Introduction, biopharmaceutic factors affecting drug bioavailability, rate–limiting steps in drug absorption, physicochemical nature of the drug formulation factors affecting drug product performance
Biopharmaceutic considerations in drug product design and In Vitro Drug Product Performance
1. Presented By:
Ms. Prajakta Sawant
First Year M.Pharm (Roll No. 5)
(Dept. of Pharmaceutics)
Sub: ADVANCED
BIOPHARMACEUTICS &
PHARMACOKINETICS (Sem-II)
Alard College Of Pharmacy,
Pune.
Under the Guidance of:
Dr. Nalanda Borkar
Head of Department
(Dept. of Pharmaceutics)
Alard College Of Pharmacy,
Pune.
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2. Introduction
Scope of Biopharmaceutics
Biopharmaceutic factors affecting Drug
Bioavailability
Rate-limiting steps in Drug absorption
Physicochemical nature of the Drug formulation
Factors affecting Drug Product Performance
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3. BIOPHARMACEUTICS studies the in vitro impact of
physicochemical properties of drugs and drug products on delivery
to body under normal or pathologic conditions.
Biopharmaceutics links the physical and chemical properties of
drug and drug product to their performance, in vivo.
The aim of biopharmaceutics is to adjust the delivery of drug from
drug products in such a manner as to provide: optimal therapeutic
activity and safety for the patient.
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4. Biopharmaceutic considerations often determine the ultimate dose
and dosage form of a drug product. For example, the dosage for a
drug intended for local activity, such as a topical dosage form, is
often expressed in concentration or as % of the active drug in the
formulation.
Drug products include the active drug substance combined with
special additional ingredients (excipients) that make up the dosage
form.
Although excipients are considered inert with respect to
pharmacodynamic activity, excipients are important in the
manufacture of the drug product and provide functionality to the
drug product with respect to drug release and dissolution.
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5. Each route of drug application
presents special biopharmaceutic
considerations in drug product design.
By carefully choosing the route of administration and properly
designing the drug product, the bioavailability of the active drug can
be varied from rapid and complete absorption to a slow, sustained
rate of absorption or even virtually no absorption, depending on the
therapeutic objective.
EXAMPLE:
An eye medication may require special biopharmaceutic
considerations including appropriate pH, isotonicity, local irritation
to the cornea, draining by tears, and concern for systemic drug
absorption.
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6. Encompass all the possible physiological factors
which may effect the drug in various dosage
forms.
Encompass all the possible effects of various
dosage forms on biological region.
A primary concern in biopharmaceutics is the
bioavailability of drugs.
Bioavailability is the assessment of
the rate and extent at which the
active drug becomes available at the
site of action. 6
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7. Pharmacodynamic considerations
Drug considerations
Drug product considerations
Patient considerations
Manufacturing considerations
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9. Drug Product Considerations
Pharmacokinetics of drug
Bioavailability of drug
Desired dose of drug
Dosing frequency
Patient Consideration
Compliance & acceptability of drug product
Cost
Manufacturing Considerations
Cost
Availability of raw materials
Stability
QC
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11. There are various factors which affect the
bioavailability of drug –
PHARMACEUTICAL FACTORS:
PATIENT RELATED FACTORS:
ROUTE OF ADMINISTRATION:
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13. PHARMACEUTICAL FACTORS:
Formulation factors:
1. Disintegration time
2. Manufacturing variables
a. Method of granulation
b. Compression force
3. Nature & type of dosage form
4. Pharmaceutical ingredients
5. Product age & storage conditions
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14. 1. Disintegration time (DT):
It is defined as the time taken by the solid dosage form to breakdown into smaller
particles in the body after their ingestion.
Order of disintegration of the solid dosage forms:
Capsules > Tablets > Coated tablets > Enteric coated tablets > sustained release tablets
Harder the tablet, greater is its disintegration time.
Disintegration of solid dosage forms can be enhanced by incorporating appropriate
amounts of disintegrants in the formulation.
2. Manufacturing variables:
a)Method of granulation:
Wet granulation: By selecting a suitable granulating liquid , the dissolution rate of
insoluble drugs can be enhanced.
Direct compression: dissolution rate of tablets prepared by this method are higher
than the wet granulation method.
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 higher compression force
cause crushing of drug particles into smaller ones with higher effective surface area
which in decrease in D.T.
So effect of compression force should be thoroughly studied on each formulation. 14
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15. 3. Nature and type of dosage form:
Depending upon the nature and type of dosage form, the absorption
pattern of a drug decreases in the following order;
Solutions > Emulsions > Suspensions > Capsules > Tablets > Coated
tablets > Enteric coated tablets > Sustained release tablets
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disintegration
fastest
16. 4. Pharmaceutical ingredients:
More the no. of excepients in dosage form, more complex it is & greater the
potential for absorption and Bioavailability problems.
a) Vehicle: Vehicles are used in parenteral and oral liquids preparations.
• Rate of absorption – depends on its miscibility with biological fluid.
• Miscible solvents-rapid absorption of drug.
• Immiscible solvent-slow absorption of drug.
• Non-Aqueous water immiscible E.g.: Vegetable oil, Sesame oil, Peanut oil.
• Aqueous - E.g.: Water, Syrup
• Non-Aqueous water miscible E.g.: Propylene glycol, Glycerol, Sorbital.
b) Diluents: Diluents are added to increase the bulk of the dosage form,
especially in tablets and capsules.
• Hydrophilic diluents-form the hydrophilic coat around hydrophobic drug
particles –thus promotes dissolution and absorption of poorly soluble
hydrophobic drug.
• Inorganic diluents - E.g.: Dibasic calcium phosphate, Calcium carbonate.
• Organic diluents - E.g.: Dextrose, Sorbitol, Mannitol. Diluents 16
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17. c) Binding Agents:
• Although binders are incorporated to produce cohesive bonding
between granules during the process of compaction of tablets.
• Hydrophilic binders are for enhancing the dissolution rate of poorly
soluble drug. e.g. starch, gelatin, PVP.
• More amount of binder increases hardness of tablet and decreases
dissolution & disintegration rate.
d) Disintegrating Agents:
• They are added to the tablet to disrupts the cohesive forces between the
granules, thereby causing the breakdown of the tablet to attain faster
dissolution.
• Mostly hydrophilic in nature, increase in disintegration increases the
bioavailability.
• e.g.: Guar gum, Starch, Microcrystalline cellulose 17
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18. e) Lubricating Agents:
• These agents when added to a tablet formulation decrease the friction
between the granules and die wall of the tablet press.
• Commonly hydrophobic in nature – therefore inhibits penetration of
water into tablet and thus dissolution and disintegration.
• Insoluble Lubricants, E.g.: Mineral oil, Talc
• Soluble Lubricants, E.g.: PEG 4000, PEG 6000.
f) Surfactants :
• They are commonly used in the formulations as solubilizers,
emulsifiers, wetting agents etc.
• At lower concentrations, they increase the rate of absorption of poorly
water soluble drugs.
• Physiologic surfactants like bile salts they promotes absorption
• e.g.: Griseofulvin, steroids
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19. g) Complexing Agents:
• They increase the absorption rate of other drugs due to ;
• Formation of soluble complexes which enhances the dissolution.
• Increased lipophilicity which enhances membrane permeability.
h) Colorants:
• Water-soluble dyes even in least concentrations get adsorbed on the
crystal faces and delay their dissolution rate.
• e.g.: Brilliant blue retards dissolution of sulfathiazole.
5. Product age and storage Conditions: Alterations in storage conditions
and prolonged duration of storage of drug products may modify their
physicochemical properties resulting in altered drug absorption
patterns.
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20. PATIENT RELATED FACTORS:
1) Age
2) Gastric Emptying
3) Intestinal Transit
4) Diseases
5) Effect of Food
6) Blood Flow to GIT
7) First pass metabolism
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21. 1) Age:
• Absorption pattern of drugs may vary among different age groups.
• Infant have less acidic G.I fluids, smaller intestinal surface area and
comparatively less blood flow than adults.
• Intestinal surface area and blood flow, bacterial overgrowth in small intestine,
altered gastric emptying, which retards the drug absorption
2) Gastric Emptying:
• Gastric emptying is the entry of gastric content into the small intestine.
• Gastric emptying rate: It is the rate at which gastric contents empty into the
small intestine.
• Gastric emptying time: It is the time required for gastric content to empty into
the small intestine.
• Rapid Gastric Emptying is required when the consumed drugs
• Are unstable in gastric pH (Penicillin G)
• Are better absorbed from the small intestine (Vit B12)
• Delayed Gastric Emptying is required when
• The drug (Griseofulvin) dissolves slowly.
• Food enhances the dissolution and absorption of drugs. 21
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22. 3) Intestinal Transit:
• The residence time of food or drug substance in intestine is known as
intestinal transit time.
• As small intestine is major site of absorption, longer or delayed transit
time is required for the complete absorption of drugs.
• Delayed intestinal transit is recommended for those drugs which
• Exhibits sustained release action.(Diclofenac sodium)
• Are enteric coated and hence dissolves only in the intestine.
4) Diseases:
(A) GI Diseases and Infections: Drug absorption may be influenced by
several pathophysiological conditions of GIT.
Malabsorption syndrome like celiac disease and Chrons disease.
(B) Gastrointestinal Surgery: Gastrointestinal surgery especially
gastrectomy may cause drug dumping in the intestine.
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23. 5) Effect of Food:
• The presence of food in the GI tract can affect the bioavailability of the drug
from an oral drug product.
• Food contain amino acids, fatty acids, and many nutrients that may affect
intestinal pH and solubility of drugs.
• The effects of food are not always predictable and can have consequences.
• Some effects are:
• Delay in gastric emptying
• Stimulation of bile flow
• A change in the pH of the GI tract
• A change luminal metabolism of the drug substance
• Physical or chemical interaction of the meal with the drug product or
drug substance.
• The absorption of some antibiotics, such as penicillin and tetracycline, is
decreased with food; whereas other drugs, particularly lipid-soluble drugs
such as griseofulvin and metazalone, are better absorbed when given with
food containing a high fat content.
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24. 6) Blood Flow to GIT: Increase in the blood flow to the site of absorption
(GIT), increases the drug absorption as rapid removal of drug from its
absorption site helps to maintain sink conditions.
7) First pass metabolism: A drug administered orally, passes through the
GIT and liver where it undergoes extensive metabolism before reaching
the systemic circulation, thereby leading to decreased bioavailability,
this phenomenon is called as first pass metabolism.
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25. Route of administration
Parenteral
Oral
Topical
Rectal
Inhalation
It is expected that bioavailability of drugs to be in this order-
Parenteral > Oral > rectal > Topical
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26. Systemic drug absorption from a drug product consists of a
succession of rate processes.
For solid oral, immediate- release drug products (e.g., tablets,
capsules), the rate processes include:-
(1) disintegration of the drug product and subsequent release of the
drug,
(2) dissolution of the drug in an aqueous environment, and
(3) absorption across cell membranes into the systemic circulation.
In the process of drug disintegration, dissolution, and absorption, the
rate at which drug reaches the circulatory system is determined by
the slowest step in the sequence. The slowest step in a series of
kinetic processes is called the rate-limiting step.
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27. Except for controlled release products, disintegration of a solid oral
drug product is usually more rapid than drug dissolution and drug
absorption.
For drugs that have very poor aqueous solubility, the rate at which the
drug dissolves (dissolution ) is often the slowest step and therefore
exerts a rate-limiting effect on drug bioavailability.
In contrast, for a drug that has a high aqueous solubility, the
dissolution rate is rapid, and the rate at which the drug crosses or
permeates cell membranes(absorption) is the slowest or rate-limiting
step.
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28. Physicochemical properties of drug substances:
A detailed study of physicochemical properties of drug molecules
may help to enhance the rate as well as the extent of drug
absorption. It also serve to formulate the drug in most suitable
dosage form.
1. Drug dissolution & solubility rate.
2. Particles size & effective surface area.
3. Salt form of drug.
4. Polymorphism & amorphism.
5. Solvates & hydrates.
6. Ionization state.
7. Drug pKa & lipophilicity & GI pH - pH partition hypothesis.
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29. 1. Drug dissolution & solubility rate
Dissolution is the process of solubilization of a substance in a given
solvent.
Drug dissolution rate is the amount of drug that goes into solution per unit
time under the standard conditions of temperature, pH, solvent composition
and constant solid surface area.
Dissolution plays a significant role as it is regarded as the rate determining
step in the process of absorption.
Solutions > Suspensions > Capsules > Tablets > Coated tablets.
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30. Solubility: The quantity of drug that dissolves in the
gastrointestinal fluid is indicative of vivo drug absorption.
A drug is said to undergo appreciable bioabsorption if it exhibits
aqueous solubility greater than 10mg/ml at 37℃ and pH ranging
between 1-7.
When the solubility is less than 1mg/ml, it undergoes undesirable
GI absorption.
Thus with the aid of solubility and dissolution data, potential
problems related to bioavailability and therapeutic activity of the
drug can be recognized.
Both solubility and absorption can be correlated by the concept of
maximum absorbable dose (MAD).
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32. 2. Particle Size & effective surface area
Types of surface area:
1) Absolute surface area: it is the total solid surface area
2) Effective surface area: it is the solid surface area of particle exposed to
the dissolution medium.
In order to convert the absolute surface area to effective surface area,
surfactants like polysorbate 80 or diluents like PEG, dextrose are used.
Griseofulvin, chloramphenicol on micronization show increased
absorption and decrease in therapeutic dose.
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33. 3. Salt form of drug
At given pH, the solubility of drug, whether acidic/basic or its salt, is a constant. While
considering the salt form of drug, pH of the diffusion layer is important not the pH of
the bulk of the solution.
E.g. salt of weak acid. ---Which increases the pH of the diffusion layer, which promotes
the solubility and dissolution of a weak acid and absorption is bound to be rapid.
4. Amorphism and Polymorphism
Amorphous forms generally dissolve faster than crystalline forms because no energy is
needed to break up the crystal lattice.
For this reason, the amorphous form is often preferred over the crystalline form and
several drugs, including hydrocortisone and prednisolone, are marketed in the amorphic
form.
The crystalline form of drugs may exist as polymorphs or molecular adducts or both.
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34. 5. Solvates & hydrates:
During their preparation, drug crystals may incorporate one or more
solvent molecules to form solvates.
The solvent trapped is known as solvent of crystallization.
The solvates may exists in varying crystalline forms known as
pseudo polymorphs and the phenomenon is known as pseudo
polymorphism.
The molecular complex is referred as hydrates if water molecules
has been reported as solvent.
Anhydrous – Drug is not associated with water, monohydrate and
dehydrated – drug is associated with one and more water molecules
respectively.
The anhydrous form have higher energy states, higher aq.
solubilities, dissolves at faster rate and hence exhibit higher
bioavailability.
Ex: anhydrous ampicillin is more soluble than their hydrous form.
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35. 6. Ionization state:
Unionized state is important for passive diffusion through
membrane, hence important for absorption.
Ionized state is important for solubility.
7. Drug pKa & lipophilicity & GI pH - pH partition hypothesis :
pH – Partition theory states that drug compounds of molecular
weight more than 100 Daltons , which are primarily transported
across the biological membrane by passive diffusion, their process
of absorption is governed by
- Pka of drug (Dissociation constant)
- The lipid solubility of unionized drug
- pH at the absorption site.
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36. 36
Defined as the release of the drug substance from the drug product leading to
bioavailability of the drug substance.
The assessment of drug product performance is important since bioavailability
is related both to the pharmacodynamic response and to adverse events.
Thus, performance tests relate the quality of a drug product to clinical safety
and efficacy.
Bioequivalence Studies in New Drug Development (NDA):
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38. 1. Physiochemical nature of the drug
The physical and chemical properties of the drug substance as well
as the excipients are important considerations in the design of a
drug product. For example,
Intravenous solutions are difficult to prepare with drugs that have
poor aqueous solubility.
Drugs that are physically or chemically unstable may require special
excipients, coatings, or manufacturing processes to protect the drug
from degradation.
The potent pharmacodynamic activity of drugs such as estrogens
and other hormones, penicillin antibiotics, cancer chemotherapeutic
agents, and others, may cause adverse reactions to personnel who
are exposed to these drugs during manufacturing.
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39. 2. The nature of the excipients in the drug product
Excipients in the drug product affect the dissolution kinetics of
the drug, either by altering the medium in which the drug is
dissolving or by reacting with the drug itself.
Suspending agents increase the viscosity of the drug vehicle and
thereby diminish the rate of drug dissolution from suspensions.
Excessive quantity of magnesium stearate (a hydrophobic
lubricant) in the tablet formulation may repel water and retard
drug dissolution and slow the rate of drug absorption.
Coatings, particularly shellac, will crosslink upon aging and
decrease the dissolution rate.
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40. Low concentrations of surfactants decrease the surface tension and
increase the rate of drug dissolution, whereas higher surfactants
concentrations tend to form micelles with the drug and thus
decrease the dissolution rate.
Excipients, such as sodium bicarbonate, may change the pH of the
medium surrounding the active drug substance.
Aspirin, a weak acid when formulated with sodium bicarbonate,
will form a water-soluble salt in an alkaline medium, in which the
drug rapidly dissolves.
Excipients in a formulation may interact directly 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.
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41. 3. The method of manufacturing
High compression of tablets without sufficient disintegrant may
cause poor disintegration of a compressed tablet.
In some cases, a drug product is designed so that it may be used in
conjunction with a specialized medical device.
For example, a drug solution or suspension may be formulated to
work with a nebulizer or metered-dose inhaler for administration
into the lungs.
Both the physical characteristics of the nebulizer and the
formulation of the drug product can influence the droplet particles
and the spray pattern that the patient receives upon inhalation of
the drug product.
Bioavailability of a drug from different dosage forms would
decrease in the following order;
solution > suspension > capsule > tablet > coated tablet
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