CE70007 - Pharmaceutical Development

Question 1

What is route selection?

Answer 1

Route Selection refers to the selection of starting materials, process intermediates, and general chemistry conditions associated with the route, but not necessarily the final “optimised” operating conditions.

Question 2

What is the manufacturing process description?

Answer 2

The Manufacturing Process Description is the defined process that must be adhered to during manufacturing. It is part of the regulatory submission, and every aspect must be backed-up with data.

A good manufacturing process:
• Provides DS that routinely meets CQAs and MAs
• Embraces the principles of inherent safety
• Is cost effective
• Is supported by accurate and reproducible analytical methods
• Consists of well understood process operations and provides the right level of control
• Embraces the principles of green chemistry and environmental sustainability

Question 3

What’s CQA, CPP, and MA?

Answer 3

Critical Quality Attribute (CQA)
Critical Process Parameter (CPP)
Manufacturing Attribute (MA)

Question 4

What are the main stages of pharmaceutical R&D?

Answer 4

1. Lead ID (lab stage)
2. Pre-clinical
3. Phase I (small pilot)
4. Phase II (small-full pilot)
5. Phase III (full pilot)
6. File and launch
7. Lifecycle management (manufacturing)

Question 5

What’s CGS?

Answer 5

Cost of goods

Question 6

What’s CMC?

Answer 6

Chemistry, Manufacturing & Control

Question 7

What is GMP?

Answer 7

Good Manufacturing Practice
It is that part of Quality Assurance which ensures that medicinal products are consistently produced and controlled to the quality standards appropriate to their intended use.

It applies to: people, products, procedures, processes, and premises.

Question 8

Why work to GMP?
Good manufacturing practise

Answer 8

Any Pharmaceutical Company has
• to ensure patient safety
• to work to best practice standards to produce quality products fit for purpose
• to provide confidence to the prescribers and patients
• to sell products

“Fit for Purpose” Pharmaceuticals
• Right product
• Right purity/strength
• Free from contamination
• No deterioration
• Right packaging/labelling
• Properly sealed and protected against
damage and contamination
• Complies with all legal & regulatory requirements

Question 9

What’s the qualification process for a new pharmaceutical design?

Answer 9

1. User requirements specification
2. Validation master plan
3. Design qualification
4. Purchase order
5. Installation qualification
6. Start-up
7. Operational qualification
8. Routine operation

Question 10

What’s process validation?

Answer 10

Process validation is the collection and evaluation of data, which establishes scientific evidence that a process is capable of consistently delivering quality product.

Process validation does not strictly apply during development, but it does in manufacturing.

Question 11

Define POL, SOP, EOP, GUI

Answer 11

POL: policies. High level outline of intent

SOP: standard operating procedure

EOP: Equipment operating procedures

GUI: Guidelines / Best Practise

Question 12

What are the objectives of the FDA?

Answer 12

FDA objectives:
– Promote new technology
– Introduce modern quality management techniques
– Risk-based approaches to R&D and inspection
– Promote science-based policies
– Improve FDA drug quality regulatory programs

Question 13

What’s an API?

Answer 13

Active pharmaceutical ingredient

Question 14

What is PAT?

Answer 14

Process Analytical Technology - a means of analysing and monitoring a process using off-line, at-line and on-line techniques.

It has been developed and used in many areas including the food and water industries and petrochemicals in particular.

Recent advances in measurement (spectrometers) and processing (data analysis) speeds has made the approach more amenable to real-time analysis.

The FDA encouraged the Pharmaceutical Industry to utilise PAT in 2003/4

Question 15

What is QbD?

Answer 15

Quality by Design.

A systematic approach to development that begins with predefined objectives and emphasises product and process understanding and process control, based on sound science and quality risk management.

Question 16

Give examples of PAT instruments:

Answer 16

• Near Infrared NIR
• Mid IR
• UltraViolet / Visible
• Raman
• Lasentec (FBRM)
• Mass Spec

Question 17

What is FBRM?

Answer 17

Focused Beam Reflectance Measurement

Question 18

How does Focused Beam Reflectance Measurement (FBRM) work?

Answer 18

A solid-state laser light source provides a continuous beam of monochromatic light that is launched down FBRM® probe. A set of lenses focuses the laser light to a small spot. This focal spot is carefully calibrated to be positioned at the interface between the probe window and the actual process. Tightly controlling the position of the focal spot is necessary for a sensitive and repeatable measurement.
A precision motor is used to rotate the optics at a constant speed. The speed is monitored and controlled throughout the measurement to ensure maximum precision in the data. Standard probes operate to provide a fixed 2 m/s scan speed.
The focused beam scans a circular path at the interface between the probe window and the particle system. As the beam sweeps across the face of the probe window, individual particles or particle structures will backscatter the laser light back to the probe.

These pulses of backscattered light are detected by the probe and translated into Chord Lengths based on the simple calculation of the scan speed (velocity) multiplied by the pulse width (time); a chord length is simply defined as the straight-line distance from one edge of a particle or particle structure to another edge.

Thousands of individual chord lengths are typically measured each second to produce the Chord Length Distribution which is the fundamental measurement provided by FBRM®.

Note that unlike other particle size analysis techniques, with FBRM® measurement there is no assumption of particle shape

Question 19

How are UV/Vis and NIR fibres formed?

Answer 19

UV/Vis (Ultraviolet/Visible) and NIR (Near-Infrared) fibres are typically made by drawing molten silica or other materials into thin strands. The process involves heating and stretching a glass preform to create long, flexible fibres.

Pure silica and surrounding the core is a doped-fluorine silica cladding. A polyimide material is then applied. Then a coiled stainless steel jacketing is applied over the core, cladding and buffer to protect the fibre and provide strain relief.

Question 20

What are the 2 main types of mid-IR fibres?

Answer 20

Chalcogenide glasses composed of sulfur (S), selenium (Se), and tellurium (Te) with the addition of other elements such as germanium (Ge), arsenic (As), and antimony (Sb) that result in the formation of stable glasses.
Typical melt temperatures range from 600°C to 900°C, depending upon composition.

Silver halide solid solution crystals - AgCl : AgBr

(Typical fibre lengths:
NIR - 1000 m+
IR - 2-3 m
UV - 5m )

Question 21

What is SAM-Spec?

Answer 21

SAM-Spec ® is a technique based on Spatially Resolved Spectroscopy
combined with several chemometric approaches. The system uses :

– A light source for irradiation
– Measurements are performed at several distances for physical characterisation
– Absorbance Spectral measurements provide chemical characterisation
– Symmetrical acquisition positions provide homogeneity evaluations.

[Technique from video on analysing tableting]

1. NIR is injected into the media and will immediately be isotropically (in all directions) scattered into the media.
2. Photons propagate at different depths. Their density decreases while receding from light source (i.e. greater density of photons nearer where light was incident).
3. NIR chemical spectra are recorded by the probe at several depths and locations simultaneously.
4. SAM-spec measures up to 12 spectra at once to provide an accurate reading (of tablet conc.). This can address issues in homogeneity and any coatings used. The more dense the material, the greater the degree of scattering.
5. Info on spatial distances gives information on hardness, density, porosity, and particle size.
6. Cracks and deformities interfere with normal scattering.
7. All this takes place in about 5 ms.

26 measurement points and 10-40 images per tablet

Question 22

What PAT techniques are suitable to monitor crystallisation?

Answer 22

UV
Mid IR
Sonic velocity
NIR
FBRM

Question 23

Which technique is most suitable for monitoring distillation?

Answer 23

NIR, monitoring distillate solvent composition
Mid IR

Question 24

What PAT technique is suitable for monitoring tableting?

Answer 24

NIR imaging

Question 25

What PAT technique is suitable for monitoring dryers?

Answer 25

NIR
Mass spec
Miniature spectrometers.

Using a linear variable filter the MicroNIR, detector, light source, collection optics, and electronics are fully integrated in one small USB-powered palm-size device weighing <60 grams. Available wavelength range is 950 – 1650 nm.

Can be attached to:
•a rotary blender
•agitated dryer
to determine the end-point

Question 26

What is PCA?

Answer 26

Principal component analysis

PCA is for the analysis (exploration) of a single data set (matrix)

Question 27

What PAT methods are suitable for monitoring reactions?

Answer 27

UV
NIR
Mid-IR
Mass spec

Question 28

What’s PLS?

Answer 28

Partial least squares

A PLS model (or calibration) is built taking spectra of known well characterised materials. Spectra acquired during the process in real-time are then compared to the model to predict component concentrations.

Question 29

What are the types of PAT process interfaces?

Answer 29

Direct via dip pipe, by-pass loop

Probe
- ATR
- Transmission
- Reflectance

Flow cell

Question 30

Define control strategy:

Answer 30

A planned set of controls, derived from current product and process understanding, that assures process performance and product quality. The controls can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control.

Question 31

Define critical quality attribute (CQA):

Answer 31

A physical, chemical, biological or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality.

Question 32

Define critical process parameter:

Answer 32

A process parameter whose variability has an impact on a critical quality attribute and therefore should be monitored or controlled to ensure the process produces the desired quality.

Question 33

Define edge of failure:

Answer 33

The boundary to a variable or parameter, beyond which the relevant quality attributes or specification cannot be met.

Question 34

What does pharmaceutical development include?

Answer 34

• Defining the target product profile as it relates to quality, safety and efficacy, considering e.g., the route of administration, dosage form, bioavailability, dosage, and stability

• Identifying critical quality attributes (CQAs) of the drug product, so that those product characteristics having an impact on product quality can be studied and controlled

• Determining the quality attributes of the drug substance, excipients etc., and selecting the type and amount of excipients to deliver drug product of the desired quality

• Selecting an appropriate manufacturing process

• Identifying a control strategy

• Identifying, through e.g., prior knowledge, experimentation, and risk assessment, the material attributes and process parameters that can have an effect on product CQAs

• Determining the functional relationships that link material attributes and process parameters to product CQAs

• Using the enhanced process understanding in combination with quality risk management to establish an appropriate control strategy which can, for example, include a proposal for design space(s) and/or real-time relea

Question 35

Describe the QbD (quality by design) approach:

Answer 35

Step 1 - Identify the desired profile of the marketable product ie the Target Product Profile and the CQA’s of the product.

Step 2 - Selection of the synthesis route for the API (Active Pharmaceutical Ingredient) and processing requirements for the formulation type, together with the associated unit operations required for these processes. (Suitable unit operations include for example, Chemical Reaction, Crystallisation, Distillation, Drying, Blending and Tableting.)

Step 3 - Gaining experimental knowledge by operating the process and exploring the effect of options and changes.
Refining and optimising the process to determine the Proven Acceptable Ranges (PAR’s).

Step 4 - Develop the process Control Strategy including Design Space definitions.

Step 5 - Technology transfer of the process from Development to the Manufacturing business.

Step 6 - Manufacture of marketable product and Regulatory Submission.

Question 36

What does CQA stand for?

Answer 36

Critical Quality Attribute (CQA): A physical, chemical, biological or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality.

Each CQA has an individual control strategy with associated elements of control to ensure that all of the CQAs are satisfied to meet the required patient safety and efficacy criteria.

Question 37

What’s a design space?

Answer 37

The multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality.

The way input attributes and process parameters affect the output quality attributes must be described through a quantitative model which permits an assessment of the level of assurance of quality for any multi-dimensional combination of input attributes and process parameters.

First Principle (Mechanistic) Approach
– A first principle, or mechanistic, model is a combination of experimental data and mechanistic knowledge of chemistry, physics, and engineering which enables the prediction of process performance. A first principle, or mechanistic model, is derived from an understanding of the underlying science e.g. chemical reaction kinetics.

Empirical Modelling Approach
– Carefully planned experimentation incorporating DoE studies (an efficient method for determining the impact of multiple parameters and their interactions) is used to obtain data which are used to derive both the form of the model and the associated unknown model coeffi

Question 38

How is a parallel coordinates plot shown?

When is it used?

Answer 38

In the parallel coordinates plot, a set of equally spaced parallel axes are drawn for each variable (eg batch descriptor: CQA, QCPP, End-point, etc). Then a given row of data (eg values for a single batch) is represented by drawing a line that connects the values of that row on each corresponding axis.

Parallel Coordinates allow multidimensional data to be visualised

1. Representation of Design Space
   • Proven Acceptable (and Normal Operating) Ranges
   can be displayed for single or multiple unit operations.
2. Representation of Continuous Verification.
   • Verification that a process Control Strategy
   maintains operation within the Design Space limits can be illustrated

Question 39

What are the elements of control?

Answer 39

A control strategy comprises 3 possible modes of control

• Attribute control - testing to specification ie. starting materials, reagents, intermediates, drug substance etc using on-line or off-line methods.

• Parametric control
– Individual PAR limits applied to process parameters.
– Interactive PAR model based (Design Space relationships) limits
applied to process parameters.

• Procedural Control - order of addition, work-up procedure, extraction wash sequences etc

Question 40

How does process validation play a part in 3 different stages of design?

Answer 40

Stage 1 – Process Design: The commercial process is defined during this stage based on knowledge gained through development and scale-up activities.

• Stage 2 – Process Qualification: During this stage, the process design is confirmed as being capable of reproducible commercial manufacturing.

• Stage 3 – Continued Process Verification: Ongoing assurance is gained during routine production that the process remains in a state of control.

Question 41

Where is process verification applied?

Answer 41

It can be applied in 2 distinct phases :
• Achieving the point of commercialisation. Before release of batches for commercial supply, a manufacturer is expected to have accumulated enough data and knowledge about the production process to support post approval distribution.

• During the production phase, continual verification or monitoring will allow evaluation of quality indicator data, changes and adverse trends. This will be performed periodically to decide if new studies or other verification experiments need to be done. This demonstrates that the process continues to work as intended and remains in control

Question 42

What are the 3 golden rules of mixing

Answer 42

A deep vortex is not a sign of good mixing

Impeller speed rarely stays constant on scale up

Mixing performance is inversely proportional to scale

Question 43

What to T, D, H, H’, C, and B refer to regarding standard vessel geometry?

Answer 43

T - tank diameter
D - baffle / stirrer diameter
B - baffle width
H - liquid level height
H’ - tank base height
C - impeller off-bottom clearance

Question 44

What does partial baffles refer to?

Answer 44

A tank having 3 or less baffles

Question 45

Explain axial and radial flow from mixers:

Answer 45

Axial:
Fluid flows up and down the vessel
- low shear
- good for suspended solids

Radial:
Propeller blades are pitched, so fluid will go sideways, hit the vessel wall, and move up and down vessel, circling in a figure of 8 manner
- high shear
- good for dispersions

Question 46

When are axial and radial mixers / impellers used?

Answer 46

Axial:
- low shear purposes
- good for suspended solids

Radial:
- high shear purposes
- good for dispersions

Question 47

What is the static volume?

Answer 47

The tank volume at the bottom of the tank below the impeller where nothing moves.

Roughly 1% nominal tank volume.

Question 48

What’s the minimum stir volume?

Answer 48

Min volume needed for impeller to stir fluid. Is useful for cleaning.

Roughly 5% nominal tank volume.

Question 49

What’s the minimum mixed volume?

Answer 49

This determines the minimum batch sized vessel.

It is about 30-40% the nominal tank volume, and is the volume required for effective mixing to take place.

Question 50

What is the issue with conical bottom shaped tanks?

Answer 50

They are very bad mixers.

They make good separators.

Question 51

What are the main impeller types?

Answer 51

Radial flow impeller
• Discharges liquid radially outwards towards vessel walls

Axial flow impeller
• Discharges liquid axially towards base or liquid surface depending on rotation direction

Mixed flow impeller
• Flow predominantly in axial direction with also a radial component

Close clearance impeller (e.g. anchor impeller)
• Ensures good motion
near vessel walls

Question 52

What are the process applications of radial flow impellers?

Answer 52

• turbulent and transitional regime
• gas-liquid
• liquid-liquid dispersions

Question 53

What are the process applications of axial and mixed flow impellers?

Answer 53

• turbulent and transitional regime
• blending
• solid suspension
• liquid-liquid dispersions

Question 54

What are the process applications of close clearance impellers?

Answer 54

• laminar regime
• blending

Question 55

What are the predominant baffle types?

Answer 55

The beaver tail baffle - oval/cylindrical with a flat end.
Can be glass lined, but is not very effective

Cylindrical baffles with additional cylindrical protrusions.

C-shaped baffles

Beavertail and finger baffles are often used in glass-lined vessels
– Smooth shape suitable for glassing

Other internals can provide a degree of baffling
– Dip pipes
– Heating/cooling coils

Question 56

What may a mixing process be controlled by?

Answer 56

A process may be controlled by one or more of:

Liquid blending
• reaction
• homogenisation

Solid-liquid mixing
• solid catalysed reaction
• dispersion

Gas-liquid mixing
• fermentation
• hydrogenation

Dispersing immiscible liquid
• reaction
• emulsions

Heat transfer

Question 57

How is power consumption calculated from torque?

Answer 57

P=2 π N Λ

Where Λ is torque and N is rotational speed.

P and Λ determine the capital and running costs
– If the impeller must start from rest in a bed of solids, the power and torque requirements for start-up can be extremely large, and depend on the characteristics of the solid.

Question 58

How is torque measured?

Answer 58

– Small scale measurements
• Mount vessel or motor on frictionless bearings and measure torque using a load cell or dynamometer
• Use a commercial torque meter
• Use a modified rheometer

– At larger scales:
• Strain gauges can be used.
• Electrical current can be used.
– Subject to many errors
– Estimate of losses in the gearbox and bearings required

Beware of:
– Vibration & resonance problems

Question 59

What does power draw refer to?

Answer 59

The power drawn by an impeller

P = Po ρ N^3 D^5

Where:
Po - power number
Rho - fluid density
N - impeller rotational speed
D - impeller diameter

Po, or Newton number, Ne – Depends on
• Impeller type
• Impeller and vessel dimensions
• Properties of the phases present

Question 60

How can flow regime be determined in a stirred tank considering the power number?

Answer 60

Re < 10 - laminar flow
Po proportional to 1/Re

10 < Re < 10^3 - transitional flow
Po = f(Re)

Re > 10^3 - turbulent
Po = constant

Fully turbulent, Re»10^4

Question 61

What is blend time?

Answer 61

Time taken to reach 95% homogeneity

Question 62

What is just suspension speed?

Answer 62

Speed at which no particle stays stationary for more than one to two seconds at the bottom of the vessel.

(Njs)

Question 63

List key drug administration routes:

Answer 63

• oral (tablets, capsules, liquids)
• pulmonary (aerosols, inhalation powders)
• transdermal (creams, controlled-release adhesive patches)
• intra-venous (e.g. vaccines, insulin, antibiotics)
• “direct application” (e.g. eye drops, skin cream)
• implantable controlled-release devices, depot systems…

Question 64

What does Tmax refer to regarding drug delivery?

Answer 64

Time until blood-drug conc. is at its highest.
With a single dose, there is an increase and decrease in blood-drug conc. Meanwhile, with chronic administration, the concentration (fluctuates but) increases and plateaus over time.

Question 65

What’s the therapeutic index?

Answer 65

Difference between minimum toxic concentration and minimum effective concentration.

The maximum blood-drug concentration must remain between these two concentrations.

Question 66

What are MTC and MEC with regards to drug delivery?

Answer 66

Minimum toxic concentration and minimum effective concentration

Question 67

What does LADME stand for, with regards to drug delivery?

Answer 67

Liberation
Absorption
Distribution
Elimination (Biotransformation/metabolism and excretion)

Question 68

What is bioavailability?

Answer 68

Bioavailability F = the fraction of the administered dose that reaches
the systemic circulation as the parent drug (not as metabolites)

F = AUC / Dose

Question 69

What is apparent volume of distribution?

Answer 69

V = Total amount of drug in the body / Plasma concentration

It is important when considering hydrophobic drugs/particles.

Question 70

What is the partition coefficient?

Answer 70

A measure of lipophilic character of drug.

A partition coefficient is the ratio of the concentration of a substance in one medium or phase (C1) to the concentration in a second phase (C2) when the two concentrations are at equilibrium; that is, partition coefficient = (C1/C2)equil.

Question 71

What does the Noyes Whitney equation show?

Answer 71

Dissolution rate of particles.

The Noyes Whitney equation,

dC/dT = kA(Cs-Ct)

describes the change in concentration over time (dC/dT) as a function of the dissolution rate constant k, surface area A, solubility Cs, and concentration in the bulk fluid Ct.

k may be replaced by D/δ = diffusivity / apparent thickness

dm/dt = -D/δA(C*-C.bulk)

Question 72

Key questions for pharmaceutical design?

Answer 72

What’s being made

How much active ingredient and in what form?

What are the requirements on dissolution / release kinetics?

Overall product composition?

Process route?

Question 73

What are the different particle milling techniques?

Answer 73

Stirred media mils (wet milling)
Impact/Jet mills (micronisation)
Attrition mills

Dry milling however is not suitable when trying to obtain very small particle sizes, due to electrostatic forces.

Question 74

What’s the mixing number, regarding powder blending?

Answer 74

Nmix - number of unit mixing operations required for the system to reach a given state of mixedness

Question 75

What’s segregation, regarding powder blending?

Answer 75

The natural tendency of powders to de-mix due to difference
in particle size, shape, density or surface properties (friction, cohesion)

• occurs during transport (conveying) or storage (IBCs) of powders
• need to “freeze” a well-mixed state immediately after blending

Question 76

Why coat tablets?

Answer 76

-Taste masking
-Visual appeal (coloured tablets)
-Protective layer (abrasion)
-Delayed release effect (gastric fluid resistance)
-Functional coating of carrier particles - API

Typical film thickness: 5-50 um

Question 77

Describe the principle of wet granulation:

Answer 77

Contact powder with a liquid binder, wet powder particles become cohesive, agglomeration occurs during particle collisions, binder sets to form mechanically stable granules.

Binder types:
- melt binders ~ melts, solidify upon cooling (e.g. PEG)
- aqueous binders ~ solutions, solidify upon drying (e.g. HPC, PVP)
- water ~ partial dissolution and recrystallisation of ingredient(s)

Binder application:
- spray (liquid atomisation) for low-shear processes
- mechanical dispersion in high-shear processes

Granulation processes:
- fluid bed granulation
- high-shear mixer granulation

Question 78

What is involved in primary and secondary manufacturing?

Answer 78

Primary - API manufacturing, reaction route selection, separations and solids isolation (crystallisation/filtration/drying)

Secondary - blending, forming, types of dosage routes, processing routes, no chemical transformation taking place, mechanical unit operations

Question 79

What are exipients?

Answer 79

A constituent of a medicine other than the active substance, added in the formulation for a specific purpose.

Question 80

What are binders (in medicine)?

Answer 80

Binding agent or binders are employed to convey the cohesiveness to the granules. Binders are added to the tablet formulation to impart plasticity as well as increases inter-particulate bonding strength in the tablet that ensure the tablet remains intact after compression.

Question 81

What are the 4 classes of the Biopharmaceutics Classification System (BCS)?

Answer 81

I) High solubility & high permeability (dissolve well and absorb fast)

II) Low solubility & high permeability (dissolution rate needs to be improved during production to enhance absorption)

III) High solubility & low permeability (rate limiting step of drug is the absorption across intestinal wall. High API conc is needed to increase driving force / supersaturating the conc’ in the intestine)

IV) Low solubility & low permeability (as above, rate limiting step is absorption across intestine wall)

Question 82

What are typical components/’ingredients’ of a tablet?

Answer 82

API / Active pharmaceutical ingredient

Filler (bulking agent)

Binder

Disintegrant or matrix-forming polymer

Lubricant / glidant

Coating polymer

Pigment

Question 83

Why would particles need to be milled during drug development?

Answer 83

To reduce particle size and improve / increase the API dissolution rate.

Question 84

Describe wet milling:

Answer 84

Wet milling, also known as wet grinding, is a process through which particles that are suspended in a liquid slurry are dispersed in that liquid by shearing or crushing. Once the milling process is complete, these particles are ready for use or can be dried and separated for incorporation into additional products.

Question 85

What quality attributes are considered for tablets?

Answer 85

Hardness
Attrition
Weight uniformity
Content uniformity
Disintegration time
Release kinetics

Question 86

What are the main steps of the overall crystallisation process design procedure?

Answer 86

1) Thermodynamics (Solid-liquid equilibria, looking at solubility)
2) Kinetics (rate of crystallisation)
3) Selection of crystalliser type
- mode of achieving super-saturation
4) Mass, energy and population balances
- to determine operating condition that meet
product specification

Question 87

What’s polymorphism?

Answer 87

The ability to crystallize in more than
one crystallographic form

Question 88

What are the 2 types of polymorph?

Answer 88

Enantiotropic - can convert into one another / interconvertible (e.g. by T). Possess points at which their solubilities at a given temperature are the same, and can then change form.

Monotropic - incapable of transformation

Question 89

What’s drowning-out crystallisation?

Answer 89

In drowning-out crystallization, supersaturation is generated by adding an anti-solvent, which reduces the solubility of the solute.

This method is used for highly soluble materials rather than evaporative or cooling crystallization, which have weak solubility temperature dependence

Question 90

What’s a eutectic system?

Answer 90

A eutectic system is a homogenous, solid mixture of two or more substances that form a super-lattice that melts or solidifies at a temperature lower than any of the individual ingredients’ melting point. The term is most usually used to describe a mix of metals.

It melts or solidifies at a temperature lower than the melting point of any one of the constituent components.

Question 91

Explain congruent melting point:

Answer 91

Congruent melting point - hydrate (or solvate) can exist in equilibrium with a solution of the same composition (point D).

Question 92

What are the labile and metastable regions of crystallisation?

Answer 92

Labile zone - where nucleation occurs

Metastable zone - growth range

In the metastable region nuclei will develop into crystals, but no nucleation will occur. In the labile region both might be expected to occur.

The final region, at very high supersaturation, is denoted the precipitation region, where this result might be most probable.

Question 93

How is supersaturation created?

Answer 93

Creating supersaturation:
- by concentration (evaporation of solvent)
- by temperature (cooling)
- by adding antisolvent

Supersaturation is the driving force for crystallisation.

Question 94

When do primary and secondary nucleation occur?

Answer 94

Primary - in the absence of crystals
- homogeneous nucleation = clusters of atoms spontaneously form in the solution
- heterogeneous nucleation = impurities (e.g. dust particles) act as nucleation centres

Secondary - in presence of crystals (seeding)
- contact nucleation mechanism (crystal-crystal and crystal-wall/impeller collisions)
- shear nucleation mechanism (fluid flow over surface creates new nuclei)

We want secondary nucleation over primary as it gives more control over the particles that are formed.

Question 95

What’s crystal habit?

Answer 95

The term crystal habit describes the favoured growth pattern of the crystals of a mineral species, whether individually or in aggregate.

Question 96

Why is the volume fraction of crystals in slurries aimed to be kept around 15%?

Answer 96

Prevent the slurry from becoming too thick.

Question 97

How is particle size distribution often considered?

Answer 97

Plot of particle size vs number of particles.
Normal distribution expected.

Question 98

What is a MSMPR crystalliser and its features?

Answer 98

Mixed-suspension mixed-product removal crystalliser

• ideally mixed
• steady-state, continuous operation
• no crystals in feed
• no agglomeration or breakage
• size independent growth rate

Question 99

What are issues to be considered during filtration?

Answer 99

Be careful about the following:
- Particle breakage in agitated filters
(resuspension)
- Cake washing: acceptable product loss vs. product purity
- Cake deliquoring: shrinkage/cracking of cake
- Filtration centrifuge: uniformity of cake thickness

Question 100

What are issues to be considered during drying process design and operation?

Answer 100

Be careful about the following:
- Geometrical similarity during scale-up
(surface/volume ratio)
- Rate-limiting step: heat vs. mass transfer
- Particle agglomeration/breakage in agitated dryers
- Phase changes in crystals (solvates/hydrates)

Question 101

What parameters effect the performance of spray drying processes?

Answer 101

Related to particle size and morphology…
- Feed conc
- Droplet size / atomisation pressure
- Solvent choice
- Additive choice

Related to product temperature and residual moisture…
- Feed flowrate
- Drying gas flowrate
- Drying gas humidity
- Drying gas temperature

Question 102

Describe the two stages of single droplet drying:

Answer 102

1st period - Evaporation from free surface. Wet bulb temperature.

2nd period - Diffusion across solid shell. Formation of hollow core. .

Question 103

What are the main types of chromatography?

Answer 103

Different mechanisms from different combinations of gaseous, solid or liquid phases give rise to the main types of chromatography.
* Adsorption
* Partition
* Ion Exchange
* Size Exclusion

Chromatography is a technique for the separation of a mixture by passing it in solution or suspension through a medium in which the components move at different rates.

Question 104

What does adsorption chromatography involve?

Answer 104

It uses a solid stationary phase e.g. silica gel, activated carbon, and a liquid or gaseous mobile phase.

Solutes are separated according to their adsorption characteristics onto the stationary phase.

Question 105

What does partition chromatography involve?

Answer 105

It is based on a thin film formed on the surface of a solid support by a liquid stationary phase.

Solutes equilibrate between the mobile and stationary phase

Question 106

What does ion exchange chromatography involve?

Answer 106

A resin (stationary solid phase) is used to covalently attach anions or cations onto it.

Solute ions of opposite charge in mobile liquid phase are attracted to the resin by electrostatic forces.

Question 107

What does molecular or size exclusion chromatography involve?

Answer 107

Aka gel permeation or gel filtration, it lacks any attractive interaction between the stationary phase and solute.

The liquid or gas phase passes through a porous gel which separates molecules based on their size.

The gel consists of spherical beads with pores of a specific size distribution. The small pores exclude the larger solute molecules, but allow smaller molecules to enter the gel, causing them to be retained.

This causes the larger molecules to pass through the column at a faster rate than the smaller ones.

Question 108

List key chromatography techniques:

Answer 108

High-performance liquid chromatography (HPLC or uHPLC)
Gas chromatography
Supercritical fluid (SFC)
Thin layer (TLC)
Capillary electrophoresis
Chiral

Question 109

Describe reverse-phase HPLC:

Answer 109

Reverse-phase HPLC involves binding organic molecules to a non-polar stationary phase, often silica derivatized with alkyl chains, in a relatively polar environment (the mobile phase), which could contain water, and then eluting the organic molecule using a gradient of a less polar organic solvent.

The compounds are therefore separated on account of their differing hydrophobic character.

The less polar and more hydrophobic solutes are more strongly retained on a reversed phase column.

Question 110

What is electroosmotic flow?

Answer 110

The motion of liquid induced by an applied potential across a porous material, capillary tube, membrane, microchannel, or any other fluid conduit.

This looks at the movement of bulk solution

Question 111

What is electrophoretic mobility?

Answer 111

Electrophoretic mobility is the solute’s response to the applied electrical field in which cations move toward the negatively charged cathode, anions move toward the positively charged anode, and neutral species remain stationary.

Question 112

Describe gel electrophoresis:

Answer 112

Electrophoresis is a process that enables the sorting of molecules based on size.

Using an electric field, molecules (such as DNA) can be made to move through a gel made of agarose or polyacrylamide.

The electric field consists of a negative charge at one end which pushes the molecules through the gel, and a positive charge at the other end that pulls the molecules through the gel. The molecules being sorted are dispensed into a well in the gel material.

The gel is placed in an electrophoresis chamber, which is then connected to a power source. When the electric field is applied, the larger molecules move more slowly through the gel while the smaller molecules move faster.

The different sized molecules form distinct bands on the gel

Question 113

How does capillary electrophoresis (CE) work?

Answer 113

The capillary of the CE system is made of fused silica, having inner negatively charged layers. Thus, when high voltage is supplied at the end of the capillary tube, the molecules in a mixture start separating based on their ionic mobility and interaction with the liquid phase or electrolyte medium.

The molecules or ions with smaller sizes or higher charges move faster in the molecules than those larger in size or having more charges. Additionally, the molecules can also be concentrated by creating a gradient in the pH or conductivity of the electrolyte solution.

The separated molecules are then detected by a detector, which displays them on screen as distinct peaks as a function of migration time. The electrophoretic mobility of molecules in response to an electric field depends on their charge, radius, and solvent viscosity.

Question 114

What is the retention factor, considering chromatography?

Answer 114

Compounds will spend some time in the stationary phase and some time in the mobile phase. The time spent by an individual molecule in each of the two phases is called the capacity or retention factor, denoted as ‘k.’ The ratio of time spent in the two phases is equal to the ratio of the mass of the compounds in the two phases.

k = time spent in stationary phase / time in mobile phase

= mass in stationary / mass in mobile

k = (tr-t0)/t0

Question 115

What is the partition coefficient, K?
How is it found?

Answer 115

K = molar conc in stationary phase / molar conc in mobile phase

It is the ratio of the conc of a compound in the two phases.

Question 116

What is phase ratio, β?

Answer 116

β = volume of mobile phase / volume of stationary phase

k = K / β

Where k is the retention factor and K is the partition coefficient.

Question 117

What’s retention time?

Answer 117

The time it takes for a compound to travel through the column (from when an analyte is injected to when it reaches the detector) is known as the retention time (tr). If a compound is not retained at all, it will still take time to travel through the column.
Therefore, to establish a relationship between ‘k’ and retention time, an adjustment must be made to account for this travel time.

Question 118

What is dead time, t0?

Answer 118

The time it takes for an unretained compound to travel through the column, t0

Question 119

How is retention factor, k, calculated considering retention time and dead time?

Answer 119

k = (tr - t0)/t0

Where t0 is dead time

Question 120

What is the number of theoretical plates, N, with regards to chromatography?

Answer 120

Also known as column efficiency, the number of theoretical plates is a mathematical concept and an indirect measure of peak width for a peak at a specific retention time.

Number of Theoretical Plates (N):
N = 5.54 * (tR / wh)^2

Where:
N = number of theoretical plates
tR = retention time
wh = peak width at half height

A column with a high number of theoretical plates will have a narrower peak at a given retention time than a column with a lower N number. High column efficiency is beneficial since it requires less peak separation (meaning lower alpha, α - selectivity) to completely resolve components. On stationary phases where the alphas (α) are small, more efficient columns are needed.

Column efficiency is a function of the column dimensions (diameter, length, and film thickness), the type of carrier gas, its flow rate or average linear velocity, and the compound and its retention. For column comparison purposes, the number of theoretical plates per meter (N/m) is often used.

Question 121

What is the height equivalent to a theoretical plate, H, with regards to chromatography?

Answer 121

A measure of column efficiency, usually reported in mm.
The shorter each theoretical plate, the more plates are ‘contained’ in any length of column. This translates to more plates per meter and a higher column efficiency.

Height Equivalent to a Theoretical Plate (H):
H = L / N

Where:
H = Height equivalent to a theoretical plate
N = number of theoretical plates
L = Length of column (mm)

Question 122

How is resolution considered for chromatography when analysing results?

Answer 122

The higher the resolution, the less overlap there is between two peaks.

Separation is simply the distance or time between two peak maxima (alpha, α). Resolution takes into consideration both alpha (α - selectivity) and the width of the peaks.

It can be calculated using either of the equations below. Baseline resolution typically occurs at a resolution number of 1.50. However, there might not be a visible baseline between the two peaks. Numbers greater than 1.50 indicate a baseline between the peaks, while numbers less than 1.50 suggest some degree of co-elution.

Theoretical Aspects:

Resolution (R):
R = 1.18 * (tR2 - tR1) / (wh1 + wh2)
or
R = 2 * (tR2 - tR1) / (wb1 + wb2)

Where:
R = Resolution
tR1 = Retention time of the first peak
tR2 = Retention time of the second peak
wh1 = Peak width at half height of the first peak (time)
wh2 = Peak width at half height of the second peak (time)
wb1 = Peak width at base of the first peak (time)
wb2 = Peak width at base of the second peak (time)

Question 123

Considering Height Equivalent to a theoretical plate, H, what does the value of H depend on?

Answer 123

The value of H relies primarily on four main factors:

The velocity of the mobile phase.
Multipath diffusion, denoted by constant A, representing diffusion due to packing non-uniformity.
Longitudinal diffusion coefficient in the mobile phase (expressed by constant B), inversely related to the mobile phase’s velocity.
Mass transfer terms, including Cs for the stationary phase and Cm for the mobile phase.
For High-Performance Liquid Chromatography (HPLC) columns packed with particles, these factors are accounted for by the following formula:

H = A + B/u + (Cs+Cm)⋅u

Where:

H represents the height equivalent to a theoretical plate.
u stands for the average linear velocity of the mobile phase.
A is a constant indicating diffusion due to non-uniform packing.
B represents the longitudinal diffusion coefficient in the mobile phase.
Cs and Cm denote the mass transfer terms in the stationary and mobile phases, respectively.

This formula combines these elements to determine the efficiency or height equivalent to a theoretical plate in HPLC columns.

Question 124

For the height of plates equation,

H = A + B/u + (Cs + Cm)*u

Explain the importance of A, B/u, and Cu.

Answer 124

A: In packed columns, peak broadening occurs due to various factors. As analyte molecules traverse the column, they follow diverse pathways around the packed particles. Certain pathways are inevitably longer than others, causing the molecules to spread out as they move through the column. The extent of this spreading is influenced by the column material’s nature and the quality of packing. Generally, this factor is directly proportional to the particle size of the packing material. It’s a crucial consideration for packed columns; however, capillary columns, lacking particles, negate this factor.

The Longitudinal Diffusion Term (B/u):
Longitudinal diffusion contributes to peak broadening as analytes diffuse from areas of high concentration to less concentrated areas before and after the moving band. The packing material reduces the extent of longitudinal diffusion to some degree. At low velocities, longitudinal diffusion negatively impacts resolution, although this effect diminishes at higher velocities. Notably, this term holds significant importance in gas chromatography due to significantly higher diffusion coefficients in gases than in liquids. In liquid chromatography, this term is typically near-zero relative to other factors.

The Mass Transfer Terms (Cu):
The mass transfer term highlights the perpetual lack of equilibrium between the mobile and stationary phases within a chromatography column. Analytes in the mobile phase require time to move into the stationary phase, but equilibrium isn’t fully attained. Consequently, some analytes are carried ahead of the main band. Equally, molecules take time to move out of the stationary phase, leaving certain analyte molecules behind due to the swift movement of the mobile phase. While both longitudinal diffusion and mass transfer are diffusion-based, they occur differently concerning flow rate. Longitudinal diffusion occurs parallel to the flow direction, inversely linked to the mobile phase flow rate, while mass transfer diffusion happens perpendicular to the flow rate. Thus, faster mobile phase movement reduces the time available for phase equilibrium, directly impacting peak broadening through the mass transfer effect.

Question 125

What does a thermal conductivity detector (TCD) involve?

Answer 125

A Thermal Conductivity Detector (TCD) comprises an electrically heated filament in a temperature-controlled cell. Typically, there is a consistent heat flow from the filament to the detector. However, when an analyte reduces the thermal conductivity of the column effluent, the filament heats up and its resistance changes. This alteration in resistance is detected by a Wheatstone bridge, resulting in a measurable voltage change.

All compounds, regardless of being organic or inorganic, possess a thermal conductivity different from that of helium (the carrier gas).
This detector can sense and detect all compounds.

A TCD exhibits similar responses to comparable concentrations of organic analytes. Hence, it can be used without calibration, allowing estimation of the sample component’s concentration by the ratio of the analyte peak area to all components (peaks) present in the sample.

However, the detector has limitations due to its relatively lower sensitivity in comparison to other detectors. Additionally, it often has a relatively large dead volume, which makes it less suitable for capillary work.

Question 126

What does a flame ionization detector (FID) involve?

Answer 126

The Flame Ionization Detector (FID) has nearly universal sensitivity to organic compounds, exhibiting excellent sensitivity and remarkable linearity.

In this detector, the column effluent is directed into a flame fuelled by hydrogen, with forced air flowing.
A potential of several hundred volts is applied between the tip of the flame burner and the collector surrounding the flame.
When sample components combust, they generate a burst of ions, resulting in a current between the flame tip and the collector.

The FID detector offers several advantages. Its response is approximately proportional to the number of carbon atoms present in the flame at any given time.
Moreover, it is insensitive to inorganic gases, water, carbon dioxide, sulphur dioxide, nitrogen oxides, and other non-combustible gases.
Additionally, the detector boasts an extremely wide linear range, spanning about seven orders of magnitude, and has a low dead volume of approximately 1 ml.

Question 127

How can data from chromatograms be quantified?

Answer 127

Chromatogram data can be utilized to determine the relative or absolute concentration of components within a mixture, assuming good resolution is achieved.

The peak area, derived from the integration of the detector signal during the elution of a component, is directly proportional to the amount of that particular component in the sample.
However, it’s important to note that a detector’s response can vary among different compounds. For instance, an HPLC ultraviolet detector relies on the absorption of electromagnetic radiation, considering the spectra of the components and the detection wavelength utilized.

To obtain quantitative information, there are four principal methods:
1. Normalizing peak areas
2. Using internal standards
3. Employing external standards
4. Applying standard addition methods.

Question 128

How is chromatography scale up factor calculated?

Answer 128

Scale up Factor = (diameter^2 * length)/(Analytical diameter^2 * analytical length)

This factor is used to calculate the preparative column loading.
For example if a 1mg sample loading is used with a 3.9mm ID analytical column, then a 24mg loading is required for a preparative column with a 19mm ID.

Flow rate (prep) = flow rate (analytical) * (prep diameter)^2 / (analytical diameter)^2

Question 129

What are the main focuses of process safety?

Answer 129

Preventing injury and death

Preventing damage to plant

Prevent loss of production

Maintain company reputation

Question 130

Why are semi-batch processes preferred in the pharma industry?

Answer 130

Easier process control

Rate of reaction can be controlled by the rate of the addition (or removal) of components

Reactive inventory is limited

Question 131

What are the 4 key considerations of process safety?

Answer 131

1. Substitue
2. Minimise
3. Moderate
4. Simplify

Can it be made inherently safer?
– Inherent safety is a philosophy - it seeks to remove hazardous procedures or reagents from the process.

Question 132

What is a key consideration in geometric similarity?

Answer 132

Using the single scale ratio, S.

This defines the relative magnitude of all linear dimensions between the large and small scales. It is important that only linear dimensions are considered (e.g. diameter, temperature, height, etc.)

E.g. S = D2/D1

Non-linear parameters e.g. volume can not be considered. Volume would increase by a factor of S^3

Question 133

What does kinematic similarity consider?

Answer 133

Velocities at geometrically similar positions remain constant
* Constant tip speed
* Constant superficial gas velocity
* Constant maximum liquid velocity in impeller discharge

Question 134

What does dynamic similarity consider?

Answer 134

That the ratio of forces (dimensionless groups) remain constant at different scales
* E.g. constant Froude number for systems in which vortexing for gas entrainment is required

• Beware:
  – The relationship between process performance and the dimensionless group may not be linear

Question 135

General scale-up advice:

Answer 135

Physical operations take longer

Heat transfer is worse

Mixing is more difficult to achieve

Distillations are less efficient

Note - on scale up, impeller speed goes down

Question 136

What are the scale-up rules for the following?

Solid distribution
Gas-liquid
Solid suspension
Liquid blending

Answer 136

Solid distribution: equal energy input (P/V)

Gas-liquid: Equal mass transfer kla

Solid suspension: Zwietering (related to mixing)

Liquid blending: Equal tip speed U

Question 137

What is the difference between minimum stirred and minimum mixed volume in a tank?

Answer 137

The minimum stirred volume in a tank is the smallest volume at which the impeller is at least partially submerged so that it will provide some fluid motion.
This is suitable for processes where proper mixing is not required, e.g. some basic distillations, or boil-outs for cleaning purposes. This volume is usually less than 10% of the nominal tank volume.

The minimum mixed volume in a tank is the smallest volume at which the agitation system in the tank (impeller(s) & baffles) can create a mixing environment that results in reproducible process performance e.g. for crystallisations. This volume is usually between 30-40% of the nominal tank volume.

When designing a batch plant or a process, it is the minimum mixed volume in a tank that determines the smallest batch size, not the minimum stirred volume.

Question 138

What materials are commonly selected for use in pharmaceutical plants?

Answer 138

Common materials of construction for a pharmaceutical plant are (in increasing cost order) glass lined mild steel, stainless steel and hastelloy.

If you need very high corrosion resistance, tantalum is also a possibility but very expensive.

What material you can choose depends on compatibility with your process. If you have to deal with HF (hydrofluoric acid) that would rule out glass (but it may depend on the concentration – if very low, you might be able to get away with special pharmaglass), so you have to check which metal alloys suit.

Question 139

How do you go about choosing a type of crystalliser to use for a solution crystallisation process?

What are the typical things to consider?

Answer 139

Primary things to consider are heat transfer and mixing. If you opt for a stirred tank, select a cost effective material of construction that is not only compatible with your process but also has good thermal conductivity.

If you have to use glass-lined steel rather than stainless steel, go for
conductive Pharmaglass and ensure that you choose a heat transfer mode of operation that allows you to keep the required cooling profile easily.

Half coiled heat transfer pipes generate higher U values than traditional baffled jackets and are also easier to maintain.

For the mixing environment, axial flow impellers (e.g. wide blade hydrofoils) are preferable as they exert lower shear and cause less particle size modification; at least three baffles are needed.

You may want to consider multi-flight agitation, if you have a large vessel or have to operate the vessel at different fill volumes.

Question 140

Are there any guidelines about choosing a desired particle size distribution?

Answer 140

You should go with the largest mean particle size that the formulators can accept, as large particles mean easier filtrations and shorter plant cycle times.
The acceptable maximum size of API that is included in the tablet is driven by its dissolution and formulation characteristics.
Most APIs get milled before being processed further into tablets, so easy powder flow of the crystals from a hopper into the mill is of prime concern.

Aim for a tight, mono-modal PSD of the API, as this input to the mill produces similar output at the smaller size which is easier to blend with excipients before going to the tablet press.

Question 141

How does a typical pharmaceutical plant handle waste?

Answer 141

The waste of a process is separated into organic solvent waste and aqueous waste. Solvent waste gets drummed up and sent to incineration. Most production sites have their own incinerator, while smaller R&D sites send this waste off-site by tanker.

Aqueous waste gets treated in an on-site biological waste processing plant, and a cleaned water stream is returned to the environment.

Waste processing is considered a non-core activity by most pharmaceutical companies and is hence outsourced to specialised contractors.

Question 142

When designing a stirred reactor, is there an upper limit for stirrer speed?

Answer 142

The upper speed limit of a stirred vessel is governed by motor size, gearbox size and mechanical stability of the vessel.

It is common to design a reactor with the smallest possible motor, gearbox and stirrer/baffle assembly agreeable with process requirements as this reduces capital and operating costs.

Question 143

How can we obtain a particle size distribution for a crystalliser output, given expressions for the growth and secondary nucleation rate?

How can we quantify the effects of re-dissolving and destroying nuclei, and the suppression of secondary nucleation through control of process variables?

Answer 143

If you have an excessively large nucleation rate, then that indicates that you haven’t yet found the right operating conditions for your crystalliser.

In principle, secondary nucleation is caused by collision of crystals with themselves or the internals of the crystalliser.
This in turn is primarily governed by the dissipated energy into the mixture and the supersaturation of the solution.

The dissipated energy into the mixture can be controlled by the rotation speed of the impeller and the type of the mixing system.

To reduce secondary nucleation, select low shear impellers such as wide blade hydrofoils in a fully baffled environment (but eliminate additional reactor inserts such as samplers, coils or plates) and choose slow agitation speeds of larger diameter multi-stage impellers.

Hydrofoils are very effective in creating good circulation in the tank at comparatively low energy input, as they have low Power but high Flow numbers.

Supersaturation can be controlled via the temperature gradient, i.e. a slower cooling profile causes less secondary nucleation.

To quantify all of the above, you have to resort to empirical formulas.
B0 = k(ρa)(εb)(rg)^c

Where:
B0 - nucleation rate
k - system constant
ρ - suspension density
ε - dissipated energy
rg - growth rate

Exponents a, b, c need to be determined experimentally, but typical values are around 1, 0.5-1, 1.3-2.3, respectively.

Question 144

What’s the Penney diagram?

Answer 144

Used for plant scale-up processes, the Penney diagram relates the increase of energy input to the scale increase in a double logarithmic plot.

Both quantities are ratios, i.e. (P/V)plant / (P/V)lab and Vplant / Vlab.

If the ratios relate to each other, the same must be true for the individual values, i.e. P/V and V. The volume is essentially a linear dimension cubed (times a constant).

P/V is N cubed D squared times a constant.
Provided that we can express the scale-up rule of ND^m as a factor of N^3D^2, we can work out their corresponding slopes in the double logarithmic plot.

Question 145

What’s the Mechanistic / First Principle approach for design (in pharma)?

Answer 145

A first principle, or mechanistic, model is a combination of experimental data and mechanistic knowledge of chemistry, physics, and engineering which enables the prediction of process performance.

A first principle, or mechanistic model, is derived from an understanding of the underlying science e.g. chemical reaction kinetics.

Question 146

What’s the Empirical modelling approach for design (in pharma)?

Answer 146

Carefully planned experimentation incorporating DoE [design of experiments] studies (an efficient method for determining the impact of multiple parameters and their interactions) is used to obtain data which are used to derive both the form of the model and the associated unknown model coefficients.

Question 147

What are the different types of HPLC & uHPLC ((ultra)-High performance liquid chromatography?

Answer 147

Normal Phase
Reversed Phase
Preparative
Simulated Moving Bed
Ion Exchange
Size Exclusion

Question 148

What are the charges of anions and cations?

Answer 148

Anions: Negatively charged

Cations: Positively charged

Question 149

How does normal phase HPLC (high-performance liquid chromatography) work?

Answer 149

Polar stationary phase
Non-polar mobile phase

Polar compounds interact more strongly with the polar stationary phase, causing them to move more slowly through the column.
Non-polar compounds interact less and move more quickly. This differential interaction leads to separation of the compounds.

Compounds elute (exit) the column at different times, known as retention times, based on their interactions with the stationary phase.
This allows for identification and quantification by comparing retention times of known standards.

Question 150

How does reversed phase HPLC (high-performance liquid chromatography) work?

Answer 150

Non-polar stationary phase
Polar mobile phase

Non-polar compounds interact more strongly with the non-polar stationary phase, causing them to move more slowly through the column.
Polar compounds interact less and move more quickly. This differential interaction leads to separation of the compounds.

Compounds elute (exit) the column at different times, known as retention times, based on their interactions with the stationary phase.
This allows for identification and quantification by comparing retention times of known standards.

Alkyl chains are covalently bonded to the solid support, creating a hydrophobic stationary phase with a stronger affinity for hydrophobic compounds.

Question 151

How does preparative chromatography work?

Answer 151

Preparative chromatography is the process of using liquid or supercritical fluids to isolate a sufficient amount of material for other experimental or functional purposes.

The goal of preparative chromatography is to isolate and purify a specific compound or compounds from a mixture.

The choice of column size, stationary phase, and mobile phase depends on the properties of the compounds being separated. (Typically, columns used in preparative chromatography are larger and can handle higher sample loads, with diameters around 2cm - 1m).

The sample containing the mixture to be separated is loaded onto the column (in larger quantities compared to analytical chromatography).
The separation process occurs similarly to analytical chromatography, with compounds interacting with the stationary phase and eluting at different rates based on their affinity for the stationary phase.

As the compounds elute from the column, they’re collected in fractions. These fractions contain the separated compounds and are collected based on their retention times.

Question 152

What’s the difference between analytical and preparative chromatography?

Answer 152

Analytical:
- It’s primary goal is to provide information about the composition, concentration, and properties of the substances present in the sample.
- Smaller scale
- Often involves continuous detection and recording of separated components but may not always collect fractions

Preparative:
- Its primary purpose is to obtain larger quantities of pure substances for further use
- Large scale
- Collects fractions containing the separated compounds of interest

Question 153

How does simulated moving bed chromatography work?

Answer 153

Continuous counter-current chromatography.

This is accomplished with a series of chromatography columns arranged in a ring. An eluent flow circulates through this ring.

SMB uses a series of switching valves that continuously redirect the flow of the mobile phase and the sample between different zones within the column. These valves control the direction of flow, allowing the stationary phase to behave as if it were moving while actually remaining stationary.

As the mobile phase flows through the column, the components of the mixture interact with the stationary phase. Due to the counter current movement and periodic switching, different components move to different sections of the column, leading to continuous separation.

Question 154

How does ion exchange chromatography (IEC) work?

Answer 154

The stationary phase consists of a solid support material with charged functional groups.
For cation exchange chromatography, the stationary phase has negatively charged functional groups (anionic groups like sulfonate or carboxylate).
For anion exchange chromatography, the stationary phase has positively charged functional groups.

When a sample containing ions of interest is introduced to the column, ions with charges opposite to those on the stationary phase are attracted and retained on the stationary phase. Ions with the same charge as the stationary phase move more quickly through the column.

A mobile phase (buffer solution) is passed through the column. By changing the composition or concentration of the mobile phase, the strength of the ionic interactions between the sample ions and the stationary phase can be altered.

As the mobile phase flows through the column, ions are selectively displaced from the stationary phase based on their interactions. The retained ions are released when competing ions in the mobile phase displace them, allowing for separation based on the differences in their affinity for the stationary phase.

The eluted ions are detected using various detectors, such as conductivity, UV-Vis spectrophotometry, or mass spectrometry, to identify and quantify the separated ions.

Question 155

Describe size exclusion chromatography (SEC):

Answer 155

The stationary phase in SEC consists of porous beads or a gel matrix. These beads have pores of defined sizes that allow molecules to enter the pores based on their size.

When a sample containing molecules of various sizes is introduced into the column, larger molecules cannot enter the pores of the stationary phase and, therefore, take a shorter path through the column.
Smaller molecules, however, can enter the pores and take a longer, more convoluted path as they move through the column.

A mobile phase (buffer solution) continuously flows through the column, carrying the sample components. As molecules elute from the column, they are detected by a detector.

Question 156

Discuss how packed GC works:

Answer 156

Packed column gas chromatography operates using a column filled with a solid support material.
This stationary phase interacts with the sample compounds as they pass through the column.

The sample, typically in a gaseous or vaporized state, is introduced into the column through an injector port. The sample is vaporized and carried by an inert carrier gas through the column.

As the sample travels through the column, different compounds interact differently with the stationary phase based on factors like polarity, size, and volatility.
Compounds with stronger interactions with the stationary phase spend more time in the column.

Question 157

Discuss how capillary GC works:

Answer 157

Capillary gas chromatography (GC) is an advanced form of gas chromatography that utilizes a capillary column for separation.

It uses a very narrow, capillary-sized column. These columns are typically coated with a thin layer of stationary phase, often a liquid film or a bonded phase, which provides the separation mechanism.

As the sample components travel through the capillary column, they interact with the stationary phase. Separation occurs based on differences in the interaction of the compounds with the stationary phase, including factors like polarity, size, and volatility.

Capillary GC offers higher resolution, sensitivity, and efficiency compared to packed column GC. It allows for better separation of complex mixtures and can handle smaller sample sizes due to its sensitivity.

Question 158

Describe supercritical fluid chromatography (SFC):

Answer 158

SFC typically uses a chromatographic column packed with a stationary phase, often silica-based or other materials designed for compatibility with supercritical fluids.
The mobile phase, usually supercritical CO2, carries the sample through the column.

Separation occurs based on differences in compound interactions with the stationary phase and the supercritical fluid. Compounds with different polarities or sizes interact differently, leading to separation as they move through the column.

Question 159

What’s the Van Deemter plot?

Answer 159

A plot of chromatography plate height (H) vs average linear velocity of mobile phase (u).

The van Deemter equation is a hyperbolic function that predicts that there is an optimum velocity at which there will be the minimum variance per unit column length and, thence, a maximum efficiency.

Question 160

Do chromatography columns have plates?
What is the number of theoretical plates for?

Answer 160

Chromatography columns don’t have physical plates like those in fractional distillation columns.

The number of theoretical plates is a measure of the efficiency of a chromatography column. It’s a theoretical concept used to describe the effectiveness of separation within the column.
Each theoretical plate represents a hypothetical stage or zone in the column where equilibration between the mobile phase and stationary phase occurs.

The higher the number of theoretical plates, the greater the column’s separation efficiency. A higher number of theoretical plates means better resolution and sharper peaks in the chromatogram.
This implies that compounds spend more time interacting with the stationary phase, resulting in better separation.

The equation used to calculate the number of theoretical plates is the Van Deemter equation, which takes into account different factors influencing the column efficiency, such as the rate of mass transfer, longitudinal diffusion, and eddy diffusion.

Question 161

What’s resolution in chromatography?

How can it be calculated?

Answer 161

Resolution refers to the ability of a column or separation method to separate two adjacent peaks or components in a mixture.
It’s a measure of the degree of separation or how well two different analytes are distinguished from each other within a chromatographic system.

For high resolution, these diffusion factors should be minimised (plate height should be small).

R = sqrt(N)/4 * ((a-1)/a) * (k2 / (k2+1))

Where:
k2 is the retention factor of the second (or later eluting) peak
a is selectivity (k2/k2)

(or 2 other existing equations)

Question 162

What’s the effect of particle size on chromatography?

Answer 162

Reducing particle size minimizes the impact of flow rate on peak efficiency.

Smaller particles have shorter diffusion paths, facilitating faster movement of solutes in and out of the particles.

The analyte spends less time within the particle, reducing the opportunity for peak diffusion to occur.

As particle size decreases, the Van Deemter curve becomes flatter, showing less susceptibility to higher column flow rates.
Smaller particle sizes result in better overall efficiencies and decreased peak dispersion across a broader spectrum of usable flow rates, albeit with significantly increased back pressures.

Question 163

What is the Giddings relationship for reduced plate height and reduced mobile phase velocity v?

Answer 163

h = H / dp
Where:
H is height equivalent of theoretical plate (um)
dp is mean particle size (um)

v = u*dp/Dm
Where:
u is linear velocity of the mobile phase
dp is the particle diameter
Dm is the diffusion coefficient of the solute in the mobile phase

A well-packed column should have a reduced plate height (h) in the range of 2-3 at a reduced velocity (v) of about 3.

With the above parameters, an empirical form of the Van Deemter equation can be derived:

h = B/v + Av^(1/3) + Cv

Question 164

What is a TCD?

Answer 164

A thermal conductivity detector

It comprises an electrically heated filament housed in a temperature-controlled cell. In standard conditions, a consistent heat transfer occurs from the filament to the detector body.
As an analyte elutes and decreases the thermal conductivity of the column effluent, the filament experiences a rise in temperature and alters its resistance.
This change in resistance is detected by a Wheatstone bridge, generating a detectable voltage shift.

Given that all compounds, both organic and inorganic, exhibit a thermal conductivity distinct from helium (the carrier gas), the TCD can detect all compounds.
Similar concentrations of organic analytes elicit comparable responses from the TCD, allowing its use without calibration.
Estimation of a sample component’s concentration can be inferred from the ratio of the analyte’s peak area to the total components (peaks) in the sample.

However, the detector’s sensitivity is relatively low compared to other detectors, and it typically possesses a relatively large dead volume. Consequently, it’s not particularly suitable for capillary work.

Question 165

What does normalising peaks areas (chromatography quantitation) involve?

Answer 165

It is simply the area of an individual peak calculated as a percentage of the total areas recorded for all peaks in the chromatogram.

Question 166

What does the internal standard method (chromatography quantitation) involve?

Answer 166

The internal standard method offers enhanced accuracy in quantitative analysis. It negates the necessity for precisely measured injections by incorporating a reference standard within each analyzed sample. An internal standard is chosen to elute at a strategic point in the chromatogram.

The process involves analyzing a test mixture sample with known quantities of each component and a predetermined amount of the internal standard (I.S.) to compute the Response Factor (RF).

RF = (Ax * Cis)/(Ais * Cx)

Ax is Area of the compound of interest
Cx is Concentration of the compound
Ais is Area of the internal standard
Cis is Concentration of the internal standard

Once the response factor is established, analysis of an unknown mixture involves adding a precisely known quantity of the internal standard and conducting chromatography.

Question 167

What does the external standard method (chromatography quantitation) involve?

Answer 167

Automated sample injection systems and multiport injection valves in High-Performance Liquid Chromatography (HPLC) exhibit excellent reproducibility, enabling a sequence of injections with minimal variation in sample volume, typically less than 1%.

In the calibration process, a series of standard mixtures with precisely known concentrations of the analytes is analyzed, and their corresponding peak areas are recorded.

This data is then used to construct a calibration graph plotting the area against the concentration for each analyte. The purpose of this graph is to verify a linear response from the detector concerning the concentration of the analyte.
Once confirmed, this calibration graph serves as a reference tool for determining the amount of the analyte present in a mixture based on its detected peak area.

Question 168

What does the standard addition method (chromatography quantitation) involve?

Answer 168

This process involves adding a standard solution of a known analyte concentration to an unknown solution. Typically, multiple solutions are prepared, each containing the same volume of the unknown solution but varying amounts of the standard. For instance, using five 25 mL volumetric flasks, 10 mL of the unknown solution is added to each.
Then, different volumes of the standard solution (e.g., 0, 1, 2, 3, and 4 mL) are added to each flask. The mixtures are subsequently diluted to the mark and thoroughly mixed.

The principle behind this procedure lies in combining the unknown and standard solutions to create varying total concentrations of the analyte. The expectation is that the total concentration varies linearly with the added standard volume.
If the signal response from the detector shows linearity within this concentration range, it generates a plot resembling the one demonstrated. This plot aids in determining the concentration of the analyte in the unknown solution based on the known concentrations of the standard and the resulting signal response.

Question 169

How does flash chromatography differ from preparative chromatography?

Answer 169

Flash chromatography is a form of preparative chromatography.

This method differs from conventional techniques in two ways:

1. It uses slightly smaller silica gel particles.
2. Due to the restricted flow of solvent caused by the smaller gel particles, pressurized gas (nitrogen or air at approximately 10-15 psi) is used to drive the solvent through the column of stationary phase.

As a result, this approach enables rapid and high-resolution chromatography, often completing the process swiftly (“over in a flash”).

Question 170

How can a chromatography system be overloaded?

Answer 170

1. By increasing sample conc whilst maintaining a constant injection volume (conc overload). Column efficiency has little effect on conc overloading.
2. By increasing the injection volume whilst maintaining a constant sample conc (volume overload). Volume overloading is heavily influenced by stationary-phase particle size and column diameter.

A column is considered overloaded when retention factors obtained at low sample concentrations, change by more than 10% as the sample size is increased.

Question 171

Mixing checklist considerations:

Answer 171

• What is the mixing duty?
• What is the volume?
• What is the success criterion?
• Operation mode:
  – batch, semi-batch or continuous?
• Operating conditions:
  – flow rates, temperature, pressure,…
• Chemical reaction:
  – reaction rates
• What phases are present?
  – Volume fraction?
  – Physical properties
• How do physical properties change during run?
• Sketch the vessel, including all major
  dimensions
• What impellers are fitted?
  – What sizes?
  – Motor/gearbox ratings?
• What vessel internals are present?
  – Baffles
  – Inlet and outlet pipes?
  – Dip pipes?
  – Surface additions?
  – Solids bed depth
  – Gas-liquid dispersion height
  – Heating/cooling coils
• Solids-liquid mixing
  – Particle size, density, concentration
  – Solids distribution
  – Solids degradation
  – Agglomeration?
• Liquid-liquid mixing
  – Interfacial tension
  – Volume fraction of liquids
  – Mass transfer with chemical reaction?
  – Phase inversion
• Heat transfer
  – Liquid heat capacity
  – Thermal conductivity
  – Temperature of heating/cooling medium
  – Heat load and transfer area

Question 172

Mixing mechanical design checklist:

Answer 172

• Power draw P must be known for sizing the motor and drive
  – Large power draw means large drive
• Gearbox is rated to run over a range of N and torque Λ
  – Torque determines the gearbox, hence the capital cost
• Gearboxes are more expensive than motors!
• P and Λ determine the capital and running costs
  – If the impeller must start from rest in a bed of solids, the power and torque
  requirements for start-up can be extremely large, and depend on the characteristics of the solid
• Power dissipated by the impeller is important for predicting process performance:
  – Mixing time, mass transfer coefficient and droplet sizes have been correlated to power
  – Power consumption calculated from torque measurements: P=2 π N Λ
• Torque is measured in different ways at different scales
  – Small scale measurements
• Mount vessel or motor on frictionless bearings and measure torque using a load cell or dynamometer
• Use a commercial torque meter
• Use a modified rheometer
  – At larger scales:
• Strain gauges can be used.
• Electrical current can be used.
  – Subject to many errors
  – Estimate of losses in the gearbox and bearings required
• Beware of:
  – Vibration & resonance problems

Question 173

How is average slurry density calculated?

Answer 173

ρ.ave = (ms + ml)/V

Where:
ms - mass of solids
ml - mass of liquids
V - volume

If their densities and solid concentration is given,
ρ.ave = ρl + ((ρs - ρl)x)/((ρs/ρl)(1-x)+x)

Question 174

What is the Zwietering correlation?

What is the Zwietering correlation equation?

Answer 174

The Zwietering correlation refers to an equation used to estimate the mixing time required to achieve a certain level of homogeneity in a tank or vessel.

N.js = S * v^0.1 * dp^0.2 * X^0.13 * D^-0.85 * ((g*dρ)/ρl)

Where:
N.js - just suspension speed
S - vessel related constant
v - kinematic viscosity
dp - particle diameter
g - gravity
dρ - density difference between solid and liquid
ρl - liquid density
X - solid to liquid mass ratio
D - impeller diameter

N.homogeneous ≈ 1.25 * N.js

Question 175

What are the 5 “million dollar questions” in pharma drug development?

Answer 175

1) What are we making?
- Tablets (size, shape, coating…)?
- Capsules?
- Suspension?
- Aerosol?
- something else?

2) How much active ingredient and in what form?
- particle size distribution?
- crystalline vs. amorphous?
- pure API vs. salt vs. co-crystal vs. solvate?

3) What are the requirements on dissolution / release kinetics?
- immediate release vs. sustained release?
- pH dependent release? (mouth, stomach, intestine)
- t10, t50, t90 ?

4) What is the overall composition of the product (formulation)?

5) What is the process route (sequence of unit operations)?

Question 176

Main steps of tabletting:

Answer 176

Cyclic operation:
- Feed
- Pre-compact
- De-aerate
- Final compaction
- Eject

Need to use lubricants (e.g. magnesium
stearate) to avoid sticking to punch or die walls and reduce wear.

Problems:
capping, de-lamination

Question 177

Describe extrusion-spheronisation:

Answer 177

Principle of operation:
-Prepare a paste from API, excipients, binder, water
-Extrude paste through screen to form “noodles”
-Contact extrudates with a high-speed rotating disk
-Dry resulting spherical pellets

Question 178

Two plant layout approaches:

Answer 178

Vertical flow principle:
- processing stations on different levels
- gravity flow

Horizontal flow principle:
- processing stations on the same floor
- transport by IBC’s or pneumatic conveying system

Question 179

Regarding particle size-dependent solubility, how is the solubility of a particle with radius r calculated?

Answer 179

c(r) = C(∞)e^((2γVm)/(rR*T))

Where:
c(r) - solubility of particle with radius r
c∞ - solubility of macroscopic particle
γ - solid-liquid interfacial tension
Vm - molar volume of solid
R - molar gas constant
T - temperature

Large particles will grow at the expense of small ones (Ostwald ripening)

Question 180

What is the meaning of a critical radius of a particle?

Answer 180

The smallest crystal that can exist in a solution of given concentration.

Typically 4-10 nm for many solids.

Question 181

List key crystal growth regimes:

Answer 181

1. Continuous growth (many growth sites on surface)
2. Surface nucleation (several nuclei on surface)
3. Spiral growth (single nucleus on surface)

Question 182

When carrying out mass balances on crystallisers, what do n and G represent?

Answer 182

G - growth rate (um / s)

n - number density (# /um /m3)

Plotting size (um) vs ln n gives a linear (-ve) plot (with a slope of -F/VG, with F/V = 1/t) and a y intercept of ln n0.

Question 183

What is Darcy’s law for filtration?

Answer 183

An empirical linear relationship between the macroscopic filtration velocity, and the macroscopic pressure gradient.

ΔP = (Rf + Rc)(µ/A)dV/dt
Where:
µ - viscosity
A - CSA for flow
Rf - filter resistance
Rc - cake resistance (hc/kc)
kc - cake permeability

Question 184

How is specific filter cake resistance, a, found?

Answer 184

a = A*Rc / ms

A - CSA for fluid flow
Rc - cake resistance
ms - mass of cake

Question 185

How is dry cake mass per filtrate volume, x, found?

Answer 185

x = ms / V

Where:
ms - mass of cake
V - filtrate volume

Question 186

What is the equation for general filtration?

Answer 186

dt/dV = µαxV/(A2∆P) + µRf/(A∆P)

Where:
V - filtrate volume
µ - fluid viscosity
α - specific cake resistance
x - dry cake mass per filtrate volume
Rf - filter resistance
A - CSA for fluid flow

SIMPLIFIED VERSION:
dV/dt = kA∆P/(µ*L)

dV/dt - rate of volume change over time (filtration rate).
k - permeability of the filter medium.
A - effective filtration area.
ΔP is the pressure drop across the filter.
μ is the viscosity of the fluid.
L is the thickness or length of the filter medium.

Question 187

What’s the solution for the general filtration equation for constant pressure, ∆P?

Answer 187

Equation:
dt/dV = µαxV/(A2∆P) + µRf/(A∆P)
∆P = const.

Integrate the filtration equation…
[µαx / (2A2∆P)] V^2 + [µRf/(A∆P)] V - t = 0

t/V vs. V is a straight line ⇒ useful for data analysis

mass balance ⇒ cake depth as function of filtrate V:
hc = xV/[Aρs(1-ε)]

x - dry cake mass per filtrate volume
hc - cake thickness
ε - void fraction of filter cake

Plotting V vs time shows an upwards curve that plateaus after enough time.

Question 188

How is moisture ratio, φ, of filter cake found?

Answer 188

moisture ratio: φ = mass of wet cake / mass of dry cake

φ = 1 + (ρL/ρS)* ε/(1-ε)

Question 189

What’s the solution for the general filtration equation for constant dV/dt?

Answer 189

Start with general equation:
dt/dV = µαxV/(A2∆P) + µRf/(A∆P)

Rearrange…
∆P = (µαx/A2)(dV/dt) V + (µRf/A) dV/dt

Plotting ∆P vs time for constant rate, ∆P increases linearly with time until ∆P.max is reached, then plateaus and remains constant.

Question 190

DELETE

Question 191

Describe how droplet morphology may vary with skin and non-skin formation:

Answer 191

If particles do not form a skin, there will be nucleation, and drying will likely result in porous particles.

Regarding skin formation, if a “strong” skin is formed, smooth particles are formed (hollowed centres).
If a “weak” skin is formed, the droplet can buckle, forming collapsed / non-spherical particles.
Weak skin can also lead to “puffing”, there the skin actually breaks, leading to collapsed shells.

Question 192

List key unit operations in pharmaceutical processing related to i) chemistry, ii) particle forming, and iii) particle processing

Answer 192

Chemistry:
- Reactions
- Separations
- Environmental (mass balances and solvent recovery)

Particle forming:
- Crystallisation
- Isolation
- Drying

Processing:
- Sieving
- De-lumping
- Micronisation
- Formulation

Question 193

‘What to watch out for’ when scaling up a pharmaceutical process:

Answer 193

Chemical Incompatibilities
* Solvent / reagent incompatibilities
* Solid/solid interactions
* Peroxide formation
– Ethers
– Aldehydes and ketones
– Secondary and tertiary alcohols

Self-Heating
* Most organic materials are unstable
* Rate of decomposition increases with temperature
* If heat losses > heat generated, temperature doesn’t increase and rate of decomposition remains slow
* When heat generated > heat losses, temperature begins to rise

Question 194

What’s the scale up rule and constant parameter for solid distribution?

Answer 194

Equal energy input (P/V = ε)

m = 0.67 so, for N*D^m = constant,

Constant parameter = N*D^(2/3)

Question 195

What’s the scale up rule and constant parameter for gas-liquid processes?

Answer 195

Equal mass transfer (kLa = ε)

m = 0.67 so, for N*D^m = constant,

Constant parameter = N*D^(2/3)

Question 196

What’s the scale up rule and constant parameter for solid suspensions?

Answer 196

Zwietering [ N.js = S * v^0.1 * dp^0.2 * X^0.13 * D^-0.85 * ((g*dρ)/ρl) ]

m = 0.85 so, for N*D^m = constant,

Constant parameter = N.js*D^(0.85)

Question 197

What’s the scale up rule and constant parameter for liquid blending?

Answer 197

Equal tip speed U

m = 1 so, for N*D^m = constant,

Constant parameter = N*D

Question 198

What’s the scale up rule and constant parameter for fast reactions?

Answer 198

Equal mixing time

Constant parameter = N

Question 199

What’s the scale up rule and constant parameter for heat transfer?

Answer 199

Equal Re

Constant parameter = ND^2

Question 200

How does impeller speed differ upon scale up?

Answer 200

It decreases (the amount it decreases to can be determined by the [6] different scale-up rules)

Question 201

What are the 2 ways crystal growth can be expressed?

Answer 201

1. By mass deposition rate
   R = K(G)Δc = 1/Adm/dt = 3ψ(v)ρ*G/ψ(A)

Where ψ(v) and ψ(A) are volume and surface shape factors

2. Linear growth rate
   G = dx/dt

Question 201

How can primary nucleation rate be calculated?

Answer 201

B = K(B)e^((-16 γ^3Vm^2)/(3R^3T^3σ^2)

Where:
σ - supersaturation
γ - interfacial tension between crystal and solution
Vm - molar volume of crystal
K(B) - function of agitation rate, equipment type, viscosity, and density

Question 203

Describe reverse phase chromatography:

Answer 203

It uses alkyl chains covalently bonded to a solid silica support.
This creates a hydrophobic stationary phase, which has a stronger affinity for hydrophobic (or non-polar) compounds.
The use of a hydrophobic stationary phase can be considered the opposite, or “reverse”, of normal phase chromatography - hence the term “reversed phase chromatography”.
The non-polar stationary phase is used with a polar mobile phase to separate solutes based on their molecular polarity.

More polar compounds will interact less with the stationary phase and will be retained less than non-polar solutes.

Question 204

Explain the relevant underpinning scientific concepts of the retention factor, and derive the
mathematical expression:

Answer 204

• The retention time, tr, is the time taken for a compound to travel through a column (from when it was injected to when it reaches the detector)
• If no compound is retained, it will still take time to travel through the column.
• The retention factor, k, is the time that a solute spends interacting with the stationary phase, found by correcting the retention time with the dead time, t0.

k = (tr-t0)/t0

Question 205

Describe relative retention time (RRT) and its calculation:

Answer 205

Relative retention time (RRT) reduces effects of variables that effect retention time, e.g. flow rate, temperature, and composition

RRT is an expression of a sample component’s retention time relative to the standard compound’s retention time.

A known compound is added to the sample matrix (an internal standard), and the relative retention times of the components is measured by:

RRT = Standard RT / Sample RT

Where:
- Sample RT is the retention time from injection of the sample of interest
- Standard RT is the RT measured from injection of the internal standard compound

Question 206

Describe the response factor and how it is calculated:

Answer 206

The response factor quantifies the relationship between the conc’ of a compound of interest and its response (typically measured as peak area or peak height) in the chromatogram.

The use on an internal standard procedure is recommended for accurate work, eliminating the need for accurate injections size a reference standard is included in each sample.
Using an internal standard, a response factor, RF, can be calculated to quantify the amounts of identified or known components.

RF = (Ax * Cis)/(Ais * Cx)

Ax is Area of the compound of interest
Cx is Concentration of the compound
Ais is Area of the internal standard
Cis is Concentration of the internal standard

Question 207

What’s the power number equation?

Answer 207

P = Po ρ N^3 D^5

Where:
Po - power number
Rho - fluid density
N - impeller rotational speed
D - impeller diameter

Po, or Newton number, Ne – Depends on
* Impeller type
* Impeller and vessel dimensions
* Properties of the phases present

Question 208

What does the aspect ratio of a vessel refer to?

Answer 208

The ratio of tank height (H) to tank width or diameter (T)

H : T

I.e. an aspect ratio of 1 means that H = 1

Question 209

How is the Penney diagram used?

Answer 209

The Penney diagram is a graphical representation for vessel scale-up purposes.

In the Penney diagram, the S^3 axis represents the scale-up factor cubed.
The scale-up factor is the ratio of the volume of the larger vessel to the volume of the smaller vessel.

The log P2/P1 axis represents the logarithm of the ratio of the power input per unit volume (P) in the larger vessel to the power input per unit volume in the smaller vessel.
This ratio helps in understanding the changes in power requirements as vessels are scaled up.

The Penney diagram allows engineers to determine whether the mixing conditions in the scaled-up vessel will be similar to those in the original vessel.
Generally, if the points representing different scale-up scenarios fall along the same curve on the Penney diagram, it suggests geometric similarity in mixing conditions between the vessels.

Here’s a summary of how the Penney diagram works:

Plot points on the Penney diagram for different scale-up scenarios, where each point represents a combination of scale-up factor and power input ratio.
Analyze the distribution of points on the diagram. If the points fall along the same curve, it indicates geometric similarity in mixing conditions.

Question 210

What are the 5 lines typically shown on the Penney diagram when considering scale up, in order of greatest to lowest gradient?

Answer 210

1. Constant mixing time (+ve gradient)
2. Constant P/V (y = 1, horizontal line)
3. Just suspension / Zwietering (-ve gradient)
4. Constant tip speed (more -ve gradient)
5. Constant heat transfer / Re (steep -ve gradient)

All line start from (0,1)

Question 211

What are the main steps involved in Direct Compression and Dry Granulation tablet manufacturing techniques?

Answer 211

Direct Compression Route: API + Filler + Lubricant > Size reduction > Blending > Tabletting > Coating (+ polymer solution) = Finished tablets

Dry Granulation Route: API + Filler > Blending > Roller compaction > Milling and Sieving > Blending (+ lubricant) > Tabletting > Coating (+ polymer solution) = Finished tablets

Unit operations:
Blending – forms homogeneous blend of API and excipients
Roller compaction – prevents segregation and forms plastically deformable particles suitable for tabletting. Improves bulk density and powder flowability
Sieving – removes oversized particles after dry granulation
Tabletting – forms actual tablets from the granules or powder blend
Coating – applied for taste masking due to bitter taste and unattractive appearance of the API

Question 212

What are the main steps involved in wet granulation tablet production?

Answer 212

API + Filler > Mix/Dissolve/Suspend > Dry > Milling and Sieving > Blending (+ lubricant) > Tabletting > Coating (+ polymer solution) = Finished tablets

Question 213

What are the main unit operations in tablet formation?

Answer 213

Blending – forms homogeneous blend of API and excipients

Roller compaction – prevents segregation and forms plastically deformable particles suitable for tabletting. Improves bulk density and powder flowability

Sieving – removes oversized particles after dry granulation

Tabletting – forms actual tablets from the granules or powder blend

Coating – applied for taste masking due to bitter taste and unattractive appearance of the API

Question 214

List tablet excipients and their functions:

Answer 214

Binder – improves tablet compressibility and mechanical properties
Filler – improves blend homogeneity and compatibility
Disintegrant – improve tablet break-up during dissolution
Lubricant – helps avoid material sticking to the tablet punch
Desiccant – binds to moisture in the packaging to avoid API degradation
Coating material – taste masking and improved appearance

Question 215

List suitable impeller designs for axial and radial flow:

Answer 215

Axial:
- 45° pitched blade
- Hydrofoil
- Propeller

Radial:
- Rushton turbine
- Smith turbine
- Disc turbine
- 45° pitched blade
- Anchor

Question 216

What are the key aims of the FDA?

Answer 216

• Promote new technology
• Introduce modern quality management techniques
• Risk-based approaches to R&D and inspection
• Promote science-based policies
• Improve FDA drug quality regulatory programs

FDA wants to move from a product centred regulatory program to a systems based regulatory programme, thereby easing the regulatory burden for both FDA and industry.

• Regulators approve investigative new drug applications (IND) as well as new drug applications (NDA).
• INDs feeds a company’s research pipeline and ensures business sustainability
• NDAs create revenue to fund R&D and provide return on investment for shareholders

Question 217

How is Reynolds number calculated for pharma processes with impellers?

Answer 217

Re = ρND^2 / μ

Where:
μ is viscosity (Pa s)
N is rotational speed (rps)
D is diameter (m)
ρ is density (kg/m3)

Question 218

Chromatography is an essential analytical method during pharmaceutical process development and there are different methods to obtain quantitative information from chromatograms.
In your opinion, which one is the most popular one in a synthetic chemistry laboratory during API route selection (early development) and which one is preferred by chemical engineers for kinetic studies (late development)?

Give reasons for your decision:

Answer 218

There are 4 main methods for identifying quantitative information:
- Normalizing peak areas
- Internal standards
- External standards
- Standard addition

• Normalising peak areas is the most popular with synthetic chemists.
• The area of an individual peak is calculated as a percentage of the total areas recorded for all peaks.
• It is simple and quick
• During route selection, there will be lots of samples, and the basic information of peak area normalisation is sufficient to make decisions on the route as it relies on major effects being seen.
• However, it does not reliably provide information on absolute concentrations, hence it is useless for kinetic studies in late development.
• For kinetic studies, internal standards, external standards, and standard addition can be used.
• To minimise sample handling and the associated inaccuracies due to volume additions and variations in injections, the internal standard method would be preferred for kinetic work.
• The internal standard method involves using a reference standard included in each sample.

Question 219

Clearly articulating a design space in a new drug application is key to receiving the regulatory authority’s approval on the manufacturing process, and an image says more than a thousand words.
How would you graphically demonstrate that your process performs reliably to expectations?

Answer 219

Technically, any diagram that compares experimental and predicted data can be used as evidence that the plant’s control strategies are working.

However, the best way to present this info is through parallel coordinate plots, allowing multidimensional data to be visualised in 2D

In the parallel coordinates plot, equally spaced parallel axes are drawn for each variable (CQA, QCPP, etc.)

Then a given row of data (values for a single batch) are represented by drawing a line that connects the values of that row on each corresponding axis

Proven acceptable ranges (PARs) can be displayed for single or multiple unit operations

As long as each batch (or overall process) always remains within the visual boundaries, there is evidence that the control strategy is working.

Question 220

In a secondary manufacturing plant, a quality control audit has revealed that some tablets do not have sufficient mechanical stability (i.e. break easily in half) and that the API is unevenly distributed in the tablet (i.e. each half contains a different amount of API).
After receiving the API from the primary process plant, it gets fed into a micronizer before the tablets are manufactured through a straightforward direct compression route.

Before being packaged, the tablets get coated.

a) Identify possible root causes of the problem in each unit operation and what should be investigated at each stage.

b) Where in the overall process do you think is the most likely cause for the fault?

Answer 220

a) Direct compression route has the following unit operations which could bring about an error:

1. Milling – API could be under or over reduced in particle size at the mill stage. Check PSD before and after microniser.
2. Blending – API gets blended with filler, binder, and lubricant. Either the blender does not mix for long enough or its efficiency is decreased somehow. A faulty solid addition system can contribute to error as the tablets have insufficient mechanical stability. Variance in composition should be checked here.
3. Compacting – in the tablet press itself, 2 sources of error could occur - an insufficient compression force or insufficient ejection which leads to impurities and changes to the composition. Operation parameters and cleanliness of the press should be investigated here.
4. Coating – does not usually impact mechanical stability unless pellets get too wet, leading to recrystallisation or dissolution. Drying rates should be checked.

b) The most likely source of error is in the blending stage (insufficient solid mixing) and the tabletting stage (solid cohesion is insufficient). A final possibility is that the API itself has changed e.g. into a different polymorph with difficult physical properties.

Question 221

List some difficulties of batch processing:

Answer 221

Longer reaction times
By-product formation
Frothing
Unexpected rheological changes
Slow filtrations
Slow phase separations
Lower yields
More impurities

Question 222

What is the smallest lab scale for which you can accurately investigate (e.g. mixing behaviour)?

Answer 222

2L

Question 223

How does equal power input P/V relate to degree of agitation?

Answer 223

0.005 - gentle
0.1 - mild
0.3 - moderate
1.0 - high
2.0 - intense

P/V values in kW/m3

Question 224

What is the baseline resolution for chromatography?

Answer 224

1.5

Baseline resolution usually occurs at resolution number of 1.50; however, there is no visible baseline between the two peaks.

Numbers greater than 1.50 indicate there is baseline between the peaks and numbers less than 1.50 indicate there is some degree of co-elution.

Question 225

How is selectivity of a chromatography device found?

Answer 225

a = k2 / k1

Where k1 and k2 are the retention factors for species 1 and 2.