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Ph@rm@ > Module 6 > Flashcards

Module 6 Flashcards

1
Q

Drug = Active +

A

Excipient

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2
Q

therapeutic ingredient

A

Active (API)

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3
Q

____ of the API is critical!

A

Purity and form

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4
Q

______ as a tool

A

Crystallization

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5
Q

Complexities of crystallization

A

Polymorphism, solvent selection,
existence of the metastable and spinodal state, etc.

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6
Q

Mechanisms of crystallization: physical landscape of
crystallization

A

Kinetic driver for nucleation
and growth?

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7
Q

Mechanisms of crystallization: energy landscape of crystallization

A

Thermodynamic driver for
nucleation and growth?

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8
Q

Relative rates to grow macroscopic crystals

A

Nucleation kinetics

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9
Q

Relative rates to grow crystals to a specific morphology

A

Crystal growth kinetics

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10
Q

Impurities affecting crystallization rates

A

Secondary nucleation
Occlusion
Inclusion
Attachment to surfaces

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11
Q

__________ is inherently random, poorly understood, difficult to study, thus very difficult to control

_________ is “reasonably” more understood

________ are two-edged swords

A

Nucleation; crystal growth; impurities

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12
Q

________ is the process of adding
homogeneous or heterogeneous crystals as a catalyst to a crystallizing solution to nucleate and/or grow more crystals.

A

Crystal seeding

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13
Q

A seed crystal… (4)

A

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.

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14
Q

_______ is the first and essential step for control of a
crystallization process.

A

Seeding

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15
Q

The seed will immediately dissolve
since the mixture is not saturated
at this region.

A

(Unsaturated) solution

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16
Q

Spontaneous crystallization would
have already occurred at this point.

A

Suspension

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17
Q

The proper region to add a seed,
since nucleation is still on-going

A

Metastable zone

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18
Q

A key consideration is the
width of the Metastable Zone. The Mzwidth of KNO3 is ____, AZ5 is ____, AZ6 is _____, AZ7 is _____, and AZ8 is _____.

A

2, 8, 19, 39, >50

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19
Q

Errors and inaccurate
temperature readings during
solubility studies can cause
________ in a
crystallization process.

A

loss of control

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20
Q

If the system is polymorphic, and stable polymorph is desired, seeding between the ________ minimizes the risk of generating the metastable polymorph.

A

two solubility curves

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21
Q

T/F: Seeding alone does NOT guarantee control of crystal form and size.

A

True

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22
Q

Possible outcomes of seeding (3)

A
  1. There could be a mixture of crystal structures.
  2. The desired crystal structure i s obtained but particle size is not controlled.
  3. The structure and size is controlled.
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23
Q

The most important factor controlling the rate of crystallization is the thermodynamic
driving force – the ________.

A

supersaturation

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24
Q

For supersaturation, applying a linear cooling rate results to __________ and _________.

A

Build up of supersaturation
at the start; nucleation
dominating over crystal growth

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25
Q

For supersaturation, applying a non-linear cooling rate results to __________ and _________.

A

Slow cooling at the start allows
S to be constant; Growth dominates over nucleation

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26
Q

Knowing how impurities _______ is
a critical step for the selection of adequate control strategies that are directed to the root cause of ________.

A

incorporate in the growing solute; impurity incorporation

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27
Q

Diagnosis of impurity incorporation

A
  • Process imaging
  • Dry powder analysis
  • Powder dissolution
  • Impurity adsorption tests
  • Single - crystal analysis
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28
Q

Diagnosis technique that uses in - situ imaging probes
integrated to crystallization
systems. Non -invasive; provides
valuable information not
possible thru offline tests.

A

Process imaging

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29
Q

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.

A

Dry powder analysis

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30
Q

Diagnosis where hypothesized impurity distribution maps based
on progressive powder dissolution tests.

A

Powder dissolution

31
Q

High degree of dissolution in the early steps is assumed to indicate that the impurities are located at the surface.

A

Zone A (Surface)

32
Q

Impurities dissolving towards the later steps indicate that they are predominantly inside the crystal.

A

Zone B (Inclusion and substitution)

33
Q

Diagnosis where they use of different particle sizes for
the diagnosis of surface impurities.

A

Impurity adsorption tests – powder-based

34
Q

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.

A

smaller; higher; lower

35
Q

Warnings for Impurity adsorption tests – powder-based

A

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.

36
Q

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.

A

Single - crystal analysis

37
Q

Strategies for impurity prevention and control

A

✓ Solvent selection for crystallization and washing
✓ Predictive models ( e.g., population balance, nucleation and
growth kinetics )
✓ Impurity complexation
✓ Slurry aging and temperature cycling

38
Q

_______ is driven by the generation of a supersaturated state for those impurities.

A

Impurity precipitation

39
Q

If impurity concentration is too high, or the solubility in the
crystallization solvent is too low – impurities may _________ with the product of interest.

A

precipitate together

40
Q

Co -formers that can form a co-crystal with the impurities will also form a _______ in solution.

A

complex

41
Q

_________ prevents impurities from
incorporating in the growing crystals.

A

Complexation

42
Q

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 __________

A

Slurry aging and temperature cycling

43
Q

________selectively dissolve impurities post - crystallization

A

Slurry aging and temperature cycling

44
Q

Strategies for slurry aging

A

§ 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.

45
Q

Strategies for temperature cycling

A

§ 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.

46
Q

Application of ______ to promote crystal breakage and expose the
impure crystal core to the wash solvent.

A

mechanical agitation

47
Q

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.

A

dissolution; re-crystallization; heating and cooling

48
Q

_________ was synthesized in the presence of sodium alginate (SA).

A

Struvite

49
Q

Struvite crystal habit changed from
________ to ________ morphology, at increasing SA concentrations.

A

prismatic; plate-like twinned

50
Q

Crystallization of API in pure system

A

End of crystallization
in <1 hour

51
Q

Crystallization of API in the presence of an additive.

A

Lower yield, change in crystal habit

52
Q

Additive-mediated glycine crystallization in _______ environments

A

quiescent

53
Q

Inorganic salts can drive _________ for glycine.

A

selective polymorphism

54
Q

__________ salts inhibited
crystallization of glycine. Taking _
days for crystals to appear.

A

Divalent; 7

55
Q

Needle-like crystals are
characteristic of ____-glycine

A

gamma

56
Q

Crystals formed after 7 days were
identified as _____-glycine.

A

alpha

57
Q

Impurities may or may not provide
control to a crystallization process.

A

Control Of Crystallization.

58
Q

Impurities may increase rates (i.e., _________) or decrease rates (i.e., inhibitors, _______).

A

secondary nucleation; complexation

59
Q

Surface - active impurities may __________ on
crystal faces – directing growth to a different _________.

A

preferentially adsorb; crystal habit

60
Q

T/F: Thermodynamics do not change with scale. Kinetics are also independent of scale. Problems with scale-up of crystallization processes still occur.

A

True

61
Q

________ is impacted with temperature control issues during scale -up.

A

Cooling crystallization

62
Q

_________ and/or seeding and the use of additive may cause _________ supersaturations in
the reactor mainly due to mixing __________.

A

Antisolvent addition; inhomogeneous; sensitivities

63
Q

The _________ nature of a crystallization set-up introduces
additional sensitivities to mixing.

A

multiphase

64
Q

API - solvent density differences may cause ________ of
API crystals which impacts mixing.

A

sinking

65
Q

Vessel design considerations (i.e., baffles, agitators, vessel
shape, etc.) to ensure good suspension and minimize other
phenomena like ________.

A

attrition

66
Q

Enabling technologies in the laboratory scale:

A
  • 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.
67
Q

Seeding behavior changes with scale - in -line monitoring
of _________ may be helpful.

A

chord length

68
Q

Use of __________ – is it useful considering our understanding of supersaturation?

A

feedback control

69
Q

In-line monitoring of _________ – is this possible?

A

crystal purity

70
Q

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.

A

Make the first seed.

71
Q

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.

A

Produce that desired crystal.

72
Q

________ 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.

A

Kinetics and thermodynamics; Monitoring

73
Q

The _______ crystallization of an API
should be performed as the _____
step of the formulation process.

A

final; first

Ph@rm@ (11 decks)

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