2. Dr. GIRI - Factors Affecting Drug Absorption.ppt

Factors affecting absorption

1. FACTORS AFFECTING ON DRUG
ABSORPTION
Dr. SREE GIRI PRASAD BERI
M. Pharm., Ph. D
Professor & Head of the Department

2. 2
ABSORPTION:
“Theprocessofmovementofunchanged
drugfromthesiteofadministrationto
systemiccirculationiscalledasabsorption”.
Itcanalsobedefinedastheprocessof
movementofunchangeddrugfromthe
siteofadministrationtothesiteof
measurementi.e.plasma.

3. Soliddosageform
Granulesor
aggregates
Fineparticles
Druginsolution
Atabsorptionsite
Ionicdrug Ionicdrug
Non-ionicdrugNon-ionicdrug1
2
3
3
3
4
BloodGILumen GIBarrier
Meansof
Sequence of events in the absorption of drugs from orally administered
solid dosage forms
3
1. Disintegration
2. Deaggregation
3. Dissolution
4. Absorption

4. Solid
dosage
form
Solid
drug
particles
Drug in
solution at
absorption
site
Drug in
the body
4

5. FACTORSAFFECTINGDRUGABSORPTION
A.Pharmaceutical Factors:
6)Lipophilicityofthedrug
7)pKaofdrug& gastrointestinalpH
pH-Partition
hypothesis
8)Drug stability
5
1) Drugsolubility& dissolutionrate
2) Particlesize& effective surfacearea
4) Pseudoploymorphism(hydrates/solvates)
5) Saltformofthedrug
3) Polymorphism&amorphism
Physicochemical Properties of Drug Substance:

6. B. Dosage Form Characteristics and
Pharmaceutical Ingredients
(Pharmaco-Technical Factors):
6
1) Disintegrationtime(tablets/capsules)
2) Dissolutiontime
3) Manufacturingvariables
4) Pharmaceuticalingredients (excipients/adjuvants)
5) Nature&typeofdosageform
6) Productage&storagecondition

7. C.Patientrelated factors:
1) Routeofadministration
2) Membranephysiology
Natureofcellmembrane
Transportprocesses
3) Age
4) GastricEmptyingTime
5) Intestinaltransittime
6)GastrointestinalpH
7) Diseasestates
8) BloodflowthroughtheGIT
9) Gastrointestinalcontents:
Food-drug interactionsFluids
OthernormalGIcontents

8. 10) Presystemicmetabolismby:
8
Hepaticenzymes
Luminalenzymes
Gutwallenzymes
Bacterialenzymes

9. PHYSICOCHEMICALFACTORS
1)Drug Solubility & Dissolution Rate:
Theratedeterminingstepsinabsorptionof
orallyadministereddrugsare:
1.Rate of dissolution
2. Rate of drug permeation through
the bio-membrane.

10. 10

11. 1
1
Dissolutionisratedeterminingstepfor
hydrophobic&poorlyaqueoussolubledrugs.
E.g.Griesiofulvin&Spironolactone.
Permeationistheratedeterminingstepfor
hydrophilic&highaqueoussolubledrugs.
E.g.CromolynSodiumorNeomycin.
Animportantprerequisitefortheabsorption
ofadrugbyallmechanismsexcept
endocytosisisthatitmustbepresentin
aqueoussolution(i.e)itturndependsonthe
drug’saqueoussolubilityanditsdissolution.

12. Absolute/InstrinsicSolubilityisdefinedas
themaximumamountofsolutedissolvedina
givensolventunderstandardconditionsof
temperature,pressureandpH.ItisaStatic
Property.
Dissolutionrateisdefinedastheamount
ofsolidsubstancethatgoesintosolution
perunittimeunderstandardconditionsof
temperature, pressure,Solvent
Composition,SolidConstantsurfacearea
andpH.ItisaDyanmicProperty.

13. Dose (mg/Kg)Desired Solubility Values (mg/ml) for drugs
with
High
Permeability
Medium
Permeability
Low
Permeability
0.1 1 5 21
1 10 52 207
10 100 520 2100
TheConceptofmaximumabsorbabledose(MAD)is
nowdaysusedtocorrelatedrugabsorptionwithits
solubilityaccordingtofollowingequation:
Desired Solubility Correlated to Therapeutic Doses
Estimatesofdesireddrugsolubilityforgoodoral
absorptiondependonthepermeabilityofthecompound
andtherequireddosewhichwasillustratedinbelowtable:

14. K
a= Instrinsic Absorption Rate Constant
t
r = Residence of drug in GI
S
GI= Solubility of Drug in GI Fluids
V
GI= Volume of GI Fluid
MAD = K
aS
GIV
GIt
r

15. Biopharmaceutics Classification System
Ketoprofen
Naproxen
Carbamazepine
Propranolol
Verapamil
Metoprolol
BCS Divides Compounds into Four Categories:
Amidonetal
Furosemide
Hydrochlorothiazide
Ranitidine
Cemetidine
Atenolol
Vancomycin

17. THEORIESOFDISSOLUTION:
Dissolutionisaprocessinwhichasolid
substancesolubilisesinagivensolvent(i.e)mass
transferfromthesolidsurfacetotheliquidphase.
Severaltheorieshavebeenputforwardtoexplain
drugdissolution.Amongthemsomeofthe
importantonesare:
I.DiffusionLayerModel/FilmTheory
II.Danckwert’sModel/PenetrationorSurface
RenewalTheory.
III.InterfacialBarrierModel/Double-Barrieror
LimitedSolvationTheory.

18. Simplest
MostCommonTheoryfordissolution
I.DiffusionLayerModel/FilmTheory
Heredissolutionofsolidparticlestakesplaceinthe
absenceofReactive(or)ChemicalForces(i.e)consistsof
twoconsecutivesteps:
Step–I:FormationofStagnant
FilmorDiffusionLayerwhichis
saturatedwiththedrug.Thisis
stepisusuallyRapidProcess.
Step–II:Diffusionofsoluble
solutefromStagnantFilmor
DiffusionLayerintobulk
Solution.Thisisstepisusually
SlowProcess&RDS.

19. Theequationthatexplainstherateofdissolution
undergoingwithoutanychemicalreactionandifitis
passivediffusioncontrolledisgivenasNoye’s
WhitneyEquation:
Where,
C
b=concentrationofdruginthebulkof
thesolutionattimet
dc/dt= dissolution rate of the drug.
K = dissolution rate constant
C
s= concentration of drug in stagnant layer
TheaboveequationisbasedonFick’s
SecondLawofdiffusion.
Nernst&BrunnerincorporatedFick’sFirst
Lawintheaboveequationandgivenmodified
Noye’sWhitneyEquationas:

20. Where,
K
w/o=water/oilpartitioncoefficientofdrug
dc/dt= dissolution rate of the drug.
D = diffusion coefficient of drug
A = surface area of dissolving solid
V = volume of dissolution medium
h = thickness of the stagnant layer
(Cs-Cb)=conc.Gradientfordiffusionoflayer

21. DissolutionRateunderNon-Sink&SinkCondition.

22. II.Danckwert’sModel(PenetrationorSurfaceRenewal
Theory)
Danckwertdidnotacceptedthe
existenceofastagnantlayer.
Butsuggestedthepresenceof
turbulenceatsolid-liquid
interface.
Asaresult,agitatedfluid
containsmacroscopicmassof
eddiesorpackets.
Theseeddiesreachsolid-liquid
interfaceduetoeddycurrents,
absorbsthesoluteandcarries
themintothebulksolution.

23. Suchsolutecontainingpacketsarecontinuouslyreplaced
withnewpacketsoffreshsolventduetowhichthedrug
concentrationatthesolid/liquidinterfaceneverreachesC
s
andhasalowerlimitingvalueofC
i.
Sincethesolventpacketsareexposedtonewsolid
surfaceeachtime,thetheoryiscalledasSurfaceRenewal
Theory.
Danckwert’s Model is expressed by:
Where,
m = mass of the Solid Dissolved
γ = rate of Surface Renewal (Interfacial Tension

24. III.InterfacialBarrierModel(DoubleBarrieror
LimitedSolvationTheory)
Accordingtointerfacialbarriermodel,an
intermediateconcentrationexistsatinterfaceasa
resultofsolvationmechanismwhichisafunctionof
solubilityratherthandiffusion.
Whenconsideringthedissolutionofacrystal,
eachfaceofthecrystalwillhaveadifferent
interfacialbarrier.
Suchaconceptisgivenbyfollowingequation:

25. 2) Particle size & Effective Surface Area:
SmallParticleSize–GreaterSurfaceArea
GreaterDissolution/Solubility
Greater Pharmacological Effect
Greater Therapeutic Effect
Greater Bioavailability

26. Particle size may play a major role in drug absorption.
Dissolutionrateofsolidparticlesisproportionaltosurface
area.
Smallerparticlesize,greatersurfaceareathenhigherwill
bedissolutionrate,becausedissolutionisthoughttotake
placeatthesurfaceareaofthesolute(Drug).
Particlesizereductionhasbeenusedtoincreasethe
absorptionofalargenumberofpoorlysolubledrugs.
2)Effectivesurfacearea
E.g.Bishydroxycoumarin,Digoxin,Griseofulvin
Twotypesofsurfacearea
1)Absolutesurfacearea

27. 11
Inabsorptionstudiestheeffectivesurfaceareaisof
muchimportantthanabsolute.
Toincreasetheeffectivesurfacearea,wehavetoreduce
thesizeofparticlesupto0.1micron.Sothesecanbe
achievedby“micronizationprocess’’.
Butinthesecaseonemostimportantthingtobekeepin
mindthatwhichtypeofdrugismicronizedifitis:
a) HYDROPHILIC b) HYDROPHOBIC
a)HYDROPHILIC DRUGS:
Inhydrophilicdrugsthesmallparticleshavehigher
energythanthebulkofthesolidresultinginanincreased
interactionwiththesolvent.

28. 10
Examples:
1.Griesiofulvin–Dosereducedtohalfduetomicronization.
2.Spironolactone –the dose was decreased to 20 times.
3.Digoxin–thebioavailabilitywasfoundtobe100%in
micronizedtablets.
Aftermicronizationitwasfoundthattheabsorption
efficiencywashighlyincreased
Note: HYDROPHOBIC DRUGS:
Inthismicronizationtechniquesresultsindecreased
effectivesurfacearea&thusfallindissolutionrate.
REASONs:
Thehydrophobicsurfaceofthedrugsadsorbsaironto
theirsurfacewhichinhibitstheirwettability.
b) HYDROPHOBIC
Examples:
Aspirin
Phenacetin
Phenobarbital

29. Theparticlesreaggregatestoformlargeparticlesdueto
theirhighsurfacefreeenergy,whicheitherfloatonthe
surfaceorsettleonthebottomofthedissolutionmedium.
Electricallyinducedagglomerationowingtosurface
chargespreventsintimatecontactofthedrugwiththe
dissolutionmedium.
Suchhydrophobicdrugscanbeconvertedtotheir
effectivesurfacearea.
Use of surfactant as a wetting agent which
Decrease the interfacial tension.
Displace the adsorbed air with the solvent.
Eg. Phenacetin
Add hydrophilic diluents like PEG, PVP, dextrose etc.
which coat the surface of hydrophobic drug particles.

30. Particle Size Reduction
Greater Surface Area
Dissolution Rate
S. No Drugs Reason
01 Penicillin–G &
Erythromycin
Unstable and undergoes
degradation in Solution
Form
02 NitrofurantoninProduceundesirable effects
(i.e) Gastric irritation
03 Glipizide,NateglinideSustained Effectis desired.

31. 3) Polymorphism & Amorphism:

32. Dependingupontheinternalstructure,asolidcan
existeitherinacrystallineoramorphousform.

33. Polymorphsareoftwotypes:
Enantiotropic Polymorph
Thispolymorphistheonewhichcanbereversibly
changedintoanotherformbyalteringthe
temperatureorpressure.
Whenasubstanceexistsinmorethanone
crystallineform,thedifferentformsaredesignated
as polymorphs,andthephenomenonas
Polymorphism.

34. 34
Monotropic Polymorph
Thispolymorphistheonewhichisunstableatall
thetemperatureorpressures.
E.g:GlycerylSterates.
Thepolymorphsdifferfromeachotherwith
respecttotheirphysicalpropertiessuchas:
Solubility
Melting Point
Density
Hardness
Compression
Characteristics
Changesinthese
physicalproperties
affects the
DissolutionRate&
AbsorptionProcess.

35. 35
Theycanbepreparedbycrystallizingthedrugfrom
differentsolventsunderdiverseconditions.
Theexistenceofpolymorphscanbedeterminedbyusing
techniquessuchas:
Optical Crystallography
X-Ray Diffraction (X-RD)
Differential Scanning Calorimetry (DSC)
Dependingofrelativestability,amongthese
severalpolymorphicforms,Oneoftheformis
stable&others(Remainingformsarecalled
asMetastable).

36. 36
Suchstableform
has:
Lowest Energy
Highest M.P
Least Aqueous Solubility
WhereasMetastable
formhas:
Highest Energy
Lowest M.P
Highest Aqueous
Solubility
Sincemetastableformhashighest
solubilitytheyshowbetterbioavailability,
sotheypreferredinmakingformulations:

37. 37
E.g:Chloramphenicolpalmitateexistsin
severalpolymorphicforms:
Chloramphenicolpalmitate-A
Chloramphenicolpalmitate-B
Chloramphenicolpalmitate-C
Highest
Bioavailability
Biologically
Inactive
E.g:ThevitaminRiboflavinexistsinseveral
polymorphicforms:
Riboflavin:Form-I
Riboflavin:Form-II
Riboflavin:Form-III
20 times
more soluble
than
Riboflavin -I

38. 38
E.g:CartisoneAcetateexistsin8
polymorphicforms:
CortisoneAcetate-I
CortisoneAcetate-II
CortisoneAcetate-III
CortisoneAcetate-IV
CortisoneAcetate-V
CortisoneAcetate-VI
CortisoneAcetate-VII
CortisoneAcetate-VIII
More Aqueous
Soluble
Less Aqueous Soluble Suspension
Note:
40% ofOrganic
Compoundsexistsin
Polymorphicforms.
Among40%only10%
ofthemexistsas
metastableforms

39. Ex:AmorphousformofNovobiocinis10times
moresolublethanthecrystallineform.
Theyhavegreateraqueoussolubilitythanthe
crystallineformsbecauseaenergyrequiredto
transferamoleculefromthecrystallatticeisgreater
thanthatrequiredfornon-crystalline(amorphous
form).
Amorphous> Meta-stable> stable
Thus,theorderofdifferentsoliddosageformsofthe
drugsis
Amorphism:
Somedrugscanexistinamorphousform(i.e.
havingnointernalcrystalstructure).Suchdrug
representsthehighestenergystate.

40. 4) Pseudoploymorphism:
Whenthesolventmoleculesareentrappedinthecrystalline
structureofthepolymorph,itis knownas
Pseudopolymorphism.
Solvates:Thestoichiometrictypeofadductswhere
thesolventmoleculesareincorporatedinthecrystal
latticeofthesolidarecalledasthesolvates,andthe
trappedsolventassolventofcrystallization.
Hydrates:whenthesolventinassociationwiththe
drugiswater,thesolvateisknownasahydrate.
OrganicSolvates(NonaqueousSolvates):whenthe
solventinassociationwiththedrugisorganicsolvent,
thesolvateisknownasaOrganicsolvates.

41. Anhydrate & Hydrates:
Example -1
Example -2

42. Example -1
Non-Aqueous Solvents & Non Solvates:
Least Solubility
Griseofulvin
C
17H
17ClO
6.CHCl
3
C
17H
17ClO
6
Low Bioavailability
Highest Solubility
Highest Bioavailability
Otherexamples:n-pentanolsolvatesof
fludrocortisoneandsuccinyl-sulfathiazolehave
greateraqueoussolubilitythanthenon-solvates.
Hydrates/Non-Solvatesarepseudo-polymorphswhere
hydratesarelesssolubleandsolvatesaremoresoluble
andthusaffecttheabsorptionaccordingly.

43. Weak Acidic Drug
SaltformofDrug:

44. Weak Basic Drug

45. Salt
of
weak
acid
Diffusion
ofsolubledrug
particles
Soluble
form of the
drug
rapid
dissolution
drug in
solution
diffusion layer
higher pH(5-6)
Bulk of
solution
relatively
lower pH(1-3)
GI
Lumen
GI
Barrier
Blood
Dissolutionandabsorptionofan acidic
drugadministeredina salt form
Drug
in
blood
45
fineprecipitate
ofweakacid
SaltformofDrug:

46. 46
In–situsaltformationresultsinincrease
DissolutionandAbsorption.
Saltformofdrugmayresultinpoorabsorption.
e.g.sodiumsaltofphenobarbitone
Whileconsideringthesaltformofdrug,pHofthe
diffusionlayerisimportantnotthepHofthebulk
ofthesolution.
E.g. Aspirin

47. Type of Salt Size of Counter Ion
Novobiocin
25 % Soluble in Water
50% Soluble in Water
1% Soluble in Water
3
–
4 times Soluble in Water

48. The pH at the absorption
site.
48
pH-PartitionHypothesis:
The dissociation constant
p
Ka
of the drug.
The lipid solubility of the
Un-ionized drug.
Amountofdrugthatexistsinun-ionizedformandin
ionizedformisafunctionofp
Ka
ofdrugandp
H
ofthe
fluidattheabsorptionsite,anditcanbedeterminedby
Handerson-Hasselbachequation:
DrugpKa,GIpH&Lipophilicity:
Assumption theory

49. Weak Acidic Drug in Stomach Diclofenac Ion
Hydronium Ion
Weak Acidic Drug in Intestine
Diclofenac Ion

50. Weak Basic Drug in Stomach
Weak Basic Drug in Intestine

51. pH=pKa+log
[ionized]
[un-ionized]..(1.1)
%Drugionized=10
pH-pKa
x100…(1.2)
1+10
pH-pKa
•Forweak bases,
pH=pKa+log[un-ionized]
[ionized]
…(1.3)
%Drugionized= 10
pKa-pHx100
1+10
pKa-pH
51
…(1.4)
•Forweakacids,

52. Ifthereisamembranebarrierthatseparatesthe
aqueoussolutionsofdifferentpHsuchastheGIT
andtheplasma,thenthetheoreticalratioRof
drugconcentrationoneithersideofthe
membranecanbegivenbythefollowing
equations:
•Forweakacids,
R
a=C
GIT
C
plasma
= 1+10
pHGIT-pKa
1+10
pHplasma-pKa
….(1.5)
•Forweakbases,
R
b=C
GIT
C
plasma
=
1+10
pKa-pHGIT
52
1+10
pKa-pHplasma....(1.6)

53. Influence of Drug p
ka
and GI p
H
on Drug Absorption
Lipophilicity& Drug Absorption:
K
o/w=
Distributionofthedrug intheorganicphase(octanol)
Distributionofthe drugintheaqueousphase

54. Limitations of pH partition Theory:
Influence of GI Surface Area & Residence time of drug.
Presence of Virtual Membrane pH.
Absorption of Ioniseddrug.
Presence of Aqueous Unstirred Diffusion Layer

55. LIPOPHILICITYANDDRUGABSORPTION:
55
Thelipidsolubilityofthedrugisdeterminedformits
oil/waterpartitionco-efficient(K
o/w)value,whereby
theincreaseinthisvalueindicatestheincreasein
percentagedrugabsorbed.
K
o/w=
Distributionofthedrug intheorganicphase(octanol)
Distributionofthe drugintheaqueousphase
…(1.7)

56. 56
DrugStability:
Adrugfororalusemaydestabilizeeither
duringitsshelflifeorintheGIT.
Twomajorstabilityproblemsresultingin
poorbioavailability

57. 8)Drugstability:
57
Adrugfororalusemaydestabilizeeitherduringits
shelflifeorintheGIT.
Twomajorstabilityproblemsresultinginpoor
bioavailabilityofanorallyadministereddrugare_
degradationofthedrugintoinactiveform,and
interactionwithoneormoredifferentcomponent(s)
eitherofthedosageformorthosepresentintheGITto
formacomplexthatispoorlysolubleoris
unabsorbable.

58. 1.DisintegrationTime(tablets/capsules):
58
PHARMACEUTICALFACTORS
Rapid Disintegration Rapid Absorption
Low Disintegration
Time
Binder
Compression Force
Higher Disintegration
Time
Fast dispersible tablets have short disintegration
time.
Note
Coated tablets have Long disintegration time.
Sugar Coated Tablet Enteric Coated Tablet

59. 2)DissolutionTime:
59
Severalmanufacturingprocessesinfluencedrug
dissolutionfromsoliddosageforms.
CompressionForce
3)Manufacturing/ProcessingVariables:
Forexample:Fortabletitis
Methodofgranulation
4)CompressionForce&IntensityofCapsulePacking:
Fig. Influenceof compressionforceon thedissolutionrateof tablets

60. 5) Pharmaceutical ingredients (excipients/adjuvants):
MorethenumberofExcipientsinthedosageform,more
complexitis&greaterthepotentialforabsorptionand
Bioavailabilityproblems.
Commonlyusedexcipientsinvariousdosageformsare:
a)Vehicle:Rateofabsorption–dependsonits
miscibilitywithbiologicalfluid
AqueousVehicles
NonAqueousWaterMisciblevehicles:causes
rapidabsorption.E.g: Propylene Glycol.
NonAqueousWaterImmisciblevehicles:
E.g.Water,SyrupBase.
E.g: Vegetable Oils.

61. b)Diluents:Addedtotablets&Capsulestoincrease
Bulkiness.
TheBioavailabilityofTetracyclinedecreaseddue
tocomplexationwithDCP.
E.g.Tetracycline+DCP.
Organic
Inorganic
Most Commonly
Used
Carbohydrates
Starch
Lactose
MCC
Di Calcium Phosphate
Most Commonly
Used
Hydrophilicdiluents–PromotesSolubilityof
HydrophobicDrugs(Spirinolactone&Triamterene–
AdsorptionMechanism

62. Moreamountofbinderincreasesthehardnessofthe
tabletandretardstheabsorptionrate.
62
c) Binders & Granulating agent:
Polymeric Material: Natural, Semi
Synthetic& Synthetic
ImpartsHydrophilic
propertiestothe
granulesurface-gives
better dissolution
properties
Starch GelatinPVP
Popular
Binders
Phenacetin
theseareusedtoholdthepowderintactduring
granulation,promotecohesivecompactsindirect
compressiontechnique,toensuretabletremainsintact
aftercompression
Acacia
Cellulose Derivatives
Hydrophilic
Binders

63. Decreaseinamountofdisintegrants–significantlylowers
bioavailability.
63
Phenobarbital+PEG6000
Non –aqueous binder like Ethyl
Cellulose
Poorly Soluble
Complex
Retard Drug
Dissolution
d)Disintegrants:
Mostlyhydrophilicinnature.
Digoxin, Alkaloids & Steroids
Adsorbents as
disintegrating agent
like
Bentonite, Veeghum
AtHigherCompressionForces
retardsDrugDissolution
Hydrophilic
Disintegrant
like MCC

64. e)Lubricants:
64
Commonly hydrophobic in nature –therefore inhibits penetration
of water into tablet and thus dissolution and disintegration.
f) Suspending agents/viscosity agent:
Stabilized the solid drug particles and thus affect drug absorption.
Macromolecular gum forms un-absorbable complex with drug e.g.
Na CMC.
Viscosity imparters –act as a mechanical barrier to diffusion of
drug from its dosage form and retard GI transit of drug.
g) Surfactants:
May enhance or retards drug absorption by interacting with drug
or membrane or both.
e.g. Griseofulvin, steroids
Itmaydecrease absorptionwhenit forms
theun-absorbable complex with drug above CMC.

65. h)Coating:
65
Ingeneral,deleteriouseffectsofvariouscoatingsonthedrug
dissolutionfromatabletdosageformareinthefollowingorder.
Entericcoat>sugarcoat>non-entericcoat
Thedissolutionprofileofcertaincoatingmaterialschangeon
aging;e.g.shellaccoatedtablets,onprolongedstorage,dissolve
moreslowlyintheintestine.Thiscanbehowever,beprevented
byincorporatinglittlePVPinthecoatingformulation.
i)Buffers:
Buffersaresometimesusefulincreatingtherightatmosphere
fordrugdissolutionaswasobservedforbufferedaspirintablets.
However,certainbuffersystemscontainingpotassiumcations
inhibitthedrugabsorptionasseenwithVitaminB
2and
sulfanilamide.

66. j) Colorants:
Evena lowconcentrationofwatersoluble
dyecanhavean inhibitory effect on dissolution
rate.
Thedyemoleculesgetabsorbedontothe
crystalfacesand inhibit the drug dissolution.
For example: Brilliant blue retards dissolution of sulfathiazole.
k) Complexing agents:
Complex formation has been used to alter the physicochemical
& biopharmaceutical properties of a drug.
Example
1)Enhanced dissolution through formation of a soluble complex.
E.g.ergotaminetartarate-caffeinecomplex &
hydroquinone-digoxin complex.
2)Enhanced lipophilicity for better membrane permeability.
E.g. caffeine-PABA complex.
66

67. 5)Nature&typeofdosageform:
Apartfromtheproperselectionofthedrug,clinical
successoftendependstoagreatextentontheproper
selectionofthedosageformofthatdrug.
As a general rule, the bio-availability of a drug form
various dosage forms decrease in the following order:
Solutions> Emulsions> Suspensions
> Capsules> Tablets> Coated
Tablets> Enteric CoatedTablets
> Sustained Release Products.
67

68. 68

69. 6)Productage&storagecondition:
Productagingandstorageconditionscanadversely
affectthebio-availabilitybychangeinespeciallythe
physico-chemicalpropertiesofthedosageforms.
For example:
1.Precipitation of the drug in solution 2.Hardening of
tablet
3.Change in particle size of suspension.
69

70. 3)Age:
Ininfants,thegastricpHishighandintestinalsurfaceand
bloodflowtotheGITislowresultinginalteredabsorption
patternincomparetoadults.
Inelderlypersons,gastricemptyingaltered,decreased
intestinalsurfaceareaandGIbloodflow,higherincidentsof
achlorhydriasoimpaireddrugabsorption.
4) Gastric emptying time:
The process by which food leaves the stomach and enters
the duodenum.
Rapid gastric emptying is required when the drug is best
absorbed from distal part of the small intestine.
70

71. Delayedgastricemptyingisrequiredwhendrugsareabsorbed
fromproximalpartofthesmallintestineandprolongeddrug
absorptionsitecontactisdesired.
Gastricemptyingisafirstorderprocess.
Gastricemptyingrate:Thisisthespeedatwhichthestomach
contentsemptyintotheintestine.
Gastricemptyingtime:Whichisthetimerequiredforthe
gastriccontentstotheSMALLINTESTINE.
Gastricemptyinghalf-life:whichisthetimetakenforhalf
thestomachcontentstoempty.
71

72. Volume of Ingested
Material
As volume increases initially an increase then a
decrease. Bulky material tends to empty more slowly
than liquids
Type of Meal Gastric emptying rate: carbohydrates > proteins >
fats
Physical state of
gastric contents
Solutions or suspensions of small particles empty
more rapidly than do chunks of material that must
be reduced in size prior to emptying.
Body Position Lying on the left side decreases emptying rate and
right side promotes it
Drugs
Anticholinergics
Narcotic analgesics
Ethanol
ReductioninrateofemptyingReductioninrateof
emptyingReductioninrateofemptying
Emotional stateAnxiety promotes where as depression retards it
Disease states gastric ulcer, hypothyroidism retards it, while
duodenal ulcer, hyperthyroidism promotes it.
72

73. 5)Intestinaltransittime:
73
Intestinaltransittimeisthemajorsiteofabsorptionofmostof
drugs.
Themixingmovementoftheintestinethatoccursdueto
peristalticcontractionspromotesdrugabsorption,firstly,by
increasingthedrugintestinalmembranecontactandsecondlyby
enhancingdrugdissolutionofespeciallyofpoorlysolubledrugs,
throughinducedagitation.
Delayed intestinal transit is desirable for
A)Drugs that dissolve or release slowly from their dosage form
(sustained release products)
B)Drugsthatdissolve onlyin intestine
(entericcoated formulations)
C)Drugs absorbed from specific sites in the intestine (several B
vitamins)

74. Intestinalregion Transittime
Duodenum 5minutes
Jejunum 2hours
Ileum 3to6hours
Caecum 0.5to1hour
Colon 6to12hours
74
Intestinaltransittimeisinfluencedbyvariousfactorssuchas
food,diseasesanddrugs
E.g.metoclopramidewhichpromotesintestinaltransit,enhance
absorptionofrapidlysolubledrugswhileanticholinergicretards
intestinaltransitandpromotestheabsorptionofpoorlysoluble
drugs.

75. 6)GastrointestinalpH:
75

76. 7)Diseasestates:
76
Gastric diseases (Achlorhydric patients):
They may not have adequate production of acids in the stomach;
stomach HCl is essential for solubilizing insoluble free bases.
Manyweak-basedrugsthatcannotformsolublesalts&remain
undissolvedthereforeunabsorbed.Saltformsofthesedrugs
cannotbepreparedbecausethefreebasereadilyprecipitatesout.
E.g.Dapsone,itraconazole,andketoconazole.
Cardio-vasculardiseases:
Severalchangesassociatedwithcongestivecardiacfailure
influencebio-availabilityofadrugviz.,edemaoftheintestine,
decreasedbloodflowtotheGITandgastricemptyingrateand
alteredGIpH,secretionsandmicrobialflora.

77. 8)Bloodflow throughtheGIT:
77
Itplaysamajorroleinabsorptionbycontinuouslymaintain
theconcentrtiongradientacrosstheepithelialmembrane.
TheGITisextensivelysuppliedbybloodcapillarynetwork.
Bloodflowisimpforactivelyabsorptionofdrugs.
Absorptionofpolarmoleculesdoesn’tdependsontheblood
flowbutlipidsolublemoleculeshighlydependsontheblood
flow.
FoodinfluencesbloodflowtotheGIT.Perfusionincreases
aftermeals&persistforfewhoursbutabsorptionisnot
affected.

78. 9)Gastrointestinalcontents:
78
1)Food-drug interactions: The presence of food in the GI tract
can affect the bioavailability of the drug .
Digestedfoodscontainaminoacids,fattyacids,and
many nutrients that may affect intestinal pH and solubility
of drugs.
Some effects of food on the bioavailability of a drug from a
drug product include:
Delay in gastric emptying Stimulation of bile flow
A change in the pH of the GI tract An increase in splanchnic blood
flow

79. Presence of food will affect absorption in following way
a)Decreasedabsorption:ex.Penicillin,erythromycin,ethanol,
tetracycline, levodopa etc.
b)Increased absorption: ex grieseofulvin, diazepam, vitamins etc.
2) Fluid volume:
Large fluidvolume results in better dissolution, rapid gastric
emptying and enhanced absorption-
Ex. Erythromycin is better absorbed when taken with a glass of
water under fasting condition than when taken with meals.
3)InteractionofdrugwithnormalGIconstituents:
TheGITcontainsanumberofnormalconstituentssuchasmucin
whichisaprotectivemucopolysaccharidesthatlinestheGImucosa,
interactwithstreptomycin.
79

80. 80
CONCLUSION

81. 81