Polymorphism in anhydrous theophylline--implications on the dissolution rate of theophylline tablets.

The objects of this investigation were (i) to prepare and characterize a new anhydrous theophylline phase that is metastable under ambient conditions, and (ii) to prepare model tablet formulations containing either this metastable anhydrate (I*) or stable anhydrous theophylline (I), store them under different relative humidity (RH) conditions, and compare their dissolution behavior. I* was prepared by dehydration of theophylline monohydrate (II). Variable temperature X-ray powder diffractometry of II revealed the following series of transitions: II-->I*-->I. The metastable anhydrate, I*, which has not yet been reported in the literature, appears to be related monotropically to I. It was characterized by ambient and variable temperature X-ray powder diffractometry, Karl Fischer titrimetry, and thermoanalytical techniques (differential scanning calorimetry and thermogravimetric analysis). Tablet formulations containing either I* or I were prepared and stored at 33 and 52% RH (room temperature). The solid state of the drug was monitored by X-ray powder diffractometry and the tablets were subjected to the USP dissolution test. In tablets, I* completely converted to I in < or = 10 days when stored at either 33 or 52% RH. Scanning electron microscopy provided direct visual evidence of recrystallization. This recrystallization was accompanied by a decrease in the dissolution rate of the stored formulations that was so pronounced in the formulations stored at 52% RH that they failed the USP dissolution test. The in situ solid-state transition appears to be responsible for the decrease in dissolution rate observed following storage. Stored tablets containing I showed neither a phase transition nor an alteration in their dissolution behavior.

Simultaneous quantification of an enantiomer and the racemic compound of ibuprofen by X-ray powder diffractometry.

PURPOSE: An X-ray powder diffractometric method was developed for the simultaneous quantification of the relative amounts of the racemic compound (+/-) of ibuprofen (I) and S(+)-ibuprofen (II), when they occur as a mixture. METHOD: The X-ray powder diffraction patterns of I and II show pronounced differences. This formed the basis for the determination of the relative amounts of I and II when they occur as a mixture. X-ray lines with d-spacings of 14.41 and 4.37 A were unique to I and II, respectively. Mixtures containing different proportions of I and II were prepared which also contained lithium fluoride (III) as an internal standard. RESULTS: A linear relationship was obtained when the intensity ratio (intensity of the 4.37 A line of II/intensity of the 2.01 A line of III) was plotted as a function of the weight fraction of II in the mixture. Similar results were obtained in the case of I. Using these standard curves, the weight fractions of I and II in "unknown" mixtures were determined. The experimentally determined analyte concentration ranged between 98 and 104% of the true value. The relative error in the analyses of individual samples was < 10%. The minimum detectable weight fraction of I and II and II in I were 0.032 (3.2% w/w) and 0.034 (3.4% w/w), respectively. The minimum quantifiable weight fractions were 0.136 for I and 0.112 for II. Since the X-ray diffraction patterns of S(+)-ibuprofen and R(-)-ibuprofen are identical, the conclusions drawn regarding mixtures of I and II will also hold true in the quantitative analyses of mixtures of I and R(-)-ibuprofen.

Identification of drugs in pharmaceutical dosage forms by X-ray powder diffractometry.

A simple X-ray powder diffractometric (XRD) method was developed for the identification of the active ingredient in a variety of dosage forms. The method was successfully used to unambiguously identify the active ingredient(s) in tablet, capsule, suppository and ointment formulations. The unique feature of the method is that it provides information about the solid-state of the drug. Thus, a capsule formulation containing anhydrous ampicillin was readily distinguished from that containing ampicillin trihydrate. The USP stipulates the use of the beta-polymorphic form of anhydrous carbamazepine in carbamazepine tablets. Contamination by the alpha-polymorph (down to a level of 1.4% w/w of the formulation) could be detected. In some of the multicomponent formulations, there was a pronounced overlap of the powder patterns of ingredients which made identification difficult. This problem was solved by using a pattern subtraction technique, which permitted selective subtraction of the XRD pattern of the constituents of the formulation from the overall XRD pattern. Such an approach enabled identification of the drug even when it constituted only 5% w/w of the formulation. The method also permitted simultaneous identification of the multiple active ingredients in trimethoprim-sulfamethoxazole and acetaminophen-aspirin-caffeine formulations.