oral drug administration and products

exam 1

what is local action

drug has little to no diffusion out of GI lumen contents (or area where drug is), acts at the site where the drug is (topical, some GI, etc)

what is systemic action

drug diffuses from GI contents to reach sites of action

what is the route of drug diffusion

GI lumen → small intestine membrane capillaries → hepatic portal vein → systemic bloodstream

what are two of the most critical factors for delivery of a drug into systemic circulation

solubility and lipophilicity

what is the sequence of oral drug absorption events

1. exposure

2. deaggregation

3. dissolution

4. diffusion

5. blood-borne transport

6. liver effects

7. absorption

what happens after a dosage form disintegrates

dosage form becomes granules → granules go into solution OR deaggregate into fine particles to go into solution

what is the purpose of wetting agents

allow water to contact the entire surface of hydrophobic drug particles → deaggregate compacted particles, increase dissolution rate

how do wetting agents work

decrease solid-liquid interfacial tension or repulsion

when are superdisintregrants used

poorly water soluble APIs, tablet matrices with higher pH values

used so that disintegration is not rate-limiting

what is dissolution

process by which a compound/solute moves from a solid state into solution in the presence of a solvent

what are the steps of dissolution

drug molecules on surface are wetted and enter solution → saturated layer around solid particle (diffusion layer) → molecules migrate from diffusion layer to bulk solution → molecules dissolve to maintain saturation of diffusion layer

what equation describes dissolution

noyes-whitney equation

C = concentration in bulk solvent

S = saturated solubility of diffusion layer

h = thickness of diffusion layer

A = surface area of the solid drug exposed to dissolution media

D = diffusion coefficient of the drug

what can the Noyes-Whitney equation (dissolution rate) tell us

greater surface area → greater dissolution rate

smaller diffusion layer → greater dissolution rate

greater difference in diffusion layer concentration and bulk concentration → greater dissolution rate

what formulation factors affect drug dissolution

particle size — smaller = faster dissolution

disintegrating agent

wetting agent — increases fluid contact with drug particles

what is an example of a disintegrating agent

microcrystalline cellulose

what is agitation

way to minimize saturated diffusion layer → accelerate dissolution of solid particle

smaller diffusion layer → faster diffusion

how does viscosity of GI contents effect drug dissolution

higher viscosity slows dissolution by maintaining a thick diffusion layer

what is the rate limiting step of absorption if dissolution is rapid

the ability of the drug to be absorbed across membrane barriers (permeability)

what is the rate limiting step of absorption if dissolution is slow

dissolution process

how long does it take for gelatin shells, film, and sugar coatings dissolve after being swallowed

~15 minutes

what are the advantages of orally disintegrating tablets

can take without water

avoids hepatic first pass if drug dissolves in mouth and diffuses through mucous membranes

what is an example of buccal/sublingual formulations

nitroglycerin — diffuses through mucus membranes and reaches heart in a few seconds

what is the purpose of film and sugar coatings on tablets or gelatin capsules

protect API from light, moisture, oxygen, and chemical contaminants

prevent premature disintegration

prevent or reduce disagreeable taste/odor

makes swallowing easier

what pH do enteric coatings dissolve or rupture at

pH >5 — usually in lower small intestine

what is the purpose of enteric coatings

delayed drug exposure

protect drug from stomach acid

protect stomach lining from drug

what drugs can cause the stomach acid to have a pH >5

antacids, H2RAs, PPIs — use enteric coating formulations in caution

what is the normal pH of the stomach

1-3

what parts of the GI tract have pH >4

dudoenum, jejunum, ileum

what is fick’s law for drug diffusion

C1 = dissolved (free or unbound) molecules in Gi contents

C2 = dissolved (free or unbound) molecules in GI membrane capillaries

P = membrane surface area and partition coefficient

what chemical factors increase diffusion rates

MW/FW <500

lipophilicity > hydrophilicity

<5 H-bonds

<10 N and O atoms

what factors of the GI contents increase drug diffusion rate

lower viscosity (more flowy)

drug not bound to material in contents (free floating)

shorter time/faster rate of stomach to duodenum emptying

what can slow stomach to duodenum transit time

more solid contents

lower pH

higher viscosity

fat > protein > carb (carbs slow transit time but are the weakest at slowing it)

why does swallowing all PO drugs with 6-12 fl oz of watery fluid increase drug diffusion

solid PO drugs — faster dissolution rate and reduced viscosity of stomach contents

liquid drugs — decreased viscosity of stomach contents

when does hepatic first pass effect occur

after diffusion but before absorption

what does the hepatic first pass effect do

decreases extent of absorption or bioavailability if it happens to a drug

how do unmetabolized drugs exit the liver

hepatic vein → inferior vena cava → right atrium → systemic circulation

what is enterohepatic circulation

absorption of drug → goes to liver → excreted in bile → reabsorbed

what can cause a PO drug to not be 100% absorbed when swallowed

incomplete dissolution, incomplete diffusion, and hepatic first pass metabolism

what measures the extent of bioavailability

AUC — area under curve, drug in plasma vs time (all drug in bloodstream over all time after a dose

F — absorbed fraction of swallowed dose

how do you find Fpo (absorbed fraction of a swallowed dose) of cipro

Fpo = AUCpo/AUCiv

Fpo = 1.77/2.88 = 0.61 → 61% of swallowed dose is absorbed

what measures the rate of bioavailability

Cmax and Tmax

what is Cmax

height of peak plasma drug C — larger C max = faster absorption

max plasma drug concentration

what is Tmax

time after ingestion until Cmax — shorter Tmax = faster absorption

what are fluid dosage forms

elixirs

solutions — all elixirs, most syrups

syrups — can be solution or suspension

what are the characteristics of suspensions

most of the drug exists as small, wet particles that dissolve fast

small % of drug strength is dissolved so diffusion starts instantly when swallowed

describe one specific cause for faster absorption of suspensions than caps or tabs

a small percentage of the drug is already dissolved so diffusion starts instantly when swallowed

true or false: faster absorption from suspensions than caps and tabs usually makes a clinically significant difference in effectiveness

false — usually not clinically significant

what are the clinical benefits of a controlled delivery system

less frequent dosing → enhanced compliance

smaller peak to trough plasma concentrations → fewer adverse effects, fewer therapeutic failures

what are different controlled delivery system designs

OROS

pulse delivery system

what are the classes in the biopharmaceutical classification system

I — high solubility, high permeability

II — low solubility, high permeability

III — high solubility, low permeability

IV — low solubility, low permeability

what are the characteristics of an ideal tablet

free of defects

strong enough to withstand mechanical stress

chemically and physically stable over time

capable of releasing medicinal agents in a predictable and reproducible manner

how are tablets manufactured

wet granulation, dry granulation, or direct compression

what are excipients

components added to APIs that have special functions but no pharmaceutical function

what are granules

small particles stick together — agglomerate of dried powders containing one or more API with other excipients

what are the advantages of granules

free flowing — better flow than powders

more stable physically and chemically

particle size and content uniformity is better than powder

easily wetted by solvent

easier to compress than powders

what is granulation

the process by which powder particles adhere to form large particles

what happens in wet granulation

powder particles are suspended in fluidized granulator by spraying liquid from below then drying

what are the different types of tablet excipients

diluents/fillers

binders and adhesives

disintegrants

lubricants, antiadherents, glidants

colors and dyes

flavoring agents

artificial sweeteners

adsorbents

what is the purpose of diluents/fillers

increase the mass and bulk volume to produce a manageable size

contributes to 40-90% of tablet content

what are examples of diluents/fillers

lactose, kaolin, mannitol, starch, powdered sugar, microcrystalline starch, calcium phosphate

what is selection of a diluent based on

compatibility with other ingredients and cost

what is the purpose of binders/adhesives

promote granulation or cohesive compacts during direct compression

what are common binders and adhesives

10-20% aqueous corn starch

25-50% solution of glucose

various natural gums

cellulose derivatives (MC, CMC, MCC)

gelatins

povidone

can be liquid or dry form

when is binding action more effective

when binder is in liquid form

what can happen when an agent is overwetted with binder

granules are produced that are too hard for tableting

what can happen when an agent is underwetted with binder

produce tablets that are too soft and tend to crumble

what is the purpose of disintegrants

aids in disintegration of tablet when tablet contact water in the GI tract

how do disintegrants work

draw water into the tablet → cause tablet to swell and burst

what are common disintegrants

cornstarch and potato starch

starch derivatives

cellulose derivatives

clays

cation exchange resins

how are disintegrants added to the drug-diluent mixture

part is added with the lubricant

part is added to the prepared granules of the drug

what is the purpose of lubricants

reduce the friction that occurs between the wall of the die cavity when the tablet is ejected

what is the purpose of antiadherents

reduce sticking of the tablet granulation or powder to the faces of the punches or die walls

what is the purpose of glidants

promote the flow of the tablet granulation or powder by reducing friction among the particles

think: stops powders from sticking together so they flow better

what are examples of lubricants/antiadherents/glidants

stearic acid and its derivatives

colloidal silicon dioxide

talc

starch

what is the purpose of colors and dyes

disguise off-color drugs, provide product identification, and produce more aesthetically pleasing product

when are flavoring agents and artificially sweeteners normally used

in chewable tablets or tablets that dissolve in the mouth

what flavoring agents are preferred

flavor oils and dry powders — water-soluble flavors have poor stability

what are some examples of artificial sweeteners

saccharin, aspartame

mannitol, lactose — come from the diluent

what is the purpose of adsorbents/absorbents

hold quantities of fluid in an apparently dry state

what are examples of adsorbents/absorbents

mag oxide, mag carbonate, bentonite, silicon dioxide

what tablet types are for oral ingestion

compressed, multiple compressed

repeat-action

enteric-coated

sugar-coated

film-coated

chewable

what tablet types are used in the oral cavity

buccal

sublingual

troches and lozenges

what tablet types are used to prepare solutions

effervescent

dispensing

hypodermic

triturates

why might tablets for oral ingestion be coated

mask taste, color, or odor of drug

control drug release

protect drug from acidic environment of stomach

incorporate another drug and provide sequential release or avoid incompatibility

improve appearance

how are compressed tablets made

formed by compression of powdered, crystalliine, or granular materials alone or in combination with excipients

how are layered tablets made

prepared by compressing tablet granulation around a previously compressed granulation

how are compression-coated tablets made

feeding previously compressed tablets into a special tableting machine that applies a thinner, more uniform coating

what are repeat-action tablets

multiple compressed tablets where the outer layer or shell rapidly integrates in the stomach — components of inner layer are insoluble in gastric media but soluble in intestinal media

part of tab works in stomach, part works in small intestine

what agents are used to coat enteric-coated tablets/capsules

fats, fatty acids, waxes, shellac, cellulose acetate phthalate

what is the purpose of sugar coating

protects tablet from moisture/atmosphere, attractive appearance, mask bad taste

what are the disadvantages of sugar-coated tablets

time and expertise required for the process

increase tablet size and weight — ~50% larger and heavier than original tablet

what are the steps of sugar-coating tablets

1. seal coating

2. subcoating

3. syrup coating

4. polishing

what are the advantages of film-coated tablets over sugar-coated tablets

more durable, less bulky, and less time-consuming

only increases weight of tablet by 2-3%

what do film-coating solutions usually contain

film former, alloying substance, plasticizer, surfactant, opacifiers, sweetners, flavors, colors, glossants, and a volatile solvent

what is an alternative to organic solvent-based film coating solutions

aqueous dispersions of polymers (eg. ethylcellulose)

why are chewable tablets typically made with mannitol

it has a sweet, cooling taste and is easy to manipulate

cooling taste is because it absorbs heat from the surrounding environment

how do buccal and sublingual tablets work

drug is absorbed through the oral mucosa after it dissolves in buccal pouch or below the tongue

what are buccal/sublingual formulations useful for

drugs that are destroyed by gastric juice or poorly absorbed from intestinal tract — avoid GI tract to get into circulation and go through mucosa instead

what is the difference between troches/lozenges and buccal/sublingual formulations

troches/lozenges primarily have a local effect — not absorbed in the mucosa like buccal/sublingual

how are effervescent tablets made

compressing effervescent salts that release CO2 when they come into contact with water