Antisolvent crystallization of Indomethacin (IMC), a nonsteroidal anti-inflammatory drug, from a ternary solvent system (acetone-methanol-water) has been investigated in this work. Acetonemethanol (66.5-33.5 wt%) binary mixture was selected as a solvent based on the solubility of IMC reported earlier. Water was selected as an antisolvent based on the solubility of IMC measured in acetone-methanol-water mixtures at 25 °C. Unseeded and seeded antisolvent crystallization was carried out for two initial concentrations of IMC (and) with stepwise addition of 0, 1 0, 2 antisolvent. The acetone solvate of IMC was crystallized during the unseeded experiments, while the desired γ-IMC was obtained with a bimodal particle size distribution (PSD) during the experiments seeded with γ-IMC. A significant increase in the productivity was observed because of increased crystal yield and faster crystallization kinetics as compared to the crystallization processes reported earlier for the production of γ-IMC. Finally, the feasibility of IMC particle size tuning through the solvent-antisolvent (dissolution-growth) addition cycles was demonstrated successfully.
In
this work, the effect of crystallization parameters, i.e., supersaturation,
seeding, and temperature, on the polymorphism and crystal size of
a nonsteroidal anti-inflammatory drug, indomethacin (IMC), was investigated.
First, several crystallization solvents (ethanol, methanol, ethyl
acetate, acetone, acetonitrile, and dichloromethane) were screened
through the measurement of IMC solubility at different temperatures.
This was followed by the investigation of IMC nucleation through measurement
of induction times in selected solvents at two supersaturations. Finally,
seeded cooling crystallization of IMC in ethanol was performed with
different process parameters to investigate the influence on the polymorphism
and crystal size distribution. Remarkably long induction times were
observed for IMC in ethanol and ethyl acetate solutions, while a shorter
induction time was observed in acetone. Cooling crystallization of
IMC from ethanol confirmed that supersaturation, operating temperature,
and seeding do affect the polymorphism as well as crystal size distribution
of IMC. Fine needle-shaped crystals of metastable α-IMC were
obtained at 5 °C with high supersaturation even in the presence
of γ-IMC seeds, while rhombic platelike crystals of thermodynamically
stable γ-IMC were obtained in the remaining experiments. The
seed loading only marginally influenced the crystal growth rate and
median particle diameter. Particle size analysis of the crystals obtained
showed a bimodal distribution in all experiments, and a larger median
particle diameter was observed at 15 °C with high supersaturation.
Crystallization
is an inevitable step in the purification of artemisinin
either from the plant Artemisia annua or from reaction
mixtures of semisynthetically produced artemisinin. Rational design
of crystallization process requires knowledge about the solid–liquid
equilibrium in a given solvent system and effect of impurities on
it. In the present work, a crystallization process was designed to
purify artemisinin from fractions of a flash chromatography column
effluent collected after injecting extracts of Artemisia annua leaves. The fractions from chromatography containing artemisinin
were combined together into one fraction, and the impurities present
in this fraction were identified. The solubility of artemisinin in
the mobile phase used for chromatography, i.e., n-hexane–ethyl acetate mixture of varying compositions, was
measured at 25, 15, and 5 °C, respectively. The collective effect
of impurities present in the combined fraction on the solid–liquid
equilibrium of artemisinin was evaluated by measuring the solubility
of artemisinin in the combined fraction at same temperatures. The
results show that the impurities present in the combined fraction
increase the solubility of artemisinin. Finally, the crystallization
of artemisinin from the combined fraction designed on the basis of
artemisinin solubility data was carried out in two steps by adding
an antisolvent and cooling crystallization. The yield of artemisinin
obtained in the process was 50%, and it was found that the impurities
present in the combined fraction at a given concentration do not affect
the crystallization of artemisinin.
A systematic method of conceptual process synthesis for recovery of natural products from their biological sources is presented. This methodology divides the task into two major subtasks namely, isolation of target compound from a chemically complex solid matrix of biological source (crude extract) and purification of target compound(s) from the crude extract. Process analytical technology (PAT) is used in each step to understand the nature of material systems and separation characteristics of each separation method. In the present work, this methodology is applied to generate process flow sheet for recovery of artemisinin from the plant Artemisia annua (A. annua). The process flow sheet is evaluated on the basis of yield and purity of artemisinin obtained in bench scale experiments. Yields of artemisinin obtained in individual unit operations of maceration, flash column chromatography, and crystallization are 90.0%, 87.1% and 47.6%, respectively. Results showed that the crystallization step is dominant to the overall yield of the process which was 37.3%.
Ternary solubility phase diagrams of mandelic acid and N-methylephedrine species in chiral solvents, (S)-methyl lactate, (S)-propyl lactate, and (S)-butyl lactate, have been determined. Solubility measurements were performed for enantiomeric compositions ranging from 50:50 mixtures to the pure enantiomers and temperatures ranging from 0 to 35 °C for mandelic acid and from 0 to 25 °C for N-methylephedrine, respectively. The ternary solubility phase diagrams of mandelic acid and N-methylephedrine showed symmetric behavior. It became obvious that increasing chain length of chiral solvents, i.e. from (S)-methyl lactate to (S)-butyl lactate, resulted in decreasing solubility. 1HNMR and Raman spectroscopy have been applied to characterize the solute-solvent interaction in the liquid phase for mandelic acid system. Molecular modeling calculations were performed for mandelic acid to get a deeper understanding of the solute−solvent interactions. The effect of the solvent on the shape of the solubility isotherms is discussed by determining the relative solubility ratios (αmol-values) just for N-methylephedrine.
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