Applicability of Bipolar Charge Analyzer (BOLAR) in Characterizing the Bipolar Electrostatic Charge Profile of Commercial Metered Dose Inhalers (MDIs).

PURPOSE: To investigate the applicability of Bipolar Charge Analyzer (BOLAR), a new commercial instrument developed by Dekati Ltd., in simultaneously characterizing the bipolar electrostatic charge profile and measuring the size distribution of commercial metered dose inhalers (MDIs). METHODS: Intal Forte(®) (sodium cromoglycate), Tilade(®) (nedocromil sodium), Ventolin(®) (salbutamol sulphate), and QVAR(®) (beclomethasone dipropionate) were used as model MDIs in this study. Three individual actuations of each MDI were introduced into the BOLAR at an air flow rate of 60 l/min. Charge and mass profiles for each actuation were determined. RESULTS: The BOLAR was found to have better performance in collecting valid charge data (≥80%) than valid mass data (≥50%). In all tested products, both positively and negatively charged particles were found in five defined size fractions between zero and 11.6 µm, with the charge magnitude decreased with increasing particle size. The net charge profiles obtained from the BOLAR qualitatively agreed with the results reported previously. In all suspension type MDIs, negligible masses were detected in the smallest size fraction (<0.95 µm), for which the charge was most likely caused by the propellant and excipients. QVAR was the only solution MDI tested and the charge and mass profiles were significantly different from the suspension-type MDIs. Its mass profile was found to follow closely with the charge profile. CONCLUSIONS: Positively and negatively charged MDI particles of different size fractions and their corresponding charge-to-mass profiles were successfully characterized by the BOLAR.

The influence of mechanical processing of dry powder inhaler carriers on drug aerosolization performance.

The influence of processing on the performance of carrier material used in dry powder inhalers was investigated. alpha-Lactose monohydrate crystals were processed by ball milling for cumulative time durations and their properties evaluated. As expected, milling reduced the median particle diameter while increasing fine particulate (<10 microm) and amorphous levels. Recrystallization of these partially amorphous samples resulted in a reduction in fines, elimination of amorphous material with little change in median diameter. To study the effects of processing on aerosolization performance, blends of lactose monohydrate with a model drug (nedocromil sodium trihydrate), were evaluated using an in vitro multistage liquid impinger (MSLI) model. In general, milling and storage of the carriers at high humidity (prior to blending) had a significant (ANOVA, p < 0.05) effect on the fine particle fractions (FPF; <6.8 microm). These effects were attributed predominantly to the fines content, showing a strong correlation between increased fines and FPF (R(2) = 0.974 and 0.982 for milled and recrystallized samples, respectively). However, this relationship only existed up to 15% fines concentration, after which agglomerate-carrier segregation was observed and FPF decreased significantly. These results suggest that, after processing, high-dose drug formulation performance is dominated by the presence of fines.

Model-free treatment of the dehydration kinetics of nedocromil sodium trihydrate.

The conventional model-fitting approach to kinetic analysis assumes a fixed mechanism throughout the reaction and therefore may be too simplistic for many solid-state reactions. Even for a reaction with a fixed mechanism, model fitting sometimes cannot identify the reaction model uniquely. The alternative model-free approach is sufficiently flexible to allow for a change of mechanism during the course of a reaction and therefore provides a more realistic treatment of solid-state reactions kinetics. The application of model-free analysis to solid-state dehydrations was investigated using the two consecutive dehydration reactions of nedocromil sodium trihydrate. The complexity of such reactions is illustrated by the variation of the activation energy as each dehydration proceeds. The 1st-step dehydration follows one-dimensional phase boundary kinetics until the fraction dehydrated reaches 0.75, and deviates from this model thereafter. The 2nd-step dehydration follows a mechanism intermediate between two- and three-dimensional diffusion that cannot be described by any of the common models. The model-free approach is clearly better than the model-fitting approach for understanding the details of these solid-state dehydration reactions.

Solvation mechanisms of nedocromil sodium from activation energy and reaction enthalpy measurements of dehydration and dealcoholation.

Two independent athermal methods of analysis have been used to determine the activation energies associated with the dehydration of nedocromil sodium hydrates. For the highest temperature reaction, monohydrate to the anhydrate, the differences in the measured activation energies indicate a three-dimensional nucleation mechanism in the bulk of the crystal with subsequent three-dimensional anhydrate crystal growth. The number of critical nuclei varies inversely with heating rate. Measured enthalpy values for successive removal of water molecules at 31.7 +/- 1.0, 91.3 +/- 0.8, and 193 +/- 0.6 degrees C are the same, within experimental error, at 21.6 +/- 2.6 kJ (mol H(2)O)(-1), as determined from differential thermal analysis traces. This result implies that an earlier concept of "strong" and "weak" water binding is not relevant and temperatures at which H(2)O molecules are removed is related to nucleation effects and not bond energies. The low temperature shoulder on the 91.3 degrees C peak is identified as an effect arising from open pan analysis conditions. The appearance of "transient" peaks in the conditioning stage of nedocromil sodium trihydrate thermal analysis experiments have been investigated and an explanation based on the presence of alcoholates [(NS)(4) small middle dot 5CH(3)OH, (NS)(5) small middle dot 9C(2)H(5)OH, and (NS)(2) small middle dot C(3)H(7)OH] in the preparations is proposed.

Crystal structure and thermal behavior of nedocromil nickel octahydrate.

The hydration behavior of a salt depends on the nature of the cation and the anion and on the molecular packing. A transition metal salt (nickel) of nedocromil was prepared and its crystal structure was elucidated in an attempt to study the influence of the nature of the bivalent cation on the structure, water interactions and molecular packing. Crystal data: nedocromil nickel octahydrate (NNi), orthorhombic, Pca2(1), a=29.5446(1) A, b=25.0444(1) A, c=13.3767(2) A, Z=16. The Ni2+, has octahedral coordination, but the coordination environments of the cations and the bonding environments of the water molecules differ. NNi contains four Ni2+ ions in the asymmetric unit, two of which are each octahedrally coordinated to five water molecules and to a carboxyl oxygen. The two remaining Ni2+ ions are linked in a Ni2(H2O)10(+4) species. Thermal analytical data for NNi show that the water molecules in this hydrate are lost in a single step dehydration, which may be attributed to the fairly continuous water layer in the ac plane of the crystal lattice.

Dehydration behavior of nedocromil magnesium pentahydrate.

The dehydration of nedocromil magnesium (NM) pentahydrate proceeds in two steps, corresponding to the loss of four water molecules in the first step and one water molecule in the second step. The effects of temperature, particle size, sample weight, water vapor pressure and dehydration-rehydration cycle on both the kinetics and activation energy of the dehydration of NM pentahydrate were studied using isothermal TGA and temperature-ramp DSC analyzed by Kissinger's method. The dehydration kinetics for both steps are best described by the Avrami-Erofeev equations, suggesting a nucleation-controlled mechanism. The high activation energy for the second dehydration step indicates that the last water molecule, which is bonded both to a magnesium ion and to a carboxylate oxygen atom, is more 'tightly bound'. The activation energy decreased with increasing sample weight and decreasing particle size. The dehydration rate increased with decreasing water vapor pressure and with repetition of the dehydration-hydration cycle. Dynamic and isothermal PXRD, and 13C solid-state NMR were employed to provide an insight into the dehydration mechanism and the nature of solid-state phase transformation during the dehydration. Molecular modeling with Cerius(2) was used to visualize the crystal structure and to construct the molecular packing diagram. A correlation was noted between the dehydration behavior and the bonding environment of the water molecules in the crystal structure.

The formulation of powder inhalation systems containing a high mass of nedocromil sodium trihydrate.

Nedocromil sodium trihydrate is not amenable to conventional methods of dry powder inhaler formulation, including the preparation of coarse carrier systems and aggregation of the pure drug powder. It is considered that the in vitro aerosol performance of such systems is governed by the cohesive drug-drug interactions. Therefore, alternative powder formulation strategies (novel to nedocromil sodium) were developed. By decreasing the particle size of the lactose carrier, the deaggregation and subsequent fine particle drug deposition were significantly improved. Further improvements were made by selecting and then optimizing high-shear mixing procedures. It was concluded, based on these findings and supportive microscopic studies (low-temperature and environmental scanning electron microscopy together with energy-dispersive X-ray analysis), that the FPL are producing their functional effects by intercalating within the drug self-agglomerates and physically disrupting the cohesive drug-drug interactions. The use of a smaller-sized lactose fraction in conjunction with a blending procedure capable of optimally disrupting the drug self-agglomerates allowed maximal intercalation of the excipient material within the drug self-agglomerates. The adhesive drug-FPL interactions are considered to be weak compared with the cohesive drug-drug particle interactions, cohesive interactions that would normally govern the aerosol performance of powder systems containing a high mass of nedocromil sodium trihydrate.

Physicochemical factors governing the performance of nedocromil sodium as a dry powder aerosol.

Previous investigations have found that the in vitro aerosol performance of nedocromil sodium is poor. A study has been undertaken to gain a better understanding of the physicochemical properties of the drug particles together with the factors governing the aerosol performance of inhalation systems containing this drug. Material previously passed through a hammer mill only and particles subsequently passed through a micronizer were characterized, and the information gathered was correlated with the in vitro aerosol performance of the pure drug systems. Optimization of particle sizing procedures revealed that both sets of materials were ultrafine powders with a volume median diameter of approximately 1 microm. It is concluded that the processing stages, employed in the manufacture of these batches of fine particle nedocromil sodium trihydrate, may not in fact be primary particle size reduction stages but instead deaggregation stages and that these govern the aerosol performance. The in vitro aerosol performance of samples of the "micronized" nedocromil sodium stored over a range of relative humidities (RHs) was characterized. Storage RHs in the range 12-76% (where nedocromil sodium is stable as the trihydrate) did not have a dramatic effect on the in vitro aerosol performance of the drug. However, conversion to the heptahemihydrate (following storage of the drug at 86% RH) significantly decreased the deaggregation performance in an in vitro model.

The change of the rate-controlling processes with temperature in the hydration of anhydrous nedocromil sodium by water vapor.

A six-stage model is proposed to describe the overall process of sorption of water vapor on and into anhydrous nedocromil sodium. The way in which temperature, pressure, and time affect the rate of reaction for each of the stages has been analyzed. Experimental data for the measured rates, where temperature, pressure, and time are variables, are compared with the predictions obtained from each of the six stages. The most useful comparator is a graphical representation of reduced time versus hydration rate. The theoretical equations presented as a shape analysis of the experimental curves show the process to have different controlling mechanisms in three temperature regions: up to 27 degrees C, hydration is controlled by a nucleation and growth mechanism; between 27 and 31 degrees C, the process is dominated by diffusion of water molecules into the crystal; and >31 degrees C, neither nucleation nor diffusion are controlling but some, as yet, undetermined physical processes.

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.

The effect of spacers on the delivery of metered dose aerosols of nedocromil sodium and disodium cromoglycate.

The effect of the spacers (Fisonair, Breath-A-Tech, Volumatic and Nebuhaler) on the in vitro aerosol characteristics of two propellant-driven metered dose inhalers (MDIs), Tilade (nedocromil sodium) and Intal (disodium cromoglycate), was studied. The measurement was carried out on a Marple-Miller impactor operating at 30 l/min. Five actuations were collected for the drug assay. The results showed that Tilade (label claim 2 mg active per actuation) and Intal (label claim 5 mg active per actuation) generated aerosols with a fine particle mass (FPM, i.e. mass of particles 5 microm in the aerosol) of 0.34 mg (S.D. 0.01, n = 4) and 0.02 mg (S.D. 0.01, n = 4) per actuation, respectively. For both inhalers, large volume spacers increased (Fisonair > Nebuhaler > Volumatic) while small volume spacer (Breath-A-Tech) decreased the FPM. The FPM (per actuation) for Tilade with Fisonair, Nebuhaler, Volumatic and Breath-A-Tech was 0.52 (0.03), 0.45 (0.03), 0.41 (0.04) and 0.09 (0.04) mg, respectively, while for Intal the corresponding values were 0.41 (0.02), 0.32 (0.04), 0.28 (0.03) and 0.08 (0.01) mg. Thus, the fine particle mass can be either increased or decreased, depending on the spacer selected. In addition, all spacers significantly reduced the coarse particle (> or = 10 microm) mass, with Fisonair, Breath-A-Tech, Nebuhaler and Volumatic producing only 7.6, 0.4, 5.2 and 2.6, respectively of that from Tilade alone and 15.6, 0.7, 5.4 and 4.1%, respectively of that from Intal alone. The general trends for Tilade and Intal were similar but not quantitatively identical. The proper choice of spacers is therefore important for the optimal delivery of Tilade and Intal.

Adsorption of water by anhydrous nedocromil sodium from 20 to 40 degrees C.

Three different powder preparations of the drug disodium 9-ethyl-4, 6-dioxo-10-propyl-4H,6H pyrano[3,2-g]quinoline-2,8-dicarboxylic trihydrate, Nedocromil sodium (trade name Tilade), have been fully dehydrated in a vacuum and their water vapor adsorption characteristics quantitatively assessed at different water vapor pressures over a temperature range 20 to 40 degrees C. At saturated vapor pressures, 100% RH, rates of adsorption are around 0.1 s(-1/2). Graphs of square root of time against reduced mass during uptake of water vapor at vapor pressures in the range 20 to 47 mm of Hg, all equivalent to 100% RH, indicate control by a diffusion mechanism with activation energies in the range 8 to 24 kJ mol(-1), dependent on the powder preparation method. In two of the powders nonlinear Arrhenius-type plots are interpreted as showing that control of the process is dependent on the surface's ability to hold water molecules at the experimental temperature. The variation in activation energies and the calculated values for diffusivities, around 1 x 10(-13) m(2) s(-1), are used to explore structural involvement in the overall water adsorption process. The measured values of water vapor diffusivity into the structure have been used to predict the water solubility of nedocromil sodium trihydrate, and the results show good agreement to reported solubilities. This approach to solubility prediction is an alternative to the Noyes and Whitney method where ions leaving the surface are monitored.

Extension of Clausius-Clapeyron equation to predict hydrate stability at different temperatures.

The objectives of this study were to verify theoretically and experimentally that the Clausius-Clapeyron equation can be applied to a hydrate system, and to use this equation to predict the equilibrium water activity for a hydrate pair existing in equilibrium at different temperatures for the determination of the ranges of hydrate stability. The Clausius-Clapeyron equation was derived for hydrate systems by assuming (a) the higher and the lower hydrates exist in equilibrium with water vapor as three pure phases; and (b) the overall volume change involved in this equilibrium process is approximated by the volume of the released water vapor, which behaves ideally. The equilibrium water vapor pressure at different temperatures for the nedocromil sodium monohydrate and trihydrate system was determined dynamically using a thermogravimetric analyzer with an attached water vapor delivery system. The enthalpy of dehydration obtained by applying the Clausius-Clapeyron equation to the experimentally determined equilibrium water vapor pressures is in fair agreement with the enthalpy of dehydration derived from differential scanning calorimetry (13.7 +/- 0.6 kcal/mol of water loss, n = 5), indicating that the Clausius-Clapeyron equation can indeed be applied to organic hydrate systems. The application of the Clausius-Clapeyron equation to predict the hydrate stability under various conditions is also discussed.

Physical characterization of nedocromil sodium hydrates.

Nedocromil sodium, which is used in the treatment of reversible obstructive airway diseases, such as asthma, is found to exist in the following hydrate phases: the heptahemihydrate, the trihydrate, a monohydrate, and an amorphous phase which contains variable amounts of water (1.5-3.0 mol). An anhydrate phase is formed from the trihydrate at zero humidity at >/= 150 degrees C, but is rapidly hydrated under ambient conditions. The physical and thermodynamic properties of the four hydrate phases were characterized using differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), powder X-ray diffraction (PXRD) at ambient and elevated temperatures, hot-stage microscopy (HSM), solid phase interconversion at various relative humidities (RH), intrinsic dissolution rate (IDR), equilibrium solubility measurements, and critical RH measurements. Below 100 degrees C in open pan TGA, the heptahemihydrate and the amorphous forms lose virtually all their water, the monohydrate loses negligible amounts of water, whereas the trihydrate loses the first two moles of water. From 130 degrees C to 200 degrees C in open pan TGA the trihydrate and the monohydrate lose their last mole of water to form the anhydrate. In crimped pan DSC, the thermal events observed are analogous to those observed in open pan TGA, but the temperatures are increased by about 75 degreesC for all except the heptahemihydrate, for which the thermal events are more complex. When the heptahemihydrate is heated in a crimped pan, a melting endotherm is observed at about 75 degrees C followed by three dehydration endotherms. For the crystalline hydrate phases at 22 degrees C, the ranges of stability are as follows: the monohydrate from 0 to 6.4% RH; the trihydrate from 6.4 to 79.5% RH; the heptahemihydrate above 80% RH. A microbalance study showed that the heptahemihydrate is kinetically stable over the range 11 to 79.5% RH. The IDR in water at 25 degrees C under constant hydrodynamic conditions decreases in the rank order: monohydrate > trihydrate > heptahemihydrate, corresponding to the rank order of free energy with respect to the aqueous solution. The equilibrium aqueous solubility of the heptahemihydrate at 25.0 +/- 0.2 degrees C is 0.956 +/- 0.010 M.

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.

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.

Physicochemical characterization of a new respirable form of nedocromil.

Elongated, respirable particles of nedocromil were prepared by its crystallization from N-methyl-2-pyrrolidone (NMP) obtained from an aqueous solution of its sodium salt by precipitation with hydrochloric acid. Aerosols of these particles were recently generated and characterized for their aerodynamic properties (Chan, H.-K.; Gonda, I. J. Aerosol Med. 1993, 6, 241-249). This paper reports the physiochemical properties of the solid form of nedocromil as characterized by polarizing optical and scanning electron microscopies, thermal analysis (DSC, TGA), X-ray powder diffraction, water vapor adsorption isotherms, mass spectrometry, solid state Fourier transform IR and solution 1H-NMR spectroscopies.