Sarma P. Duddu

Improved Lung Delivery from a Passive Dry Powder Inhaler Using an Engineered PulmoSphere® Powder

AbstractPurpose. To assess the pulmonary deposition and pharmacokinetics of an engineered PulmoSphere® powder relative to standard micronized drug when delivered from passive dry powder inhalers (DPIs). Methods. Budesonide PulmoSphere (PSbud) powder was manufactured using an emulsion-based spray-drying process. Eight healthy subjects completed 3 treatments in crossover fashion: 370 μg budesonide PulmoSphere inhaled from Eclipse® DPI at target PIF of 25 L·min-1 (PSbud25), and 50 L·min-1 (PSbud50), and 800 μg of pelletized budesonide from Pulmicort® Turbuhaler® at 60 L·min-1(THbud60). PSbud powder was radiolabeled with 99mTc and lung deposition determined scintigraphically. Plasma budesonide concentrations were measured for 12 h after inhalation. Results. Pulmonary deposition (mean ± sd) of PSbud was 57 ± 7% and 58 ± 8% of the nominal dose at 25 and 50 L·min-1, respectively. Mean peak plasma budesonide levels were 4.7 (PSbud25), 4.0 (PSbud50), and 2.2 ng·ml-1 (THbud60). Median tmax was 5 min after both PSbud inhalations compared to 20 min for Turbuhaler (P < 0.05). Mean AUCs were comparable after all inhalations, 5.1 (PSbud25), 5.9 (PSbud50), and 6.0 (THbud60) ng·h·ml-1. The engineered PSbud powder delivered at both flow rates from the Eclipse® DPI was twice as efficiently deposited as pelletized budesonide delivered at 60 L·min-1 from the Turbuhaler. Intersubject variability was also dramatically decreased for PSbud relative to THbud. Conclusion. Delivery of an engineered PulmoSphere formulation is more efficient and reproducible than delivery of micronized drug from passive DPIs.

Effect of glass transition temperature on the stability of lyophilized formulations containing a chimeric therapeutic monoclonal antibody.

AbstractPurpose. The purpose of this study is to highlight the importance of knowing the glass transition temperature, Tg, of a lyophilized amorphous solid composed primarily of a sugar and a protein in the interpretation of accelerated stability data. Methods. Glass transition temperatures were measured using DSC and dielectric relaxation spectroscopy. Aggregation of protein in the solid state was monitored using size-exclusion chromatography. Results. Sucrose formulation (Tg ~ 59°C) when stored at 60°C was found to undergo significant aggregation, while the trehalose formulation (Tg ~ 80°C) was stable at 60°C. The instability observed with sucrose formulation at 60°C can be attributed to its Tg (~59°C) being close to the testing temperature. Increase in the protein/sugar ratio was found to increase the Tgs of the formulations containing sucrose or trehalose, but to different degrees. Conclusions. Since the formulations exist in glassy state during their shelf-life, accelerated stability data generated in the glassy state (40°C) is perhaps a better predictor of the relative stability of formulations than the data generated at a higher temperature (60°C) where one formulation is in the glassy state while the other is near or above its Tg.

The relationship between protein aggregation and molecular mobility below the glass transition temperature of lyophilized formulations containing a monoclonal antibody

AbstractPurpose. To find out if the physical instability of a lyophilized dosage form is related to molecular mobility below the glass transition temperature. Further, to explore if the stability data generated at temperatures below the glass transition temperature can be used to predict the stability of a lyophilized solid under recommended storage conditions. Methods. The temperature dependence of relaxation time constant, τ, was obtained for sucrose and trehalose formulations of the monoclonal antibody (5 mg protein/vial) from enthalpy relaxation studies using differential scanning calorimetry. The non-exponentiality parameter, β, in the relaxation behavior was also obtained using dielectric relaxation spectroscopy. Results. For both sucrose and trehalose formulations, the variation in τ with temperature could be fitted Vogel-Tammann-Fulcher (VTF) equation. The two formulations exhibited difference sensitivities to temperature. Sucrose formulation was more fragile and exhibited a stronger non-Arrhenius behavior compared to trehalose formulation below glass transition. Both formulations exhibited <2% aggregation at tτ values <10, where t is the time of storage. Conclusions. Since the relaxation times for sucrose and trehalose formulations at 5°C are on the order of 108 and 106 hrs, it is likely that both formulations would undergo very little (<2%) aggregation in a practical time scale under refrigerated conditions.

Stereoselective Dissolution of Propranolol Hydrochloride from Hydroxypropyl Methylcellulose Matrices

Since many chiral pharmaceutical excipients, such as cellulose polymers and cyclodextrins, are used as stationary phases for the separation of enantiomers by high performance liquid chromatography (HPLC), it is hypothesized that one enantiomer of a chiral drug will be released faster than the other from a pharmaceutical formulation containing a racemic drug and a chiral excipient. The mechanism of such an event may arise from preferential intermolecular interaction between the chiral excipient and one of the enantiomers. To test this hypothesis, the release of the enantiomers of propranolol hydrochloride into water from formulations containing the chiral excipients, hydroxypropyl methylcellulose (HPMC) or β-cyclodextrin, was investigated by stereospecific HPLC analysis of the dissolved concentrations of each of the enantiomers from the formulations. The release of the enantiomers of propranolol hydrochloride from the formulations containing HPMC, although variable, was found to be stereoselective. However, the release of propranolol hydrochloride enantiomers from the β-cyclodextrin complex was found to be non-stereoselective.

The use of thermal analysis in the assessment of crystal disruption

Abstract The highly ordered crystal lattice of small organic molecules, such as drugs, contains defects resulting from the crystallization process. Pharmaceutical processing and impurities introduce further defects which cause partial disruption of the crystalline order decreasing the crystallinity and increasing the crystal energy, enthalpy, entropy and free energy. As a result, the intrinsic dissolution rate increases and other solid state properties, including the compaction (tableting) behavior, are changed, thereby accounting for interbatch variations. Differential scanning calorimetry (DSC) or differential thermal analysis (DTA) are used to measure the enthalpy of fusion at the melting point and hence the entropy of fusion. The negative slope of the plot of the entropy of fusion against the ideal entropy of mixing of a guest impurity in solid solution in the host solid affords the disruption index (d.i.) resulting from the presence of the guest. The significance and magnitude of d.i. are discussed. The change in the entropy of fusion resulting from the processing of the solid is used to calculate the entropy of processing, ΔS p , which is related to changes in various pharmaceutical properties. The uses of d.i. and ΔS p are illustrated using a variety of pharmaceutical examples.

Microcalorimetric investigation of phase transitions. I: Is water desorption from theophylline .HOH a single-step process ?

Abstract The dehydration of theophylline - HOH has been followed via isothermal calorimetry at 40 and 47°C. The power ( P )-time relationship found at 47°C can be fitted as a single Gaussian distribution where the cumulative area up to time t relative to the total area measures fractional dehydration (α). An Avrami-Erofeev plot for solid state nucleation reactions with power 0.25 best linearizes the a vs time relationship yielding a rate constant which corroborates that found by others who used a gravimetric method. At 40°C, endothermic heat flow in the microcalorimeter, temperature difference between sample and reference in differential thermal analysis (DTA), and weight loss in thermogravimetric analysis (TGA), each operated in the isothermal mode indicate that water loss is a multi-step process. Power ( P )-time data from the thermal activity monitor at 40°C were deconvoluted into two Gaussian relationships yielding rate constants via Avrami-Erofeev plots for each step with excellent reproducibility. The rate constants for the two steps are about equal at 40°C but there are significant differences in lag times.

Effect of the opposite enantiomer on the physicochemical properties of ( - ) -ephedrinium 2-naphthalenesulfonate crystals

Abstract During the growth of optically active crystals (host), trace quantities of the opposite enantiomer (guest) present in the solution may be taken up by the host. However, the enantiomeric guest, due to its opposite chirality, may distort the crystal lattice of the host. Thus, the incorporation of the guest may lead to changes in the pharmaceutically important properties of the host, such as dissolution rate and thermodynamic properties, perhaps through lattice disruption. This hypothesis was tested by growing crystals of a model compound, ( - )-ephedrinium 2-naphthalenesulfonate, from aqueous crystallization media containing various trace quantities of its opposite enantiomer. A Stereoselective HPLC method was developed to determine the trace amounts of the opposite enantiomer within and on the surface of the homochiral host crystals. Increasing concentrations of the guest in solution led to its increasing incorporation into the host crystals and to increasing intrinsic dissolution rate of the host. The enthalpy and entropy of fusion of the host decreased with increasing incorporation of the guest, suggesting the disruption of the crystal lattice of the host and an increase in its lattice strain. The water content and the melting point were not significantly affected. At higher levels of the incorporated guest, the enthalpy and entropy of fusion increased, suggesting a relaxation of the lattice strain, and subsequently reached a plateau value. A value of 20.6 was obtained for the ‘disruption index’, which is defined as the rate of change of the difference between the entropy of the solid and that of the liquid, with respect to the ideal entropy of mixing of the host with the guest (York and Grant, Int. J. Pharm ., 25 (1985) 57–72). This relatively high disruption index indicates significant disruption of the crystal lattice of the host by the incorporated guest, suggesting changes in the nature and concentration of the crystal defects.

Effects of crystallization in the presence of the opposite enantiomer on the crystal properties of (SS)-(+)-pseudoephedrinium salicylate

Abstract Previous work ( Int. J. Pharm. , 94 (1993) 171–179) with (RS)-(-)-ephedrinium 2-naphthalenesulfonate, which forms a racemic compound with its opposite enantiomer, has shown that crystallization of the homochiral crystal (host) from aqueous solution containing traces of the opposite enantiomer (guest) leads to uptake of the guest with significant changes in various thermodynamic properties, including an increase in the intrinsic dissolution rate (IDR), perhaps through lattice disruption. The present work tests this possibility with a different but related chiral drug, (SS)-( + )-pseudoephedrinium salicylate, which forms a racemic conglomerate, instead of a racemic compound, with its opposite enantiomer. Increasing concentrations of the guest in the aqueous crystallization solution led to its increasing incorporation into the host crystals, corresponding to a segregation coefficient of 0.24. With increasing mole fraction, x 2 , of the guest in the crystals, the IDR of the compacts increased to a maximum (12% increase at x 2 = 0.0076) and then decreased. Meanwhile, with increasing x 2 , the enthalpy of fusion, ΔH f , entropy of fusion, ΔS f , and enthalpy of solution, ΔH s , decreased to minima (4–5% decreases at x 2 = 0.0028), suggesting disruption of the crystal lattice of the host and an increase in lattice strain, and then increased, suggesting a release of lattice strain. The water content (0.006 mole fraction) and melting point (405.2 ± 1.2 K) were not significantly affected. The change in the free energy of solution, estimated from the IDR, was approximately linearly related to the calorimetric ΔH s , suggesting enthalpy-entropy compensation. ΔS f and ΔS s decreased linearly with increasing ideal entropy of mixing, corresponding to values of 24.7 and 21.4, respectively, for the ‘disruption index’ ( Int. J. Pharm. , 25 (1985) 57–72, 28 (1986) 103–112). These relatively high values indicate significant disruption of the crystal lattice of the host, suggesting potentiation of crystal defects by the incorporated guest.

Formation of the Racemic Compound of Ephedrine Base from a Physical Mixture of Its Enantiomers in the Solid, Liquid, Solution, or Vapor State

Physical mixtures (conglomerates) of the two enantiomers of ephedrine base, each containing 0.5% (w/w) of water, were observed to be converted to the 1:1 racemic compound in the solid, liquid, solution, or vapor state. From a geometrically mixed racemic conglomerate of particle size 250–300 µm (50–60 mesh), the formation of the racemic compound follows second-order kinetics (first order with respect to each enantiomer), with a rate constant of 392 mol−1 hr−1 at 22°C. The reaction appears to proceed via the vapor phase as indicated by the growth of the crystals of the racemic compound between diametrically separated crystals of the two enantiomers in a glass petri dish. The observed kinetics of conversion in the solid state are explained by a homogeneous reaction model via the vapor and/or liquid states. Formation of the racemic compound from the crystals of ephedrine enantiomers in the solution state may explain why Schmidt et al. (Pharm. Res. 5:391–395, 1988) observed a consistently lower aqueous solubility of the mixture than of the pure enantiomers. The solid phase in equilibrium with the solution at the end of the experiment was found to be the racemic compound, whose melting point and heat of fusion are higher than those of the enantiomers. An association reaction, of measurable rate, between the opposite enantiomers in a binary mixture in the solid, liquid, solution, or vapor state to form the racemic compound may be more common than is generally realized.

Liquid chromatographic analysis of the enantiomeric impurities in various (+)-pseudoephedrine samples

An HPLC method has been developed for the separation of four stereoisomers of ephedrine using precolumn derivatization with S( + )-l-(l-naphthyl)-ethyl isocyanate. The formed derivatives are subsequently separated on a normal-phase column and are detected at a UV wavelength of 220 nm. This method was used to quantitate the differences in the enantiomeric impurity of various samples of ( + )-pseudoephedrine. The reported method can differentiate between samples of ( + )-pseudoephedrine which differ in their enantiomeric impurity by as little as 0.02%. Possible racemization of ( + )-pseudoephedrine in aqueous solutions was also studied. Samples of ( + )-pseudoephedrine from various suppliers and, indeed, different lots from the same supplier, differed significantly in their degree of enantiomeric impurity.