Crystallization Diagram for Antisolvent Crystallization of Lactose: Using Design of Experiments To Investigate Continuous Mixing-Induced Supersaturation

Abstract

This study investigates the effects of key process parameters of continuous mixing-induced supersaturation on the antisolvent crystallization of lactose using D-optimal Design of Experiments (DoE). Aqueous solutions of lactose were mixed isothermally with antisolvents using a concentric capillary mixer. Process parameters investigated were the choice of antisolvent (acetone or isopropanol), concentration of lactose solution, total mass flow rate, and the ratio of mass flow rates of lactose solution and antisolvent. Using a D-optimal DoE a statistically significant sample set was chosen to explore and quantify the effects of these parameters. The responses measured were the solid state of the lactose crystallized, induction time, solid yield and particle size. Mixtures of α-lactose monohydrate and β-lactose were crystallized under most conditions with β-lactose content increasing with increasing amount of antisolvent. Pure α-lactose monohydrate was crystallized using acetone as the antisolvent, with mass flow ratios near 1:1, and near saturated solutions of lactose. A higher resolution DoE was adopted for acetone and was processed using multivariate methods to obtain a crystallization diagram of lactose. The model was used to create an optimized process to produce α-lactose monohydrate and predicted results agreed well with those obtained experimentally, validating the model. The solid state of lactose, induction time, and solid yield were accurately predicted.

A novel hollow fiber membrane‐assisted antisolvent crystallization for enhanced mass transfer process control

“…Because of the high supersaturation degree generated in antisolvent adding period and the limited micromixing in the conventional stirred tank crystallizer, developing a method for the effective control of the antisolvent mass transfer process is still a key concern . The most common approach to antisolvent addition is a batch droplet or capillary‐based mixing . The limited interfacial mass transfer area used for the droplet approach and the undesired mixing result in a wide particle‐size distribution and an irregular crystal morphology, which are the fatal drawbacks for pharmaceutical and other chemical manufacture.…”

Influence of gas addition on crystallisation behaviour of lactose from supersaturated solution

“…Many attempts have been made to devise a quick nucleation method in order to obtain the desired lactose crystal size. Previous studies have demonstrated that seeding, use of anti-solvent, agitation, sonocrystallisation and combined high power ultrasound (US) and carbonation (Kougoulos et al, 2010;Parimaladevi and Srinivasan, 2014;Patel and Murthy, 2009;Zeng et al, 2000;Zamanipoor and Mancera, 2014;Zisu et al, 2014;Dincer and Zisu, 2016;MacFhionnghaile et al, 2017;Xun et al, 2017) can modify nucleation kinetics, thereby lactose crystal size, shape and yield are enhanced.…”

Characterization and Prediction of the Non-Bonded Molecular Interactions between Racemic Ibuprofen and α-Lactose Monohydrate Crystals Produced from Melt Granulation and Slow Evaporation Crystallization

“…Ibuprofen has an aromatic ring, a methyl, and a carboxyl functional group in its structure, whilst α-lactose monohydrate has two pyranose rings and a water molecule, forming a dimer in its structure. An αlactose monohydrate is built from a moiety of β-Dgalactose and α-D-galactose, joined by a 1,4 glycosidic bond between C1 of galactose and C4' of the glucose unit [29,[31][32][33]. Fig.…”