Dynamic Modeling of Encrust Formation and Mitigation Strategy in a Continuous Plug Flow Crystallizer

Abstract

Encrustation, also known as fouling or scale formation, on the wall of plug flow crystallizers (PFC) can cause major operational and economic problems in pharmaceutical industries. These include increased energy requirements due to increment of thermal resistance and pressure drop, and clogging of the crystals due to reduction of flow area. In this work, a mathematical model for predicting the dynamic behavior of a PFC undergoing encrustation is presented. This model describes the formation of encrust layer by considering various mechanisms such as rate of solute transport from bulk to the wall, integration and removal due to shear stress induced by fluid turbulence. A population balance model for describing the crystallization process in the PFC is also coupled with the encrustation model in order to obtain the appropriate concentration profile in the PFC as well as product crystal size distribution (CSD). Based on this model, a mitigation strategy is proposed that relies on injection of pure solvent to dissolve the encrust layer.

Oscillatory Flow Reactors (OFRs) for Continuous Manufacturing and Crystallization

“…Nagy et al 222 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 We specifically operated a continuously seeded crystallization process for LGA in a 25 m glass COBC system (d = 15 mm). 223 Attempting to operate the process without seeding led to significant encrustation such that the crystallizer had to be shut down.…”

Continuous manufacturing: Is the process mean stationary?

“…To be noted that research efforts related to the continuous crystallization of organic molecules have also been made before the concept of continuous manufacturing of pharmaceuticals took-off. 13 Some of the challenges tackled regarding continuous crystallization operation are seed generation, [14][15][16][17] fines removal, 18 polymorphic control, 19 investigation of crust formation, 20 and fouling monitoring. 12 Continuous crystallization has been tested in an integrated continuous pharmaceutical pilot plant.…”

Modeling simultaneous deposition and aggregation of colloids

“…2 Besides heat exchangers, also reactors can undergo fouling in a great deal of applications, relevant to the chemical and pharmaceutical industries. 1,3,4 In fact, both in established as well as in novel, emerging processes, this is a significant issue, potentially leading to product loss, decreased heat exchange, reactor obstruction (i.e. clogging), and increase in pressure drop.…”

“…Several authors already dealt with the full problem, especially when considering crystal systems, and proposed models accounting for most of the above mentioned phenomena. 4,14 A quite thorough analysis has been made by Kostoglou and Karabels, who developed a population balance equation (PBE) based model to approach the precipitation problem in a turbulent flow reactor. 14 Another interesting model is the one proposed by Majumder and Nagy, who studied the encrust formation in a continuous plug flow crystallizer by means of PBE and accounted for the time-evolution of the encrust layer and its impact on the crystal size distribution.…”