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Size control of azilsartan by drowning-out crystallization with phase transformation

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Abstract

To complement the insufficient bioavailability of azilsartan, particle size reduction of azilsartan by drowning-out was attempted. By injecting an azilsartan/ethanol solution into the antisolvent of water, two phases of azilsartan, amorphous and crystalline type A, were found along with phase transformation. The crystal size was strongly affected by the operating parameters such as the volume ratio of antisolvent/azilsartan solution, crystallization temperature, and additives. The crystal size decreased upon increasing the antisolvent/azilsartan solution volume ratio and lowering the temperature. Furthermore, addition of carboxylic acids to the antisolvent of water produced nano-meter sized crystals. In particular, 200 nm particles were obtained with acetic acid. An enhancement in the dissolution rate was found for size-reduced azilsartan crystals, especially when the crystals’ sizes were in the nanometer range.

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Abbreviations

A:

collision factor [m−3 s−1]

ao :

mean effective diameter [m]

C:

concentration of azilsartan in ethanol [mmol L−1]

C*:

saturation concentration of azilsartan in the ethanol/water mixture [mmol L−1]

J:

heterogeneous nucleation rate [m−3 s−1]

k:

heterogeneous nucleation rate [J K−1]

N0 :

number of solute molecules per unit volume [m−3]

R:

gas constant [Jmol−1 K−1]

S:

solubility of azilsartan [-]

T:

temperature [K]

T hm :

harmonic mean of the experimental temperature [K]

tind :

induction time [s]

ttrs :

total phase transformation time [s]

V:

frequency of molecular transport at the nucleus-liquid interface [s−1]

X:

solubility of azilsartan [mol L−1]

x:

azilsartan saturation concentration of ethanol/water mixture [gL−1]

ΔG:

thermodynamic driving force for phase transformation [k] mol−1]

ΔGcrit :

critical free energy for nucleation [J]

ΔsolnH0 :

standard molar enthalpy of solution [kJ mol−1]

ΔsolnGo :

standard molar free energy of solution [kJ mol−1]

ΔsolnSo :

standard molar entropic change of solution [J mol−1 K−1]

η:

heterogeneous nucleation rate [kg m−1 s−1]

φ:

heterogeneous nucleation factor [-]

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Acknowledgement

This work was supported by Kolon Life Science, Inc. (Seoul, Korea).

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Authors and Affiliations

  1. Department of Chemical and Biomolecular Engineering, Sogang University, Seoul, 04107, Korea

    Chun-Il Park, Wang-Soo Kim & Kee-Kahb Koo

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  1. Chun-Il Park
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Correspondence to Kee-Kahb Koo.

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Park, CI., Kim, WS. & Koo, KK. Size control of azilsartan by drowning-out crystallization with phase transformation. Korean J. Chem. Eng. 37, 716–723 (2020). https://doi.org/10.1007/s11814-019-0352-5

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