ceutics 8 drug release and dissolution

_______________ is the process by which drug solutes leave a finished dosage form into the medium

drug release

what 4 factors affect drug release

Order of Release (zero vs first)

Physicochemical parameters

Physiological factors

Formulation Factors

(OPPF)

which drugs are typically zero-order release?

non-disintegrating tablets (topical, transdermal)

oral controlled (osmotic, low solubility matrix)

zero order processes take place at a ________ rate

constant

do zero order processes depend on concentration

no

If a patient was given 100mg of drug A, which absorbs at a rate of 10mg/min at ZERO ORDER kinetics, how much will be absorbed after 5 minutes?

5*10mg= 50mg

equation for zero order release

Qt=Q0 +Kt

Qt= cumulative amount of drug released at time t

Q0= initial amount of drug

K= constant

t= time

in a drug release vs time graph, what slope does a zero order process follow?

linear slope

first order processes takes place at a constant ______________ of the drug concentration

proportion

(not a constant rate!)

which drug release kinetics is dependant on concentration

first order

If a patient was given 100mg of a drug that follows first order kinetics and absorbs 10%/min, how much is absorbed after 2 minutes?

minute 1= 100(.1)= 10mg absorbed

minute 2= 90(.1)= 9mg absorbed

which kinetics absorption process theoretically never comes to an end

first order

first order release equation

Log Qt= LogQ0 +Kt/2.303

to get a straight line of a first order kinetics process, what is put on the x and y axis?

x= time

y= LOG % of drug release

[note in zero order, its time vs % of drug release]

describe how a zero order vs a first order release line would look on a graph of time vs release rate

zero order: horizontal line (constant)

first order: non-linear decrease (depends on concentration)

what are the formulation factors and physicochemical properties that can affect drug release

pH

temp

Ionic strength

Enzymes

dissolution rate is defined as the amount of solute dissolved in a given solvent under standard conditions of ________(4 things)____

Temp

constant solid surface Area

pH

solvent composition

TAPS

what is the difference between solubility and dissolution

dissolution: kinetic; process of solute dissolving to form solution

solubility: thermodynamic; outcome of dissolution

what is the rate determining step of a drug with low solubility? Which BCS class is this?

RDS= dissolution

-this step is often the slowest

BCS class 2 and 4

for soluble drugs, what is the rate determining step? what BCS class is this?

RDS= absorption

BCS class 1 and 3

prerequisites for drug absorption

release, dissolution, and permeation

what can affect the rate of dissolution

-particle size

-solubility

-salts

-crystalline state

- drug formulation

-manufacturing methods

-environmental factors

-physiological factors

what can be added to prevent clumping of very small particles during dissolution to increase absorption

a wetting agent (ex: Tween 80)

explain the particle size and solubility equation

log (s/s0)= [2yV]/[2.303RTr]

s= solubility of fine particles

s0= solubility of large particles

y= surface tension

V= molar volume

r= final radius (cm)

R= gas constant= 8.314*10^7

T= temp in KELVIN (C+273.15)

*remember to convert Celsius to kelvin and micro to cm

what is pHp

-below which an acid will precipitate

-above which a base will precipitate

[not on exam]

pHp equations for base and acid

base: pHp= pKw-pKb + log [s0/(s-s0)]

acid: pHp= pKa + log [s0/(s-s0)]

s0= molar solubility of acid/base

s= molar concentration of Salt initially added

**both are M or mol/L

[not on exam]

explain what salts you would use for an IM injection vs an oral drug

oral: whichever has highest concentration (for better absorption) [fast release]

IM: whichever absorption is more constant (not necessarily highest absorption) [slow release]

what are polymorphs

drugs with various crystal forms

= different solubility and dissolution properties

as solubility increases, stability ___________

decreases

if drug A has 3 polymorphs with

A= stable

B= metastable

C= unstable

which polymorph has the lowest solubility?

A because it is more stable, longer shelf life, less likely to dissolve

what does amorphous mean

any non-crystalline drug

does an amorphous or crystalline drug dissolve more rapidly

amorphous (bc less stable)

what would happen if an amorphous drug began to convert to a crystalline form

crystalline forms are more stable and therefore slower to dissolve= less effective

explain what happened when the diluent for sodium phenytoin capsules changed from calcium sulfate dehydrate to lactose

when lactose was used as a diluent, drug absorption increased

= dose lowering was necessary

T/F: excipients do not have an effect on drug dissolution

false

which lubricants and glidants were shown to reduce absorption and for which drugs?

cyanocobalamin: talc and magnesium stearate (slows dissolution)

if magnesium stearate slows drug dissolution, why might it still be used as an excipient

you may want to slow absorption if you are giving a drug via IM

how do viscous solutions affect drug dissolution rate

= increase amount of time spent in stomach

= decrease in rate of movement of drug to SI for absorption

*this LOWERS dissolution rate

what is the order of dosage forms going from most to least bioavailable

aqueous solution (most)

aqueous suspension

SGC

HGC

uncoated tablets

coated tablets (least)

what are the factors affecting the rate of dissolution of tablets related to composition/manufacturing

1-3. diluent, disintegrant*, surfactant amount/type

4. granule size

5. tablet machine type

6. compression force/speed

7. wet or dry method

what are the factors affecting the rate of dissolution of capsules related to composition/manufacturing

1. diluent, lubricant*, surfactant amount/type

2. granulation vs slugging

3. granule/powder size

4. compression force

5. capsule shell composition/properties

what environmental factors can affect drug dissolution

1. humidity

2. storage conditions

3. shelf-life/aging (ex: SGC swelling=crosslinking= hard to open)

how do you know which kinetics model to use for a drug?

based on correlation coefficient (r)

=model with highest r value is used

which 5 math models did we learn about for drug release

1. zero order (constant)

2. first order (depends on initial concentration)

3. Noyes-Whitney (constant SA; depends on solubility)

4. Hixson-Crowell

5. Higuchi

In the noyes-whitney equation, what is assumed to be constant

surface area of particle (S) and static diffusion layer (h)

In the noyes-whitney equation, what determines the dissolution of a drug?

aqueous solubility

Noyes-Whitney equation

dissolution (mass/time)= (DS/Vh)(Cs-C)

D= diffusion coefficient (cm2/sec)

S= SA (cm2)

V= solvent volume

h= thickness of stagnant layer (cm)

*remember thickness is in cm

in the Noyes whitney model, what is Cs vs C

Cs= concentration of drug in stagnant layer

C= concentration of solute in bulk solvent (lower)

**C is not present under sink conditions!!

what are sink conditions

solvent in which drug is dissolved in is constantly replenished to mimic GI conditions

**no influence of concentration gradient

using the Noyes Whitney equation, how can you enhance solubility?

1. increase SA by decreasing particle size

2. reduce diffusion layer thickness (h) by mechanically stirring

for Noyes Whitney equation, how can you decrease "h" (static layer thickness)

mechanical stirring

what dosage form could the Noyes Whitney model work for

medication with constant SA

ex: transdermal patches

Hixon-Crowell model applies for what drugs and assumes what?

- applies for powder drugs (tablets, capsules, suspensions)

assumes

1. spherical particles

2. shape remains spherical

3. all particles have same size (uniform)

Hixon Crowell equation

W0^(1/3) - W^(1/3)= kt

w0= original mass

w= mass of drug remaining

k= dissolution rate constant

**uses cube roots

Higuchi equation

Q= Kh t^(1/2)

Q= cumulative amount of drug released at time t

Kh= higuchi constant

t= time in HOURS!

x and y axis for linear higuchi model

x= square root of time in HOURS

y= cumulative amount of drug released

which drugs is a higuchi model used for

drugs released from a matrix

T/F: dissolution is a good predictor of therapeutic efficiency

false! its a qualitative tool for bioavailability and batch-to-batch consistency

*good quality control tool

rotating basket method vs paddle method

basket: USP 1

-capsules, suppositories with LOW DENSITY and tend to FLOAT

paddle: USP 2

- tablets and capsules that SINK

disadvantages of rotating basket method

1. gummy substance can clog basket screen

2. inadequate flow rates when particles leave basket and float up

which mesh size is USUALLY used for the rotating basket method?

40-mesh

in which dissolution method is degassing important

rotating basket method

standard volume for rotating basket method and paddle method

900/1000ml

advantages of the rotating basket method

1. more than 200 monographs

2. full pH change during test!

3. easily automated

advantages of paddle method

1. easy and robust

2. easily adapted to apparatus 5

3. long experience

4. pH change possible

(**full pH change in basket method)

5. easily automated

what is the method of first choice to assess dissolution

paddle method (USP 2)

most distinct disadvantage of paddle method (USP 2)

coning problem (clumping of drug under paddle)

what is the basket/paddle method aimed to replicate?

process of the GI tract

*NOT anatomy/ physiology

paddle and rotating basket methods have a pH ranging from _____

1.1-7.5

what are some composition differences btwn simulated gastric vs intestinal fluid

gastric: NaCl, HCl, deionized water

intestines: KH2PO4

NaOH

deionized water

for delayed release tablets:

paddle and rotating basket methods have pHs of

2 medias:

pH= 1.1

pH= 6.8-7.5