Biopharmaceutics

BiopharmaceuticsDr. Basavaraj K. Nanjwade M. Pharm., Ph. D

Department of PharmaceuticsFaculty of Pharmacy

Omer Al-Mukhtar UniversityTobruk, Libya.

E-mail: [email protected]

2014/03/01 1Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.

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. 2014/03/01 2Faculty of Pharmacy, Omer Al-Mukhtar University,

Tobruk, Libya.

Mechanism of drug absorption

• The three broad categories of drug transport mechanisms involved in absorption are:-

A.Transcellular/intracellular transportB.Paracellular/intercellular transportC.Vesicular transport


Mechanism of drug absorption

2014/03/01 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. 4

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.2014/03/01 5Faculty of Pharmacy, Omer Al-Mukhtar University,

Tobruk, Libya.

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.


Passive transport process


Active transport process


• 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.

Comparison between active and passive transport


Passive transport process

• Passive transport processes can be further classified into following types

a. Passive diffusionb.Pore transportc. Ion-pair transportd.Facilitated or mediated diffusion.


a. Passive diffusion


• 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.

b. Pore transport


• 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.

c. Ion-pair transport


• It is another mechanism is able to explain the absorption of such drugs which ionize at all pH condition.

d. Facilitated or mediated diffusion


• 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.


• Active transport processes are of two types

a. Primary active transportb.Secondary active transport-this process is

further subdivided in two- (i) Symport (co-transport) (ii) Antiport (counter-transport)


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.


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.


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


Pinocytosis (cell drinking)


This process is important in the absorption of oil soluble vitamins & in the uptake of nutrients.

Phagocytosis (cell eating)


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.


A. PHARMACEUTICAL FACTORSI. Physicochemical Properties of Drug Substances1. Drug solubility and dissolution rate2. Particle size and effective surface area3. Polymorphism and amorphism4. Pseudopolymorphism (hydrates/solvates)5. Salt form of the drug6. Lipophilicity of the drug7. pKa of the drug and gastrointestinal pH8. Drug stability9. Stereochemical nature of the drugII. Dosage Form Characteristics and Pharmaceutical Ingredients (Pharmaco-technical Factors)1. Disintegration time (tablets/capsules)2. Dissolution time3. Manufacturing variables4. Pharmaceutical ingredients (excipients/adjuvants)5. Nature and type of dosage form6. Product age and storage conditions


pH-partition hypothesis

B. PATIENT-RELATED FACTORS

1. Age2. Gastric emptying time3. Intestinal transit time4. Gastrointestinal pH5. Disease states6. Blood flow through the GIT7. Gastrointestinal contents: (a) Other drugs, (b) Food, (c) Fluids, (d) Other

normal GI contents8. Presystemic metabolism by: a. Luminal enzymes b. Gut wall enzymes c. Bacterial enzymes d. Hepatic enzymes


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


In-vitro dissolution testing


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


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.


Rotating Basket Apparatus

Cylindrical basket of 22 mesh. Rotating speed-100 rpm.


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.


Rotating Paddle Apparatus


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.


Rotating Basket and Paddle Apparatus


The Reciprocating Cylinder Method


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.


Paddle over Disk method

Sample holder or disk assembly that holds the product.

Temperature 32oC. Paddle is placed over the disk assembly. For testing the release of drug from transdermal

products.



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.


Rotating Cylinder method

A stainless steel cylinder is used to hold the sample. Sample is mounted on to cuprophan. Temperature 32oC. For testing transdermal preparations.


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.


Reciprocating Disc/Holder method

A motor drive assembly is used to reciprocate the system vertically.

Temperature 32oC. 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.


Reciprocating Disc/Holder method



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.


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.


3. Dialysis concept


Non-Official Methods

1. The Rotating Filter Method.2. Rotating Flask Dissolution Method.3. Rotating and Static Disk Methods.


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.


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.


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.


Factors affecting dissolution of drug from different forms

1. Pharmaceutical excipients Vehicle Diluents Lubricants Binders Surfactants Colorants2. Manufacturing processes Method of granulation – Wet granulation Direct compression Agglomerative phase of communication (APOC)


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.



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.



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


2. Manufacturing processes

Method of granulation –

Wet granulation Direct compression Agglomerative phase of communication

(APOC)


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Tobruk, Libya. 56

Compression ForceCompression Force :-:-

Rat

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dru

g di

ssol

utio

n

A B C D

Compression force

Influence of compression force on dissolution rate of tablet

2. Manufacturing processes

Nature and Type of Dosage Form


• Rate of release of drug from dosage form is depend on complexity of dosage form

• Selection of proper dosage form is important


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



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.




Tablet

Sequence of events in the absorption of drug from tablet dosage form


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Biopharmaceutics

Health & Medicine

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