Revisiting the Solubility Concept of Pharmaceutical Compounds

Summary.  The kinetic and thermodynamic solubilities of Roche (Ro) pharmaceutical compounds were determined by HPLC, titrimetry, and UV/Vis spectroscopy in aqueous buffers and in non-buffered systems. For kinetic solubility, a turbidimetric method that allows the rapid determination of solubilities using small amounts of compounds (5–50 mg) was used. Two types of precipitation were observed during the kinetic solubility determinations: i) a disperse precipitation where the solution became foggy with very small particles uniformly distributed in the solution, and ii) discrete precipitation characterized by formation of crystals that rapidly sediment. The thermodynamic solubility was determined by shake flask and titrimetrically using a pH-STAT. The pH-STAT titrimetric method for the pH-thermodynamic solubility profile determination eliminates the buffer species and represents a new way to approach the solubility characterization of pharmaceutical compounds. The strengths of the turbidimetric method for determining the kinetic solubility are its rapidity, minimal compound requirements, and suitability for high throughput screening. The limitations are that the maximum solubility is limited to less than 100 mg · cm⁻³, and the precipitation of trace impurities cannot be distinguished from precipitation of the analyte. The pH-STAT titrimetric approach for the thermodynamic solubility has a lower throughput and is suitable for the characterization of the lead candidate. It is not limited in its solubility range and provides a common basis for the comparison of the solubility values at different pH values in contrast to traditional buffered systems. Received August 21, 2000. Accepted (revised) February 5, 2001     

Sound exposures and hearing thresholds of symphony orchestra musicians

To assess the risk of noise-induced hearing loss among musicians in the Chicago Symphony Orchestra, personal dosimeters set to the 3-dB exchange rate were used to obtain 68 noise exposure measurements during rehearsals and concerts. The musicians' Leq values ranged from 79-99 dB A-weighted sound pressure level [dB(A)], with a mean of 89.9 dB(A). Based on 15 h of on-the-job exposure per week, the corresponding 8-h daily Leq (excluding off-the-job practice and playing) ranged from 75-95 dB(A) with a mean of 85.5 dB(A). Mean hearing threshold levels (HTLs) for 59 musicians were better than those for an unscreened nonindustral noise-exposed population (NINEP), and only slightly worse than the 0.50 fractile data for the ISO 7029 (1984) screened presbycusis population. However, 52.5% of individual musicians showed notched audiograms consistent with noise-induced hearing damage. Violinists and violists showed significantly poorer thresholds at 3-6 kHz in the left ear than in the right ear, consistent with the left ear's greater exposure from their instruments. After HTLs were corrected for age and sex, HTLs were found to be significantly better for both ears of musicians playing bass, cello, harp, or piano and for the right ears of violinists and violists than for their left ears or for both ears of other musicians. For 32 musicians for whom both HTLs and Leq were obtained, HTLs at 3-6 kHz were found to be correlated with the Leq measured.