BIOPHARMACEUTICS CONCIDERATIONS IN DRUG PRODUCT DESIGN AND IN VITRO DRUG PRODUCT PERFORMANCE

biopharmaceutics

studies the in vitro impact of physicochemical properties of drugs and drug products on delivery to body under normal or pathologic conditions

biopharmaceutics

inks the physical and chemical properties ofdrug and drug performance, in vivo

biopharmaceutics

The aim is to adjust the delivery of drug product in such a manner as to provide: optimal therapeutic activity and safety for the patient

the dosage for a drug intended for a local activity, such as topical dosage form, is often expressed in concentration or as % of the active drug in the formulation

Biopharmaceutic considerations often determine the ultimate dose and dosage form of a drug products. For example, __

drug product

include the activity drug substance combined with special additional ingredients (excipients) that make up the dosage form

excipients

Although __ are considered inert with respect to pharmacodynamic activity, they are important in the manufacture of the drug product and provide functionality to the drug product with respect to drug release and dissolution

drug product design

Each route of drug application presents special biopharmaceutic considerations in __

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 absorption.

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

• Encompass all the possible physiological factors which may affect 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 extend at which the active drug becomes available at the site of action

scope of biopharmaceutics

• Pharmacodynamic considerations

• Drug considerations

• Drug products considerations

• Patient considerations

• Manufacturing considerations

biopharmaceutics consideration in drug product design

• Toxic effects

• Adverse reactions

THERAPEUTIC OBJECTIVE

• chemical and physical properties of drug

• pKa & pH profile

• Particle size

• Polymorphism

• Hygroscopicity

• Partition coefficient

• Excipient interactions

• pH stability profile

• Solubility

• Pharmacokinetics of drug

• Bioavailability of drug

• Desired dose if drug

• Dosing frequency

DRUG CONSIDERATIONS

1. compliance and acceptability of drug products

2. cost

patient consideration

1. cost

2. availability of raw materials

3. stability

4. QC

manufacturing consideration

• Pharmaceutical Factors

• Patient Related Factors

• Route of administration

There are various factors which affect the bioavailability of drug on

Solution > Suspension > Capsule > Tablet > Coated tablet

It is expectation that, bioavailability of drugs to be in this decreasing order

1. Disintegration time

2. Manufacturing variables

3. Nature & type of dosage form

4. Pharmaceutical ingredients

5. Product age & storage conditions

Formulation factors:

a. Method of granulation

b. Compression force

manufacturing variables

disintegration time

It is defined as the time taken by the solid dosage form to breakdown into smaller particles in the body after their ingestion.

Capsules > Tablets > Coated tablets > Enteric coated tablets > sustained release tablets

Order of disintegration of the solid dosage forms:

greater

Harder the tablet, __is its disintegration time.

disintegrants

Disintegration of solid dosage forms can be enhanced by incorporating appropriate amounts of __in the formulation

wet granulation

direct compression

method of granulation (2)

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.

higher compression force

yields a tablet with greater hardness and reduced wettability & hence have a long D.T

higher compression force

cause crushing of drug particles into smaller ones with higher effective surface area which in decrease in D.T.

• Solutions > Emulsions > Suspensions > Capsules > Tablets > Coated tablets > Enteric coated tablets > Sustained release tablets

Depending upon the nature and type of dosage form, the absorption pattern of a drug decreases in the following order;

pharmaceutical ingredients

More the no. of excipients in dosage form, more complex it is &greater the potential for absorption and Bioavailability problems.

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 solvents

slow absorption of drug

Vegetable oil, Sesame oil,Peanut oil

Non-Aqueous water immiscible

water, syrup

Aqueous

Propylene glycol, Glycerol,Sorbitol

Non-Aqueous water miscible

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

inroganic diluents

E.g.: Dibasic calcium phosphate, Calcium carbonate.

organic diluent

E.g.: Dextrose, Sorbitol, Mannitol. Diluents

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.

decreases dissolution and disintegration rate

More amount of binder increases hardness of tablet and __dissolution & disintegration rate.

increases hardness of tablet

more amount of binders

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

disintegrating agents

Mostly hydrophilic in nature, increase in disintegration increases the bioavailability.

e.g.: Guar gum, Starch, Microcrystalline cellulose

disintegrating agents examples

lubricating agents

These agents when added to a tablet formulation decrease the friction between the granules and die wall of the tablet press.

lubricating agents

Commonly hydrophobic in nature - therefore inhibits penetration of water into tablet and thus dissolution and disintegration

mineral oil, talc

Insoluble Lubricants examples

PEG 4000, PEG 6000

Soluble Lubricants examples

surfactants

They are commonly used in the formulations as solubilizers, emulsifiers, wetting agents etc.

surfactants

At lower concentrations, they increase the rate of absorption of poorly water-soluble drugs

bile salts

Physiologic surfactants like __they promotes absorption•

Griseofulvin, steroids

examples of surfactants

complexing agents

They increase the absorption rate of other drugs due to formation of soluble complexes which enhances the dissolution

complexing agents

Increased lipophilicity which enhances membrane permeability

colorants

Water-soluble dyes even in least concentrations get adsorbed on the crystal faces and delay their dissolution rate

colorants

ex. Brilliant blue retards dissolution of sulfathiazole.

product age and storage condition

Alterations in storage conditions and prolonged duration of storage of drug products may modify their physicochemical properties resulting in altered drug absorption patterns

1) Age

2) Gastric Emptying

3) Intestinal Transit

4) Diseases

5) Effect of Food

6) Blood Flow to GIT

7) First pass metabolism

patient related factor

age

(true or false) Absorption pattern of drugs may vary among different age groups

infants

have less acidic G.I fluids, smaller intestinal surface area and comparatively less blood flow than adults.

gastric emptying

Intestinal surface area and blood flow, bacterial overgrowth in small intestine, altered __, which retards the drug absorption

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.

 Are unstable in gastric pH (Penicillin G)

 Are better absorbed from the small intestine (Vit B12)

Rapid Gastric Emptying is required when the consumed drugs

 The drug (Griseofulvin) dissolves slowly.

 Food enhances the dissolution and absorption of drugs.

Delayed Gastric Emptying is required when

intestinal transit time

The residence time of food or drug substance in intestine is known as intestinal transit time. intestine.

small intestine

is major site of absorption, longer or delayed transit time is required for the complete absorption of drugs.

delayed intestinal transit

recommended for those drugs which exhibits sustained release action. (Diclofenac sodium)

delayed intestinal transit

recommended for those drugs that enteric coated and hence dissolves only in the intestine.

GI diseases and infections

Drug absorption may be influenced by several pathophysiological conditions of GIT

celiac disease and Chron’s disease

Malabsorption syndrome like

gastrointestinal surgery

especially gastrectomy may cause drug dumping in the intestine

effect of food

The presence of food in the GI tract can affect the bioavailability of the drug from an oral drug product.

amino acids, fatty acids, and many nutrients

Food contain__that may affectintestinal pH and solubility of drugs. • The effects of food are not always predictable and can have consequences.

 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.

Some effects are of foods are

decreased with food

The absorption of some antibiotics, such as penicillin and tetracycline, is __with food;

griseofulvin and metazalone

particularly lipid-soluble drugs such as __, are better absorbed when given with food containing a high fat content

increase in the blood flow to the site of absorption(GIT), increases the drug absorption as rapid removal of drug from its absorptionsite helps to maintain sink condition

Blood Flow to GIT

decreased bioavailability

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 __, this phenomenon is called as first pass metabolism.

Parenteral > Oral > rectal >Topical

route of administration:

It is expected that bioavailability of drugs to be in this order - _

(1) disintegration of the drug product and subsequent release of the drug,

(2) dissolution of the drug in an aqueous environment,

(3) absorption across cell membranes into the systemic circulation

For solid oral, immediate- release drug products (e.g.,tablets, capsules), the rate processes include:-

rate- limiting

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 ___

solid oral drug product

Except for controlled release products, disintegration of a ___is usually more rapid than drug dissolution and drug absorption.

very poor aqueous solubility

For drugs that have ___, the rate at which the drug dissolves (dissolution) is often the slowest step and therefore exerts a rate-limiting effect on drug bioavailability

high aqueous solubility

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.

physicochemical properties

A detailed study of __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.

PHYSICOCHEMICAL NATURE OF THE DRUG FORMULATION

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.

Solutions > Suspensions > Capsules > Tablets > Coated tablets.

Dissolution plays a significant role as it is regarded as the rate determining step in the process of absorption.

solubility

The quantity of drug that dissolves in the gastrointestinal fluid is indicative of in vivo drug absorption.

greater than 10 mg/ml at 37°Cand pH ranging between 1–7.

A drug is said to undergo appreciable bio absorption if it exhibits aqueous solubility__

less than 1 mg/ml

When the solubility is __, it under goes undesirable GI absorption.

solubility and dissolution data

Thus, with the aid of ___, potential problems related to bioavailability and therapeutic activity of the drug can be recognized.

maximum absorbable dose (MAD)

Both solubility and absorption can be correlated by the concept of __

class I

high solubility

high permeability