Effect of process parameters on the recrystallization and size control of puerarin using the supercritical fluid antisolvent process

摘要

Abstract The purpose of this study was to investigate the influence of the supercritical CO₂ processing on the particle size and morphology of puerarin crystals. The process parameters included solvents, temperature, pressures, antisolvent times, addition volumes, antisolvent addition rates and solute concentrations. After being processed, the dramatic reduction of the dimensions and the change of the crystal shape were noticed. Decreasing the antisolvent addition rate, increasing the temperature and the addition volume below 50?ml led to a decrease in size. The new crystal of puerarin generated at the optimal conditions was 30.34?μm. The solvent of methanol and the concentration of 60?mg/ml were found to determine the type and degree of crystallinity of particles. These results showed that this process has the potential to produce a drug recrystallization product with newly generated crystal forms and the size of drug particles could be controlled through the tuning of various experimental conditions. Graphical Abstract Figure options Download full-size image Download as PowerPoint slide Keywords Puerarin ; Microparticles ; Supercritical fluid ; GAS ; Crystallization ; Particle size prs.rt("abs_end"); 1. Introduction For most orally administered poorly-soluble compounds, the bio-absorption process is rate-limited by dissolution in gastrointestinal fluids; in the case of parenteral administration, the effective bio-availability of compounds is limited by solubility issues. As for the crystal drug, two key characteristics of crystalline solid dosage forms are crystal habit and the crystal size distribution [1] . The conventional techniques for reduction of particle size include mechanical comminution (through milling, crushing and grinding), lyophilization and recrystallization of the solute particles from solution (through solvent-antisolvent techniques, spray drying and freeze-drying). All these techniques suffer from one or more disadvantages, such as thermal and/or chemical degradation, high solvent requirements or difficult removal of solvent traces from the final product. Besides, the classical crystallization techniques usually lead to a mixture of polymorphs because of the multi-step process used. Therefore, there is increasing interest in developing technologies which, particularly in the case of pharmaceuticals, allow one to produce microparticles with controlled particle size distribution and product quality (crystallinity, purity, morphology) under mild and inert conditions. Since the mid-1980s, a new method of powder generation has appeared involving crystallization with supercritical fluids. CO₂ is the most widely used solvent and its innocuity and “green” characteristics make it the best candidate for the pharmaceutical industry. Supercritical fluid technology, particularly when using CO₂, offers different possibilities to tackle the above-mentioned challenges [2] and [3] . And it is also interesting to check if the supercritical crystallization (a single-step unit) may give different results. These include the processes called rapid expansion of supercritical solutions (RESS), precipitation with compressed antisolvent (PCA, sometimes referred to as SAS, i.e., supercritical antisolvent process, or ASES, i.e., aerosol spray extraction system) and gas antisolvent recrystallization (GAS) [4] , [5] , [6] and [7] . In the GAS process, high pressure CO₂ is injected into the liquid phase solution, which causes a sharp reduction of the solute solubility in the expanded liquid phase. As a result, precipitation of the dissolved compound occurs. The potential advantages of the GAS recrystallization process lie in the possibility of obtaining micron and submicron particles with a narrow size distribution and lower residual solvent. By varying the process parameters, the particle size, size distribution and morphology can be “tuned” to produce a product with desirable qualities. This makes the GAS technique attractive for the micronization of high-valued products such as pharmaceuticals [8] and [9] . Adopting a GAS process to recrystallize pharmaceutical compounds will provide highly versatile methodology to generate new polymorphs of drugs. Many researchers have employed the GAS process for micronization and recrystallization of various pharmaceutical substances [10] , [11] and [12] . They have concentrated on the size reduction of pharmaceutical compounds and they observed changes in the external shape and size distribution of the resulting particles. The diversity of experimental parameters of the GAS process can vary the conditions for nucleation and crystal growth steps in a wide range. It is possible to produce drug particles with different crystalline arrangements but identical chemical compositions. Such behavior is called polymorphism, meaning the ability of any compound to crystallize into more than one distinct crystalline state [13] . This can be imp