James A Mccauley

A Spectroscopic Investigation of Losartan Polymorphs

Losartan, an antihypertensive agent in clinical development, was found to exist in two enantiotropic polymorphic forms, a low-temperature stable form (Form I) and a high-temperature stable form (Form II), the temperatures at which they are stable being related to the transition temperature. X-ray powder diffraction patterns indicated differences in the crystal packing of the two forms. The vibrational data from infrared and Raman spectroscopy suggested a subtle change in molecular conformation and crystal packing in the two forms. Solid-state 13C NMR data of the polymorphs concurred with the vibrational data and indicated that, while the observed line widths reflect no major changes in crystallinity, signal multiplicities and chemical shifts do reflect differences in molecular packing in the respective unit cells. Thus, in the absence of crystal-lographic data, useful structural information could be derived from spectroscopic results to identify each of the crystalline forms.

A Spectroscopic and Crystallographic Study of Polymorphism in an Aza‐Steroid

The crystal structures of two enantiotropic polymorphs of the aza-steroid finasteride (N-(1-1-di-methylethyl)-3-oxo-4-aza-5 alpha-and rost-1-ene-17 beta-carboxam ide ) have been determined. The solid-state nuclear magnetic resonance spectra, infrared spectra, and physical property data of these two polymorphs are discussed in relation to both their solid-state structures and hydrogen-bonding networks.

High resolution spectroscopic evidence and solution calorimetry studies on the polymorphs of enalapril maleate

Abstract Enalapril maleate, a potent angiotensin converting enzyme inhibitor, exists as polymorphs, Form I and Form II. X-Ray powder diffraction measurements have shown slightly different patterns. Differential scanning calorimetric thermograms failed to show any significant differences during melting. High resolution spectroscopic techniques, including solid state carbon-13 NMR, Fourier-transform IR and Raman, detect differences between Form I and Form II. Heats of solution data obtained also indicate measurable energy differences. It was concluded that these two polymorphic forms of enalapril maleate are energetically very similar. Virtual equivalence of in vitro dissolution rate was obtained from formulations of enalapril maleate made from either Form I, or Form II, or mixtures.

Study of the polymorphism of 3-(((3-(2-(7-chloro-2-quinolinyl)-(E)-ethenyl)phenyl) (( 3-( dimethylamino-3-oxopropyl) thio) methyl)-thio) propanoic acid (MK571) by DSC, TG, XRPD and solubility measurements

Abstract Two polymorphs of the free acid of MK571 have been characterized unambiguously by differential scanning calorimetry (DSC), thermal gravimetric analysis (TG), X-ray powder diffraction (XRPD) and solubility measurements. These two species are designated forms I and II, respectively. The solubilities of the two crystal forms of MK571 were determined at several temperatures (5–55° C) in isopropyl alcohol (IPA) and methyl ethyl ketone (MEK). In all cases, Form II shows higher solubility than Form I which indicates that the latter is the thermodynamically stable form in this temperature range. The melting point of Form I (164° C) is higher than that of Form II (152° C), indicating that Form I is the more stable polymorph in the high temperature range. These data suggest that the two forms are monotropic polymorphs.

Two methods for the measurement of the dissociation pressure of a crystalline hydrate

Two methods for the measurement of the characteristic dissociation pressures of a system containing water vapor and two different crystalline hydrates of the pharmaceutical compound MK-0677 are described. One method involves the spectroscopic determination of water in gases equilibrated with the solids at controlled temperatures, using an infrared spectrometer. The second method utilized the extrapolated onset temperature of the transition from one hydrate to the other at controlled humidities, as observed by differential scanning calorimetry. The methods give similar results for the system of interest.

Polymorphic behavior of an NK1 receptor antagonist

Four anhydrous polymorphic forms (I, II, III and IV) of an NK1 receptor antagonist, Compound A, have been discovered. The pure compound can exist as either Forms I or II at room temperature and Forms III or IV at elevated temperatures. The four polymorphs were characterized by differential scanning calorimetry (DSC), thermogravimetric analysis, X-ray powder diffraction (XRPD) and solid-state NMR spectroscopy (SSNMR). Polymorphic transformations in the solid phase were studied using DSC, hot stage XRPD, temperature-modulated SSNMR and hot stage optical microscopy. The solubilities of Forms I and II in tert-butyl acetate at different temperatures were measured and the relative stability of the two forms was established. The thermodynamic transformation temperatures between Forms I and III, as well as Forms II and IV, were estimated by DSC. Transformation from Form III to IV, which is undetectable in a normal calorimetric run, was revealed through careful thermal programming. An interesting conversion route from Form I, a more stable form at room temperature, to Form II, a less stable form at room temperature was discovered.

The effect of polymorphism and metastability on the characterization and isolation of two pharmaceutical compounds

L-706,000, a class III antiarrhythmic compound, has been found to exist in several different crystalline structures including two anhydrous polymorphs, two dihydrated enantiotropic polymorphs, a monohydrate, and several organic solvent solvates. The isolation of the desired crystal modification, dihydrate type A, can be accomplished under thermodynamic or kinetic control depending on the conditions. Under kinetic control, the isolation depends on a suspended transformation of a metastable state, L-700,462, a thrombotic agent, has been found to exist in three crystalline structures: a monohydrate and two anhydrous monotropic polymorphs. Both anhydrous polymorphs, when hydrated, yielded the single monohydrate. Drying of the monohydrate, depending on the conditions and sample, will give either anhydrous form. The varying results obtained upon drying are, once again, indicative of the presence of metastable states and suspended transformations in connection with the solid state of L-700,462.

Compound Separation by Cyclic, Selective Dissolution. Isolation of Diastereomeric, 1β-Methylcarbapenem Key Intermediates

Abstract A practical method for separation of the methyl esters of two diastereomeric, α-methylated, 2-azetidinon-4-ylacetic acid derivatives by selective dissolution using two solvents in which their relative solubilities are distinctly different is described. The less soluble diastereomer was first isolated from isopropanol in which the solubility of the more soluble diastereomer is 1.65 times that of the less soluble diastereomer. The more soluble diastereomer was then isolated from the mother liquor after a solvent switch to toluene in which the solubility of the more soluble diastereomer is only 1.15 times that of the less soluble diastereomer. The isolation cycle was then repeated to separate more of the diastereomers. This method is particularly useful for isolation of the more soluble component. A proposed explanation of the solubility differences suggests that the approach may be widely applicable to the separation of other structurally similar compounds.