Lecture 2: Influential Factors in Pharmaceutical Dosage Forms Flashcards
What are the three key reasons for dosage forms and drug delivery systems?
- Optimum drug effectiveness
- Maximum drug reliability
- Maximum drug safety
What is the rationale/design for dosage forms and drug delivery systems?
- disease
- drug
- disease site
- delivery systems
Why pharmaceutical dosage forms?
- for safe and convenient delivery of accurate dosing
- to protect drug substance from atmospheric oxygen or humidity
- to protect drug substance from gastric acid after oral administration
- to conceal bitter, salty or offensive taste or odor of a drug substance
- to provide liquid preparations of an insoluble or unstable drug in desired vehicle
- to provide rate-controlled drug action
- to provide site-specific drug delivery
What are the influential factors in dosage form design?
- molecular size and volume
- drug solubility and pH
- partition coefficient
- polymorphisms
- stability
- pKa/dissociation constant
- particle size and dissolution rate
- membrane permeability
How can drug diffusion be expressed?
Stokes-Einstein equation
What is the Stokes-Einstein equation
D = RT/6pir
D = cm2/sec
Relationship between drug diffusion and molecular weight
drug diffisivity is inversely proportional to molecular volume
dependent on molecular weight and conformation
What are five ways drug solubility and pH can be enhanced?
- salt formation
- ester formation or introduce polar functional group
- cosolvent
- complex formation
- micronization
Salt formation and drug solubility and pH
solubility of an acidic or basic drug is pH dependent
Polar functional groups
hydroxy groups amines ammoniums aldehydes carboxylates
Cosolvents and drug solubility
solubility of phenobarbital in a mixture of water, alcohol and glycerol is significantly higher compared to any of these single solvents
Complex formation and drug solubility
can be increased by addition of a third substance which forms an intermolcular complex with drug
What does micronization do?
reduce drug’s particle size
What is pH one of the most important factors in the formulation process?
it affects solubility and stability
B-cyclodextrin
enhanced solubility
inclusion complex with indomethacin sodium
Partitioning
When two immiscible liquids contain a weak acid or base drug, a part of the drug goes to the nonpolar phase and the remaining part of the drug goes to the aqueous layer
Like dissolves like
nonpolar species migrates (partitioins) to the nonpolar layer and polar species migrate to the polar aqueous layer
Partition coefficient (P)
measure of the drug’s distribution in a lipophilic-hydrophilic phase system and indicates its ability to penetrate biologic multiphase systems
Octanol-water partition coefficient
commonly used in formulation development
P = (Drug conc. in octanol) / (drug conc. drug in water(
Ionizable drug octanol-water partition coefficient
P (drug conce in octanol or nonpolar phase) / (1-a) (drug conc. in water or polar phase)
a = degree of ionization
log P = measure of lipophilicity
What can the partition coefficient be used in?
- drug extraction from plants or biologic fluids
- Transport/permeation of drugs
- Drug absorption from dosage forms
- Antibiotics recovery from fermentation broth
Polymorphism
barbiturates
steroids
sulphonamides exhibits polymorphisms
Crystalline
poorly soluble
Amorphous
more soluble
Ritonavir or Norvir
protease inhibitor
What does the physical forms of drugs affect?
dissolution rate and its extent of its absorption
What does changes in crystal characteristics influence?
bioavailability and stability
important implications in dosage form
What are pKa and dissociation and constants dependent on?
- pH of medium containing drug
- affects drug’s absorption, biodistribution and elimination
- adjust vehicle pH to obtain optimum drug’s solubility and stability
Weak acid equation
HA = H+ + A-
Ka = K1/K2 = [H+][A-]/[HA]
pKa equation weak acid
pKa = pH + log [HA]/[A-]
pKa equation weak base
pKa = pH + log [BH+]/[B] = henderson-hasselbach
pH-partition theory
drugs are absorbed by passive diffusion depending on the fraction of un-ionized form of the drug at the biological membrane
pH-partition theory degree of ionization
depends on both their pKa and the solution pH
Ionized drugs are more hydrophilic and have minimal membrane transport compared to unionized form of the drug
Solution pH of pH partition theory
will affect overall partition coefficient of an ionizable substance
pKa and pH relationship
pKa of the molecule is the pH at which there is a 50:50 mixture of conjugate acid-base forms
HH equation for weakly acidic drugs
log ionized conc. (salt) / un-ionized conc (acid)
HH equation for weakly basic drugs
log un-ionized conc (base) / ionized conc. (salt)
Limitations of the pH-partition theory
- does not hold true for most weak acids
- quaternary ammonium compounds are ionized at all pHs but are readily absorbed from GI tract
What does the pH-partition theory not take account for?
- large epithelial SA of small intestine compensates for ionization effects
- long residence time in small intestine compensates for ionization effects
- charged drugs may interact with opposite charged organic ions, resulting in neutral species which are absorbable
- some drugs are absorbed via active pathways
- drug absorption is affected by its lipid solubility
Why does aspirin often cause gastric bleeding?
- most of the administered aspirin remains un-ionized in the stomach, it is rapidly taken up by the stomach
