Excipients

Question 1

What does the appearance and palatability have to do with drug design

Answer 1

Most drugs taste bad in their natural form. Improving their look and taste increases compliance

Question 2

When is the taste of a drug important

Answer 2

When the medicine will come into direct contact with the taste buds (oral liquid/chewable tables)

Question 3

Does the addition of flavours and colours impact the behaviour of the formulation

Answer 3

Not usually as the concentrations of them is limited

Question 4

What are the sweeteners we can use

Answer 4

Sucrose - not usually used due to health implications
Saccharin - can be used in much lower concs than sugar
Aspartame - degradation product = phenylalanine. Cant be used in patients with phenylketonuria

Question 5

What makes organic compounds sweet

Answer 5

An increase of -oh groups. Hence, in general, organic esters, alcohols and aldehyde taste present as they are volatile (which gives them an odor)

Question 6

What other ways can be used to mask the taste of a drug

Answer 6

Coating. This is used for capsules and coated tablets to prevent contact between the drug and the tastebuds

Question 7

How does a coating affect drug release

Answer 7

The coatings thickness and composition will determine drug release. It will inhibit (and decrease) dissolution to some extent

Question 8

How does a sugar coating work

Answer 8

The tablet core is sealed with a think film of poorly water soluble polymer (shellac or cellulose acetate pthalate) this retards drug release

Question 9

Give an example of a hydrophobic, water insoluble film (used as an alternative to a sugar coating)

Answer 9

Ethylcellulose - will delay or reduce drug release influencing absorption

Question 10

What is an enteric coating (give examples)

Answer 10

A barrier which prevents the drug from coming into contact with the stomach acid but is disrupted by the higher pH of the duodenum. Example - cellulose acetate phthalate and polyvinyl acetate which dissolve at pH5

Question 11

What is a diluent

Answer 11

A substance that makes up the major proportion of the dosage form to enable the drug to be handled and seen

Should be inert, non-hygroscopic (don’t absorb water from the environment), biocompatible, cheap, have good compatibility and dilution capacity, good water solubility and acceptable taste

Question 12

Give some examples of drug diluents

Answer 12

Lactose, sucrose, mannitol, sorbitol, calcium phosphate, calcium carbonate, cellulose

Question 13

Can changing the diluent affect the absorption of the dosage form

Answer 13

Yes - see lecture for case study

Question 14

Hydophilic diluents ….. the rate of dissolution.

Explain

Answer 14

Increase

The particles of hydrophilic diluent dissolve in the gastrointestinal fluids leaving gaps in the capsule mass. These gaps can be penetrated by the GI fluids leading to an increased dissolution rate (as the surface area is increased)

Question 15

What is a disintegrant and how do they work

Answer 15

Natural, synthetic or chemically modified polymers. They are used to promote the breakdown of solid dosage forms.

When they come into contact with intestinal fluid they absorb liquid and start to swell, dissolve or form gels. This causes the tablet to rupture, increasing surfactants area and enhancing the dissolution.

Question 16

What are the 4 mechanisms by which disintegrants work

Answer 16

1. Capillary action (wicking) - water is pulled into pores by the disintegrant and reduce the physical bonding forces between particles
2. Swelling - particles swell and break up the matrix from within, swelling sets up localised stress spreads throughout the matrix
3. Deformation - particles swell to precompression size and break up the matrix
4. Repulsion - water is drawn into the pores and particles repel each other because of the resulting electrical force (water is ionic and gives the drug molecules a charge)

Question 17

Give examples or non-ionic and anionic polymers

Answer 17

Non-ionic- natural or physically modified polysaccharides such as starches, cellulose or cross-linked pvp

Anionic - chemically- modified cellulose products or low crosslinked polyacrylates

Question 18

Disintigrants can …. bioavailibility

Answer 18

Regulate. Case study - toldutamide see lecture

Question 19

What is a drug lubricant

Answer 19

A substance which reduces frictional forces between particles and between particles and the metal contact surfaces of manufacturing equipment. They assist smooth tablet formation and promote powder flow
They can be solids or liquids

Question 20

How do boundary lubricants work

Answer 20

By adhering to solid surfaces (granules and machine parts) ro reduce friction

Question 21

Give some examples of lubricants

Answer 21

Salts of long chain fatty acids (magnesium strearate) or fatty acid esters (sodium steady fumarate)

Question 22

What is a fluid film lubricant

Answer 22

Melt under pressure and create a thin fluid film around particles, but resolidify after the pressure is removed (hydrogenated vegetable oil, glyceryl distearate or stearic acid)

Question 23

What is a liquid lubricant

Answer 23

A lubricant which is released from the granules under pressure and create a fluid film. They do not resolidify when the pressure is removed but are reabsorbed or redistributed through the tablet matrix

Question 24

What is the issue around adding lubricant

Answer 24

They are often hydrophobic (lipid based) and retard liquid penetrative into a solid dosage form in the gi tract - can be overcome by inclusion of a wetting agent and hydrophilic diluent

Question 25

What is a binder

Answer 25

Binders to cause adhesion of the powdered drug to other excipients. Cause agglomeration of powder into granules during mixing with a granulation fluid by altering inter-particle adhesion. They ensure the tablets can be formed with the required mechanical strength

Question 26

How is the binder incorperated into the dosage form

Answer 26

The binder may be either dissolved or dispersed in the granulation liquid or blended in a dry state

Question 27

Give some examples of binders

Answer 27

Binders may be natural polymers, synthetic polymers or sugars Examples: polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), sucrose, starch

Question 28

What do chemical stabilisers do

Answer 28

Promote longevity of formulations. Drug formulations may be subject to oxidation. Oxidation usually causes a colour change and may also cause precipitation or a change in odour

Question 29

How do we minimise the likelihood of the drug becoming oxidised

Answer 29

Oxidation is minimised by incorperatingantioxidants, which delay the onset and/or significantly reduce the rate of complex oxidative reactions

Question 30

Which type of antioxidants do we use for each type of preparation (Aqueous preparations of variable pHs an lipid preparations)

Answer 30

Sodium sulfite is used in aqueous preparations with high pH sodium bisulfite is used in aqueous preparations with neutral pH Sodium metabisulfite and ascorbic acid are used in aqueous preparations with low pH Alpha-tocopherol and ascorbyl palmitate (lipid soluble) are used in lipid-based preparations

Question 31

What is a chelator

Answer 31

Chelators such as EDTA are used to form soluble, stable complexes with certain metal ions e.g. copper, iron and calcium This removes the ions from solution to prevent them reacting with other elements and/or precipitating preventing them from oxidising. Chelators are used in oral, parenteral and topical formulations and are also referred to as chelants or sequestering agents

Question 32

What is a buffer

Answer 32

A buffer is defined as a mixture of a weak acid or base and one of its salts It is designed to maintain the pH of an aqueous system within very narrow limits

Question 33

Why might we want to keep formulations within a particular defined pH range?

Answer 33

In suspension formulations, if a particular pH is required due to the route of administration if the solubility of the drug is significantly affected by changes in pH

Question 34

Why might a buffer be a hinderance to the dosage form

Answer 34

Due to its ionic nature (buffers arer usually WA/WB), a buffer system will contribute charges to the formulation, which may affect flocculation behaviour the ionization state of other components

Question 35

When would we include antimicrobial preservatives

Answer 35

If water is present in a non-sterile formulation, an antimicrobial preservative is required to prevent microbial contamination (solutions, suspensions, topical products)

Question 36

Give some examples of preservatives and what theyre used for

Answer 36

sorbic acid, benzoic acid - often used in oral formulations and they are most effective when they are unionized as they will not interfere with the flocculation parabens - included in topical or parental preparations benzalkonium chloride -used in aqueous eye drop formulations

Question 37

What are sorbic and benzoic acid's pKas

Answer 37

The pKa of sorbic acid is 4.8 and the pKa of benzoic acid is 4.2. So as you might expect, they will be partially ionized at the pH conditions likes to be found in an oral formulation

Question 38

Is benzalkonium chloride cationic or anionic. How does it ellicit its antimicrobial effects?

Answer 38

It is a cationic surfactant Benzalkonium chloride’s hydrophilic, cationic region destabilises the pathogen’s cell membrane by forming electrostatic interactions with negatively charged components. Once in close contact with the pathogen, benzalkonium chloride’s hydrophobic tail region penetrates the hydrophobic bilayer to cause cell leakage and lysis.

Question 39

Why do we use viscocity enhansing agents

Answer 39

To stabilise colloidal disperse systems They control palatability (can improve mouth feel), ease of pouring and the rate of sedimentation of dispersed particles

Question 40

How can viscocity enhansing agents negatively impact the drugs percormance

Answer 40

Complex formation between a drug and a hydrophilic viscosity enhancing agent could reduce the concentration of drug in solution that is available for absorption These agents may also increase the viscosity of the gastrointestinal contents, decreasing dissolution and/or uptake rates of the drug

Question 41

Give some example of viscocity-enhancing agents

Answer 41

hydrophilic polymers (e.g. tragacanth, gum arabic) or insoluble inorganic materials (e.g. clays - bentonite)

Question 42

How is viscocity enhansed

Answer 42

Entrapment of the solvent by the flocculated colloidal particles, which disrupts laminar flow

Question 43

What is the difference when using natural vs synthetic viscocity enhansing agents

Answer 43

Clays and gums are natural materials and are subject to much greater batch to batch variation than synthetic materials

Question 44

Cellulose is a very commonly used viscocity enhanser. Give examples of some chemically altered versions of it

Answer 44

Cellulose ethers are obtained from native cellulose by chemical treatment, replacing the hydrogen of the –OH group on the glucose residues with a different functional group Methyl (–CH3) group substitution gives methylcellulose (MC) Ethyl (–CH2CH3) group substitution gives ethylcellulose 2-hydroxypropyl (–CH2CH(OH)CH3) substitution gives hydroxypropylcellulose (HPC) Mixed substitution of (–CH3) and (–CH2CH(OH)CH3) gives hydroxypropyl methylcellulose (HPMC) Carboxymethyl group (–CH2COOH) substitution gives carboxymethylcellulose (CMC)

Question 45

What is a key benefit of using cellulose based polymers

Answer 45

These polymers do not interfere with the flocculation behaviour of the system

Question 46

Why do we use surfactants

Answer 46

Surfactants are used as emulsifying agents, wetting agents and suspension stabilisers

Question 47

What are the benefits of using surfactants

Answer 47

Release of poorly soluble drugs can be increased by inclusion of a surfactant, as it reduces the solid/liquid interfacial tension. This allows gastrointestinal fluids to wet the tablet more easily, promoting dissolution and therefore absorption

Question 48

What are the drawbacks of using polymers

Answer 48

Poorly soluble drugs may get incorporated into surfactant micelles, reducing absorption as micelles are excreted not absorbed => this reduces the concentration of free drug available Surfactant monomers can potentially disrupt the integrity and function of a biological membrane enhancing absorption, but may also have toxic side effects

Question 49

What are wetting agents

Answer 49

Wetting agents are typically surfactants below their critical micelle concentration They improve the flow of the liquid vehicle across the particle surface They reduce the interfacial tension between the solid particle and liquid medium, promoting dissolution

Question 50

Give examples of wetting agents used in oral liquid dosage forms

Answer 50

sodium lauryl sulfat, lecithin and polysorbate (Tween)

Question 51

How do wetting agents aid drug delivery

Answer 51

They reduce the interfacial tension between the solid particle and liquid medium, promoting dissolution The wetting effect aids penetration of GI fluids into the mass of a solid capsule Wetting agent are also used to increase the ease of skin spread for topical lotions and sprays

Question 52

What is a flocculation modifier

Answer 52

Flocculation modifiers are ionic materials which ionize once in solution in the suspension medium e.g. sodium chloride Flocculation modifiers can either promote or prevent flocculation; we are usually trying to prevent it. It depends on the relative extent of the attractive and repulsive energies

Question 53

Which parts of the drug are moslt likely to flocculate

Answer 53

Materials which ionize in solution, such as preservatives and buffers, will contribute charges to individual drug particles which generally leads to increased flocculation behaviour

Question 54

Excipients can directly interact with drugs via physical and chemical interactions. Explain how each works and what impact this will have on the drug

Answer 54

Physical: adsorption of drug molecules onto the surface of excipients can make the drug unavailable for dissolution and reduce bioavailability Chemical: a chemical reaction between drug and excipient alters bioavailability or stability