Optimizing Sample Dissolution Methods of Low Water Soluble Intermediate Organic Compounds to Support Environmental Risk Assessment during Active Pharmaceutical Ingredient Manufacturing.

Abstract: This project focus on investigating the dissolution of low water-soluble intermediate organic compounds called active pharmaceutical ingredients (API) and organic substances that are manufactured by a pharmaceutical company, Cambrex Karlskoga in Sweden. Several dissolution methods were used and evaluated using methods including total organic carbon (TOC), chemical oxygen demand (COD), biochemical oxygen demand (BOD) and Microtox toxicity test. The selection of solvents were based on previous studies and specifications from the Swedish Institute of Standards, SIS.The performance of eight solvents for different organic substances were evaluated using the above mentioned methods. Solvents that are highly volatile and have low solubility in water were excluded. Therefore, dimethyl sulfoxide (DMSO), dimethylformamide (DMF) and Pluronic F-68, that had highest water solubility, low acute toxicity and not degradable by microorganisms, were further used to dissolve four organic substances. Furthermore, DMSO and DMF were then also used to dissolve four censored chemicals with addition of physical treatment and solvent mixtures (DMF:DMSO with ratio 1:2).Results from each method were discussed and statistical tests were also performed in order to compare different dissolution methods. In addition, quality control and quality assurance were made in order to ensure the quality of measured values from analytical methods. Four organic substances were dissolve in DMSO, DMF and Pluronic F-68 with dissolution ≥79% using six ratios of DMSO and DMF and five ratios of Pluronic F-68 which were analyzed using TOC. Physical treatment increased dissolution of two APIs with 40%. Using BOD, para-aminobenzonic acid (PABA) and 5-nitroisophthalic acid (5-NIPA) had values higher than the guideline values, which indicate high biodegradability of these organic substances. PABA, 5-NIPA and bupivacaine base were acute toxic where PABA showed EC50 values of 27.9 mg/L using DMSO and 36.0 mg/L using DMF, and EC50 values of 5-NIPA were 102 mg/L using DMSO and 84.0 mg/L using DMF, and bupivacaine base had EC50 value of 174 mg/L using solvent mixture (DMF:DMSO with ratio 1:2). With increasing amount of Pluronic F-68, 5-NIPA had increased values of EC50, thereby Pluronic F-68 was not appropriate to use.In conclusion, DMSO and DMF were most appropriate solvents to use in order to dissolve APIs and organic substances with analyte: DMSO ratio of 1:0.5 and analyte: DMF ratio of 1:0.25. In addition, physical treatment could be used in order to increase dissolution of the APIs.