Module 5 Flashcards
______ will challenge more Pfizer patents.
United Laboratories, Inc. (Unilab)
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.
crystalline; anti-cholesterol; amorphous
Unilab continues to sell its own version of Pfizer’s atorvastatin calcium drug _________ even as a patent infringement case is ongoing.
Lipitor
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.
Pharmaceutical co-crystal compositions
Researched during first screening step in a crystallization experiment.
First crystalline form of a newly discovered compound
Discovery of new polymorphs
Screen for possible hydrates and salts
Checked during process development in crystallization experiment
Yield and purity
Robustness
Crystallization influence on subsequent processes:
Filtration, size reduction, drying, storage, formulation, drug performance, etc.
For process 1:
10 g of solute
1 L of solvent
9.5 g of solute crystallized out
What is the recovery?
95%
For process 2:
100 g of solute
1 L of solvent
90 g of solute crystallized out
90%
Solubility data in productivity
measures: The yield from a _______ is linked to the variation in solubility with temperature.
cooling crystallization
Formula for supersaturation
S = (Css-Cs)/(Cs)
Css = supersaturated
Cs = equilibrium
Solubility is determined by the balance of two factors: 1. The free energy change when ________; and 2. The free energy change of _______.
the solid melts; mixing of the solute and solvent molecules
Solubility may be modified by the
addition of a secondary solvent. If the solvents are chemically similar,
then solubility varies ______ with
solvent ratio.
linearly
If the solvents are very different, the variation in solubility may be
________ and may pass through a
maximum.
nonlinear
The ability of a solid material to exist in more than one solid phase.
POLYMORPHISM
Polymorph of calcium carbonate: ________ for egg, _________ for mussels, ______ for snails.
Calcite; aragonite; vaterite
Polymorphs of titanium dioxides
Rutile
Anatase
Brookite
Polymorphs of dyes
ROY (Red prisms, orange needles, orange plates, yellow needles, yellow prisms, yellow prisms 2)
Polymorphs of explosives
TNT, BTF, HMX
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.
disappearing polymorphs (metastable phase)
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”.
kinetic; thermodynamic
________ is a way to control polymorphism. Adding _______ favors Form I paracetamol and __________ favor Form II paracetamol.
Seeding; IPA; IPA, paracetamol
Challenges for polymorphism
- The process must make the required polymorph robustly. How?
- If the desired polymorph changes, so must the crystallization process to make it, based on appropriate solubility data.
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.
hydrates
As the vapor pressure of water is above zero, _________
can occur in ambient conditions such as storage.
hydration and rehydration
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.
anhydrous; hydrated; solubility; in vitro/in vivo
________ 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 (________)
Oiling out; emulsion; suspension
Oiling out mostly occurs when the integration of solute molecules into the crystal lattice is _________, _______ or the system experiences very high _________.
kinetically hindered; delayed; supersaturation
Oiling is a _________ separation of one liquid phase into two liquid phases.
thermodynamic
___________ occurs when a homogenous phase becomes thermodynamically unstable. An unstable phase lies at a maximum in free energy.
Spinodal decomposition
___________ occur when a homogenous phase becomes metastable.
Nucleation and growth
Spinodal decomposition mostly works on the principle of ______
diffusion
Oiling occurs in the absence of ________ since spinodal
decomposition allows phase separation from ______ and does not require overcoming a ________.
nucleation; energy
fluctuations; free
energy barrier
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 ____________.
crystal growth;
crystal morphology; product purity
Due to impurities in crystallization, at the basic level, once the crystals are dried, all non-volatile impurities are _______ with the product crystal.
isolated
Due to impurities in crystallization, at the basic level, impurities may crystallize __________.
separately
Impurities can be _______ onto crystal surfaces or be present in
_________ within crystals or __________ between crystals.
adsorbed; inclusions; occlusions
Impurities adsorption
- Adsorbed on the surface of the aggregate
- Adsorbed on the surface of a specific crystal
- Impurity crystallized separately
- Impurity forms a partial or complete solid
solution with the product - Impurity as an inclusion within the crystal
- Impurity as an occlusion between the crystal
______ occurs when the impurity
occupies a lattice site in the crystal
structure of the carrier.
Inclusion
______ occurs when an adsorbed
impurity gets physically trapped inside the crystal as it grows.
Occlusion
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.
impurities; rejected
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.
entrapping
Impurity precipitation (either during crystallization, or during washing) is driven by the generation of a ________ for those impurities.
supersaturated state
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.
concentration; solubility; precipitate together
Impurities don’t necessarily incorporate evenly
throughout the ________.
crystal lattice
Some impurities may preferentially interact with ________, either because of their ________ or because of their ______.
certain faces; growth rate; surface chemistry
Differences in __________ throughout crystal growth may lead to different impurity profiles in a grown crystal
kinetics
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
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.
ANTISOLVENT
Antisolvent precipitation technique is a very promising approach to crystallize ________________
in presence of ______ for solubility and dissolution enhancement
curcumin; polyvinyl pyrrolidon
The addition of an antisolvent involves the mixing of two liquids, which adds to the complex interactions between _______ of crystallization.
thermodynamics and kinetics
The major driving force of _________ is the supersaturation of a solution caused by mixing with an
________.
particle formation; antisolvent
The _______ must show a high miscibility with the solution and also should exhibit nearly zero solubility toward the _____.
antisolvent; solute
It is well known that the _________ supersaturation at feeding points can reach an extremely high level if the solubility of solute changes fast with ___________.
instantaneous local; solvent composition
_____ supersaturation can cause ______ effects on crystal products,
i.e., generation of undesired solid forms, inadequate rejection of impurities, etc.
High; deleterious
________ supersaturation can be leveraged on to generate small particles with ________ that can be directly used in formulations without further _____________________.
High; narrow size distribution; size reduction
The ____ at which antisolvent is
added directly influences the level of supersaturation.
rate
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.
faster ; higher ; relieved
To make large crystals, generate
supersaturation ______.
slowly
To make small crystals, generate
supersaturation ________
quickly
Advantages of antisolvent
- Induced crystallization due to solubility changes in the system
- Faster processing
Disadvantages of antisolvent
- Sensitivity to mixing and localized supersaturation
- Supersaturation free-fall
- Complexity in solubility data
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.
Trouble shooting of anti-solvent crystallization.
The _______ of solvents/anti-solvents seems to be the most
important decision in anti-solvent crystallization development.
choice
_______ has proved effective in mitigation of oiling out, polymorph and size control. However, ______ elements still exist in seeding protocol determination.
Seeding; arbitrary
______ 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.
Micron-sized; milling
_____ are solids that are ______ crystalline single phase materials
composed of two or more different molecular and/or ionic compounds
which are neither _____ nor _____.
Cocrystals; neutral; solvates; simple salts
A cocrystal has a __________ crystal structure to either of the starting
materials and as a result different ____________ properties.
different; physicochemical
If at least one of the ______ is an API and the other is pharmaceutically acceptable, then it is recognized as a pharmaceutical _________.
coformers; cocrystal
The spontaneous formation of __________ via mixing of pure API and coformer under a
controlled atmospheric environment is __________ as a solid state method.
cocrystals; Contact Formation
Issues for _________ include failure to form a cocrystal, incomplete conversion to the cocrystal, and
crystalline defects with possible generation of some amorphous content.
Solid State Grinding
The lack of control over the nucleation makes _______
promising at a green chemistry perspective.
mechanochemical techniques
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.
Extrusion (Twin Screw Extrusion)
A specialist technique combining simultaneous melting and mixing of the target molecule
and coformer via the use of a heated screw extruder.
Hot Melt Extrusion
This technique involves the agglomeration of powder particles via a liquid medium in
the presence of a binder.
High Shear Wet Granulation
The mechanism of cocrystal formation by _________ is not exactly known but suspected to be either similar to __________ or slurry transformation.
high shear granulation; liquid assisted grinding
A variety of methods exist to cocrystallize from solution called _________.
Solution Based Methods
The driving force for crystallization is supersaturation: the difference between the __________ concentration and the reported _________ concentration at that temperature in that solvent.
actual experimental, solubility
With a cocrystal system, there are two concentrations to consider: the
___________ and the _______ .
target molecule; coformer
The concentrations of both target molecule and coformer relative to the solubility of the _______ dictate the supersaturation for cocrystallization.
cocrystal
The __________ represent solution minima where the solvent content is at its lowest value (i.e., solubility is at its highest value).
eutectics
A ________ will exist where at one fixed solution concentration, a mixture of cocrystal and the target molecule is the_______ phase for the system
eutectic point; stable solid
A _______ exists for a mixture of the cocrystal and coformer.
second eutectic point
The cocrystal will only be stable, less soluble than target molecule or coformer, at concentrations lying between the __________.
eutectic points
The solubility of a cocrystal system is most accurately represented in a
ternary phase diagram (TPD)
Solution Based Methods that require extremely slow evaporation of solvents.
Evaporative Crystallization
Solution Based Methods where Solvent selection and the identification cocrystal operating range is key to this method
Cooling Crystallization
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.
Isothermal Slurry Conversion
Three different supercrtical fluid approaches based on distinct supercritical CO2 properties
solvent, antisolvent, and atomization enhancement
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
solvent
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.
antisolvent
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
atomization enhancer
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.
new crystal structure; new set of physical properties
As a result of potential physical property improvements, _________ are many and continue to grow.
cocrystal applications
COCRYSTALS: Application Areas
- Solubility
- Bioavailability
- Controlled release
- Solid state Property Enhancement
- Taste masking
- Multidrug cocrystals
- Generation/Extension of intellectual property
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.
solubility
Enhanced _____ is desirable but excessive enhancement can lead to undesirable precipitation of the starting material due to the
generation of a supersaturated solution.
solubility
Solubility: Cocrystals bear the potential to enhance the delivery and clinical performance of drug
products by modulating: (3)
drug solubility,
pharmacokinetics, and bioavailability.
Bioavailability: Particularly, using cocrystals to improve drug absorption of BCS _________ drugs has been a strong focus of several case studies published in the literature.
class II and IV
Controlled release: Cocrystallization provides an opportunistic approach to modulate the physicochemical
properties of pharmaceutical drugs (e.g., __________).
solubility and dissolution rate
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.
dissolution rate
Solid state property enhancement: Cocrystallization helps to improve chemical and physical properties of powders including _________ and __________.
mechanical strength (compressibility); flow properties
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.
readily disintegrating tablets; sugar-based excipients
Taste masking: Cocrystallization could be a promising strategy for improving the dissolution rate using ____________.
sugar-based coformers
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)
synergistic
MDC could offer potential advantages, such as:
- 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.
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 _______.
IP; patent life cycle
