EXAM 1

Dissolution

the process by which drug (particles) dissolve

For drug absorption, it must be first dissolved in the fluid at the

absorption site

What factors affect drug dissolution?

physicochemical factors, physiological factors

What are examples of physicochemical factors?

drug, dosage form

Noyes Whitney equation

describes dissolution

• dc/dt = rate of dissolution
• k = dissolution rate constant
• S = Surface area of the dissolving solid
• Cs = saturation concentration of drug in the diffusion layer
• Ct = concentration of the drug in the dissolution medium at time

Sometimes, ______ of drugs may be used because of greater stability than
the corresponding amorphous forms

crystalline form

When a drug particle is reduced to a larger number of smaller particles, the total surface area

created is ___________.

increased

For drug substances that are poorly or slowly soluble, decreasing particle size generally

results in an ___________ in the rate of dissolution.

increase

Which form of a compound has more solubility?

amorphous form of a compound has more solubility than its crystalline form

Sodium and potassium salts of weak organic acids and hydrochloride salts of weak
organic bases dissolve ___________ than do their respective free acids or bases.

more readily

What form is more readily soluble than the hydrated form?

anhydrous

Anhydrous ampicillin has _________ solubility than ampicillin trihydrate

higher aqueous

Formation of less soluble complexes resulting in reduced

absorption

What happens to tetracycline absorption when it forms complexes with Ca²⁺, Mg²⁺, or Al³⁺?

Absorption decreases because these minerals form complexes with tetracyclines.

Adsorption – to the insoluble material in the GIT
▪ ___________ availability for absorption

decreased

types of dosage forms

tablet, capsule, solution

Bioavailability

The rate and extent to which an active drug ingredient or therapeutic moiety is absorbed from a drug product and becomes available at the site of drug action.

Bioequivalence

The comparison of bioavailabilities of different formulations, drug products, or batches of the same drug product

Proprietary drug products are also known as ___

brand drugs

Non-proprietary drug products are also known as ____

generic drugs

Standardized nomenclature of drugs are established by:

▪ USAN (United States Adopted Names) Council

▪ WHO (World Health Organization)

Generic drug product

A pharmaceutical product that can substitute a brand product.

▪ Must show similar drug profile in plasma as its brand product (bioequivalent).

What should be the same for brand and generic products?

▪ The active ingredient (drug) & strength

▪ The dosage form

The following equivalencies play an important role in establishing a generic drug

▪ Pharmaceutical equivalent

▪ Pharmaceutical alternative

▪ Bioequivalent

▪ Therapeutic equivalent

Pharmaceutical equivalents are drug products that:

▪ Contain identical active ingredient, i.e., the same salt or ester of the parent drug

▪ Are identical in strength or concentration (of the drug)

▪ Contain identical dosage forms

▪ Have identical route of administration

▪ Meet the identical compendial or other applicable standard of identity, strength, quality, and purity, including potency and, where applicable, content uniformity, disintegration times, and/or dissolution rates

Pharmaceutical equivalents may differ in:

Shape, drug release mechanism, labeling, excipients (including colors, flavors, etc.)

Pharmaceutical alternatives

drug products that contain the identical therapeutic moiety, or its precursor, but not necessarily in the same amount or dosage form or as the same salt or ester.

Bioequivalent drug products

pharmaceutical equivalents or pharmaceutical alternatives whose rate and extent of absorption do not show a significant difference when administered at the same molar dose of the therapeutic moiety under similar experimental conditions, either single dose or multiple dose.

Therapeutic equivalents

Used to indicate pharmaceutical equivalents which, when administered to the same individuals in the same dosage regimens, will provide essentially the same therapeutic effect.

The FDA classifies therapeutically equivalent products as those that meet the following

general criteria:

▪ They are approved as safe and effective

▪ They are pharmaceutically equivalent

▪ They are bioequivalent

▪ They are manufactured incompliance with Current Good Manufacturing Practice

(cGMP) regulations

▪ They are adequately labeled

how does gastric emptying rate affect drug absorption with a fasting stomach?

speeds up the rate of drug absorption because most oral drugs are absorbed in the small intestine rather than the stomach.

What are typical GI absorption times?

stomach: 2-4 hrs

small intestine: 4-10 hrs

How does Co-administration of other drugs affect drug absoprtion?

Other drugs can increase or decrease drug absorption

How does age of the patient affect drug absorption?

Most physiological functions are decreased, absorption mostly stays the same

How does food taken by the patient affect drug absoprtion?

Most drugs are absorbed more slowly with food

How does disease state of the patient affect drug absoprtion?

Disease can alter drug absorption by changing GI function

Explain the effect of particle size on surface area

Explain the effect of particle size on surface area

Explain the effect of particle size on surface area

lower particle size = higher surface area

Explain the effect of particle size on solubility

lower particle size = higher solubility

Explain the effect of particle size on dissolution rate

lower particle size = higher dissolution rate

Explain the effect of particle size on absorption rate of a poorly water soluble drug

lower particle size = increased absorption

For a drug to exert its biological effect, it must:

• Be transported by the body fluids

• Travers the required biological membrane barriers

• Escape widespread distribution to unwanted areas

• Endure metabolic attack (body’s mechanism to eliminate the drug)

• Penetrate in adequate concentration to the sites of action

• Interact in a specific fashion, causing an alteration of cellular function

Drugs must be absorbed first so that

distribution, metabolism, excretion can take place after the administration of drugs

Body membranes generally classified into

1) Those composed of several layer of cells,
e.g. skin

2) Those composed of a single layer of cells,
e.g. intestinal epithelium

3) Those composed of less than one cell in
thickness, e.g. membrane of a single cell

A drug must pass more than one of the membrane types before it reaches ___

its site of action.

Drugs are thought to penetrate these biologic membranes in two general ways:

Passive Diffusion

Specialized Transport Mechanisms

Diffusion

Process of mass transfer of individual molecules of a substance brought about by random molecular motion and associated with a driving force such as a concentration gradient

Where does drug absorption (diffusion) happen?

the skin, gastric mucosa, etc.

Drug distribution (diffusion)

throughout the body, into tissues and organs

Drug elimination(diffusion)

the process of getting a drug out of the body, and the drug may have to cross different barriers to be metabolized or excreted.

Drug release(diffusion) in a topical product/patch

drug moves out of a topical product/patch and through the skin from high → low concentration.

Passive diffusion définition

Used to describe the passage of (drug) molecules through a membrane that behaves inertly (i.e., membrane does not actively participate in the process).

What drives passive diffusion?

the concentration gradient existing across the membrane

Occurs primarily from a region of ____ drug conc. to a region of ___ drug concentration

Fick’s first law of Diffusion

The rate of diffusion or transport across a membrane (dc/dt) is proportional to the difference in drug concentration on both sides of the membrane

Gastrointestinal absorption of most drugs from solution follow which law?

Fick’s First Law of Diffusion

Rate of absorption is dependent on

drug concentration

The magnitude of P (permeability coefficient) depends on

the diffusion coefficient of the drug (D)

the thickness and area of the absorbing membrane (S)

the partition coefficient of the drug (k)

Absorption from GI tract

the drug moves from where there is a lot of drug (the GI tract) to where there is less drug (the blood). (From high drug concentration in the lumen to lower drug concentration in the blood.)

Passive diffusion depends on the

surface area of the membrane available for drug absorption

Due to the presence of villi and microvilli, the ____ is the major site for drug absorption
via passive diffusion

duodenum

The degree of a drug’s ionization depends both on

the pH of the solution and on the pKa

pH partition hypothesis

Drugs are absorbed from the GIT by passive diffusion depending on the
fraction of undissociated or unionized drug at the pH of the intestine.

The pKa of a drug molecules determine if the drug is going to be in

unionized or ionized form in the biological fluids.

Cell membranes are more permeable to the

unionized forms of drugs compared to their ionized forms.

Drug absorption is therefore a function of the ___

pH of the intestine and pKa of the drug.

Specialized transport mechanisms

Involves membrane components that may be enzymes or some other type of
agent capable of forming a complex with the drug (or other agent) at the
surface membrane

After the carrier releases the drug on the other side of the membrane, where does the carrier return?

original surface.

Specialized transport mechanisms account for drugs that are ______insoluble and do not dissolve in the lipid boundary, and too _____ which cannot flow or filter through the pores

Water, large

Facilitated diffusion

Specialized transport mechanism for movement of specific molecules

A concentrated gradient is ___

Energy is ___. Similar to “ordinary” diffusion, it is entirely passive

diffusion takes place with the help of

special channels and/or gates (carrier proteins)

Cell membrane contain special ____ that provide hydrophilic passageways for
certain ions and molecules

channel proteins

Diffusion through these channel proteins is called ___

facilitated diffusion

Each _____ has its own shape and only allows one molecule (or one group of closely related molecules) to pass through. Selection is by size, shape, and charge

carrier protein

Active Transport

Drug transport across the membrane against a concentration gradient

In active transport, transport is from a region of ______ conc. to a region of _______ conc.

For an ionized drug, transport is

against an electrochemical potential gradient

Energy (via ATP breakdown) is _________.

how does active transport occur?

• Occurs via transporter proteins in the cell membrane.
  
  

• Each transporter protein is specific to just one type of ion or molecule.
  
  

• Cells contain many different transporter proteins in their membranes.

For a drug mostly absorbed by passive diffusion, rate of absorption is directly proportional to

diffusion coefficient (D) and Surface area

For a weakly basic drug (pka=8.5) what will be the ionization in the stomach?

higher

For a weakly basic drug (pka=8.5) absorption from the stomach will typically be

lower

For a weakly basic drug (pka=8.5) solubility in the stomach will typically be

higher

What will typically decrease the rate of drug absorption?

higher thickness of the biological membrane

Diffusion coefficient definition

measures how fast a substance moves through a medium from an area of high concentration to an area of low concentration

Drug

An agent intended for use in the diagnosis, mitigation, treatment, cure,
or prevention of disease in humans or in other animals (Food, Drug, and
Cosmetic Act, 1938)

Excipients

Inactive ingredients used in the preparation of dosage forms

Formulation/ Pharmaceutical formulation

the process in which different chemical substances, including the active drug, are combined to produce a final medicinal (drug) product

Drug product

A specific combination of an active pharmaceutical ingredient,
and generally, but not necessarily other inactive ingredients.

Dosage form defintion

Drug products in the form in which they are marketed for use (tablets, capsules, solutions), with a specific combination of active ingredients and inactive components (excipients) in a particular configuration

Drug substance (Active Pharmaceutical Ingredient)

It is the material that exerts the pharmacological action. Along with other ingredients (excipients, inactives), it is subsequently used to formulate the drug product

Impurity:

Any component present in the excipient, drug substance, or drug product that is NOT:
• The desired product
• A product-related substance
• Or excipient, (including buffer components)

Prescription Drug:

A human drug that is not safe for use except under the supervision of licensed medical practitioner

Drug Standards

• Uniform standards to ensure quality
• Development/publication of monographs and reference books
• Organized sets of monographs/books of standards – pharmacopeias or formularies

United States Pharmacopeia (USP)

Public organization, established in 1820

National Formulary (NF)

Initially developed to include drugs omitted by USP, merged with USP in 1975

Gene or Genome Sequencing

Building a library of gene/protein (genome/proteome) sequences to mine for information.