Crystallization of sulfamethizole using the supercritical and liquid antisolvent processes

Sulfamethizole was crystallized using both the supercritical and liquid antisolvent processes. Acetone and N,N-dimethyl formamide (DMF) were selected as solvents for the pharmaceutical compound, and carbon dioxide and distilled water were used as antisolvents. In the supercritical antisolvent process, the effects of experimental conditions such as carbon dioxide injection rate, type of solvent, and temperature were investigated. In the liquid antisolvent process, the effect of ultrasound on the properties of crystal was examined. The various crystal habits such as tabular, platy, acicular, and prismatic were observed depending on the process and experimental conditions. Differential scanning calorimetry (DSC) measurement revealed that the carbon dioxide injection rate affected the crystallinity of sulfamethizole particles. Larger crystals were obtained at higher temperatures in the two antisolvent processes. The particle size distribution was mostly affected by the antisolvent injection rate and the application of ultrasound.     

Effect of CO2-antisolvent techniques on size distribution and crystal lattice of theophylline

Recrystallization of theophylline was carried out from an ethanol:methylene chloride solution, using carbon dioxide as antisolvent. The two variants of the technique - bubbling CO₂ (GAS) or spraying the solution (SAS) - were investigated in order to explore the effect of specific conditions on physical (particle size distribution) and chemical (crystalline form) attributes of the product. The particle size analysis showed that particles were almost insensitive to the operating conditions in the GAS mode. The analysis of phase behavior revealed that precipitation occurred for a CO₂ mole fraction above 0.63 and when the CO₂-solvent system crossed the L-V coexistence line, i.e. when the bi-phasic mixture merged as a single phase. In the SAS mode, the vicinity of the mixture critical point allowed for reducing the mean size and the size distribution as well. Most X-ray diffraction patterns of CO₂-processed powders were found to exhibit new peaks, with an occurrence influenced by process version, pressure and temperature. The comparison with theoretical patterns obtained through various crystal modifications indicated that the new patterns were attributable to a change of the symmetry group rather to a textural effect. Finally, SAS mode was proven to be more efficient at producing narrower and smaller particle size than GAS especially when co-flow injectors were used.     

Recrystallization of erlotinib hydrochloride and fulvestrant using supercritical antisolvent process

Recrystallization of two anti-cancer active pharmaceutical ingredients (APIs), erlotinib hydrochloride (erlotinib HCl) and fulvestrant, using supercritical antisolvent (SAS) process was investigated in this study. The most commonly used supercritical carbon dioxide was employed as the antisolvent. Effect of three process parameters including the operating temperature, pressure and solution flow rate have been studied. Analyses of the recrystallized erlotinib HCl and fulvestrant were examined by SEM, XRD and DSC. Erlotinib HCl was recrystallized from its mean particle size of 20 μm to 2 μm with different crystal habits. Different polymorphs of erlotinib HCl were obtained and confirmed from the XRD and DSC results. The prior art polymorph form A of erlotinib HCl showed enhanced dissolution rate by 3.6 times to its original polymorph form B. Significant particle size reduction was also obtained for fulvestrant. The mean particle size was reduced from its original value of 22 μm to 2 μm with much narrower particle size distribution. The cross-interaction effect between the operating temperature and pressure observed in the SAS treatment of fulvestrant was verified by the method of calculated mixture critical point (MCP). The micronized fulvestrant particles showed consistent polymorph as the original API, but with different crystal habits. It is confirmed that the SAS method is applicable for controlling the crystal properties of two APIs, erlotinib HCl and fulvestrant, which require rigorous control of physical characteristics.     

Process performances and characteristics of powders produced using supercritical CO2 as solvent and antisolvent

A carbon dioxide (CO₂) soluble compound (cholesterol) was successfully precipitated either by rapid expansion of SCCO₂ solutions (RESS process, acronym for Rapid Expansion of Supercritical Solution), or from methylene chloride solutions by antisolvent precipitation (SAS-process, acronym for Supercritical Antisolvent process). The same fluid was thus used either as a solvent or as an antisolvent to precipitate cholesterol. Performances of RESS and SAS were compared through the analysis of the particle characteristics and production rates. Differences were related to supersaturation and time scale of nucleation/growth involved in both processes. Polydispersity, large size and elongated shape were characteristics of particles produced by SAS, especially when experiments were performed under conditions of total miscibility of CO₂ and organic solvent. Conditions where vapor-liquid equilibrium exists promoted a confinement of the growth that consequently reduced the final particle size. RESS, by comparison, produced smaller and monodispersed particles. Production of small particles is a key advantage for RESS, but lower production rates and yield might be disadvantages. The combination of the two processes offers the opportunity of tunable sizing of powder, switching from a large production of particles ranging from 10 to 100 μm, to a limited production of fine crystals below 10 μm.     

水杨酸在CO2-乙酸乙酯体系中重结晶过程的相平衡及结晶形态

在308．15K和318．15K温度下、0～8MPa压力范围内,研究了二氧化碳一乙酸乙酯-水杨酸体系的相平衡．结果表明,水杨酸在液相中的浓度随体系压力升高而降低,随温度升高而增大．用CO2作抗溶剂可以使乙酸乙酯中的水杨酸沉淀结晶．在相平衡研究的基础上,研究了水杨酸在CO2-乙酸乙酯中的结晶,得到针状空心晶体．     

Isothermal by Design: Comparison with an Established Isothermal Nucleation Kinetics Analysis Method

The nucleation kinetics of the alpha form of p-aminobenzoic acid from ethanolic and aqueous solutions is examined through a comparative examination of temperature-jump and anti-solvent drown-out isothermal crystallization methodologies. Analysis of the data reveals the measured induction times, and the calculated effective interfacial tensions as a function of the supersaturation show broadly equivalent behavior for the aqueous-ethanol mixed-solvent drown-out and temperature-jump ethanol solution systems, confirming the comparability of the two methodologies. The results also demonstrate poorer agreement with the temperature-jump pure aqueous system, highlighting the importance of the strength of solvation/desolvation as the key rate-limiting process for the overall nucleation behavior.     

Expanding production regions of α-form and β-form glycine using an antisolvent crystallization method assisted by N2 fine bubbles

To develop a crystallization technique that can enhance the production of metastable α-form and unstable β-form glycine, we studied the antisolvent crystallization of glycine using the gas–liquid interfaces around N₂ fine bubbles as novel crystallization fields. In the regions near the gas–liquid interfaces, local supersaturation is generated because of the accumulation of glycine and alcohol as an antisolvent as a result of the negative electric charge on the fine bubble surface. Hence, the produced glycine polymorphs change from the stable γ-form to a α-form or β-form glycine. Additionally, local supersaturation at the gas–liquid interfaces can be expected to change via modification of the accumulation of the glycine and alcohol molecules and the interaction of glycine-water-alcohol with the different alcohol additives. At a solution temperature of 303?K, methanol (MeOH), ethanol (EtOH), or isopropanol (IPA) as an antisolvent were rapidly mixed into the saturated glycine solution. While mixing MeOH, EtOH, or IPA with the saturated glycine solution, N₂ fine bubbles with an average size of 10?µm were continuously supplied to the mixed solution using a self-supporting bubble generator and a glycine polymorph was crystallized within 5?min. For comparison, an antisolvent crystallization free of N₂ fine bubbles was conducted using a propeller type mixer. During antisolvent crystallization with/without fine bubble injection, the additional alcohol volume was varied to control the generation rate of the supersaturation in the bulk solution (r_C/CS). Consequently, the production regions of the α-form and β-form glycine were broadened to lower r_C/CS via N₂ fine bubble injection. The expansion behavior for α-form or β-form glycine significantly increased because of the enhancement of local supersaturation at the regions near the gas–liquid interfaces of the N₂ fine bubbles owing to the decreasing carbon number in the alcohol.     

Modeling and Growth Kinetics of Antisolvent Crystallization Applied to the Pharmaceutical Industry

With the aim of simulating the product crystal size, which is one of the important physical properties for active pharmaceutical ingredients, an antisolvent crystallization model is proposed, including only six experimentally determined kinetic parameters to develop a concise model. As a first step, the methodology to assess the growth rate parameters, which are some of the six kinetic parameters, is discussed. An approach for appropriately treating the size distribution data obtained by means of the laser diffraction/scattering method is suggested. The determined growth rate parameters could be used to simulate the crystal size indicating that the simulation by crystallization modeling is a practical application for the pharmaceutical industry.     

Enhanced water-solubility of Licorice extract microparticle prepared by antisolvent precipitation process

In this study, Licorice extract (LE) microparticles were successfully prepared using antisolvent precipitation process. Ethyl acetate and dimethyl sulfoxide, were used as the antisolvent and solvent, respectively. By means of orthogonal experimental design, the influences of several process parameters on the mean particle size (MPS) were investigated. The concentration range of the LE solution, the volume ratio of solvent to antisolvent, dripping speed, and temperature were 4.3–34.5 mg/mL, 1:1–1:12, 1–10 mL/min, and 20–35 °C, respectively. Based on the above orthogonal experiments, the optimum antisolvent precipitation process conditions were found to be: temperature 20 °C, concentration of the LE solution 17.2 mg/mL, volume ratio of solvent to antisolvent 1:4, dripping speed 10 mL/min. The LE microparticles were characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier transform-infrared (FT-IR) spectroscopy, thermal gravimetric analysis (TG), differential scanning calorimetry (DSC), HPLC analysis and dissolution test. And the morphology, crystalline state and chemical structure, drug purity, dissolution rate and bioavailability of LE microparticles were investigated. Under optimum antisolvent precipitation process conditions, the MPS of LE microparticles reached to 85.3 nm, and with uniform distribution. And the LE microparticles had the same chemical structure as the unprocessed drug, but the crystallinity was reduced, purity was increased. Furthermore, the water solubility increased from 4.82 mg/mL to 16.10 mg/mL, and bioavailability is increased by 64.36%.     

Micronization of the Pharmaceutically Active Agent Genipin by an Antisolvent Precipitation Process

Due to its low water solubility and slow dissolution rate, genipin was micronized by an antisolvent precipitation process using ethanol as solvent and n‐hexane as antisolvent. The effects of various experimental parameters on the mean particle size (MPS) of micronized genipin were investigated. By analysis of variance, only the concentration of the genipin solution has a significant effect on the MPS in genipin micronization. Under the optimum conditions, micronized genipin with an MPS of 1.8 μm was obtained. The micronized genipin was characterized by various methods, e.g., scanning electron microscopy and thermogravimetry. The analysis results indicated that the chemical structure of micronized genipin was not changed, but the crystallinity was reduced. The dissolution rate and solubility of the micronized genipin were 2.08 and 1.64 times that of the raw drug. In addition, the residual amounts of n‐hexane and ethanol were less than the International Conference on Harmonization limit for solvents.