ABSTRACT
PURPOSE: To use an inverse gas chromatographic (IGC) method to determine the glass transition temperature (Tg) of some amorphous pharmaceuticals and to extend this technique for the in situ study of the plasticizing effect of water on these materials. METHODS: Amorphous sucrose and colyophilized sucrose-PVP mixtures were the model compounds. Both IGC and differential scanning calorimetry (DSC) were used to determine their Tg. By controlling the water vapor pressure in the IGC sample column, it was possible to determine the Tg of plasticized amorphous phases. Under identical temperatures and vapor pressures, the water uptake was independently quantified in an automated water sorption apparatus. RESULTS: The Tg of the dry phases, determined by IGC and by DSC, were in very good agreement. With an increase in the environmental relative humidity (RH), there was a progressive decrease in Tg as a result of the plasticizing effect of water. Because the water uptake was independently quantified, it was possible to use the Gordon-Taylor equation to predict the Tg values of the plasticized materials. The predicted values were in very good agreement with those determined experimentally using IGC. A unique advantage of this technique is that it provides complete control over the sample environment and is thus ideally suited for the characterization of highly reactive amorphous phases. CONCLUSIONS: An IGC method was used (a) to determine the glass transition temperature of amorphous pharmaceuticals and (b) to quantify the plasticizing effect of water on multicomponent systems.
Subject(s)
Phase Transition , Plasticizers/chemistry , Transition Temperature , Water/chemistry , Calorimetry, Differential Scanning , Chemical Phenomena , Chemistry, Physical , Chromatography, Gas/methods , Crystallography, X-Ray , Povidone/chemistry , Sucrose/chemistry , Technology, PharmaceuticalABSTRACT
This study presents a model to predict the solubility of a nonpolar drug D(A) in the presence of other nonpolar drugs D(1) em leader D(n) in a complexing ligand L system such as hydroxypropyl-beta-cyclodextrin (HPbetaCD). Using an equilibrium approach, the model describes the molecular interactions among these drug species and the ligand. The model indicates that the solubility of D(A) invariably decreases as a result of the presence of D(1) em leader D(n). Furthermore, the decrease in D(A) solubility is related to the sum of the products of the intrinsic solubilities of the other drugs and drug-ligand complexation constants. To test the model, three steroids (prednisolone, 17alpha-hydroxyprogesterone, and progesterone) were used as model compounds in HPbetaCD solutions. The experimental data showed that the solubility of any particular drug decreased in the presence of other drugs. At all tested HPbetaCD concentrations, these experimental solubility data were in good agreement with the predicted solubility data. This result lends strong support to the reliability and effectiveness of the proposed model.
Subject(s)
Cyclodextrins/chemistry , Models, Chemical , Progesterone/analogs & derivatives , beta-Cyclodextrins , 2-Hydroxypropyl-beta-cyclodextrin , Drug Stability , Predictive Value of Tests , Prednisolone/chemistry , Progesterone/chemistry , SolubilityABSTRACT
PURPOSE: To study the effect of cooling rate, the influence of phosphate buffers and polyvinylpyrrolidone (PVP) on the crystallization behavior of mannitol in frozen aqueous solutions. METHODS: Low-temperature differential scanning calorimetry and powder X-ray diffractometry were used to characterize the frozen solutions. RESULTS: Rapid cooling (20 degrees C/min) inhibited mannitol crystallization, whereas at slower cooling rates (10 degrees C and 5 degrees C/min) partial crystallization was observed. The amorphous freeze-concentrate was characterized by two glass transitions at -32 degrees C and -25 degrees C. When the frozen solutions were heated past the two glass transition temperatures, the solute crystallized as mannitol hydrate. An increase in the concentration of PVP increased the induction time for the crystallization of mannitol hydrate. At concentrations of > or =100 mM, the buffer salts significantly inhibited mannitol crystallization. CONCLUSIONS: The crystallization behavior of mannitol in frozen solutions was influenced by the cooling rate and the presence of phosphate buffers and PVP.
