Purification of commercial 2,3-dimethyl phenol using supercritical fluid extraction

The commercial value of phenols is often reduced due to the presence of colored impurities. Several conventional techniques have been used for the purification of phenols. However, conventional purification techniques are tedious and make use of hazardous and expensive organic solvents. In this study, we present a new method for purification of an aged-discolored (orange) commercial 2,3-dimethyl phenol (2,3-DMP) reagent (~97%) using supercritical fluid CO2 (SCF CO2), as an extraction solvent. A supercritical fluid extraction (SFE)/purification apparatus was constructed and purification of the reagent under different extraction conditions was investigated. Based on the differential solubility of the 2,3-DMP and the impurities in SCF CO2, the commercial reagent was successfully purified by SFE; the purified 2,3-DMP was a white solid of high purity (\u3e 99.5%). The SFE method was also applied to purify a recently purchased batch of 2,3-DMP reagent. We found that the reagent purified by SFE was of a higher quality than a commercially available analytical standard. © Taylor & Francis Group, LLC

Polar mixed-solid solute systems in supercritical carbon dioxide: Entrainer effect and its influence on solubility and selectivity

The equilibrium solubilities of benzoic acid (BA), salicylic acid (SAL), and acetylsalicylic acid (ASA) were determined in binary (solute + CO 2), ternary (two solutes + CO2), and quaternary systems (three solutes + CO2) at temperatures ranging from (308 to 328) K and pressures ranging from (10.1 to 28.0) MPa. Solubility data were obtained using a dynamic approach with a simple and reliable apparatus. Polar mixed-solid solute systems demonstrated solubility enhancements, which were consistent with the entrainer effect. In all the polar ternary systems studied, at least one component exhibited solubility enhancements. In the polar quaternary system studied, the solubility of each component increased in comparison to each binary system; the solubility of ASA, SAL, and BA was enhanced up to 484 %, 248 %, and 43 %, respectively. The high solubility enhancements observed in our study indicate that solute-solute interactions are significant in the supercritical fluid (SCF) phase. The solubility enhancements observed in the polar mixed-solid solute systems studied resulted in a decrease in selectivity of SCF CO 2. However, in a quaternary system consisting of BA, SAL, and fluoranthene (FLU), the selectivity of SCF CO2 for SAL versus FLU increased by a factor of 2.7 due to specific solute-solute interactions. This study showed that solute-solute interactions in mixed solid solute systems can result in an increase in the solubility of solutes and also the selectivity of SCF CO2. © 2008 American Chemical Society

Solubilities of substituted phenols in supercritical carbon dioxide

The binary (solute + CO 2) equilibrium solubilities of six substituted phenols (2,5-dimethyl phenol, 2,3-dimethyl phenol, 2,4,6-trimethyl phenol, 2,3,5-trimethyl phenol, 4-phenyl phenol, and 4-tert-butyl phenol) were determined at a temperature of 308 K in the pressure range of 10.1 to 28.0 MPa. Solubility data were obtained using a dynamic approach with a simple and reliable apparatus. The mole fraction solubilities of substituted phenols ranged from 5.14 × 10 -5 to 2.56 × 10 -2. Solubilities of three ternary (two solutes + CO 2) systems were investigated at a temperature of 308 K in the pressure range of 10.1 to 28.0 MPa. In the 4-phenyl phenol + 2,3,5-trimethyl phenol and 4-phenyl phenol + 2,4,6-trimethyl phenol systems, the solubility of 4-phenyl phenol was enhanced relative to its binary solubility by 22.9 % and 217 %, respectively. The 2,3,5-trimethyl phenol and 2,4,6-trimethyl phenol did not exhibit any solubility enhancements in the two ternary systems. Accurate solubilities could not be measured for the 2,5-dimethyl phenol + 4-tert-butyl phenol ternary system due to the existence of a liquid phase under the conditions studied. © 2006 American Chemical Society

A phase I safety study of topical calcitriol (BPM31543) for the prevention of chemotherapy-induced alopecia

Chemotherapy-induced alopecia (CIA) negatively affects psychosocial health and quality of life (QoL). Currently, there are no approved pharmacologic agents to prevent CIA. Here, we evaluated the safety, tolerability, and potential signal of efficacy of topical calcitriol (BPM31543) on CIA prevention. This Phase 1 trial included 23 female patients with breast cancer, gynecologic cancer, or sarcomas receiving a taxane-based chemotherapy. Patients received a 3 + 3 dose-escalation regimen at 5, 10, 20, 40, 60, and 80 μg/mL, with 3-6 patients per group. Patients applied topical BPM31543 to the scalp twice a day for 2 weeks prior to chemotherapy and continued until chemotherapy treatment was completed. The maximum tolerated dose (MTD) during first 28 day application was determined. Adverse event (AE) monitoring, pharmacokinetics, blinded photographic assessments, and patient self-assessment were evaluated. Out of 23 patients treated with BPM31543, 8 patients experienced at least 1 treatment-related adverse event (AE). The majority of AEs were mild to moderate in severity. Only 1 patient experienced SAEs (vomiting, nausea, fever, and flank pain) considered treatment related. Alopecia < 50% from baseline was observed in 8 patients at Week 7, and, of which 2 patients had < 50% alopecia maintained at Week 15. There were no detectable effects of topical BPM31543 on serum levels of calcitriol. BPM31543 applied topically twice daily to the scalp is safe and well tolerated in patients receiving taxane-based chemotherapy. No DLT was observed at up to 80 µg/mL, and MTD was not reached. Based on the data from this trial, BPM31543 represents a promising therapy and warrants further investigation in Phase 2/3 trials

A phase I safety study of topical calcitriol (BPM 31543) for the prevention of chemotherapy-induced alopecia (CIA)

e14064 Background: Chemotherapy-induced alopecia (CIA) may lead to significant psychosocial and quality of life issues. Currently there are no FDA approved oral or topical agents available to prevent CIA. In murine studies, topical calcitriol reduced CIA, likely due to arrest of cell cycle in healthy hair follicles, and reduction in the sensitivity of follicular epithelium to chemotherapy. Methods: A prospective dose escalation study is being performed in up to 31 women with breast cancer, gynecologic cancer and sarcomas. Each patient is applying 1mL of BPM 31543 to her scalp BID, ≥ 5 days prior to initiation of taxane-based chemotherapy for at least 3 months or until the completion of chemotherapy. The study cohorts are: 5/10/20/40/60/80 μg/mL. All 6 cohorts have been completely enrolled. Each patient undergoes PK analysis, adverse event (AE) monitoring, patient self-assessment diaries (1-10 scale), and blinded photographic assessments. Results: Twenty-eight patients have been enrolled (evaluable, n = 21). PK data (n = 21; 5-80 μg/mL) showed inter-individual variability, with increases in serum vitamin D in the 10/20/40/60/80 μg/mL cohorts (range, < 21.3-110 pg/mL). Treatment-related AEs (probably/possibly) were mild/moderate in nature and included scalp pain (n = 1; 5 μg/mL), elevated vitamin D levels in 3 patients (20/40/60 μg/mL) and passage of renal calculus in another (n = 1; 40 μg/mL). A clinical response was observed at each dose level. The study will be complete and final study data will be available and presented at ASCO. Conclusions: Data have shown that the twice daily application of BPM 31543 in patients receiving taxane-based chemotherapy was safe and well-tolerated. The Maximum Tolerated Dose (MTD) was not detected. No Dose Limiting Toxicities (DLTs) or severe treatment-related adverse events occurred in any of the dose cohort. A signal of efficacy was detected at each dose level. Clinical trial information: NCT01588522