Lecture 02 - Dosage form design

What are the major steps that occur after a drug is administered?

Release; Absorption; Distribution; Elimination.

What is drug release?

The process of the drug being released from its dosage form so it can __________

eventually be absorbed

What is disintegration?

The breakdown of a dosage form into smaller particles.

What happens during tablet disintegration?

Tablet; granules; fine particles

What is dissolution?

The transfer of drug molecules from the solid state into solution

What is the difference between disintegration and dissolution?

Disintegration breaks the dosage form into smaller particles; dissolution moves drug molecules from the solid state into solution

Why is dissolution important?

Drugs must be in solution to move across biological membranes.

What is absorption?

The movement of dissolved drug across a cell membrane and into a cell.

What is systemic absorption?

The movement of a drug into systemic circulation.

What is permeability?

The ability of a molecule to pass through a cell membrane.

How do many drugs cross cell membranes?

Through passive diffusion.

What is passive diffusion?

Movement of molecules from an area of high concentration to an area of low concentration until __________

equilibrium is reached

Where does blood from the GI tract drain?

Into the portal vein.

What happens to an orally administered drug before reaching systemic circulation?

It travels from the GI tract → portal vein → liver → systemic circulation.

What are drug-metabolizing enzymes (DMEs)?

Enzymes that chemically modify drugs.

Where are drug-metabolizing enzymes found?

In GI epithelial cells and especially the liver.

What is first-pass loss?

Drug lost to metabolism and biliary elimination before reaching systemic circulation

Why can an oral drug have less than 100% bioavailability?

Some drug may not be absorbed or may be metabolized/eliminated before reaching systemic circulation.

What is bioavailability?

The fraction of an administered dose that reaches systemic circulation.

What is the bioavailability of an IV drug?

100%.

Why is an IV drug 100% bioavailable?

It is placed directly into systemic circulation.

Does an IV drug undergo an absorption step?

No.

What must happen for an oral drug to have 100% bioavailability?

All drug must be released, cross GI lipid membranes, and pass through the gut and liver without being metabolized

How is bioavailability reported?

As a fraction from 0–1 or percentage from 0–100%.

What is drug distribution?

Movement of a drug from its administration site to its site of action and/or other parts of the body.

What is the major route of drug distribution?

The circulatory system.

What is a lesser route of drug distribution?

The lymphatic system.

What is elimination?

The removal of a drug from the body.

What are the two major processes of drug elimination?

Metabolism and excretion of unchanged drug.

What is drug metabolism?

The chemical modification of a drug molecule.

What does drug metabolism produce?

Metabolites.

How can unchanged drugs or metabolites be excreted?

Through urine or bile → feces.

What are the three major steps of dosage form design?

1. Preformulation → 2. Dosage form selection and formulation → 3. Determine manufacturing/compounding processes.

What is preformulation?

The characterization of a drug's physicochemical properties before formulating it into a dosage form.

What is the purpose of preformulation?

To help determine the _________ for further development

optimum drug candidate

What does physicochemical mean?

The physical and chemical properties of a substance.

What physicochemical properties are important in preformulation?

Molecular weight, solubility, lipophilicity, dissolution rate, ionization, stability, and solid-state properties

What is solubility?

The extent to which a drug dissolves in a given solvent at a given temperature.

What are two types of solubility discussed in the slides?

Aqueous solubility and lipid solubility.

What does hydrophilic mean?

Water-loving; the drug has an affinity for water.

What does lipophobic mean?

Lipid-hating.

What does hydrophobic mean?

Water-hating.

What does lipophilic mean?

Lipid-loving

What is lipophilicity?

The extent to which a drug likes lipids.

What terms describe a drug that likes water?

Hydrophilic or lipophobic.

What terms describe a drug that dislikes water?

Hydrophobic or lipophilic.

What is dissolution rate?

The time it takes for a drug to dissolve completely.

What is the difference between dissolution and dissolution rate?

Dissolution is transfer from solid state into solution; dissolution rate describes how long that process takes

What is ionization?

The conversion of neutral molecules into electrically charged molecules.

Are most drugs ionizable?

Yes, most drugs are ionizable organic compounds

Approximately what percentage of drugs are weak bases?

75%.

Approximately what percentage of drugs are weak acids?

20%.

What examples of ionizable drugs are shown in the slides?

Aspirin and lidocaine

What is Step 2 of dosage form design?

Dosage form selection and formulation.

What is the goal of dosage form selection and formulation?

Maximize efficacy and minimize toxicity

What factors should be considered when selecting a dosage form?

Physicochemical properties, patient/disease factors, therapeutic considerations, and biopharmaceutical considerations.

What patient and disease factors affect dosage form selection?

Patient needs and therapeutic considerations for the disease

What therapeutic considerations affect dosage form selection?

Systemic vs. local treatment, acute vs. chronic disease, and desired onset of action.

What is biopharmaceutics?

The study of how drug properties, dosage forms, and routes of administration affect the onset, duration, and intensity of drug action.

What three things can affect the onset, duration, and intensity of drug action?

The drug molecule, dosage form, and route of administration

What is onset of drug action?

How quickly drug action is seen.

What determines onset of drug action?

How quickly the drug appears in the blood/plasma.

What is duration of drug action?

How long the drug action lasts.

What determines duration of drug action?

How long drug concentrations remain above a certain level.

What is intensity of drug action?

How strong the drug action is.

What is intensity associated with?

Drug concentration.

What is the goal when choosing a dosage form based on biopharmaceutics?

Provide appropriate drug release while minimizing side effects.

What is Step 3 of dosage form design?

Determine the processes needed for manufacturing or compounding.

What factors must be considered during manufacturing or compounding?

Stability, compatibility, packaging, CGMPs, and quality standards

What does CGMP stand for?

Current Good Manufacturing Practices.

Who must follow CGMPs?

Pharmaceutical manufacturers

What is the purpose of CGMPs?

To ensure proper design, monitoring, and control of pharmaceutical manufacturing processes and facilities.

What drug product characteristics do CGMPs help assure?

Identity, strength, quality, and purity.

What organization communicates CGMP requirements through guidance documents?

The FDA.

What does USP stand for?

United States Pharmacopeia.

What is the USP?

A nonprofit organization that establishes standards for medications, food ingredients, and dietary supplements

What qualities does USP establish standards for?

Identity, strength, purity, and quality.

Does USP enforce its own standards?

No.

Who can enforce USP standards?

The FDA; USP standards are also often adopted by state boards of pharmacy.

What does USP-NF stand for?

United States Pharmacopeia - National Formulary

What is the USP-NF?

A publication of pharmacopeial standards

Is the USP-NF regularly updated?

Yes, it is constantly updated.

What are the major sections of the USP-NF?

General chapters and monographs.

What information do USP General Chapters provide?

Information about tests and procedures

How are USP General Chapters identified?

By numbers, such as

Which USP General Chapters are enforceable?

Chapters below

What do USP chapters

Informational material with no mandatory requirements.

What do USP chapters above

Dietary supplements.

What is USP

Pharmaceutical Compounding—Nonsterile Preparations.

What is USP

Pharmaceutical Compounding—Sterile Preparations.

What is USP

Hazardous Drugs—Handling in Healthcare Settings.

What information do USP monographs provide?

Detailed information about drug substances, dosage forms, and compounded preparations.

What products can have USP monographs?

Bulk drug substances, official dosage forms, and compounded preparations.

What requirements can USP monographs contain?

Analytical assays, storage, labeling, and packaging requirements.

What is the purpose of USP monograph requirements?

To ensure drug strength, purity, and quality.

When can a product be labeled USP grade?

When the manufacturer follows all applicable requirements in the USP monograph.

What information do NF monographs provide?

Information about excipients.

What is an excipient?

A component of a dosage form other than the active drug.

What requirements can NF monographs contain?

Analytical assays, storage, labeling, and packaging requirements for excipients

What is the purpose of NF monographs?

To ensure the strength, purity, and quality of excipients.