Insight
into nucleation kinetics and other nucleation parameters
can be obtained from probability distributions of induction time measurements
in combination with the classical nucleation theory. In this work,
induction times of crystallization were recorded using a robust and
automated methodology involving a focused beam reflectance measurement
probe. This methodology is easily interchangeable between different
crystallizers which allowed us to investigate the effects of scale-up
on the kinetics of crystal nucleation of paracetamol from 2-propanol
in four different crystallizers, ranging from small magnetically stirred
10 mL solutions to overhead-stirred solutions of 680 mL. The nucleation
rate was an order of magnitude faster in the magnetically stirred
crystallizer as compared to the crystallizers involving overhead stirring.
The thermodynamic part of the nucleation rate expression did not significantly
change the nucleation rate, whereas the kinetic nucleation parameter
was found to be the rate-determining process when the crystallization
process was scaled-up. In particular, the shear rate was rationalized
to be the part of the kinetic parameter that changes most significantly
when the crystallization process was scaled-up. The effect of shear
rate on the nucleation kinetics decreases with increasing volume and
plateaus when the volume becomes too large. In this work, the nucleation
mechanism was also investigated using the chiral sodium chlorate system.
These experiments showed that the single nucleus mechanism is the
underlying nucleation mechanism in all four tested crystallization
setups when supersaturation remains the same. When the supersaturation
was changed continuously through cooling, crystallization was driven
by a multinucleus mechanism. The automated and robust method used
to measure induction times can easily be extended to other crystallizers,
enabling the measurement of induction times beyond small crystallizer
volumes.
This
paper describes a new nonintrusive method for the determination
of high-temperature solubility data. Accurate high-temperature solubility
data is vital to many industrial manufacturing processes such as cooling
crystallization with direct implications for yield, throughput, and
solvent usage. However, the provision of such data is notably absent
from published literature for many active pharmaceutical ingredients.
Pressurized-synthetic methodology is presented as a new technique
for determining high-temperature solubility data. Paracetamol (acetaminophen)
is used as a reference active pharmaceutical ingredient to validate
the methodology. Solubility data determined using the pressurized-synthetic
approach is reported for several pure solvents across a significantly
extended temperature range. In the case of methanol, solubility data
is obtained up to 354.15 K, above the atmospheric boiling point of
the solvent, 337.65 K, and far in excess of the temperature range
for which data exists in the literature, 268.15–303.15 K. The
data obtained using the pressurized-synthetic method is validated
against an extended gravimetric data set at temperatures up to the
atmospheric boiling point for each solvent. Sensitivity studies were
conducted to determine the influence of factors such as temperature
gradient on the ultimate solubility determination. A temperature-based
standard deviation of 0.1 K was established for paracetamol in 2-propanol
at 303.15 K, comparing favorably with the temperature-based equivalent
standard deviation of 0.2 K for the gravimetric approach. Binary interaction
parameters for the pressurized-synthetic solubility data are derived
and estimated for four different activity coefficient models, namely
Margules, Van-Laar, Wilson, and non-random two-liquid (NRTL), along
with the empirical solubility equation of Apelblat. For each solvent,
the quality of fit of each of the activity coefficient models is analyzed.
The NRTL model was found to best fit the experimental data for methanol,
ethanol, 2-propanol, and acetone with mean square errors of 5.73 ×
10–5, 3.00 × 10–4, 1.70 ×
10–4, and 7.35 × 10–5, respectively.
The pressurized-synthetic approach provides a nonintrusive, validated,
and readily automated approach for the provision of valuable high-temperature
solubility data that can be readily extended to binary and ternary
systems.
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