Revisiting the solubility concept of pharmaceutical compounds

被引：9

作者：

Blasko, A ^{[1
]}

Leahy-Dios, A ^{[1
]}

Nelson, WO ^{[1
]}

Austin, SA ^{[1
]}

Killion, RB ^{[1
]}

Visor, GC ^{[1
]}

Massey, IJ ^{[1
]}

机构：

[1] Roche Biosci, Palo Alto, CA 94304 USA

来源：

MONATSHEFTE FUR CHEMIE | 2001年 / 132卷 / 07期

关键词：

solubility; aqueous solutions; pH-STAT; UV/Vis turbidimetry; shake flask;

D O I：

10.1007/s007060170065

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

The kinetic and thermodynamic solubilities of Roche (Ro) pharmaceutical compounds were determined by HPLC, titrimetry, and UV/Vis spectroscopy in aqueous buffers and in nonbuffered 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 fort-nation 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.

引用

页码：789 / 798

页数：10

共 15 条

[1] A THEORETICAL BASIS FOR A BIOPHARMACEUTIC DRUG CLASSIFICATION - THE CORRELATION OF IN-VITRO DRUG PRODUCT DISSOLUTION AND IN-VIVO BIOAVAILABILITY [J].