Stuff needed to memorise Flashcards
drugs with decreased dissolution
aspirin, phenobarbitone, phenacetin
drugs with increased dissolution
theophylline, nitrofurantoin
digoxin
grisefolvin (micropartilised)
desired API characteristics when developing an oral solid dosage form
Melting point >90 (degrees Celsius)
contact angle with water <90 degrees
Particle size 50-500microns
bulk density >0.3mg/mL
Describe the flow of blood through a glomerulus for USEFUL MATERIALS
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
Describe the flow of blood through a glomerulus for WASTE materials
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
Where does glomerular filtration occur?
Bowman’s capsule only
drugs lost by renal elimination
- Acyclovir
- Ampicillin
- Cimetidine
- Metformin
Methotrexate in the kidney cells
1) Uptake transporter(s)
2) Efflux transporter(s)
1) OCT1 and OAT1
2) MRP4 and ABCB1 (P-gp)
Pitvastatin in the kidney cells
1) Uptake transporter(s)
2) Efflux transporter(s)
1) OAT3
2) ABCG2 (BCRP)
Rosuvastatin in the kidney cells
1) Uptake transporter(s)
2) Efflux transporter(s)
1) OAT3
2) ABCG2 (BCRP)
Fexofenidine in the kidney cells
1) Uptake transporter(s)
2) Efflux transporter(s)
1) OAT3
2) ABCB1 (P-gp)
Digoxin in the kidney cells
1) Uptake transporter(s)
2) Efflux transporter(s)
1) OATP1
2) ABCB1 (P-gp)
3 big groups of blending and mixing equipment
- Diffusion blending
- Pneumatic mixers
- Convection mixers
Examples of diffusion blending (tumble) equipment
- V blenders
- Double cone blenders
- Bin blenders
- Static continuous blenders
- Dynamic continuous blenders
Examples of Convection mixers (equipment)
- Diffusion blenders with agitator
- Vertical high intensity mixers
- Ribbon blenders
- Orbiting screw blenders
- planetary blenders
Diffusion bin blenders key parameters
- Fill volume 40-60%
- rotation speed (rpm)
- blending time (min)
- Number of revolutions=speedxtime
Dynamic continuous mixer
-enables fully continuous processing
-reduces segregation risk
Types:
-Weir design
-inclined design
why granulate?
- improve homogeneity
- improve bulk density (solids handling, packaging, transport)
- Deliver dissolution profile by manipulating structure
How can segregation happen?
- Fluidisation/eludritation - higher drag:weight ratio
- sifting (big particles at top - brazil nut effect)
- Trajectory (big particles go further than small particles)
Types of granulation (bigger topics)
- 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
Types of dry granulation machines
- slugging
- roller compaction
types of wet high-shear granulators
vertical
horizontal
Types of wet low-shear granulators
- planetary
- kneading
- screw
Types of low-shear tumble granulators
- slant cone
- double cone
- v blender
types of extrusion granulators
- radial or basket
- axial
- Ram
- Roller, gear or pelletizer
Rotary granulator types
- open
- closed
Aims of solid fraction (solid to air proportion)
Powders: 0.2-0.5
Ribbons: 0.6-0.8
Tablet: 0.8-0.95
Types of high shear wet granulators
- Twin screw
- batch high shear
What happens in a high shear wet granulator?
- consolidation
- nucleation
- rate processes
- growth
- attrition
- breakage
Summarise rate processes
- wetting and nucleation
- consolidation and coalescence (agglomeration)
- attrition and breakage
Capsules vs tablets
Name 3 hard capsule advantages
- fewer excipients and formulation problems
- reproducible disintegration
- fewer manufacturing stages
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)
Describe the capsule filling cycle
empty capsules→aligning and rectification→opening and separation→ filling→joining and closing→discharge
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
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
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
Define anticoagulant
Give examples
an agent that prevents the clotting of blood
e.g. EDTA, Citrate, Heparin
Define capillary
Small blood vessel that connects arterioles and venules
Define haemoglobin
the oxygen-carrying molecule of red blood cells
Define haemolysis
The breakdown of red blood cells, with the release of haemoglobin into the plasma or serum
Define Lipemic
having an abnormally high level of fat, milky-looking samples
Define plasma
Pale yellow component of whole blood, contains all clotting factors
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.
Define serology
the study of antigen-antibody reactions using laboratory tests
Normal WBC blood level
4k-10k/mL
Normal haemoglobin blood levels
Male and female
Male:13.5-17.5g/dL
Female: 12-16g/dL
Normal INR
0.8-1.2
RBC blood levels
Male and female
Male: 4.5-5.9x 106cells/mL
Female: 4.0-5.2x106cells/mL
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
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
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
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
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
Define attrition (pharmaceutical definition)
Wearing away by friction or rubbing
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
Effect of low disintegrant level
0-1% w/w
on quality attributes
(High shear wet granulation)
Longer disintegration time and slower dissolution rate
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
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
Define agglomeration
Agglomeration, the sticking of particles to one another or to solid surfaces, is a natural phenomenon.
Name 2 diluents used in wet high shear granulation
- Mannitol
- MCC
Effect of mannitol on process parameters
High shear wet granulation
- Lower water quantity required (10-20% w/w)
- shorter drying times
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
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
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
Name 2 macro scale flow regimes
High shear wet granulation
- Bumping flow
- Roping flow (faster)
goes from bumping flow→roping flow
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
Describe Roping flow
- Good mixing
- good mixing distribution, more unimodal granule size distribution
- higher consolidation rates may lead to dense granules
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)
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)
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
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
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
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
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
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
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
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.
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
Why in granulation is an increase in density sometimes a bad thing?
Can cause problems when pressing tablets
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
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
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.
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
