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Ph@rm@ > Module 5 > Flashcards

Module 5 Flashcards

1
Q

______ will challenge more Pfizer patents.

A

United Laboratories, Inc. (Unilab)

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2
Q

Unilab plans to ask authorities to junk Pfizer’s patent on the _____________ variant of an ____________ drug after raising objections to the multinational’s patent on the _________ variant.

A

crystalline; anti-cholesterol; amorphous

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3
Q

Unilab continues to sell its own version of Pfizer’s atorvastatin calcium drug _________ even as a patent infringement case is ongoing.

A

Lipitor

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4
Q

A pharmaceutical composition comprising a co-crystal of an API and a co-crystal former, wherein the API has at least one functional group and the co-crystal has at least the functional group such that they are capable of co-crystallizing from a solution phase under crystallization conditions.

A

Pharmaceutical co-crystal compositions

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5
Q

Researched during first screening step in a crystallization experiment.

A

First crystalline form of a newly discovered compound

Discovery of new polymorphs

Screen for possible hydrates and salts

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6
Q

Checked during process development in crystallization experiment

A

Yield and purity

Robustness

Crystallization influence on subsequent processes:
Filtration, size reduction, drying, storage, formulation, drug performance, etc.

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7
Q

For process 1:
10 g of solute
1 L of solvent
9.5 g of solute crystallized out

What is the recovery?

A

95%

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8
Q

For process 2:

100 g of solute
1 L of solvent
90 g of solute crystallized out

A

90%

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9
Q

Solubility data in productivity
measures: The yield from a _______ is linked to the variation in solubility with temperature.

A

cooling crystallization

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10
Q

Formula for supersaturation

A

S = (Css-Cs)/(Cs)

Css = supersaturated
Cs = equilibrium

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11
Q

Solubility is determined by the balance of two factors: 1. The free energy change when ________; and 2. The free energy change of _______.

A

the solid melts; mixing of the solute and solvent molecules

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12
Q

Solubility may be modified by the
addition of a secondary solvent. If the solvents are chemically similar,
then solubility varies ______ with
solvent ratio.

A

linearly

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13
Q

If the solvents are very different, the variation in solubility may be
________ and may pass through a
maximum.

A

nonlinear

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14
Q

The ability of a solid material to exist in more than one solid phase.

A

POLYMORPHISM

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15
Q

Polymorph of calcium carbonate: ________ for egg, _________ for mussels, ______ for snails.

A

Calcite; aragonite; vaterite

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16
Q

Polymorphs of titanium dioxides

A

Rutile
Anatase
Brookite

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17
Q

Polymorphs of dyes

A

ROY (Red prisms, orange needles, orange plates, yellow needles, yellow prisms, yellow prisms 2)

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18
Q

Polymorphs of explosives

A

TNT, BTF, HMX

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19
Q

A phenomenon in which a seemingly stable crystal structure is suddenly unable to be
produced, instead transforming into a polymorph, or differing crystal structure with the same chemical composition, during nucleation.

A

disappearing polymorphs (metastable phase)

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20
Q

Every crystallization is a competition between
_____ and _____ factors. As such, “it is always possible to obtain [the old form] again; it is only a matter of finding the right experimental conditions”.

A

kinetic; thermodynamic

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21
Q

________ is a way to control polymorphism. Adding _______ favors Form I paracetamol and __________ favor Form II paracetamol.

A

Seeding; IPA; IPA, paracetamol

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22
Q

Challenges for polymorphism

A
  1. The process must make the required polymorph robustly. How?
  2. If the desired polymorph changes, so must the crystallization process to make it, based on appropriate solubility data.
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23
Q

Unexpected _______ of an API can cause a frustrating detour in the drug development pathway. Up to 75 percent of all pharmaceutical compounds form _______ during
the manufacturing process, affecting many of the physicochemical properties of an active ingredient. _______ formation relies on water and is not easily recognized during
screening.

A

hydrates

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24
Q

As the vapor pressure of water is above zero, _________
can occur in ambient conditions such as storage.

A

hydration and rehydration

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25
Q

If a drug were dosed in an ______ form that converts during storage
or in the body to a lower-solubility _________ form, for example, it may
affect the observed _______ and dissolution of the API, making _______ correlation more difficult.

A

anhydrous; hydrated; solubility; in vitro/in vivo

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26
Q

________ is a process in which supersaturation causes the initially
dissolved compound to separate from solution by creating a secondary liquid phase (______) instead of a solid, crystalline phase (________)

A

Oiling out; emulsion; suspension

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27
Q

Oiling out mostly occurs when the integration of solute molecules into the crystal lattice is _________, _______ or the system experiences very high _________.

A

kinetically hindered; delayed; supersaturation

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28
Q

Oiling is a _________ separation of one liquid phase into two liquid phases.

A

thermodynamic

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29
Q

___________ occurs when a homogenous phase becomes thermodynamically unstable. An unstable phase lies at a maximum in free energy.

A

Spinodal decomposition

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30
Q

___________ occur when a homogenous phase becomes metastable.

A

Nucleation and growth

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31
Q

Spinodal decomposition mostly works on the principle of ______

A

diffusion

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32
Q

Oiling occurs in the absence of ________ since spinodal
decomposition allows phase separation from ______ and does not require overcoming a ________.

A

nucleation; energy
fluctuations; free
energy barrier

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33
Q

Oiling is a liquid-liquid phase separation usually seen in
highly supersaturated solutions crystallizing at extremely high temperatures. The process normally results in slow _________, uncontrollable ___________, and low ____________.

A

crystal growth;
crystal morphology; product purity

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34
Q

Due to impurities in crystallization, at the basic level, once the crystals are dried, all non-volatile impurities are _______ with the product crystal.

A

isolated

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35
Q

Due to impurities in crystallization, at the basic level, impurities may crystallize __________.

A

separately

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36
Q

Impurities can be _______ onto crystal surfaces or be present in
_________ within crystals or __________ between crystals.

A

adsorbed; inclusions; occlusions

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37
Q

Impurities adsorption

A
  1. Adsorbed on the surface of the aggregate
  2. Adsorbed on the surface of a specific crystal
  3. Impurity crystallized separately
  4. Impurity forms a partial or complete solid
    solution with the product
  5. Impurity as an inclusion within the crystal
  6. Impurity as an occlusion between the crystal
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38
Q

______ occurs when the impurity
occupies a lattice site in the crystal
structure of the carrier.

A

Inclusion

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39
Q

______ occurs when an adsorbed
impurity gets physically trapped inside the crystal as it grows.

A

Occlusion

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40
Q

For impurity incorporation outside the crystals (i.e. by agglomeration, co-precipitation, or adhering mother liquor) the mechanisms are: The crystallization mother liquor tends to be rich
in ________ that have been ______ from the crystalline phase.

A

impurities; rejected

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41
Q

For impurity incorporation outside the crystals (i.e. by agglomeration, co-precipitation, or adhering mother liquor) the mechanisms are: The formation of aggregates during crystallization
has the possibility of ______ this mother liquor, leading to impurities in the product.

A

entrapping

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42
Q

Impurity precipitation (either during crystallization, or during washing) is driven by the generation of a ________ for those impurities.

A

supersaturated state

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43
Q

Impurities: If their _________ is too high, or the _______ in the crystallization solvent is too
low, impurities may ________ with the product of interest, generating a powder that contains multiple solid phases.

A

concentration; solubility; precipitate together

44
Q

Impurities don’t necessarily incorporate evenly
throughout the ________.

A

crystal lattice

45
Q

Some impurities may preferentially interact with ________, either because of their ________ or because of their ______.

A

certain faces; growth rate; surface chemistry

46
Q

Differences in __________ throughout crystal growth may lead to different impurity profiles in a grown crystal

A

kinetics

47
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
48
Q

A different/new solvent added to the solute-solvent mixture in which the solute has poor solubility in order to isolate it as a solid.

A

ANTISOLVENT

49
Q

Antisolvent precipitation technique is a very promising approach to crystallize ________________
in presence of ______ for solubility and dissolution enhancement

A

curcumin; polyvinyl pyrrolidon

50
Q

The addition of an antisolvent involves the mixing of two liquids, which adds to the complex interactions between _______ of crystallization.

A

thermodynamics and kinetics

51
Q

The major driving force of _________ is the supersaturation of a solution caused by mixing with an
________.

A

particle formation; antisolvent

52
Q

The _______ must show a high miscibility with the solution and also should exhibit nearly zero solubility toward the _____.

A

antisolvent; solute

53
Q

It is well known that the _________ supersaturation at feeding points can reach an extremely high level if the solubility of solute changes fast with ___________.

A

instantaneous local; solvent composition

54
Q

_____ supersaturation can cause ______ effects on crystal products,
i.e., generation of undesired solid forms, inadequate rejection of impurities, etc.

A

High; deleterious

55
Q

________ supersaturation can be leveraged on to generate small particles with ________ that can be directly used in formulations without further _____________________.

A

High; narrow size distribution; size reduction

56
Q

The ____ at which antisolvent is
added directly influences the level of supersaturation.

A

rate

57
Q

When antisolvent is added at the ________ rate, the supersaturation level is ________ throughout the process - due to a buildup that cannot be ________ fast
enough through crystal growth and
nucleation.

A

faster ; higher ; relieved

58
Q

To make large crystals, generate
supersaturation ______.

A

slowly

59
Q

To make small crystals, generate
supersaturation ________

A

quickly

60
Q

Advantages of antisolvent

A
  • Induced crystallization due to solubility changes in the system
  • Faster processing
61
Q

Disadvantages of antisolvent

A
  • Sensitivity to mixing and localized supersaturation
  • Supersaturation free-fall
  • Complexity in solubility data
62
Q

Various quality issues may arise during anti-solvent crystallization, e.g., oiling out, appearance of undesired solid forms, unacceptable solvent residual or crystal habit, failure to pass clarity test or dissolution test, etc.

A

Trouble shooting of anti-solvent crystallization.

63
Q

The _______ of solvents/anti-solvents seems to be the most
important decision in anti-solvent crystallization development.

A

choice

64
Q

_______ has proved effective in mitigation of oiling out, polymorph and size control. However, ______ elements still exist in seeding protocol determination.

A

Seeding; arbitrary

65
Q

______ particles, usually prepared by milling, are needed for various delivery vehicles. Anti-solvent crystallization is a promising alternative to ______. However, measures must be taken to address practical problems in anti-
solvent crystallization such as agglomeration during drying, Ostwald ripening, solvent residual, etc.

A

Micron-sized; milling

66
Q

_____ are solids that are ______ crystalline single phase materials
composed of two or more different molecular and/or ionic compounds
which are neither _____ nor _____.

A

Cocrystals; neutral; solvates; simple salts

67
Q

A cocrystal has a __________ crystal structure to either of the starting
materials and as a result different ____________ properties.

A

different; physicochemical

68
Q

If at least one of the ______ is an API and the other is pharmaceutically acceptable, then it is recognized as a pharmaceutical _________.

A

coformers; cocrystal

69
Q

The spontaneous formation of __________ via mixing of pure API and coformer under a
controlled atmospheric environment is __________ as a solid state method.

A

cocrystals; Contact Formation

70
Q

Issues for _________ include failure to form a cocrystal, incomplete conversion to the cocrystal, and
crystalline defects with possible generation of some amorphous content.

A

Solid State Grinding

71
Q

The lack of control over the nucleation makes _______
promising at a green chemistry perspective.

A

mechanochemical techniques

72
Q

This unit consists of two co-/counter-rotating screws in a single barrel operating at
temperatures below the melting point of either starting material. Screw action provides
simultaneous mixing and movement of material.

A

Extrusion (Twin Screw Extrusion)

73
Q

A specialist technique combining simultaneous melting and mixing of the target molecule
and coformer via the use of a heated screw extruder.

A

Hot Melt Extrusion

74
Q

This technique involves the agglomeration of powder particles via a liquid medium in
the presence of a binder.

A

High Shear Wet Granulation

75
Q

The mechanism of cocrystal formation by _________ is not exactly known but suspected to be either similar to __________ or slurry transformation.

A

high shear granulation; liquid assisted grinding

76
Q

A variety of methods exist to cocrystallize from solution called _________.

A

Solution Based Methods

77
Q

The driving force for crystallization is supersaturation: the difference between the __________ concentration and the reported _________ concentration at that temperature in that solvent.

A

actual experimental, solubility

78
Q

With a cocrystal system, there are two concentrations to consider: the
___________ and the _______ .

A

target molecule; coformer

79
Q

The concentrations of both target molecule and coformer relative to the solubility of the _______ dictate the supersaturation for cocrystallization.

A

cocrystal

80
Q

The __________ represent solution minima where the solvent content is at its lowest value (i.e., solubility is at its highest value).

A

eutectics

81
Q

A ________ will exist where at one fixed solution concentration, a mixture of cocrystal and the target molecule is the_______ phase for the system

A

eutectic point; stable solid

82
Q

A _______ exists for a mixture of the cocrystal and coformer.

A

second eutectic point

83
Q

The cocrystal will only be stable, less soluble than target molecule or coformer, at concentrations lying between the __________.

A

eutectic points

84
Q

The solubility of a cocrystal system is most accurately represented in a

A

ternary phase diagram (TPD)

85
Q

Solution Based Methods that require extremely slow evaporation of solvents.

A

Evaporative Crystallization

86
Q

Solution Based Methods where Solvent selection and the identification cocrystal operating range is key to this method

A

Cooling Crystallization

87
Q

Solution Based Methods that involves the suspension of the target molecule and coformer, usually in a fixed molar
ratio, in a solvent with the solid fraction always remaining in excess.

A

Isothermal Slurry Conversion

88
Q

Three different supercrtical fluid approaches based on distinct supercritical CO2 properties

A

solvent, antisolvent, and atomization enhancement

89
Q

Cocrystallization with Supercritical Solvent (CSS) technique uses the ________ power of supercritical CO2 to suspend the API and the coformer as a slurry in liquid or supercritical CO2

A

solvent

90
Q

Using supercritical CO2 as an __________ works on the principle that solubility of API and the
coformer is reduced in supercritical CO2, allowing them to precipitate together in a cocrystalline
structure.

A

antisolvent

91
Q

Using supercritical CO2 as an __________ is based on the supercritical fluids’ ability
to enhance the breakup of liquid jets into fine droplets when depressurized simultaneously with
liquid solutions

A

atomization enhancer

92
Q

Cocrystal formation results in a _________, which is entirely independent from
any of the starting materials. This new crystal structure imparts a ________ also independent of and indifferent to the physical properties of any of the
starting materials.

A

new crystal structure; new set of physical properties

93
Q

As a result of potential physical property improvements, _________ are many and continue to grow.

A

cocrystal applications

94
Q

COCRYSTALS: Application Areas

A
  1. Solubility
  2. Bioavailability
  3. Controlled release
  4. Solid state Property Enhancement
  5. Taste masking
  6. Multidrug cocrystals
  7. Generation/Extension of intellectual property
95
Q

Inherently, a cocrystal will have a different _____ than that of either of the starting materials due to the altered underlying crystal
structure. The __________ alteration can be in either direction.

A

solubility

96
Q

Enhanced _____ is desirable but excessive enhancement can lead to undesirable precipitation of the starting material due to the
generation of a supersaturated solution.

A

solubility

97
Q

Solubility: Cocrystals bear the potential to enhance the delivery and clinical performance of drug
products by modulating: (3)

A

drug solubility,
pharmacokinetics, and bioavailability.

98
Q

Bioavailability: Particularly, using cocrystals to improve drug absorption of BCS _________ drugs has been a strong focus of several case studies published in the literature.

A

class II and IV

99
Q

Controlled release: Cocrystallization provides an opportunistic approach to modulate the physicochemical
properties of pharmaceutical drugs (e.g., __________).

A

solubility and dissolution rate

100
Q

Controlled release: Depending on the coformer that cocrystallizes with the API, the ________ of the API in water or a buffer solution can be increased or decreased over time.

A

dissolution rate

101
Q

Solid state property enhancement: Cocrystallization helps to improve chemical and physical properties of powders including _________ and __________.

A

mechanical strength (compressibility); flow properties

102
Q

Taste masking: ____________ necessitate the use of taste masking agents to improve the patients’ experience. The use of ___________ has been the main approach; however, poor
dissolution rate is still a limiting factor in developing oral disintegrating formulations.

A

readily disintegrating tablets; sugar-based excipients

103
Q

Taste masking: Cocrystallization could be a promising strategy for improving the dissolution rate using ____________.

A

sugar-based coformers

104
Q

Multidrug cocrystals: Combining multiple _________ active pharmaceutical ingredients (APIs) into one unit dose has become a
popular trend in the drug formulation industry. Helps in the effective treatment of complex diseases (e.g., cancer and diabetes)

A

synergistic

105
Q

MDC could offer potential advantages, such as:

A
  • enhanced solubility and dissolution of at least one of
    the components,
  • enhanced bioavailability,
  • improved stability of unstable APIs via intermolecular
    interactions, and
  • increased mechanical strength and flowability.
106
Q

Generation/Extension of intellectual property: Screening of novel solid forms of marketed drugs, including polymorphs, salts, and cocrystals provides the opportunity to grant new _____ on those drugs and extend their _______.

A

IP; patent life cycle

Ph@rm@ (11 decks)

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