Secondary Manufacturing Flashcards
What are primary pharmaceutical processes
The Reactions and separations involved in the manufacturing of the pure API
What are secondary pharmaceutical prcesses
The blending and formulation steps required to formulate the dosage form of the product
Why are tablets not jsut pure API?
Need the tablet to be large enough to be taken by a person so even if only a very small amount of API is required, bulking agents etc are required
Differentiate between sustained release and immediate release
Immediate release is ensuring the API reaches the desired area asap
Sustained release is attempting to maintain as constant as possible levels of the API over a long period
These are influenced more by the formulation of the drug than the API itself
6 drug Administration routes
- Oral
- Pulmonary (e.g. inhaler)
- Transdermal (e.g. cream)
- Intravenous
- “Direct Application” (e.g. eye drops)
- Implantable controlled-release devices
Define Pharmacokinetics
The rate at which the API is released from dosage form, absorbed into the system ciruclation, metabolised and excreted
Define the minimum toxic concentration (MTC)
The [API] that once exceeded will begin to result in undesirable side effects and (potentially irreversible) toxicity (e.g. liver damage) being observed
Define minimum effective concentration (MEC)
[API]min that has a measureable pharmaceutical effect on a statistically representative group of patients
Define Therapeutic Index (TI)
The [API] window rhar we want to maintain for the duration of the treatment
TI = MTC - MEC
Define the LADME model
- Liberation
- Absorption
- Distribution
- Elimination
4a. Metabolism
4b. Excretion
Define Bioavailability (F)
The fraction of the administered dose that reaches the systemic circulation as the parent drug (not as metabolites)
- Tells us to what extent API was dissolved and already metabolised absorption
- If low either need to change the route of administration or the physical/chemical properties of the API
Bioavailability Equation
F = AUC/Dose
AUC = Area Under Curve
F = Value between 0 & 1
The lower it is the more waste there is
Define Apparent Volume Distribution
V = Total Amount of drug in the body/ Plasma Concentration
Partition Coefficient Equation
P = [Octanol]/[Water]
Uses of the Partition Coefficient
- Gives the ability of the API to be liberated, absorbed and distributed
- if substance is lipophilic conc in plasma wil be low but amount in body will be high as it will have accumulated in lipophilic tissues
Biopharmaceuticals Classification System
I) High solubility & High Permeability
II) Low Solubility & High Permeability
III) High Solubility & Low Permability
IV) Low Solubility & Low Permeability
Methods of improving solubility
- Milling the API it so it is well distributed in the tablet
- Change the form of the API to amorphous or metastable crystal
Dissolution rate of particles equation
dm/dt = D/delta x A(c* - c_bulk)
Delta = thickness of the boundary layer
c* dependent on pH, Temperature & solid phase form
Typical Components of a tablet
- API
- Filler (bulking agent)
- Binder
- Disintergrant or Matrix-forming polymer
- Lubricant/glidant
- Coating Polymer + Pigment
Role of a filler/bulking agent
- No active role
- Usually for low dose APIs
- Usually sugars
Must be:
- Tolerated by population
- Soluble
- Easy to handle, compress, blend etc
- Be of a specific grade (differing properties)
Role of a binder
Increase adhesion between particles
Role of Disintergrant or Matrix forming polymer
Disintergrant - Swells in contact with liquid to help break up the tablet
Matrix forming polymer - Forms gel upon contact with liquid; helping tablet keep together to slow dissolution
Roe of lubricant/glidant
Reduce friction between tablet particle and walls of the process equipment
Role of Coating polymer or pigment
- Increase shelf life
- May prevent acid hydrolysis so that tablet is absorbed in intestine not stomach
- May add a visual appeal
Why is milling required
Crystalline form of the API may not have sufficient distriution rate so will need to reduce its size/increase its surface area
Give 3 types of milling
- Stirred media or wet milling (particles suspended in solvent then pumped through agitated chamber) - gives smallest sizes
- Impact/Jet milling (Particles broken up by impact with other particles or compressed gas)
- Attrition milling
In tabletting what are the types of compaction behaviour
- Rearrangement
- Elastic Deformation
- Plastic Deformation
- Viscous Flow
- Brittle Failure
- Elastic Recovery
What type of deformation is desirable in tabletting?
- Plastic deformation as the increase in contact area increases the strength of VdW holding the tablet together increase
Measure of mixedness equation
sigma^2 = SUM{(w_i - w_avg)/n}
Define mixing number
Number of unit mixing operations required for the system to reach a given state of mixedness
Define segregation
Natural tendency of powders to de-mix (due to difference in particle size, shape, density or surface properties)
What are the quality attributes of tablets
- Hardness
- Attrition
- Weight Uniformity
- Content Uniformity
- Disintegration Time
- Release Kinetics
What are the aims of tablet coating
- Tase Masking
- Visual appeal (Colouring)
- Protective layer
- Delayed release effect
- Functional coating of carrier particles (e.g. sometimes one API is in tablet core and another is in the coating)
What is the criteria required for agglomeration?
Stv < Stv*
(Viscous Stokes Number)
Stv = 8mu/(3pi x mu x D^2)
Stv* = 2ln(lambda/h_a)
Sequence of processes for wet granulation
Wet Granulation -> Mix/Dissolve/Suspend -> Dry -> Mill/Size -> Blend
Sequence of processes for dry granulation
Dry granulation -> Blend -> Compact -> Mill/Size -> Blend
Sequence of processes for direct compression
Direct Compression -> Blend
Sequence of processes for melt granulation
Melt Granulation -> Mix/Melt/Dissolve -> Congeal -> Mill/Size -> Blend
Sequence of processes for Spray Drying
Spray Drying -> Dissolved/Suspend -> Spray/Dry -> Blend
Sequence of processes for Freeze Drying
Freeze Drying -> Dissolve -> Freeze -> Vacuum/Dry -> Blend
Sequence of processes for Tabletting
Tabletting -> Compact -> Coating -> Dissolve/Suspend -> Spray/Dry
Why does granulation need to perform
To turn elastic material into elastoplastic granules to aid in tablet formation
- Change material behaviour + flow properties. Therefore increase production rate
What is the principles of wet granulation
Contact powder with a liquid binder, wet powder particles become cohesive, agglomeration occurs during particle collisions, binder sers to form mechanically stable granules
Steps in extrusion
- product extruded as a long noodles
- It is then broken up by contact with high speed rotating disk
- It then spheronises over time
- It is finally dried to form spherical pellets
