ABSTRACT
Unexpected poor flowability during commercial production of a direct compression tablet formulation initiated an investigation of the flow properties of the powder mixture and its components by means of a uniaxial tester. The failure function--a curve describing the strength of the powder bed as a junction of the maximum main stress that has consolidated the bed--of the powder mixture and its components was determined. The drug was more cohesive than the filler, which was somewhat more cohesive than the powder mixture. Three excipients--a hinder, a glidant and a lubricant constituting 3.5 w/w% of the formulation improved the flowability of the mixture of active ingredient and filler. The failure function discriminated powder mixtures with poor flow from mixtures with medium or good flow. However, it was not possible to discriminate medium from good flow by means of the failure function. Attempts to correlate univariately the flow property parameters of the powder mixtures with particle size data or flow property data of included active ingredient and filler batches failed. Therefore a multivariate approach was tested. Principal component analysis (PCA) and projection to latent structures by means of partial least squares (PLS) were employed. An excellent PCA model was obtained with the flow properties of the powder mixture. A good PCA model of tableting performance--based on tablet weight variation and tablet machine speed-was obtained.
Subject(s)
Drug Compounding , Powders/chemistry , Excipients/chemistry , Particle Size , Porosity , TabletsABSTRACT
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.
Subject(s)
Estramustine/analysis , Nitrogen Mustard Compounds/analysis , Chemical Phenomena , Chemistry , Chemistry, Physical , Crystallization , Isomerism , Magnetic Resonance Spectroscopy , Microscopy, Electron, Scanning , Spectrophotometry, Infrared , Temperature , Water/analysis , X-Ray DiffractionABSTRACT
Rats given streptozotocin showed varying degrees of glucose intolerance, ranging from mild to overt symptoms of diabetes mellitus. After being deprived of food overnight, both mild and overt diabetics consumed more food than controls did during 5-hr or 7-hr feeding tests. All animals ate large amounts of food during the first hour of the tests, but both groups of diabetics began to eat again sooner than controls did. Rats demonstrating the greatest degree of glucose intolerance before the test ate the most during the test. These and other findings suggest that feeding by diabetic rats after an overnight fast is an inverse function of their residual capacity for glucose utilization, which occurs despite elevations in blood glucose levels, and is not simply a compensatory response to glucose loss in urine. A modified glucostatic hypothesis is proposed in which insulin may normally promote satiety by influencing peripheral metabolism and making ingested calories utilizable.
