Absorbation of biopharmacist and pharmacokinetic

Absorbation of biopharmacist and pharmacokinetic of bacaloruse student

1. Biopharmaceutics and
Pharmacokinetics
Dr. Yousef Algaradi

2. Introduction
Pharmaceutics: is the general area of study concerned
with the formulation, manufacture, stability and
effectiveness of pharmaceutical dosage forms.
Biopharmaceutics: the study of the physicochemical
properties of drugs, dosage forms and routes of
administration and its activity in the living body.
Pharmacokinetics: It is the study of the time course of
drug absorption, distribution, metabolism and excretion.
Refers to what the body does to the drug.
Pharmacokinetics relates changes in concentration of
drug within the body withtime after its administration
BiopharmaceuticsDr.Yousef Algaradi

3. Biopharmaceutics involves factors that influence the:
1)The designof the drug product.
2)protectionand stabilityof the drug within the drug
product.
3)The rate of dissolution/release of the drug at the
absorption site.
4)Delivery of drug to the site of action.
5)The availability of the drug at its site of action.
Introduction
BiopharmaceuticsDr.Yousef Algaradi

4. Introduction
BiopharmaceuticsDr.Yousef Algaradi

5. The importance of the drug substance and the drug
formulation on absorption, and in vivo distribution of the
drug to the site of action, is described as a sequence of
events that precede explanation of a drug's therapeutic
effect.
A general scheme describing this dynamic relationship
Introduction
BiopharmaceuticsDr.Yousef Algaradi

6. A pharmacologic responseresults when:
The drug concentration at the site of action reaches or
exceeds the minimum effective concentration (MEC).
The suggested dosing regimen provide the drug
concentrationsthat are therapeutically effective in most
patients.
This sequence of events is profoundly affected by the
designof the dosage form and the physicochemical
properties of the drug
Introduction
BiopharmaceuticsDr.Yousef Algaradi

7. ADME:
Absorption: is defined as the process by which a drug
proceedsfrom the site of administration to the site of
measurement (usually blood, plasma or serum).
Distribution: The dispersionof a drug throughout fluids
and tissues of the body.
It is a reversible process.
Elimination: Irreversibleloss of drugs from the site of
measurement.
Metabolism : The irreversibletransformation of parent
compounds to daughter compounds (also called
biotransformation).
Introduction
BiopharmaceuticsDr.Yousef Algaradi

8. Excretion: is the removal of drug from the body in an
unchanged form through various routes.
Ex-urine, saliva, sweat, respiratory route, biliary
secretion.
Introduction
BiopharmaceuticsDr.Yousef Algaradi

9. Introduction
BiopharmaceuticsDr.Yousef Algaradi

10. Bioavailability
Bioavailability(F):
The fraction of an administered dose of a particular drug that
reachesthe systemic circulation intact
Bioavailable dosePlasma level-time curve:
The plasma level-time curve is generated by measuring the
drug concentration in plasma samples taken at various time
intervalsafter a drug product is administered.
The concentration of drug in each plasma sample is plotted
against the corresponding time at which the plasma sample
was removed
BiopharmaceuticsDr.Yousef Algaradi

11. Bioavailability
BiopharmaceuticsDr.Yousef Algaradi

12. BiopharmaceuticsDr.Yousef Algaradi

13. Absorption
BiopharmaceuticsDr.Yousef Algaradi

14. Absorption
Absorption can be defined as thetransfer of a drug from
its site of administration to the blood stream.
If the drug is intended for systemicactivity, the drug
should ideally be completely and consistently absorbed
from the application site.
In contrast, if the drug is intended for local activity, then
systemic absorption from the application should be
minimalto prevent systemic drug exposure and possible
systemic side effects.
Basically, absorption of a drug is dependent on the
anatomy and physiology of the drug absorption site.
BiopharmaceuticsDr.Yousef Algaradi

15. Nature of cell membrane
Systemic drugs that are administered by extravascular
routes (eg, oral, topical, intranasal, inhalation, rectal) are
designed to be absorbed from the site of administration
into the systemic circulation.
The drug must cross cellular membranesto reach systemic
circulation.
The permeabilityof a drug at the absorption site into the
systemic circulation is mainly related to:
1)The molecular structure and properties of the drug
2)The physical and biochemical properties of the cell
membranes.
Therefore, biological membranes represent a significant
barrierto drug delivery
BiopharmaceuticsDr.Yousef Algaradi

16. The cell membrane is made up of lipid, Protein and other
macromolecules(Carbohydrate)
1)Lipid :as phosopholipids
Phospholipid bilayer -made up of phosphates and lipids.
The phosopholipids make up a bilayer which contains
hydrophilic and hydrophobic molecules.
It is semi permeable which is allow certain molecule to pass
through the membrane
Nature of cell membrane
BiopharmaceuticsDr.Yousef Algaradi

17. 2)Protein :
The proteins in the cell membrane are located withinthe
phospholipid bilayer as:
Channel protein: it allows free passage for some specific
moiety and ions.
Carrier protein –it allows to cross the plasma membrane by
interact selectively with some specific moiety and ions (Na+ or
K+).
So, the biologic
membrane is lipid
in nature but
contain small
aqueous channels
or pores
Nature of cell membrane
BiopharmaceuticsDr.Yousef Algaradi

18. Drugs are transported across the membranes by:
1)Passive diffusion
2)Carrier mediated
a)Active transport
b)Facilitated diffusion
3)Vesicular transport
4)Pore (convective) transport
5)Ion pair formation
Drug absorption mechanisms
BiopharmaceuticsDr.Yousef Algaradi

19. Passive diffusion
Passive diffusion is the process by which molecules
spontaneously diffuse from a region of higher
concentration to a region of lowerconcentration.
This process is passive because no externalenergy is
expended.
Drug molecules can move forward and back across a
membrane.
Passive diffusion is the majorabsorption process for
most drugs.
The driving force for passive diffusion is higher drug
concentrations, typically on the mucosal side compared
to the blood as in the case of oral drug absorption.
BiopharmaceuticsDr.Yousef Algaradi

20. Passive diffusion
BiopharmaceuticsDr.Yousef Algaradi

21. This mechanism of drug transport across the cell
membrane involve the use of drug transporter(carrier).
Numerous specialized carrier-mediated transport systems
are present in the body, especially in the intestine for the
absorption of ionsand nutrients required by the body.
Active transport:
A few lipid-insolubledrugs (e.g.5-flurouracil) that
resemble natural physiologic metabolites (e.g. glucose,
amino acids) are absorbed from the GIT by this process.
These drugs are usually absorbed from specific sites in the
small intestine.
It is an energy-consumingsystem
Carrier mediated
BiopharmaceuticsDr.Yousef Algaradi

22. Transport of a drug against concentration gradient (from
regions of low drug concentrations to regions of high
concentrations).
Carrier mediated
BiopharmaceuticsDr.Yousef Algaradi

23. b)Facilitated diffusion:
Certain molecules with low lipid solubility penetrate
membranes more rapidly than expected.
Carriers are numerous in number & are found dissolved in
cell membrane.
The transport is aided by integral membrane proteins.
The driving force is concentration gradient, particles move
from a region of high concentration to low conc.
Facilitated diffusion is a form of carrier transport that does
not require the expenditure of cellular energy.
Carrier mediated
BiopharmaceuticsDr.Yousef Algaradi

24. Facilitated diffusion mediates the absorption of some
simple sugars, steroids, amino acids from the small
intestine
e.g. vitamin B12 transport.
Carrier mediated
BiopharmaceuticsDr.Yousef Algaradi

25. It is the process of engulfingparticles or dissolved materials
by the cell.
Also termed as endocytosis transport which is three types
Pinocytosis , phagocytosis and transcytosis
Pinocytosis and phagocytosis are forms of vesicular
transport that differ by the type of material ingested.
Pinocytosis: refers to the engulfment of small molecules or
fluid.
Phagocytosis: refers to the engulfment of larger particles or
macromolecules.
During pinocytosis or phagocytosis, the cell membrane
invaginates to surroundthe material, and then engulfs the
material into the cell.
Vesicular transport
BiopharmaceuticsDr.Yousef Algaradi

26. Transcytosis; the process by which various macromolecules
are transported across the interior of a cell.
In transcytosis, vesicles are employed to intake the
macromolecules on one side of the cell, draw them across
the cell, and ejectthem on the other side.
Transcytosis is the process for the absorption of orally
administered various
large proteins.
Vesicular transport is
the proposed process
for the absorption of
Vitamin A, D, E, and K,
peptides in new born
Vesicular transport
BiopharmaceuticsDr.Yousef Algaradi

27. Mechanism through the protein channelspresent in the cell
membrane.
The driving force is hydrostatic or osmotic pressure
differences across the membrane.
Thus, bulk flow of water along with the small solid molecules
through aqueous channels.
The process is important in the absorption of low molecular
weight (<100D), low molecular size (smaller than the
diameter of the pore) & generally water soluble drugs
through narrow, aqueous filled channels or pores e.g. urea,
water & sugars
Pore (convective) transport
BiopharmaceuticsDr.Yousef Algaradi

28. Strong electrolyte drugs are highly ionized or charged
molecules, such as quaternary nitrogen compounds.
These drugs penetrate membranes poorly.
When linked up with an oppositely charged ion, an ion pair is
formed in which the overall charge of the pair is neutral.
This neutral complex diffuses more easily across the
membrane.
e.g. the formation
of an ion pair for
propranolol (basic
drug) with oleic acid
Ion pair formation
BiopharmaceuticsDr.Yousef Algaradi

29. Drug absorption mechanisms
BiopharmaceuticsDr.Yousef Algaradi

30. Oral drug absorption
The oral route of administration is the mostcommon and
popular route of drug dosing.
The gastrointestinal tract (GIT) comprises of a number of
components, their primary function being secretion,
digestion and absorption.
The major functional components of the GIT are
stomach, small intestine (duodenum, jejunum and ileum)
and large intestine (colon) which grossly differ from each
other in terms of anatomy, function, secretions and pH.
BiopharmaceuticsDr.Yousef Algaradi

31. Figure . Schematic representation of the main parts of the gastrointestinal tract
(GIT) showing the differences in pH and surface areas at each part.
Oral drug absorption
BiopharmaceuticsDr.Yousef Algaradi

32. Considerations for the design of
oral dosage forms
1)The environment within the lumen
2)Gastro intestinal contents
3)Gastric emptying and motility
4)Disease state
5)Presystemicor First pass metabolism
BiopharmaceuticsDr.Yousef Algaradi

33. The environment within the lumen
The pH of fluids varies along the length of the GIT.
The gastrointestinal pH may influence the absorption of
drugs in a variety of ways:
Disintegration: some dosage forms is PH sensitive , with
enteric coating and the coat dissolves only in in intestine.
Dissolution: A large no. of drugs whose solubility is
affected by pH are weak acidic and weak basic drugs.
Absorption: Depending on drug pKaand whether it is
acidic or basic , absorption depends on the amount of
unionized form at site of absorption.
Stability: GI pH affects chemical stability of drug. Eg. Acidic
pH of stomach degrades Penicillin G and erythromycin.
BiopharmaceuticsDr.Yousef Algaradi

34. Gastro intestinal contents
1)Food-drug interaction: In general presences of food
delay, reduce, increase or may notaffect absorption.
2)Fluid volume: High volume betterabsorption e.g.
erythromycin
3)Interaction of drug with normal GI contents:
The primary enzyme found in gastric juice is pepsin
Lipases, amylases and proteases are secreted from the
pancreas into the small intestine.
Pepsins and proteases are responsible for the digestion of
protein and peptide drugs in the lumen.
The lipases may affect the release of drugs from fat / oil
containing dosage forms.
Bile salts:increases lipid soluble drugs e.g. gresiofulvin,
and increase drug permeability.
BiopharmaceuticsDr.YousefAlgaradi

35. Bile salts can form insoluble and non-absorbable
complexes with some drugs, such as neomycin and
kanamycin
Bacteria : which are localized within the colonic region of
the GIT secrete enzymeswhich are capable of a range of
reactions. e.g. Sulphasalazinewhich is a prodrugused to
target the colon:
4)Drug-Drug interaction in the GIT:
A) Physicochemical drug-drug interaction:
Adsorption: Eg; anti diarrheal preparations contains
adsorbents like kaolin, preventsa absorption of many
drugs co-administered with them.
Gastro intestinal contents
BiopharmaceuticsDr.Yousef Algaradi

36. Complexation: Eg; calcium, aluminiumsalts decreases
tetracycline.
pH changes: Basic drugs changesgastric pH
E.g. tetracycline with antacids
B) Physiological interaction:
Decreased GI transit: Anticholinergicslike propanthelin
decreaseGI transit and increased absorption of ranitidine
and digoxin
Increase GI emptying: Metoclopramide increases GI
motility and increased GI absorption of tetracycline,
levodopa etc.
Altered GI metabolism: Antibiotics decreasebacterial
metabolism of drug e.g. erythromycin increases efficacy
of digoxin
Gastro intestinal contents
BiopharmaceuticsDr.Yousef Algaradi

37. Gastric emptying and motility
The time a dosage form takes to traversethe stomach is
usually termed: the gastric residence time, gastric emptying
time or gastric emptying rate.
Gastric emptying time is a rate-limitingstep in drug
absorption because the major site of drug absorption is
intestine(because of the larger surface area compared to
the stomach).
Rapid gastric emptying increases absorption and
bioavailability of a drug.
Also slower stomach emptying can cause increased
degradationof drugs in the stomach's lower pH; e.g. L-dopa.
BiopharmaceuticsDr.Yousef Algaradi

38. Delay in gastric emptying is
recommended
Rapid gastric emptying is
advisable
1-Food promotes drug dissolution &
absorption eg. Griseofulvin
1-Rapid onset of action is desired
eg. Sedatives
2-Disintegration & dissolution of dosage
form is promoted by gastric fluids
2-Dissolution of drug occurs in
intestine, eg. Enteric coated tablets
3-Drugs dissolve slowlyeg. Griseofulvin3-Drugs not stable in gastric fluid
eg. Penicillin G & erythromycin
4-Drugs irritate gastric mucosa
eg. Aspirin, phenylbutazone&
nitrofurantoin
4-Drugs absorbed from distal part
of intestineeg. Vitamin B 12
5-Drugs absorbed from proximal part of
small intestine eg.Vitamin B & C
Gastric emptying and motility
Rapid gastric emptying and delay in gastric emptying:
BiopharmaceuticsDr.Yousef Algaradi

39. Factors influencing gastric emptying:
1)Volume of meal: Larger bulk longergastric emptying time
2)Composition of meal : Carbohydrates > Proteins > Fats
3)Physical state & viscosity : Liquid meals (hour to empty)
> solid meals (6 to 7 hrs)
4)Temperature of meal: High or low temperature of ingested
(in comparison with to body temperature) reducegastric
emptying
5)Body posture :Gastric emptying favouredwhile standing
and lying on right side and vice versa
6)Emotional state : Stress & anxiety promotes while
depression retards it
7)Exercise :Vigorous physical activity retards
Gastric emptying and motility
BiopharmaceuticsDr.Yousef Algaradi

40. 8)Disease states:
Diseases like gastroenteritis, gastric ulcer, pyloric
stenosis, diabetes and hypothyroidism retardgastric
emptying.
Partial or total gastrectomy, duodenal ulcer and
hyperthyroidism promotegastric emptying rate.
9)Drugs:
Drugs that retardgastric emptying include poorly soluble
antacids (aluminiumhydroxide), anticholinergics
(atropine, propantheline), narcotic analgesics (morphine)
and tricyclic antidepressants (imipramine, amitriptyline).
Metoclopramide, domperidoneand cisapride(prokinetic
agents) stimulategastric emptying
Gastric emptying and motility
BiopharmaceuticsDr.Yousef Algaradi

41. Disease state
Several disease states may influencethe rate and extent
of drug absorption.
Three major classes of disease may influence
bioavailability of drug.
1)GI diseases:
Achlorhydria : Decreasedgastric emptying and absorption
of acidic drugs like aspirin
Malabsorptionsyndrome and celiac disease: decreased
absorption
Gastrectomy: may cause drug dumpingin intestine,
osmotic diarrhea and reduceintestinal transit time.
-This may increase rate of absorption of drugs that are
absorbed in the small intestine.
BiopharmaceuticsDr.Yousef Algaradi

42. -However, drugs that require a period of time in the
stomach to facilitate their dissolution may show reduced
bioavailability in such patients
2)CVS disease:
In CVS diseases blood flow to GIT decrease, causes
decreased drug absorption.
3)Hepatic disease:
Disorders like hepatic cirrhosis influences bioavailability
of drugs which under goes first pass metabolism
Disease state
BiopharmaceuticsDr.Yousef Algaradi

43. Presystemic metabolism
The loss of drug as it passes through GIT membrane, liver
for the first time during the absorption process.
The main reason for the decreasein bioavailability of a
drug is decreased absorption or first pass metabolism.
Four primary systems which affect pre systemic
metabolism of a drugs
1)Luminal enzymes:
These are enzymes present in gut fluids and include
enzymes from intestinal and pancreatic secretions. E.g.
hydrolases
2)Gut wall enzymes:
Also called mucosal enzymes they are present in wall of
gut and intestine, colon. E.g. alcohol dehydrogenase
BiopharmaceuticsDr.Yousef Algaradi

44. 3)Bacterial enzymes:
GI microflorasscantily present in stomach and small
intestine and are rich in colon. e.g. sulphasalazine
sulphapyridine+ 5 ASA
4)Hepatic enzyme:
Several drug undergo firstpasshepatic metabolism,
highly extracted ones being isoprenaline, nitroglycerin,
morphine etc.
Presystemic metabolism
BiopharmaceuticsDr.Yousef Algaradi

45. Effect of food on GI drug
absorption
The presence of food in the GIT can influencethe rate
and extent of absorption, either directly or indirectly via
a range of mechanisms.
1)Complexation of drugs with components in the diet:
e.g.Tetracycline: it is advised that not take products
containingcalcium or iron, such as milk, iron
preparations or indigestion remedies, with tetracycline.
2)Alteration of pH:
Food tends to increasestomach pH by acting as a buffer.
This effect the rate of dissolution and absorption.
3)Alteration of gastric emptying
Fatsand some drugs tend to reduce gastric emptying
and thus delay the onset of action of certain drugs.
BiopharmaceuticsDr.Yousef Algaradi

46. 4)Stimulation of gastrointestinal secretions:
E.g. pepsin produced in responseto food may result in the
degradation of drugs .
Fats stimulate the secretion of bile.
5)Competition between food components and drugs for
specialized absorption mechanisms
There is a possibility of competitive inhibition of drug
absorption in case of drugs that have a chemical structure
similar to nutrients.
6)Increased viscosity of gastrointestinal contents
The food provides a viscousenvironment ,may result in:
-Reductionin the rate of drug dissolution
-Reduction in the rate of diffusion of drug in solution from.
Effect of food on GI drug
absorption
BiopharmaceuticsDr.Yousef Algaradi

47. 7)Food-induced changes in presystemicmetabolism
Interactingof food with the metabolic process.
-E.g. Grapefruit juice is capable of inhibitingthe intestinal
cytochrome P450 (CYP3A) and thus taken with drugs that
are susceptible to CYP3A metabolism which result in
increase of their bioavailability.
Blood flow to the GIT and liver increasesafter a meal.
-The faster the rate of drug presentation to the liver; the
larger the fraction of drug that escapesfirst-pass
metabolism.
-This is because the enzyme systems become saturated.
Effect of food on GI drug
absorption
BiopharmaceuticsDr.Yousef Algaradi

48. Physicochemical factors
affecting oral drug absorption
1)Ionization and pH -Partition Theory
2)Lipophilicityof the drug
3)Dissolution rate and solubility .
4)Drug stability and hydrolysis in GIT
5)Complexation
6)Adsorption
BiopharmaceuticsDr.Yousef Algaradi

49. According to the pH-partition hypothesis, the
gastrointestinal epithelia acts as a lipid barrier towards
drugs which are absorbed by passive diffusion, and those
that are lipid soluble will pass across the barrier.
As most drugs are weak electrolytes, the unionizedform
of weakly acidic or basic drugs (the lipid-soluble form)
will pass across the gastrointestinal epithelia, whereas
the gastrointestinal epithelia is impermeableto the
ionized (poorly-lipid soluble) form of such drugs.
Consequently, the absorption of a weak electrolyte will
be determined by the extent to which the drug exists in
its unionized form at the site of absorption.
Ionization and pH -Partition
Theory
BiopharmaceuticsDr.Yousef Algaradi

50. pH-partition theory states that for drug compounds ,
which are primarily transported across the biomembrane
by passive diffusion, the process of absorption is
governed by:
pKaof drug
The lipid solubility of the unionized drug
pH at the absorption site.
pKaof drug: Amount of drug that exist in unionizedform
and in ionizedform is a function of pKaof drug & pH of
the fluid at the absorption site and it can be determined
by Henderson-hasselbachequation
Ionization and pH -Partition
Theory
BiopharmaceuticsDr.Yousef Algaradi

51. The extent to which a weaklyacidic or basic drug
ionizes in solution in the gastrointestinal fluid may be
calculated using Henderson -Hasselbachequation.
Weak acids:
Taking the negative log of both sides:
Rearranging gives the following equation:
Dissociation Constant equation -Weak Acids
Henderson -HasselbachEquation -Weak Acids
Ionization and pH -Partition
Theory
BiopharmaceuticsDr.Yousef Algaradi

52. Weak Bases:
Limitations of the pH-partition hypothesis:
Despite their high degree of ionization, weak acids are
highly absorbed from the small intestine and this may be
due to:
1)The largesurface area that is available for absorption in
the small intestine.
2)A longer small intestine residence time.
3)A microclimate pH, that exists on the surface of
intestinal mucosa and is lower than that of the luminal
pH of the small intestine
Henderson -HasselbachEquation -Weak bases
Ionization and pH -Partition
Theory
BiopharmaceuticsDr.Yousef Algaradi

53. Ideally for optimum absorption, a drug should have
sufficient aqsolubility to dissolve in fluids at absorption
site and lipid solubility high enough to facilitate the
partitioning of the drug in the lipoidalbiomembranei.e.
drug should have perfect HLBfor optimum Bioavailability.
Some drugs are poorly absorbed after oral administration
even though they are non-ionized in small intestine.
Low lipid solubility of them may be the reason.
The best parameter to correlate between water and lipid
solubility is partition coefficient.
Lipophilicityand drug absorption
BiopharmaceuticsDr.Yousef Algaradi

54. Partition coefficient (p) = [ L] conc/ [W] conc
where, [ L] concis the concentration of the drug in lipid
phase.
[W] concis the concentration of the drug in aqueous
phase.
The higherp value, the more absorption is observed.
Lipophilicityand drug absorption
BiopharmaceuticsDr.Yousef Algaradi

55. Many drugs are given in solid dosage forms and therefore
must dissolve before absorption can take place.
The rate determining steps in absorption of orally
administered drugs are:
Rate of dissolution( forlipophilic drugs)
Rate of drug permeation through the biomembrane(for
hydrophilicdrugs)
If dissolution is the slow, it will be the rate determining
step (the step controlling the overall rate of absorption)
then factors affecting dissolution will control the overall
process
Dissolution rate and solubility
BiopharmaceuticsDr.Yousef Algaradi

56. Physicochemical factors affecting the dissolution rate of
drugs
1)Particle size and effective surface area
2)Internal structure of compound (Crystal form):
3)Salt form of drug
Dissolution rate and solubility
BiopharmaceuticsDr.Yousef Algaradi

57. 1)Particle size and effective surface area:
Particle size may play a major role in drug absorption.
Dissolution rate of solid particles is proportionalto surface
area.
Smaller the particle size (by micronization) greateris the
effective surface area more intimate contact b/w solid
surface and aqsolvent higheris the dissolution rate
increase in absorption efficiency
To increase the effective surface area, we have to reduce
the size of particles up to 0.1 micron.
So these can be achieved by “micronisationprocess’’.
Dissolution rate and solubility
BiopharmaceuticsDr.Yousef Algaradi

58. But in these case one most important thing to be keep in
mind that which type of drug is micronisedif it is:
a) Hydrophilic OR b) Hydrophobic
1)Hydrophilic drugs:
Small particles have higher energy than the bulk of the
solid resulting -increased interaction with the solvent.
Micronisation results highly increased absorption
efficiency.
Eg. Griseofulvin–Dose reduced half after micronisation.
Dissolution rate and solubility
BiopharmaceuticsDr.Yousef Algaradi

59. 2)Hydrophobic drugs :
Micronisationresults decreased effective surface area &
thus fall in dissolution rate.
Due to:
Air entrapment –wettability
Surface free energy –float
Prevented by:
Use of surfactantas a wetting agent which decreases the
interfacial tension and displaces the absorbed air with
the solvent. (Eg: Phenacetin)
Add hydrophilic diluents like PEG, PVP, dextrose etc
Dissolution rate and solubility
BiopharmaceuticsDr.Yousef Algaradi

60. 2)Internal structure of compound (Crystal form):
1-Polymorphism:
Some drugs exist in a number of crystal forms or
polymorphs.
These different forms may havedifferent solubility
properties and thus different dissolution characteristics.
Chloramphenicol palmitateis one example which exists in
three crystalline forms A, B and C.
A is the stable polymorph
B is the metastable polymorph (more soluble)
C is the unstable polymorph
Dissolution rate and solubility
BiopharmaceuticsDr.Yousef Algaradi

61. The plasma profiles of chloramphenicol from oral
suspensions containing different proportions of
Polymorphic forms A and B were investigated
The extent of absorption of Chloramphenicol increases as
the Proportion of the polymorphic
form
B is increased in each suspension.
This is attributed to the more
rapid dissolution of the
metastable Polymorphic form B.
Shelf-life could be a problem as
the more soluble (less stable)
form maytransform into the less
soluble form (more stable).
Dissolution rate and solubility
BiopharmaceuticsDr.Yousef Algaradi

62. 2-Amorphous solid:
The amorphous form dissolves more rapidlythan the
corresponding crystalline form.
The more soluble and rapidly dissolving amorphous form
of novobiocinantibiotic was readily absorbed following
oral administration of an aqueous suspension to humans.
However, the less soluble and slower-dissolving
crystalline form of novobiocinwas not absorbed
(therapeutically ineffective).
The amorphous form of novobiocinslowly convertsto
the more stable crystalline form, with loss of therapeutic
effectiveness.
Dissolution rate and solubility
BiopharmaceuticsDr.Yousef Algaradi

63. 3-Solvates (Pseudoploymorphism)
Solvates: If the drug is able to associate with solvent
molecules to produce crystalline forms known as solvates.
Hydrates: drug associates with water molecules.
The greater the solvation of the crystal, thelower are the
solubility and dissolution rate in a solventidentical to the
solvation molecules.
The faster-dissolving anhydrousform of ampicillin was
absorbed to a greater extent from both hard gelatin capsules
and an aqueous suspension than was the slower-dissolving
trihydrateform.
Dissolution rate and solubility
BiopharmaceuticsDr.Yousef Algaradi

64. Order of dissolution, Anhydrate > Monohydrate >
Dihydrate> Trihydrate
Reason: Hydrates are already in interactionwith water
So, thermodynamically higher energy state, So, less
energy for crystal breakup
Dissolution rate and solubility
BiopharmaceuticsDr.Yousef Algaradi

65. 3)Salt form of drug:
Salts of weak acids and weak bases generally have much
higher aqueous solubility than the free acid or base.
The dissolution rate of a weakly acidicdrug in gastric
fluid (pH 1 –3.5) will be relatively low.
If the pH in the diffusion layer increased, the solubility of
the acidic drug in this layer increase , and hence its
dissolution rate in gastric fluids would be increased.
The pH of the diffusion layer would be increased if the
chemical nature of the weakly acidic drug was changed
from that of the free acid to a basic salt (the sodium or
potassium form of the free acid.
Dissolution rate and solubility
BiopharmaceuticsDr.Yousef Algaradi

66. The pH of the diffusion layer would be higher (5-6) than
the low bulk pH (1-3.5) of the gastric fluids because of
the neutralizing action of the strong (Na+, K+) ions
present in the diffusion layer.
The drug particles will dissolve at a faster rate and diffuse
out of the diffusion layer into the bulk of the gastric fluid,
where a lower bulk pH.
Thus the free acid form of the drug in solution, will
precipitate out , leaving a saturated solution of free acid
in gastric fluid.
Dissolution rate and solubility
BiopharmaceuticsDr.Yousef Algaradi

67. This precipitated free acid will be in the form of:
Very fine,
Non-ionized,
Wetted particles which have a very largesurface area in
contact with gastric fluids, facilitating rapid redissolution
when additional gastric fluid is available.
Dissolution rate and solubility
BiopharmaceuticsDr.Yousef Algaradi

68. One example is the dissolution and bioavailability profiles
of Penicillin V with various salts.
These results might support the use of the benzathineor
procainesalts for IM depot use and the potassium salt
for better absorption orally
Dissolution rate and solubility
BiopharmaceuticsDr.Yousef Algaradi

69. Drugs that are susceptible to acidic or enzymatic
hydrolysis in the GIT, suffer from reduced bioavailability.
How to protect drugs (erythromycin) from degradation in
gastric fluid ??
1)Preparing enteric coated tablets containing the free
base of erythromycin.
The enteric coating resists gastric fluid but disrupts or
dissolves at the less acid pH range of the small intestine.
2)The administration of chemical derivatives of the parent
drug.
These prodrugs(erythromycin stearate) exhibit limited
solubility in gastric fluid, but liberate the drug in the
small intestine to be absorbed
Drug stability and hydrolysis in
GIT
BiopharmaceuticsDr.Yousef Algaradi

70. Complexation of a drug may occur within the dosage
form and/or in the gastrointestinal fluids, and can be
beneficial or deterimentalto absorption.
1)Intestinal mucosa (mucin) + Streptomycin = poorly
absorbed complex
2)Calcium + Tetracycline = poorlyabsorbed complex
(Food-drug interaction)
3)Carboxyl methylcellulose (CMC) + Amphetamine =
poorly absorbed complex (tablet additive –drug
interaction)
4)Lipid soluble drug + water soluble complexingagent =
well-absorbed water soluble complex ( cyclodextrin)
Complexation
BiopharmaceuticsDr.Yousef Algaradi

71. Certain insoluble substances may adsorbedco-
administrated drugs leading to poor absorption.
Charcoal (antidote in drug intoxication).
Kaolin (antidiarrheal mixtures)
Talc (in tablets as glidant)
Adsorption
BiopharmaceuticsDr.Yousef Algaradi

72. Formulations for Oral
Absorption
The roleof the drug formulation in the delivery of drug
to the site of action should not be ignored.
Since a drug must be in solution to be absorbed
efficiently from the G-I tract, you may expect the
bioavailability of a drug to decrease in the order:
Solution > suspension > capsule > tablet > coated tablet.
A.Solution dosage forms:
In most cases absorption from an oral solution is rapid
and complete, compared with administration in any
other oral dosage form.
BiopharmaceuticsDr.Yousef Algaradi

73. Some drugs which are poorlysoluble in water may be:
1)Dissolved in mixed water/alcoholor glycerol solvents
(cosolvency),
2)Given in the form of a salt (in case of acidic drugs)
3)An oily emulsion or soft gelatin capsules have been
used for some compounds with lower aqueous
solubility to produce improved bioavailability.
Formulations for Oral
Absorption
BiopharmaceuticsDr.Yousef Algaradi

74. B. Suspension dosage forms:
A well formulated suspension is second to a solution in
terms of superior bioavailability.
A suspension of a finely divided powder will maximize
the potential for rapid dissolution.
A good correlation can be seen for particle size and
absorption rate.
The addition of a surface active agent will improvethe
absorption of very fine particle size suspensions
Formulations for Oral
Absorption
BiopharmaceuticsDr.Yousef Algaradi

75. C. Capsule dosage forms:
The hard gelatin shell should disruptrapidly and allow
the contents to be mixed with the G-I tract contents.
If a drug is hydrophobic a dispersing agent should be
added to the capsule formulation.
These diluents will work to disperse the powder,
minimize aggregation and maximize the surface area of
the powder.
Tightly packed capsules may have reduced dissolution
and bioavailability
Formulations for Oral
Absorption
BiopharmaceuticsDr.Yousef Algaradi

76. D. Tablet dosage forms:
The tablet is the most commonly used oral dosage form.
It is also quite complex in nature.
Coated tablets are used to mask an unpleasant taste, to
protect the tablet ingredients during storage, or to
improve the tablets appearance.
This coating can add another barrierbetween the solid
drug and drug in solution.
This barrier must break down quickly or it may hinder a
drug's bioavailability.
-Sustained release tablet:
Another form of coating is enteric coated tablets which are
coated with a material which will dissolve in the intestine
but remain intactin the stomach
Formulations for Oral
Absorption
BiopharmaceuticsDr.Yousef Algaradi

77. Tablet dosage forms
Tablet Disintegration is impotent issue for oral absorption
Disintegration time:
Rapiddisintegration is important to have a rapid
absorption so lower D.T is required.
D.T of tablet is directly proportionalto:
-Amount o f binder
-Compression force.
One thing should be remembered that in vitro
disintegration test gives no means of a guaranteeof drugs
absorption , because if the disintegrated drug particles do
not dissolve then absorption is not possible.
BiopharmaceuticsDr.Yousef Algaradi

78. Manufacturing variables:
a). Method of granulation:
Wet granulation yields a tablet that dissolves fasterthan
those made by other granulating methods.
But wet granulation has several limitations like formation
of crystal bridge or chemical degradation.
Other superior recent method named APOC
(agglomerative phase of communition) that involves
grinding of drug till spontaneous agglomeration and
granules are prepared with higher surface area.
So tablet made up of this granules have higher
dissolution rate.
Tablet dosage forms
BiopharmaceuticsDr.Yousef Algaradi

79. b) Compression force:
Higher compression force yields a tablet with greater
hardness and reduced wettability & hence have a long
D.T.
But on other hand Lower compression force cause
crushing of drug particles into smaller ones with higher
effective surface area which in decrease in D.T., but this is
disadvantages in some cases
So effect of compression force should be thoroughly
studiedon each formulation
Tablet dosage forms
BiopharmaceuticsDr.Yousef Algaradi

80. Effect of excipients in
formulation
The advantages of using excipients on drug product
performance:
1)Improve the manufacturability of the dosage form.
2)Stabilize the drug against degradation.
3)Decrease gastricirritation.
4)Controlthe rate of drug absorption from the absorption
site.
5)Increase drug bioavailability
BiopharmaceuticsDr.Yousef Algaradi

81. The mechanisms by which excipients affect the dissolution
kinetics of the drug
1)Altering the medium in which the drug is dissolving:
Suspending agents can increase the viscosity of the drug
vehicle and thereby diminish the rate of drug dissolution
from suspensions.
Tablet lubricants, such as magnesium stearate, may repel
water and reducedissolution when used in large
quantities (Next figure).
Coatings, particularly shellac, will crosslink upon aging
and decrease the dissolution rate.
Effect of excipients in
formulation
BiopharmaceuticsDr.Yousef Algaradi

82. The effect of adding different concentrations of magnesium stearate to a tablet formulation on the
dissolution profile (left panel) and plasma conc.-time profile( right panel)
Effect of excipients in
formulation
BiopharmaceuticsDr.Yousef Algaradi

83. Surfactants: low concentrations of surfactants decrease
the surface tension and increase the rate of drug
dissolution, whereas higher surfactant concentrations
tend to form micelleswith the drug and thus decrease
the dissolution rate.
Some excipients, such as sodium bicarbonate, may
changethe pH of the medium surrounding the active
drug substance.
•Example: Aspirin, a weak acid when formulated with
sodium bicarbonate, will form a water-soluble saltin an
alkaline medium, in which the drug rapidlydissolves.
The term for this process is dissolution in a reactive
medium.
Effect of excipients in
formulation
BiopharmaceuticsDr.Yousef Algaradi

84. 2)Directly in interaction with the drug to form a water-
soluble or water-insoluble complex.
For example, if tetracycline is formulated with calcium
carbonate, an insoluble complex of calcium tetracycline is
formed that has a slow rate of dissolution and poor
absorption
Effect of excipients in
formulation
BiopharmaceuticsDr.Yousef Algaradi

85. Effect of excipients in
formulation
BiopharmaceuticsDr.Yousef Algaradi