Physical state of L-histidine after freeze-drying and long-term storage.

Liquid samples of L-histidine of varying pH values and mixed with salt, metal ions, polysorbate 80 and sucrose have been analysed by differential scanning calorimetry to evaluate the influence of these additives on the glass transition temperature and crystallisation of L-histidine during freezing and thawing. L-Histidine solutions of varying pH were freeze-dried with and without a thermal cycle and the physical state of the freeze-dried cakes, following long-term storage, were studied by powder X-ray diffraction. Amorphous L-histidine crystallised when it was exposed to moisture, and the identity of the crystalline materials is reported. The crystallisation of L-histidine during freezing and thawing is dependent on the pH of the solution and is shown to be at a minimum at pH 6, which coincides with the pK(a) of the imidazoline function. Sucrose inhibited the crystallisation of L-histidine during thawing, while sodium chloride or polysorbate 80 did not. The addition of metal ions (Ca2+ and Mg2+) up to 10% (w/w) did not depress the glass transition temperature significantly, while the addition of Zn2+ increased it. The physical state of L-histidine after freeze-drying is shown to be dependent on both the pH of the solution and the freezing cycle. The risk of crystallisation of amorphous L-histidine is low if the freeze-dried material is protected from moisture.

Polymorphism of estramustine.

As the solubility in water of the cytotoxic drug estramustine is less than 1 mg/L, polymorphism can have an impact on the bioavailability of orally administered drug. Therefore, the solid state characteristics of estramustine samples, crystallized from different solvents, were investigated by means of X-ray crystallography, thermal analysis, and IR spectroscopy. The DSC data indicated the existence of several phases. Four forms--A, B, C, and D--were confirmed. Phase A was obtained when crystallizing from solvents with a moderate or low dieletric constant (less than approximately 24). This form was an anhydrate and found to be the stable one. When crystallizing from methanol, metastable solvates, with approximately 0.5 mol for phase B or approximately 1 mol for form C, were precipitated. Both types were transformed to phase A during storage. This desolvation was accelerated by heating. Crystallizing from a mixture of acetone and water resulted in a monohydrate, form D, which was converted to the anhydrous type A upon heating. As forms B, C, and D were solvates which transformed to another crystal form upon desolvation, they were polymorphic solvates of the anhydrate, type A. Symmetry and unit cell dimensions of the stable form of estramustine (phase A) were determined by means of a single-crystal X-ray technique (orthorhombic, a = 23.90, b = 20.69, c = 8.76, space group P212121). In addition, the crystallographic parameters of form D were deduced from calculations based on powder diffraction data.

Phase diagram and aqueous solubility of the lidocaine-prilocaine binary system.

The phase behavior of the lidocaine-prilocaine binary system has been studied by X-ray diffraction, differential thermal analysis, hot-stage microscopy, and IR spectrometry. No intermediate compounds or solid solubilities have been detected. The eutectic composition is close to 1:1, and the eutectic temperature is 18 +/- 1 degrees C. Aqueous solubility studies show that the lidocaine heat of solubility from the eutectic mixture is different from that of the pure drug, whereas it is the same for prilocaine. Investigations of various lidocaine-prilocaine ratios indicate that the two local anesthetics decrease the solubility of each other. The total solubility, however, is affected only to a minor extent.