m2 bipharmaceutics consideration in product design

drug and drug product characteristics

drug release and dissolution is determine by _ characteristics

drug

permeation acoress GI linings is determined by - characteristics

drug and physiologic (biologic)

disposition during GI transit are both affected by the _ and the - characteristics

rate-limiting step

slowest step in kinetic process

troches, chewable tablets, sustained release, prolonged or repeat action

exemptiom in USP disintegration test (solid oral dosage form)

Complete disintegration

the state in which any residue of the tablet, except fragments of insoluble coating, remaining on the screen of the test apparatus in the soft mass have no palpably firm core

-

dissolution

the process by which a solid drug substance becomes dissolved in a solvent

dynamic property

measure how fast drug dissolves, formulation sensitive

solubility

the mass of solute that dissolves in a specific mass or volume of solvent at a guven temperature

static property

does not change with time, independent of formulation

dynamic

property of dissolution

static

property of solubility

dissolution test

may be used to predict bioavailability (test)

dissolution test

test required for all US-FDA approved solid oral drug products

Noyes and Whitney equation

describes the overall rate of drug dissolutiom

aqueous environment

The in vitro dissolution system stimulated the in vivo process in terms of:

environment:

same GIT temp

The in vitro dissolution system stimulated the in vivo process in terms of:

temperature:

held at specific rom

The in vitro dissolution system stimulated the in vivo process in terms of:

agitation:

basket

dissolution apparatus type I

paddle

dissolution apparatus type II

reciprocating cylinder

dissolution apparatus type III

flow through cell

dissolution apparatus type IV

Paddle over disk

dissolution apparatus type V

revolving cylinder

dissolution apparatus type VI

reciprocating holder

dissolution apparatus type VII

biopharmaceutics

to adjust the delivery of drug from the product in such a manner as to provide optimal therapeutic activity and safety for the patient

polymorphism

the ability of a drug to exist in various crystal forms may change the solubility of the drug. Also, the stability of each form is important, because polymorphic may convert from one form to another

alkaline buffer

What to add to improve solubility of aspirin

stability-ph profile

a plot of the reaction rate constant for drug degradation vs pH

acidic medium (stomach)

eythromycin, in _ medium decompose rapidly, but is relatively stable in neutral or alkalone ph

enteric-coated

erythromycin tablets are _-coated to protect against acid degradation in the stomach

erythromycin estolate and erythromycin ethylsuccinate (suspensions both)

erythromycin that has better stability (less water soluble)

inversely

particle size and surface area are _ related

directly

dissolution rate is _ proportional to the surface area

micronized

agriseolfulvin, nitrofurantoin and many other steroids having poor absorption are milled to _ form

increased surface area enhance water penetration , thus _ increase disssolution

disintegration

adding this will ensure rapid disintegration and release of drug

surface-active agengs

increases wetting as well as solubility

hydrophobic

excessive particle size reudction does not always increase dissolution rate (in case of _ drugs)

polymorphism

refer to the arrangement of a drug substance in various crystal forms of polymorph

anhydrous

no water of hydration (polymorph)

solvates

(polymorph) contain a solvent or water

desolvad

(polymorph) solvates - solvent remove

• solubility

• density

• hardness

• compression characteristic

different polymorphs similar chemical structure but diffrent physical properties:

B-polymorph

the concentration or chloramphenicol in the body depends on the _ in the suspension

B-polymorph

form of cholamphenicol which is more soluble and better absorbed

diamond to graphite

some polymorph are metastable and may convert to a more stable form over time example:

anhydrous

this form of ampicillin dissolves faster and is more rapidly absorbed that the hydrated form

partition coefficient

ratio of the solubility of the drug, at equilibrium, in nonaqueous solvents to that in an aqueous solvent

partition coefficient

measure of the relative affinity of a drug for ttwo immiscible solvents

1. pKa of the weak acid/base

2. pH of the solutiom

extent of ionization depends on

more

protonated form is _ lipophilic than the unprotonated, so can cross membrane more rapidly

Henderson-Hasselbalch Equation

describes the relation between the ionized and nonionized forms of a drug

ph = pka

ph __ pka

lower

for weak acids, if ph is _ than the pKa, it is relatively unionized and more lipid soluble(well absorbed from the stomach)

higher

for weakacids, if ph is _ than the pKA, it is relatively ionzed and more soluble

higher

for weakacids, if ph is _ than the pKA, imcreases gastric solubility with decreasing pH

higher

for weak base, if ph is _ than the pKA, it is relatively unionized and more lipid soluble

salt form

this form is preferred if water solubility is desired

• slower dissolution

• slower bioavailability

• longer duration of action

certain salts are designed to provide;

Sodium ascorbate

other salts are selected for

• greater stability

• less local irritation at the absorption site

  • __ preferred over ascorbic acid to avoid irritation

• less systemic toxicity

tartaric acid (2), citric acid (1), sodium bicarbonate (3.4)

parts of effervescent granules

more

K and Na salts are _ soluble than cation salts (Ca, Mg)

more soluble : Penicillin Na

less soluble : MgSo4, Al(OH)3

more and less soluble salts for weak acids

more soluble : hcl, sulfate, citrate, gluconate salts (lidocaine hcl, atropine so4)

less soluble : estolate, napsylate, stearate salts

more and less water soluble salts for weak bases

chirality

ability of a drug to exist as optically active stereoisomers or enantiomers

S(+); R(-)

Metachloline _ is 250x more potent than _ enantiomers

S (+)

Ibuprofen (_) is pharmacologically active

S(-); R(+)

Carvedilol (_) is a potent beta-receptor blocker than (_) enantiomer

+; -

Ketamine (_) is more potent and less toxic than _ enantiomer

racemic mixture

most chiral drugs

D and L

an equal mixture of __ enantiomers is optically inactive

complex

a species formed by reverisble or irreversible association of two or more interacting molecules or ions

complex

drugs + (clay, protein, or zimc) is an example of

chelate

complexes that typically involve a ring-structure formed by the interaction between a partial ring of atoms and a metal central atom

iron

entral atom of hemoglobinc

cobalt

central atom of cyanocobalamin

insoluble

chelation leads to __ complex

less

tetracycline + calcium = __ water soluble

more

Theophylline + ethylenediamine (aminophylline) = _ water soluble

increase

cyclodextrins + drug = _ water solubility

drug-protein

_ complexes do not cross membranes easily

insoluble = mask bitter taste of caffeine

caffeine + gentrisic acid =

dissociate

drug complex must _ to free drug for absorption and excretion