Dosage form design II Flashcards
What are the main components of the pulsincap release dosage form?
enteric coat capsule cap hydrogel plug drug water ghost capsule body
what is the enteric coat?
the outermost layer. When the pulsincap is released into the stomach this enteric coat dissolves
what is the capsule cap?
A layer which only covers the top part of the capsule. when this is exposed to lumenal fluids, the body of the capsule remains intact while the cap rapidly dissolves
what is the hydrogel plug?
a plug which sits inside the capsule body when it is exposed to lumenal contents it swells, after 3 hours it can no longer be accomodated by the capsule body and is ejected
at this time the pulsincap is likely to have reached the colon
what is drug wafer?
this is contained inside the body of the capsule and behind the hydrogel plug.
when the plug is ejected, the drug wafer is exposed to colonic contents and undergoes rappid dissolution which is facilitated by the freeze drying
this causes the other contents of the capsuleto be expelled
what is the ghost capsule body?
when the inside of the gelatin is exposed to colonic contents, it is dissolved. the ehtyl cellulose coat is crushed by a peristaltic wave.
what is bioavailability?
the relative amount of an administered dose of a drug that reaches the systemic circulation unchanged and the rate at which it occurs
Are chemically equivalent products bioequivalent?
not always as they may have different bioavailabilities
what is bioequivalence?
this compares the total amount of a particular drug that is absorbed intact into the systemic circulation from a test and recognised dosage form to determinewhether the test and standard dosage forms containing equal doses of the same drug are equivalent or not in terms of their rates and extents of absorption
What are the requirements for a drug to be bioavailable?
be completely released from the dosage form
fully dissolved in body fluids at the route of administration
stable in fluids in a solution form
pass through the mucosal barrier into the bloodstream without being metabolised
why are some drugs not interchangeable in practice?
although they contain the same active ingredient and dosage form, they are not bioequivalent due to formulation differences
how may differences in bioavailability arise?
they can rise whether or not the drugs are administered as
same dosage/different ROA,
same ROA/different dosage forms
Same ROA/Same dosage form/different formulations
What are the 8 different types of dosage forms?
oral recta topica parenteral respiratory nasal eye ear
What are examples of oral dosage forms?
solutions syrups suspensions emulsions gels powders granules capsules tablets
what are examples of rectal dosage forms?
suppositories ointments cream powders solutions
what are examples of topical dosage forms?
ointments creams pastes lotions gels solutions topical aerosols transdermal patches
what are examples of pareneteral dosage forms?
injections (solutions, suspensions, emulsion forms, implants, irrigation and dialysis solutions)
what are examples of respiratory dosage forms?
aerosols
solutions, suspensions, emulsions, powder forms, inhalations, sprays, gases
what are examples of nasal dosage forms?
solutions, inhalations
what are examples of ocular dosage forms?
solutions, ointments, creams
what are examples of ear dosage forms?
solutions
suspensions
ointments
creams
what governs the choice of a particular dosage form and ROA?
the target site and what you are treating.
e.g. Diclofenac is an NSAID and is available as injection (IM and IV infusion)
dispersible tablets
enteric coated tablets
eye drop
topical gel
rectal suppositories
however for a patient wanting to handle her eye infection, you would just want the drug in an eyedrop form (not injection!)
what does dosage form design depend on? (3 main factors)
biopharmacuetical parameters of drug
physical and chemical properties of the drug
therapeutic factors (clinical indication and patient factors)
what are biopharmaceutical factors?
How the drug properties, dosage forms, routes of administration affect the rate and extent of drug absorption in the body.
These are summarised into 4 main processes: ADME
what is adme?
absorption
distribution
metabolism
excretion
what is absorption?
transfer of drug into blood stream through the ROA
what is distribution?
existence of equilibrium between concentration of drug in plasma and at target site
what is metabolism?
transformation of drug (enzymatically or biochemically) into forms which can be eliminated
what is excretion?
elmination of the drug (unchanged and metabolised) from the body
What must a drug substance be to be absorbed?
it must be soluble
what are the systemic absoprtion sites?
GI lining membranes including buccal, gastric, intestinal and rectal membranes
skin epithelium
lung epithelium
nasal epithelium
vaginal epithelium
What are the 8 different types of dosage forms?
oral recta topica parenteral respiratory nasal eye ear
What are examples of oral dosage forms?
solutions syrups suspensions emulsions gels powders granules capsules tablets
what are examples of rectal dosage forms?
suppositories ointments cream powders solutions
what are examples of topical dosage forms?
ointments creams pastes lotions gels solutions topical aerosols transdermal patches
what are examples of pareneteral dosage forms?
injections (solutions, suspensions, emulsion forms, implants, irrigation and dialysis solutions)
what are examples of respiratory dosage forms?
aerosols
solutions, suspensions, emulsions, powder forms, inhalations, sprays, gases
what are examples of nasal dosage forms?
solutions, inhalations
what are examples of ocular dosage forms?
solutions, ointments, creams
what are examples of ear dosage forms?
solutions
suspensions
ointments
creams
what governs the choice of a particular dosage form and ROA?
the target site and what you are treating.
e.g. Diclofenac is an NSAID and is available as injection (IM and IV infusion)
dispersible tablets
enteric coated tablets
eye drop
topical gel
rectal suppositories
however for a patient wanting to handle her eye infection, you would just want the drug in an eyedrop form (not injection!)
what does dosage form design depend on? (3 main factors)
biopharmacuetical parameters of drug
physical and chemical properties of the drug
therapeutic factors (clinical indication and patient factors)
what are biopharmaceutical factors?
How the drug properties, dosage forms, routes of administration affect the rate and extent of drug absorption in the body.
These are summarised into 4 main processes: ADME
what is adme?
absorption
distribution
metabolism
excretion
what is absorption?
transfer of drug into blood stream through the ROA
what is distribution?
existence of equilibrium between concentration of drug in plasma and at target site
what is metabolism?
transformation of drug (enzymatically or biochemically) into forms which can be eliminated
what is excretion?
elmination of the drug (unchanged and metabolised) from the body
What must a drug substance be to be absorbed?
it must be soluble
what are the systemic absoprtion sites?
GI lining membranes including buccal, gastric, intestinal and rectal membranes
skin epithelium
lung epithelium
nasal epithelium
vaginal epithelium
What are the modes of absorption?
Passive diffusion: for lipophilic, small drugs. Utilises concentration gradient.
Facilitated diffusion: for larger drugs. Also utilises concentration gradient and does not require energy
Active transport: utilises energy to go against the concentration gradient
What drives passive diffusion?
the concentration gradient
what is the difference between active transport and facilitative transport?
facilitative ustilises the concentration gradient
active transport utilises energy to go against the concentration gradient
what are the two most important drug factors affecting passive diffusion across a membrane?
ionisation
lipophilicity
partition coefficient is also important
why is distribution of a drug important?
once absorbed the drug can exert a biological effect either locally or at a remote site of action. whether it is local or systemic depends on the extent of drug distribution
what is metabolism important?
Most drugs need to be broken down into metabolites to be excreted from the system
some drugs however, can be eliminated without being metabolised
why is elimination important?
drug molecules are foreign bodies and thus need to be eliminated either unchanged or metabolised via the urine, faeces, saliva, skin or lungs
what physicochemical properties of the drug affect its dosage form design?
particle size solubility dissolution partition coefficient acid-base properties stability organoleptic properties
why are physicochemical properties of the drug importnat?
they can significantly affect the stability and effectiveness of the final dosage form
Could also have significant effects on the bioavailability of the drug
How does particle size affect drug dissolution and absorption?
Reducing particle size increases particle surface area which would increase contact with the dissolution medium. Thus drug dissolves at a faster rate leading to increased drug absorption by passive diffusion
(Recall Noyes Whitney equation)
What are some disadvantages of reducing particle size?
Reducing particle size may also mean that some drugs may cause more side effects e.g. Nitrofurantoin has an optimal size of 150μm. This is necessary to reduce gastric stress while also permitting sufficient urinary excretion.
Stability may also be compromised (e.g. In suspensions and emulsions)
What formulation additives or processes can affect particle size?
Lubricants in tablets
Air adsorption or state charge during milling and mixing of powders
Polymorphic changes
What are polymorphic changes?
Drug substances can exist in more than one form, each with different molecular packing arrangements in the crystal lattice
What are crystalline polymorphs?
Compounds with the same chemical formula but different crystalline structure
What are liquid crystalline polymorphs?
Liquid crystals with the same chemical formula but different mesomorphous structures
Why is solubility important for drug design?
Minimal solubility is required for therapeutic activity as the drug must be dissolved in order to pass the lipid bilayer to achieve its therapeutic action
How can the solubility of a drug modify its bioavailability ?
A change in the drug solubility upon contact with biological fluids is always a possibility. Biological fluids can be saturated solutions a.k.a critical systems, which may mean that drugs are vulnerable to precipitation when in contact, thus modifying the bioavailability of the drug
Why do drug molecules with acid base properties exhibit pH dependent solubility?
Drugs with acid base properties will have a pKa. Depending on the pH of the environment, they will either have a higher proportion of ionised or unionised drug. In an aqueous environment, the ionised form would be more soluble
Which would be more susceptible to pH fluctuations? Salts of strong acids or salts of weak acids?
Salts of weak acids and bases are more susceptible to pH fluctuations as they have a dissociation constant pKa which is dependent on the pH. Strong acids and bases dissociate 100%, they are not as susceptible to pH fluctuations
What is the common ion effect?
When the addition of a common ion significant reduces the solubility of a slightly soluble electrolyte (drug) due to a change to the equilibrium of the system resulting in the system undoing this change (le chateliers principle)
The addition of a common ion would decrease the solubility of the electrolyte as the equilibrium would try to use up this excess ion
, as
What is dissolution? Why is it an important phenomenon in pharmacy?
This describes the process by which the drug particles dissolve
This is very important in pharmacy because it will influence drug abosrption rates, drug bioavailability, and the therapeutical response.
Describe the steps involved in the dissolution of a poorly soluble drug formulated as a tablet intended for oral administration
Tablets to disintegrate and form smaller granules which are further broken down into small particles. Later the molecules dissolve into solution and eventually be absorbed through the epithelial wall
What is the rate limiting step of dissolution for a poorly water soluble drug ? How does this compare with a freely water soluble drug?
The rate limiting step for a poorly water soluble drug is dissolution.
A freely water soluble drug will have Low lipophilicity will experience difficulty crossing the membrane.
Hence the permeability is the rate limiting step for a freely water soluble drug
What is the mathematical equation that describes the dissolution process? How does each term in the equation affect the dissolution process?
Noyes Whitney equation
Higher surface area increases dissolution rate
Higher drug solubility increases dissolution rate
Higher concentration of the bulk also increases dissolution rate as it drives the diffusion process
What is the partition coefficient?
An indication of lipid solubility
What is the relationship between log p and biological activity?
A drug of log p = 3.3 exhibits the highest biological activity
A higher log p is poorly water soluble drug so you would encounter absorption problems, and thus see a decrease i drug bioavailability
If the pH changes, the log ratio of unionised and ionised drug changes.
If we have small log p, that means the drug is extremely water soluble and will have a difficulty crossing the bilayer.
Why are crystal properties of a drug relevant?
Crystal properties may have significant effects on the drug bioavailability and melting point. This is important as Most substances are handled in the powder form at some stage during the manufacturing process and may undergo compression and be exposed to temperature fluctuations upon long term storage
What are huge main differences between an amorphous and crystalline solid? Which form would be more preferable to formulate?
Crystalline solids have their atoms arranged in orientational and positional long range order in 3 dimensions. They are more stable but are less soluble, and would have a lower bioavailability.
Amorphous solids have their atoms arranged with no orientational or positional long range order. They are less stable but are more soluble and hence offer a higher bioavailability
Each type of solid can be used in different cases e.g. Low solubility of the crystalline solid can be utilised as a controlled release dosage form as it takes longer to dissolve and exhibit its effect.
An amorphous solid can be utilised as a immediate release dosage form as its solubility is much higher and can be absorbed and exhibit therapeutic effects quickly
How are crystalline and amorphous solids used for different dosage forms of insulin?
We formulate insulin with zinc and an acetate buffer for stability. Amorphous solids (2microns or less) are used for a rapid onset of action and a short duration as they dissolve quickly
Crystalline solids (10-40microns) are used for slow onset and prolonged action as they dissolve slower
Combinations of the two are formulated for intermediate action
Why is stability important?
An important principle of dosage form design is ensuring the maintenance of the chemical integrity of the drug during its usable life. Likewise, the integrity of the additives and overall physical chemical stability of the finished protect should also be closely monitored
What affects the stability of general drug substances?
Heat Oxygen Moisture Light PH changes
How can drugs be classified according to their sensitivity to break down?
Class 1: stable under all conditions e.g. Kaolin
Class 2: stable if handed correctly e.g. Aspirin
Class 3: moderately stable even with special handling e.g. Vitamins
Class 4: very unstable e.g. Certain antibiotics in solution
What general measures are taken in handling and formulating moisture sensitive drugs?
Minimal exposure to moisture during preparation
Minimal moisture content in the final product
Moisture resistant packaging
What precautionary measures would you take when handling and formulating light or oxygen sensitive drugs?
Light sensitive:
Preparation of the drug in a dark room
Brown or amber bottle packaging of the final product
Reduce light exposure whenever possible
Oxygen sensitive:
Vacuum packaging
Addition of antioxidants
What stability issues should be considered for drugs administered in solution and intended for oral adminstration?
Stability of solution
PH changes across the GIT
Role of buffers, preservatives and other additives
Avoiding interactions between additives
What are organoleptic properties?
Properties which make the drug acceptable and palatable to the patient
E.g, drugs intended for oral administration may require addition of an approved flavour and/or colour
What should be considered when choosing flavours in drug design?
This primarily applies to liquid dosage forms intended for oral administration
Flavours are available as concentrated extractsm solutions, absorbed onto powders or micro encapsulated systems
What are the ways of overcoming an unacceptable taste of a drug?
We can use water insoluble derivatives rather than a water soluble salt. E.g. Amitrptyline pamoate. However if this is the case we must also consider dissolution and bioavailability issues
The drug can also be administered in a capsule or prepared as coated particles, or as a tablet that can be swallowed easily without contacting the taste buds
How would you go about making the taste of an unpleasant tasting drug intended for oral adminstration?
Consider Sugar coating,
Insoluble material coating,
Encapsulation, including Nano and micro encapsulation.
We can also use Colour masking
What are colouring agents used for?
Standardising drug colour
Mask a colour change
Complement a flavour
These can be natural or synthetic, oil soluble or water soluble
What is the advantage of using insoluble dyes?
They will not be broken down in the water.
Why is the general trend nowadays leaning towards colour free compounds?
Because all colours are from additives which enhance drug side effects, increase toxicity, and bring incompatibilities.
What issues need to be considered regarding the clinical indication of the patient in drug design?
Whether the drug is for local or systemic use
Acute or chronic use
Use in emergency?
E.g. Asthma requires aerosol + oral medication
Angina requires buccal spray + tablets
Diabetes requires insulin + oral hypoglycaemic
Why is the age of the patient an important factor in drug design?
Different aged patients can have different preferences and needs e,g, children prefer liquid dosage forms as they are easy to swallow, dose can be diluted if necessary, can be flavored and coloured.
Adults prefer solid dosage forms because of their preference
Therapeutical response also depends on age because there are different absorption rates between kids, adults and elderly.
What are some recent drug developments for the future?
Novel delivery systems
Drug targeting
What are some common colour flavour pairings?
Lemon yellow
Orange orange
Strawberry red (or pink)
Black currant purple (or violet)
