Structure-solubility relationship and thermal decomposition of furosemide.

Furosemide, a high ceiling diuretic, decomposes on heating and is very sparingly soluble in water. The aim of this study was to identify the thermal decomposition product(s) of furosemide and to calculate the activation energy needed for this reaction. This was done to gain a better understanding of the unusually low water solubility of this drug. The main thermal decomposition product was identified by nuclear magnetic resonance (NMR), mass spectrometry (MS), and infrared (IR) analysis as 4-chloro-5-sulfamoylanthranilic acid (saluamine), and the activation energy, calculated from thermogravimetric analysis (TGA) measurements, for this reaction was 47.7 (+/- 1.93) kcal/mol. The experimentally measured activation energy was well below the normal 59 +/- 4 kcal/mol needed for the cleavage of the C-N bond to form saluamine. This could possibly be explained by the weakening of the C-N bond through the I-effect of the furane ring and the delocalization of the electrons of the aniline nitrogen in the chlorosulfamoyl benzoic acid entity of furosemide. This decomposition of furosemide indicates the breaking of intramolecular bonds before those of intermolecular bonds (separation of individual furosemide molecules). Strong inter- and intramolecular bonds are a probable cause for the poor water solubility of furosemide because, when some of the inter- and intramolecular bonds that form part of the hydrogen bond network disappeared, as in the structurally related decomposition product saluamine, the aqueous solubility increased.

Physicochemical Stability of Compounded Creams Containing a-Hydroxy Acids.

The stability of creams containing the a-hydroxy acids (AHAs), lactic acid and glycolic acid, extemporaneously added to aqueous cream, BP or hydrophilic oinment, USP and subjected to five freeze-thaw cycles ranging form -4 to 40 deg C was studied. The pH, viscosity, spreadability, density, appearance and potency were measured after each freeze-thaw cycle. Compounding with hydrophilic ointment, USP produced the most stable creams; but the addition of the AHAs caused a significant decrease in preservative levels. The preservatives methylparaben and propylparaben were not hydrolyzed in the hydrophilic creams if the AHA ws partially neutralized to pH above 3.5.

Pharmacokinetic evaluation in dogs of theophylline in a novel zero-order release core-in-cup tablet.

A new core-in-cup tablet that is manufactured from a novel adjustable punch, has been formulated and evaluated for its ability to release with subsequent absorption of theophylline via a zero-order rate of absorption. The core-in-cup tablets were compared with core only tablets and immediate release capsules. Pharmacokinetic parameters used to test the effectiveness of the formulations included, elimination rate, rate and kinetic order of absorption, relative availability as compared with an immediate release capsule of pure theophylline, and percentage area under the curve fluctuation (%AUCF) at steady state. The correlation coefficient, Akaike's information criterion (AIC) and the F-ratio probability were used to test the applicability of a zero-order, first-order, or square root of time model, for the rate of release of theophylline from the core-in-cup and core only tablets. The zero-order rate model was most applicable to the core-in-cup tablet, whereas the square root of time release model was most applicable to the core only tablet. The average %AUCF for the core-in-cup tablet was 9.26+/-3.15 while that for the core only tablet was 16.19+/-2.37 (p = 0.0545). The results of this study suggest that the core-in-cup tablet is a versatile zero-order release rate dosage form that are simple to produce.

A study of the changes during heating of paracetamol.

The orthorhombic form of paracetamol has been shown to exhibit greater compressibility and faster dissolution than the monoclinic form. The orthorhombic form is produced by melting of monoclinic crystals of paracetamol followed by cooling at specific rates. Cooling rate, although a very important factor, is not the only factor influencing the formation of either of the two morphs. To study the cooling rate required for production of form II, paracetamol samples were melted in a differential scanning calorimeter, cooled at three specific rates, and melted again. In all of the samples, cooling resulted in the glassy form followed by recrystallization and the melting of form II. On the hot-stage microscope both forms were produced in one sample. Standardizing conditions for prediction of the resulting form remains a problem. There seems to be a great deal of overlap of the two forms' transition phases, which would make it difficult to force the crystallization of one form by keeping the solution or melt at a specific temperature. The thermal behavior of paracetamol during the heating and cooling phases must be understood in order to manipulate the process. A video camera mounted on a hot-stage microscope was used to follow the changes during heating and cooling of both forms. Nucleation, crystal growth, habit transformation, sublimation, and the final melt are shown on snap shots taken from the video.

Zero-order release of theophylline from a core-in-cup tablet in sequenced simulated gastric and intestinal fluid.

Core-in-cup tablets containing theophylline were evaluated for their dissolution characteristics in sequenced simulated gastric fluid (SGF) followed by simulated intestinalfluid (SIF). Core-in-cup tablets containing 10% w/w, 20% w/w, and 30% w/w acacia as binder were evaluated for their effects on the time course of release of theophylline. This was done to optimize a formula that could release theophylline at a zero-order rate of release for 8-16 hr in simulated gastrointestinal fluids. Theophylline was released and dissolved from the core-in-cup tablets at a rate that is more consistent with a zero-order dissolution rate than a first-order dissolution rate in both SIG and SIF. The dissolution rates of theophylline from the 10%, 20%, and 30% acacia core-in-cup tablets were 0.87 mg/min, 0.53 mg/min, and 0.27 mg/min, respectively in SGF, and 0.61 mg/min, 0.30 mg/min, and 0.20 mg/min, respectively in SIF. The results indicate that a concentration of 32% w/w acacia in the core tablet will release theophylline at a rate of 0.14 mg/min in SGF for 2 hr followed by SIF for 10 hr.

The measurement of mixture homogeneity and dissolution to predict the degree of drug agglomerate breakdown achieved through powder mixing.

Interactive mixing of agglomerates of small, cohesive particles with coarse carrier particles facilitate the deaggregation of agglomerates. In this study dispersion of agglomerates of microfine furosemide particles by such a mixing process was followed by measuring changes in the content uniformity and area under the dissolution curve. Interactive mixtures between agglomerates of different sized furosemide particles and coarse sodium chloride particles were prepared using different mixers, mixing times and mixer speeds. The dissolution rate of the drug from and content uniformity of the mixtures were measured, and degrees of dispersion were calculated. These degrees of dispersion were compared to the dispersion values obtained from the decrease in agglomerate size after mixing. An increase in mixing time led to an increase in dispersion. An initial fast deagglomeration, indicated by an increase in dissolution, increase in content uniformity and a decrease in particle size, was followed by substantially slower deaggregation of remaining agglomerates and smaller aggregates. For all mixtures studied the degree of dispersion estimated from dissolution measurements, when compared to equivalent content uniformity measurements, agreed closely with the degree of dispersion as indicated by the decrease in particle size. The use of the area under the dissolution curve to predict agglomerate breakdown proved useful and may find application in situations where it is impossible to follow directly deagglomeration through particle size measurements.

Physical and structural comparison of oxyphenbutazone monohydrate and anhydrate.

Two crystal forms of oxyphenbutazone (a monohydrate and an anhydrate) were prepared by recrystallization. The forms were characterized by means of differential scanning calorimetry, thermogravimetry, infrared spectrophotometry, X-ray powder diffraction patterns, thermomicroscopy, scanning electron microscopy, as well as powder and intrinsic dissolution rates. The crystal structure of the anhydrate has been elucidated and compared with that of the monohydrate.

Physical characterization of two oxyphenbutazone pseudopolymorphs.

Two pseudopolymorphic forms of oxyphenbutazone, a benzene solvate (Solvate B) and a cyclohexane solvate (Solvate C), were prepared by recrystallization from benzene and cyclohexane, respectively. The forms were characterized by means of differential scanning calorimetry, thermogravimetry, infrared spectrophotometry, X-ray powder diffraction, and thermomicroscopy, as well as powder and intrinsic dissolution rates. The dissolution rates of the two pseudopolymorphs were shown to be superior to those of the anhydrate, hemihydrate, and monohydrate which were previously reported. A brief stability report is included.

Physicochemical properties and X-ray structural studies of the trigonal polymorph of carbamazepine.

The trigonal polymorph of carbamazepine (alpha-carbamazepine) was obtained by crystallization from a number of solvents. It was characterized by means of differential scanning calorimetry, thermogravimetric analysis, infrared spectroscopy, X-ray power diffraction, thermal microscopy, and powder and intrinsic dissolution rates. The crystal and molecular structures were determined by single-crystal, three-dimensional X-ray analysis. A comparison is drawn between the physicochemical properties of the monoclinic (beta) and trigonal (alpha) forms. Structural features of carbamazepine occurring in these forms and in the acetone solvate are compared. Substantial differences were detected between the two polymorphic forms with regard to infrared and differential scanning calorimetry data, thermomicroscopical behavior, morphology, and molecular conformation.