Module 6 Flashcards
Drug = Active +
Excipient
therapeutic ingredient
Active (API)
____ of the API is critical!
Purity and form
______ as a tool
Crystallization
Complexities of crystallization
Polymorphism, solvent selection,
existence of the metastable and spinodal state, etc.
Mechanisms of crystallization: physical landscape of
crystallization
Kinetic driver for nucleation
and growth?
Mechanisms of crystallization: energy landscape of crystallization
Thermodynamic driver for
nucleation and growth?
Relative rates to grow macroscopic crystals
Nucleation kinetics
Relative rates to grow crystals to a specific morphology
Crystal growth kinetics
Impurities affecting crystallization rates
Secondary nucleation
Occlusion
Inclusion
Attachment to surfaces
__________ is inherently random, poorly understood, difficult to study, thus very difficult to control
_________ is “reasonably” more understood
________ are two-edged swords
Nucleation; crystal growth; impurities
________ is the process of adding
homogeneous or heterogeneous crystals as a catalyst to a crystallizing solution to nucleate and/or grow more crystals.
Crystal seeding
A seed crystal… (4)
provides a starting point for nucleation and growth.
can be used to create a specific crystal structure.
can be used to grow larger, more uniform crystals.
can be used to grow crystals in a controlled manner.
_______ is the first and essential step for control of a
crystallization process.
Seeding
The seed will immediately dissolve
since the mixture is not saturated
at this region.
(Unsaturated) solution
Spontaneous crystallization would
have already occurred at this point.
Suspension
The proper region to add a seed,
since nucleation is still on-going
Metastable zone
A key consideration is the
width of the Metastable Zone. The Mzwidth of KNO3 is ____, AZ5 is ____, AZ6 is _____, AZ7 is _____, and AZ8 is _____.
2, 8, 19, 39, >50
Errors and inaccurate
temperature readings during
solubility studies can cause
________ in a
crystallization process.
loss of control
If the system is polymorphic, and stable polymorph is desired, seeding between the ________ minimizes the risk of generating the metastable polymorph.
two solubility curves
T/F: Seeding alone does NOT guarantee control of crystal form and size.
True
Possible outcomes of seeding (3)
- There could be a mixture of crystal structures.
- The desired crystal structure i s obtained but particle size is not controlled.
- The structure and size is controlled.
The most important factor controlling the rate of crystallization is the thermodynamic
driving force – the ________.
supersaturation
For supersaturation, applying a linear cooling rate results to __________ and _________.
Build up of supersaturation
at the start; nucleation
dominating over crystal growth
For supersaturation, applying a non-linear cooling rate results to __________ and _________.
Slow cooling at the start allows
S to be constant; Growth dominates over nucleation
Knowing how impurities _______ is
a critical step for the selection of adequate control strategies that are directed to the root cause of ________.
incorporate in the growing solute; impurity incorporation
Diagnosis of impurity incorporation
- Process imaging
- Dry powder analysis
- Powder dissolution
- Impurity adsorption tests
- Single - crystal analysis
Diagnosis technique that uses in - situ imaging probes
integrated to crystallization
systems. Non -invasive; provides
valuable information not
possible thru offline tests.
Process imaging
Diagnosis of analysis of powders by X-ray powder diffraction (XRPD) can
reveal information on crystallizing impurities, seen as the
appearance of a new pattern revealing a mixture of
crystalline phases or formation of a co- crystal.
Dry powder analysis
Diagnosis where hypothesized impurity distribution maps based
on progressive powder dissolution tests.
Powder dissolution
High degree of dissolution in the early steps is assumed to indicate that the impurities are located at the surface.
Zone A (Surface)
Impurities dissolving towards the later steps indicate that they are predominantly inside the crystal.
Zone B (Inclusion and substitution)
Diagnosis where they use of different particle sizes for
the diagnosis of surface impurities.
Impurity adsorption tests – powder-based
For Impurity adsorption tests – powder-based, if the impurities are located at the surface, ______ crystals with a _______ surface area per unit volume will present a ______ purity.
smaller; higher; lower
Warnings for Impurity adsorption tests – powder-based
Make sure that impurities did
not co-precipitate during
crystallization.
Lower purities for larger
crystals could be a
consequence of a spread in
nucleation times, solution
entrapment, or agglomeration.
This analysis is used to:
i . diagnose the location of impurities within a crystal,
ii. provide the highest level of fundamental understanding of the
relationship between surface chemistry, crystal growth, and
impurity incorporation.
Single - crystal analysis
Strategies for impurity prevention and control
✓ Solvent selection for crystallization and washing
✓ Predictive models ( e.g., population balance, nucleation and
growth kinetics )
✓ Impurity complexation
✓ Slurry aging and temperature cycling
_______ is driven by the generation of a supersaturated state for those impurities.
Impurity precipitation
If impurity concentration is too high, or the solubility in the
crystallization solvent is too low – impurities may _________ with the product of interest.
precipitate together
Co -formers that can form a co-crystal with the impurities will also form a _______ in solution.
complex
_________ prevents impurities from
incorporating in the growing crystals.
Complexation
In cases where prevention of impurity incorporation is not trivial or practical, an alternative to improve the purity of the final product is to implement
strategies to selectively dissolve impurities post- crystallization by __________
Slurry aging and temperature cycling
________selectively dissolve impurities post - crystallization
Slurry aging and temperature cycling
Strategies for slurry aging
§ Suspension of impure crystals in a wash solvent.
§ Application of mechanical agitation to promote crystal breakage and expose the
impure crystal core to the wash solvent.
§ Preferential dissolution of the impure core.
Strategies for temperature cycling
§ A method to accelerate the purge of impurities in equilibrium suspensions.
§ The dissolution of impure crystals and re-crystallization at low supersaturations is
promoted by heating and cooling cycles, triggering small increases and drops in
solubility for both the solute and the impurities.
Application of ______ to promote crystal breakage and expose the
impure crystal core to the wash solvent.
mechanical agitation
The ______ of impure crystals and _________ at low supersaturations is
promoted by ______ cycles, triggering small increases and drops in solubility for both the solute and the impurities.
dissolution; re-crystallization; heating and cooling
_________ was synthesized in the presence of sodium alginate (SA).
Struvite
Struvite crystal habit changed from
________ to ________ morphology, at increasing SA concentrations.
prismatic; plate-like twinned
Crystallization of API in pure system
End of crystallization
in <1 hour
Crystallization of API in the presence of an additive.
Lower yield, change in crystal habit
Additive-mediated glycine crystallization in _______ environments
quiescent
Inorganic salts can drive _________ for glycine.
selective polymorphism
__________ salts inhibited
crystallization of glycine. Taking _
days for crystals to appear.
Divalent; 7
Needle-like crystals are
characteristic of ____-glycine
gamma
Crystals formed after 7 days were
identified as _____-glycine.
alpha
Impurities may or may not provide
control to a crystallization process.
Control Of Crystallization.
Impurities may increase rates (i.e., _________) or decrease rates (i.e., inhibitors, _______).
secondary nucleation; complexation
Surface - active impurities may __________ on
crystal faces – directing growth to a different _________.
preferentially adsorb; crystal habit
T/F: Thermodynamics do not change with scale. Kinetics are also independent of scale. Problems with scale-up of crystallization processes still occur.
True
________ is impacted with temperature control issues during scale -up.
Cooling crystallization
_________ and/or seeding and the use of additive may cause _________ supersaturations in
the reactor mainly due to mixing __________.
Antisolvent addition; inhomogeneous; sensitivities
The _________ nature of a crystallization set-up introduces
additional sensitivities to mixing.
multiphase
API - solvent density differences may cause ________ of
API crystals which impacts mixing.
sinking
Vessel design considerations (i.e., baffles, agitators, vessel
shape, etc.) to ensure good suspension and minimize other
phenomena like ________.
attrition
Enabling technologies in the laboratory scale:
- Turbidity for nucleation and dissolution
- Chord length for seed and particle fingerprinting
- In-process cameras for morphology
- NIR and Raman for polymorph screening
- ATR- FTIR and ATR UV-Vis for solution concentration.
Seeding behavior changes with scale - in -line monitoring
of _________ may be helpful.
chord length
Use of __________ – is it useful considering our understanding of supersaturation?
feedback control
In-line monitoring of _________ – is this possible?
crystal purity
One should know what they are trying to make. Multiple experiments need to be done just to determine the desired crystal
form. Yield and productivity are not even relevant.
Make the first seed.
With a good choice of solvent and a
proper way to generate supersaturation, API crystallization can be designed to be fast, high yielding, and productive while maintaining robustness.
Produce that desired crystal.
________ go hand -in- hand in ensuring a controlled crystallization process. _______ the crystallization process (whether it be cooling crystallization or antisolvent crystallization) is an
important step in crystallization.
Kinetics and thermodynamics; Monitoring
The _______ crystallization of an API
should be performed as the _____
step of the formulation process.
final; first
