Biomedical subjects

Paul M Young

Publications and source records attributed to Paul M Young.

At least 19 recordsLinked to original sources

PubMed2007

The use of organic vapor sorption to determine low levels of amorphous content in processed pharmaceutical powders.

Organic dynamic vapor sorption (organic-DVS) was used to characterize amorphous content in known amorphous-crystalline mixtures of lactose and salbutamol sulfate. N-octane was chosen as an apolar probe and measurements were carried out by exposing mixtures of each sample to partial pressures 0-90% p/p(0). A linear relationship between amorphous content and n-octane partial pressure was observed for both lactose and salbutamol sulfate with R(2) values of 0.992 and 0.999, respectively. In addition, the influence of sequential mechanical processing in a ball mill on the amorphous content in crystalline lactose was investigated. Cumulative milling times resulted in an exponential increase in amorphous content (using the linear relationship obtained for lactose), with a maximum amorphous content of 14% being induced after 60 min milling. In comparison, analysis of the 60 min mill time samples after exposure to 85% relative humidity suggested 0.00% amorphous content.

Albuterol↗

PubMed2006

In vitro investigation of drug particulates interactions and aerosol performance of pressurised metered dose inhalers.

PURPOSE: To determine a relationship between adhesive and cohesive inter-particulate forces of interactions and in vitro performance in pressurised metered dose inhalers (pMDIs) suspension formulations. METHODS: Interparticulate forces of salbutamol sulphate (SS), budesonide (BUD) and formoterol fumarate dihydrate (FFD) were investigated by in situ atomic force microscopy (AFM) in a model propellant 2H, 3H perfluoropentane (HPFP). Experimental data were analysed using the recently developed cohesive/adhesive analysis method (CAB) and compared with in vitro deposition performances in pMDIs systems using Andersen cascade impactor (ACI). RESULTS: The in vitro investigation suggested that the micronised drug materials had significantly different aerosolisation profiles when manufactured as single or combination formulations. In general, the greatest significant differences were observed between SS single drug and SS-BUD and SS-FFD combinations. Analysis of the in vitro performance for the SS only formulation suggested that the cohesive nature of SS (as predicted by the CAB and observed with AFM) led to tightly bound flocs that did not fully deaggregate upon aerosolisation. CONCLUSIONS: It is suggested that the relationship between interparticulate interactions and in vitro performance of pMDIs suspension systems, when compared to direct measurement of the adhesion/cohesion forces, indicated good correlation. This approach may be useful in expediting the development of pMDI formulation and predicting performance.

Adhesiveness↗

PubMed2006

The use of colloid probe microscopy to predict aerosolization performance in dry powder inhalers: AFM and in vitro correlation.

The atomic force microscope (AFM) colloid probe technique was utilized to measure cohesion forces (separation energy) between three drug systems as a function of relative humidity (RH). The subsequent data was correlated with in vitro aerosolization data collected over the same RH range. Three drug-only systems were chosen for study; salbutamol sulphate (SS), triamcinolone acetonide (TAA), and di-sodium cromoglycate (DSCG). Analysis of the AFM and in vitro data suggested good correlations, with the separation energy being related inversely to the aerosolization performance (measured as fine particle fraction, FPF(LD)). In addition, the relationship between, cohesion, RH, and aerosolization performance was drug specific. For example, an increase in RH between 15% and 75% resulted in increased cohesion and decreased FPF(LD) for SS and DSCG. In comparison, for TAA, a decrease in cohesion and increased FPF(LD) was observed when RH was increased (15-75%). Linear regression analysis comparing AFM with in vitro data indicated R(2) values > 0.80, for all data sets, suggesting the AFM could be used to indicate in vitro aerosolization performance.

Administration, Inhalation↗

PubMed2006

Novel temperature controlled surface dissolution of excipient particles for carrier based dry powder inhaler formulations.

The surface of lactose monohydrate was modified by solution phase variable temperature dissolution. Lactose monohydrate crystals were added to a known volume of a saturated solution of lactose monohydrate at 25 degrees C. The temperature of the mixture was then ramped to either 30, 35, 40, or 50 degrees C to produce lactose monohydrate batches with reduced levels of fines and lower surface roughness. A dramatic decrease in surface roughness with increasing dissolution temperature was visually observed using scanning electron microscopy. Particle size analysis suggested that the level of lactose fines was reduced after treatment at the lowest dissolution temperature, 30 degrees C. Evaluation of the samples' drug aerosolization using a twin stage impinger, after blending with salbutamol sulphate, suggested that even though there were dramatic changes in roughness and particle size distribution after surface dissolution at 30 degrees C, there was no significant difference in aerosolization as measured by fine particle fraction. However, after surface dissolution at 35 degrees C, there was an increase in fine particle fraction. Surface dissolution at even higher temperatures did not result in any further increase in fine particle fraction. These observations suggest that surface roughness and fines play an important role in the aerosolization of salbutamol sulphate, but the inter-relationships are not straightforward.

Adrenergic beta-Agonists↗

PubMed2005

Comparative study of erythritol and lactose monohydrate as carriers for inhalation: atomic force microscopy and in vitro correlation.

The adhesion of micronised salbutamol sulphate to two carrier excipients, lactose monohydrate and erythritol, was investigated using the atomic force microscope (AFM) colloid probe technique and correlated with their respective physico-mechanical properties and aerosolisation performance. The particle size, morphology and moisture sorption properties of the carriers were similar thereby allowing direct comparison of functionality. AFM force measurements (n = 1024 force curves) were obtained between salbutamol sulphate drug probes (n = 4) and the excipients, as 63-90 microm sieve fractions and atomically smooth crystals. In general, significant differences in drug adhesion to lactose monohydrate and erythritol were observed (ANOVA, p<0.05), with erythritol exhibiting relatively greater adhesiveness. A linear relationship between drug probe adhesion to lactose monohydrate and drug probe adhesion to erythritol was established with salbutamol sulphate-lactose monohydrate adhesion being 60-70% of that of the erythritol system. In vitro analysis suggested good correlation with the adhesion measurements. The aerosolisation of salbutamol sulphate from erythritol carrier particles was significantly less (ANOVA, p<0.05) than from lactose monohydrate, with a fine particle dose (<6.4 microm) of 41.9 +/- 7.4 microg and 24.9 +/- 3.1 microg for the lactose monohydrate and erythritol carriers, respectively (n = 3).

Administration, Inhalation↗

PubMed2005

The influence of dose on the performance of dry powder inhalation systems.

The relationship between drug/lactose ratio and aerosolisation performance of conventional carrier based formulations was investigated using the twin stage impinger. A dose range of approximately 10-450 microg of drug in a 50 mg lactose carrier formulation was studied. Statistical differences in both the fine particle dose and fine particle fraction were observed across the dosage range (ANOVA, p<0.05). In general, no statistically significant difference (Fishers Pairwise, p<0.05) in fine particle dose was observed between drug levels of approximately 10 microg and 135 microg, whereas a linear decrease in fine particle fraction was observed across the same drug level range (R2=0.977). Increasing the dose from approximately 135 microg to 450 microg resulted in a statistically significant increase in both fine particle dose and fraction (ANOVA p<0.05). Such observations may be attributed to the occupation of 'active' carrier sites by drug particles at low drug concentration, since the quantity of drug particles liberated from the carrier during aerosolisation remains constant at the lower dosing regimes.

Drug Delivery Systems↗

PubMed2005

On the physical transformations of processed pharmaceutical solids.

Atomic force microscopy Phase Imaging, an adaptation of Tapping Mode AFM was used to visualise physico-mechanical variations on the surface of crystalline materials after being subjected to mechanically induced lattice damage. Large crystals (100-500 microm) of lactose were nucleated on AFM sample stubs, imaged and subjected to a milling process. The milled samples were then imaged at specific humidity using Phase Imaging. Phase and Amplitude images of the re-crystallised lactose suggested an ordered crystalline state with multiple platelets present across the surface. In comparison, the morphology and surface properties after a 1-min mill time suggested milling had a dramatic effect on the surface characteristics of the re-crystallised lactose. Phase and Topographical imaging during exposure to elevated humidities (70% RH) indicated both morphological and physico-mechanical changes that may be linked to surface amorphous re-crystallisation.

Crystallization↗

PubMed2005

Dynamic vapor sorption properties of sodium starch glycolate disintegrants.

Dynamic vapor sorption (DVS) was used to determine the moisture sorption properties of sodium starch glycolates. The results were compared to similarly obtained data for potato starch, pregelatinized starch, microcrystalline cellulose (MCC), and crystalline lactose. As expected, sodium starch glycolates exhibit a large mass gain at 90% relative humidity (RH), compared to the other anhydroglucose-based excipients. However, the sorption capacities of potato starch and the modified starches between 10%-70% RH were similar. Analysis of the DVS data using the Brunauer-Emmett-Teller (BET) and Guggenheim, Anderson, and deBoer (GAB) theories to obtain the so-called monolayer (Xm), as expected, showed that there was an increasing Xm with apparent mass gain that is probably related to crystallinity, purity, and surface area and represents the number and accessibility of amorphous anhydroglucose units present. The value of x(m) was related to the degree of crystallinity or order as determined by X-ray diffraction, suggesting that x(m) can be used to further describe the amorphous nature of semi-crystalline polymers containing anhydroglucose units, in particular the chemically modified sodium starch glycolate. Additionally, it appears that the sorption capacity between 10%-70% RH is not dramatically affected by the presence or type of cross-linking and sodium carboxymethylation (in sodium starch glycolates) and gelatinization (in pregelatinized starch) and that the superdisintegrant properties of the sodium starch glycolates are a consequence of some water-structure interaction that is well beyond the available number of hydration sites, as represented by x(m). Further evaluation of the structure and sorption properties of excipients may aid the development of disintegrants for solid dosage forms.

Absorption↗

PubMed2004

The potential use of Raman mapping to investigate in vitro deposition of combination pressurized metered-dose inhalers.

Scanning near-infrared Raman microscopy has been used to map aerosol particulate deposits produced from pressurized metered-dose inhalers (pMDI). A commercially available combination asthma therapy pMDI (Ventide, Allen and Hanbury, UK), containing salbutamol and beclometasone dipropionate, was analyzed by conventional in vitro quantitative analysis and scanning Raman microscopy. Raman maps, taken from Andersen cascade impactor plate stages 3 and 5 (over 100 x 100 microm areas) suggested good correlation with chemical analysis of the respective stages. Scanning Raman microscopy allows visual differentiation between formulation components (not possible using conventional imaging techniques), while potentially allowing chemical quantification.

Aerosols↗

PubMed2004

Visualization of the crystallization of lactose from the amorphous state.

The physical stability and solid-state recrystallization of spray-dried 'amorphous' lactose particles were visualized using environmentally controlled atomic force microscopy (EC-AFM) and conventional optical microscopy. The morphology and crystalline state were investigated as a function of relative humidity (RH) and were correlated with bulk gravimetric vapor sorption measurements that were run in parallel. The metastable nature of amorphous spray-dried lactose particles was apparent at low RHs (<30% RH). Visualization of the recrystallization transformation of amorphous lactose during moisture uptake at 58 and 75% RH suggested only a proportion of the collapsed particles undergoes nucleation and crystal growth. The irregular surface morphology of the recrystallized particles suggested a secondary nucleation and growth process. Primary nucleation of alpha-lactose monohydrate within the non-recrystallized particles required exposure to elevated RH (94% RH). In relation to bulk measurements of moisture-induced amorphous recrystallization of spray-dried lactose, the results suggest that recrystallization of amorphous lactose, above a critical RH, may be induced by the presence of very low levels of a seed material, which may dramatically reduce the activation energy barrier for nucleation and crystal growth.

Crystallization↗

PubMed2004

The influence of relative humidity on the cohesion properties of micronized drugs used in inhalation therapy.

The influence of relative humidity (RH) on the cohesion properties of three drugs: salbutamol sulphate (SS), triamcinolone acetonide (TAA), and disodium cromoglycate (DSCG) was investigated using the atomic force microscope (AFM) colloidal probe technique. Micronized drug particles were mounted in heat-sensitive epoxy resin for immobilization. Multiple AFM force-distance curves were conducted between each drug probe and the immobilized drug particulates at 15, 45, and 75% RH using Force-Volume imaging. Clear variations in the cohesion profile with respect to RH were observed for all three micronized drugs. The calculated force and energy of cohesion to separate either micronized SS or DSCG increased as humidity was raised from 15 to 75% RH, suggesting capillary forces become a dominating factor at elevated RH. In comparison, the separation force and energy for micronized TAA particles decreased with increased RH. This behavior may be attributed to long-range attractive electrostatic interactions, which were observed in the approach cycle of the AFM force-distance curves. These observations correlated well with previous aerosolization studies of the three micronized drugs.

Bronchodilator Agents↗

PubMed2004

The influence of humidity on the aerosolisation of micronised and SEDS produced salbutamol sulphate.

The influence of storage humidity on the aerosolisation efficiency of micronised and supercritical fluid salbutamol sulphate formulations (containing a lactose carrier) were investigated using the twin stage impinger (TSI). Storage humidity had a significant effect on the aerosolisation efficiency of both micronised and solution enhanced dispersion by supercritical fluids (SEDS) salbutamol sulphate (ANOVA P <0.05), suggesting capillary interactions to be an important factor when considering formulation performance. Furthermore, significant differences between the aerosolisation performance of micronised and SEDS salbutamol sulphate were observed at elevated humidities (>63% RH) (Fishers pairwise P <0.05). It is suggested that such variations may be due to differences in physical stability of the micronised and SEDS produced material. Dynamic vapor sorption, and atomic force microscopy (AFM) phase imaging suggested the micronised material to contain amorphous content that was most likely present on the micronised particulate surfaces. Thus, at high humidity, surface amorphous regions may have the ability to re-crystallize and effectively 'fuse' to the lactose carrier surface. This would potentially reduce the ability for the micronised material to be aerosolized and thus result in a greater decrease in FPF when compared to SEDS produced material at equivalent RH.

Aerosols↗

PubMed2004

The development of a novel high-dose pressurized aerosol dry-powder device (PADD) for the delivery of pumactant for inhalation therapy.

The performance of a novel dry powder inhaler designed to deliver exceptionally high doses was investigated using pumactant as a model powder. Pumactant (a synthetic lung surfactant consisting of a phospholipid mixture), with a 90th percentile particle size of 2.92 microm is highly cohesive, has a high moisture affinity (6.2% w/w at 45% RH), and is predominantly amorphous. The device (pressurized aerosol dry-powder delivery [PADD]) utilizes pressurized gas to aerosolize a powder bed from a reservoir and delivers it through a conventional mouthpiece. The influence of loaded dose on dry powder delivery and can pressure on aerosolization efficiency was investigated. Analysis of the delivered dose studies suggested a linear relationship between loaded dose and delivered dose (R(2) = 0.96, for loaded doses of 0-250 mg), with a delivery efficiency of 70%. Analysis of the aerosolization efficiency using a Marple Miller type impactor suggested fine particle fractions (particles with an aerodynamic diameter of <5 microm) of approximately 30% using canister pressures of 8-14 bars. These results indicate that the PADD device may be a useful tool in delivering high-dose medicaments, as a carrier-free formulation, to the deep lung.

Administration, Inhalation↗

PubMed2003

Under pressure: predicting pressurized metered dose inhaler interactions using the atomic force microscope.

Drug particulate interactions in pressurized metered dose inhalers (pMDI) may lead to a decrease in aerosolization efficiency and subsequent efficacy in patient treatment. The interactions between salbutamol sulfate (commonly used in Ventolin pMDIs) and a series of pMDI canister materials were investigated using the atomic force microscope (AFM) colloid probe technique. Approximately 4000 individual force-distance curves were determined for a drug probe and three surfaces (10 x 10 mum areas) in situ, in a model propellant. The area under each force-distance curve was integrated to obtain separation energy values. Median separation energy values followed the rank order borosilicate glass > aluminum > PTFE, suggesting PTFE to be the most suitable canister coating.

Administration, Inhalation↗

PubMed2003

Investigation into the effect of humidity on drug-drug interactions using the atomic force microscope.

The atomic force microscope (AFM) has been used to characterize the cohesive nature of a micronized pharmaceutical powder used for inhalation therapy. Salbutamol sulfate (also referred to as albuterol sulfate), a therapeutic drug commonly delivered from dry powder inhalers (DPI), was chosen as a model system because the cohesion and subsequent de-agglomeration during inhalation are critical aspects to the efficacy of such a delivery system. Salbutamol sulfate drug particulates were mounted on V-shaped AFM cantilevers using a novel micromanipulation technique. Force-distance curves obtained from the measurements between cantilever drug probes and model compacts of salbutamol sulfate were integrated to determine separation energies. The effect of humidity (15-75% RH) on the energy required to separate a drug particle from model drug surface was determined using a custom-built perfusion apparatus attached to the AFM. Separation energy measurements over 10 x 10-microm areas of the compact surface (n = 4096) exhibited log normal distributions (apparent linear regression, R(2) >or= 0.97). Significant increases in the median separation energies (p < 0.05) between the salbutamol sulfate drug probes and salbutamol sulfate model surfaces were observed as humidity was increased. This result is most likely attributed to capillary interactions becoming more dominant at higher humidities. This investigation has shown the AFM to be a powerful technique for quantification of the separation energies between micronized drug particulates, highlighting the potential of the AFM as a rapid preformulation tool.

Albuterol↗

PubMed2003

The effect of mechanical processing on surface stability of pharmaceutical powders: visualization by atomic force microscopy.

Atomic force microscopy was used to investigate the influence of mechanical processing (milling) on the surface stability of salbutamol sulfate. Phase imaging, a development of tapping mode atomic force microscopy, was used to elucidate variations in the physico-mechanical properties on the surface of salbutamol sulfate crystals by measuring the phase lag of an oscillating tip in contact with the surface. Simultaneous measurements of topographical and phase images indicated an increase in disorder on the surface as milling time was increased. Specific regions on the milled samples, independent of topography, showed large variations in phase shift (> 30 degrees). These regions (not observed on the crystalline salbutamol sulfate) suggested large differences in the physical properties on the surface. It is therefore reasonable to conclude that these regions were likely attributed to mechanically induced amorphous domains.

Drug Stability↗

PubMed2003

Effect of humidity on aerosolization of micronized drugs.

The variation of aerosolization with humidity for three micronized drugs used in the treatment of asthma was evaluated by using in vitro methods. Micronized samples of disodium cromoglycate (DSCG), salbutamol sulphate, and triamcinolone acetonide (TAA) were stored for 12hr at 15, 30, 45, 60, and 75% relative humidity (RH). A suitable "reservoir" dry powder inhaler was loaded and tested by using a twin-stage impinger at each specific humidity. The aerosolization efficiency of all three micronized drugs was affected by variations in humidity. The percentage of the delivered dose and the fine particle fraction of the loaded dose (FPFLD) for both DSCG and salbutamol sulphate decreased with increasing humidity; with the largest decrease in FPFLD occurring between 45% and 60% RH for DSCG and 60% to 75% RH for salbutamol sulphate. These observations suggest that the adhesion properties for both DSCG and salbutamol sulphate, which govern the aerosolization efficiency, are predominately influenced by capillary interactions. In contrast, the FPFLD for TAA significantly increased as the humidity increased over the range 15% to 75% RH, suggesting that triboelectric forces predominate particle-particle interactions. These variations in drug particulate behavior highlight the importance of an individual formulation approach when developing dry powder inhalation systems.

Administration, Inhalation↗

PubMedDate not supplied

Continued investigation into the influence of loaded dose on the performance of dry powder inhalers: surface smoothing effects.

The aerosolization of salbutamol sulfate, measured as fine particle dose (FPD LD) and fine particle fraction (FPF LD) (<6.4 microm mass median aerodynamic diameter), from two sieved (63-90 microm) lactose monohydrate carriers, one as supplied, one smoothed by controlled surface dissolution, was studied. In general, no significant variation in FPD LD was observed at drug loadings between 10 and 63.5 microg and 10 and 135 microg for the surface dissolved and as supplied lactose monohydrates, respectively. Increasing the drug load above these levels resulted in linear increases in FPD LD with increasing drug load with the surface dissolved lactose monohydrate exhibiting higher FPD LD and FPF LD. This suggests that, at lower drug loadings, areas of the carrier exhibiting higher adhesion, so-called active sites, were being preferentially occupied and filled. Since there was no evidence of drug agglomeration using scanning electron microscopy, the observations suggest that the number and range of such higher energy "active sites" can be reduced by modifying the surface roughness, that is, energies, of the carrier.

Administration, Inhalation↗