Characterization of prednisolone in controlled porosity osmotic pump pellets using solid-state NMR spectroscopy.

The overall objective of this study was to demonstrate the influence of formulation and processing variables on the physical state of prednisolone (PDL) in formulations consisting of PDL, microcrystalline cellulose (MCC), and sulfobutylether-beta-cyclodextrin (CD). PDL was used as a model drug in controlled porosity osmotic pump pellet (CP-OPP) formulations, and was characterized using solid-state NMR spectroscopy and other complimentary analytical techniques. Dosage forms and the solid-state properties of drugs and excipients in a formulation may be influenced by the processing conditions used. Several processing parameters, such as amount of water used in wet granulation and subsequent drying conditions, were found to affect the solid-state transformation of PDL. In addition, the presence of excipients in the CP-OPP was observed to decrease the degree of PDL crystallinity, presumably by creating an inclusion complex with the CD. A hydrated form of PDL was created when PDL was ground with water alone; however, this form was not observed in formulated products. Solid-state NMR spectroscopy was shown to be a powerful technique for the analysis of drug formulations and investigations of the effects of processing conditions.

Nuclear magnetic resonance and infrared spectroscopic analysis of nedocromil hydrates.

PURPOSE: Nedocromil sodium (NS), which is used in the treatment of reversible obstructive airway diseases, such as asthma, has been found to exist in the following solid phases: the heptahemihydrate, the trihydrate, a monohydrate, an amorphous phase, which contains variable amounts of water, and a recently discovered methanol + water (MW) solvate. Our aim was to apply 13C solid-state nuclear magnetic resonance (NMR) spectroscopy and solid-state Fourier transform infrared (FTIR) spectroscopy to the study of specific interactions in the various solid forms of NS. METHODS: The 13C solid-state NMR and FTIR spectra of the various solid forms of NS were obtained and were related to the crystal structures of NS, the conformations of the nedocromil anion, and the interactions of the water molecules in these crystals. RESULTS: The 13C solid-state NMR spectrum is sensitive to the conformation of the nedocromil anion, while the solid-state FTIR spectrum is sensitive to interactions of water molecules in the solid state. In NS monohydrate, for which the crystal structure has not yet been solved, and in the amorphous phase, the information about the conformations of the nedocromil anion and the interactions of the water molecules are deduced from the 13C solid-state NMR spectra and solid-state FTIR spectra, respectively. CONCLUSIONS: 13C solid-state NMR spectroscopy and solid-state FTIR spectroscopy are shown to be powerful complementary tools for probing the chemical environment of molecules in the solid state, specifically the conformation of the nedocromil anion and the interactions of water-molecules, respectively.

Study of the conversion of methanol to dimethyl ether on zeolite HZSM-5 using in situ flow MAS NMR.

The conversion of methanol to gasoline (MTG) range hydrocarbons on zeolite catalyst HZSM-5 has been studied extensively using solid-state NMR. We have studied the reaction under batch and flow conditions using an isolated flow variable-temperature (VT) MAS NMR probe. This probe was developed to study heterogeneous catalysis reactions in situ at temperatures greater than 300 degrees C with reactant flow. In the batch studies, when 13C-labeled methanol was adsorbed on zeolite HZSM-5, sealed, and heated to 250 degrees C, dimethyl ether was formed. Two-dimensional exchange NMR shows that dimethyl ether was in equilibrium with methanol at 250 degrees C. When 13C-methanol was flowed over HZSM-5 at temperatures > or = 200 degrees C, only dimethyl ether was observed. Between 160 degrees C and 200 degrees C, both methanol and dimethyl ether were observed. The flow results are significant in that they suggest that there is no equilibrium between methanol and dimethyl ether in the catalyst at high temperatures, and that surface methoxy groups do not exist on the catalyst at high temperatures.

Characterization of racemic species of chiral drugs using thermal analysis, thermodynamic calculation, and structural studies.

The identification of the racemic species, as a racemic compound, a racemic conglomerate, or a racemic solid solution (pseudoracemate), is crucial for rationalizing the potential for resolution of racemates by crystallization. The melting points and enthalpies of fusion of a number of chiral drugs and their salts were measured by differential scanning calorimetry. Based on a thermodynamic cycle involving the solid and liquid phases of the enantiomers and racemic species, the enthalpy, entropy and Gibbs free energy of the racemic species were derived from the thermal data. The Gibbs free energy of formation, is always negative for a racemic compound, if it can exist, and the contribution from the entropy of mixing in the liquid state to the free energy of formation is the driving force for the process. For a racemic conglomerate, the entropy of mixing in the liquid state is close to the ideal value of R ln 2 (1.38 cal.mol-1. K-1). Pseudoracemates behave differently from the other two types of racemic species. When the melting points of the racemic species is about 30 K below that of the homochiral species, is approximately zero, indicating that the racemic compound and racemic conglomerate possess similar relative stabilities. The powder X-ray diffraction patterns and 13C solid-state nuclear magnetic resonance spectra are valuable for revealing structural differences between a racemic compound and a racemic conglomerate. Thermodynamic prediction, thermal analysis, and structural study are in excellent agreement for identifying the nature of the racemic species.

Solid-state characterization of two polymorphs of aspartame hemihydrate.

From the known crystal structure of aspartame hemihydrate, designated form 1, the theoretical powder X-ray diffraction (PXRD) pattern was calculated. This PXRD pattern differs significantly from that of the commercially available aspartame hemihydrate, which is therefore a different polymorph, designated form II. Form II transforms to form I during ball-milling or on heating for 30 min at 160 degrees C in the presence of steam. The two polymorphs were compared by PXRD, differential scanning calorimetry, thermogravimetric analysis, Karl Fischer titrimetry, Fourier transform infrared (FTIR) absorption spectroscopy, 13C solid-state nuclear magnetic resonance (SSNMR) spectroscopy, scanning electron microscopy, particle size analysis, and measurements of true density and intrinsic dissolution rate. Comparison of the 13C SSNMR and FTIR spectra of the two polymorphs suggests that the crystal structure of form II is less symmetric, with the side chains located in multiple environments. Although both hemihydrate polymorphs on heating in the absence of moisture dehydrate to a crystalline anhydrate, form I does so at a lower temperature, suggesting weaker interactions of water with aspartame molecules. At higher temperatures the anhydrate from both hemihydrate polymorphs yields 3-(carboxymethyl)-6-benzyl-2,5-dioxopiperazine (DKP) by a cyclization reaction for which the temperature, reaction enthalpy, and activation energy are very similar. Both hemihydrate forms, when in contact with liquid water, yield the 2.5-hydrate.

Hydration and dehydration behavior of aspartame hemihydrate.

Previous studies have shown that aspartame in the solid state can exist as a hemihydrate which occurs in two different polymorphic forms (I and II). The present work shows that equilibration of either hemihydrate at 25 degrees C with water vapor at relative humidities > or = 58% or with liquid water produces a 2.5-hydrate. Upon subjecting each of these crystalline hydrates to increasing temperature, the same crystalline anhydrate is formed which thermally cyclizes at a higher temperature to form the known compound 3-(carboxymethyl)-6-benzyl-2,5-dioxopiperazine. The activation energy of the cyclization reaction appears to depend on the degree of crystallinity of the anhydrate that is formed at a lower temperature. On increasing the temperature of the 2.5-hydrate, a hemihydrate intervenes before the anhydrate is formed. This intervening hemihydrate is similar to the commercial form (II) of aspartame hemihydrate but exhibits greater amorphous character. The techniques employed were Karl Fischer titrimetry, powder X-ray diffractometry, differential scanning calorimetry, thermogravimetric analysis, solid-state 13C nuclear magnetic resonance spectroscopy, and Fourier transform infrared absorption spectroscopy.

Physicochemical characterization of nedocromil bivalent metal salt hydrates. 2. Nedocromil zinc.

Salts are usually considered as alternatives for drug delivery when the physicochemical characteristics of the acidic or basic parent drug are unsuitable or inadequate for a satisfactory formulation. The physical, chemical, and biological characteristics of nedocromil sodium, which is used in the treatment of reversible obstructive airways diseases such as asthma, can be altered by its conversion to other salt forms. Nedocromil zinc (NZ), a bivalent metal salt, was found to exist in several hydration states, an octahydrate, a heptahydrate, and a pentahydrate, which itself exists in two modifications, designated as A and B. The relationships between these, NZ hydrates and the nature of the water interactions in the solid phases were studied through characterization by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Karl Fischer titrimetry (KFT), hot-stage microscopy (HSM), ambient- or variable-temperature powder X-ray diffraction (PXRD), Fourier-transform infrared (FTIR) spectroscopy, solid-state nuclear magnetic resonance (SSNMR) spectroscopy, environmental scanning electron microscopy (ESEM), water uptake at various relative humidities (RH), intrinsic dissolution rate (IDR), and solubility measurements. The integral water stoichiometries of the NZ hydrates were deduced from KFT and TGA and were confirmed by elemental analysis. For the heptahydrate, the loss of 1 mol of water at a higher temperature than for the others is attribute to an identifiable water molecule that is linked directly to the zinc and to two carboxylate oxygen atoms but not to the other water molecules, as deduced from the crystal structure previously determined. Similarly, for both pentahydrate modifications, 1 mol of water was also lost at a higher temperature than the others. Results from studies using DSC, TGA, HSM, PXRD, SSNMR, and FTIR suggested that the octahydrate contains loosely bound water in its structure and is partially amorphous. The course of the dehydration processes depended on the water vapor pressure and temperature. The octahydrate and heptahydrate underwent an apparently irreversible phase transformation to the pentahydrate at an elevated temperature and water vapor pressure. Pentahydrate modifications A and B differ in their long-range order (deduced from differences in their PXRD pattern and their thermal analytical behavior), but their short-range order (i.e., molecular environments) are identical (deduced by identical SSNMR spectra). The rank order of both IDR and solubility in water at 25 degrees C was octahydrate > heptahydrate > pentahydrate modification A approximately pentahydrate modification B, corresponding to the rank order of free energy with respect to the aqueous solution and the order of preparation according to Ostwald's rule of stages.

A Quantitative Method for Determination of Lactide Composition in Poly(lactide) Using (1)H NMR.

A method has been developed to quantitatively determine the composition of d-lactide and meso-lactide stereoisomer impurities in poly(lactide) containing predominantly l-lactide. In this method, the stereosequence information obtained from a few well-resolved resonances in the (1)H NMR spectrum representing RR and R stereogenic defects is used. The d-lactide and meso-lactide as minor components lead to RR and R stereogenic defects, respectively, which influence the isotactic chain length distribution and hence affect the polymer properties. Analytical equations relating the stereosequence probability to the lactide feed composition are not available due the complicated kinetics involved for the melt polymerization; viz. the preference for syndiotactic lactide addition decreases with reducing residual lactide concentration in the batch process. Hence, empirical correlations were determined by least-squares fit to the predictions for the specific stereosequence probabilities provided by Monte Carlo calculations of a number of lactide stereocopolymerizations. The Monte Carlo calculations simulate the kinetics observed for melt polymerization at 180 °C catalyzed by Sn(II) bis(2-ethylhexanoate) (Sn(II) octoate) in a 1:10 000 catalyst/lactide ratio.

Physicochemical characterization of nedocromil bivalent metal salt hydrates. 3. Nedocromil calcium.

A crystalline pentahydrate and a crystalline 8/3 hydrate of nedocromil calcium (NC) were prepared. The relationships between these solid phases and the nature of the water interactions in their structures were studied through characterization by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Karl Fischer titrimetry (KFT), hot-stage microscopy (HSM), ambient- or variable-temperature powder X-ray diffraction (PXRD), Fourier-transform infrared (FTIR) spectroscopy, solid-state nuclear magnetic resonance (SSNMR) spectroscopy, water uptake at various relative humidities (RH), intrinsic dissolution rate (IDR) and solubility measurements. The solubility and intrinsic dissolution rate of the pentahydrate in water at 25 degrees C are approximately 17% greater than the corresponding values for the 8/3 hydrate, corresponding to a greater Gibbs free energy of only 380 J.mol-1 (91 cal.mol-1) for the pentahydrate. The results of DSC, TGA, and FTIR and SSNMR spectroscopy indicate that the water of hydration is more loosely bound in the pentahydrate than in the 8/3 hydrate. On increasing the temperature in open-pan DSC and TGA, the water in the pentahydrate is released in four steps (three steps in crimped pans), whereas the water in the 8/3 hydrate is released in three steps (three steps also in crimped pans). These three stepwise dehydrations are fundamentally explained by their different water environments in the crystal structure of the 8/3 hydrate, which was determined by single-crystal XRD [crystal data: triclinic, space group P1, a = 13.2381(3) A, b = 13.3650(2) A, c = 17.8224(2) A, alpha = 68.202(1) degrees, beta = 86.894(1) degrees, gamma = 82.969(1) degrees, Z = 6]. The asymmetric unit contains three nedocromil anions and three calcium cations associated with eight water molecules. The nedocromil anions act as polyfunctional ligands to the Ca2+ ions, coordinating through both the carbonyl oxygen and the carboxylate oxygen atoms. The molecular conformations of the three nedocromil anions in the asymmetric unit are almost identical. However, the crystal structure contains two different calcium environments, one of which has the Ca2+ ion hydrated by four water molecules in the equatorial plane and by two carbonyl oxygens in its axial coordination sites. In the second environment, the Ca2+ ion has four carboxylate oxygen atoms in its equatorial plane and two water molecules in its axial coordination sites. Two of the carboxylate ligands are twisted out of the tricyclic ring, and the other two carboxylate ligands are nearly coplanar with the tricyclic ring. All of the eight water molecules in the 8/3 hydrate are linked to calcium and carboxylate ions and none are linked to other water molecules.

Physicochemical characterization of nedocromil bivalent metal salt hydrates. 1. Nedocromil magnesium.

Nedocromil sodium is used in the treatment of reversible obstructive airways diseases, such as asthma. The physicochemical, mechanical, and biological characteristics of nedocromil sodium can be altered by its conversion to other salt forms. In this study, three crystalline hydrates, the pentahydrate, heptahydrate, and decahydrate, of a bivalent metal salt, nedocromil magnesium (NM), were prepared. The relationships between these hydrates were studied through their characterization by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA). Karl Fischer titrimetry (KFT), hot stage microscopy (HSM), ambient or variable temperature powder X-ray diffraction (PXRD), Fourier-transform infrared (FTIR) spectroscopy, solid-state nuclear magnetic resonance (SSNMR) spectroscopy, scanning electron microscopy (SEM), water uptake at various relative humidities (RH), intrinsic dissolution rate (IDR), and solubility measurements. The pentahydrate showed two dehydration steps, corresponding to two binding states of water, a more temperature-sensitive tetramer and a more stable monomer, deduced from the crystal structure previously determined. The heptahydrate and decahydrate each showed a dehydration step with a minor change in slope at about 50 degrees C, which was analyzed by derivative TGA and confirmed by DSC. HSM and variable temperature PXRD also confirmed the thermal dehydration behavior of the NM hydrates. The decahydrate underwent an apparently irreversible phase transformation to the pentahydrate at 75 degrees C at an elevated water vapor pressure. The PXRD, FTIR, and SSNMR of the decahydrate were similar to those of the heptahydrate, suggesting that the three extra water molecules in the decahydrate are loosely bound, but were significantly different from those of the pentahydrate. The rank order of both IDR and solubility in water at 25 degrees C was heptahydrate approximately decahydrate > pentahydrate, corresponding to the rank order of free energy with respect to the aqueous solution.