Dosage Form Considerations Lecture 1 Flashcards
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
Why do we need different types of dosage forms?
Drug delivery
Stability
Patient Compliance
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)
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)
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)
Physicochemical Properties of the drug
Physical Description
Microscopic Examination
Particle Size
Polymorphism
Solubility
Dissolution / Dissociation
Partition Coefficient
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)
Liquid state
liquid state processed into different dosage forms
Gas state
Microbubbles are designed to deliver gases such as perfluorocarbons for ultrasound mediated diagnosis
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
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
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
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
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
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
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
