Direct Observation of Growth Rate Dispersion in the Enzymatic Reactive Crystallization of Ampicillin

Abstract

Prediction and control of crystal size distributions, a prerequisite for production of consistent crystalline material in the pharmaceutical industry, requires knowledge of potential non-idealities of crystal growth. Ampicillin is one such medicine consumed in crystal form (ampicillin trihydrate). Typically it is assumed that all crystals of the same chemical and geometric type grow at the same rate, however a distribution of growth rates is often observed experimentally. In this study, ampicillin produced enzymatically is crystallized and a distribution of growth rates is observed as individual crystals are monitored by microscopy. Most studies of growth rate dispersion use complex flow apparatuses to maintain a constant supersaturation or imprecise measurements of size distributions to reconstruct growth rate dispersions. In this study, the controllable enzyme reaction enables the same information to be gathered from fewer, less complicated experiments. The growth rates of individual ampicillin trihydrate crystals were found to be normally distributed, with each crystal having an intrinsic growth rate that is constant in time. Differences in the individual crystals, such as different number and arrangement of dislocations and surface morphology, best explain the observed growth rates. There is a critical supersaturation below which growth is not observed, thought to be caused by reactants adsorbing to the crystal surface and pinning advancing growth steps. The distribution of critical supersaturation also suggests that individual crystals’ surface morphologies cause a distribution of growth rates.

Crystal Growth Cell Incorporating Automated Image Analysis Enabling Measurement of Facet Specific Crystal Growth Rates

“…Such population-based approaches carry the advantage that crystal growth rates are established as an average of many crystals that are kept at hydrodynamic conditions mimicking those used in production facilities. Any growth rate dispersion potentially originating from imperfections of single crystals are averaged out and a representative mean of the growth rate is obtained. − While such averages are robust and in many contexts sufficient, , measuring facet-specific information on the often imperfect crystals present in such experimental studies has proven to be difficult . Such facet-specific growth rates would, however, be useful to advance the mechanistic understanding of crystal growth.…”

Growth of Abraded Crystals Tracked in Three Dimensions

“…The new model also considers the abraded, faster-growing regions. In the literature, , fast growth of damaged crystals is attributed to strain and dislocations in the crystals. Our results demonstrate that the presence of fast-growing surfaces may also contribute to a faster increase in volume.…”

Improved Crystallization of Ampicillin Trihydrate Based on the Use of Ultrasound

“…Solubility data of AT at different temperatures was determined experimentally. McDonald et al in their work reported that the solubility of ampicillin drops at a pH of 8 or above. Such a decrease in solubility resulted in crystallization of ampicillin sodium salt as opposed to ampicillin trihydrate.…”

“…A jacketed reactor with an inner diameter of 5 cm and a height of 7 cm connected to the chiller, which allowed the solution to cool until 10 °C, was used for the experiments. Continuous mixing was achieved with the help of 21 in their work reported that the solubility of ampicillin drops at a pH of 8 or above. Such a decrease in solubility resulted in crystallization of ampicillin sodium salt as opposed to ampicillin trihydrate.…”