Crystallization Kinetics of Ampicillin Using Online Monitoring Tools and Robust Parameter Estimation

Abstract

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.

The effect of introducing antibiotics into organic light-emitting diodes

“…Occasionally, a large fluctuation in 40% ampicillin-PEDOT:PSS devices efficiency was observed (shown as standard deviation in Fig. 5b-d) and on investigation the reason was found to be the absence/presence of long rod-like ampicillin crystals 60,61 ( Supplementary Fig. 11) in the spin coated 40% ampicillin-PEDOT:PSS layer.…”

“…11) in the spin coated 40% ampicillin-PEDOT:PSS layer. As the ampicillin crystal formation could be supported by instability of various factors such as temperature 60 and pH 61 , the temperature was kept constant during the preparation of ampicillin solution. However, as the pH of 40% ampicillin-PEDOT:PSS solution was around the same as reported crystal formation region (pH 7.8~6) 61 , the observed infrequent crystallization ( Supplementary Fig.…”

Multiobjective Dynamic Optimization of Ampicillin Batch Crystallization: Sensitivity Analysis of Attainable Performance vs Product Quality Constraints

“…The crystallization of ampicillin has been demonstrated in the literature by pH-variation, including a model with detailed growth and nucleation kinetics and solubility as a function of pH, allowing detailed prediction of attainable crystallization yields and mean crystal sizes for different pH variation profiles and seeding conditions. 18 Dynamic optimization of pH-profiles for the batch crystallization of ampicillin subject to various product specifications and operational constraints may present improved process performances vs. straightforward linear pH variations demonstrated in the literature thus far. 19 In this work, the recently published crystallization model for ampicillin is utilized for dynamic optimization of pH manipulation profiles over the batch runtime in order to optimize product quality attributes subject to different operational and performance constraints.…”

“…19 In this work, the recently published crystallization model for ampicillin is utilized for dynamic optimization of pH manipulation profiles over the batch runtime in order to optimize product quality attributes subject to different operational and performance constraints. 18 The paper is structured as follows. First, the published dynamic model for the batch crystallization of ampicillin that is used in this work for optimization purposes is described in detail.…”

Dynamic Modelling and Optimisation of the Batch Enzymatic Synthesis of Amoxicillin

“…The demonstrated enzymatic synthesis of amoxicillin paves the way for the elucidation of optimal design and operating parameters via modelling and optimisation [12,13].Dynamic modelling and optimisation of batch processes have been substantially implemented in the literature for a variety of bioprocesses, including fermentations [14,15], antibiotic synthesis [16,17] and many other applications, illustrating the utility and versatility of such methods in bioprocess design. Enzymatic synthesis, crystallisation and reactive crystallisation studies for β-lactam antibiotics have been implemented in the literature [16][17][18][19]. A demonstrated batch enzymatic synthesis of amoxicillin paves the way for theoretical studies [20].…”