Both
primary and secondary nucleation rates are considered in a
model developed for unseeded batch crystallization. A carefully designed
strategy was employed to minimize the effects of the stochastic nature
of induction time; nucleation was induced at designed supersaturations
on known temperature plateaus. Crystallization kinetics of paracetamol
from ethanolic solutions were extracted from measurements of in situ
solute concentrations and combined with sieve (ex situ) data on the
final product. Parameters in models for primary and secondary nucleation
and for crystal growth rate were estimated by fitting a full population
balance model to the measurements, and the evolution of the crystal
size distribution was compared against in situ estimation from focused-beam
reflectance measurements using the technique that we previously developed.
The resulting models suggest that primary nucleation produces fewer
surviving crystals than had been expected and that most of the product
crystals from the process involving a temperature plateau result from
secondary nucleation.
Sodium naproxen is an antiinflammatory nonsteroidal drug used in the treatment of rheumatoid and arthritic diseases. Three pseudopolymorphic forms have been reported in the literature, along with characterizations of anhydrous and dihydrated forms. In the present work, the monohydrated form of sodium naproxen was prepared by dehydration of the dihydrated form and investigated with thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and microscopy. Characteristic properties of the monohydrated form were compared to the anhydrous and the dihydrated forms, and the transformation of higher hydrated forms to lower ones was performed in an oven or a desiccator without generating other polymorphic forms. DSC and isothermal TGA experiments determined the structural characteristics and mechanisms by which two types of water were removed from the hydrated species.
Crystallization kinetics
of ampicillin were estimated from induction-times
and seeded and unseeded experiments. The concentration of ampicillin
in solution was monitored by polarimetry and refractometry, while
crystals were analyzed by focused beam refractive measurements and
light microscopy. Variations of solute concentration with time, along
with measured induction times were used to estimate parameters in
kinetic expressions for primary nucleation, secondary nucleation,
and crystal growth rate. Experimental data were obtained in runs involving
different rates of change of pH, mass of seed crystals, and initial
supersaturation. These data were used in parameter-estimation routines
consisting of a stochastic minimization to localize a set of parameters
spanning all the experiments, followed by a deterministic minimization
to refine the parameters. The result was a set of parameters that
fit a range of conditions of seeded and unseeded crystallizations
and gave good estimates of desupersaturation rates.
In the present research, batch cooling crystallization of paracetamol from ethanol solutions is used as a model system for exploring the utility of focused beam reflectance measurement (FBRM) data in detection of the formation and/or transformations of polymorphs in situ. Paracetamol is known to exist in three different polymorphic forms. The transition between Form I crystals (octahedrons) and Form II crystals (needle-like) is considered here. Such different shapes generate different chord length densities, and by tracking the chord-length density and the total chord counts through an efficient use of the FBRM, we show that it is possible to monitor the transition from Form II to Form I.
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