Drug Delivery Flashcards
What are excipients in a drug?
Non- active processing materials e.g dilutents
What are the three main features for using a different solid form of the same drug?
1) Alters the bioavailability of the drug
2) Alters the stability of dosage forms (physical and chemical)
3) Important in the way the dosage forms can be processed and manufactured
What is the most common rate limiting step in absorption?
Dissolution rate
What is bioavailability?
The % of dose that enters systemic circulation
What are polymorphs and what can be their effects?
They are the same drug but different physical forms so can have different therapeutic and biological effects
How can different excipients affect the same drug?
Can have profound effects e.g. disintegrants which can cause break up of tablets into particles
What do polymorphs differ in?
1) Stability- chemical reactivity
- conversion to other forms
2) Processing- different physical forms have different flow
What is a molecule?
Entity containing a number of atoms containing covalent bonds
What is a particle?
Distinct microscopic structure, made from millions of molecules held with non- covalent bonds.
What is a powder?
Visible mass of particles
Give three features of crystalline materials:
1) Ordered arrangement
2) Distinct melting point
3) Structure has unit cell repeated in three dimensions
What is a unit cell?
Small part which can be repeated
Give three features of amorphous materials:
1) No long range order
2) Non- random local structure
3) Have a glass transition temp (Tg)
What type of drug crystals are most drugs?
Triclinic, monoclinic, orthorhombic
Does polymorphism exist in solution?
NO only in a solid
What is true about polymorph stability?
At a given temperature and pressure only one form can be stable, the one with the lowest free Gibbs energy. Others are metastable (kinetically stable)
What is a mono-tropic relationship?
The same form is stable irrespective to temperature
What is an enantiotropic relationship?
Either of the two forms may be stable depending on the temperature
Why is it difficult to tell if you have a stable polymorph?
The metastable form may take a very long time to transform to the stable form.
State and describe two ways for a crystal formation:
1) Supersaturation of solution- conc higher than equilibrium solubility
- can be induced by cooling
2) Nucleation- very small particles form around which crystals grow
- May be homogeneous, same material of crystal or
heterogeneous, foreign material before nucleation
What is a crystal habit and give two examples?
The external shape of a crystal e.g platy and acicular
What does an increase in the degree of supersaturation do to the crystal habit?
Tends to yield longer needles and thinner plates
What happens to the crystal habit and the unit cell of a crystal if the growth conditions change?
Unit cell remains the same however the crystal unit can change
What is the difference between polymorphs and habitats?
Different habitats (external) may indicate the presence of polymorphs (internal) but are different and may change independently
Give four ways to prepare amorphous materials:
1) Rapid cooling from the melt, cooling is too fast to allow crystallisation
2) Fast precipitation from certain solvent systems
3) High energy milling
4) Freeze drying
What are the features below a glass transition (Tg)?
Glassy state, brittle material e.g. PET and glass, low molecular mobility
What are the features above a glass transition (Tg)?
Rubbery state, deformable, plastic material e.g rubber, no melting transition
Is an amorphous material more easily or badly dissolved compared to a crystalline solution, why?
Easier as less stable than crystalline
Give an advantage of using amorphous drugs:
Rapid dissolution so higher bioavailability
Give a disadvantage of using amorphous drugs:
They will recrystallise eventually, more complicated than crystalline and these systems aren’t understood as well.
What is a solvent?
The liquid in which the material is dissolved
What is a solvate?
Crystalline material that contains one or more molecule(s) of the solvent as part of the unit cell structure
What is a hydrate?
A solvate where the solvent molecule is water, i.e., water of crystallisation
What does anhydrous mean?
No water of crystallisation is present
How are solvates made?
By crystallisation from the solvent in question
What is an issue with solvates in a drug form?
Solvates can form unexpectedly when the drug is in contact with a liquid (processing, storage, use)
Potential toxicity issues with included solvent
Includes humidity from ambient air
What is a hemihydrate?
1 water molecule to one drug molecule
What is hydrate stereochemistry?
Usually highly specific ratios of water to drug
What is the general trend for solubilities of the hydrous form and the anhydrous form?
Hydrates usually have lower solubilites and dissolution rates
What is the general trend of solubility for non- aqueous solvates and anhydrates?
Non-aqueous solvates tend to have higher solubility than the anhydrous form
What are multi-component solid forms?
Contain the drug and another molecule or ion e.g
o Solvates
o Salts (e.g., sulfate or chloride salt of the drug)
o Co-crystals (another ‘solid’ molecule in the structure)
o Note that these all can be polymorphic
Are amorphous forms considered solvates, even though…..?
NO, even though they can usually absorb a significant amount of water
How do you determine the flow properties of a drug?
By particle size, shape and particle- particle interactions
What are the two main properties you need to consider to manufacture a drug?
Flow properties and how well it mixes
Prior to absorption, where must the drug dissolve?
In the GI tract
How do you work out drug dissolution?
Noyes- Whitney equation
What are polycrystalline systems composed of?
Aggregates of ‘microcrystals’
What is a complication of particle properties?
Individual particles can clump together to form aggregates/agglomerates
Each particle in a powder will be different
What does it mean if a powder is monosized or monodispersed?
Every particle is the same size and hence the population may be defined by a single parameter
How would you display the ranges of particle sizes in a powder?
Via a histogram, where the proportion (% frequency) is plotted against size
What does a bimodal distribution mean?
Two peaks in the histogram
What is sieve analysis?
Set of sieves with widest mesh at top, finest at the bottom
Sieves usually automatically shaken for a predetermined period of time (usually around 20 minutes)
What is a modification of sieving and what are its benefits?
Air jet sieving- more accurate and reproducible that mechanical vibration, but lengthy
What is the smallest particle size that a light microscope can measure?
10 micrometers
What is the smallest size that an electron microscope can measure?
100nm
What is a projected perimeter diameter?
All the particle enclosed in a small circle
What is a projected area diameter?
Area of circle enclosed around the particle has the same area of the particle.
How does Electrical stream sensing zone method (Coulter Counter) work?
Works on the basis of particles suspended in an electrolyte solution
Particles pass through an aperture of known diameter. Electrodes either side of aperture will register increase in resistance as particle displaces its own volume of electrolyte
What size range of particles does electrical stream sensing zone method work for?
0.1-1000 micrometers
Give one advantage and three disadvantages of the electrical stream sensing zone method:
Fairly quick and easy to use but assumes each particle passes through individually – dispersal can be a problem
Also have to disperse in aqueous solvent – may have to saturate medium first to prevent dissolution
Aperture blockage tends to be persistent problem
What is laser light scattering and how does it work?
Use diffraction of light as means of calculating diameter and size range
Laser applied to suspension of particles in aqueous or non- aqueous medium
What are the two types of laser light scattering?
Large-particle analysers and photon correlation spectroscopy
Why is flow important?
Uniform feed into tableting or capsule filling equipment, leading to uniform weight and mechanical properties
Ease of handling and transfer of powders
What is adhesion?
Attraction between a material and a different material
What is cohesion?
Attraction between a material and an identical material
What does it mean in respect to flow if a powder is cohesive?
It doesn’t flow very well
What is the correlation between particle size and shape in respect to flow?
Large particles flow better than small particles
Round particles flow better than needles or complex shapes
What is the angle of response and how do you measure it?
Pour powder onto a plate and the angle to the horizontal is measured.
What sizes do angles need to be to represent how well they flow?
High angle means high cohesion
• Generally angles > 50° – poor flow
• Angles circa 25° – good flow
How do you find the flow from bulk density measurements?
Add powder to cylinder, measure volume, tap it in a controlled manner, usually by machine, measure the volume after the tapping. This is done by final bulk density/ initial bulk density. To find density is mass/ volume.
Why should difference in volume before and after tapping be a reflection of cohesion?
Because cohesive powders tend to form arches and bridges in a powder bed due to interparticulate forces, which collapse on tapping
What are the two types of stopped flow in a hopper?
Ratholing and bridging
Why is ratholing problematic?
Rat-holing problematic because of non-sequential drainage, but also danger of rat hole collapsing leading to sudden flooding
When flowability is measured, what numbers represent good and poor flow?
Hausner ratio of circa 1.2 reflects good flow, higher than 1.6 poor flow
What is bridging?
Cohesive powders form a bridge over the hole
What is random- mixing?
Random mix – probability of finding a type of particle is proportional to total number in mix (14/30)
State and describe the three mechanisms of mixing:
Convective mixing: take a portion of material from a pile, move it to another location
Shear mixing: powder heap will collapse into hole created (shear plane generated)
Diffusive mixing: if powder bed lifted and dropped. Particles then tumble over each other and mix on particulate basis
What is trajectory segregation?
Larger particles will have greater momentum and move larger distances than smaller ones
Often see larger particles at edge of powder bed after mixing
What are the three main methods for manufacturing tablets:
- Wet granulation
- Dry granulation
- Direct compression
What is an API?
Active Pharmaceutical Ingredient
What is granulation and why is it a better method for making tablets:
Combining the powder ( API and excipients) together to make granules
The granules flow easier than powder
What four things would you have to consider when choosing a manufacturing process for a tablet?
- Compression properties of the therapeutic agent (TI)
- Particle size of the TI
- Types of excipient
- Chemical stability of the TI
What happens to a drug before being manufactured?
Milling- to make particles a more smaller even size.
What is the purpose of a diluent/ filler and what properties should they have?
Added to ALL tablets to increase the bulk of the tablet
Need to exhibit good compression properties and not be expensive
Give four examples of diluents and why are they useful for:
Lactose- inert
Starch- used as a liquid but can also act as binder and disintegrant
Pre-gelatinised starch- allows free flowing powder
Diabasic calcium phosphate- Excellent flow and compression- caution as its basic
What is the purpose of binders?
Used in wet granulation to bind, can be added as a solution or powder
Give an example of a binder and its properties:
Microcrystalline Cellulose (MCC)- binder, diluent and disintegrant
What are the purpose of disintegrants in manufacturing tablets?
They facilitate the breakdown of the tablet upon entry as they increase porosity and wettability so GI fluids can enter, so pressure increases and breaks the tablets
What is the structure of disintegrants?
Cross-linked- so water enters these gaps
Give two examples of disintergrants:
Starch
Microcrystalline Cellulose
How do effervescent tablets break down?
Water enters the pores and this increases pressure and co2 is released so the leaving of the co2 breaks the tablets
What are the functions of lubricants?
Added to the interface of the die and tablet- reduces friction during ejection of the tablet
What is an insoluble lubricant and give two examples:
Added to final mixing stage before compression, however adding too much can affect degradation
Magnesium stearate
Stearic acid
What are soluble lubricants and give an example:
Used when insoluble lubricants affect disintegration, they also enhance dissolution of poorly soluble substances
Polyethylene
What are glidants?
Enhance the flow properties of powders within the hopper, reduces friction between powder/ granulate and surface of the hopper
What are the physical structure and properties of glidants?
Between granulate mixture, so must be fine and small to adhere to granules
Generally hydrophobic
Give two examples of glidants and which one is better?
Talc- needed in high conc, can be inhaled causing granulomas
Colloidal silicon dioxide- need in lower conc
What are adsorbents and give an example:
When a starting material is a liquid and want to make it into a solid
Magnesium carbonate/ oxide
Give three other types of excipients and their function:
- Sweetening agents - taste
- Colouring agents- identification
- Surface acting agents- enhance wettablilty of hydrophobic tablets, aids rate of degradation
What type of mixing is needed when mixing excipients and TI?
Homogenous
What three pieces of equipment can be used to mixed excipients and TI together?
Planetary bowl mixer
Rotating drug mixer
Highspeed mixer
What are four advantages for using granules rather than a direct powder for tablet formulation?
- Prevention of segregation of powder
- Enhances flow properties
- Enhances compaction properties
- Lower incidences of dust production
What three fluids could you use for wet granulation?
Water
Ethanol
Isopropanol
What are three ways of making a granule in wet granulation?
Oscillating granulator
High- speed mixer
Fluidised- bed granulation
How does oscillating granulation work?
Low shear mixing of the powder, granulation fluid spray over the powder and then passed through oscillating granulator
How does fluidised bed granulation work?
Air passes underneath which suspends the powder, causes a fluid like floating powder. Spray is then sprayed and the air underneath drys it also.
What is used to mill granules?
Quadro comil
What type of state do granules ideally need to be once wet granulation is completed?
Funicular state or capillary state
Give two disadvantages of wet granulation:
Several processes required
Drug may solubilise in granulation fluid
State and describe two dry granulation methods:
- Slugging- mixture formed, powder compressed into oversized tablets in high stress pressure machine, forcing compassion, then milled to produce granules
- Roller compaction- mixture formed, compressed using roller compactor forming a sheet. Milling to form granules
What type of diluent would be used for dry granulation?
ANHYDROUS lactose, starch
What’s an advantage of dry granulation?
No heat or solvents required
What are two disadvantages of dry granulation?
Segregation of components may occur
Final tablet may be softer due to no binder
What are the steps for direct compression?
Pre- milling of the formulation components using a quadrilateral comil
Mixing of the TI with the excipient
Compression
What’s one benefit and one disadvantage of direct compression?
+ fewer steps so ideal for APIs which are degradable
- issues with powder flow, segregation in solvent
How can you change the size of the tablet?
Change the position of the lower punch
Give the steps in the tablet compression process:
Filling of the die with granules
Compression, upper punch descent to powder bed and stress is applied, lower punch remains static
Upper and lower punch then elevates, flush with die plate and the shoe ejects the tablet
What two types of tablet presses are there and how many do they make?
Single punch press- 200 per min
Rotary tablet press- 10000 per min
During the elastic region, if the powder undergoes stress, can it reform into a powder?
Yes it is reversible
When can a tablet no longer reform back into a powder?
Plastic region, when stress and strain has gone high
What are two technical problems when manufacturing tablets and what are they caused by?
Capping- separation of the upper and lower layer, due to dried powder or insufficient binder/ lubricant
Lamination- separation of tablets into two to three layers, due to presence of oil or waxy material in the granules
Give four reasons why tablets are coated:
- To protect the drug from degradation in stomach
- To prevent drug induced irritation at specific site
- Provide a controlled modified release of drug
- Mask taste
What are two type of tablet coatings?
Solutions
Emulsions
State and describe two ways tablets are coated:
Pan coater- tablet is placed in metal pan, drum rotates and coating is sprayed, warm air is released
Air suspension coaters- spraying and drying
What are hard capsules made from?
Gelatin
What is the composition of a hard gelatin capsule (HGC) and how does it relate to its function?
Consist of a cap and body, both having a locking device (indentations)
Normally filled with powders but can also be liquids
How many different capsule sizes are there and what is the smallest and largest size?
8 different types
000- largest, fitting 1.36ml
5- smallest, fitting 0.13ml
Why would you use a HGC over a tablet?
Normally would use a tablet, capsules are used if they can’t be made into a tablet due to:
- change polymorphic form on compression
- degrade on compression
- water sensitive and not easily dry granulated
How is gelatin made for capsules?
Prepared by hydrolysis of collagen from an animal source
Non toxic, good film former and readily disperses in body fluids
Skins usually acid processed, bones decalcified to form ossein and base processed
What is bloom strength?
Measurement based on force required to force a plunger a set distance into a 6.66% solution at 10ºC
Would a higher or lower bloom strength be used for HCG and Soft Gelatin Capsules?
Use high bloom for hard gelatin capsules and lower bloom for soft
What are colourants made up of?
Either soluble dyes or insoluble pigments
What type of pigments are used to colour an HGC?
Titanium dioxide also iron oxides which may be black, red or yellow
What type of dyes are used to colour an HGC?
Azo or non- azo
Erythrosine (pink)
How would you manufacture a HGC?
Stick metal pin of desired shape into gelatin solution, rotate evenly to coat liquid, dry, cut to size, join cap and body
How is a HGC filled on an industrial scale?
Powder hopper which feeds powder into a reservoir A dosator (containing a dosing tube) is used to fill capsules
What is a dosing tube?
Dosing tube in which there is a spring loaded piston
The volume of the dosing tube is a measure of the chamber between the tip of the tube and the bottom of the piston.
The volume can be adjusted by moving the position of the piston
How would you calculate the dissolution of the powder content in a HGC?
Noyes Whitney equation
What is changed from the normal Noyes Whitney equation when calculating the dissolution of the drug?
A - effective surface area, rather than just surface area
What could effect surface area of a powder and therefore slow down the rate of drug dissolution?
Particle aggregation caused by a range of reasons such as strong compaction
Tightly packed small particles will hinder water penetration and slow down the wetting of the particles, lubricants and glidants tend to reduce wetting.
What are unconventional capsules and why are they normally used?
Mostly for controlled release purpose
Multi-particulate systems or pellets (mini tablets)
What other type of unconventional HGC is there and what needs to happen for it to work?
Liquid or semi-solid filled hard gelatin capsules- ‘banding’and the lock to prevent leakage
What are soft gelatin capsules (SGC) made of?
A continuous gelatin shell with pliable gelatin coat containing liquids or semisolids
Can be coated with enteric- resistant or delayed-release material
Give four advantages of SGC:
Improved drug oral bioavailability
Dose uniformity of low-dose drugs
Safety for potent and cytotoxic drugs
Means of formulating liquids, such as oils and low melting- point drugs
Give two disadvantages of SGC:
Specialist equipment required
Increased cost compared to conventional capsules and tablets
What does the shell of a SGC consist of and give the % of each:
- gelatin (40-50%, tends to be low bloom strength)
- plasticizer (20-30%) e.g. glycerol, sorbitol, propylene glycol
- water (30-40% initially, less than 7% after drying)
- plus flavours, colourants, opacifiers
Why would you need to add a preservative to a SGC?
A lot of the capsule is made of water, gives conditions for mould to grow, needs a preservative to prolong this from happening
What is the rotary die process in manufacturing SGC?
The continuous formation of a heat seal between two ribbons of gelatin, simultaneous with dosing of the fill liquid into each capsule
Give five examples of materials used to fill SGC’s:
- Water-immiscible (lipophilic) liquids/oils, such as triglyceride oils
- Water-miscible (hydrophilic) liquids, such as polyethylene glycol (PEG) 400
- Self-emulsifying oils, such as oil+Polysorbate 80
- Microemulsion and nanoemulsion systems
- Suspensions
Give three type of compounds that are not suitable to be filled in a SGC:
- Liquids that can easily migrate through the gelatin shell, such as water (if more than 5 percent of the fill), and hygroscopic and volatile compounds.
- Aldehydes, which have the ability to harden the shell, affecting its dissolution properties.
- Acidic or alkaline solutions, unless they are adjusted to become neutral, as the pH can cause hydrolysis and leakage of the gelatin shell.
Which type of SGC’s are absorbed by the lymphatic system?
Poorly water-soluble drugs often can be dissolved in oil or a mixture of oil and surfactants.
Transported through lymphatic system to plasma and then to liver where they are broken down – metabolites in part go to form bile acids
What is a disadvantage of travelling through the lymphatic system rather than the blood stream?
Lymph flow is 500 times slower than blood flow and lipid content of lymph is only 1-2% w/v – so the effect is potentially low.
What is kinetics?
The study of rates of chemical reactions: how quickly changes happen
Do pharmaceutical products have stability?
Most will be thermodynamically unstable, but kinetically stable
What is a transition state?
The high energy state between products and reactants
How would this equation be put in a rate equation?
N2 + 3 H2 → 2 NH3
v= – 1/1 d[N2]/dt = –1/3 d[H2]/dt = 1/2 [NH3]/dt
What are the three ways in which you can directly measure concentrations?
Spectroscopy (use Beer-Lambert law)
Chromatography (peak area)
Titrations
What in quenching in terms of measuring reaction rates and give examples:
Stopping the reaction after sampling
Examples
• cooling down (if reaction requires high temp.)
• addition of base (to stop acid catalysed reaction)
What is a continuous way to measure the rate of a reaction?
Immersion probes
Give the overall rate equation for this reaction:
p A + q B → r C + s D
𝑣 = 𝑘[𝐴]^𝛼 [𝐵]^𝛽
What is an elementary reaction?
Reactions that occur in a single step, through a single transition state (e.g. SN2 substitution)
Involve only one or two specific molecules
They are the basic steps in the mechanisms of more
complex reactions (e.g. in SN1 substitution)
What is the difference between K and k in equations?
K= equilibrium constant k= rate constant
What is molecularity?
The number of molecules involved in an elementary reaction
What is the difference between a unimolecular and a bimolecular reaction?
Unimolecular: a single molecule
Bimolecular: two molecules
What does the rate of an elementary reaction depend on?
The concentration of the reactants
How often can molecules cross the barrier
How would you find the overall order of the reaction from this equation?
𝑣 = 𝑘[𝐴]𝛼[𝐵]𝛽
The overall order of the reaction is the sum of all individual orders (α+β)
For first order reactions, what is the correlation between reaction rate and concentration?
Reaction rate is proportional to concentration of a single reactant
Give the equation for the first order reaction on a graph and what does it represent?
ln𝐴 =ln[𝐴]º−𝑘𝑡 Intercept = ln [A]º Gradient = -k InA on Y-axis Time on X-axis
What is half life and how would you calculate it for a first order reaction?
t1/2 is the time after which half of the initial reactant has reacted ([A] = [A]0/2)
t1/2=In2/k
For zero order reactions, what is the correlation between reaction rate and concentration?
Reaction rate is independent of reactant concentrations and is constant
𝑣=𝑘
How can the reaction rate be independent of the concentrations in zero order reactions?
Something else limits the progress of the reaction e.g. Amount of photons passing through a solution during a photo reaction
Give the equation for the zero order reaction on a graph and what does it represent?
[A] = [A]º –kt Intercept = [A]º Gradient = -k Y-axis [A] X-axis= time
Give the second for the zero order reaction on a graph and what does it represent?
1/[A] = kt + 1/[Aº] Intercept = 1/[A]º Gradient = k Y axis = 1/[A] X axis= time
How would you calculate half life for a second order reaction?
𝑡1/2 = 1/ k[A]º
What is a pseudo first order reaction?
Empirical reaction rate orders will appear independent of the concentration of reactants that are in large excess
e.g.If ethanol is the solvent and acetic acid is present in a very small amount, the concentration of ethanol is virtually constant
o 𝑣 ≈ 𝑘 C2H5OH 0 CH3COOH = k′[CH3COOH]
o The reaction appears to be first order with a rate constant 𝑘′ = 𝑘 C2H5OH 0
How would you calculate the rate constant of a pseudo first order reaction?
From the first order graph, use gradient of -k/ [concs in excess]
Give two forms of the Arrhenius equation:
𝑘 = 𝐴 𝑒−𝐸𝑎/RT Ink = Ina – 𝐸𝑎/R x 1/T o Intercept = ln A, gradient = -Ea/R o A: frequency factor (specific for each reaction) o Ea: activation energy (specific for each reaction) o T: temperature in K o R: gas constant (8.314 J∙K-1mol-1)
What does Ea/RT describe?
How many molecules have sufficient energy to react at a given temperature
How would you estimate long term stability from the Arrhenius equation?
o Draw an Arrhenius plot
o Extrapolate to the temperature of interest (low)
o Calculate k at temperature of interest (storage)
How would you determine which order of reaction a graph has?
Measure the concentration of a reactant (c)
Plot graphs, see which is linear
o c vs time linear: zero order reaction
o ln c vs time linear: first order reaction
o 1/c vs time linear: second order
How would you use the isolation method to determine the rate orders?
Example:NH4+ +NO2- →N2 +2H2O o [NH4+] = [NO2-] = 0.1 M
• No linear graph is obtained for either compound (c vs time and ln c vs time)
o [NH4+] = 0.5 M and [NO2-] = 0.01 M • ln [NO2-] vs time graph is linear
o [NH4+] = 0.01 M and [NO2-] = 0.5 M
• ln [NH4+] vs time graph is linear
What is steady-state approximation?
Used to simplify description of complex mechanisms
Assumes that the concentration of inter- mediate does not change (much) after an initial induction period
What two experiments can be carried out if rate depends on more than one reactant?
o Isolation method: pseudo-orders
o Initial rates: different starting concentrations
How can you calculate the steady state concentration of the intermediate?
[I] = ka/kb [A]
What would be the reaction rate if both reactions were first order?
A → B
B → A
𝑣1 = 𝑘1[𝐴] 𝑣−1 = 𝑘−1[𝐵]
How would you find the rate constant of a reaction in equilibrium?
𝑘1[𝐴]𝑒𝑞= 𝑘−1[𝐵]𝑒𝑞
𝑘1/𝑘-1 = [B]eq/[A]eq =
How would you find the rate constant of a reaction in equilibrium?
𝑘1[𝐴]𝑒𝑞= 𝑘−1[𝐵]𝑒𝑞
𝑘1/𝑘-1 = [B]eq/[A]eq = K
What would be the rate constant of a backward irreversible reaction?
0
What is the equation to calculate the concentrations of reactants and products when there is relaxation at equilibrium? Annotate:
𝑥 = 𝑥º𝑒−(𝑘1+𝑘−1)𝑡 = 𝑥º𝑒−𝑡/𝜏
τ= relaxation time 𝑥 = 𝐴 − 𝐴 𝑒𝑞 = 𝐵 𝑒𝑞 − [𝐵]
What does a catalyst do?
Increase reaction rates by providing a different route for the reaction
What is the equation to work out the Vmax from Kcat?
Kcat x [E]
What is the rate limiting step?
The step which defines the rate
What is the equation to work out the rate of product formation?
𝑑[𝑃]/dt = 𝑘𝑐𝑎𝑡[𝐸𝑆]
What is the Michaelis constant?
𝐾 = 𝑘−1+𝑘𝑐𝑎𝑡/𝑘1
What is the Michaelis-Menten equation?
𝑑[𝑃]/𝑑𝑡 = 𝑘𝑐𝑎𝑡[𝐸]º[𝑆]º/ 𝐾𝑀+ [S]º
At a low [S]º, what is the rate dependant on and give the equation:
Linearly on substrate conc
𝑣 ≈ 𝑘𝑐𝑎𝑡 [𝐸]º[𝑆]º/ 𝐾𝑀
At a high [S]º, what is the rate dependant on and give the equation:
Rate is independent of substrate conc.
𝑣 ≈ 𝑘𝑐𝑎𝑡 [𝐸]º[𝑆]º/ [𝑆]º
What is the correlation between reaction rate and Vmax if [S]0 = KM
The reaction rate is half of vmax
What are the four factors important for shelf life and stability?
- Drug content remains above specified level
2.No accumulation of degradation products that could
represent a risk to patient
3.Physical characteristics remain suitable - Biological and microbiological stability critical for sterile products
What are the three common chemical routes of degradation?
- Hydrolysis
- Oxidation
- Photolysis
What factors can increase the rate of hydrolysis?
Heat, light , trace metals
What is the shape of the rate reaction of reaction curve for hydrolysis and why?
U- shaped, due to it being catalysed by acids and bases
Which ones, out of esters and amides, are less susceptible to hydrolysis and why?
Give an exception to this:
Amides are less because N less electronegative than O
Lactams are less stable than esters due to ring strain
What is the difference between proteolysis and deamidation?
Proteolysis is the breaking of amide bonds in backbone
Deamidation is the breaking of amide bonds in Gln, Asn
What are five strategies to reduce the chance of hydrolysis?
Solid or suspension instead of solution formulation
Buffers to ensure optimal pH
Reduced solvent polarity (e.g. ethanol or polypropylene glycol added to water)
Low temperature storage
Packaging to exclude humidity
What is oxidation?
The loss of electrons to an oxidizing agent
What happens to organic compounds when they are oxidised?
The molecule gains oxygen, loses hydrogen
Which compounds are commonly oxidised?
Alcohols, amines, thiols, thioethers, compounds with multiple bonds
What are thiols/ thioethers,
They have an S rather than an O
What are five factors oxidation is influenced by?
exposure to oxygen (or other oxidizing agents) exposure to light trace metals (catalysis) temperature (less than hydrolysis) free radicals
What is a free radical?
An atom or molecule with an unpaired electron (A•)
What are the stages of reaction with free radicals?
- Initiation stage- bond breaks to make a free radical
- Propagation stage- Free radical reactions with a paired radical to give a different free radical and paired radical
- Termination- Two free radicals pair up
What are four strategies to reduce oxidation?
- Antioxidants are compounds that are oxidised more easily than the drug or that form relatively stable free radicals (e.g.ascorbic acid)
- Chelating agents form complexes with trace metals and prevent their catalytic activity (e.g. ethylenediamine tetraacetic acid – EDTA)
- Low pH can stabilise liquid formulations
- Packaging in inert atmosphere, light excluded
What is photolysis?
Chemical degradation induced by exposure to light and the absorption of photons
What excipient can catalyse the photodegradation of a drug?
Titanium dioxide
What are two ways to decrease photodegradation?
Packaging to reduce exposure to light (e.g. amber glass containers, aluminium foil blister packs, external cardboard container)
Temperature has only a small influence on the rate of photolysis reactions
What are three other types of degradation and describe what they are:
- Isomeric changes- Geometrical isomers (cis/trans, e.g. retinol)
- Chiral centres - Reduction- the molecule gains electrons, gains hydrogen or loses oxygen
- Dimerization and polymerization: the molecule reacts with another molecule of the same kind
What does ADME stand for?
Absorption
Distribution
Metabolism
Excretion
What is absorption?
The process of getting the drug from the delivery site to the bloodstream
What is distribution?
A description of where in the body the drug goes to after administration and absorption
What is metabolism?
How the body chemically changes foreign compounds so that they can be more easily removed from the body
What is excretion?
How the body removes drugs or metabolites, also called elimination
What is the Therapeutic Window?
As the drug exposure increases, the more adverse the effects. In the therapeutic window, this is where the drug has the best/ safest effect.
What are the types of testing occurring in the industrial perspective?
Pre- clinical testing: - In vitro and animal testing Clinical (human) testing: - Phase 1 - Phase 2 - Phase 3
Name six sites of where drugs can be tested from the body:
- blood plasma
- blood serum
- whole blood
- breath
- milk
- urine
How is blood plasma separated to find the drug concentration in the blood?
Whole blood is centrifuged after adding an anticoagulant. Cells are precipitated. The supernatant fluid, contains proteins that often bind drugs. The concentration in plasma comprises bound and unbound drugs.
What type of drugs can pass through the membrane?
Unionised nonpolar drugs
What are the five types of routes of absorption from the gastric lumen?
- Transcellular route: passive diffusion
- Transcellular route: active transporter utilisation
- Paracellular route (tight junctions)
- Lipid absorption via micelles / bile salts
- Particulate absorption via GALT: (Gut-Associated Lymphatic Tissue)
What are the three factors of a drug for it to be orally absorbed?
- pKa of drug
- pH of gastric site
- Log P of drug
What is the equation to find the oral absorption of acidic drugs?
% of [A-] = 100 x 10^ ( pH -pKa)/ 1 + 10^ ( pH -pKa)
What does transcellular mean in drug transport?
Involves passage of the drugs through cells
What does paracellular mean in drug transport?
Between blood and lumen ( gap junctions) as too polar
What is the partition co-efficient?
P = conc in water/ conc in oil
What do the values from the partition co-efficient mean in regards to solubility?
Log P = 0 = Equally soluble in both
Log P = -ve = More soluble in water
Lop P = +ve = More soluble in oil
What is a disatvantage of using LogP in the partition co-efficient and what is used instead?
Only considers un-ionised material
Use Log Papp,
What is the equation to work out the rate of oral absorption?
Rate= P x A x (C1- C2)
P = partition coefficient
A = effective surface area
(C1- C2) = conc gradient
What is the correlation between molecular weight and solubility?
The larger the molecular weight the lower the permeability
What is the normal pH of blood plasma?
7.4
What are the two types of plasma protein in the blood?
Globulins and albumin
Which is the most important binding protein and describe its characteristics:
Albumin
- soluble in water
- soluble in dilute salt solutions
- mw approx 69,000
- pI=4.9
• Binds anionic, cationic and non-ionic drugs
• High affinity : low capacity - “specific” binding sites and
low affinity : high capacity - “non-specific” binding sites
Can bound/ unbound drugs be distributed?
Only un bound
Describe the one compartment model:
Simplest possible representation of PK - drug goes in - drug comes out - no complications No metabolism, no protein binding, no sequestration by other tissues
What are the main five pharmacokinetics parameters?
- Volume of Distribution
- Clearance
- Exposure
- Mean residence time
- Fraction of dose remaining
In first order kinetics, what does the rate depend on?
The concentration
What is the equation to work out the initial concentration of a drug in reservoir?
𝐶= e^y intercept
What is the equation to work out the rate of elimination (clearance) of a reservoir and annotate:
Vd x Ke
Vd= volume of distribution Ke= elimination constant
What are the equations to determine the extraction ratio, E?
E = 𝑅𝑎𝑡𝑒 𝑜𝑓 𝑒𝑙𝑖𝑚𝑖𝑛𝑎𝑡𝑖𝑜𝑛/ Rate of presentation
𝐸=𝑄 (𝐶−𝐶out)/ Qx C = (𝐶−𝐶out)/ C
What is clearance?
Clearance is the volume of the fluid presented to the eliminating organ (extractor) that is effectively completely cleared of the drug per unit of time.
ml/min or L/hr
What does volume of distribution predict?
The concentration for a given amount of drug in the body in the plasma.
Theoretical, how much volume would drug be in if whole dose would be equally distributed at initial conc.
What is the equation to work out the fraction rate of elimination?
k = rate of elimination/ amount in reservoir
k = CL/ V
What is the other equation to measure the rate of first order elimination?
Put this equation into a linear equation:
− 𝑑𝐶/dt = 𝑘elim x 𝐶
𝑙𝑛𝐶(𝑡) =ln𝐶(0) −𝑘elim x 𝑡
What does the gradient in an IV bolus plasma vs time graph represent?
Elimination contant, kelim
How would you calculate the half life of a drug in plasma from a normal graph?
e.g.
get a large conc e.g. 80μg/mL and draw horizontal line to curve, then draw vertical line down to time
do the same with half the conc, so 40μg/mL
t 80μg/mL - t 40μg/mL = half life
What is the equation to calculate half life from an equation?
𝑙𝑛2/ kelim = t1/2
What are three important pharmacokinetics parameters?
- Volume of Distribution
- AUC (Exposure)
- Clearance
What is the apparent volume of distribution and how is it calculated?
The total volume of fluid the drug would occupy if the total amount of drug in the body was in solution at the same conc it is in the plasma
Vd= dose/ initial plama conc (sometimes also over weight in kg)
What do high, low and intermediate values of volume of distribution indicate?
Low= vascular system e.g plasma Medium = distributed to other tissues High= tightly bound to very specific tissues
What is another way of calculating the volume of distribution and what does it mean?
Using the Area Under the Curve (AUC)
Larger areas under the curve, has a larger exposure to the drug as it is a slower process
Initial conc/ kelim
What is another equation to calculate half life?
t1/2 = In2 x V/ CL
What is the mean residence time?
The average time molecules of drug stay in the body
What is the equation to calculate mean residence time (MRT)?
MRT= 1/kelim
How do you calculate the kelim from a plasma conc vs time graph?
Find the gradient
How do you calculate the initial concentration from a plasma conc vs time graph?
e^-y intercept
How do you calculate the half life from a plasma conc vs time graph?
ln2/kelim
How do you calculate the area under the curve, also known as exposure from a plasma conc vs time graph?
Initial conc/ kelim
How do you calculate volume of distribution from a plasma conc vs time graph?
Dose/ initial conc
What is the volume of distribution?
Theoretical value of how much is in plasma
How much volume would drug be in if the whole dose would be equally distributed at initial conc
How do you work out clearance from a plasma conc vs time graph?
Volume of distribution x kelim
