Isolation of Pharmaceutical Intermediates through Solid Supported Evaporation. Batch Operation Mode

Abstract

Solid supported evaporation (SSE) is a simple method to isolate dissolved compounds as a solid material. The solution is put in contact with granular porous polymer beads onto which the compounds deposit upon evaporation of the solvent. This brings some advantages over direct evaporation to dryness in terms of safety and handling of the solids. In this paper, SSE in batch mode is explored where the solution is added to the polymer beads at once, i.e. opposite to the semicontinuous mode where the solution is sprayed over a bed of beads. A number of compounds varying widely in their physical and chemical properties is studied. It is found that all compounds could be loaded onto the beads; however, the loading capacity depends on the properties of the compound and in general was lower than in the semicontinuous operating mode studied in an accompanying paper. For highly soluble compounds, higher loadings could be achieved when solvent evaporation was slow. In cases where tested, bead loading was found to be homogeneous within a batch. Recovery of compound from loaded beads was achieved by dispersing the beads in a solvent and washing of the filter cake after filtration. A relatively large amount of solvent is required to achieve full recovery.

Isolation of Pharmaceutical Intermediates through Solid Supported Evaporation. Semicontinuous Operation Mode

“…bulk liquid within which the beads are dispersed was observed. Under these conditions, the process resembles batch mode SSE 6 and in order to isolate the compound the solvent had to be evaporated in absence of feeding. As learned from our previous study, the outcome of batch mode SSE is controlled by the solubility of the compound and depends on the rate of evaporation with respect to mass transfer into the pores.…”

“…Bath temperature was 40 °C, and the vacuum pressure was 100 mbar; the mass of beads was 1 g. Sticking of beads was observed already after the addition of the second portion, resulting in a feasible bead loading of 0.9 g/g of beads. Likewise as in methanol, 6 the solubility of inakalant in acetone is very high. Evaporation of the solvent is thus likely to form a highly concentrated viscous liquid that accumulates on the surface of the beads where it acts as a glue to stick beads to the wall of the flask.…”

“…Characterization by sieve analysis, SEM, and literature data is presented in our accompanying work. 6 Tapped density was estimated as 0.120 ± 0.002 g/cm 3 .…”

“…direct evaporation to dryness that leaves behind the solidified nonvolatile intermediate, however, has some drawbacks that limit its applicability. These include poor solid handling, dusting, and the risk for thermal decomposition and side reactions during evaporation. , A method that overcomes these limitations but preserves the simplicity and ease of development of direct evaporation has recently been proposed by Muller and Whitlock . In their solid supported evaporation (SSE) the solution containing the nonvolatile intermediates is put in contact with an inert porous polymer matrix in the form of granular beads onto which the compound deposits upon evaporation of the solvent.…”

“…In this series of two papers, a detailed investigation of SSE is undertaken in order to explore its feasibility and applicability for isolation of typical pharmaceutical intermediates. While in the first paper, we studied SSE in batch mode where the polymer beads are dispersed into the solution and the solvent is evaporated thereafter, here, we consider a semicontinuous operation mode where the solution is continuously fed to the vacuum system of an evaporator where it is sprayed over an agitated bed of dry beads under simultaneous evaporation of the solvent (Figure ). Such an operating mode appears particularly attractive in combination with microreactor , and continuous flow reactor technology , and continuous separators, such as SMB chromatography or extraction columns.…”