The Medicine Flashcards
1
Q
What are dosage forms?
A
Forms we use to turn the drug into a medicine
2
Q
What types of tablets are there?
A
Swallowable Effervescent Chewable Buccal/sublingual Lozenges Coated Controlled-release Dispersible/soluble Compressed for rectal/vaginal
3
Q
What types of capsules are there?
A
Hard gelatin capsules
Soft gelatin capsules
4
Q
Advantages of tablets
A
Improved patient compliance Convenient and safe Easy to carry multiple doses Accurate and reproducible doses Aesthetically pleasing Easy to store and dispense
5
Q
Disadvantages of tablets
A
Manufacture requires a series of unit processes and product may be lost at each stage
Drug absorption dependent of gastric emptying rate so patient variability
Compression difficulties due to powder physical properties
Administration of tablets to certain patients may be a problem
6
Q
What excipients are in a tablet?
A
API Diluent Binder Disintegrant Lubricant Antiadherent Flavour/colourant
7
Q
What is an excipient?
A
An inert substance that is used as a diluent or vehicle for preparing a drug product
8
Q
In a high dose tablet, how much of the tablet is API?
A
> 50%
9
Q
In a low dose tablet, how much of the tablet is API?
A
<5% weight
10
Q
What is the minimum tablet weight we can obtain reliably?
A
50mg, so low dose tablets would require a filler
11
Q
What is the concentration range of disintegrant?
A
1%-10% w/w
12
Q
How do disintegrants work?
A
Facilitate water uptake
Rupture the tablet
13
Q
Examples of disintegrants
A
Starch
Cellulose
Crosslinked PVP
calcium carbonate
14
Q
What is the concentration range of binders?
A
2%-10% w/w
15
Q
Examples of binders
A
Gelatin, PVP, HPMC, PEG, Sucrose, Starch
16
Q
What is the role of a glidant?
A
To improve flowability of the powder
17
Q
Examples of glidants
A
Talc, colloidal silica, magnesium stearate
18
Q
Role of lubricant
A
To ensure that tablet formulation and ejection can occur with low friction between the tablet and the die
19
Q
Concentration range of the lubricant
A
0.25-1% w/w
20
Q
Examples of lubricants
A
Magnesium stearate stearic acid PEG SLS Liquid paraffin
21
Q
Role of antiadherent
A
To reduce the adhesion between the powder and the punches
22
Q
Concentration of antiadherent
A
about 0.5% w/w
23
Q
Examples of antiadherent
A
Magnesium stearate
Talc
Starch
24
Q
What physiochemical properties of the drug need to be considered?
A
site of absorption
stability of the drug
25
What are the unit processes for tabletting
```
Weighing
Mixing
Granulation
Tabletting
QA check
Dissolution
Coating
QC check
```
26
Cohesion and adhesion bulk solid parameters
Particle size, shape, texture and distribution
Particle hardness and surface characteristics
Moisture content
Particle density/bulk density
Temperature
27
Cohesion and adhesion container parameters
Wall surface roughness affects adhesion
chemical composition
Temp, pressure and humidity
Environmental parameters
28
What is tensile strength and how is it determined
How well powder can cling together
Determines by tilting table method
Dual plates - one fixed and one free
correlates with angle of repose
29
What is true density
Density of each individual particle
30
What is bulk density
Density of the whole powder
31
What properties of particles affect bulk flow
Particle size
Particle shape
Particle density (true density)
Packing geometry of powder
32
Why is bulk density important?
```
Affects packing geometry
Die filling
Particle size and distribution
Packaging, handling and processing conditions
Stability
```
33
How to improve powder flow
```
Particle size increase
Uniform particle size
Control temp
Humidity
Storage and processing
Glidants, lubricants and antiadherants
Vibration assisted hoppers
Force feeders
```
34
What happens during granulation
Primary powder particle are made to adhere to form larger milt-particle entities called granules - form liquid then solid bridges
35
What are the three steps of granulation
Nucleation
Transition (nuclei growth)
Granule Growth
36
Advantages of dry granulation
```
Economical
Versatile
Low equipment costs
Easy to scale up
Uniform mechanical strength of flakes
Roller compaction is gentler
```
37
What are positive mixtures?
Mixtures in which components mix spontaneously and irreversibly by diffusion (almost perfect mix)
38
What are negative mixtures?
Components that tend to separate and need a constant input energy to maintain the desired dispersion
39
What are neutral mixtures?
The components have no tendency to mix or separate spontaneously
40
What is a random mixture?
The components are perfectly mixed, so probability of selecting a type of particle is the same in all the position in the mixture
41
What is ordered mixing?
Components are not independent of each other, resulting in a spontaneous degree of order in the mix
42
Why is mixing important?
Ensure quality
Even distributions
Guarantee drugs released with desired rate
Give even appearance to dosage forms
43
What is the scale of scrutiny?
The amount of material (weight or vol) used to test the quality of a mixture
44
What is the general rule for choosing size of scale of scrutiny?
The lower the conc of active drug in the mixture, the bigger scale of scrutiny used
45
How much powder is used in a tumbling mixer?
50g to 100kg
46
What are the mechanisms of mixing powders?
Convection
Shear
Diffusion
47
What does the mixing index compare?
The content standard deviation from sample under investigation with the one from a fully random mix sample
48
How to minimise mixture segregation?
```
SImilar size particles
Smaller than 30um
Control shape
Similar densities
Granulate
Reduce mechanical stresses
Use equipment for multiple operations
Ordered mixtures
```
49
What properties are assessed in every tablet formulation for conformity?
```
Uniformity of content
Tablet weight
Disintegration
Dissolution
Mechanical strength - friability/ fracture resistance
Tablet appearance
```
50
Is dissolution an exo or endothermic process
Endothermic - increase temp, more dissolution
51
What is the difference between attrition and fracture?
Attrition is continual low level force (tumbling) such as carrying around a tablet in pockets
Fracture is one continual unidirectional force
52
What is tablet coating used for?
```
Improve physical attributes
Control release of drug
Improve taste
Standardize colour
Make more easy to handle, identify, package
Protect from physical elements
```
53
What types of tablet coating are there?
Film coating
Sugar coating
Compression coating
54
What methods of coating are there?
Pan coating
| Fluidised bed coating
55
Examples of polymers for coatings
cellulose acetate
Methylmethacrylate copolymer
phthalate esters of HPMC and PVP
56
Examples of plasticizers for coatings
```
PEG
PG
Diethyl phthalate
triethyl citrate
fractioned coconut oil
```
57
Examples of colourants for tablet coatings
Iron oxide pigmenent
| Titanium dioxide
58
Examples of solvents for tablet coatings
Organic polymer solutions
| Aqueous polymer dispersions
59
Give examples of pulmonary, systemically delivered drugs
Sodium cromoglicate - anti-allergy, anti-inflammatory
Isoprenaline -bradycardia, heart block
Ergotamine - migraines
Biopharmaceuticals - insulin, vaccines, growth hormone
60
What particle size is required for pulmonary drug delivery? What sizes cause problems?
1-5 um ideal
>10 um are deposited in mouth and throat
<0.5 um exhaled
61
What are the two ways in which an aerosol may be prepared?
Dispersion and condensation
62
How is an aerosol prepared by dispersion?
Use of a pressurised container, with liquefied gas, using a propellant
Solution/suspension of active ingredients is in the liquefied propellant or within an additional solvent
When the container is opened or deployed, the vapour pressue of the propellant force the liquid out of the container producing a dispersion in the air
63
How is an aerosol prepared by condensation?
A sample of vapour-saturated gas is subjected to rapid volume expansion (called supercooling)
Lowers temp and causes supersaturation
Vapour condenses on any ions or particles - forms colloidal particles
Packaged for delivery
Collect precipitate at the end
64
Explain how an accuhaler works
Drug/carrier mix preloaded into the device in 60 foil covered blisters
Foil peeled off each as each dose advance (blisters amd lids seperate in the device by the end)
Drugs are not exposed to humidity
65
How does a nebuliser work?
Compressed gas going in constantly, reaches nozzle, drop in pressure pulls in liquid drug suspension
Baffles break up drug particles into appropriate sized vapour when they hit it
Inhalation then occurs
66
Give examples of classes of drugs administered via the LOCAL nasal delivery
Antihistamines
Corticosteroids
Sodium cromoglicate
Antiseptics/antibiotics
67
Give examples of classes of drugs administered via the SYSTEMIC nasal delivery
```
Sympathomimetics
Analgesics
Erectile dysfunction
Proposed portal for vaccine delivery
Potential for drugs to cross BBB so for Alzheimers, tumours, epilepsy, pain, sleep
```
68
What is the nasal vestibule?
The narrowest part of the nose and contains cilia that filter out particles <10 um
69
Describe the turbinate region of the nose
Filled with projections of tissue from the nasal septum - composed of mucus secreting goblet cells, ciliated cells and non-ciliated cells
Particles 5-10um deposit on the mucus lining in here
The epithelium lining of the nasal turbinates is the main drug absorption site
70
How do drugs cross the nasal epithilium?
Passive diffusion - transcellular or paracellular
71
What is PecFent and what is its purpose?
Nasal spray containing Fentanyl - an opiod analgesic
| Used to relieve breakthrough pain in people already receiving opioids on a regular basis
72
What classes of drugs are given rectally?
```
Antiseptics
Local anaesthetics
Vasoconstrictors
Anti-inflammatory compounds
Soothing and protective agents
Laxatives
```
73
Can any orally admistered drugs be given rectally?
Yes - anti asthmatics, anti inflammatory. analgesics
74
Give advantages of using rectal delivery
```
Avoids oral (if reason)
For very young, old, mentally ill
Avoids adverse GI effects, instability at low pH and 1st pass
If unacceptable taste
Small and large doses can be given
No protease activity
Skilled practitioner not needed
```
75
Give disadvantages of rectal drug delivery
```
Generally disliked route
Slow and often incomplete
Variability between patients
Devleopment of proctitis
Leakage and insertion problems
Short shelf life
Market size low
```
76
What is the rectum?
The final 15-20cm prior to the anus, a circular muscle
Flat - no villi, 3 major folds (valves)
Wall - single layer epithelium of cylindrical cells and goblet cells that secrete mucus
77
How much mucus is in the rectum?
3ml
78
What is the pH of the rectum?
7.5 and slightly more alkaline in children
| So no buffering capacity so need neutral meds
79
What are the 3 veins that serve the rectum?
Inferior and middle haemorrhoidal veins - drain into vena cava
Superior haemorrhoidal vein - drains into portal vein
80
Why is rectal drug delivery bioavailability variable?
Inter individual variability and venous drainage of the rectum
81
Why is rate and extent of drug absorption in the rectum lower than the oral route?
Limited surface area
| Low fluid volume for dissolution
82
What affect do surfactants have in rectal drug delivery?
Effective at improving drug delivery but may cause irritation of the rectal mucosa longer term
83
Why might the rectal wall exert pressure on a suppository?
Abdominal organs may press stimulating spreading and absorption
Motality of muscles of the rectal wall may stimulate spreading and absorption
84
How much do suppositories weigh and what is their drug content
1-4g
| <0.1 to 40% drug
85
What are the types of suppository bases
Glyceride type fatty bases (laxative purposes
| Water soluble bases (used less)
86
What are the ideal suppository properties?
Solidify rapidly after prep so drug dispersed
Volume contraction to remove from mould
Melt/dissolve/disperse at body temp
Dissolve in rectal fluid if water based
Chem and physically stable during storage
Non-irritant
Appropriate viscosity
87
Expalin Polyethylene glycol bases
Melting point well abvove body temp so dissolve in rectal fluid to release drug but are miscible with water
Drug may remain in base - drug release may be slow as little fluid
Suited for tropical climates
Can oxidise to form peroxides so airtight packaging
88
What is the first choice of suppository formulation?
Readily water soluble form of the drug dispersed in a fatty base
Particles <150 um to stop sedimentation
Particles <50 um do not irritate patient
Smaller particles to speed up dissolution rate
89
What can you add to suppositories to stop leakage?
Viscosity enhancers - colloidal silicon oxide, aluminium monostearate
90
What types of rectal preparations are there?
```
Suppositories
Lipid based ointments
Rectal capsules
Rectal tablets
Rectal solutions, emulsions, suspensions(enemas)
```
91
Examples of LOCAL vaginally delivered drugs
Anti fungals/antibacterial
Spermicides
Microbicides
92
Examples of SYSTEMICALLY vaginally delivered drugs
Oestrogens, Progesterone(higher bioavailability than orally), prostaglandin analogues
93
Give examples of vaginal dosage forms
```
Pessaries
Tablets
Films
Capsules
Rings
Tampons
Solutions
Emulsions
Suspensions
Creams, gels, ointments, sprays, foams
```
94
What is the pH of the vagine
3.5-4.5
95
Why is the vagina the pH that it is?
Lactobacillus convert glycogen from the epithelium to lactic acid
96
Why is vaginal ecology dynamic?
Responds to hormones, contraceptive, topical drugs, age, infection, semen
97
What can cause the vaginal fluids and composition and environment to vary?
Age, stage of menstrual cycle, pregnancy, sexual activity, infections
98
When does blood drain in the vagina
Via vaginal vein into the vena cava
99
Explain the ideal vaginal dosage form
```
Long acting - less Frequent admin
stable in climatic conditions
Appropriate viscosity
Not lead to irritation
Easy to insert/apply
```
100
Explain the ideal pessary
Shape, vol, weight 1g suitable
,50 um particles
base soluble or dispersible in water or melts at body temp
Base gives rapid solidification after prep
From glycerol-gelatin bases
101
What are the limitations to steady state plasma conc by repetitive dosing
Conc of drug fluctuates over successive doing intervals even when at steady state
Short half lives = more frequent doses
Maintenance of concs is susceptible to forgotten and overnight no dose period
102
What dose the ideal dose regimen provide?l
An acceptable therapeutic conc of drug at the site of action immediately
103
What does the USP define a modified release dosage form as?
Drug release characteristics of time course and/or location are chosen to accomplish therapeutic or convenience objectives not offered by conventional forms
104
Advantages of MR drugs
```
Peaks and troughs minimised
Improved compliance
Better safety margin
Efficient use of drug
Reduction in healthcare costs - less monitoring, shorter treatment time, less dispensing
```
105
Disadvantages of MR drugs
Risk of dose dumping if something goes wrong
Instability of drug
More costly manufacturing process
106
What is a delayed release drug?
The drug is not released immediately following administration but at a later time - ec
107
What is a repeat action drug?
An individual dose is released soon after administration. Second or third doses are released at later intervals
108
What is a prolonged release drug?
The drug is absorbed over a longer period of time than from a conventional dosage form. Implication that onset is delayed because of slower release rate from the dosage form.
109
What is a sustained action drug?
An initial release of drug sufficient to provide a therapeutic dose soon after administration. Then a gradual release over an extended period.
110
What is an extended release drug
Release drug slowly.
| Plasma concentrations are maintained for a prolonged period of time (usually between 8 and 12 hours)
111
What is a controlled release drug?
Release drug at a constant rate and provide plasma concentrations that remain invariant with time.
112
MR products are generally designed to provide either:
Remaining constant - within TR for a prolonged time
| Declining at such a slow rate that conc remains in TR for prolonged time
113
What properties of a drug make it suitable for MR?
```
t1/2 is 2-8 hours
High TW
logP - 2.2-3.3
Uniformly absorbed and not too unstable throughout the GIT
Moderate potency
```
114
Which physiochemical properties of a drug influence the choice of dosage form? What is the best BCS classification?
Aqueous solubility
Stability
pKa
Partition coefficient (intestinal permeability values)
Salt form
BCS - High solubility and high permeability
115
Why is it hard to achieve ideal drug release rates and clearance rates
Variable physiological conditions of GIT
Clearance rate can be patient dependent, age, race ect
Disease status
Food/diet intake
116
How long is the transit time through the SI?
3 hours
117
How long does solution and pellets (<2mm) stay in the stomach?
They don't, they leave rapidly
118
How long do single dose units (>7mm) stay in the stomach for?
Up to 10 hours if taken with a heavy meal
119
Give examples of single- unit dosage forms
Tablets, coated tablets, matrix tablets, capsules
120
Give examples of multiple unit dosage forms?
Granules, beads, capsules and microcapsules
121
Give examples of MR dosage forms
Inert, insoluble matrices, hydrophilic matrices, ion-exchange resins, osmotically controlled formulations and reservoir systems
122
For convenience, what are the MR oral delivery system headings?
Monolithic or matrix systems
Reservoir or membrane controlled systems
Osmotic pump systems
123
What are the four processes operating within the MR mechanisms?
Hydration of the system
Diffusion of water INTO the system
Dissolution of the drug
Diffusion of the dissolved drug OUT of the system
124
Which formulation techniques are used to build the barrier into the peroral dosage form?
```
Coatings
Embedding of the drug in a wax or plastic matrix
Microencapsulation
Chemical binding to ion-exchange resin
Incorporation in an osmotic pump
```
125
What are the components of an oral modified release system?
```
Active drug
Release controlling agents
(Filler)
Matrix or membrane modifier
Solubilizer, pH modifier
Lubricant and flow aid
Supplementary coatings
```
126
How does a wax matrix work?
Drug in hydrophobic matrix which remains intact during release of the drug
In contact with the aqueous media, the channeling agent dissolves out of the compact leaving a porous matrix of tortuous capillaries
The drug dissolves and diffuses out of the system via the capillaries
127
Examples of wax matrix forming agents
```
Any hydrophobic material that is solid at room temp and does not melt at body temp
Hydrogenated vegetable oil type 1
Hydrogenated cottonseed oil
Hydrogenated caster oil
Hydrogenated soya oil
Microcrystalline waxes
Carnauba wax
Stearic acid
Combination of these and other waxes (Beeswax)
```
128
What are channeling agents for wax matrix delivery systems?
Almost any water soluble pharmaceutically acceptable solid material could be used as a channeling agent - the drug may act as its own channeling agent
May comprise 20-30% of the formulation
Leaches out of the matrix to leave tortous capillaries through which the drug must diffuse to be released for absorption
E.g. salts, sugars, plyols ect
129
How do hydrophilic matrix delivery systems function?
Hydrophilic colloids swell in contact with water to form a hydrated matrix
This matrix controls further diffusion of the drug through the hydrated matrix layer controls the rate of release through the drug
Outer hydrated matrix layer erodes as it becomes more dilute - rate of erosion depends of nature of the colloid
(System is a mixture of drug, hydrophilic colloid, any release modifiers and lubricant/glidant)
130
What is in the core and coating of a reservoir system?
Core - active drug, filler or substrate, (solubilizer), lubricant/glidant
Coating - Membrane polymer, plasticizer, (membrane polymer),(colour/opacifier)
131
What is the requirement for release controlling membrane polymers? Give examples
```
Polymer must remain intact for the period of release
Ethyl cellulose
Acrylic copolymers
Shellac
Zein
```
132
What is the structure of an elementary osmotic pump?
Tablet dosage form
Consists of a core of drug usually combined with osmotically active agent, coated with a rigid, non-swelling semi-permeable membrane such as cellulose acetate. (permits passage of GI fluid but not drug or electrolyte
133
How does the osmotic pump delivery system work?
Drug in soluble tablet core which will solubilize the drug in the presence of water
Core is coated with a semi-permeable membrane which allows water to pass through into the core which dissolves
As the core dissolves, a hydrostatic pressure builds up which forces drug solution through a hole in the coating
Rate of release controlled by rate water is able to pass through the membrane and how fast drug solution can pass out.
134
Advantages of an osmotic pump system
Well characterized and understood
Modification of the rate of water diffusion is more straightforward than for many drugs
Release mechanism not dependent on drug
Coating technology is straight forward
Suitable for range of drugs
Typically gives a zero order release profile after an initial lag
135
What are the 2 types of monolithic MR systems
Drug dispersed in wax matrix or hydrophilic matrix
136
What are the 2 types of reservoir MR systems
Drug core surrounded by an insoluble polymeric membrane
| Osmotic pump
137
What is microencapsulation?
Simply coating the surface of drug particles with polymer to slow down water penetration and hence dissolution
138
What are common materials for MR oral delivery and how do they release?
Waxes - coatings that are slow to break down
Shellac and zein - remain intact until pH in the gut is less acidic
Ethylcellulose - to provide membrane, stable in GIT and lets water permeate
Cellulose acetate - forms semi permeable membrane
139
What is the release mechanism of an ion exchange resin? What is the advantage?
Simple ion exchange in the GIT where electrolyte conc being high can exchange the drug for another counter ion
Reduces risk of dose dumping
140
What is the mechanism of release of Continus tablets?
Dissolution of the higher aliphatic alcohol and dissolution of the drug through the hydrate hydroxyalkyl cellulose
141
What is the mechanism of release of MST Continus suspension granules?
Morphine displaced by sodium and potassium ions present throughout the GI tract. Plasma profile is comparable to that of the MST CONTINUS tablet
Morphine free resin is excreted
142
What is the mechanism of Zomorph?
Diffusion of the active material across the ethylcellulose coat - thickness of the coat decides release characteristics
143
What is the mechanism of release of MXL capsules?
Capsules disintegration, water enters the multiparticles and morphine diffuses out of each particle
144
What is the biggest barrier to TD drug delivery?
The Stratum corneum
145
What does the dermis comprise of?
```
Collagen
Elastin
polysaccharides
Water rich
Blood supply
Maintain temp
Can remove permeating solutes
Has nerve supply
SINK CONDITIONS FOR DRUG ABSORPTION
```
146
What properties does a substance that has good permeation of the Stratum Corneum have? Give examples
```
Moderately polar, amphiphilic (logP 1-5)
Unionized
Tend to form hydrogen bonds
Low Mr (<500)
Estradiol, Fentanyl, Nicotine
```
147
What factors can increase permeation of TD drug into the skin?
Hydration of the skin
Higher temp
Broken or peeled skin
How thick the skin is
148
What are the basic components of a TD patch?
```
Drugs in a polymer matrix or reservoir
Penetration enhancers
Adhesive
Protective release linear
Outer backing layer
```
149
What is the TDS design criteria?
Constant delivery rate
Adhesive and vehicle non irritating
Vehicle has necessary physiochemical properties permitting prompt release of drug (doesn't hold onto too much)
System should occlude the skin to ensure one way flux of drug
150
What can you do to maximise TD drug delivery?
Drug at its saturation solubility in the vehicle
Use a vehicle which modifies the skin barrier
Use a vehicle having a low affinity for the drug
Choose a skin site with low thickness
151
What characteristics should the adhesive have?
Allow migration of the active drug
Enable the device to adhere to contours and flexible points of the skin
Contains active drug to act as quick priming dose
Enable device to remain on the skin for a specified period of time
152
Why are lipid formulations less toxic?
They spontaneously self assemble into bilayer structures when hydrated forming liposomes.
Drug encapsulated in liposome via lipophilic part
Liposomes are too big for glomerular/renal elimination
153
What does particle size of API and other excipients influence?
```
Physical performances
Pharmacological effects of the drug
Accumulation of micro particulates after parenteral admin
Manufacturing steps
QC of intermediate and final products
```
154
Why is an equivalent sphere used to measure particle dimensions?
It reduces the three dimensionality to a single number which simplifies the QC
155
When using the equivalent sphere to measure diameter, what can more than one sphere represent?
An irregular particle
156
When might a single equivalent diameter be inappropriate to measure a particle?
Some particles deviate markedly from circularity and sphericity
157
```
What are the particle sizes for:
Course powder
Medium/fine powder
Fine powder
Very fine powder
Micronised powder
```
```
>350 um
100-350 um
50-100 um
10-50 um
<10 um
```
158
Which methods can be used to analyse particle size?
Sieve method
Microscope method
Sedimentation method
Laser diffraction
159
What is the ideal particle size distribution?
Monodispersed particle population consisting of spheres of the same diameter
160
What happens if you mill for too long?
Rather than a finer bimodal population you get a finer unimodal distribution that is unfit for purpose
161
What size particles does each method obtain?
```
Cutting - 100um-100mm
Compression - 10um-100mm
Impact methods: 1um – 10 mm (grinding)
Attrition methods: 1um – 100um
Combination of impact and attrition: 1 um – 10mm
(more on slides)
```
162
What must you consider if reducing particle size to 1-5um?
Particle to particle forces predominates commutation stresses
Particle agglomeration might happen - increases particle size
163
Explain the cutting method of comminution
Series of knives/blades on a rotor - Particles fracture during milling between
Screen retains materials larger than a specified size
Coarse degree of size reduction in dried granules due to high shear rates
164
Explain the compression method of communition
Material is compressed by frictional forces as it passes between rollers
One roller is mechanically driven and the other is by force transmission
Can use a series of rollers
165
Explain the impact method of communition
Fill with stainless steel balls:
Conventional ball mill - 80%
Vibrational ball mill - 50-70%
Size reduction occurs by repeated impact and attrition
A screen at the base of the mill allows particles to exit
Efficacy of vibratory>conventional
166
Which methods are used to separate particles?
Sieving
Sedimentation
Elutriation
Cyclone
167
What are the methods of sieving?
Agitation
Brushing
Centrifugal
168
Which methods are used for particle size analysis?
Sieve
Microscope
Laser diffraction
169
Which material properties influence the final size?
Crack propagation
Surface hardness
Energy requirements
170
Which two methods are used to measure hardness of materials?
Mohs' Scale (qualitative)
| Brinell or Vickers (quantitative)
171
How much energy is involved in the size reduction process?
2% of the total energy
172
How is energy lost during the size reduction process?
```
Elastic deformation
Plastic deformation (without fracture)
Deformations initiating cracks (with fracture)
Interactions with mechanical parts
Heat
Vibration
```
173
What is a disperse system made up of?
A disperse/internal phase (particles or droplets) dispersed in another component (continuous phase)
174
What types of disperse systems are there and what is the formulation of these?
Colloidal dispersion 1nm-1um
Coarse dispersion >1um
Sol - solid particles in a liquid
Emulsions - mixture of two immiscible liquids
Foam - gas particles trapped in a liquid or a solid
Aerosol - solid or liquid dispersed in a gas
175
What is the difference between lyophilic and lyophobic?
Lyophilic - solvent loving
| Lyophobic - solvent hating
176
Are lyophobic sol's sensitive to electrolytes?
Very sensitive
Causes irreversible aggregation
Depends on type and valency of counter ion and conc of electrolyte
177
Are lyophilic sol's sensitive to electrolytes?
No, generally stable except in high concentrations (desolvation occurs-all water been attrcated to electrolytes so none to dissolve in)
Proteins more sensitive at the pI
178
What controls stability in lyophobic and lyophilic sol's?
Lyophobic - charge or particles
| Lyophilic - charge and solvation of particles
179
Describe the formation of lyophobic sol's
Metals, inorganic crystals
Never formed spontaneously
Particles remain dispersed due to electric repulsion
Need methods to get them dispersed
180
Describe the formation of lyophilic sol's
Proteins, macromolecules
Disperse spontaneously
Free energy from formation is negative - thermodynamically stable
181
Describe the formation of lyophobic sol's
Low viscosity
Particles unsolvated
Usually asymmetric
Viscosity doesnt change
182
Describe the formation of lyophilic sol's
Usually high
Gel can form if high enough conc of dispersed phase
Particles solvated and usually asymmetric
183
Give examples of lyophilic colloids?
Polymers
Gums (tragacanth, methylcellulose)
Proteins
184
Give examples of lyophobic colloids?
Aggregate particles e.g. protein aggregates or breakdown of larger particles into colloidal dispersions
185
How do you prepare a lyophobic colloidal system?
By dispersion or condensation
Dispersion - breakdown of course material using colloidal mill or ultrasonic treatment
Condenstaion - rapid production of supersaturated solutions under conditions that could formation of colloidal particles and not a precipitate
Change of solvent can be used
186
What are the three ways of purifying colloidal systems?
Dialysis
Ultrafiltration
Electrodialysis
All involve colloids not being able to cross the membrane
187
How do we determine the size of colloidal particles? What information does this give?
Light scattering
>0.5 um - will sedimesnt under gravity
<0.5um - require centrugation
188
What may the brownian movement in colloidal dispersions lead to?
Permanent contact (coagulation)
Temporary contact (flocculation)
Aggregation
remain freely Dispersed.
189
What happens to hydrophilic colloids in the prescence of high concentrations of electrolytes?
They loose their solvation water to these ions and salt out
190
What happens to surfactants above the cmc?
All interface has been covered and they start to form micelles
191
What are the 4 types of surfactant and give and example of each
Anionic - SLS
Cationic - benzalkonium chloride
Non-ionic - polysorbates
Zwiterionic - CHAPS, phosphatidylcholine
192
What is the usual size of micelles?
50-100 surfactant molecules and about 3nm diameter
193
What are some of the roles of surfactants?
Improve wetting
Stabilise emulsions
Reduce adsorption of mAbs at interfaces
194
Which phenolic compounds are frequently solubilised with surfactant and why?
Cresol and Thymol
| To form a clear solution for disinfection
195
What does a low solubility of steroids in water cause?
Problems for optical use
196
Are oil based solutions and suspensions optically clear?
No
197
What are non-ionic surfactants such as polysorbates used for?
Used to produce clear solution stable to sterilisation
| Preparation of aqueous injection of the water soluble vitamins A, D, E and K (non-ionic so less toxic)
198
Are micellar solutions of penicillin G more stable than monomeric ones?
Yes, 2,5x more stable
199
What is an emulsion?
2 Immiscible liquids, one dispersed in the other
200
What is required for an emulsion, give examples?
Emulsifiers - surfactants, polymers
Solid particles - graphite w/o, aluminium sulphate o/w
Phospholipids - woolfat, beeswax
201
What size are the droplets in emulsions and are they stable?
0.1 to 100um
| Inherently unstable
202
What is a stable emulsion?
Globules retain initial character and remain uniformly distributed throughout the continuous phase
203
What do emulsifiers do and what happens if this is destroyed?
Form an interfacial film around the droplets
| If agents destroy, the emulsion will be cracked
204
What agents can crack an emulsion
Chemicals incompatible with emulsifier
Bacterial growth
Temperature change
205
How can you increase the stability of an emulsion?
Reducing the droplet size
Decreasing the density differences
Increasing the viscosity of the continuous phase
206
How can you assess the stability of an emulsion?
Visualisation
| Monitor particle size over time
207
What is coalescence of an emulsion?
small droplets combine to form larger ones – any electric charge on the particles will repulse this
208
What is flocculation of an emulsion?
droplets form clusters - the combined result of attractive and repulsive forces
209
What is creaming of an emulsion?
the disperse phase rises to the top (or sinks to the bottom) – the result of density differences between phases. It can be redistributed, but may result in inappropriate dosage
210
What is phase inversion of an emulsion?
Emulsions stabilised with non-ionic emulsifying agents may undergo phase inversion on heating
211
What does choice of oil, emulsifier and emulsion type depend on?
Route of administration, clinical use and toxicity.
212
What components are used for emulsions for external application?
liquid paraffin with soft or hard paraffin used for dermatological conditions.
Turpentine oil
Silicone oils
213
What components are used for oral emulsions?
Castor oil or liquid paraffin (non biodegraedable and laxative effect)
PS80 non ionic, Pluronic 68 polymeric surfactant
214
What components are used for parental emulsions?
Purified mineral oil used in some depot for i.m. injections
| Vegetable oils containing long chain triglycerides have been used.
215
Give examples of emulsifiers and what does a mixture of these depend on?
```
PS8
Sorbitans
Pluronic 68
Lecithins for parental,
Cetrimide or SLS for topical
Methylcellulose, aluminium hydroxide for oral
HLB of oil phase influences mixtures
```
216
Are creams usually o/w or w/o emulsions?
o/w
217
What might be used to structure the aqueous continuous phase of a cream?
Clays or polymers
By direct interactions between various emulsifier agents.
Sparingly soluble fatty amphiphiles combined with more water-soluble ionic surfactants
218
Why do cream emulsions have a long term stability?
There is formation of a viscoelastic gel network phase, trapping oil droplets and preventing their movement/interaction.
219
What is the gel network theory of emulsion stability?
Coherent explanation how fatty amphiphiles and surfactants combined as emulsifiers not only stabilize these creams but also control their consistencies
Structure and stability of o/w creams are dominated by swelling properties of an a-crystalline gel network phase
220
Is a gas continuous phase or liquid continuous phase in colloids more stable?
Liquid - gas does not keep them separated very easily
221
How big are particles in aerosols and what happens to the prduct if they are bigger than this?
within colloidal range
| If bigger than 1um, life of product is short
222
How might a aerosol preparation be achiever to expel?
Pressurised containers containing liquefied gases as propellant. When opened the vapour pressure forces out droplets of liquid solution .
223
Are foams stable?
Tend to be unstable
224
Pure liquids do not foam, how are unstable and persistent foams obtained?
Unstable - use with short chains acids and alcohols which are mildly surface active
Persistent - use surfactants
225
Why are foams thermodynamically unstable?
Due to their vast interfacial area
226
What does the stability of a foam depend on?
Ability to drain and become thinner
| Tendency to rupture in the presence of stress (shaking, heat)
227
How are foams destabilized?
Gas diffuses from small bubbles to large ones, reducing the surface area
228
How are most gels formed?
Aggregation of sol particles forming a network
| The solid or semi-solid is interpenetrated by a liquid (only a small amount of dispersed phase is needed)
229
If the liquid of a gel is removed, what remains?
Xerogel
230
Give examples of gels that are flocculated lyophobic sols (regarded as a continuous floccule)
aluminium hydroxide and magnesium hydroxide gels (they are hydrated aluminium/magnesium silicates)
231
Give examples of clays that form gels by flocculation and how do they do this?
Bentonite
Aluminium magnesium silicate (veegum) and
Kaolin
Flat planes that contain O- atoms and the edge contains Al3+/Mg2+
Al3+/Mg2+ create linkages forming a card house floc
232
What does thixotrophy mean?
doesn’t flow initially then suddenly flows faster and faster
233
Which forces hold particles in gels?
Weak VdW and secondary minimum, electrostatic interactions
234
What happens if a thrixotropic gel is sheared and then left standing?
if thixotropic gel is sheared , weak bonds are broken and lyophobic particles are formed
On standing particles collide and flocculation: gel is re-formed
235
Describe a Type I lyophilic gel and give examples. What are they used for?
Gels are held together by covalent bonds between macromolecules - swell in water
e.g. Poly(HEMA) crosslinked with EGDMA
Used for expandable implants to imbibe body fluids and controlled release, especially antibiotics
236
Describe a Type II lyophilic gel and give examples. What are they used for?
Held together by weaker interaction bonds such a H bonds
Reversible
Pluronic surfactants form micelles but water becomes a poorer solvent at higher temperature.
Warming solution results in more micelles and if the concentration is high enough they form a gel
237
What has Smart Hydrogel development been based on?
Graft copolymer of poly(acrylic) acid and a poloxamer
At concentration of 1%:3% they undergo gelation at body temperature.
They also have bioadhesive properties
238
What has Timolol maleate been developed for and what is the release controlling agent?
Beta blocker for treatment of glaucoma
| Gellan gum
239
What has Loteprednol etabonate been developed for and what is the release controlling agent?
Corticosteroids for treatment of post operative pain and inflammation
Polycarbophil
240
What has Fusidic acid been developed for and what is the release controlling agent?
Antibacterial use
| Carbomer
241
How big are particles in a colloidal dispersion vs a course dispersion?
```
Colloidal = 1nm-1um diameter
Course = >1um
```
242
What is the tablet tensile strength target?
>2 MPa
243
What is the tablet friability target?
<1% (Pharmacopoeia criteria)
244
What is the tablet porosity target?
Product specific
245
What is the tablet content uniformity target?
Pharmacopeial criteria (Acceptance values < 15)
246
What is the tablet product performance target?
Pharmacopeial dissolution and disintegration criteria (product specific)
247
What is the tablet appearance target?
No visual defects e.g. edge damage, pitting or mottling
248
Why do we do tests?
```
Quality Control
Quality Assurance
Patient Safety
Compliance
100% visual inspection
Reputation
```
249
What must a tablet be strong enough to withstand?
Mechanical stresses
Manufacturing
Shipping
Handling by patients
250
What might happen if a tablet is too strong?
May not disintegrate in the required period of time to meet the dissolution specification
251
How do we quantify mechanical properties of pharmaceutical tablets?
Friability
Crushing Force
Hardness
Tensile strength
252
What is friability? How do you measure it?
Tendency for a tablet to chip, crumble or break following compression
Weighed before and after testing and friability is expressed as a % of weight loss and calculate maximum mean weight loss
Equipment specified in pharmacopoeia
If unit weight equal to or <650 mg, use sample with weight near as possible to 6.5 g
If unit weight >650mg, use 10 whole tablets
Rotate the drum 100 times (4 minutes at 25 RPM).
253
What is the crushing force? What are the units? Why can you not compare across different tablet sizes and shapes?
force required to break the tablet along a given axis.
Newtons or kiloponds (1 kP = 9.81 N).
Can't compare as it is an extensive property so depends on sample size
254
What is the tensile strength? Can it be used to compare? What can you use to work it out?
The stress required to induce flow in the material
Yes as its normalised for tablets - not specific to size
Can work out from crushing force
255
What is the hardness of a tablet?
Resistance of a material to a permanent shape change such as resistance to scratching or indentation.
256
Which theory links the crushing force of flat faced tablets to the tensile strength? What are the parameters?
Hertz Contact Theory
F=Crushing force (Newtons)
D=tablet diameter(mm)
t=Tablet thickness(mm)
257
What is used to estimate the tensile strength form the crushing force of curved tablets? How much error is reported? What should be done for complex tablet shapes?
Pitt’s equation and Shang model
20% error
Multiply Pitt's equation by 2/3
258
What is tensile strength dependent on?
Porosity of the tablet core - a more porous tablet gives a lower crushing force
259
What is the porosity of a tablet and how is it calculated?
total volume of void inside the tablet relative to the total volume of the tablet expressed as a percentage
Porosity = 100 x 1 – (apparent density ÷ true density)
260
How do you work out true density and how do you measure?
True density = mass ÷ volume of solids
Measured by Helium Pycnometry (apply helium as it penetrates anything and meausre before and after) or calculated using the true density calculator
261
How do you calculate apparent density?
Apparent density = mass of tablets ÷ envelop volume of tablets (total)
262
How do you measure envelop volume?
by Envelope Density Analyser or calculated using basic volume equations:
Flat and oval tablets - Tablet volume: Cross Section Area x Thickness
Curved round or oval tablets - Tablet volume: (2 x cap volume)+(Cross Section Area x (Thickness-Height of cap)
263
What is porosity dependent on and what is the correlation?
Punch pressure
A higher punch pressure gives a less porous tablet
Porosity of the granules
More porous granules produce more porous tablets at a given TS
264
What can porosity correlation be used to detect?
Over compression or elastic recovery
265
What may the porosity of a tablet influence?
Disintegration rate
| Less porous will have a slower disintegration rate
266
What is used to measure disintegration time? What is the mesh size?
USP disintegration tester
| Mesh: 1.8-2.2mm
267
What is the disintegration target for IR tablets?
<15 minutes
268
Why is uniformity of dosage units tested? What are the methods?
```
To ensure the consistency of dosage units, each unit in batch should have a drug substance content within a narrow range around the label claim.
Content Uniformity (dissolve and how much recovery from solution)
Weight Variation (weight of the individual tablets to calculate the acceptance value)
```
269
What appearance factors should tablets be examined for?
```
Picking and sticking
Orange peel
Roughness
Capping and lamination
Twinning
Erosion
Bridging
```
270
What are some IR tests that are less common, but used if there is an issue?
Pore size distribution (Mercury Porosometry)
Wettability (Inverse Gas Chromatography, contact Angel)
Water uptake
Dissolution using Magnetic Resonance Imaging (MRI)
Imaging to see rate of dissolution (usually HPLC)
The hybrid QicPic-dissolution system
Micro X Ray Computed Tomography (micro-CT)
271
During formulation design for children, why and when can adult clinical trial data be used?
If pediatric product is intended for a different indication than the adult product, using the same molecular mechanism of action but targeted at a different disease.
272
How old is a neonate?
0-27 days
273
How old is an infant?
1-23 months
274
How old is a child?
2-11 years
275
How old is an adolescent?
12-18 years
276
How old is an adult?
>18
277
What does the formulation type you select for an age group depend on?
Desired PK profile (rate and extent of exposure)
Acceptability for the intended age group - swallowability, taste, texture, ease of admin
Pharmaceutical factors - API properties, dose range, excipients such as ethanol
278
What is biopharmaceutics?
The study of the factors influencing the bioavailability of drug in man and the use of this information to optimise pharmacologic or therapeutic activity of drug products in clinical applications.
279
Which factors influence biopharmaceutics?
Solubility
Dissolution
Permeability
First pass metabolism
280
What physiological changes occur in children as they grow which alter absorption and PK?
```
Saliva production
Gastric pH and emptying rate
Intestinal transit, surface area and motility
Drug metabolising enzymes
Drug efflux transporters
```
281
What happens to the stomach pH from neonatal to adult?
Neonate has a higher pH (6-8) then this drops in line with adults as they become a child ect
282
What does reduced acid secretion in neonates cause? Which formulations does this affect?
Increased bioavailability of acid labile drugs
Increased gastric solublity of acidic drugs
Decreased solubility of basic drugs in neonates.
Affects pH sensitive coatings
283
Which types of formulations does saliva flow rate affect?
Orally retained dosage forms e.g. orally disintegrating tablets, chewable tablets and thin films
284
What impact does the stomach capacity have on formulation choice?
Impacts the volumes you can dose, which then affects available dissolution volumes and gastric concentrations.
285
Why doe pediatric patients have variable transit times and what does this effect?
They have irregular intestinal motility - causes a source of variability in product performance, especially in CR drugs
286
What happens to the length and diameter of the GIT as you age?
The length and diameter increase
287
What happens to the permeability of the gut wall with age?
Generally permeability appears to decrease with age, but unclear when adult values are reached
Conflicting P-Gp efflux number trends in mice and humans so proceed with caution
288
What is the difference in liver size and hepatic blood flow in children compared to adults and what is the impact of this?
Children have a larger liver size and hepatic blood flow per body weight, increases clearance and 1st pass metabolism
289
What is formulation bridging?
Assessing the rate and extent of absorption from one formulation vs another - will switching between formulation give the same Cmax and AUC.
290
Formulation bridging - how do you work out Relative Bioavailability?
Compare Cmax and AUC between two products
291
Formulation bridging - how do you work out Bioequivalence?
assessing statistical equivalence of Cmax and AUC from two different products using a confidence intervals approach
292
What is Cmax?
The maximum concentration
293
What is AUC?
Total exposure
294
Why do we need formulation bridging for paediatrics?
To select an appropriate dose (avoid unanticipated side effects)
For chronic illnesses, the patient may be receiving treatment from a young age into adulthood – need to know whether any dose adjustment is required when switching between the different formulation types
295
Which tests/studies are dose during formulation bridging? Explain
Relative bioavailability study - healthy adults, compare formulation to support doing in paediatric clinical trials, Comparing the final pediatric formulation to be used in pivotal studies to earlier formulations.
In vitro testing
Dissolution studies
Consider biorelevant media, volumes, agitation
In silico
PBPK modelling
So market adult dose then come back and develop childrens product
296
Why may PK data in adults not always sufficient to ensure formulations will perform as expected in children?
Smaller volumes for dissolution
Different gastric pH
Age-related changes in first pass metabolism
Lower colonic pH in children - MR
297
What does In silico PBPK modelling help to do?
Put all the pieces together and work out the OVERALL impact on formulation performance
298
How does PBPK modelling work?
Mechanistically simulates the processes involved in absorption and PK performance - develop model based on adult data, then alter parameters for children
Can use biorelevant in vitro dissolution as an input for formulation release rate
Can simulate ‘virtual populations’ to look at potential variability
299
Why might PBPK modelling be limited?
Gaps in measured parameters
| Sparse paediatric PK when clinical studies begin
300
In what ways can food affect formulation performance and drug absorption?
altered composition of GI fluid
different gastric emptying rates
altered blood flow
drug binding to food components
301
Why does food have a different effect on formulation performance and drug absorption in children and adults?
They eat differently - meal types, compositions, volumes
302
What are the 3 main modes of mixing and what are the differences?
Convection - macroscopic transport of parts of the mixture reducing segregation
Diffusive - random motion of individual powder particles reducing intensity of segregation
Shear - mixing cohesive particles at the microscopic level
303
What are the types of diffusion blenders?
```
V-blenders
Double Cone Blenders
Bin Blenders
Static Continuous Blenders
Dynamic Continuous Blenders
```
304
What are the key parameters of bin blenders?
```
Fill volume: 40-60%
Rotation speed (rpm)
Blending time (min)
```
Number of revolutions = speed x time
305
What are the two types of Dynamic continuous mixing?
Incline
| Weir
306
Why do we granulate?
```
Wall adhesion
Segregation
Ratholing
Bridging
Flowability
Improve homogeneity
Improve bulk density
Deliver dissolution profile by manipulating structure
```
307
Give three segregation mechanisms
Elutriation/Fluidastion
Sifting/Percolation
Trajectory
308
What are the 9 types of granulation?
```
Dry
Wet High-shear
Wet Low-shear
Low-shear tumble
Extrusion
Rotary
Fluid bed
Spray dry
Hot melt
```
309
What are the solid fractions of a powder, ribbon and tablet?
```
Powder = 0.2-0.5
Ribbon = 0.65-0.8
Tablet = 0.8-0.95
```
310
Which mechanical properties of powders need to be considered when developing a roller compaction process?
Compressibility
Tabletability
Compactability
311
What is the optimum result from roller compaction?
Not too dense and not too porous
| Good strength and good granule flow
312
What happens in a high shear granulator?
Liquid hits powder – start to create granules
Stick to other granules
Depends on process parameters and material properties
313
What are the two powder flow regimes and which is better?
Bumping flow and Roping flow
Roping flow gives a better distribution
314
Explain Hot Melt Extrusion
API dissolved in a polymer (aim to improve solubility of poorly soluble drug)
Barrel heated and polymer melts (continuous)
Extrudate cut into small particles/pellets for processing
315
What are the stages of powder compaction?
Particle rearrangement
Deformation and bonding (breaking bonds)
Over-compression
316
What are the 5 stages of powder compression?
```
Filling
Metering
Precompression
Compression
Ejection
```
317
How does compaction pressure affect tablets?
Increased compaction pressure=more compression
Tablets with lower porosity so increased disintegration time and lower dissolution performance but increased tensile strength and toughness
318
How does linear velocity affect tablets?
Speed of compaction increase=speed which the tablet punch enters the die is increased = drop in tensile strength
319
How does dwell time affect tablets?
Speed of compaction increased= time of max exertion of tablet punch pressure decreased = drop in tensile strength
320
What are the three types of typical tablet compressors?
Single stroke/single punch press
Slow-speed single sided rotary
High-speed single sided rotary
321
What are the three non-standard types of tablet compressors?
Double sided rotary
Special machines
Slugging machines
322
What are the advantages of hard capsules compared to tablets?
Fewer excipients and formulation problems
Reproducible disintegration
Fewer manufacturing stages
323
What are the disadvantages of hard capsules compared to tablets?
```
Lower production rate
Higher pack volume
Greater weight variation
Less protection to hydroscopic materials
Limited in size and shape
Capsule shell supplier dependent
Sensitive to extremes of temp and humidity (brittle/soften)
```
324
What are the stages of the capsule filling cycle?
```
Empty capsules
Aligning and rectification
opening and separation
Filling
Joining and closing
Discharge
```
325
What does a fluidised bed coater do?
Pellet coating
Pellets in Wurster tube
Spray concurrent to pellet flow in Wurster tube
Coated pellets fall back down for re-entertainment into Wurster tube
Chance to dry before next coat - multiple layers onto inert pellets
326
Why do we wet granulate?
```
Enhance flow, reduce dustiness
Product appearance
Control solubility and porosity
Bulk density
Prevent drug segregation
Improve compressibility/tablettability
```
327
Which API's can you not use wet granulation for?
Those sensitive to moisture and temperature
328
What can the granulating liquid in a wet granulator be?
Plain (purified) water
An aqueous solution containing a polymer such as hydroxypropyl cellulose (HPC) or polyvinylpyrrolidone (PVP).
An organic solvent (ethanol)
329
How does water affect the size of granules?
Liquid quantity controls the maximum number of liquid bridges and affects the stickiness
The more liquid, the more the granules consolidate and grow
330
Which granule properties are important to measure and why?
Density/porosity - affects hardness and dissolution
Moisture content - affects tabletting and hardness
Size and size distribution - affects flow, hardness and dissolution of dense granules
Drug content uniformity - desirable to have even distribution
331
What are the two types of flow regimes and which is better?
Bumping flow
| Roping flow - better mixing
332
What is the optimum bowl fill range for mixing?
>25% but <65%
333
What happens as we scale up the manufacturing process?
API consumption increase
Number of excipients decreases
Impeller RPM decreases
Batch homogenity decreases - flow transition changes
334
What is the operating window in drug development? How do you get it?
range of settings that have proven product will deliver
Mixed enough to get as homogenous as possible but not too much that you get too dense granules that you cant make into tablets
Change each parameter one by one and get optimum
335
If Solid>>liquid, which wetting mechanism is used?
Distribution mechanism
336
If Solid<
Immersion mechanism
337
What does granule consolidation rate depend on?
Liquid saturation level
Mixing time
Forces acting on the granule
338
What is attrition dominated granule homogenity?
Like bits being picked off the outside
Limited redistribution of granule components
Granule homogeneity depends on quality of pre-granulation mixing
339
What is fragmentation dominated granule homogenity?
Extensive redistribution of granule components
Granulation process contributes to granule homogeneity
More useful – helps distribute components- helps with mixing mechanism
Don’t get granules of just drug or just excipients
340
What is the twin screw filling optimum range?
>25% but <75%
341
What are the 5 stages of granulation?
C1 -nucleation to give large initial granules.
C2 – significant consolidation and breakage
C3 – moderate coalescence and breakage
C4 – coalescence and consolidation
C5 – mainly breakage
342
What happens to granule strength and shape along the barrel?
More spherical
| Strength increases
343
What effect do kneading elements have in breakage and coalescence?
Show simultaneous breakage and coalescence
344
What effect do conveying elements have in breakage and coalescence?
Cause some coalescence, generally by layering
345
What does increasing the viscosity of granulation liquid cause?
```
Increased residence time
Increased screw torque
More mono-modal size distribution
Increasing granule strength
Improved granule flow
```
346
What is de-lumping used for?
To ensure no excessively large granules remain that would be difficult to dry
347
What is moisture content defined as?
The amount of water contained in a material
%Moisture by volume (MV) = the molecules of water per unit volume by the total number of molecules per unit volume
In air - kg of contained water per kg of dry air
348
What is relative humidity defined as?
Amount of water vapour present in air as a percentage of max amount of moisture the air can hold AT A SPECIFIED TEMP
349
What happens to the relative humidity as temperature increases?
Increases
| higher the temperature, the higher is the amount of water vapor that can be held until saturation
350
During drying, moisture content and temp can vary due to...
Evaporation of water from the material to the drying air
| Cooling of drying air to reduce heat-exchange with the material
351
What is moisture content?
Quantity of water contained in a material
352
What are hygroscopic substances?
They attract and hold water molecules from the surrounding environment
353
What is TOTAL moisture?
The total amount of water associated with a solids
| so... FREE+EQUILLIBRIUM
354
What is FREE moisture content?
is the amount of water that can be easily removed e.g. evaporation
UNBOUND
355
What is EQUILIBRIUM moisture content?
The portion of water that is more difficult to be removed
| BOUND
356
What can influence the equilibrium moisture content?
Variation of the external condiqtions
357
What can be used to remove water from the conditioned air?
Silica gels or Phosphorous pentoxide
358
What is Inter-granular migration?
the solute moves between granules towards the surface
| Differences in solute composition between granules
359
What is Intra-granular migration?
granules are separated during the process so even distribution of solute within a granule
360
Inhomogenity between granules impacts on:
Manufacturing
Appearance
Dose
361
Which factors can be considered to reduce solute migration phenomena?
Initial Moisture Content
Slow convective drying
Drying with microwave radiation
Dynamic Drying Methods
362
What must be considered for the drying process?
Heat sensitivity of materials used
Materials physical characteristics
Solvent/liquid to be removed (boiling point)
Efficient vapour removal from drying air
Amount of material to be processed (scale up considerations)
Sterility
363
Which mechanisms are used to dry wet solids? Give an example of each
Convection - fluidized-bed dryer
Conduction - Vaccum dry oven
Radiation - microwave
364
What does a fluidized-bed dryer induce?
Particle mixing with good contact with air
Maximised surface area of the powder bed to guarantee good removal
Efficient heat and mass transfer
365
What is the capacity of a fluidized-bed dryer?
0.4-1.2kg
366
What is the drying time of a fluidized-bed dryer>
20-40 minutes
367
What are the advantages of a fluidized-bed dryer?
Efficient heat transfer
Homogeneous process
Free movement of particles reduces migration and separation/aggregation
368
What are the advantages of a fluidized-bed dryer?
Turbulence might damage granules
Small particles might need specific attention to be removed from the fluidizing air
Particle movement in turbulence and warm environment might cause charges of static electricity
369
What is the pressure in a vacuum oven and why?
0.03-0.06 bar - low air content minimises the risk of oxidation
370
Which temperatures are used in a vacuum oven and why?
25-35 degrees Celsius
| Reducing pressures so can reduce temp
371
Which types of molecules does microwave drying have better results for?
Small polar molecules
372
What is loss factor in microwave drying?
ratio of absorbed microwave energy to the provided energy
373
What are the advantages of microwave drying?
Rapid dry at controlled temperatures
Energy absorbed in the wet material, not in the air
Stationary conditions DECREASES small particles movement
Uniform heating reduces solute migration effect
374
What are the disadvantages of microwave drying?
Small batch size
| Shielding from radiation is essential
375
What do you want to optimise in a spray dryer?
Droplet size (1-500 μm),
Jet stream (uniformity),
Solution feed rate (up to 100 L/hour),
etc.
376
In a spray dryer, what happens to the droplet size as flow rate increases?
The higher the flow rate, the smaller the droplets.
377
Describe the obtained products from freeze drying
Porous with faster solubility due to larger surface area
378
What are the stages of freeze drying?
Freezing - well below water freezing point
Vacuum - pressure below triple point
Sublimation - ice transformed to vapour
Packaging
379
What is the dew point?
related to the quantity of moisture in the air
| the temperature to which moisture condense and evaporate at the same rate
380
What happens when the dew point is reached?
If temp in reduced, the water vapour will condense - %RH cannot exceed 100%
381
What is subjective quality?
Subjective - Attribute, characteristic, or property of a thing or phenomenon that can be observed and interpreted, and may be quantified but cannot be measured
382
What is objective quality?
Measurable and verifiable aspect of a thing or phenomenon, expressed in numbers or quantities, such as lightness or heaviness, thickness or thinness, softness or hardness.
383
What is manufacturing quality?
Strict and consistent adherence to measurable and verifiable standards to achieve uniformity of output that satisfies specific customer or user requirements.
384
What is ISO standard quality?
the totality of features and characteristics of a product or service that bears its ability to satisfy stated or implied needs.
'meet the requirements'
385
What is quality control ?
Process dedicated to sample, test and specify materials at each level of manufacturing
386
Pharmaceutical products must meet the following specifications:
```
Identity
Purity
Strength or potency
Uniformity
Bioavailability
Stability
```
387
Which analytical methods are used in quality control?
```
Accuracy
Precision- Repeatability: 1% relative standard deviation and intermediate Precision
Specificity
Detection Limit
Quantitation Limit
Linearity
Range
```
388
What is specificity in analytical testing?
the ability to register only the desired analyte, while all other components in the formulation do not influence the results.
389
What is sensitivity in analytical testing?
the smallest absolute amount of change in analyse that can be detected by a measurement.
390
What is accuracy in analytical testing?
the sense of trueness and precision
391
What is repeatability in analytical testing?
Minimum of 9 determinations e.g. 3 concentrations x 3 replicates each
Minimum of 6 determinations at 100% of the test concentration
392
What is intermediate precision in analytical testing?
Evaluate the effects of random events on the precision of the analytical method/procedure
393
What is reproducibility in analytical testing?
The same analytical method/procedure should be validated inter-laboratory
394
What is acceptance criteria in analytical testing?
Numerical limits, ranges or other criteria defined for each test/instrument.
395
What is the acceptance range for API content?
±10% of target value, with accepted 5% standard deviation
After stability tests 90-100% of target value
Acceptance range varies with method used - HPLC ± 2% of target value
396
What is the detection limit in analytical testing?
The lowest amount detected
397
What is the quantitation limit in analytical testing?
The lowest amount quantitated
398
What is quality assurance?
A wide range concept covering all matters that influence the quality of a pharmaceutical product
399
What is good manufacturing practice?
GMP ensures that pharmaceutical products are produced and controlled to meet appropriate quality standards
400
What is the quality management system?
a set of procedures, policies, guidelines and regulations that are designed to maintain products robustness and quality
401
Which document provides a single authoritative source of European and UK guidance, information and legislation relating to the manufacture and distribution of human medicines?
The Rules and Guidance for Pharmaceutical Manufacturers and Distributors 2017
402
What are the ten GMP principles?
```
Have the correct written instructions
Follow instructions precisely
Have the correct materials
Have the correct equipment - clean
Prevent contamination and mix up
Be on guard for labelling errors
Work accurately and precisely
Keep everything clean and tidy
Be on the look out for mistakes and defects
Make clear accurate records of what was done and the checks carried out
```
403
What is a clinical trial?
a systematic investigation in human subjects for evaluating the safety and efficacy of any new drug
404
What are the phases of clinical trials?
Phase 0: exploratory studies, micro dose administration
Phase I: safety, tolerability, pharmacokinetic/dynamics, dose/response
Phase II: dosing, efficacy
Phase III: efficacy compared to gold standard treatment
Phase IV: post-marketing surveillance, pharmacovigilance
405
Give examples of drugs which agglomerate and decrease dissolution
Aspirin
Phenobarbitone
Phenacetin
406
Give examples of drugs which have increase dissolution as particles get smaller
Griseofulyin (micronised)
Theophylline
Nitrofurantoin
Digoxin
407
How does granulation affect dissolution rate?
It makes the surface of hydrophobic drugs hydrvvophilic
| It may produce viscous layers around drug particles which reduces dissolution rate
408
What is the rotation and use of the basket apparatus?
50-120 rpm
| Conventional and chewable tabs
409
What is the rotation and use of the paddle apparatus?
25-50 rpm
| Orally disintegrating tabs, chewable tabs, suspensions
410
What is a flow through cell apparatus used for?
Poorly sol API's, powder, granules, microparticles, implants
411
What's the difference between intravascular and extravascular injection?
Intravascular - directly into the blood
| Extravascular - into other body tissues
