Physical state of the drug: - Solid - Liquid - Gases - Majority of the drugs are available in solid form - Liquid drugs (nitroglycerin, propofol, methyl salicylate) - Gases (perfluorocarbons)

Dosage Form Considerations Lecture 1 Flashcards by Les Chow

How would you define “drug”?

A drug is defined as an agent intended for use in the diagnosis, mitigation, treatment, cure, or prevention of disease in humans or other animals

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Why do we need different types of dosage forms?

Drug delivery

Stability

Patient Compliance

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Drug Delivery

Safe and convenient delivery of accurate dosage of a drug

Examples:
- To administer a high dose of insoluble drug in liquid dosage form (e.g. emulsion, suspension)
- To provide optimal drug action from topical administration sites (e.g. ointments, creams, transdermal patches, ophthalmic, Otic, and nasal routes)
- To provide delivery of drugs by insertion into one of the body’s orifices (e.g. suppositories)
- To administer drug directly into the body tissues (e.g. injections)
- To provide optimal drug action by inhalation therapy (e.g. aerosols)
- To provide controlled drug action (e.g. sustained release tablets, patches)

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Stability

Examples:
- To protect the drug from destructive influences of atmospheric oxygen and humidity (e.g. coated tablets, sealed ampules, etc.)
- To protect from the destructive influences of gastric acid during oral administration (e.g. enteric-coating)
- cellulose acetate phthalate, Eudragit L100-55 (polymers for enteric coating)

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Patient Compliance

Examples:
- To mask the unpleasant taste of odor of drug substance (e.g. flavored syrup, coated tablet or capsule)
- To ensure drug delivery to pediatric and geriatric patients (e.g. solution, suspension, emulsion)

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Physicochemical Properties of the drug

Physical Description

Microscopic Examination

Particle Size

Polymorphism

Solubility

Dissolution / Dissociation

Partition Coefficient

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Physical Description

Physical state of the drug:
- Solid
- Liquid
- Gases

Majority of the drugs are available in solid form
Liquid drugs (nitroglycerin, propofol, methyl salicylate)
Gases (perfluorocarbons)

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Liquid state

liquid state processed into different dosage forms

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Gas state

Microbubbles are designed to deliver gases such as perfluorocarbons for ultrasound mediated diagnosis

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Polymorphism

Crystalline forms with the SAME CHEMICAL COMPOSITION but DIFFERENT INTERNAL STRUCTURES (packaging, conformation, etc.)

Polymorphism can result in changes in the physicochemical properties of a drug
- Solubility
- Melting Point

Some chemicals exist in a non-crystalline or amorphous state

All of these factors can ultimately affect the bioavailability of a compound

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Particle Size

Particle size can affect:
- Dissolution rate (surface area effect; affects solubility and absorption)
- Bioavailability
- Taste
- Color
- Stability
- Flow characteristics
- Sedimentation rates

One can calculate the decrease in particle size necessary to increase solubility

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Solubility

One of the most important physicochemical properties of the drug
- Drugs need to have some degree of aqueous solubility in order to be absorbed across biological membranes

Drug solubility can be affected by:
- Chemical structure
- Particle size
- pH

Examples:
- Indomethacin = -COOH
- Chlorpromazine = tertiary amine
- Oxytetracycline = -OH and tertiary amine

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Dissolution

Factors affecting dissolution
- Particle size (surface area)
- Chemical nature of the drug (Base/Acid/Salt/Neutral)

Thus, dissolution can affect the pharmacokinetics of the drug
- Overall bioavailability
- Onset of activity
- Duration of action
- Efficacy

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Dissociation Constant

Can impact drug solubility, partitioning, and ADME

An important consideration in the characteristics of dosage form is the extent of dissociation / ionization, many drugs are ionizable
- The degree of ionization affects pharmacokinetics, specifically absorption (ex. NH3 vs. NH4+)
- The degree of ionization is significantly affected by the pH

In certain formulations, the pH of the vehicle is maintained for solubility / stability
- The pH also may affect the absorption, so these factors must be considered when formulating a drug product

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Partition Coefficient

Measure of the lipophilicity of a compound

It is helpful in estimating how a drug will behave in the physiological environment

If a given a mixture of two immiscible liquids (one oil and one water), a drug placed in the mixture will distribute between the 2 phases until an equilibrium exists

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Drug Stability

Prior to their use, drugs should possess:
- Chemical stability
- Physical stability
- Metabolic stability
- Microbiological stability

The most common mechanisms of drug degradation are:
- Hydrolysis = reaction with water molecules to yield an inactive compound
- Oxidation = loss of electrons leading to an inactive compound
- Autoxidation = reaction with atmospheric oxygen
- Photooxidation

Inactive Pharmaceutical Ingredients OR Excipients

Virtually all pharmaceutical preparations contain additional ingredients besides the active drug substance

Other compounds are added to the drug for a variety of reasons (there MUST be a reason)
- Drug stability
- Improve taste
- Enhance dissolution / absorption
- Preservatives to retard antimicrobial growth
- Diluents/fillers to increase bulk of the preparation

Routes of Administration

Route of administration impact the time required for the onset of drug action and dosage form design

Intravenous (IV)

30-60 seconds

Intraosseous

30-60 seconds

Inhalation

2-3 minutes

Sublingual

2-3 minutes

Oral

30-90 minutes

Rectal

5-30 minutesT

Transdermal

Variable (minutes to hours)

Asthma / Cystic Fibrosis / COPD

Route of Administration: Inhalation Examples: - Aerosol - Dry Powder Inhalers

Superficial Skin Infection / Acne

Route of Administration: Dermal Examples: - Creams - Gels - Ointments

Inflammatory Bowel Disease

Route of Administration: Oral / Rectal Examples: - Pills - Suppositories - Enema

Early-Stage Bladder Cancer

Route of Administration: Intravesical (into the bladder) Examples: - Solution - Gel - Devices

Vaginal Infections

Route of Administration: Vaginal Examples: - Gel - Cream - Ointment

Contraception

Route of Administration: Intra-uterine / Intra-muscular / Vaginal Examples: - Implants - Rings - Microparticles

Ovarian Cancer

Route of Administration: Intravenous / Intraperitoneal Examples: - Solution - Gel - Microparticles

Patient

Age Physical condition Disease type and severity Patient condition - Compliant / Non-compliant / Conscious / Vomiting

Biopharmaceutical Properties of the drug

Permeability Pharmacokinetics (PK) - Absorption, Distribution, Metabolism, Excretion Bioavailability Dose (Potency)

Permeability

Transport of the drug across biological membrane BCS Classification System Class I = easy to formulate in various dosage forms - High solubility - High permeability - Example: Metoprolol Class II = formulate dosage form that can improve drug solubility - Low solubility - High permeability - Example: Celecoxib Class III = formulate dosage form with permeation enhancers - High solubility - Low permeability - Example: Acyclovir Class IV = formulate dosage form with solubility and permeation enhancers - Low solubility - Low permeability - Example: Paclitaxel

Drug Absorption

Very important property that governs drug development and dosage form design Drug absorption is dependent on the physicochemical properties of the drug, drug permeability, site of absorption and the route of administration Right drug delivery strategy and proper choice of route of administration could help in improving drug absorption

Drug Metabolism

Pre-systemic Systemic Drugs that are extensively metabolized after oral administration are typically administered via other routes of administration and require suitable dosage form design

Bioavailability

% bioavailability = ( area under the curve (AUC) of oral dose / area under the curve (AUC) of IV dose) x 100 Oral bioavailability of the drug is one of the major considerations in drug development and dosage form design

Drug Dose

High dose drugs - Tablets, powder/granules, suspension - Limitations on the drug dose that can be delivered via certain routes - Consider change in the dosage form (speed of processing, volume of process) Very potent drugs - Consider accuracy and uniformity of dose in the dosage form