particulant flow (get a well mixed blend)
What are the organoleptic senses to consider when coating/blinding in clinical trials?
- sight → size, shape, color, markings, packaging (aesthetics!)
- smell → odor of dosage form
- sound → tablet/pellet inside a capsule does not rattle
- taste → mask any unique taste
- touch → coatings, isotonicity, viscosity
What is the effect of compression force on a bed of powder?
There is a combination upon decompression between an elastic response and a plastic response: if elastic → tablet does not form, powder is still present
if plastic → just compressed into uneven disks and is brittle and could break apart (very compact)
What are the requirements for a solid dosage form?
- must have content uniformity (every tablet needs 85-115% API or tighter for controlled substances)
- have good organoleptic properties for patients
- need to be stable for a shelf life of 2 years
- reproducible release metrics as measured by dissolution for batch release
- must not be friable
What goes into a solid dosage form having content uniformity?
- mixing and powder flow
- glidants allow powders to flow over one another
- excipient concentrations should also be correct
What is the importance of having good organoleptic properties for patients?
patient compliance issues and excipients are able to change colors, adjust taste, and mask smell (coatings)
What is the importance of having a shelf life of 2 years for solid dosage forms?
solvents in the formulation may increase degradation → excipient compatibility is key!
What is the importance of having reproducible release metrics measured by dissolution for batch release?
disintegrants that swell when hydrated can be used and other excipients can be used to control release
What does being friable mean?
Friable means that it can break into smaller pieces → binders and coatings can be used to avoid this and keep it solid
