BIOPHARMACEUTIC

Dr. Muslim Suardi, MSi., Apt.

School of Pharmacy, Faculty of Sciences
University of Andalas
 Biopharmaceutic

“The study of the in vitro impact of the

physicochemical properties of the drug & drug
product on drug delivery to the body under
normal or pathologic conditions”
 Considers

The interrelationship:

 Physicochemical properties of the drug

 The dosage form in which the drug is given
 The route of administration

on the rate & extend of systemic absorption.

 Factors Influences
 Protection of the activity of the drug within the
drug product
 The release of the drug from a drug product
 The rate of dissolution of the drug at the
absorption site
 The systemic absorption of the drug
 OBJECTIVE

“To adjust the delivery of drug from the drug

product in such manner as to provide optimal
therapeutic activity & safety
for the patient”
 Rational design of drug products
based on

1. Physical & chemical properties of drug

2. Route of adm including the anatomic &
physiologic nature of the application site
3. Desired pharmacodynamic effect.
4. Toxicologic properties of drug
5. Safety of excipients
6. Effect of excipients & dosage form on
delivery
 Route of Drug Applications
“Each route presents special biopharmaceutics
considerations in drug product design”

Examples
 Vaginal tablet formulations: Consider ingredients
compatible with vaginal anatomy & physiology.
 Eye medications: May require special biopharmaceutic
considerations; pH, isotonicity, sterility, local irritation
to the cornea, draining by tears.
Route of Administration

 Extravascular
 Intravascular
 Extravascular
I.M injection, topical
Consider:
 Local irritation, drug dissolution, & drug
absorption from the intramuscular site area.
 Absorption is influenced by the anatomic &
physiologic properties of the site & the
physicochemical properties of the drug/product.
 Intravascular
 I.V
 Systemic drug absorption is considered
complete or 100% bioavailable because the drug
is placed directly into the circulation.
RATE LIMITING STEP IN DRUG
ABSORPTION
For solid oral (tablet, capsule), the rate process include:
 Disintegration of the drug product & subsequent
release of the drug
 Dissolution of the drug in an aqueous environment

 Absorption across cell membranes into circulation.

“In that process above, the rate at which drug reaches

the circulatory is determined by the slowest step”
 Rate Limiting Step
“The slowest step in a series of kinetic processes”

 Very poor aqueous solubility drugs,

The rate at which the dissolution is often the
slowest step & exert a rate-limiting effect on
drug BA.

 High aqueous solubility drug

Dissolution rate is rapid, & the rate at which the
drug crosses cell membranes is the slowest or
RLS
 PHARMACEUTIC FACTORS
AFFECTING BIOAVAILABILITY

 Type of drug product

 The nature of the excipients
 The physicochemical properties of the drug
 The route of administration
 Disintegration

 For intermediate-release, solid oral dosage

forms, the drug product must disintegrate into
small particles & release the drug.

 For monitoring uniform tablet disintegration,

the FI established an official disintegration test.
 Dissolution

“The process by which a drug becomes

dissolved in a solvent”

 Drug dissolution in an aqueous medium is an

important prior condition of absorption.
 Controls the rate of systemic drug absorption.
 Noyes & Whitney
 The steps in dissolution: the process of drug
dissolution at the surface of the particle, thus
forming a saturated solution around the particle

 The dissolved drug in the saturated solution

known as the stagnant layer diffuses to the bulk of
the solvent from regions of high to low conc
b
a. Stagnant layer b. Solid Drug Particle

a
a
c. Bulk b
Solvent c
 Noyes-Whitney Equation
dC/dt = DA(Cs-C) /h
 dC/dt = rate of drug dissolution at time t
 D = diffusion rate constant
 A = surface area of the particle
 Cs = conc of the drug in the stagnant layer
 C = conc of drug in the bulk solvent
 h = thickness of the stagnant layer
 Ficks Equation
dC/dt = DAK(Cs-C) /h
 dC/dt = rate of drug dissolution at time t
 D = diffusion rate constant
 A = surface area of the particle
 K = partition coeffisien of water-oil
 Cs = conc of the drug in the stagnant layer
 C = conc of drug in the bulk solvent
 h = thickness of the stagnant layer
 Ficks’s Equation

CGI-Cp

The difference between the concentrations of

drug in the gastrointestinal tract and in the
plasma
 Physicochemical Properties for
Consideration in Product Design
pKa & pH Necessary for optimum stability & solubility of
profile the final product

Particle Size May affect the solubility of the drug & therefore
the dissolution rate of the product

Polymorphism The ability of a drug to exist in various crystal

forms may change the solubility of the drug. The
stability of each form is important, because
polymorphs may convert from one to another.
Hygroscopicity Moisture absorption may affect the physical
structure as well as stability of the product.
 Physicochemical Properties for
Consideration in Product Design
Partition Give some indication of the relative affinity of the
Coefficient drug for oil & water. A drug that has high affinity for
oil may have poor release & dissolution

Excipient Compatibility of the excipients with the drug

Interaction Sometime trace elements in excipients may affect the
stability of the product. Specification is important

pH Stability Stability of solutions is often affected by the pH of

Profile vehicle. pH in the stomach & gut is different, know-
ledge of stability would help to avoid degradation
 Solubility, pH, & Absorption
 pH environment of the GIT varies from acidic in the
stomach to slightly alkaline in the small intestine
 A basic drug is more soluble in an acidic medium
 Solubility may be improved with the addition of an
acidic or basic excipient
 Buffering agent may be added to slow or modify the
release rate of a fast dissolving drug
 Controlled release drug product must be a non
disintegrating dosage form.
 Stability, pH, & Absorption
 If drug decomposition occurs by acid or based
catalysis, some prediction for degradation of the
drug in GIT may be made

 Erythromycin decomposition occurs rapidly In

acidic medium. It has to be enteric coated to
protect against acid degradation in the stomach
 Particle Size & Absorption
 Surface area of the drug is increase enormously
by a reduction in the particle size. The greater
the surface area the more rapid the rate of diss

 Particle size & distribution studies are important

for drug that have low water solubility. Many
hydrophobic drugs are very active IV-ly but are
not very effective orally due to poor absorption.
 Particle Size & Absorption
 Griseofulvin, nitrofurantoin & many steroids are
drug with low aqueous solubility; micronized
form has improved absorption.
 Smaller particle size results in an increase in the
surface area, enhances water penetration, an
increases the dissolution rates.
 A disintegrant may be added to the formulation
to ensure rapid disintegration
 Surface-active may increase wetting & solubility
 Polymorphic Crystals, Solvates, &
Absorption
 Polymorphism (drug in various crystal forms). Same
chemical structure but different physical properties
 Crystals have lower solubility than the amorphous
 Chloramphenicol, has several crystal forms, when given
as a suspension, the conc is dependent on % of β-
polymorph. β-form is more soluble & better absorbed
 Crystal form has the lowest free energy is the most
stable. A drug that exists as an amorphous form,
dissolves more rapidly than rigid crystalline form
 Polymorphic Crystals, Solvates, &
Absorption
 Some polymorphs are metastable, a change in crystal
form may cause problems in manufacturing. A change
in the crystal structure may cause cracking in a tablet.
 Some drugs interact with solvent to form a crystal
called solvate.
 Water may form a special crystal called hydrates.
Erythromycin hydrates have different solubility
compared to the anhydrous form.
 Ampicillin 3H2O was reported to be less absorbed than
the anhydrous forms.
 FORMULATION FACTORS
AFFECTING DISSOLUTION

Addition of Excipients
 To provide certain functional properties to the
drug & dosage form

 To improve the compressibility of the active

drug, stabilize the drug from degradation,
decrease gastric irritation, control the rate of
absorption, increase drug bioavailability
 Common Excipients Used
Lactose Diluent
Dibasic calcium phosphate Diluent
Starch Disintegrant, diluent
Microcrystalline cellulose Disintegrant, diluent
Mg stearate Lubricant
Stearic acid Lubricant
Hydrogenated vegetable oil Lubricant
 Excipients Used in Solid
Talc Lubricant
Sucrose (solution) Granulating agent
PVP (solution) Granulating agent
HPMC Tablet-coating agent
Titanium dioxide Combined with dye as colored coating
Methylcellulose Coating or granulating agent
CAP Enteric coated agent
 Excipients Used in Oral Liquid
EXCIPIENT PROPERTY
Sodium CMC Suspending agent
Tragacanth Suspending agent
Sodium Alginate Suspending agent
Xanthan gum Thixotopic suspending agent
Veegum Thixotopic suspending agent
Sorbitol Sweetener
 Excipients Used in Oral Liquid
Alcohol Solubilizing agent, preservative
PEG Solubilizing agent
Methyl, propyl-paraben Preservative
Sucrose Sweetener
Sucrose Sweetener
Polysorbates Surfactant
Sesame oil, Corn oil For emulsion vehicle
 Excipient may affect dissolution
 Mg stearate, may repel H2O & reduce dissolution when
used in large quantities. Coatings, particularly shellac
upon aging can decrease the dissolution rate.
 Low conc of surfactants decrease the surface tension &
increase the rate of drug dissolution. Higher surfactans
conc tend to form micelles with the drug & decrease
the dissolution rate.
 Large drug particles have a smaller surface area dissolve
more slowly than smaller particles.
 High compression of tablets without sufficient
disintegrant may cause poor disintegration.
 Excipient may affect dissolution
 NaHCO3 may change the pH of the medium. Aspirin, a
weak acid when formulated with NaHCO3 will form a
water-soluble salt, in which the drug rapidly dissolves.
 Excipients in a formulation may interact directly with
the drug to form a water soluble/insoluble complex.
 If tetracycline is formulated with CaCO3, an insoluble
complex of Ca tetracycline is formed that has a slow
rate of dissolution & poor absorption.
 Excipients
 That increase the solubility of the drug increase the rate of
dissolution & absorption
 May increase retention time drug in GIT & increase absorbtion
 May act as carries to increase drug diffusion across the intestinal
wall. Many excipients may retard dissolution & absorption.
 Various excipients that are pharmacodynamically inert but that
functionally enhance the drug & the dosage form
 Tablets: diluent (lactose); disintegrant (starch); lubricant (Mg
stearate ); binding & stabilizing agents. Improperly used: the rate
& extent of absorption may be affected.
 Increasing the amount of disintegrant may overcome the
retarding effect of lubricant on dissolution. Some poorly soluble
drugs increase in disintegrant level has little effect on dissolution
because the fine drug particles are not wetted
IN VITRO DISSOLUTION
TESTING

Dissolution test in vitro measure the rate &

extent of dissolution of the drug in an aqueous
medium in the presence of one or more
excipients contained in the drug products
COMPENDIAL METHODS OF
DISSOLUTION
Apparatus 1
Rotating Basket Method

Apparatus 2
Paddle Method
 Rotating Basket Method
 Consists of a cylindrical basket held by a motor shaft
 The basket holds the sample & rotates in a round flask
containing the medium
 Flask is immersed in a bath set at 37’C (constant)
 Rotating speed & basket position must meet specific
 Calibration: To make sure mechanical & operating
requirements are met
 Calibration tab: Prednisone (disintegrating), Salicylic
acid (non-disintegrating)
 Preferred for caps & float or disintegrate slowly
 Paddle Method
 Special paddle that minimizes turbulence due to
stirring
 Vertically attached to motor, rotates (controlled
speed)
 Tab/cap is placed into the bottom flask
 Housed in a water bath at 37oC (constant)
 Paddle method is very sensitive to tilting. 50
rpm
 Preferred for tablets
 A sinker, a few turns of Pt wire, to prevent a cap
from floating. Sinker should not alter dissolution
 MEETING DISSOLUTION
REQUIREMENTS
 Dissolution profile data. Selected time points be
to characterize adequately the ascending &
plateau phases of the curve
 Amount of drug dissolved within a given time
period, Q is expressed as a % of label content. Q
is generally specified in the monograph for a
drug product. 6 tab/cap are tested, &
 Q is set at 75% in 45’ or 85% in 30’ ; 75% in 60’
 Consideration that the dissolution test must
ensure consistent B.A of the product
 BIOPHARMACEUTIC
CONSIDERATION
(In drug product design)
Principle
 The prime considerations in the design of a drug
product are safety & efficacy
 The finished drug product should meet the
therapeutic objective by delivering the drug with
max BA & min adverse effects
 BIOPHARMACEUTIC
CONSIDERATIONS

 Pharmacodynamic
 Drug
 Drug Product
 Patient
 Manufacturing
 Pharmacodynamic Considerations

 Therapeutic objectives
 Toxic effects
 Adverse reaction
 Drug Considerations

Chemical & physical properties of drug

 Drug Product Considerations
 Pharmacokinetics of drug
 Bioavailability of drug
 Route of drug administration
 Desired drug dosage form
 Desired dose of drug
 Patient
 Compliance & acceptability of drug product
 Cost
 Manufacturing Considerations
 Cost
 Availability of raw materials
 Stability
 Quality control
 Route of administration
 Oral Preparations
 Buccal & Sublingual Tablets
 Nasal Preparations
 Colonic drug delivery
 Rectal & vaginal drug delivery
 Parenteral products
 References
 Notari, R.E. (1975). Biopharmaceutics and Pharmacokinetics:
An Introduction. New York: Marcel Dekker.
 Paradkar, A.R. & Bakliwal, S.R. (2008). Biopharmaceutics
& Pharmacokinetics.
 Shargel, L. & Yu, A. (1999). Applied Biopharmaceutics &
Pharmacokinetics. 4th Ed. New York: Appleton & Lange.
 Wagner, J.G. (2008). Biopharmaceutics and Relevant
Pharmacokinetics. Drug Intelligen Publications.
 Related articles in several journals: J. Pharm.Sci, J Clin.
Pharmacokin., Eur. J. Pharm. Biopharm.