Resolution of Racemic Guaifenesin Applying a Coupled Preferential Crystallization-Selective Dissolution Process: Rational Process Development

Abstract

Preferential crystallization is a cost efficient method to provide pure enantiomers from a racemic mixture of a conglomerate forming system. Exploiting small amounts of pure crystals of both enantiomers, several batch or continuous processes were developed, capable of providing both species. However, an intermediate production step has to be used when pure enantiomers are not available. In such cases, partially selective synthesis, chromatography, or crystallization processes utilizing chiral auxiliaries have to be used to provide the initial seed material. Recently, it was shown that a coupled Preferential Crystallization-selective Dissolution process (CPCD) in two coupled crystallizers can be applied if at least one pure enantiomer is available to produce both antipodes within one batch. The corresponding process is carried out in one reactor (crystallization tank) by seeding a racemic supersaturated solution with the available enantiomer at a certain temperature. The second reactor (dissolution tank) contains a saturated racemic suspension at a higher temperature. Both reactors are coupled via the fluid phase, allowing for a selective dissolution of the preferentially crystallizing enantiomer from the solid racemic feed provided in the dissolution vessel. The dissolution and crystallization processes continue until the solid racemic material is completely resolved and becomes enantiopure. At this point, both enantiomers can be harvested in their pure crystalline form. For a specific pharmaceutically relevant case study, a rational process design and the applied empirical optimization procedure will be described. The achieved productivities after optimization show the great potential of this approach also for industrial applications. Also, a strategy to control this process based on inline turbidity measurement will be presented.

Linear Analysis of a Continuous Crystallization Process for Enantiomer Separation

“…It is applicable, if the chiral system occurs as conglomerate-i.e., if the enantiomers crystallize as separate enantiopure crystals [3,4]. Continuous processes for preferential crystallization have been suggested in [5][6][7]. A simple process variant is shown in Figure 1.…”

“…The number size densities in the red and blue regions in the right-hand side diagram at time T min are just copies of the number size densities at time t = 0 in the left-hand side diagram. The number size densities in the white unshaded area of the right-hand side diagram depend on nucleation and can be determined with Equation (6).…”

“…The number size densities at the white points are computed by linear interpolation along the black lines. show where the crystals at the black points in diagram (a) have moved at t = T min after passing the mill; the number size densities at the black points are calculated from (4); green points are intersections between black lines (original grid lines) and green lines (resulting from the black lines after passing the mill); the number size densities at the white points are calculated by linear interpolation from the green points; number size densities at the light blue points are calculated directly from the boundary condition (6).…”

“…Finally, the number size densities at some further grid points, shown as light-blue points, are given by the boundary condition (6). This concludes a step forward in time with step length T min .…”

Deracemization in a Complex Quaternary System with a Second‐Order Asymmetric Transformation by Using Phase Diagram Studies

“…Phase diagrams are important tools for understanding and controlling crystallization. Indeed, the construction of a phase diagram is essential for rationally 1) determining the appropriate crystallization conditions for molecules exhibiting multiple solid phases, 2) assessing the thermodynamic stability of solid phases, and 3) controlling the supersaturation . Recently, our group demonstrated that PC could be applied to a metastable conglomerate of diprophylline, which crystallizes in multiple crystal forms depending on the conditions .…”