Biomedical subjects

Paul B Myrdal

Publications and source records attributed to Paul B Myrdal.

16 recordsLinked to original sources

PubMed2006

Chiral separation of lipoxygenase metabolites utilizing high-performance liquid chromatography.

An isocratic, reversed-phase HPLC assay has been developed for the separation of the enantiomers of four lipoxygenase metabolites, without the need for a derivatization step. Separation of the enantiomers was studied on a polysaccharide type chiral stationary phase column. Upon determination of suitable mobile phase composition, the assay was evaluated at various temperatures. In all cases the R enantiomer eluted before the S enantiomer. The best separations were observed at 0 degrees C.

Chromatography, High Pressure Liquid↗

PubMed2006

Evaluation of the TSI aerosol impactor 3306/3321 system using a redesigned impactor stage with solution and suspension metered-dose inhalers.

The purpose of this research was to evaluate a redesigned impactor stage for the TSI Model 3306 Impactor Inlet with nozzles adjusted to obtain a target cut-point of 4.7 microm. It has been determined that the previous cut-point used in the Model 3306 was nominally closer to 4.14 microm, thus potentially impacting the characterization of aerosol mass. The reassessment of the Model 3306 was performed on 4 solution and 2 suspension metered-dose inhaler (MDI) formulations. The redesigned impactor stage resulted in a 5% to 6% increase in aerosol mass when compared with the previous impactor stage for the products Ventolin-HFA, Proventil-HFA, and 2 cyclosporin solution formulations with high ethanol concentrations (15% wt/wt). For the formulations with low ethanol concentrations (3% wt/wt), minimal differences were observed between the 2 cut-points. In addition, this study reevaluated the requirement of a vertical inlet extension length when using the TSI 3306/3321 system with the redesigned cut-point. It was shown that the use of a 20-cm extension provides mass and aerosol size distributions that are comparable to the Andersen 8-stage Cascade Impactor, for both solution and suspension MDIs. This work indicates that the TSI 3306/3321 system is suitable for preformulation studies of both suspension and solution MDI systems.

Aerosols↗

PubMed2006

Application of heated inlet extensions to the TSI 3306/3321 system: comparison with the Andersen cascade impactor and next generation impactor.

Pharmaceutical aerosol size distribution analysis based on multi-stage inertial impaction is well accepted, though laborious. The TSI 3306 Impactor Inlet/3321 time-of-flight (TOF) Aerodynamic Particle Size Analyzer (APS) has been evaluated for its ease of use and potential for time savings during product development. However, instrument inlet modifications may be necessary for increased correlation with equivalent measurements obtained by inertial impaction following pharmacopeial methods. A heated inlet extension tube was located between the USP/Ph.Eur. throat and the Single-Stage Impactor (SSI) to promote evaporation of residual ethanol from aerosol droplets, generated from two formulations containing ethanol as semi-volatile solubilizer (8 and 20% w/w) for the active pharmaceutical ingredient. As temperature and extension length increased, the SSI-measured fine particle fraction (aerosol < 4.7 microm aerodynamic diameter) also increased, for the aerosols used in this study. These values correlated quite closely with equivalent measures made by multi-stage cascade impactor equipped with the same throat. Particle size distribution profiles measured with the APS for either formulation did not significantly change utilizing the heated extensions, suggesting that ethanol evaporation was largely complete at any condition by the time the aerosol entered the measurement zone of the TOF analyzer. The addition of a heated inlet extension may be useful to facilitate evaporation of residual semi-volatile species, especially when an agreement of APS-derived particle size mass distribution data from the SSI with multi-stage cascade impactors is desired. However, complete evaporation of the semi-volatile species may not be necessary for SSI-generated mass distribution to match conventionally used cascade impactors.

Administration, Inhalation↗

PubMed2005

Effects of extreme temperatures on drug delivery of albuterol sulfate hydrofluoroalkane inhalation aerosols.

PURPOSE: The effects of extreme temperatures on drug delivery of two albuterol sulfate hydrofluoroalkane, metered-dose inhalers (MDIs) were evaluated. METHODS: Three Proventil HFA and three Ventolin HFA MDIs were stored at room temperature and served as controls while three of each product were placed in the trunk of a vehicle in Tucson, Arizona. The temperature in the vehicle was monitored for six months. Product performance for each of the MDIs was evaluated at room temperature. An additional study was performed to investigate the performance of the two products when actuated at 4, 22, 47, and 60 degrees C. RESULTS: The products subjected to extreme environmental temperatures had a modest increase in propellant-leak rate, but the emitted-particle size, dose per actuation, respirable mass, and non-respirable mass were unaffected. The inhalers tested at temperatures outside the recommended storage conditions exhibited a decrease in particle size, dose per actuation, shot weight, and non-respirable mass as temperature increased. Conversely, increased temperature caused an increase in respirable mass. CONCLUSION: Despite exposure to extreme temperatures exceeding the manufacturers' recommended storage conditions, drug delivery from Proventil HFA and Ventolin HFA MDIs was not significantly altered. However, drug delivery did change appreciably when the inhalers were tested at different temperatures outside recommended storage conditions.

Aerosols↗

PubMed2005

Development of an HPLC method for the analysis of Apomine in a topical cream formulation.

A stability indicating, reversed-phase high performance liquid chromatographic method was developed for the quantification of Apomine, tetraisopropyl 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-ethyl-1, 1-bisphosphonate, in a topical cream formulation. Analysis of Apomine in the cream formulation was performed through a dilution of the cream base with tetrahydrofuran. This allowed the current method to bypass extraction and/or centrifugation for direct injection and analysis. Separation was achieved using an Alltima C18 5 microm, 150 mm x 2.1 mm column and employed a gradient procedure, beginning with acetonitrile-water (65:35, v/v), at 0.6 mL/min for 9 min, followed by a rinse with isopropyl alcohol for 9 min. The complete gradient method has been optimized to separate Apomine from the nonpolar cream components, wash and equilibrate the column in a 30-min assay. This report demonstrates that this method is effective for quantification of Apomine in a cream formulation.

Administration, Topical↗

PubMed2005

A comparison of two methods to determine the solubility of compounds in aerosol propellants.

A new on-line reverse phase HPLC method for determining the solubility of compounds in propellant based metered dose inhaler (MDI) formulations was compared with a conventional method. The new method employs a direct injection from a MDI vial into the needle injector port of a manual injector. To evaluate the two methods, beclomethasone dipropionate (BDP), 5,5-diphenyl hydantoin and 3,3'-diindolylmethane, were used as model compounds in propellant HFA-134a. Comparison was performed by analyzing known and unknown concentrations of BDP in various combinations of HFA-134a and ethanol. In addition, the solubility of 5,5-diphenyl hydantoin and 3,3'-diindolylmethane were determined in HFA-134a using both the new and the conventional methods. The two methods were found to be in good agreement with each other, with the new direct injection technique offering enhanced precision and accuracy along with considerable reduction in analysis time.

Aerosol Propellants↗

PubMed2005

An HPLC method for quantitation of perillyl alcohol in a topical pharmaceutical cream formulation.

A reverse phase high performance liquid chromatographic method for quantitation of perillyl alcohol in a topical cream pharmaceutical formulation was developed. Previously reported methods for analyzing drugs in lipid formulations are relatively complex and time consuming, with extraction, purification and derivatization involved. Through a simple dilution of the cream formulation in isopropyl alcohol, the present assay method enables the direct injection of the samples, on an Alltima C18 5 mu, 150 mm x 2.1 mm, narrow bore column (Alltech Associates, Deerfield, IL). The method includes an isocratic run with acetonitrile-water (40:60, v/v) at 0.35 mL/min for 12 min, followed by a gradient wash with isopropyl alcohol for 20 min, to ensure that all formulation excipients are eluted. Ultraviolet detection was performed at 210 nm with a retention time for perillyl alcohol of 7 min. The high sensitivity assay utilizes a small (5 microL) injection volume for the accurate and precise analysis of perillyl alcohol from a complex cream formulation.

Administration, Topical↗

PubMed2005

Comparison of three pharmaceutical products obtained from Mexico and the United States: a case study.

In recent years, there has been much debate concerning the relative pros and cons of purchasing medications from foreign markets such as Mexico and Canada. The following study compares the content uniformity and weight variation for three medicinal products, acquired from pharmacies in both Mexico and the United States: amoxicillin capsules (500 mg), amoxicillin/clavulanic acid suspension (400 mg and 57 mg/5 mL, respectively), and furosemide tablets (40 mg). Twenty capsules/tablets were individually weighed and a designated aliquot was taken. Following dissolution in an appropriate solvent and sonication, a sample was taken and analyzed via high performance liquid chromatography (HPLC). The suspensions were prepared according to directions on the label. Five samples of the suspensions were then taken and analyzed via an appropriate HPLC method. The content uniformity for the amoxicillin capsules was found to be 15.4 +/- 2.4% and 99.4 +/- 9.3%, for Mexican and U.S. capsules, respectively. The percent relative standard deviation (% RSD) for weight variation was found to be 8.7% and 1.5% for capsules obtained from Mexico and the United States, respectively. Content uniformity analysis for the Mexican suspension product resulted in an average of 85.5 +/- 1.2% for amoxicillin and 98.6 +/- 1.9% for the clavulanic acid content, while the results for the U.S. suspension product were 104.4 +/- 3.1% and 117.8 +/- 3.6% for amoxicillin and clavulanic acid, respectively. Content uniformity for the furosemide tablets was found to be 90.3 +/- 4.8% and 95.6 +/- 2.1% for Mexican and U.S. tablets, respectively. The % RSD of weight variation for the Mexican tablets was 2.1%, while the % RSD for the U.S. tablets was found to be 1.0%. From the three products tested, content analysis revealed that the amount of active ingredients for two of the products acquired in Mexico were appreciably less than the concentrations for their U.S. counterparts.

Amoxicillin↗

PubMed2004

On-line high-performance liquid chromatography method for analyte quantitation from pressurized metered dose inhalers.

A sensitive and rapid, on-line reversed-phase high-performance liquid chromatographic method for quantitation of compounds at low concentrations in pressurized metered dose inhaler (MDI) systems was developed. Traditional methods for the quantitation of compounds in MDI formulations involve the opening of the MDI vial along with sample dilution prior to quantitation. The new method, reported in this study, involves a direct injection from the MDI vial into the needle injector port of a manual injector. Since there is no dilution step involved, this method can be used to quantitate low concentrations of compounds in MDIs with excellent precision. In addition, since the method requires a small injection volume of 5 microl, repeated analyses can be performed in order to generate multiple data points using the same MDI vial. Validation of the method was performed using ethanol-1,1,1,2-tetrafluoroethane (134a)-based MDIs. Beclomethasone dipropionate (BDP), a corticosteroid used for the treatment of asthma, was used as a model compound. Phase separation studies were conducted to investigate the miscibility of the ethanol-134a mixtures with different mobile phase solvent compositions. For the MDI systems in this study, an acetonitrile-water (90:10, v/v) mobile phase at a flow rate of 0.9 ml/min was found to give acceptable chromatography for BDP on a Apollo C18 5 microm, 150 mm x 4.6 mm column (Alltech Associates, Deerfield, IL, USA). Ultraviolet detection was done at 240 nm and the retention time of BDP was 2.7 min. The on-line HPLC method was characterized to be accurate, precise, sensitive, and specific.

Chromatography, High Pressure Liquid↗

PubMed2004

Development of a perillyl alcohol topical cream formulation.

Perillyl alcohol (POH) is a relatively non-toxic agent that has been shown to be a promising anticancer monoterpene in preclinical models. Studies have indicated that topical application of POH may prove to be effective as a skin cancer chemoprevention therapy. The main aim of this study was to determine the influence of several factors on the stability of POH in solution and develop a topical formulation of POH. During preformulation, the influence of pH, temperature, ionic strength, and organic solvents, on the stability of POH was evaluated at four different temperatures: 4, 25, 37, and 48 degrees C. POH was found to degrade under acidic conditions with degradation following apparent first-order kinetics. A hydrophilic topical cream formulation of POH was developed and prepared for toxicology and clinical studies. A reverse phase gradient HPLC method was developed to quantitate POH in the complex formulation. Stability studies of the formulation and a placebo were performed and the formulation was found to be physically and chemically stable over a period of 1 year at 4 and 25 degrees C.

Administration, Topical↗

PubMed2004

Optimized dose delivery of the peptide cyclosporine using hydrofluoroalkane-based metered dose inhalers.

The goal of this study was to illustrate the potential to deliver relatively high doses of a therapeutic peptide using hydrofluoroalkane (HFA) metered dose inhaler (MDI) drug delivery systems. For the purposes of this study, cyclosporine was used as the model compound. Cyclosporine formulations, varying in peptide concentration, ethanol cosolvent concentration, and propellant type, were evaluated and optimized for product performance. As ethanol concentration was decreased from 10 to 3% by weight, fine particle fraction (the mass of cyclosporine which passes through a 4.7-micron cut point divided by the total mass of cyclosporine delivered ex-valve) increased from 34 to 68% for 227 and 33 to 52% for 134a formulations. Because of the excellent solubility properties of cyclosporine in HFA-based systems, minimal or no ethanol was needed as a cosolvent to achieve cyclosporine concentrations of 1.5% w/w. With these formulations, it was possible to obtain a fine particle mass (mass of particles <4.7 microns) greater than 500 microg per actuation. In addition, one formulation was chosen for stability analysis: 0.09% w/w cyclosporine, 10% w/w ethanol, 134a. Three different types of container closure systems (stainless steel, aluminum, and epoxy-coated canisters) and two storage configurations (upright and inverted) were evaluated. Cyclosporine was determined to be stable in HFA 134a-based MDI systems, regardless of container closure system and configuration, over a 2-year period. Cyclosporine represents a compelling example of how significant peptide doses are attainable through the use of solution-based MDIs. It has been shown that through formulation optimization, 2-3 mg of the peptide, cyclosporine, may be delivered in five actuations to the lung for local or systemic therapy.

Administration, Inhalation↗

PubMed2004

A theoretical and experimental analysis of formulation and device parameters affecting solution MDI size distributions.

The influence of formulation and device configurations on the initial droplet and residual particle size distribution from solution MDIs was theoretically and experimentally examined. Aerodynamic size distribution tests were conducted to characterize the size distribution of the residual particles formed when a solution MDI is actuated. The measured size distributions were approximately log-normally distributed, and did not show evidence of a secondary large particle mode. Theoretical relationships were developed to relate the residual particle size distribution to the initial size distribution of the atomized droplets. The residual particle size distribution was shown to be proportional to the nonvolatile concentration to the one-third power. Ethanol concentration, propellant type, valve size, and actuator orifice diameter were all shown to affect the initial droplet size distribution. Deposition of drug in the mouthpiece and USP inlet affect the measured size distribution during aerodynamic particle size measurements. Although there is a significant increase in the size of initial droplets as ethanol concentration increases, there is only a minor increase in the size of the residual particles measured when the USP Inlet is used due to size dependent deposition in the USP inlet and actuator mouthpiece. Vapor pressure was shown to explain only part of the differences in the size of the atomized droplets for various formulations. Theoretical and empirical equations were developed that make it possible to predict the residual particle size distribution for solution MDIs.

Chemistry, Pharmaceutical↗

PubMed2004

Novel method for the determination of solubility in aerosol propellants.

A new on-line reverse-phase high-performance liquid chromatography method to determine the solubility of compounds in propellant-based metered-dose inhaler (MDI) formulations was developed. The new method uses a direct injection from an MDI vial into the port of a manual injector. The MDI vials were coupled with a filtration and injection assembly to filter the excess compound, and deliver the filtrate of the MDI vials to the injector port of the manual injector. A backpressure regulator was connected to the manual injector, to maintain the propellant in the liquid state after injection from the MDI vial. Phase separation studies were conducted to investigate the miscibility of hydrofluoroalkane 134a with different mobile-phase solvent compositions. Characterization of the new direct injection method was done by evaluating sample presentation and chromatography variables to determine the robust nature of the method. Beclomethasone dipropionate in ethanol/hydrofluoroalkane 134a was used as a model system for development. A chemically diverse set of nine compounds was used to evaluate solubility measurement reproducibility. Solubilities were determined at two different temperatures (25 and 37 degrees C) and the average relative standard deviation for all of the solubility measurements was <4%.

Aerosol Propellants↗

PubMed2004

Comparison of the TSI Model 3306 Impactor Inlet with the Andersen Cascade Impactor: solution metered dose inhalers.

The product performance of a series of solution Metered Dose Inhalers (MDIs) were evaluated using the TSI Model 3306 Impactor Inlet and the Andersen Cascade Impactor (ACI). The goal of the study was to test whether the fine particle and coarse particle depositions obtained using the Model 3306 were comparable to those results obtained by ACI testing. The analysis using the Model 3306 was performed as supplied by the manufacturer as well as with 20 cm and 40 cm vertical extensions that were inserted between the Model 3306 and the USP Inlet. Nine different solution formulations were evaluated. The drug concentrations ranged from 0.08 to 0.8% w/w and the ethanol cosolvent concentration varied between 5 and 20% w/w. In general, it was found that good correlations between the two instruments were obtained. However, for formulations containing 10-20% w/w ethanol it is shown that an extension fitted to the Model 3306 yielded an improved correlation to those obtained from the ACI.

Beclomethasone↗

PubMed2003

Evaluation of a new Aerodynamic Particle Sizer Spectrometer for size distribution measurements of solution metered dose inhalers.

The ability of the Model 3320 and newer Model 3321 Aerodynamic Particle Sizer Spectrometer (APS) to make accurate mass-weighted size distribution measurements of solution metered dose inhalers (MDIs) was evaluated. Measurements of experimental HFA-134a beclomethasone dipropionate MDIs were made with both the APS 3320 and APS 3321 and compared to the Andersen Cascade Impactor (ACI). The mass-weighted size distribution measurements from the ACI and APS 3321 agreed well but were very different than the APS 3320 measurements. Evaluation of the APS 3320 size distribution measurements indicated that the presence of a few erroneous particle measurements caused a gross overestimation of the mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD). When a previously described technique was used to eliminate erroneous particle size measurements from the size distribution calculation, the MMAD and GSD from the APS 3320 agreed well with those from the ACI and APS 3321. The GSD from the APS 3321 and the APS 3320 after a mask was applied were slightly larger than from the ACI. It is believed that both APS instruments slightly underestimate the GSD while the ACI slightly overestimates the GSD. Further experiments were conducted using the APS 3321 to examine the influence of drug concentration and cosolvent level on the size distribution of solution formulation MDIs. The MMAD was shown experimentally and theoretically to be proportional to drug concentration to the one-third power. Cosolvent concentration had minimal influence on MMAD over the range examined. The measurements reported in this paper demonstrate that it is possible to obtain accurate mass-weighted size distribution measurements with the APS 3320 and APS 3321. These instruments allow for accurate size distribution measurements to be made in minutes as opposed to the hours required to conduct and analyze size distribution measurements from cascade impactors.

Aerosols↗

PubMed2003

Balancing ethanol cosolvent concentration with product performance in 134a-based pressurized metered dose inhalers.

The effects of formulation parameters on the product performance characteristics of solution metered dose inhalers (MDIs) were determined using ethanol as the cosolvent and HFA 134a as the propellant. Solubility of beclomethasone dipropionate (BDP) was determined in various blends of 134a and ethanol and was shown to increase with ethanol concentration. Product performance was assessed using the APS Model 3306 Impactor Inlet in conjunction with APS Model 3320 Aerodynamic Particle Sizer (APS). Nine solution formulations containing various BDP and ethanol concentrations were studied. Chemical analysis of the Impactor Inlet was performed in order to determine the "respirable" deposition of the MDI system. With increased ethanol concentration, the throat deposition and plate deposition increased and the respirable deposition decreased. The mass median aerodynamic diameter (MMAD) increased with the increasing drug concentration, but did not show a significant increase with an increase in ethanol concentration. This indicates that the efficiency of solution MDIs decreases with increased ethanol concentration. A Maximum Respirable Mass (MRM) was calculated based on the drug solubility at a particular ethanol concentration and the respirable deposition for a 50mcl valve and QVAR actuator for that ethanol concentration. The MRM represents the maximum amount of a given drug that can be delivered to the lungs theoretically and is very sensitive to the solubility profile of the drug. The MRM increased with the increasing ethanol concentration in the formulation until a plateau was reached at an ethanol concentration of 10-15% w/w. The MRM initially increases with increase in ethanol concentration due to the increase in drug solubility. However, at higher ethanol concentrations the increase in drug solubility was negated by a decrease in the respirable deposition. This study illustrates the importance of considering both formulation properties and product performance characteristics when optimizing a metered dose inhaler drug delivery system.

Administration, Inhalation↗