Biopharmaceutics

Biopharmaceutics

1. Biopharmaceutics
Dr. Basavaraj K. Nanjwade M. Pharm., Ph. D
Department of Pharmaceutics
Faculty of Pharmacy
Omer Al-Mukhtar University
Tobruk, Libya.
E-mail: [email protected]
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Faculty of Pharmacy, Omer Al-Mukhtar University,
Tobruk, Libya.

2. CONTENTS
1.Mechanism of drug absorption.
2.Factors affecting drug absorption from G. I. T.
3.In-vitro dissolution testing.
a. Official and non-official methods.
b. Factors affecting dissolution of drug from
different forms.
4. References.

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3. Mechanism of drug absorption
•The three broad categories of drug transport
mechanisms involved in absorption are:-
A.Transcellular/intracellular transport
B.Paracellular/intercellular transport
C.Vesicular transport
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4. Mechanism of drug
absorption
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5. A. Transcellular/intracellular
transport
•Transcellular/intracellular transport is defined as the
passage of drugs across the GI epithelium. It is the
most common pathway for drug transport. The 3 steps
involved in transcellular transport of drugs are-
1. Permeation of GI epithelial cell membrane, a lipoid
barrier-this is the major obstacle to drug absorption.
2. Movement across the intracellular space (cytosol)
3. Permeation of the lateral or basolateral membrane-
this is of secondary importance.
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6. A. Transcellular/intracellular
transport
•The various transcellular transport processes involved in
drug absorption are:-
1.Passive transport process: These transport processes do
not require energy other than that of molecular motion
(Brownian motion) to pass through the lipid bilayer.
2.Active transport process: These transport processes
require energy from ATP (adenosine tri phosphate) to
move drug molecules from extracellular to intracellular
milieu.
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7. Passive transport process
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8. Active transport process
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•More important process than facilitated diffusion.
•The driving force is against the concentration gradient or uphill transport.
•Since the process is uphill, energy is required in the work done by the barrier.
•As the process requires expenditure of energy, it can be inhibited by metabolic
poisons that interfere with energy production.

9. Comparison between active
and passive transport
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10. Passive transport process
•Passive transport processes can be further
classified into following types
a.Passive diffusion
b.Pore transport
c.Ion-pair transport
d.Facilitated or mediated diffusion.
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11. a. Passive diffusion
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• Also known as non-ionic diffusion.
• It is defined as the difference in the drug concentration on either side of the
membrane.
• Absorption of 90% of drugs.
• The driving force for this process is the concentration or electrochemical
gradient.

12. b. Pore transport
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• Also known as convective transport, bulk flow or filtration.
• Important in the absorption of low mol. Wt. (less than 100). Low molecular size
(smaller than the diameter of the pore) & generally water-soluble drugs through
narrow, aqueous filled channels or pores in the membrane structure.
e.g. urea, water & sugars.
• The driving force for the passage of the drugs is the hydrostatic or the osmotic
pressure difference across the membrane.

13. c. Ion-pair transport
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•It is another mechanism is able to explain the absorption
of such drugs which ionize at all pH condition.

14. d. Facilitated or
mediated diffusion
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•This mechanism involves the driving force is concentration gradient.
•In this system, no expenditure of energy is involved (down-hill transport),
therefore the process is not inhibited by metabolic poisons that interfere
with energy production.

15. Active transport process
•Active transport processes are of two types
a.Primary active transport
b.Secondary active transport-this process is
further subdivided in two-
(i) Symport (co-transport)
(ii) Antiport (counter-transport)
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16. Active transport process
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17. B. Paracellular/intercellular
transport
•Paracellular/intercellular transport is defined as the
transport of drugs through the junction between the GI
epithelial cells. This pathway is of minor importance in
drug absorption.
•Paracellular transport differs from pore transport in that
the former involves transfer of drug across epithelium
and through the cellular junctions whereas in the case of
latter, the molecules are transferred from outside of the
epithelial cell into the cell through pores present in the
cell membrane.
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18. B. Paracellular/intercellular
transport
•The two paracellular transport mechanisms involved in
drug absorption are-
1.Permeation through tight junctions of epithelial cells:
this process basically occurs through opening which are
little bigger than the aqueous pores. Compounds such as
insulin and cardiac glycosides are taken up by this
mechanism
2.Persorption: is permeation of drug through temporary
openings formed by shedding of two neighboring
epithelial cells into the lumen.
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19. C. Vesicular transport
•Vesicular or Corpuscular transport (Endocytosis): Like
active transport, these are also energy dependent
processes but involve transport of substances within
vesicles into cell. Since the mechanism involves transport
across the cell membrane, the process can also be
classified as transcellular.
•Vesicular transport of drugs can be classed into two
categories-
1.Pinocytosis (cell drinking): uptake of fluid solute.
2.Phagocytosis (cell eating): adsorptive uptake of solid
particulates
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20. Pinocytosis (cell drinking)
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This process is important in the absorption of oil soluble vitamins &
in the uptake of nutrients.

21. Phagocytosis (cell eating)
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22. Factors affecting
drug absorption from G. I. T.
A.PHARMACEUTICAL FACTORS: include factors
relating to the physicochemical properties of the
drug and dosage form characteristics and
pharmaceutical ingredients.
B.PATIENT-RELATED FACTORS: include factors
relating to the anatomical, physiological and
pathological characteristics of the patient.
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23. A. PHARMACEUTICAL FACTORS
I. Physicochemical Properties of Drug Substances
1.Drug solubility and dissolution rate
2.Particle size and effective surface area
3.Polymorphism and amorphism
4.Pseudopolymorphism (hydrates/solvates)
5.Salt form of the drug
6.Lipophilicity of the drug
7.pKa of the drug and gastrointestinal pH
8.Drug stability
9.Stereochemical nature of the drug
II. Dosage Form Characteristics and Pharmaceutical Ingredients (Pharmaco-technical Factors)
1.Disintegration time (tablets/capsules)
2.Dissolution time
3.Manufacturing variables
4.Pharmaceutical ingredients (excipients/adjuvants)
5.Nature and type of dosage form
6.Product age and storage conditions
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pH-partition hypothesis

24. B. PATIENT-RELATED FACTORS
1.Age
2.Gastric emptying time
3.Intestinal transit time
4.Gastrointestinal pH
5.Disease states
6.Blood flow through the GIT
7.Gastrointestinal contents: (a) Other drugs, (b) Food, (c) Fluids, (d) Other
normal GI contents
8.Presystemic metabolism by:
a. Luminal enzymes
b. Gut wall enzymes
c. Bacterial enzymes
d. Hepatic enzymes
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25. In-vitro dissolution testing
•For an in vitro test to be useful, it must predict the in
vivo behavior to such an extent that in vivo
bioavailability test need not be performed.
•Despite attempts to standardize the test
performance, the in vitro dissolution technique is till
by no means a perfect approach.
•The efforts are mainly aimed at mimicking the
environment offered by the biological system
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26. In-vitro dissolution testing
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27. Official and Non-Official Methods
•There are basically three general categories
of dissolution apparatus in Official Methods:
1.Beaker methods
2.Open flow-through compartment system
3.Dialysis concept
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28. 1. Beaker methods
1.Rotating Basket Apparatus.
2.Rotating Paddle Apparatus.
3.The Reciprocating Cylinder Method.
4.Paddle over Disk method.
5.Cylinder method.
6.Reciprocating Holder method.
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29. Rotating Basket Apparatus
Cylindrical basket of 22 mesh.
 Rotating speed-100 rpm.
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30. Rotating Basket Apparatus
It is basically a closed-compartment, beaker type
apparatus.
It comprising of a cylindrical glass vessel with
hemispherical bottom of one litter capacity partially
immersed in a water bath.
A cylindrical basket made of #22 mesh is located
centrally in the vessel at a distance of 2 cm from the
bottom and rotated by a variable speed motor
through a shaft.
All metal parts like basket and shaft are made of
stainless steel 316.
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31. Rotating Paddle Apparatus
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32. Rotating Paddle Apparatus
Instead of rotating basket, a paddle used.
The paddle is vertically attached to variable speed
motor.
Position & alignment of the paddle are specified in
USP.
50 rpm-for oral dosage forms, 25 rpm-suspensions.
A small, loose, wire helix may be attached to the
dosage form that would otherwise float.
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33. Rotating Basket and Paddle
Apparatus
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34. The Reciprocating Cylinder
Method
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35. The Reciprocating Cylinder
Method
Set of cylindrical, flat-bottomed glass vessels
equipped with reciprocating cylinders.
For testing of extended release products.
This method adopts the USP disintegration “basket
and rack” assembly for the dissolution test.
The disks are not used.
This method is less suitable for precise dissolution
testing due to the amount of agitation and vibration
involved.
E.g. Chlorpheniramine ER tablets, Carbamazepine chewable tablet.
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36. Paddle over Disk method
Sample holder or disk assembly that holds the
product.
Temperature 32
o
C.
Paddle is placed over the disk assembly.
For testing the release of drug from transdermal
products.
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37. Paddle over Disk method
Modification of Apparatus 2.
Here, stainless steel disk designed for holding
transdermal system at the bottom of the vessel.
The disk/device should not sorb, react with, or
interfere with the specimen being tested.
The disk holds the system flat and is positioned such
that the release surface is parallel with the bottom of
the paddle blade.
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38. Paddle over Disk method
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39. Rotating Cylinder method
A stainless steel cylinder is used to hold the sample.
 Sample is mounted on to cuprophan.
 Temperature 32
o
C.
 For testing transdermal preparations.
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40. Rotating Cylinder method
Same as apparatus 1, except to replace the basket
and shaft with a stainless steel cylinder stirring
element.
Temperature 32 ± 0.5°
The dosage unit is placed on the cylinder.
Distance between the inside bottom of the vessel
and cylinder is maintained at 25 ± 2 mm.
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41. Reciprocating Disc/Holder
method
A motor drive assembly is used to reciprocate the
system vertically.
 Temperature 32
o
C.
 Reciprocating frequency is about 30 cycles per
minute.
The assembly consists of a set of calibrated solution
containers, a motor and drive assembly to
reciprocate the system vertically.
Various type of sample holder are used.
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42. Reciprocating Disc/Holder
method
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43. 2. Open flow-through
compartment system
Reservoir.
Pump forcing medium through the cell.
For modified release dosage forms, containing active
ingredients with limited solubility.
The dosage form is contained in a small vertical glass
column with built in filter through which a
continuous flow of the dissolution medium is
circulated upward at a specific rate from an outside
reservoir using a peristaltic or centrifugal pump.
Dissolution fluid is collected in a separate reservoir.
E.g. lipid filled soft Gelatin capsule.
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44. 2. Open flow-through
compartment system
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45. 3. Dialysis concept
Here, dialysis membrane used as a selective
barrier between fresh solvent compartment
and the cell compartment containing dosage
form.
It can be used in case of very poorly soluble
drugs and dosage form such as ointments,
creams and suspensions.
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46. 3. Dialysis concept
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47. Non-Official Methods
1.The Rotating Filter Method.
2.Rotating Flask Dissolution Method.
3.Rotating and Static Disk Methods.
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University, Tobruk, Libya.

48. The Rotating Filter Method
 It consists of a magnetically driven rotating
filter assembly and a 12 mesh wire cloth
basket.
 The sample is withdrawn through the
spinning filter for analysis.
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49. Rotating Flask Dissolution
Method
 This consists of a spherical flask made of glass
and supported by a horizontal glass shaft that
is fused to its sides.
 The shaft is connected to a constant speed
driving motor.
 The flask is placed in a constant temperature
water bath and rotates about its horizontal
axis.
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Faculty of Pharmacy, Omer Al-Mukhtar
University, Tobruk, Libya.

50. Rotating and Static Disk
Methods
The compound is compressed into
non disintegrating disc.
Mounted - One surface is exposed
to medium.
Assumption - Surface area remains
constant.
Used to determine the intrinsic
dissolution rate.
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51. Factors affecting dissolution
of drug from different forms
1. Pharmaceutical excipients
Vehicle
Diluents
Lubricants
Binders
Surfactants
Colorants
2. Manufacturing processes
Method of granulation –
Wet granulation
Direct compression
Agglomerative phase of communication (APOC)
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52. 1. Pharmaceutical excipients
Vehicle
•Aqueous, non-aqueous water miscible (E.g. propylene
glycol) and non-aqueous water immiscible (vegetable oil).
•Bioavailability of drug depends upon its miscibility with
body fluid.
•Viscosity of vehicle also affect absorption.
Diluents
•Organic diluents- e.g. starch, lactose promote dilution of
poorly water soluble, hydrophobic drugs like
spironolactone.
•Inorganic diluents – Dicalcium Phosphate divalent calcium-
tetracycline complex – poorly soluble – unobservable.
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53. 1. Pharmaceutical excipients
Lubricants / Antifrictional agent
• Use to ensure good flow property of granules.
• To reduce the sticking of particle to dyes or punches.
E.g. SLS (Sodium laural sulphate) , Carbowaxes etc.
Binders / Granulating agents
•Used to hold the powder together in granulation
• To promote the cohesive compact for directly
compressible material.
•Proportion of binder is important
E.g. Starch, Acacia etc.
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54. 1. Pharmaceutical excipients
Surfactants
•Used as wetting agent, solubilizes, emulsifier.
•Enhance or retard drug absorption.
Colorants
•May decreased the dissolution rate of crystalline
drug by absorb onto crystalline face.
E.g. Brilliant Blue retards dissolution of sulphathiazole
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55. 2. Manufacturing processes
Method of granulation –
Wet granulation
Direct compression
Agglomerative phase of communication
(APOC)
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56. 03/21/17
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Compression ForceCompression Force :-:-
R
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e
o
f

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u
g

d
i
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s
o
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u
t
i
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A B
C D
Compression force
Influence of compression force on dissolution rate of tablet
2. Manufacturing processes

57. Nature and Type of Dosage
Form
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•Rate of release of drug from dosage form is depend on
complexity of dosage form
•Selection of proper dosage form is important

58. Nature and Type of Dosage
Form
Solution
Rapid absorption because dissolution step is absent
Bioavailability of drug depends upon nature of vehicle,
viscosity, stabilizer etc.
Emulsion
Superior than suspension in case of poorly aqueous soluble
lipophilic drug
E.g. Indoxole
Suspension
Rate limiting step is dissolution
Depend on particle surface area, viscosity of medium,
suspending agents
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59. Nature and Type of Dosage
Form
Powders
•Superior than tablet and capsule.
•Depend upon particle size, wetting ability.
Capsules
•Hard gelatin capsule:-powder and granules.
•Soft gelatin capsule:-viscous fluid.
•Depend upon particle size, density, nature of
diluents, intensity of packing etc.
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60. Nature and Type of Dosage
Form
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Tablet
Sequence of events in the absorption of drug from tablet dosage form

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University, Tobruk, Libya.EC-LSv/12
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