Crystallization of Azilsartan with Acidification of Azilsartan Disodium Salt

Abstract

A reactive crystallization process induced by acidification of azilsartan disodium salt was proposed to produce sub-micron-sized crystals. In the present work, azilsartan crystals were obtained by mixing two aqueous solutions of azilsartan disodium salt (ADS solution) and acetic acid (AA solution). When ADS solution was injected into AA solution, the crystalline azilsartan (type I), the thermodynamically stable form, could be obtained by the phase transformation of amorphous intermediates of azilsartan initially precipitated. Azilsartan crystals transformed from amorphous phase were found to be much smaller than those obtained directly with no transformation by addition of AA solution into ADS solution. The spectra of ATR-FTIR and particle counts from the focused beam reflectance measurement (FBRM) were utilized to investigate the effect of temperature on the transformation process. Final crystal size of azilsartan was found to be influenced by the relative scale of dissolution time for amorphous intermediates. Furthermore, the recovery of azilsartan crystals was found to be strongly affected by the final pH of mixed suspension. Finally, azilsartan crystals with size of about 500 nm and the recovery of higher than 90% were successfully produced from the proposed process with pH 5 mixed suspension at 20 °C.

Parameter Estimation of the Stochastic Primary Nucleation Kinetics by Stochastic Integrals Using Focused-Beam Reflectance Measurements

“…The CLD was measured with focused beam reflectance measurement (FBRM, made by Mettler Toledo International Inc., Columbus, OH, USA). The FBRM technique is often applied to obtain the size distribution [19][20][21]. However, the CLD obtained with FBRM is different from CSD, and hence, the CLD needs to be converted into the CSD [22,23].…”

“…Fourthly, the derivation of the second step is substituted into that of the third step, and the relation between the µ 3,seed and the averaged µ 3 is derived. Finally, the derivation of the fourth step is substituted into Equation ( 20) at i = 0, and this equation is integrated with t substituted by ∆T/R to derive Equation (21). Here, ∆T is a decrease in the solution temperature.…”

Partial Seeding Policy for Controlling the Crystal Quality in Batch Cooling Crystallization

“…The FBRM measuring range was 0-1000 μm and was divided into 100 equal parts by a linear scale. Not the CSD but the chord length distribution (CLD) can be directly determined by FBRM [17][18][19]. However, the CLD can be converted into the CSD with statistical methods via a mapping matrix based on the crystal shape [20][21][22].…”

Polymorph and Morphology Formation of Cerium Carbonate from Reactive Crystallization

“…In reactive crystallization, only the target product can crystallize from the solution and the reactants and byproducts remain in solution by selecting appropriate system conditions, and the driving force for crystallization of the target product is created by its synthesis . Thus, reactor type, − temperature, , concentration of the reactants, , feed profile, reaction time, additive, and many other factors − that influence the reaction process and crystallization process may have a fundamental effect on the quality of the final crystals such as crystal phase, morphology, and particle size. The reactive crystallization mechanism and the process development of the industrial materials has been investigated widely.…”

“…PVM, attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy, and focused beam reflection measuring (FBRM) were the mostly used process analysis tools to investigate the kinetics of reactive crystallization. Kim et al 14 applied ATR-FTIR and FBRM to investigate the effect of temperature and dissolution time on the particle size of azilsartan disodium salt from reactive crystallization induced by acidification, and the dissolution time for amorphous intermediates was found to be the key factor that determines the final particle size. Zhao et al 15 applied a laser method to investigate the effect of supersaturation and temperature on the nucleation mechanism of the reactive crystallization of lithium carbonate and found that heterogeneous nucleation and the homogeneous nucleation governs by supersaturations and temperature.…”