Drug Absorption From Gastrointestinal tack

1. Department Of Pharmaceutics
H.R.Patel Institute Of Pharmaceutical
Education& Research, Shirpur
Presented By:
Mr.Badhe Shubham
Pradip
Guided By :
Dr. L.R.Zawar
Dept. of P’ceutics
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2. 1 • Dissolution methods.
2
• Correlation of in vivo data with in vitro dissolution data.
3
• Transport model : Permeability-Solubility-charge state &
The pH partition Hypothesis.
4 • Properties of the Gastrointestinal Tract(GIT).
5
• pH Microclimate Intracellular pH Environment.
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• Tight-Junction Complex.
7 • References
Content:
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3. Dissolution
• Definition :
Dissolution is a process in which a solid substance
solubilizes in a given solvent i.e. mass transfer from
the solid surface to the liquid phase.
Dissolution is the rate determining step for
hydrophobic, poorly aqueous soluble drugs.
E.g. Griseofulvin, spironolactone
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4. • The USP describes the official dissolution apparatus
and includes information for performing dissolution
tests on a variety of drug products including tablets,
capsules, and other special products such as
transdermal preparations.
Various methods are classified according to the USP
they are as follows :
1. Apparatus 1 (rotating basket)
2. Apparatus 2 (paddle assembly)
3. Apparatus 3 (reciprocating cylinder)
4. Apparatus 4 (flow-through cell)
5. Apparatus 5 (paddle over disk)
6. Apparatus 6 (Rotating cylinder)
7. Apparatus 7 (reciprocating holder)
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5. Methods
1. Apparatus 1 (rotating basket) :
The rotating basket apparatus (Apparatus 1) consists of a
cylindrical basket held by a motor shaft. The basket holds
the sample and rotates in a round flask containing the
dissolution medium. The entire flask is immersed in a
constant-temperature bath set at 37°C. Agitation is
provided by rotating the basket. The rotating speed and the
position of the basket must meet specific requirements set
forth in the current USP. The most common rotating speed
for the basket method is 100–150 rpm. A disadvantage of
the rotating basket is that the formulation may clog to the
40-mesh screen.
5

6. 2. Apparatus 2 (paddle assembly) :
The paddle apparatus consists of a special, coated paddle
that minimizes turbulence due to stirring. The paddle is
attached vertically to a variable-speed motor that rotates at a
controlled speed. The tablet or capsule is placed into the
round-bottom dissolution flask, which minimizes turbulence
of the dissolution medium. The most common operating
speeds for Apparatus 2 are 50 or 75 rpm for solid oral
dosage forms and 25 rpm for oral suspensions. Apparatus 2
is generally preferred for tablets.
3. Apparatus 3 (reciprocating cylinder) :
The reciprocating cylinder apparatus consists of a set of
cylindrical, flat-bottomed glass vessels equipped with
reciprocating cylinders for dissolution testing of extended-
release products, particularly bead-type modified-release
dosage forms. Reciprocating agitation moves the dosage
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7. form up and down in the media. The agitation rate is
generally 5–30 dpm (dips per minute). The reciprocating
cylinder can be programmed for dissolution in various
media for various times. The media can be changed easily.
This apparatus may be used during drug product
development to attempt to mirror pH changes and transit
times in the GI tract such as starting at pH 1 and then pH
4.5 and then at pH 6.8.
4. Apparatus 4 (flow-through cell) :
• Reservoir : -For dissolution medium
• Pump : -Forces dissolution medium through cell
• Holding a sample
• Flow rate 10-100ml/min
• Laminar flow is maintained
• Peristaltic/centrifugal pumps are not recommended
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8. Water bath:- Maintain at 37±0.5°C
USE:
1. Low solubility drugs ,micro particulates ,implants,
suppositories.
2. controlled release formulations.
 Method :
• The flow through cell is transparent & inert mounted
vertically with filters.
• Standard cell diameters are 12 & 22.6 mm.
• The bottom cone usually filled with glass beads of 1 mm
diameter.
• Tablet holder used for positioning special dosage form e.g.
Inlay tablets.
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9. • Place the glass beads into the cell as specified in the
monograph.
• Place one dosage unit on top of the beads or on a wire
carrier.
• Assemble the filter head and fix the parts together by means
of a suitable clamping device.
• Introduce by the pump of the dissolution medium warmed
to 37±0.5 through the bottom of the cell to obtain the flow
rate specified and measured with an accuracy of 5%.
• Collect the eluate by fractions at each of the times stated.
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10. 5. Apparatus 5 (paddle over disk) :
• This method is used for testing the release of
drugs from transdermal product.
• The apparatus consists of a sample holder or
disc assembly that holds the product.
• The entire preparation is placed in dissolution
flask filled with specified medium maintained
at 32ºC.
• The paddle is placed directly over the disc ass-
embly.
• The disk assembly holds the system flat and is positioned
such that release surface is placed parallel with the bottom
of the paddle blade. Vessel is covered to minimize
evaporation during test.
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11. • Samples are drawn midway between the surface of
dissolution medium and the top of the paddle blade at
specified times.
6. Apparatus 6 (Rotating cylinder) :
• The cylinder method (Apparatus 6) for testing transdermal
preparation is modified from the basket method (Apparatus
1). In place of the basket, a stainless steel cylinder is used to
hold the sample.
• Testing is maintained at 32°C. Apparatus 6 may be used for
reservoir transdermal patches that cannot be cut smaller.
Samples are drawn midway between the surface of the
dissolution medium and the top of the rotating cylinder for
analysis.
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12. 7. Apparatus 7 (reciprocating holder) :
The reciprocating disk method for testing transdermal
products uses a motor drive assembly (Apparatus 7) that
reciprocates vertically. The samples are placed on disk-
shaped holders using cuprophan supports. The test is also
carried out at 32°C, and reciprocating frequency is about 30
cycles per minute
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13. Correlation of in vivo data with in vitro
dissolution data
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14. IVIVC - Definition
• FDA :
A predictive mathematical model describing the relationship
between an in vitro property of dosage form (usually the
rate or extent of drug dissolution or release) and a relevant
in vivo response, e.g., plasma drug concentration or amount
of drug .
• USP :
The establishment of a relationship between a biological
property or a parameter derived from a biological property
(Cmax, AUC) produced by a dosage form, and a
physicochemical characteristic (in vitro release) of the same
dosage form.
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15. • The concept of IVIVC has been extensively discussed for
modified release dosage forms
• In recent times, IVIVC for parenterals, transdermals,
pulmonary formulations etc. are also coming.
Correlation :
The word Correlation has two different definitions:
1. Mathematical
2. Biopharmaceutical
• Mathematically-The word correlation means
interdependence between qualitative and quantitative data,
or relationship between measurable variable or rank.
• From Biopharmaceutical point of view, it simply
means relationship between observed parameters derived
from in vitro and in vivo studies.
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16. LEVELS OF CORRELATION
• Based on the ability of the correlation to reflect the
complete plasma level profile, which will result from
administration of the given dosage form.
1. Level A
2. Level B
3. Level C
 Level A :
• Highest category of correlation.
• Linear correlation.
• Represents point to point correlation
between in vitro dissolution time course and in vivo
response time course.
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17. • The major advantage of a Level A correlation is that a point-
to-point correlation is developed. All in vitro dissolution
data and all in vivo plasma drug concentration–time profile
data are used .
• Once a Level A correlation is established, an in vitro
dissolution profile can serve as a surrogate for in vivo
performance.
• A change in manufacturing site, method of manufacture,
raw material supplies, minor formulation modification, and
even product strength using the same formulation can be
justified without the need for additional human studies.
 Level B :
• The mean in vitro dissolution time is compared either to
the mean residence time (MRT) or to the mean in vivo
dissolution time.
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18. • Uses the principles of statistical moment analysis.
• Is not a point-to-point correlation.
• Reason - because a number of different in vivo curves will
produce similar mean residence time values.
• Level B correlations are rarely seen in NDAs.
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19. Level C :
• A Level C correlation is not a point-to-point correlation. A
Level C correlation establishes a single-point relationship
between a dissolution parameter such as percent dissolved
at a given time and a pharmacokinetic parameter of interest
such as AUC and Cmax. Level C correlation is useful for
formulation selection and development but has limited
application .
• Several examples of Level C correlation are given below.
1. Dissolution rate versus absorption rate.
2. Percent of drug dissolved versus percent of drug absorbed.
3. Maximum plasma concentrations versus percent of drug
dissolved in vitro.
4. Serum drug concentration versus percent of drug dissolved.
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20. Transport model : Permeability-Solubility-
charge state & The pH partition Hypothesis.
• Fick’s first law applied to a membrane shows that passive
diffusion of a solute is the product of the diffusivity and the
concentration gradient of the solute inside the membrane.
For an ionizable molecule to permeate by passive diffusion
most efficiently, the molecule needs to be in its uncharged
form at the membrane surface.
• Consider a vessel divided into two chambers, separated by a
homogeneous lipid membrane. The left side is the donor
compartment, where the sample molecules are first
introduced; the right side is the acceptor compartment,
which at the start has no sample molecules.
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21. 21
Figure 2.1 Transport model diagram, depicting two aqueous cells
separated by a membrane barrier.
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22. PROPERTIES OF THE GASTROINTESTINAL
TRACT (GIT)
• Oral Drug Absorption :
The oral route of administration is the most common and popular
route of drug dosing. The oral dosage form must be designed to
account for extreme pH ranges, the presence or absence of food,
degradative enzymes, varying drug permeability in the different
regions of the intestine, and motility of the gastrointestinal tract.
• Anatomic and Physiologic Considerations :
The normal physiologic processes of the alimentary canal may be
affected by diet, contents of the gastrointestinal (GI) tract,
hormones, the visceral nervous system, disease, and drugs. Thus,
drugs given by the enteral route for systemic absorption may be
affected by the anatomy, physiologic functions, and contents of
the alimentary tract. Moreover, the physical, chemical, and
pharmacologic properties of the drug and the formulation of the
drug product will also affect systemic drug absorption from the
alimentary canal
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23. Fig. Gastrointestinal Tract
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24. Drugs administered orally pass through various parts of the
enteral canal, including the oral cavity, esophagus, and
various parts of the gastrointestinal tract. Residues
eventually exit the body through the anus. The total transit
time, including gastric emptying, small intestinal transit,
and colonic transit, ranges from 0.4 to 5 days.
The small intestine, particularly the duodenum area, is the
most important site for drug absorption. Small intestine
transit time (SITT) ranges from 3 to 4 hours for most
healthy subjects.
 Oral Cavity :
Saliva is the main secretion of the oral cavity, and it has a
pH of about 7. Saliva contains ptyalin (salivary amylase),
which digests starches. Mucin, a glycoprotein that lubricates
food, is also secreted and may interact with drugs. About
1500 mL of saliva is secreted per day.
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25.  Esophagus :
The esophagus connects the pharynx and the cardiac orifice of the
stomach. The pH of the fluids in the esophagus is between 5 and
6. The lower part of the esophagus ends with the esophageal
sphincter, which prevents acid reflux from the stomach.
Tablets or capsules may lodge in this area, causing local irritation.
Very little drug dissolution occurs in the esophagus.
 Stomach :
The stomach is innervated by the vagus nerve. However, local
nerve plexus, hormones, mechanoreceptors sensitive to the
stretch of the GI wall, and chemoreceptors control the regulation
of gastric secretions, including acid and stomach emptying. The
fasting pH of the stomach is about 2–6. In the presence of food,
the stomach pH is about 1.5–2, due to hydrochloric acid secreted
by parietal cells .Generally Basic drugs are solubilized rapidly in
the presence of stomach acid.
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26. If the stomach pH is too high, the enteric-coated drug product
may release the drug in the stomach, thus causing irritation to
the stomach.
 Duodenum :
A common duct from both the pancreas and the gallbladder
enters into the duodenum. The duodenal pH is about 6–6.5,
because of the presence of bicarbonate that neutralizes the
acidic chyme emptied from the stomach. The duodenum is the
major site for passive drug absorption due to both its anatomy,
which creates a high surface area, and high blood flow.
 Jejunum :
The jejunum is the middle portion of the small intestine,
between the duodenum and the ileum. Digestion of protein and
carbohydrates continues after addition of pancreatic juice and
bile in the duodenum.
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27.  Ileum :
The ileum is the terminal part of the small intestine. This site
also has fewer contractions than the duodenum and may be
blocked off by catheters with an inflatable balloon and
perfused for drug absorption studies. The pH is about 7,
with the distal part as high as 8. Due to the presence of
bicarbonate secretion, acid drugs will dissolve in the ileum.
Bile secretion helps dissolve fats and hydrophobic drugs.
 Colon :
The colon lacks villi and has limited drug absorption due to
lack of large surface area, blood flow, and the more viscous
and semisolid nature of the lumen contents. The colon is
lined with mucin that functions as lubricant and protectant.
The pH in this region is 5.5–7. A few drugs, such as
theophylline and metoprolol, are absorbed in this region.
Drugs that are absorbed well in this region are good
candidates for an oral sustained-release dosage form.
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28.  Rectum :
The rectum is about 15 cm long, ending at the anus. In the
absence of fecal material, the rectum has a small amount of
fluid (approximately 2 mL) with a pH of about 7.
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29.  pH Microclimate :
The absorption of short-chain weak acids in the rat intestine, as a
function of pH, does not appear to conform to the pH partition
hypothesis . Similar anomalies were found with weak bases . The
apparent pKa values observed in the absorption– pH curve were
shifted to higher values for acids and to lower values for bases,
compared with the true pKa values. Such deviations could be
explained by the effect of an acid layer on the apical side of cells,
the so-called acid pH microclimate.
 Intracellular pH environment :
Intracellular pH (pHi) is the measure of the acidity or basicity
(i.e., pH) of intracellular fluid. The pHi plays a critical role in
membrane transport and other intracellular processes.
Physiologically normal intracellular pH is most commonly
between 7.0 and 7.4. Intracellular pH is typically lower than
extracellular pH due to lower concentrations of HCO3
−.
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30. Tight junction complex
Tight junction also known as occluding junction.tight
junction are composed of branching network of sealing
strands, each strand acting independently from the other.The
function of tight junction is to hold the cell together & also
the tight junction are help to maintain the polarity of cell by
preventing the lateral diffusion of integral membrane
protein between apical and lateral/basal surface.
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31. References
1. Leon Shargel, Andrew B.C.YU “Applied biopharmaceutics
and pharmacokinetics”Seventh edition,Mc Graw Hill
Education, pg no.390-393,429-431.
2. Avdeef alex “Absorption and drug development ’’A john
Wiley & sonc Inc publication, pg no.7-18.
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32. Introduction to Liposome 32