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

Pól Macfhionnghaile,Jan Sefcik,Alison Nordon,Vaclav Svoboda,John Mcginty

doi:10.1021/acs.cgd.7b00136

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.

Highlights

Lactose is found in the milk of most mammals and is a commercial commodity in the food and pharmaceutical industries.[1]
These samples were left to stir in an incubator set at 25 °C for 5, 7, and 11 days to ensure the solution was in equilibrium (α-lactose monohydrate and the solvent solution, and α↔β mutarotation in solution)
Reference samples of α-lactose monohydrate were recrystallized from water and used to collect reference IR spectra and PXRD patterns.[12,48]

Summary

Introduction

Lactose is found in the milk of most mammals and is a commercial commodity in the food and pharmaceutical industries.[1]. In aqueous solution the hydroxyl group on the C1 carbon of the glucose interchanges between the α or β anomer (Figure 1).[10,11] This phenomenon known as mutarotation occurs with ease so that either the α or β anomer of lactose can precipitate from solution, posing a unique challenge in lactose crystallization.[12] In an aqueous solution at neutral pH lactose will equilibrate at 37% α-lactose and 63% β-lactose.[13] This equilibrium has been reported to be achieved within 3.5−6 h at room temperature.[11,14,15] Previous studies have shown the effects in reducing the rate of mutarotation by using dimethyl sulfoxide as a solvent hindering transformation to β-lactose, and allowing specific crystal growth of α-lactose to dominate.[16] α-Lactose and β-lactose exist in several solid forms (Figure 1). Lactose is known to crystallize as β-lactose anhydrous prepared from near boiling aqueous lactose solutions[17] or heated pyridine solutions.[18−20] The most common commercial solid state of α-lactose is the hydrate form, α-lactose monohydrate obtained from cooling crystallization in pH neutral aqueous solutions. A 1:1 α/β co-crystal has been reported.[22−24] Amorphous lactose has been prepared using spray drying, and depending on the conditions during preparation it can consist of varying degrees of both anomers, ranging from >95% α-lactose to

Methods

Results

Conclusion