Sd. Clas et al., ASSESSMENT OF THE PHYSICAL STABILITY OF LYOPHILIZED MK-0591 BY DIFFERENTIAL SCANNING CALORIMETRY, Thermochimica acta, 288(1-2), 1996, pp. 83-96
MK-0591, a potent indirect leukotriene biosynthesis inhibitor, is poor
ly absorbed when administered orally as a crystalline sodium salt, pri
marily because of its low aqueous solubility (5 mu g/mL). However, the
lyophilized X-ray amorphous form with much higher aqueous solubility
is very well absorbed and physically stable for long time periods. To
better understand the physical stability of the amorphous state, condi
tions at which the compound will crystallize from the amorphous state
were investigated in the context of its glass transition temperature.
The physical stability of X-ray amorphous MK-0591 was evaluated by DSC
with enhanced sensitivity using the crystallization exotherm at ca. 1
85 degrees C (10 degrees C/min) to detect crystallization in the solid
matrix. No crystal formation was observed at 30 degrees C for 6 month
s, 60 degrees C for 6 months or 30 degrees C at 75% RH for 6 months. T
his prolonged physical stability was attributable to two factors: its
high glass transition temperature (ca. 125 degrees C) and liquid cryst
al formation in aqueous solutions at concentrations greater than 60 mg
/mL. Crystallization could not be induced after isothermally holding t
he X-ray amorphous MK-0591 at 120 degrees C for 17 h. Seeding with cry
stalline MK-0591 (10%) also failed to induce crystallization at 50 deg
rees C for 6 months or at 30 degrees C at 75% RH for 6 months. Water p
lasticizes lyophilized MK-0591, lowering the T-g and inducing the onse
t of crystallization to 100 degrees C. Crystallization at room tempera
ture does not occur with equilibration at high relative humidites prob
ably because of the additional stability imparted to the system by the
formation of a lyotropic liquid crystalline phase. The behaviour of a
morphous MK-0591, with its high T-g in the solid state and its liquid
crystalline properties in concentrated aqueous solution, provided suff
icient physical stability to permit its use in oral formulations.