ceutics exam 1

define pharmaceutics

The science of dosage form design

-> turning a NCE or API into safe and effective dosage form

NCE

'New chemical entity'. A newly discovered drug, in the early stages of testing

API

Active pharmaceutical ingredient (exerts pharmacological effect)

generally, while drugs are made with the disease in mind, pharmaceutics caters to?

patient needs

pre-formulation

involves the characterization of a drug's physical, chemical, and mechanical properties in order to choose what other ingredients (excipients) should be used in the preparation

ex: vaccine formulation-> under what temp will it survive? what ingredients will curb stress?

excipients

inactive substances used as a carrier for the active ingredients of a medication

describe what characteristics are considered during pre-formulation

1. particle size/distribution

2. polymorphism

3. solubility

4. dissolution rate

5. membrane permeability

6.pKa

7. stability

8. partition coefficient

why wouldn't you give a pure drug to a patient?

small doses, unstable, patient compliance

a dosage form relies on what 2 elements

1. formula

2. process

define dosage form

a preparation devised to make possible the administration of medication in measured amount

(API + excipients)

drug substance

Active Pharmaceutical Ingredient (API)

what makes a drug product

drug substance (API) and excipients

identify 8 benefits of dosage forms

1. correct dose

2. protect API during storage

3. protect APi from gastric acid

4. conceal bad taste/odor

5. rate-controlled drug action (extended release, etc)

6. optimal drug action topically

7. insertion into cavities

8. inhalation therapy

pharmacokinetics vs pharmacodynamics

Pharmacokinetics: What the BODY does to the drug (metabolism, excretion)

Pharmacodynamics: What the DRUG does on the body

(pharmacological effect)

biopharmaceutics

the study of the physical and chemical properties of drugs and their proper dosage as related to the onset, duration, and intensity of drug action

(release, dissolution, absorption)

passive vs facilitated diffusion

passive: passes through membrane from high to low

facilitated: passes through membrane from high to low through CARRIER PROTEIN

**no energy needed for both (unlike active)

active transport

requires both carrier protein and ENERGY

endocytosis

process by which a cell takes material into the cell by infolding of the cell membrane

where does most drug absorption take place

small intestine

what drives absorption in passive diffusion

concentration gradient

Fick's first law states what 2 things are proportional

The rate of drug diffusion is proportional to the concentration gradient.

What is Fick's first law of diffusion?

-dQ/dt = DAK /h (Ca-Cp)

dQ/dt= rate of drug diffusion

D= diffusion rate coefficient

A: surface area

K: partition coefficient (oil/water)

h= thickness of membrane

Ca-Cp: concentration gradient

*note: (DAK/h)=P or permeability coefficient

increase in D, A, K means increased diffusion

increase in h (thickness) means less

example of drug that uses active transport

5-fluoracil

anti-cancer drug that uses active transport to go from low to high concentrations using energy

example of drug that uses facilitated diffusion

cephalosporin

-> goes from high to low but uses carrier protein (no energy)

describe the necessary protonation state for a drug to pass through a membrane

only the NON ionized (no charge) form of a drug passes through a cell membrane

how can an acid pass through a membrane? a base?

HA: protonated acids can pass (no charge)

B: unprotonated bases can pass (no charge)

A- and HB+ cannot pass

what is pKa

the pH at which there are equal amounts of the unprotonated and protonated form of weak acid or base

Henderson-Hasselbalch equation

pH = pKa + log [A-]/[HA]

(base over acid)

EX:

A drug is a weak acid with pKa=3. At a pH of 2, will the drug be absorbed?

pH = pKa + log [A-]/[HA]

2 = 3 + log(x)

-1= log(x)

10^-1 = x

x= 1/10 so 1 A- for every 10 HA so more uncharged molecules= it is absorbed

EX:

A drug is a weak base with pKa=10. At a pH of 8, will the drug be absorbed?

8 = 10 + log [A-]/[HA]

-2 = log (B/BH+)

1/100 =x

so 1 base (uncharged) per 100 acid (charged)

more charged molecules so it will not be absorbed

*note for bases, it is not A- and HA. instead, it is B and BH+

ADME

Absorption (small intestine), Distribution (blood), Metabolism (liver), Excretion (urine/feces)

describe how the route of administration can affect time course of drug in body by giving examples

sublingual: quick to absorb but quick to be eliminated

intravenous: constant amount in body since continuously supplied

Bioavailability

how much of an oral dose reaches systemic circulation (ex: a metabolized drug is no longer bioavailable)

when is bioavailability 100%

never, unless through IV

why does bioavailability decrease when drugs are taken orally

1. incomplete absorption

2. first pass metabolism (liver)

what category of pharmacy is bioavailability crucial

pharmacokinetics

necessary to know how body responds to drug to calculate dose

oral bioavailability equation

F= fa* Fg * FH

oral bioavailability= (fraction of dose released and passes through gut) (fraction not metabolized in intestine) (fraction escaped metabolism in liver)

Describe the 5 graph markers seen on a concentration vs time curve of a drug

Cmax= peak concentration

Tmax= time of peak concentration

AUC= area under curve= entire amount of drug in blood/plasma

MEC= minimum effective concentration

MTC= minimum toxic concentration

what does MEC on graph tell us

the minimum effective concentration

if drug does not surpass this, then t is not effective

what happens to Cmax and Tmax if the rate of drug absorption is increased

Cmax is increased and Tmax is decreased

what happens to Cmax and Tmax if the rate of drug absorption is decreased

Cmax is lowered and Tmax is longer/ later

Drug A has a later Tmax but more time spent above MEC. Drug B has an earlier Tmax but less time spent above MEC. What does this mean?

Drug A has a later onset but longer duration of action.

Drug B has rapid onset of action but shorter duration of time.

AUC

area under the curve

measure of the total amount of drug absorbed into circulation

Can 2 curves with different C max and Tmax have same AUC?

yes. AUC is measure of the total amount of drug absorbed into circulation. excipients may be different.

what does it mean 2 equivalent doses of the same drug are given but they provide different AUC values

there is a difference in how much of each drug is absorbed

absolute bioavailability

fraction of drug absorbed through non IV compared to IV (which is 100% bioavailable)

relative bioavailablity

fraction of certain drug absorbed when compared to another formulation of same drug

absolute vs relative bioavailability

Absolute = IV to not IV (one drug oral vs IV)

Relative = not IV to not IV (2 drugs given orally)

bioequivalence

AUC and Cmax are similar

drugs are similar in both rate and extent of bioavailability (superimposable concentration vs time graphs)

BCS

biopharmaceutics classification system

classifies drugs based on aqueous solubility and membrane permeability for ORALLY administered drugs

Which BCS class has best absorption

BCS1= high solubility, high permeability

Which BCS class is least likely to make it to market due to issues pertaining to bioavailability?

BCS 4= low solubility, low permeability

BCS 2=

low solubility, high permeability

what makes up an emulsion

2 immiscible liquids

-internal/dispersed phase: droplets

-external/continuous phase: outer portion

types of emulsions

water-in-oil (w/o) & oil-in-water (o/w)

internal phase

dispersed phase

inner droplets

external phase

continuous phase

outer portion

droplets in emulsions are usually greater than _____ in size, giving a _________ appearance

0.1 micrometers; milky appearance

(microemulsion: 10-200nm)

o/w

oil in water emulsion

w/o

water in oil emulsion

w/o/w

water-in-oil-in-water

multiple emulsion

purpose of doing multiple emulsion (ex: w/o/w)

1. separates incompatible substances

2. adjusts drug release rates

advantages of emulsions

-more palatable (taste)

- greater chemical stability

- smaller oil globules = more digestible and increased absorption

- enhanced skin absorption

- less irritating to skin in internal phase

why are smaller oil globules in emulsions advantageous

1. more digestible

2. increases absorption

why are emulsions beneficials for topical drugs

1. enhanced skin absorption

2. drugs that irritate the skin are less irritating in the internal phase

castor oil

emulsion laxative

simethicone

emulsion defoaming agent

surface active agents are also known as

surfactants, amphiphiles, emulsifying agents, SAAa

amphiphilic

molecules possessing both hydrophobic (nonpolar) and a hydrophilic (polar) parts

all SAAs are amphiphilic

adsorbed

held on the surface

what allows SAAs to be adsorbed on interfaces

amphiphilic nature allows polar heads to face water and nonpolar tails to face water

where do heads and tails of surfactants face

head= polar= water

tail= nonpolar= oil

_______ must be nontoxic, stable, and compatible with water, oil, and drug

SAAs

SAAs provide droplets with ____________________ to make mutual repulsions

adequate electric potential

SAAa must be effective in __________ concentrations

low

Critical Micelle Concentration (CMC)

The surfactant concentration at which micelles form

HLB

hydrophillic/lipophilic balance (0-20), low HLB is more oil, high HLB is more water

HLB increases as

polarity/ hydrophilicity increases

HLB>9

vs

HLB

greater than 9: o/w (think hit hard, up= ow)

less than 9: w/o

mineral oil HLB in o/w vs w/o

4 in w/o

10.5 in o/w

how do you determine what HLB an emulsifier should have

should be similar to oils

overall HLB value=

sum of (each fraction * HLB)

increasing the concentration of the internal phase to >75% can cause

inversion

why does inversion lead to instability

if SAA favors o/w and it is inverted to w/o, then it is no longer stable

4 classifications of SAA based on ionic contents

1. anionic= negative charge on head

ex: sodium layryl sulfate in toothpaste, tri ethanolamine dodecyl sulfate, sodium dodecyl benzene sulfonate

2. cationic= positive charge on head

= bacteriostatic, reacts w cell wall

ex: quaternary ammonium, cetyl trimethyl ammounium Br

3. ampholytic= both + and - zwitterionic head, depends on pH

4. non-ionic= water soluble head that does NOT have charge

Spans (w/o) and Tweens (o/w)

which SAAs are bacteriostatic

cationic

Spans vs Tweens

both nonionic SAAs

Spans (Sorbitan fatty acid esters)= oil soluble, promote w/o

Tweens (PEG-sorbitan fatty acid ester)= water soluble, promote o/w

(think tweens= mean= ow)

3 theories of emulsification (summary)

1. surface tension theory

= liquids assume shape with least amount of area exposed

=SAA lowers interfacial tension= break globules into smaller parts= reduce coalescence

2. oriented-wedge theory

= formation of MONOmolecular layer around drops = prevent coalescence via 1) electrical repulsion 2) physical separation via layer

3. interfacial-film theory

= MULTImolecular film at interface prevents coalescence

1) increases viscosity 2) charge repulsion

interfacial tension

Interphase between two liquids

SAA vs interfacial tension and coalescence

SAAs LOWER interfacial tension and REDUCE coalescence

high pressure homogenizer

uses high pressure to make homogenized product

continental/ dry gum method

1. add gum/SAA to oil

2. add water all at once and triturate= crackle and white

3. add other ingredients

fixed(4o:2w:1g)

mineral (3o:2w:1g)

volatile (2o:2w:1g)

English/wet gum method

(think england= wet)

1. add gum/SAA to water

2. add oil slowly and triturate

3. add other ingredients

Bottle Method

*used for volatile oils or low viscosities

1. gum and oil shaken in bottle

2. add water and then oil in proportions

micro/nano emulsions

clear

transparent

thermodynamically stable systems of two immiscible fluids

size of micro/nano emulsions

10-200nm

why are nanoemulsions not true solutions

they are dispersions of oil, so even though they are transparent, they arent completely soluble like a solution

example of SAA used in micro/nano emulsions

polysorbate 60 and 80

micro/nano emulsion advantages

- rapid oral absorption

-increased diffusion into skin

-targets cytotoxic drugs to cancer cells

how can you dilute emulsions

o/w: dilute with water (external phase)

w/o: dilute with oil