Molecular Pharmaceutics,
Год журнала:
2024,
Номер
21(9), С. 4576 - 4588
Опубликована: Авг. 20, 2024
The
use
of
different
template
surfaces
in
crystallization
experiments
can
directly
influence
the
nucleation
kinetics,
crystal
growth,
and
morphology
active
pharmaceutical
ingredients
(APIs).
Consequently,
templated
is
an
attractive
approach
to
enhance
kinetics
preferentially
nucleate
desired
polymorphs
for
solid-form
drug
molecules,
particularly
large
flexible
molecules
that
are
difficult
crystallize.
Herein,
we
investigate
effect
polymer
templates
on
clotrimazole
ketoprofen
with
both
computational
methods.
Crystallization
was
carried
out
toluene
solvent
APIs
a
library
consisting
12
polymers.
In
complement
experimental
studies,
developed
workflow
based
molecular
dynamics
(MD)
derived
descriptors
from
simulations
score
rank
API–polymer
interactions.
were
used
measure
energy
interaction
(EOI),
hydrogen
bonding,
rugosity
(surface
roughness)
similarity
between
templates.
We
variety
machine
learning
models
(14
total)
along
these
predict
outcome
found
simply
rank-ordering
polymers
by
their
yielded
92%
accuracy
predicting
ketoprofen.
most
accurate
model
be
random
forest
model.
Using
models,
able
outcomes
all
Additionally,
have
performed
feature
importance
analysis
using
trained
predictive
features
descriptors.
These
results
demonstrate
energies
correlated
heterogeneous
outcomes.
Nature,
Год журнала:
2023,
Номер
623(7986), С. 324 - 328
Опубликована: Ноя. 8, 2023
The
physicochemical
properties
of
molecular
crystals,
such
as
solubility,
stability,
compactability,
melting
behaviour
and
bioavailability,
depend
on
their
crystal
form1.
In
silico
form
selection
has
recently
come
much
closer
to
realization
because
the
development
accurate
affordable
free-energy
calculations2-4.
Here
we
redefine
state
art,
primarily
by
improving
accuracy
calculations,
constructing
a
reliable
experimental
benchmark
for
solid-solid
differences,
quantifying
statistical
errors
computed
free
energies
placing
both
hydrate
structures
different
stoichiometries
anhydrate
same
energy
landscape,
with
defined
error
bars,
function
temperature
relative
humidity.
calculated
have
standard
1-2
kJ
mol-1
industrially
relevant
compounds,
method
place
landscape
can
be
extended
other
multi-component
systems,
including
solvates.
These
contributions
reduce
gap
between
needs
experimentalist
capabilities
modern
computational
tools,
transforming
structure
prediction
into
more
actionable
procedure
that
used
in
combination
evidence
direct
establish
control5.
The
rise
of
open
science
and
the
absence
a
global
dedicated
data
repository
for
molecular
dynamics
(MD)
simulations
has
led
to
accumulation
MD
files
in
generalist
repositories,
constituting
dark
matter
—
that
is
technically
accessible,
but
neither
indexed,
curated,
or
easily
searchable.
Leveraging
an
original
search
strategy,
we
found
indexed
about
250,000
2000
datasets
from
Zenodo,
Figshare
Open
Science
Framework.
With
focus
on
produced
by
Gromacs
software,
illustrate
potential
offered
mining
publicly
available
data.
We
identified
systems
with
specific
composition
were
able
characterize
essential
parameters
simulation
such
as
temperature
length,
could
identify
model
resolution,
all-atom
coarse-grain.
Based
this
analysis,
inferred
metadata
propose
engine
prototype
explore
To
continue
direction,
call
community
pursue
effort
sharing
data,
report
standardize
reuse
valuable
matter.
Communications Chemistry,
Год журнала:
2024,
Номер
7(1)
Опубликована: Авг. 28, 2024
Organic
solvents
host
the
synthesis
of
high-value
crystals
used
as
pharmaceuticals
and
optical
devices,
among
other
applications.
A
knowledge
gap
persists
on
how
replacing
hydrogen
bonds
polar
attraction
that
dominate
aqueous
environments
with
weaker
van
der
Waals
forces
affects
growth
mechanism,
including
its
defining
feature,
whether
grow
classically
or
nonclassically.
Here
we
demonstrate
a
rare
dual
mode
etioporphyrin
I
crystals,
enabled
by
liquid
precursors
associate
crystal
surfaces
to
generate
stacks
layers,
which
then
laterally
incorporating
solute
molecules.
Our
findings
reveal
mesoscopic
solute-rich
clusters,
unique
phase
favored
weak
such
those
between
organic
solutes.
The
lateral
spreading
precursor-initiated
layers
crucially
relies
abundant
supply
directly
from
solution,
bypassing
diffusion
along
surface;
direct
incorporation
pathway
may,
again,
be
solvents.
Clusters
evolve
amorphous
particles
do
not
seamlessly
integrate
into
lattices.
Crystals
growing
fast
mostly
nonclassically
at
high
supersaturations
are
excessively
strained.
interactions
typical
systems
promote
nonclassical
modes
supporting
enabling
multilayer
stacks.
Crystal Growth & Design,
Год журнала:
2024,
Номер
24(17), С. 7342 - 7360
Опубликована: Июнь 21, 2024
The
antiepilepsy
drug
carbamazepine
is
one
of
the
most
studied
pharmaceuticals
in
world.
rich
story
its
solid
forms,
cocrystals,
and
formulation
a
microcosm
topical
world
pharmaceutical
materials.
Understanding
has
required
time,
money,
dedication
from
numerous
researchers
companies
worldwide.
This
wealth
knowledge
provides
opportunity
to
reflect
on
progress
within
crystal
engineering
field
general.
Perspective
covers
extensive
form
landscape
applies
these
examples
discuss
answer
fundamental
questions
discipline.
encompasses
screening
methods,
computational
discovery,
power
influence
understanding
controlling
crystals
amorphous
state,
environmental
legacy
modern
pharmaceuticals.
broad
but
in-depth
analysis
vehicle
into
engineering,
not
only
own
right
across
spectrum
organic
materials
science
formulation.
Discoveries
demonstrate
potential
richness
chemistry
every
drug.
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2023,
Номер
unknown
Опубликована: Май 2, 2023
The
rise
of
open
science
and
the
absence
a
global
dedicated
data
repository
for
molecular
dynamics
(MD)
simulations
has
led
to
accumulation
MD
files
in
generalist
repositories,
constituting
Crystal Growth & Design,
Год журнала:
2024,
Номер
24(8), С. 3205 - 3217
Опубликована: Март 9, 2024
The
formulation
of
active
pharmaceutical
ingredients
involves
discovering
stable
crystal
packing
arrangements
or
polymorphs,
each
which
has
distinct
pharmaceutically
relevant
properties.
Traditional
experimental
screening
techniques
utilizing
various
conditions
are
commonly
supplemented
with
in
silico
structure
prediction
(CSP)
to
inform
the
crystallization
process
and
mitigate
risk.
Predictions
often
based
on
advanced
classical
force
fields
quantum
mechanical
calculations
that
model
potential
energy
landscape
but
do
not
fully
incorporate
temperature,
pressure,
solution
during
search
procedure.
This
study
proposes
an
innovative
alchemical
path
utilizes
polarizable
atomic
multipole
field
predict
structures
direct
sampling
NPT
ensemble.
use
(i.e.,
nonphysical)
intermediates,
a
novel
Monte
Carlo
barostat,
orthogonal
space
tempering
bias
combine
enhance
efficiency
deposition/sublimation
phase
transition.
proposed
algorithm
was
applied
2-((4-(2-(3,4-dichlorophenyl)ethyl)phenyl)amino)benzoic
acid
(Cambridge
Crystallography
Database
Centre
ID:
XAFPAY)
as
case
showcase
algorithm.
Each
experimentally
determined
polymorph
one
molecule
asymmetric
unit
successfully
reproduced
via
approximately
1000
short
1
ns
simulations
per
group
where
simulation
initiated
from
random
rigid
body
coordinates
cell
parameters.
Utilizing
two
threads
recent
Intel
CPU
(a
Xeon
Gold
6330
at
2.00
GHz),
using
AMOEBA
can
be
acquired
4
h
(equating
more
than
300
ns/day
all
112
threads/56
cores
dual
node)
within
Force
Field
X
software
(https://ffx.biochem.uiowa.edu).
These
results
demonstrate
step
forward
rigorous
ensemble
CSP
open
door
future
algorithms
continuum
solvation
methods.
The
rise
of
open
science
and
the
absence
a
global
dedicated
data
repository
for
molecular
dynamics
(MD)
simulations
has
led
to
accumulation
MD
files
in
generalist
repositories,
constituting
dark
matter
—
that
is
technically
accessible,
but
neither
indexed,
curated,
or
easily
searchable.
Leveraging
an
original
search
strategy,
we
found
indexed
about
250,000
2000
datasets
from
Zenodo,
Figshare
Open
Science
Framework.
With
focus
on
produced
by
Gromacs
software,
illustrate
potential
offered
mining
publicly
available
data.
We
identified
systems
with
specific
composition
were
able
characterize
essential
parameters
simulation
such
as
temperature
length,
could
identify
model
resolution,
all-atom
coarse-grain.
Based
this
analysis,
inferred
metadata
propose
engine
prototype
explore
To
continue
direction,
call
community
pursue
effort
sharing
data,
report
standardize
reuse
valuable
matter.
The
rise
of
open
science
and
the
absence
a
global
dedicated
data
repository
for
molecular
dynamics
(MD)
simulations
has
led
to
accumulation
MD
files
in
generalist
repositories,
constituting
dark
matter
-
that
is
technically
accessible,
but
neither
indexed,
curated,
or
easily
searchable.
Leveraging
an
original
search
strategy,
we
found
indexed
about
250,000
2,000
datasets
from
Zenodo,
Figshare
Open
Science
Framework.
With
focus
on
produced
by
Gromacs
software,
illustrate
potential
offered
mining
publicly
available
data.
We
identified
systems
with
specific
composition
were
able
characterize
essential
parameters
simulation,
such
as
temperature
simulation
length,
identify
model
resolution,
all-atom
coarse-grain.
Based
this
analysis,
inferred
metadata
propose
engine
prototype
explore
collected
To
continue
direction,
call
community
pursue
effort
sharing
data,
increase
populating
standardizing
reuse
valuable
matter.