Lecture 3: Pharmaceutical Formulations And Delivery Systems Flashcards
Pharmaceutics
Area of study concerned with the formulation, manufacture, stability and effectiveness of dosage forms
Biopharmaceutics
- study of the relationship between the physical, chemical and biological properties of a drug substance, dosage form and drug action
- study of physiochemical factors of drug dosage forms that influence the rate and extent of systemic drug absorption
- aim of biopharmaceutics is to adjust the delivery of the drug substance to the site of action to provide optimal therapeutic activity
Importance of drug delivery
- a drug is not effective unless it is present at its site of action for an adequate period of time
What percentage of drugs that are developed fail because they cannot be adequately delivered to the desired target?
50%
What are two approaches to achieve efficient drug delivery?
- suitable drug delivery system/dosage form
- drug modification
What is a drug substance?
Active pharmaceutical ingredient (API)
What are pharmaceutical ingredients?
AKA excipients or non-medicinal agents
Components other than the active drug included in the final dosage form
Generally viewed as being inert
What makes up the drug product?
Drug substance + excipients (pharmaceutical ingredients)
Why creat dosage forms?
- consistent accurate dosage administration
- convenient administration
- palatable form of administration
- controlled-release of drug upon administration
- protect drug substance from environmentally-induced degradation
Types of dosage forms
- liquid
- solid
- semi-solid
- pharmaceutical inserts
- parenterals
- novel drug delivery systems
What are these examples of:
Powders, granules, tablets, aerosols, creams…
Dosage forms
What are these examples of?
Binders, flavors, sweeteners, film coatings, disintegrants…
Pharmaceutic ingredients
What is the purpose of pharmaceutic ingredients?
- improve patient acceptability
- improve product stability
- optimize production processes
- enable product identification
What are some preformulation considerations?
- physiochemical characteristics of the drug
- target site for the drug
- intended therapeutic use
- age of target population
- compatibility
Preformulation studies of drug substance
- solubility
- dissolution rate
- particle size and distribution
- membrane permeability
- polmorphism
- pKa/dissociation constants
- stability
Dissolution
Process by which a solid of only fair solubility enters solution
Time for drug substance to dissolve in fluids at absorption site
Dissolution rate
A solid particle with surface area S [cm2] dispersed in a solvent of volume V is surrounded by a stagnant layer of thickness h [cm]
Diffusion coefficient D [cm2/sec]
M is the mass of solute dissolved in time t
Noyes-whitney equation for dissolution rate
DM/dt = DS/h(Cs - C)
dC/dt = dS/vh (Cs-C)
Modified release
Dosage forms with drug release features based on time, course, or location that are designed to accomplish therapeutic or convenience objectives not achieved with immediate-release forms
Modified released products examples
Orally administered tablets and capsules
Transdermal patches
Ocular, parenteral, subdermal, vaginal forms
USP differentiates modified release as
Extended release
Delayed release
Delayed release dosage forms
Release drug at a time other than immediately after administration
Enteric-coated tablets
Extended release dosage forms
Sustained
Those that allow a reduction in dosing frequency compared with a conventional (immediate release) dosage form
Controlled release systems include what?
A component that can be engineered to regulate essential characteristic (rate or duration of release) and have a duration of action longer than a day
Rationale for extended release
- many drugs are inherently short-lasting and require multiple daily dosing
- multiple daily dosing is inconvenient for the patient
- conventional immediate release forms cause sequential therapeutic blood level peaks and valleys
Advantages for extended-release dosage forms
- Less fluctuation in drug blood levels
- Frequency reduction in dosing
- Enhanced convenience and compliance
- Reduction in adverse side effects
- Reduction in overall health care costs
What makes drugs suitable for extended release?
- Neither very slow nor very fast rates o absorption and excretion
- Uniformly absorbed from the gastrointestinal tract
- Administered in small doses
- Good margin of safety
- Treatment of chronic rather than acute conditions
What are some advantages for the patient for using tablets and capsules?
- accuracy of dosage
- ease of administration
- compactness
- portability
- readily identified
- blandness of taste
What are some advantages for the manufacturer using tablets and capsules?
- simplicity of preparation
- stability
Capsules
- Enclosed in hard or soft shell
- Primary composition of shell is gelatin
- Commonly used in clinical drug trials
- flexibility of being filled extremporaneously or in large quantities commercially
Capsule size ranges
Largest = 000 (~600mg) Smallest = size 5 (~5mg)
What are the goals of capsule formulation?
- provide accurate dosage
- insure good bioavailability
- ease of production
- good stability
- attractive appearance
What is gelatin NF made up of?
Partially hydrolyzed collagen of animal skin, CT and bones
What is gelatin type A?
Acid processing of pork skins
What is the pI of type A gelatin?
7.0 - 9.0
What is type B gelatin made out of?
Alkali processing of bones and animal skins
What is the pI of type B gelatin?
4.8 - 5.0
Bone and pork skin gelatin contributions
- bone gelatin contributes firmness
- pork skin gelatin contributes plasticity and clarity
What are the two main physiochemical properties of gelatin?
- bloom strength
- viscosity
What is bloom strength?
Empirical measure of gel strength
Measured in bloom gelometer
Properties of gelatin
- insoluble in cold water
- soluble in hot water
- soluble in warm gastric fluid
- tasteless
- biodegradable
- stable in dry form
- susceptible to microbial decomposition
Why is gelatin ideal material?
- swells, but is insoluble in cold water and readily soluble in water
- ability to form thermally reversible gel
- excellent film forming properties
- freely soluble in stomach secretions
- as a protein, gelatin is digested to AAs that can be absorbed
Soft gelatin capsules
- Gelatin + glycerin or sorbital + preservative
- Preservative need because of higher % water in final capsule
- may be single or two tone in color
- filled and formed simultaneously
Two general classes of tablets
Compressed (large scale production)
Molded (small scale operations)
Types of compressed tablets
- sugar coated
- film coated
- enteric coated (delayed release)
- controlled reelase
Qualities of a good tablet
- accurate and uniform weight
- homogeneity
- absence of incompatibilities
- stability and hardness
- ease of disintegration
- reasonable size and shape
- pleasing appearance
- ease of manufacturing
- economy of production
Enteric-coated tablets
- form of delayed-release
- designed to pass unchanged through stomach
- tablet disintegration in intestine allowing drug dissolutioin and absorption
What type of drugs are enteric coatings used for?
- shown to have substantially higher absorption in intestine when stomach is by-passed
- unstable at gastric pH
- irritating to gastric mucosa
Diluents (fillers bulking agents)
- increase bulk for ease of compression and adjust to desired size and shape
EX: dicalcium phosphate, lactose, kaolin, mannitol, sodium cholride
Binders or adhesives
- promote particle adhesion
- impart cohesiveness to formulation for tablet integrity
What is the optimum binder amount and type are used to ensure?
- sufficient tablet harness
- timely disintegration and dissolution
Common binders or adhesives
Starch paste Gelatin Sugars Waxes Poly (PVP) Gums Polyethylene glycol Cellulose derivatives
Lubricants and antiadherents
- prevent adhesion of material to machine components
- facilitate ejection of tablets from the die by reducing adherence to die walls
- ## minimize wear of the punches and dies
Common compounds with lubricants and antiadherents
- talc
- magnesium stearate
- calcium stearate
- polyethylene glycol
Disintegrants
- promote the breakup of the tablet (after administration) into smaller particles
- pre-requisite to drug absorption
- draw water into the tablet by capillary effect. Causes tablet to swell and burst apart
Commonly used disintegrants
Starches
Modified starches
Colorants
- enhance aesthetic appearance
- aid product identification
- lack of international agreement on approved list of pharmaceutical colors limits globally acceptable choices
Flavoring agents and sweeteners
- routinely used for chewable tablets
- flavors are available as oils or spray dried beadlets
Commonly used sweeteners
Mannitol
Xylitol
Lactose
Dextrose
Wetting agents
- used along with poorly soluble drug
- enhance dissolution rate
