(214d) Continuous Crystallization Process for Resolution of Diastereomeric Salts: Ibuprofen Lysine Case Study

Simon, M., University College Dublin
Jones, R., University College Dublin
Donnellan, P., University College Dublin
Glennon, B., University College Dublin
Ferguson, S., University College Dublin

Continuous crystallization process
for resolution of diastereomeric salts: Ibuprofen lysine case study

M. Simon1, R.C. Jones1,
P. Donnellan1 and B. Glennon1

1Synthesis and Solid State Pharmaceutical Centre (SSPC), University College Dublin, School of
Chemical and BioProcess Engineering, University College Dublin, Belfield,
Dublin 4, Ireland

Keywords: diastereomeric salt,
continuous crystallization, phase diagram


than half of the active pharmaceutical ingredients are found to be chiral[1]; hence, enantioseparation is of
significant interest to the pharmaceutical industry.[2] In the case of a racemic mixture, typically
only one enantiomer possesses the active therapeutic activity while the other
is regarded as an impurity constituting 50% of the mixture.[3] This undesired enantiomer can cause
undesired side effects[4]
e.g., the tragic incident of the drug thalidomide in the 1960s, which resulted
in physical birth defects (the R-enantiomer was proven to be a teratogen
whereas the S-enantiomer was used to treat morning sickness for pregnant

is broadly applied at small and large scales to 
eliminate impurities, including enantiomeric impurities.[2] An in-depth understanding of the
solid-liquid equilibrium (SLE) data in terms of phase diagrams is vital for
devising and optimizing crystallization processes.[6]

method to isolate high purity enantiomer from a racemic mixture is by
diastereomeric salt formation.  Racemic
basic (or acidic) target compounds are reacted with optically active compounds
such as enantiopure acidic (or basic) resolving agents to form a pair of
diastereomeric salts that can [7]
be separated by fractional crystallization.[8]
The resulting salt is subjected to neutralization process to give a pure
enantiomer. The crystallization process can be either kinetically (separation
of salts depending on the rate of crystals formed) or thermodynamically
(separation of salts depending on their solubility differences) controlled.[7, 9] Unlike enantiomers, diastereomeric
salts do not possess symmetry.[10]
The properties of diastereomeric salts are as follows: high solubility
difference, distinct crystal morphology, good thermal stability, rapid
dissolution rate, and varied inclination to crystallize.[11] The high solubility difference
between the salt pairs is accomplished by the appropriate choice of resolving
agents and/or a solvent system during the resolution.[12]

systematic study of the diastereomeric salt formation of R-ibuprofen-S-lysinate
(R-salt) and S-ibuprofen-S-lysinate (S-salt) were explored in the binary and
ternary phase diagram using 94 wt% aqueous ethanol as a solvent. Based on the
phase diagram, a continuous crystallizion process with crystal-free mother
liquor exchange streams was devised.

Section 1: Solubility Studies

data (binary and ternary phase diagram of the two diastereomeric salts in the
solvent system at different temperatures) and kinetic properties (metastable
zone widths in an appropriate solvent) are required to design appropriate
crystallization process.[13]The ternary phase diagram of the salt pairs in
94 wt% aqueous ethanol were determined by classical isothermal and polythermal
methods. The metastable zone widths of the pure salts were measured. The ternary phase diagram depicted in Fig. 1, confirms
that the eutectic point exists at a salt composition of ~34:66 wt%
R-salt:S-salt. The phase diagram and X-ray Powder diffraction patterns of the
salt mixtures confirmed the formation of a simple eutectic behaviour in the
system of the diastereomeric salts.

Section 2: Design of a Continuous Coupled
Crystallization Process

thermodynamic data depicted in Fig. 1 was
used to design the resolution method to resolve both salts with high purity. The
aim was to investigate the applicability of a continuous coupled MSMPR
crystallizers for simultaneous separation of the diastereomeric salts by
crystal growth with pure seed crystals. Crystal-free mother liquor exchange
streams were operated continuously between the two MSMPR.

Figure 1: Ternary phase diagram of diastereomeric salts of
ibuprofen lysine: R-salt & S-salt (axes in weight fraction (W); lines are
guides to the eye; tie lines are drawn for 15 °C and 40 °C)


The financial support of the
Synthesis and Solid State Pharmaceutical centre (SSPC) and Science Foundation
Ireland (SFI, 12/RC/2275) are gratefully acknowledged.


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