Transcript What Factors affect Drug Absorption

FACTORS AFFECTING DRUG
ABSORPTION
TOPICS :• Absorption
• Introduction to factor’s affecting absorption
• Theories of Dissolution
Drug Absorption
Enteral Route
Absorption
Topical Route
Parenteral Route
Distribution
Metabolism
Elimination
Drug Absorption after oral administration
• An oral drug has to be absorbed to have an effect
• Drug absorption is a multi-step process that is affected by multiple factors
• Rate & extent of drug absorption has a direct impact on drug efficacy
Rapid
Slow
Drug Absorption Process for a solid dosage
form
GI Barrier
GI Lumen
Solid Dose form
Disintegration
Deaggregation/Drug
release
Drug in solution
Blood
What Factors affect Drug Absorption ??
Physicochemical
factors
• Solubility, dissolution rate, particle size
• Chemical form, stability
Formulation related
• Dissolution time , disintegration time, nature of dosage form
• Excipients role, manufacturing variables
Physiological factors
• Age, gastric emptying, residence time, pH
• Disease state
Physico-chemical factors affecting Drug
absorption
• Solubility:
• Absolute/Intrinsic solubility Definition: Max amount of solute dissolved in
given solvent under standard conditions of temp, pH, solvent composition
• Only drug in solution absorbed
• Solubility is static property of drug
• Dissolution Rate:
• Simply defined as “Rate of solubilisation of drug”
• Dynamic process
• Drug solubility has affect on drug dissolution
Drug Absorption Process
GI Barrier
GI Lumen
Rate determining Steps
Solid Dose form
Disintegration
Deaggregation/Drug
release
Drug in solution
Blood
Theories of Dissolution
• Several theories proposed to explain process of Dissolution
1. Diffusion layer model/film theory
2. Interfacial barrier model/Double-barrier
3. Danckwert’s model/Penetration or Surface renewal theory
Theories of Drug Dissolution
GI Barrier
Diffusion Layer Model/Film Theory
GI Lumen
Two Step
process
Solid Drug
Diffusion of molecules
Second Step (Rate limiting)
Standard
Diffusion Layer
First Step
(Rapid)
Thickness (h),
Conc (Cs)
Bulk of drug in
solution (Cb)
Blood
Theories of Drug Dissolution
GI Barrier
Diffusion Layer Model/Film Theory
GI Lumen
Solid
Stagnant
film
Bulk Liquid
Cs
Ct
h
Bulk, rapid mixing
Blood
Theories of Drug Dissolution
Equation to explain the rate of
𝑑𝐶
dissolution ( ):
𝑑𝑇
Diffusion Layer Model/Film Theory
Solid Core
Diffusion of molecules
Noyes & Whitney proposed the
following based on Fick’s 2nd
law of diffusion
𝑑𝐶
= k (Cs − Cb)
𝑑𝑇
Standard
Diffusion Layer
Thickness (h),
Conc (Cs)
Bulk of drug in
solution (Cb)
Where k is dissolution rate
constant (1st order)
Theories of Drug Dissolution
Diffusion Layer Model/Film Theory
𝑑𝐶
𝑑𝑇
Equation to explain the rate of dissolution ( ):
Nernst & Brunner modified previous equation to
incorporate fick’s 1st law
𝑑𝐶
𝐷 𝐴 𝐾𝑤/𝑜 (𝐶𝑠 − 𝐶𝑏)
=
𝑑𝑇
𝑉ℎ
Solid Core
Standard
Diffusion Layer
Thickness (h),
Conc (Cs)
Bulk of drug in
solution (Cb)
Where : D is diffusion coeff
A – surface area
𝐾𝑤/𝑜 - Water/oil partitioning of drug
V – volume of dissolution med
h - thickness of stagnant layer
Theories of Drug Dissolution
Diffusion Layer Model/Film Theory
Diffusion rate is a 1st order process where
(𝐶𝑠 − 𝐶𝑏) is the driving force under Non-sink
conditions
Solid Core
Standard
Diffusion Layer
Thickness (h),
Conc (Cs)
𝑑𝐶
𝐷 𝐴 𝐾𝑤/𝑜(𝐶𝑠 − 𝐶𝑏)
=
𝑑𝑇
𝑉ℎ
Bulk of drug in
solution (Cb)
In-vivo 𝐶𝑠 ≫ 𝐶𝑏 since the drug is absorbed thus
removed, thus all factors in equation constant
under Sink condition
Equation converts to zero order
𝑑𝐶
=K
𝑑𝑇
Theories of Drug Dissolution
𝑑𝐶
𝐷 𝐴𝐾𝑤/𝑜(𝐶𝑠 − 𝐶𝑏)
=
𝑑𝑇
𝑉ℎ
1st Order
In-vivo 𝐶𝑠 ≫ 𝐶𝑏 since the drug is absorbed thus
removed, thus all factors in equation constant under Sink
condition
Equation converts to zero order
𝑑𝐶
=K
𝑑𝑇
Conc of
Drug
Diffusion rate is a 1st order process where
(𝐶𝑠 − 𝐶𝑏)
is the driving force under Non-sink conditions
Zero Order
Time
Theories of Drug Dissolution
Influence of some parameters on dissolution rate of drug:
𝑑𝐶
𝐷 𝐴 𝐾𝑤/𝑜 (𝐶𝑠 − 𝐶𝑏)
=
𝑑𝑇
𝑉ℎ
Where : D is diffusion coeff
A – surface area of solid
𝐾𝑤/𝑜 - Water/oil partitioning of drug
h - thickness of stagnant layer
So what can we do to
improve dissolution ??
Theories of Dissolution
• The Interfacial Barrier Model
Cs
Ct
Free energy barrier
Bulk, rapid mixing
• Assumes a similar stagnant film around solid
• Reaction at the solid/liquid interface however is
NOT instantaneous
• This is due to a high activation free energy
barrier which has to be overcome before the
solid can dissolve
• Simple diffusion of drug from interface to end of
stagnant layer
• Rate of diffusion in layer fast
• Rate limiting step is reaction at interface to
dissolve solid
Theories of Dissolution
• Danckwert’s Model (Surface renewal
model)
Solid-liquid
interface, Ci < Cs
Solvent packet with
drug leaving interface
Solid
Drug
Fresh Solvent
packet
• No stagnant layer around solid surface
• Solvent packets approach solid, drug
moves by diffusion
• Drug transports out via solvent packets
• Since the solvent exposed to new
surface= “Surface Renewal Model”
• Ci (Drug conc at interface) is less than
Cs (Max solubility)
•
𝑑𝑚
𝑑𝑡
= A Cs − Cb sqrt (γ 𝐷)
Particle Size and Effective Surface Area
Particle Size and Effective Surface Area
Decrease in
particle size
Increase in
Surface Area
Decrease in
particle size
below 0.1 micron
(micronisation)
Increase in particle
energy leading to
increased interaction
with solvent
Increase in Dissolution
rate, intrinsic solubility
Spironolactone,
griseofulvin
dose reduced
by particle
reduction
Challenges & Solutions to Particle Size
Reduction
Challenges
Solutions:
Hydrophobic surface adsorbs air,
lowers wettability
• Re-aggregation of particles
• Agglomeration
• Net effect is lower dissolution
rate
• Use of surfactants as wetting
agents (polysorbate 80)
• Add hydrophilic diluents to make
drug surface hydrophilic (PVG, PVP,
Dextrose)
Particle reduction NOT suited for
• Unstable drugs in solution
• Undesirable effects
• Sustained effect desired
Chemical State
Internal structure
of compound
Crystalline
Polymorphs
Enantiotropic
Monotropic
Amorphous
Molecular
adducts
Chemical State
Crystalline
More than 1
forms
Polymorphs
Enantiotropic
Reversibly
changes to
different form
Molecular
adducts
Monotropic
Unstable at all
temp
• Most stable form has lowest
energy state, lowest solubility
• Others are metastable forms,
preferred form for
formulation
Salt form
• Most drugs weak Acids/Base
• Convert to salt = easiest way to increase solubility/dissolution
• Weak acid + strong base = strong base salt ( sodium, K)
• Weak base + strong acid = Strong acid salt (HCL, sulphate)
pH of diffusion
layer higher (5-6)
Salt of
Weak Acid
pH of bulk sol lower
Soluble drug
absorbed
Diffusion of soluble
particles
Fine ppt of acid drug &
then leads to dissolution
Issues & Challenges of using Salt form
• Selection of appropriate salt important
• Size of counter ion matters in increasing dissolution
• In general, smaller the size of ion greater is solubility
• Larger ions have other benefits: Prolong action, taste mask, enhance GI stability
In-situ (At site, locally) Salt formation to
increase solubility/dissolution
Alkaline buffer around
Acid promoting solubility
Salt concept used to create insitu salt environment ,
promoting dissolution
Acid
Drug
Acid Drug
Advantages:
• Enhanced bioavailability
• Better tolerability (less gastric irritation)
• Better solubility
Increase pH around
micro-environment of
drug
Drug pKa
• pH Partition Theory of “Drug Absorption”
• Theory states that drugs (> 100) absorption via passive diffusion is
governed by 3 Factors
1. Dissociation constant of drug (pKa)
2. pH of environment
3. Lipid solubility of drug
Only the un-ionized drug is absorbed
More lipophilic the drug, faster is absorption rate
Extent of Drug Ionisation
• Amount of drug in ionized/un-ionized form depends on pKa & pH
Stronger
ACIDS
pKa
0
BASE
7
Stronger
14
Some basics on acidity
ACIDS
Un-ionised
0
BASE
ionised
ionised
7
pKa
Un-ionised
14
Effect of Drug pKa on absorption
ACIDS
BASE
Very Weak
pKa > 8
Moderate
pKa: 2.5 - 7
Strong
pKa: < 2.5
Very Weak
pKa < 3
Moderate
pKa: 5 - 11
Strong
pKa: > 11
Un-ionized
along all pH in
GI (2 – 8)
Un-ionized in
stomach,
ionized in
intestine
Ionised at all
pH, poor
absorption
Un-ionized
along all pH in
GI (2 – 8)
ionized in
stomach, Unionized in
intestine
Ionised at all pH,
poor absorption
Pentobarbital
Hexobarbital
Cloxacillin
Aspirin
Disod
cromoglycate
Theophylline
Caffeine
Reserpine
Codeine
Mecamylamine
Limitations to pH partition theory
• Theory presents an oversimplified model of drug absorption
• Theory has limitations, some deviations from theory
1. Presence of micro pH environment
1.
Difference exists between luminal pH and micro pH around cell membrane
2. Absorption of ionized drug
1.
2.
3.
4.
Ionised forms of drugs also get absorbed from intestine
Absorption of ionised form however is slower
Big lipid groups on structure help the movement through lipid membrane (morphinan
deriv)
In addition, other mechanism of transport (carrier mediated )
Limitations to pH partition theory
• Theory presents an oversimplified model of drug absorption
• Theory has limitations, some deviations from theory
1. Influence of GI surface area & residence time
1.
Intestine remains a major region of absorption for both acidic & basic drugs due to
large surface area and residence time
2. Presence of unstirred aqueous layer
1.
2.
3.
4.
Aqueous layer around mucosal wall
Several 100 microns thick
Affects rate of absorption of drugs
Effect more on high MW drugs
Total Aqueous Solubility (ST)
• Total aqueous solubility of ionisable drug important determinant of
passive diffusion
• Total aq solubility = Solubility of ionized form + Solubility of un-ionized
• Solubility of un-ionized also called “intrinsic solubility (Sa/Sb)”
Weak Acids
When pH
Weak Base
When pH
<pKa, ST = Sa
=pKa, ST = 2Sa
>pKa, ST >> Sa
<pKa, ST >> Sb
=pKa, ST = 2Sb
>pKa, ST = Sb
Lipophilicity and Drug Absorption
• Only un-ionized drug IF sufficiently lipid soluble can be absorbed
• Ideally for optimum absorption the drug should be
• Sufficient aqueous solubility to dissolve in fluids close to site of absorption
(Kw/o)
• Sufficient lipid solubility to cross the lipid membrane (Ko/w)
• In other words an optimum hydrophilic-lipophilic balance (HLB)
• Experimentally Ko/w is calculated by solubility in n-octanol/pH 7.4 buffer
• Strong correlation between Ko/w & degree of absorption
Other Physico-chemical factors
• Drug permeability & Absorption
• Lipophilicity
• Polarity of drug ( H-bond acceptors & donors)
• Molecular size
• Drug Stability
• Degradation
• Stereochemical nature
Dosage form factors affecting absorption
Manufacturing
Process
Excipients
(Non-Drug
component)
Manufacturing process affecting absorption
• Granulation Method:
• Wet granulation widely used but has limitations
• Crystal bridge
• Hydrolysis
• Thermolabile drugs
• Direct compression offers faster dissolution rate
• Newer methods offering even faster dissolution rate
• APOC (Agglomerative Phase of Communition)
• Extensive grinding by ball mill to promote agglomeration
• Tablets stronger, faster dissolution rate due to increased surface area
Manufacturing process affecting absorption
• Compression Force:
• Affects density, porosity, hardness, disintegration time, dissolution time
Rate of
dissolution
Compression Force
Non-Drug component affecting drug
absorption
• Drug Product = Drug (API) + Non-drug component (Excipient)
Vehicle
Lubrican
ts
Diluents
Excipients
Surfacta
nts
Binders
Disintegr
ants
Non-Drug component affecting drug
absorption
Vehicle
Lubrican
ts
Diluents
Excipients
Surfacta
nts
Binders
Disintegr
ants
• Vehicle:
• Important component of Oral/Parenterals
• Rapid absorption from aqueous/watermiscible solvents (propylene glycol)
• Water-immiscible solvents (Veg oils):
• Dissolution rate depends on drug moving from oil
to water phase & Viscosity of solvent
Non-Drug component affecting drug
absorption
• Diluents (Fillers):
Vehicle
Lubrican
ts
Diluents
Excipients
Surfacta
nts
Binders
Disintegr
ants
• Hydrophilic diluents promote dissolution in case
of hydrophobic drugs by coating
• Dicalcium phosphate most widely used inorganic diluent
• Unwanted interactions with drug might result in
lower bioavailability
• Dicalcium phosphate + Tetracycline = insoluble
complex, poor absorption
Non-Drug component affecting drug
absorption
• Binders & Granulating Agents:
Vehicle
Lubrican
ts
Diluents
Excipients
Surfacta
nts
Binders
Disintegr
ants
•
•
•
•
•
Used to hold together granules or powders
Keep dosage form intact
Aqueous binders promote dissolution
Amount of binders critical for optimal dissolution
Polymeric binders: Starch, PVP, cellulose
derivatives
• Gelatin, sugar solution
Non-Drug component affecting drug
absorption
Vehicle
Lubrican
ts
Diluents
Excipients
Surfacta
nts
Binders
Disintegr
ants
• Disintegrants:
• Overcome binding, break tablet on water
contact
• Most of binders are hydrophilic in nature
• Lower amount can affect dissolution
• Challenges with Adsorption of drugs, high
compression force retarding dissolution
Non-Drug component affecting drug
absorption
Vehicle
Lubrican
ts
Diluents
Excipients
Surfacta
nts
Binders
Disintegr
ants
• Surfactants:
• Widely used as wetting agents, solubilizers,
emulsifiers
• Effect on absorption is complex
• Increase in absorption mechanism:
• Promote wetting, dissolution of drugs
• Better membrane contact, increased
permeability of drug
• Polysorb-18 + phenacetin
Non-Drug component affecting drug
absorption
Vehicle
Lubrican
ts
Diluents
Excipients
Surfacta
nts
Binders
Disintegr
ants
• Surfactants:
• Widely used as wetting agents, solubilizers,
emulsifiers
• Effect on absorption is complex
• Decrease in absorption mechanism:
• Form drug-micelle complex that cannot be
absorbed
• Occurs at surfactant conc >> critical micelle conc
• Laxative action due to high surfactant conc
Non-Drug component affecting drug
absorption
Vehicle
Lubrican
ts
Diluents
Excipients
Surfacta
nts
Binders
Disintegr
ants
• Lubricants:
• Promote flow of granules
• Mostly hydrophobic so inhibit dissolution
(Stearates)
• Use of soluble lubricant’s should be preferred
(SLS< carbowax)
Non-Drug component affecting drug
absorption
• Suspending agents:
• Complexation with drugs, increased viscosity preventing drug movement affect
drug absorption
• Complexation to improve absorption:
• Inert complex formation to improve absorption through
• Enhanced dissolution, lipophilicity, membrane permeability
• Ex. Ergotamine-caffeine, hydroquinone-digoxin
• Colorants:
• Dyes are known to adsorb on crystal surface affecting dissolution of drugs
• Ex. Brilliant blue slows dissolution of sulphathiazole
THANK YOU
-PHARMA STREET