Nomeir, AA; Burka, LT; Matthews, HB
The stability of dimethyl-hydrogen-phosphite (868859) (DMHP) under simulated physiological conditions was investigated. Solutions of 2, 5, or 10 percent DMHP in methanol, tetrahydrofuran, deionized water, 0.9 percent sodium-chloride, sodium-phosphate buffered to pH 7, 7.4, and 8, or hydrochloric-acid buffered to pH 2 were kept at -80, -8, 8, 22, or 37 degrees-C. The pHs of 2, 8, and 7.4 were chosen to simulate those of the stomach, intestinal contents, and plasma, respectively. Aliquots were taken at various times from 1 minute to 7 days after preparation and analyzed for DMHP by capillary gas chromatography using a flame ionization detector. DMHP decomposition products were identified by high performance liquid chromatography and proton nuclear magnetic resonance spectroscopy. A 10 percent solution of DMHP in water was stable at 22 degrees for 8 hours, after which it decomposed. Between 8 and 24 hours, 76 percent of the DMHP decomposed. No significant additional decomposition occurred between 24 hours and 7 days. The rate of decomposition showed first order kinetics. The stability of DMHP increased with decreasing temperature. The half times for decomposition of 10 percent aqueous DMHP increased from 8 hours at 22 degrees to 187 hours at -8 degrees. When 5 and 10 percent DMHP were tested at 37 degrees under various physiological pHs, both the stability period and the half time of decomposition were greatest for the 5 percent concentration at pH 8. Methanol (67561), monomethyl-hydrogen-phosphite, and ortho-phosphorous-acid (10294561) were identified as decomposition products. The authors conclude that DMHP is stable in water at 37 degrees for a short time before it starts to decompose by hydrolysis. The rate of hydrolysis depends on temperature, DMHP concentration, and pH of the solution. DMHP is more stable in slightly alkaline than in acidic or neutral solution.
