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PH2107 Formulation Science 1 > Solutions, Colloids & Suspensions > Flashcards

Solutions, Colloids & Suspensions Flashcards

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1
Q

What is meant by Active Pharmaceutical Ingredient, API?

A
  • substance intended to have pharmacological activity or
  • have a direct effect in diagnosis, cure, treatment etc of disease or
  • to have direct effect in restoring, correcting or modifying physiological functions
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2
Q

Excipient meaning?

A

Any component in medicinal product other than active ingredient

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3
Q

Formulation meaning?

A

A means of administering drugs to the body in safe, efficient, accurate etc manner

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4
Q

What three areas does formulation improve?

A
  1. Patient compliance
  2. API stability
  3. Pharmacokinetic profile
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5
Q

How can poor formulation affect activity?

A

HIGH drug-excipient interaction = poor release

LOW drug-excipient interaction = dump dosing

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6
Q

What is meant by ‘invasive’ delivery routes?

A

Methods of drug delivery that access the target via physical trauma e.g. to the skin

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7
Q

What is meant by ‘non-invasive’ delivery routes?

A

Methods of drug delivery that access the target without physical damage to the tissue e.g. via crossing epithelium lining organs, mucous membranes etc

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8
Q

What is meant by systemic delivery?

A

Drug enters circulation and is transported around the body

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9
Q

How do drugs delivered systemically reach their intended targets?

A
  • transported to tissues via RBF (regional blood flow)
  • diffuses from blood to target
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10
Q

What is a benefit to systemic drug delivery?

A

Can target sites inaccessible by local application e.g. myocardium, brain

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11
Q

What are some disadvantages to systemic drug delivery?

A
  • some sites served poorly by RBF e.g. joint capsules, epidermis
  • high doses needed
  • non-specific dosing of other tissues occurs, can cause side effects
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12
Q

What is meant by local delivery?

A

Drug administered at or close to target site

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13
Q

What are the advantages of local drug delivery?

A
  • drug restricted to area of application
  • rapid onset
  • reduced dose
  • reduced metabolism (avoids first pass metabolism)
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14
Q

What are the disadvantages of local drug delivery?

A
  • some tissues difficult to deliver to
  • transfer/spread of drug can occur
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15
Q

What is the buccal delivery route?

A

Topical route by which drugs are held between the cheek and gum to be distributed through oral mucosa

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16
Q

What is the pulmonary drug delivery route?

A

Patients use an inhaler and medications are absorbed into the bloodstream via lung mucous membrane

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17
Q

What is bioavailability?

A

The fraction of unchanged drug reaching the systemic circulation by any route

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18
Q

What is the % bioavailability following an IV injection?

A

100%

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19
Q

Why is bioavailability via oral route not usually 100%?

A
  • poor absorption
  • first pass metabolism
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20
Q

What factors of an entire dose of orally-delivered drug must be met to ensure 100% bioavailability?

A
  • be completely released from dosage form
  • be fully dissolved into molecular form in GI fluids
  • be stable in GI fluids
  • pass through GI barrier without metabolising
  • pass through liver without metabolising
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21
Q

What does a pharmacokinetic profile of a drug show?

A

Varying concentration in systemic circulation

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22
Q

What is Cmax on a pharmacokinetic profile?

A

Maximum concentration of a drug in the body following administration

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23
Q

What is the aim of a dosage regimen?

A

To maintain constant therapeutic plasma concentration for the duration of the therapy

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24
Q

What are the effects of poor patient compliance or low-quality formulations on dosage regimens?

A
  • irregular dosing
    Can cause sub-optimal plasma concentrations
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25
Q

What sorts of formulations can be used to deliver and maintain consistent drug levels in the circulation?

A
  1. Transdermal patch
  2. Modified release tablets
  3. Depot injections
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26
Q

How do IV injections, tablets and oral solutions compare in terms of speed of onset of action?

A

IV injection > oral solution > tablets

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27
Q

Why are tablets slower in terms of speed of onset of action compared to oral solutions?

A

Drug must be released from tablets then dissolve in GI fluids before crossing GI mucosa and entering systemic circulation

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28
Q

What factors should be considered to ensure patient compliance when selecting a formulation?

A
  1. Discomfort e.g. injections unpopular
  2. Convenience - self admin and simple regimes better
  3. Taste/odour
  4. Appearance e.g. colour can affect view of quality
  5. Cost - expensive formulation = expensive product
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29
Q

Why are excipients included?

A

To produce a functional formulation, work around the active ingredient(s)

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30
Q

What factors should be considered when selecting excipients?

A
  • irritants/toxicity
  • compatibility with API/packaging/other excipients
  • stability
  • colour, flavour, smell
  • cost
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31
Q

When should adding a preservative (excipient) be considered?

A
  • for all preparations not for immediate use
  • especially when water and or natural products are present
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32
Q

What are good characteristics for potential preservatives?

A
  • high water solubility (low o/w partition coefficient)
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33
Q

What are some consequences to a formulation of microbial contamination?

A
  • hazard to health
  • odours or discolouration
  • pH changes
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34
Q

What are commonly used viscosity modifiers as excipients?

How do they affect viscosity?

A
  • polysaccharides
  • water-soluble celluloses
  • hydrated silicas

Increase

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35
Q

How does density affect a formulation?

A

The smaller the density difference between phases, the less sedimentation will occur

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36
Q

What are some common density modifiers used as excipients?

What are their limitations?

A
  • sucrose
  • glycerol
  • propylene glycol

Work over limited temperature range

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37
Q

Why are antioxidants often included as excipients?

A

Oils are susceptible to oxidation, can cause rancidity

Antioxidants will slow the oxidation process

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38
Q

What is rancidity from oil oxidation?

Why is rancidity bad?

A
  • fatty acid esters become free fatty acids
  • rancid oils contain potentially carcinogenic free radicals
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39
Q

What is a preferable characteristic of an antioxidant?

A

Oil soluble

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40
Q

What is the role of buffers as excipients?

A

Influence
- chemical stability
- tonicity
- physiological compatibility

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41
Q

What are organoleptic substances?

A

Act upon the senses e.g. flavourings, colourants, sweeteners

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42
Q

For what are organoleptic substances commonly used?

A

To mask the taste of oily drugs in emulsions

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43
Q

What can synthetic sweeteners affect in a formulation? Why?

A

Flocculation because they are often salts

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44
Q

What is the role of humectants in formulations?

What should be considered when adding humectants?

A

Decrease evaporation of water either from formulation in container or while in use

High concentration will remove water from skin

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45
Q

What are some examples of humectants as excipients?

A

Propylene glycol

Glycerol

Sorbitol

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46
Q

Why are sweeteners with high sugar concs potentially a bad idea?

A
  • could be inappropriate for diabetic patients
  • affects rheology (flow) of product
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47
Q

What is the definition of solution?

A

A mixture of two or more components that forms a single phase which is homogenous down to the molecular level (monophasic)

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48
Q

What is the definition of solute?

A

Component which is dispersed as discrete molecules/ions in the solvent

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49
Q

What is a disperse system containing a solid dispersed phase called?

A

A suspension

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50
Q

What is a disperse system?

A

Mixture consisting of 2 or more components in a heterogeneous mixture (disperse phase and continuous phase)

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51
Q

What is a disperse system with a liquid dispersed phase called?

A

Emulsion

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52
Q

What are the benefits to using a solution as a dosage form?

A
  • drug in molecular form so rapid onset of action. (ESP. Parenteral delivery)
  • no dissolution required so rapid uptake following delivery
  • homogenous allowing for precise and tailored dosing
  • easy to swallow
  • straightforward manufacture
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53
Q

What are some disadvantages to choosing a solution as a drug form?

A
  • some drugs unstable in solution
  • not all drugs have adequate aqueous solubility to make a suitably potent solution
  • generally heavier and take up more space than solid oral dosage forms so increased cost and reduced convenience
  • challenging packaging
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54
Q

What is dissolution?

A

Transfer of molecules/ions from solid state into solution

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55
Q

How does dissolution happen?

A

Forces that bind adjacent solute molecules together are overcome by attractive forces of molecules of solvent

Liberated molecule comes solvated - surrounded by solvent molecules in solvation shell

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56
Q

What three forces/interactions must we be aware of during dissolution?

A

Solute-solute
Solvent-solvent
Solute-solvent

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57
Q

What happens if solvent/solvent forces are too strong?

A

Solvent molecules stick together so no space made for solute molecules therefore no dissolution

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58
Q

What happens if the solute/solute forces are very strong?

A

Solute will not break apart, solute molecules cannot be liberated for dissolution

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59
Q

How can the rate of dissolution be sped up?

A
  • adding heat
  • kinetic energy increase
  • ultrasonication (transmission of ultrasound waves through liquid)
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60
Q

What is the definition of solubility?

How is it expressed?

A

Extent to which dissolution proceeds under a given set of experimental conditions

Expressed as maximum of in given conditions eg. %w/v, w/w, v/v

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61
Q

What is meant by miscibility?

A

The ability of one liquid to completely dissolve on another liquid solvent

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62
Q

What is a saturated solution?

A

Solution in which no more solvent molecules are available to form salvation shells

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63
Q

How does temperature affect solubility?

A

Higher temperature = higher solubility

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64
Q

What are the possible consequences of storing certain solutions at too cool a temperature?

A
  • precipitation of solute which can cause
  • irreversible damage to formulation

Taking a dose from a solution containing precipitated active will lead to underdosing

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65
Q

What does solubility convey?

A

The maximum amount of solute that can be dissolved in the solvent

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66
Q

How is solubility measured/how are solvent/temperature conditions defined?

A
  1. Pure solute added to solvent to create saturated solution (long mixing time or heating then cooling)
  2. Centrifugation separates undissolved solute
  3. Supernatant collected, may be diluted for analysis to determine amount of solute present e.g. via UV spec, HPLC
  4. Replicates performed to determine accurate value
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67
Q

What factors can affect drug solubility?

A
  • molecular structure (FG polarity)
  • logP value
  • drug ionisation
  • drug salts (ionic state can be manipulated to suit route of administration)
  • solution pH
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68
Q

Why is the free base/acid form used for topical drug delivery?

A

Lipophilic form will penetrate lipophilic environment of the skin

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69
Q

Counterions of drugs in their salt form have no pharmacological action but may affect what?

A
  • ion pair association constant (annoy be too strong)
  • toxicity levels of counter ion in formulation
  • interactions with excipients/packaging e.g. Cl- is corrosive
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70
Q

Drug molecules arranged into a regular pattern are called what?

A

Crystalline

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71
Q

Drug molecules arranged randomly are called what?

A

Amorphous

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72
Q

Drug molecules with multiple crystalline arrangements are called what?

A

Polymorphic

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73
Q

Why can polymorphism create issues in formulation?

A

Different crystalline forms have different rates of dissolution, stability in storage etc

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74
Q

How can poor solubilisation be improved?

A
  • choice of solvent
  • employing a cosolvent
  • using different drug salt
  • manipulation of solution pH
  • couple action of cyclodextrins
  • producing a different formulation type
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75
Q

Why are lipophilic solvents rarely used for oral delivery?

A
  • poor taste
  • toxicity
  • irritany
  • lack of miscibility with physiological fluids
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76
Q

What types of formulations can lipophilic solvents be useful in?

A
  • parenteral (depot injections)
  • topical formulations
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77
Q

What are some examples of non-aqueous solvents?

A
  • alcohols e.g. ethanol, propylene glycol
  • fixed vegetable oils
  • esters
  • dimethyl sulfoxide (DMSO)
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78
Q

What is a co-solvent?

A

A drug is dissolved in a more lipophilic solvent and the resulting solution is mixed with water

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79
Q

Why might multiple co-solvents be used?

A

To maximise the solubility of the drug and optimise efficacy, stability etc of solution

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80
Q

A co-solvent must be what?

A

Miscible with water

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81
Q

What is the most commonly used alcohol as a co-solvent?

A

Ethanol

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82
Q

Phenobarbitone is virtually insoluble in water so how can it be made into a clear product?

A
  • dissolving in ethanol
  • diluting with glycerol and water
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83
Q

What is the indication for phenobarbitone?

A

Control of seizures

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84
Q

Methyl hydroxybenzoate is a preservative in many oral medications with poor water solubility. How is it added?

A

By dissolving in propylene glycol

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85
Q

What are polyethylene glycols?

A

Long chain polyethers that can be employed as co-solvents

General structure HO-CH2-(CH2-O-CH2)n-CH2-OH
Where if n < 400 then liquid, > then solid

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86
Q

What is the most common PEG?

A

PEG400

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87
Q

When manipulating the pH of a solution for use in meds what must be considered?

A

Balancing dilution of formulation (weak acids/bases) vs. Degradation of drug or excipient (strong //)

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88
Q

What is the working range of the buffer Hydrochloric acid + sodium citrate?

A

PH 1-5

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89
Q

What is the working range of the buffer Borax + sodium hydroxide?

A

PH 9.2-11

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90
Q

What are cyclodextrins?
What is their structure?

A

Semi-synthetic polysaccharides made up of glucose molecules bound together in a cyclic ‘bottomless bucket’ structure

  • hydrophobic interior (HC)
  • hydrophilic exterior (hydroxyls)
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91
Q

How does the type of glucose molecules in cyclodextrins affect their structure?

A

Alpha - 6 molecules
Beta - 7 molecules
Gamma - 8 molecules

Have different cavity sizes

92
Q

What do cyclodextrins form? What does this allow?

When does it work best?

A

Guest-host inclusion complexes
- allows dissolution by increasing the aqueous solubility of the guest molecule

Works best when drug molecules have
- lipophilic moiety
- correct size to fit cavity

93
Q

What does the use of guest-host inclusion complexes rely on with regards to drugs reaching their targets?

A

Dissociation at target membrane

94
Q

What are two other examples of excipient types that may be added to ensure manufacture success/drug compliance etc?

A
  • isotonicity adjusters
  • chelating agents
95
Q

In colloids and suspensions, what sorts of particles make up the disperse and continuous phases?

A

disperse - solid

continuous - liquid

96
Q

What size are the particles in a colloidal dispersion?

How can colloids be distinguished from solutions?

A

1nm - 1micrometer in diameter (cannot see)

distinguish because of effect that dispersed phase has on light

97
Q

How do colloids differ from suspensions (coarse dispersions) ?

How can the different phases in a colloid be separated?

A

particles in colloid too small for gravity to have an effect therefore cannot settle

must be separated by centrifugation

98
Q

Why will the particles in a colloid diffuse?

A

move by random Brownian motion

99
Q

What are some examples of colloids?

A

milk, blood (plasma proteins not RBC as they settle with time)

100
Q

What are coarse dispersions AKA?

What are the size of the particles in a coarse dispersion?

A

suspensions

> 1 micrometer diameter

101
Q

What must be considered when designing a formulation as a suspension?

A
  • large particles are liable to sedimentation
  • formulation must be designed to ensure sedimentation can be reversed e.g. by shaking (energy input)
  • sedimentation must be slow enough that a homogeneous dose can be obtained e.g. in syringe, following shaking
102
Q

why are suspensions unsuitable for certain injection formulations?

A

particle size dictates delivery route - capillary diameter is 8-10 micrometers

103
Q

What are the advantages to disperse systems?

A
  • suitable for drugs susceptible to aqueous degradation
  • increased absorption speed compared to solid oral dose
  • high SA of active, good for absorption (particle size can be tailored for absorption)
  • allows flexibility of formulation e.g. taste masking
104
Q

What are the disadvantages to disperse systems?

A
  • accurate dosing cannot be assured if not shaken properly before each use

(same for all liquid formulations)
- stability problems of API/excipients
- liquids susceptible to microbial contamination
- size/weight/packaging issues
- more difficult to mask taste in liquid than solid

105
Q

Why do particles in suspension have little taste?

A

particles >10 micrometers cannot enter taste bud pore,

only individual molecules can interact with gustatory cells to elicit response

106
Q

What are some properties of an ideal disperse system?

A
  • even distribution of particles throughout continuous phase
  • relatively slow sedimentation rate
  • easy re-dispersal of sediment
  • easy flow from container
  • small and uniform particle size
107
Q

How can colloid systems be classified?

Into what three classes?

A

based on interaction with dispersed and continuous phases

  1. lyophobic - solvent ‘hating’
  2. lyophilic - solvent ‘loving’
  3. amphiphilic - ‘both loving’
108
Q

What are the characteristics of a lyophobic colloid?

A
  • particles and dispersant have different characteristics therefore
  • minimal attraction for dispersant from particles
  • thermodynamically unstable system; particles aggregate to lower their surface energy
  • require careful formulation
109
Q

what are some examples of lyophobic colloids?

A
  • water insoluble drugs
  • clays, oils
110
Q

What are the characteristics of a lyophilic colloid system?

A
  • particles have affinity for dispersant , therefore
  • solvation occurs as particles interact with dispersant
  • inherently stable therefore
  • more straightforward to formulate
111
Q

what is the word to describe solvation when water is the solvent?

A

hydration

112
Q

why are lyphophilic colloid systems inherently stable?

A

solvation forms solvent shells - act as protective coat and prevent coagulation

113
Q

what are some examples of lyophilic colloid systems?

A

starch, gums e.g. acacia in water

114
Q

What are the characteristics of amphiphilic colloids?

A
  • some molecules have regions with different affinities for continuous phase e.g hydrophobic tails
    they will orientate themselves so each part is in contact with preferred phase
  • molecules will arrange @ surface until no space left
115
Q

what is the ‘critical micelle concentration’ ?

A

the concentration at which there is no surface space left for molecules to arrange themselves

amphiphiles will form spherical structures - micelles - to allow them to remain oriented towards preferred phase

116
Q

What is a liposome?

A

bilayer-containing structures that some amphiphiles will artange themselves in
- ‘pocket’ of continuous phase within them (can encapsulate lyophilic materials)

117
Q

How can colloidal systems be utilised?

A

dissolving of lyophobic drugs in micelle or liposome bilayer to ‘solubilise’ poorly soluble drugs

118
Q

Why are micelles and liposomes referred to as ‘association colloids’ ?

A

they constantly disassociate and reassociate with one another to form new structures

119
Q

What are nanoparticles?

What is an advantage to using nanoparticles?

A

solid particles between 1-100nm diameter
(can be used as disperse phase in some colloids)

their properties can be tailored to maximise their usefulness e.g.
size, surface structures, shape, material

120
Q

What are the optical properties of colloids?

How does particle size influence their optical properties?

A

colloidal particles can interfere with path of light travelling through
- scatter light depending on particle size

small particles ‘bend’ light more than big particles

121
Q

What is the Tyndall Effect?

A

occurs when shining light through colloidal suspension

scattering of light causes beam path to become illuminated

(individual particles visible in suspensions)

122
Q

What two factors influence the light scattering abilities of colloids?

A
  1. particle size
  2. wavelength of light
123
Q

How does light wavelength influence light scattering through a colloid?

A

short wavelength e.g. violet/blue is scattered MORE than
long wavelength e.g. red

124
Q

How can light scattering be utilised to measure particle size in a disperse system?

A
  1. a laser diffraction particle size analyser shines beam of laser light onto particles in single file
  2. detector measures amount of deflection of light
  3. size of particle is calculated from amount of deflection
125
Q

Why are larger particles (suspensions) more commonly used in formulations than colloids?

A
  • had to generate small enough particulates for some materials as surface energy may cause clumping
  • ‘wetting’ (solvating) can be hard due to air adsorption at the surface of particles
126
Q

What is the definition of a suspension?

A

a formulation of insoluble solid particles (over 1 micrometer in size) distributed throughout a liquid continuous phase

127
Q

What sorts of drugs are commonly formulated as oily suspensions (depots) ?

Why?

A

antipsychotics and steroids e.g. hormones

  • remain as oily globules after injection
  • reduce SA in contact with body fluids
  • slowed absorption rate
128
Q

what is meant by ‘wetting’ ?

why must it be the first stage of forming suspension?

A

the ability of a solid particle to stay in contact with a liquid

particles will remain on liquid surface, attach to container or form clumps

129
Q

What are diffusible solids?

A

easily wetted particles so straightforward to suspend in aqueous phase

130
Q

what are indiffusible solids?

A

show some hydrophobicity, not easily wetted therefore need wetting agent

131
Q

Why are finely divided substances particularly hard to wet?

A

due to presence of an adsorbed layer of air around the particles

132
Q

how do wetting agents aid wetting and dispersion?

A

decrease interfacial tension

133
Q

What is interfacial tension? Why does it exist?

A
  • cohesive forces exist between molecules in each phase
  • tend to be larger force
  • adhesive forces exist between two different phases

inbalance of forces creates tension at surface

134
Q

What is the degree of wettability determined by?

A

the difference between the adhesive and cohesive forces

135
Q

What are three types of wetting agent?

A
  1. Surface active agents AKA detergents
  2. hydrophilic colloids
  3. solvents
136
Q

How do detergents (SAAs) work as wetting agents?

A

HC chains adsorbed to hydrophobic particle surfaces, polar groups enter liquid and become hydrated

137
Q

Why might they cause excessive foaming?

What else can detergents cause?

A

due to stabilisation of bubbles created when air is mixed in the system

deflocculation of the system

138
Q

How do hydrophilic colloids work as wetting agents?

A

give particles hydrophilic character by coating them with a layer

  • can be used in combo with detergents
  • may also cause deflocculation
139
Q

How do solvents work as wetting agents?

A

water miscible solvents decrease interfacial tension by penetrating powder clumps and displacing air

140
Q

What is the minimum particle size for which gravity becomes significant in causing sedimentation?

A

0.5 - 1 micrometer

141
Q

What is Ostwald ripening?

A

when smaller particles dissolve and redeposit onto larger particles

  • potential issue in suspensions with a range of particle sizes
142
Q

What is the process of Otswald ripening e.g. when temp increases, decreases

A

increase in temp means increase in solubility therefore
- loss of molecules to solution from particle surface
- smaller particles have greater SA:mass therefore lose high proportion

when temp decreases again
molecules want to re-join surface of particle ie. precipitate out
- larger SA on large particles therefore more available space for molecules

143
Q

What is the net effect of an increase then decrease in temperature, due to Otswald ripening?

A

formation of larger particles, higher proportion of large:small

144
Q

Why are ‘insoluble’ actives favoured to reduce the likelihood of Otswald ripening?

A

insoluble actives will have vv low solubility in continuous phase

the lower the solubility the better as less likely to lead to Otswald ripening

145
Q

How can substances with borderline solubility have their solubilities reduced to ensure stability of suspension?

A
  1. antisolvents (opposite of cosolvents)
  2. pH
  3. drug salts
146
Q

What determines the effect of density upon the sedimentation rate?

How can density be altered?

A

the density difference between the particles and vehicle (continuous phase)

density modifiers - lessen the difference in density between the two phases

147
Q

What is the definition of viscosity?

What is the physical definition?

A

the resistance of a fluid to flow/movement

the internal friction of a fluid, produced by intermolecular forces within the liquid phase

148
Q

What five factors can influence viscosity?
with explanation

A
  1. molecular size e.g. larger molecules are more viscous
  2. molecular shape e.g. influences area for IMFs, branched chain will act smaller (viscosity wise) than straight chain
  3. molecular chemistry e.g. polar molecules form H bonds, increase viscosity due to movement resistance
  4. molecular concentration - high conc means more molecule interaction, higher viscosity
  5. temperature - increasing temp adds energy, more movement, less viscous
    plus can break IMFs
149
Q

what is shearing stress?

A

force per unit area required to cause a liquid to flow

150
Q

what is the ‘rate of shear’ ?

A

the difference in velocity between two planes of liquid a given distance apart

(think of liquid as deck of cards, moving top layer; each layer moves at different speed proportional to its distance from the bottom layer, which is stationary)

151
Q

What did Newton notice in regards to flow?

A

rate of flow of a liquid is directly proportional to the force applied by the constant viscosity

ie. the higher the viscosity, the greater force per unit area required to produce a given flow rate

152
Q

What is Newtonian flow?

A

substances that continue to flow in the same way, regardless of the forces acting upon them

ie. when pushed/pulled, they move/change shape in proportion to force applied e.g. water

RARE in pharmaceutical formulations

153
Q

What are non-Newtonian substances?

A

fluids that do not behave in linear ways,
do not have constant viscosity (changes with applied shear force),
properties change in response to movement

154
Q

What is plastic flow characterised by?

When can it be seen?

A

minimum force beyond which the material flows (yield stress/value)

in concentrated suspensions with flocculated particles and high viscosity continuous phases

155
Q

What is pseudoplastic flow characterised by?

When can it be seen?

A

viscosity decreases with the rate of shear AKA shear thinning fluid

seen in flocculated dispersions containing long, high molecular weight molecules

156
Q

What is dilatant flow characterised by?

When can it be seen?

A

viscosity increases with the rate of shear AKA shear thickening fluid

can be seen in dispersions containing a high conc of small, deflocculated particles

157
Q

How does shear thinning/thickening influence particle alignment?

A

eqbm - random arrangement

shear thinning - in-plane alignment; easier slipping past eachother

shear thickening - out of plane alignment, aggregation (prevents slipping)

158
Q

What is thixotropy?

What is it characterised by?

A

reversible, time-dependent change in viscosity, in some non-Newtonian fluids

  • particles form loose 3D gel structure @ rest
  • shear stress (shaking) disrupts bonds, structure, allows aligning of particles, therefore flow (shear thinning)
  • when applied stress stops, down curve is displaced to the left of the up curve indicating reform of gel structure (not immediately)
  • shear rate is lower on upward curve than downward
159
Q

What must be considered with regards to rheology when designing pharmaceutics?

A

manufacturing considerations
- mixing
- passing through machinery
- pouring/packing bottles

patient //
- physical stability
- ease of use e.g. spreading
- safety ie. consistent dosing

160
Q

Why is high viscosity preferable during storage?

A

(low shear stress during storage)
slows/reduces sedimentation

161
Q

Why is low viscosity preferred during shaking?

A

(high shear stress during shaking)
to redisperse particles

162
Q

What is ‘dynamic viscosity’ ?

A

(for a Newtonian liquid)
the coefficient describing the directly proportional relationship between the rate of flow (shear) and applied force (stress)

163
Q

What is ‘kinematic viscosity’ ?

A

relates a liquid’s viscosity to it’s inertial force
- inertial force is equivalent to density

164
Q

What three ways can viscosity be measured practically?

What sorts of equipment might be used?

A
  1. capillary methods - test how fast the sample flows
    using capillary viscometers
  2. rotating methods - test how hard it is to stir
    using rotating viscometers e.g. concentric cylinder or cone-plate
  3. falling methods - test how long it takes something to fall through the sample
    using falling ball/sphere viscometers
165
Q

In what three ways can a surface acquire an electrical charge when they come into contact with water?

A
  1. ion dissolution
  2. ionisation
  3. ion adsorption
166
Q

How does ion dissolution cause a surface to have an electrical charge?

A
  • different ions have different solubilities
    e.g. silver iodide (Ag+ I-)

solid silver iodide in water
- Ag+ more soluble, dissolve
- I- left behind therefore
surface has overall negative charge

167
Q

How does ionisation result in an electrical charge on a surface?

A

if particle made of ionisable molecules they may ionise at surface and particle will acquire surface charge

168
Q

What factors influence whether or not a particle will acquire a surface charge due to ionisation?

A
  • pKa of ionisable groups
  • pH of dispersant

when pH above pKa of group, neg charged molecule

when pH lower than pKa, pos charged

169
Q

How does ion adsorption result in the production of an electrical charge at a surface?

A

by unequal adsorption of ions onto the surface e.g. if more anions (-) adsorb, surface will have net neg charge

170
Q

Why are solid particle surfaces more often neg charged than pos due to ion adsorption?

A

because cations (+) are generally more hydrated than anions (-) so tend to stay in water phase, leaving anions free to adsorb to surface

171
Q

How does the surface charge of particles in a disperse system influence the distribution of ions in the rest of the liquid?

What is the overall effect of this?

A

the electrical double layer

uneven distribution of ions in a disperse system

172
Q

What is the electrical double layer?

How can it be split?

A

layer around each particle with different composition from rest of system

inner region - includes charged surface and adsorbed ions of opposite charge to surface (counterions)

diffuse region - lies beyond adsorbed ions and up to edge of electrically neutral region
contains counterions and co-ions

electrically neutral region - outside edl; bulk continuous phase
uniform distribution of ions

173
Q

What is a difference in charge between two areas called?

A

a potential

174
Q

How are electrical potentials measured in regards to colloids and suspensions?

What will the highest potential be between?

Potential decreases with what? In what pattern?

A

measured against electrically neutral region (ENR) ie bulk solution

highest potential between ENR and particle surface

decreases with distance from surface of particle (rapidly and linearly to Stern plane)
then gradual exponential decrease to zero?

175
Q

What is the DeBye Huckel length, 1/k ?

What is k and what does it depend on?

A

the distance to the electrically neutral region
ie. thickness of electrical double layer, covers exponential region of graph

value varies with system - depends on electrolyte conc of liquid phase

176
Q

How can the thickness of the EDL be decreased?

A

addition of electrolytes; increases k and decreases 1/k

177
Q

What is the Nernst potential?

A

the potential difference between the actual surface of the particle and the electroneutral region of the solution

178
Q

What is the Stern potential?

A

potential between the Stern plane and the ENR

179
Q

What is the zeta potential?

What does it indicate?

A

potential between the shear plane and the ENR - can be used as measure of forces acting in a system

indicates degree of repulsion between adjacent, similarly charged, dispersed particles

180
Q

Why does a higher zeta potential indicate more stability for a system?

What values indicate stable dispersion system?

A

As zeta value approaches zero, attractive forces exceed repulsive forces and particles stick together

zeta value >+30 or <-30 mv

181
Q

Why do particles tend to associate when they meet?

A

to decrease their SA in contact with liquid

182
Q

Why is the balance of attractive and repulsive forces between particles important important for system stability?

A

decides whether particles rebound and stay separate after collisions or stay permanently attached which could lead to irreversible sedimentation

183
Q

What are attractive interactions, Va?

what is the relationship between attraction and distance?

A

result from VDW forces between molecules in surface layers of interacting particles

attraction decreases as distance between particles increases

184
Q

What are repulsive interactions, Vr?

A

result from electrical charges on surface of particles due to

  • adsorption of charged polymers or surfactants @ interface
  • polarity differences between solid and liquid
  • ionisation of chemical groups @ surface of particles
  • adsorption of small inorganic ions onto particle surfaces
185
Q

Over what distance do repulsive interactions, Vr, act?

A

approximate thickness of the EDL

186
Q

What is the relationship between repulsive interactions and distance?

A

Vr decreases with distance but more sharply than Va

187
Q

What is DVLO theory used to describe?

What is the equation?

A

The interaction between two particles in terms of vdw attractive forces, Va and electrical repulsive forces Vr

Vt = Va + Vr

Where Vt is the total of the attractive and repulsive forces

188
Q

What is the ‘primary minimum’ on a DVLO graph?

A

When Va (attractive interactions) dominate at very low inter particulate distance (particles close together)

189
Q

What is the primary maximum on a DVLO graph?

What two factors does it’s height depend on?

A

Occurs at intermediate distances (within thickness of EDL)

  • Vr
  • surface and zeta potential
190
Q

What is the secondary minimum on a DVLO graph?

What does the depth depend on?

A

The trough - occurs at v large H value because even though Va decreases with distance, Vr decreases more sharply

Depth depends on particle size

191
Q

What are three types of aggregation?

Are they reversible?

A
  1. Coagulation/full flocculation - irreversible
  2. Deflocculation (becoming non-aggregated)
  3. Partial flocculation - reversible
192
Q

At what point of a DVLO graph does coagulation occur?

What is formed? How?

Is it possible to redisperse?

A

The primary minimum

particles settle quickly and are closely aggregated - forms single large aggregate

Difficult or impossible

193
Q

At what point on a DVLO graph does deflocculation occur?

What is happening to the particles?

Why are the particles able to slide past each other as they sediment?

Are the particles redispersable upon shaking?

A

At primary maximum

Particles remain separate (are small), settle slowly

Vr

Not easily

194
Q

At what point on a DVLO graph does (partial) flocculation occur?

What does flocculation involve?

Why is sedimentation rapid?

A

At secondary minimum

Formation of loose aggregates of particles which constantly break up and reform

Aggregates are relatively large

195
Q

Why is the sedimentation volume high during flocculation?

How can a homogeneous system be obtained?

A

Liquid is trapped within and between aggregates

Shaking - can re-disperse the sediment

196
Q

What happens to flocculated particles upon storage?

A

They become clayed

197
Q

What happens to deflocculated particles upon storage?

A

They become caked

198
Q

How does distance between particles differ between flocculated and deflocculated material?

A

Flocculated - clumped particles

Deflocculated - separate particles

199
Q

How does speed of particle settling differ between flocculated and deflocculated materials?

A

Flocculated - quickly

Deflocculated - slowly

200
Q

How does vehicle trapping differ between flocculated and deflocculated materials?

A

Flocculated - vehicle is trapped

Deflocculated - vehicle is not trapped

201
Q

How does the appearance of the liquid differ between settled flocculated and deflocculated materials and what do they become?

A

Flocculated - clayed - clear liquid

Defloccculated - caked - turbid

202
Q

How does sediment packing differ between clayed (flocculated) and caked (deflocculated) materials?

A

Clayed - loosely packed

Caked - densely packed

203
Q

In clayed and caked sediments, which forces dominate?

A

Clayed - attractive forces

Caked - repulsive forces

204
Q

Why are pharmaceutical calculations often designed as flocculated instead of de-flocculated?

A
  • easy to re-disperse
  • can increase viscosity using modifiers to minimise sedimentation but so it still remains pourable
205
Q

In what three ways can suspensions and colloids be stabilised?

A
  1. Altering zeta potential
  2. Bridging agents
  3. Steric stabilisation
206
Q

What two factors can be manipulated to change zeta potential?

A

Electrolyte conc and pH

207
Q

What is the result of adding an electrolyte with the opposite charge of the particle surface?

A
  • electrolyte will associate with the particle
  • Vr will decrease, so will zeta potential

Particles will therefore repel less and flocculation can occur

208
Q

How does the amount of electrolyte added alter the degree of flocculation (assuming the electrolyte is oppositely charged to the particles) ?

A

Small amount - flocculation

Large amount - coagulation

Very large amounts - charge reversal - deflocculation

209
Q

What does the Schultz-Hardy rule show?

A

Ability of an electrolyte to flocculate particles depends on its valency

Trivalent > divalent > monovalent

210
Q

What two sorts of bridging agents are there?

What can charged SAAs act in combo with?

A

Non-ionic surface active agents (SAAs) and hydrophilic polymers ie. Long chain branched molecules

Electrolytes

211
Q

How do Surface Active Agents (SAAs) work as bridging agents?

A

Can adsorb onto more than one particle at once to form bridge and therefore loose flocculated structures

212
Q

How do hydrophilic polymers work as bridging agents?

What does it form?

A

Part of chain adsorbs onto a particle and the rest bridges to other particles

Forms gel-like network, flocculates system

213
Q

How does steric stabilisation work? What is involved?

A

Non-ionic polymers can adsorb onto particle surface,
Polymer chain keeps particles apart due to repulsive steric interaction

214
Q

How can suspension stability be assessed?

A
  1. Rate of sedimentation
  2. Final volume or height of sediment
  3. Ease of redispersion
  4. Particle size distribution
215
Q

Why is accelerated stability testing used? Is there a disadvantage?

What two methods are there?

A

Shortens time of some experiments but not always possible to accurately predict normal behaviour from results

  1. Centrifugation
  2. Temperature cycling
216
Q

What are the disadvantages to using Centrifugation to assess suspension stability?

A
  1. Increases sedimentation rate by increasing acceleration due to gravity
  2. May destroy structure of flocculated system by forming tightly packed sediment (may not have occurred under normal conditions)
217
Q

What is the disadvantage to using temperature cycling as a stability test for suspensions?

A

Moving between extremes of temp - ie. 40 degrees and zero - increases rate of degradation, esp crystal growth

218
Q

Why do we use sedimentation volume, F?

A

Plots of F vs time allow comparisons between formulations

219
Q

For a graph of F/time, what does it mean when F plateaus?

A

Sedimentation is complete

220
Q

For a plot of F/time, what does it mean when F = 1?

A
  1. Volume of sediment = original volume of suspension
  2. No clear supernatant is seen on standing
  3. Product is in ‘flocculation equilibrium’
221
Q

What is a desirable value for sedimentation volume, F, for a pharmaceutical?

A

F = 1

222
Q

F is usually < 1 but under what circumstances can F be > 1?

A

If the flocs in a system are loose and fluffy

223
Q

What is the value beta, for degree of flocculation?

A

Relates volume of flocculated sediment to that in a deflocculated system

(More useful than F)

224
Q

What can the ‘pocket’ of continuous phase within a liposome be used for?

What other feature of a liposome makes them good for drug delivery?

A

To encapsulate lyophilic materials to control delivery, protect the, from enzymatic degradation when coming into contact with physiological fluids etc

Lipid bilayer is able to fuse with cell membranes to deliver drugs

225
Q

What would be the consequence if a drug was too small to fit a cavity in a cyclodextrin?

A

Drug will not interact enough with the cyclodextrin and will not be transported

226
Q

What would be the consequence if the association constant between a drug and the cyclodextrin was too high?

A

Drug would not be delivered to target site as it would not be released from cyclodextrin

227
Q

What would be the consequence of the association constant between a drug and the cyclodextrin being too low?

A

The drug will not enter the pore and solubility will not be improved

PH2107 Formulation Science 1 (2 decks)

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