Stuff needed to memorise Flashcards
1
Q
drugs with decreased dissolution
A
aspirin, phenobarbitone, phenacetin
2
Q
drugs with increased dissolution
A
theophylline, nitrofurantoin
digoxin
grisefolvin (micropartilised)
3
Q
desired API characteristics when developing an oral solid dosage form
A
Melting point >90 (degrees Celsius)
contact angle with water <90 degrees
Particle size 50-500microns
bulk density >0.3mg/mL
4
Q
Describe the flow of blood through a glomerulus for USEFUL MATERIALS
A
Blood flows in via afferent arteriole→glomerulus which sits in the Bowman’s capsule (filtration occurs)→proximal convulted tubule→proximal straight tubule→useful materials reabsorbed via the vasa recta, also known as the peritubular capillary
5
Q
Describe the flow of blood through a glomerulus for WASTE materials
A
Blood flows in via afferent arteriole→glomerulus which sits in the Bowman’s capsule (filtration occurs)→proximal convulted tubule→proximal straight tubule→loop of Henle→cortical and medullary connecting ducts
6
Q
Where does glomerular filtration occur?
A
Bowman’s capsule only
7
Q
drugs lost by renal elimination
A
- Acyclovir
- Ampicillin
- Cimetidine
- Metformin
8
Q
Methotrexate in the kidney cells
1) Uptake transporter(s)
2) Efflux transporter(s)
A
1) OCT1 and OAT1
2) MRP4 and ABCB1 (P-gp)
9
Q
Pitvastatin in the kidney cells
1) Uptake transporter(s)
2) Efflux transporter(s)
A
1) OAT3
2) ABCG2 (BCRP)
10
Q
Rosuvastatin in the kidney cells
1) Uptake transporter(s)
2) Efflux transporter(s)
A
1) OAT3
2) ABCG2 (BCRP)
11
Q
Fexofenidine in the kidney cells
1) Uptake transporter(s)
2) Efflux transporter(s)
A
1) OAT3
2) ABCB1 (P-gp)
12
Q
Digoxin in the kidney cells
1) Uptake transporter(s)
2) Efflux transporter(s)
A
1) OATP1
2) ABCB1 (P-gp)
13
Q
3 big groups of blending and mixing equipment
A
- Diffusion blending
- Pneumatic mixers
- Convection mixers
14
Q
Examples of diffusion blending (tumble) equipment
A
- V blenders
- Double cone blenders
- Bin blenders
- Static continuous blenders
- Dynamic continuous blenders
15
Q
Examples of Convection mixers (equipment)
A
- Diffusion blenders with agitator
- Vertical high intensity mixers
- Ribbon blenders
- Orbiting screw blenders
- planetary blenders
16
Q
Diffusion bin blenders key parameters
A
- Fill volume 40-60%
- rotation speed (rpm)
- blending time (min)
- Number of revolutions=speedxtime
17
Q
Dynamic continuous mixer
A
-enables fully continuous processing
-reduces segregation risk
Types:
-Weir design
-inclined design
18
Q
why granulate?
A
- improve homogeneity
- improve bulk density (solids handling, packaging, transport)
- Deliver dissolution profile by manipulating structure
19
Q
How can segregation happen?
A
- Fluidisation/eludritation - higher drag:weight ratio
- sifting (big particles at top - brazil nut effect)
- Trajectory (big particles go further than small particles)
20
Q
Types of granulation (bigger topics)
A
- Dry granulation
- Wet high-shear granulator
- Wet low-shear granulator
- Low shear tumble granulator
- Extrusion granulation
- Rotary granulator
- Fluid bed granulator
- Spray dry granulator
- Hot-melt granulator
21
Q
Types of dry granulation machines
A
- slugging
- roller compaction
22
Q
types of wet high-shear granulators
A
vertical
horizontal
23
Q
Types of wet low-shear granulators
A
- planetary
- kneading
- screw
24
Q
Types of low-shear tumble granulators
A
- slant cone
- double cone
- v blender
25
types of extrusion granulators
- radial or basket
- axial
- Ram
- Roller, gear or pelletizer
26
Rotary granulator types
- open
| - closed
27
Aims of solid fraction (solid to air proportion)
Powders: 0.2-0.5
Ribbons: 0.6-0.8
Tablet: 0.8-0.95
28
Types of high shear wet granulators
- Twin screw
| - batch high shear
29
What happens in a high shear wet granulator?
- consolidation
- nucleation
- rate processes
- growth
- attrition
- breakage
30
Summarise rate processes
- wetting and nucleation
- consolidation and coalescence (agglomeration)
- attrition and breakage
31
Capsules vs tablets
| Name 3 hard capsule advantages
- fewer excipients and formulation problems
- reproducible disintegration
- fewer manufacturing stages
32
Capsules vs tablets
| Name 7 disadvantages capsules have compared to tablets
- lower production rate
- higher pack volume
- greater weight variation
- less protection to hygroscopic materials
- limited in size and shape
- capsule shell supplier dependent
- sensitive to extremes of temperature and humidity (brittle/soften)
33
Describe the capsule filling cycle
empty capsules→aligning and rectification→opening and separation→ filling→joining and closing→discharge
34
Describe a OSD coating mechanism
```
•Atomisation of coating solution
into a fine mist by the spray
guns
•Mass transfer of spray droplets
through the air, until they
contact
•Tablet surface
•Drum surface
•Baffles
or travel to exhaust
•Wetting of surface contacted
by droplets, spreading of
droplets
•Adhesion of droplets to
surface, cohesion of droplets to
each other
•Evaporation of water from the
coating solution, resulting in a
dry, coated surface
```
35
Describe how a fluidised bed coaster (Wurster)
Typically used for pellet coating
• Pellets entrained through Wurster tube
• Spray concurrent to pellet flow in Wurster tube
• Coated pellets fall back down to the bottom of the
fluidised bed for re-entrainent into the Wurster tube
36
Describe the case for Continuous Manufacture
Continuous manufacturing opportunities being raised in
response to changing Pharma models
– Greater flexibility of batch size allows a more agile response
to changing demand.
– Greater robustness, increased consistency of product
quality, reduced cycle time, stock holding and increased
margins.
– Minimal scale up, improved robustness and better control.
– The smaller footprint of continuous processes enables close
to market manufacture.
– Efficiency gains in development
37
Define anticoagulant
| Give examples
an agent that prevents the clotting of blood
| e.g. EDTA, Citrate, Heparin
38
Define capillary
Small blood vessel that connects arterioles and venules
39
Define haemoglobin
the oxygen-carrying molecule of red blood cells
40
Define haemolysis
The breakdown of red blood cells, with the release of haemoglobin into the plasma or serum
41
Define Lipemic
having an abnormally high level of fat, milky-looking samples
42
Define plasma
Pale yellow component of whole blood, contains all clotting factors
43
Define serum
the clear yellowish fluid that remains from blood plasma after clotting factors (such as fibrinogen and prothrombin) have been removed by clot formation.
44
Define serology
the study of antigen-antibody reactions using laboratory tests
45
Normal WBC blood level
4k-10k/mL
46
Normal haemoglobin blood levels
| Male and female
Male:13.5-17.5g/dL
Female: 12-16g/dL
47
Normal INR
0.8-1.2
48
RBC blood levels
| Male and female
Male: 4.5-5.9x 106cells/mL
Female: 4.0-5.2x106cells/mL
49
Why wet granulate?
- improve handling
- improve product appearance
- enhances flow and mixing properties
- control of solubility and porosity
- increase bulk density for storage
- creation of non-segregating beads
- improve compressability/tabletability whih is something dry granulation cannot do
50
Effect of low binder level
0-1% w/w
on process parameters
(High shear wet granulation)
- higher water quantity needed to produce a given level of agglomeration
- higher level of attrition during drying and adhesion of material to dryer walls, which could effect yields and ease of cleaning
51
effect of low binder level of 0-1%
on quality attributes
(High shear wet granulation)
- shorter disintegration time and faster dissolution rate
| - more granule attrition during drying, could impact flow and weight uniformity
52
Effect of high binder level of
4-6% w/w
on process parameters
(High shear wet granulation)
-Lower water quantity needed to produce a given level of agglomeration
53
Effect of high binder level of
4-6% w/w
on quality attributes
(High shear wet granulation)
- Improved granule flow due to lack of attrition of large granules
- Longer disintegration time and slower dissolution rate
54
Define attrition (pharmaceutical definition)
Wearing away by friction or rubbing
55
Effect of low disintegrant level
0-1% w/w
on process parameters
(High shear wet granulation)
- lower quantity required to give a given level of agglomeration
- shorter drying times
56
Effect of low disintegrant level
0-1% w/w
on quality attributes
(High shear wet granulation)
Longer disintegration time and slower dissolution rate
57
Effect of high disintegrant level
5-10% w/w on process parameters
(High shear wet granulation)
- Higher water quantity needed to achieve a given level of agglomeration
- longer drying times required
58
Effect of high disintegrant level
5-10% w/w on quality attributes
(High shear wet granulation)
- reduced disintegration time and increased dissolution rate
| - my cause dissolution drop on stability
59
Define agglomeration
Agglomeration, the sticking of particles to one another or to solid surfaces, is a natural phenomenon.
60
Name 2 diluents used in wet high shear granulation
- Mannitol
| - MCC
61
Effect of mannitol on process parameters
| High shear wet granulation
- Lower water quantity required (10-20% w/w)
| - shorter drying times
62
Effect of mannitol on quality attributes
| High shear wet granulation
- solubility may aid dissolution
| - needs to be well lubricated if appearance defects are to be avoided
63
Effect of MCC on process parameters
| High shear wet granulation
- Significant levels of water required (30-60% w/w)
- makes process less sensitive to small changes in water quantity
- long drying times
64
Effect of MCC on quality attributes
| High shear wet granulation
- Imparts high tensile strength to tablets
- Insoluble and so may be detrimental to dissolution of some components
- can absorb a larger amount of water on storage if allowed to do so
65
Name 2 macro scale flow regimes
| High shear wet granulation
- Bumping flow
- Roping flow (faster)
goes from bumping flow→roping flow
66
Describe bumping flow
| High shear wet granulation
- poor vertical mixing
- longer dry mix times may be necessary
- poor liquid distribution during granulation
- wide and multi-modal particle size distribution
67
Describe Roping flow
- Good mixing
- good mixing distribution, more unimodal granule size distribution
- higher consolidation rates may lead to dense granules
68
in high shear wet granulation, what conditions will risk uniformity of dosage units?
Low water quantity
Low impeller speed
Low mixing time
(content due to insufficient mixing and weight due to insufficient size enlargement)
69
In high shear wet granulation, what conditions will risk dissolution and manufacturability?
High water quantity
high impeller sped
high mixing time
(due to high degree of granule consolidation)
70
How does particle size in high shear wet granulation effect the granules?
- big granules have more liquid in than smaller granules as a bigger liquid to solid ratio BUT when dried, this liquid is removed, leaving a porous structure. This is beneficial for tablet compression
- small granules tend to be relatively dry
71
If high granule porosity in high shear wet granulation is desirable, how can you change processes to help this?
- granulate with smaller primary powder particles
- low impeller speeds
- short mixing times
- don't add too much liquid
72
With continuous (wet screw) granulation...
How easy is it to predict the process?
How is the mixing?
What is liquid distribution like?
- The process at macro scale is easier to predict – effect of each screw element can be characterised
- Mixing is more uniform (primarily due to smaller scale)
- Liquid distribution and particle size are more homogeneous and vary mostly with position along the barrel
73
What are the consequences of an under-filled barrel in continuous (wet screw) granulation?
i.e. <25% working volume
- Poor mixing and liquid distribution (limited granule-granule and granule-machine contact restricts amount of breakage that occurs)
- Wider granule size distribution – limited breakage to distribute granulation liquid
74
What are the consequences of an over-filled barrel in continuous (wet screw) granulation?
i.e. >75% working volume
- Increased granule breakage and consolidation – dense granules detrimental to tablet compression
- Granule size distribution gets narrower – increased breakage distributes liquid across all material
75
Describe how granulation occurs in continuous wet screw granulation
C1 - nucleation to give large initial granules.
C2 – significant consolidation and breakage – size decrease (significant). kneading section-flat discs
C3 – moderate coalescence and breakage – size increase or decrease (depending on materials and conditions).
C4 – coalescence and consolidation – size increase.
C5 – mainly breakage – size decrease
76
Along the length of the barrel of wet screw granulation... what pattern happens?
Granules become more spherical.
Granule strength increases. Become denser
Granule size decreases across the barrel
Granule size decreases along barrel and with decreasing L/S ratio
Granule strength increases along barrel and with increasing L/S ratio
77
what is the effect of element types in wet screw granulation?
Kneading elements show simultaneous breakage and coalescence.
Conveying elements caused some coalescence, generally by layering.
78
In wet screw granulation, what happens with the increase of viscosity of the granulation liquid?
```
Increased residence time
Increased screw torque
More mono-modal size distribution
Increasing granule strength
Improved granule flow (due to mean size increase and narrower size distribution)
```
Surface tension of granulation liquid has only minor influence on residence time, torque and granule properties
79
Why in granulation is an increase in density sometimes a bad thing?
Can cause problems when pressing tablets
80
With continuous (wet screw) granulation, what effects feeding rate?
Kneading blocks
Need a full feed channel
High feed rates have forces on the granules
produces denser granules
81
Describe what de-lumping is
De-lumping (milling of large, wet granules) is optional and is used to ensure that no excessively large granules remain that would be difficult to dry.
- wet granules fed through mill to make granules smaller
- drying process is key because moisture affects ability to form good tablets
82
De-lumping - breakup of lumps post drying, what does it do?
Breakup of lumps post drying can release trapped moisture into the dried granules, which may affect manufacturability (sticking), microbiological quality, assay or degrade the drug substance.
83
De-lumping
why do they require drying before further processing?
Effects of the quantity of water on granules?
Wet granules require drying before further processing. The quantity of water added during wet granulation will have the most significant impact on drying times. This may have subsequent effects on:
Extent of granule attrition
Thermal degradation of components
Compressibility of dried granules
