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Isothermal calorimetry: A predictive tool to model drug-propellant interactions in pressurized metered dose systems
... Isothermal calorimetry was used to characterize the physicochemical changes (Ooi, Gaisford, Boyd, Young, & Traini, 2014) and to assess stability pharmaceuticals (Chan et al., 2004;S.;Gaisford, 2005;Skaria, Gaisford, O'Neill, Buckton, & Beezer, 2005). ...
Oxidative stability is critical in guaranteeing the declared shelf life of new formulations and contributes significantly to time-to-market efficiencies. In this study an innovative method based on isothermal calorimetry is proposed for monitoring the stability of vitamin A acetate formulations with one or more antioxidants, such as butylated hydroxytoluene, ethoxyquin, tocopherol and rosemary extract. The results were correlated with conventional stability tests utilizing liquid chromatography (LC). The efficiency of three drying technologies (spray drying, spray granulation, and beadlet) were compared. The initial heat flow values obtained from isothermal calorimetry experiments were used to identify the most efficient drying technology, antioxidant system, that is beadlet. The resulting rate constants of vitamin degradation calculated from the LC data were positively correlated with the initial heat flow values. This study demonstrated that the performance of isothermal calorimetry was far superior when compared with traditional methods. In addition, this methodology allowed the detection of micronutrient stability in complex powder mixtures in only a few hours without the need for sample preparation. This approach could therefore potentially be applied to industry and academic environments for the prediction of micronutrients stability.
... Similar findings were reported in work by Lewis, Haghi, and colleagues (Haghi et al., 2014;Lewis et al., 2014). Further studies with BDP solution pMDIs and with model propellant systems (Bouhroum et al., 2010;Ooi et al., 2014) indicate that BDP may form solvates or clathrates with ethanol or propellants during drug particle formation. ...
The effects of propellant type, cosolvent content, and air humidity on the morphology and solid phase of the particles produced from solution pressurized metered dose inhalers containing the corticosteroid beclomethasone dipropionate were investigated. The active ingredient was dissolved in the HFA propellants 134a and 227ea with varying levels of the cosolvent ethanol and filled into pressurized metered dose inhalers. Inhalers were actuated into an evaporation chamber under controlled temperature and humidity conditions and sampled using a single nozzle, single stage inertial impactor. Particle morphology was assessed qualitatively using field emission scanning electron microscopy and focused ion beam-helium ion microscopy. Drug solid phase was assessed using Raman microscopy. The relative humidity of the air during inhaler actuation was found to have a strong effect on the particle morphology, with solid spheroidal particles produced in dry air and highly porous particles produced at higher humidity levels. Air humidification was found to have no effect on the solid phase of the drug particles, which was predominantly amorphous for all tested formulations. A critical level of air relative humidity was required to generate porous particles for each tested formulation. This critical relative humidity was found to depend on the amount of ethanol used in the inhaler, but not on the type of propellant utilized. The results indicate that under the right circumstances water vapor saturation followed by nucleated water condensation or ice deposition occurs during particle formation from evaporating propellant-cosolvent-BDP droplets. This finding reveals the importance of condensed water or ice as a templating agent for porosity when particle formation occurs at saturated conditions, with possible implications on the pharmacokinetics of solution pMDIs and potential applications in particle engineering for drug delivery.
... Isothermal titration calorimetry (ITC) is a quantitative physical technique used to determine reaction thermodynamics and kinetics. It can be used to study solutions, solids and heterogeneous mixtures because it is invariant to sample physical form [8]. This label-free technique is based on heat measurement absorbed or generated during binding event in a sequential (titrating) manner. ...
Nanoparticles (NPs) offer a number of advantages over small organic molecules for controlling protein behaviour inside the cell. Protein binding to the surface of NPs depends on their surface characteristics, composition and method of preparation (Mandal et al. in J Hazard Mater 248–249:238–245, 2013). It is important to understand the binding affinities, stoichiometries and thermodynamical parameters of NP–protein interactions in order to see which interaction will have toxic and hazardous consequences and thus to prevent it. On the other side, because proteins are on the brink of stability, they may experience interactions with some types of NPs that are strong enough to cause denaturation or significantly change their conformations with concomitant loss of their biological function. Structural changes in the protein may cause exposure of new antigenic sites, “cryptic” peptide epitopes, potentially triggering an immune response which can promote autoimmune disease (Treuel et al. in ACS Nano 8(1):503–513, 2014). Mechanistic details of protein structural changes at NP surface have still remained elusive. Understanding the formation and persistence of the protein corona is critical issue; however, there are no many analytical methods which could provide detailed information about the NP–protein interaction characteristics and about protein structural changes caused by interactions with nanoparticles. The article reviews recent studies in NP–protein interactions research and application of isothermal titration calorimetry (ITC) in this research. The study of protein structural changes upon adsorption on nanoparticle surface and application of ITC in these studies is emphasized. The data illustrate that ITC is a versatile tool for evaluation of interactions between NPs and proteins. When coupled with other analytical methods, it is important analytical tool for monitoring conformational changes in proteins.
The level of drug confining to plasma proteins, directed by assessing the free powerful bit, altogether influences the pharmacokinetics and pharmacodynamics of a medicine. It is subsequently exceptionally essential to gauge drug-restricting limit initially periods of prescription revelation and clinical practice. Generally, balance dialysis is used to study these interactions as an old method and is introduced as the reference technique, however it experiences numerous disadvantages. While trying to dodge these, a huge range of various techniques has been created to investigate the interactions between ligands and macromolecules. This review paper centers around the main methodologies used to portray drug-protein binding. The usable strategy for the examination of medication restricting with protein is assessed and the benefits and disbenefits of the different strategies have been discussed here. Medication restricting with the protein might be examined by the technique including balance dialysis, ultrafiltration, circular Dichroism, Isothermal calorimetry, Differential Scanning calorimetry, spectroscopic technique.
Background
Dry powder inhaler (DPI) formulations are highly efficient in pulmonary drug delivery because devices for their delivery are portable and aerosolization does not require a propellant. The performance of DPIs depends on various physical properties of particles for their manufacture, including aerodynamic diameter, density, particle shape, surface composition, morphology, roughness, and energy. Among these, particle surface properties are the most important factors in determining the interparticulate interactions, which affect the aerosolization efficiency, physicochemical stability, and subsequent in vivo lung deposition efficiency.Area coveredFor a better understanding of the correlation between surface properties and the performance of DPI, there is the need to perform surface characterization of the DPI. This review focuses on analysis of the technology used in the design of DPIs. Thus, the surface crystallinity and polymorphism, surface energy, surface roughness, and changes in solid-state properties of the particles used in DPI formulation will be determined.Expert opinionThe commonly used solid-state techniques may not be appropriate for the characterization of DPIs because their detection is mainly limited to the fine changes in physicochemical surface properties such as partial amorphous contents generated on the drug particle surface. Thus, sophisticated technologies with higher detection limits and superior spatial resolutions are required for in-depth characterization. Data obtained from surface analytical techniques can lead to an in-depth understanding of inhalable dry powder at the particle surface. This can provide unique predictive insights into rationally designing inhalable particles with optimal surface properties to provide optimal aerosolization performance for a given DPI formulation.
Metered dose inhalers (MDIs) are the mainstay of asthma and COPD therapy worldwide. MDIs are pocket-size hand-held drug delivery devices utilizing the energy of compressed propellant(s) for the aerosol generation. They have the drug in solution or suspension in the propellant(s), or a mixture of propellant(s) and co-solvent(s). MDIs deliver small metered drug doses either directly, or via add-on devices to the patients, like spacers or Valved Holding Chambers (VHCs) that can be used with a fast mask for children. Add-on devices hold the aerosol to eliminate the problem with correct synchronisation of dose release and inhalation. They also provide the possibility to inhale a single dose in multiple breaths. Alternatively, breath-actuated MDIs have been developed. MDIs have the disadvantage that the currently used hydrofluoroalkane (HFA) propellants contribute to the greenhouse effect and re-formulation of the drug formulations on short notice with more environment-friendly propellants may be necessary.
Protein purification is of vital importance in food industry, drug discovery and other related fields. Among many separation methods, polyelectrolyte (PE)-based phase separation is developed and recognized as a low-cost purification technique. In this work, spherical polyelectrolyte brushes (SPBs) with high specific surface area was utilized to study the protein accessibility and selective protein binding on highly charged nanoparticles (NPs) as well as the selective phase separation of proteins. The correlation between charge anisotropy, protein binding, and phase separation was investigated on various protein systems including those proteins with similar isoelectric points (pI) such as bovine serum albumin (BSA) and β-lactoglobulin (BLG), proteins with similar molecular weights such as BSA and hemoglobin (HB), and even protein variants (BLG-A and -B) with tiny difference of amino acids. The non-specific electrostatic interaction studied by turbidimetric titrations and isothermal calorimetry titration (ITC) indicates a specific binding between proteins and SPBs arising from the charge anisotropy of proteins. An optimized output based on selective protein binding on SPBs could be correlated for efficient protein separation through tuning external conditions including pH and ionic strength. These findings therefore proved that phase separation based on selective protein adsorption by SPBs was an efficient alternative for proteins separation compared with traditional practice.
In this study, beclomethasone dipropionate nanocrystals were formulated using an antisolvent sonoprecipitation technique. The aim of this study was to assess the ability of these nanocrystals to actively accumulate in skin layers for the treatment of atopic dermatitis with minimal systemic levels. A three-factor, three-level central composite design was employed to optimize the formulation parameters. The following formulation variables were adopted: stabilizer concentration, antisolvent volume, and stabilizer type. The nanocrystals were assessed for particle size, zeta potential and polydispersity index. Saturation solubility and ex vivo studies were carried out on the optimized formula (PN1). The saturation solubility of PN1 was approximately 745.5 times that of raw BDP in water. Ex vivo studies showed that the calculated Local Accumulation Efficiency (LAC) in the case of PN1 was 6.20, which was significantly higher (p < 0.05) than that of the brand formula, with a LAC ratio of 0.25. Our results confirmed the enhancement of drug deposition, ascertaining the successful use of nanocrystals for the topical delivery of poorly soluble drugs.
Isothermal microcalorimeters (IMC) measure the heat change in a sample as it is held at a constant temperature—since nearly all processes, chemical and physical, occur with a change in heat, IMC analysis can be applied to the investigation of almost any material. The inherent sensitivity of the measurement means that small samples, or slow processes, may be investigated. This makes IMC a very powerful tool, especially in pharmaceutical analyses, since complex, heterogeneous samples can be studied directly. In this chapter, the basic principles of IMC are introduced, the most common experimental arrangements are defined and applications to pharmaceutical analyses are discussed. Applications discussed progress from preformulation characterization, through stability testing and amorphous content quantification to analyses of formulated products.
Advances in particle engineering techniques, such as spray drying, freeze drying and supercritical fluid precipitation, have greatly enhanced the ability to control the structure, morphology, and solid state phase of inhalable sized particles (1 - 5 µm) for formulation in pressurized metered dose inhalers (pMDI). To optimize the properties of these engineered particles for formulation in hydrofluoroalkane propellants (HFA 134a / 227) it is necessary to measure both bulk and individual particle properties before, after, and during formulation. This review examines established and recently developed methods for evaluating a variety of particle properties including but not limited to size, surface and internal morphology, chemical composition, and solid state phase. Novel methods for evaluating particle physical and chemical stability directly in propellant or similar environments are also discussed.
Introduction:
Pressurised metered dose inhalers (pMDIs) are subject to rigorous physical and chemical stability tests during formulation. Due to the time and cost associated with product development studies, there is a need for online techniques to fast screen new formulations in terms of physical and chemical (physico-chemical) stability. The problem with achieving this is that pMDIs are by their definition, pressurised, making the direct observation of physico-chemical properties in situ difficult. Areas covered: This review highlights the characterisation tools that can enhance the product development process for pMDIs. Techniques investigated include: laser diffraction, Raman spectroscopy, isothermal ampoule calorimetry, titration calorimetry and gas perfusion calorimetry. The operational principles behind each technique are discussed and complemented with examples from the literature. Expert opinion: Laser diffraction is well placed to analyse real-time physical stability as a function of particle size; however, its use is restricted to suspension pMDIs. Raman spectroscopy can be potentially used to attain both suspension and solution pMDI spectra in real time; however, the majority of experiments are ex-valve chemical composition mapping. Calorimetry is an effective technique in capturing both chemical and physical degradations of APIs in real time but requires redevelopment to withstand pressure for the purposes of pMDI screening.
This review aims at pinpointing the issues commonly associated with the production of pharmaceutical formulations and biomedical devices regarding adhesion and cohesion interactions through utilisation of atomic force microscopy (AFM) techniques. Adhesion and cohesion phenomena
have been of interest for many years as they are encountered on a daily basis from activities such as walking to geckos climbing a tree. Many models for adhesion interactions have been developed since the early 1970s: Derjaguin, Landau, Verwey, and Overbeek (DLVO) assumed a physical approach
to understanding adhesion; whilst, Johnson, Kendall, and Roberts (JKR) as well as Derjaguin, Muller and Toporov (DMT) both assumed a mechanical approach for understanding the adhesion phenomena. However, these theories were not without limitations, therefore models have been developed including
the extended DLVO (xDLVO), as well as mathematical models based on data collected using AFM.This review highlights the issues in the development of pharmaceutical formulations and where adhesion impacts the development of medical preparations. As many pharmaceutical products
possess aspects of colloidal systems, so they are often affected by adhesion and cohesion interactions causing problems such as aggregation, sedimentation and flocculation. These phenomena can influence the overall adhesion and alter the outcome of formulations causing undesirable effects
to medications; these issues are governed by the physicochemical properties of materials. Such characteristics include surface topography and morphology and are influenced by humidity, and all these parameters can be analysed using the AFM. Therefore, such methodology has shown advantages
over traditional techniques employed in the pharmaceutical industry including centrifugation, near-infrared spectroscopy and inverse gas chromatography in the understanding of adhesion at the nanoscale.
The poly (aryl ether ketones) are used as matrices in advanced composites with high performance due to its high thermal stability, excellent environmental performance and superior mechanical properties. Most of the physical, mechanical and thermodynamic properties of semi-crystalline polymers depend on the degree of crystallinity and morphology of the crystalline regions. Thus, a study on the crystallization process promotes a good prediction of how the manufacturing parameters affect the developed structure, and the properties of the final product. The objective of this work was to evaluate the thermoplastics polymers PEKK e PEEK by DSC, aiming to obtain the relationship between kinetics, content, nucleation and geometry of the crystalline phases, according to the parameters of the Avrami and Kissinger models. The analysis of the Avrami exponents obtained for the studied polymers indicates that both showed the formation of crystalline phases with heterogeneous nucleation and growth geometry of the type sticks or discs, depending on the cooling conditions. It was also found that the PEEK has a higher crystallinity than PEKK.
To develop a new technique, spray freeze drying, for preparing protein aerosol powders. Also, to compare the spray freeze-dried powders with spray-dried powders in terms of physical properties and aerosol performance.
Protein powders were characterized using particle size analysis, thermogravimetric analysis, scanning electron microscopy, X-ray powder diffractometry, and specific surface area measurement. Aerosol performance of the powders was evaluated after blending with lactose carriers using a multi-stage liquid impinger or an Anderson cascade impactor. Two recombinant therapeutic proteins currently used for treating respiratory tract-related diseases, deoxyribonuclase (rhDNase) and anti-IgE monoclonal antibody (anti-IgE MAb), were employed and formulated with different carbohydrate excipients.
Through the same atomization but the different drying process, spray drying (SD) produced small (approximately 3 microns), dense particles, but SFD resulted in large (approximately 8-10 microns), porous particles. The fine particle fraction (FPF) of the spray freeze-dried powder was significantly better than that of the spray-dried powder, attributed to better aerodynamic properties. Powders collected from different stages of the cascade impactor were characterized, which confirmed the concept of aerodynamic particle size. Protein formulation played a major role in affecting the powder's aerosol performance, especially for the carbohydrate excipient of a high crystallization tendency.
Spray freeze drying, as opposed to spray drying, produced protein particles with light and porous characteristics, which offered powders with superior aerosol performance due to favorable aerodynamic properties.
In this work, isothermal microcalorimetry (IMC) was utilized to measure the exothermic heat flow from specimens of ultra-high-molecular-weight polyethylene (UHMWPE), that had been sterilized by various standard methods, under simulated shelf storage (air at 25 degrees C, 30% r.h.) and simulated implantation (phosphate buffered saline, PBS, at 37 degrees C) conditions. Gamma-radiation sterilized UHMWPE yielded initial heat flow rates approximately 7-10 times higher in simulated shelf storage and 2-3 times higher in simulated implantation (even after 1 month in PBS) than specimens which were unsterilized or sterilized using either ethylene oxide gas (ETO) or gas plasma (GP). These results show that gamma sterilization of UHMWPE produces many more unstable bonds in the polymer than is the case when ETO or GP is used, and that the net exothermic physico-chemical change proceeds steadily in a diffusion-limited manner in air or saline. In addition, gamma sterilization in nitrogen rather than in air did not prevent the creation of unstable bonds, but did defer physico-chemical change until the UHMWPE was exposed to oxygen. These results demonstrate the usefulness of IMC as a viable method for studying the stability of polymeric implant materials.
Beclomethasone dipropionate (BDP) is a long-acting inhaled corticosteroid, used for the treatment of asthma, and as an inhalation therapy with HFA-134a. The sample studied by X-ray crystallography was grown in a mixture of the aerosol propellant HFA-134a, C2H2F4, and 200-proof ethanol. The formula of the crystalline material is C28H37ClO7·2C2H6O·C2H2F4. In the crystal structure, disordered solvent occupies a channel which is perpendicular to the BDP molecules. The latter are are stacked together by hydrogen bonding.
Historically, infrared spectroscopy made its debut as an analytical tool during World War II. At that time it was used for quality control by several major chemical manufacturing companies. The instrumentation, which was essentially home-made, was adapted for the quantitative measurements of components in polymeric and petroleum products. In the 1950s, with the introduction of gas chromatographic instrumentation, infrared spectroscopy gradually fell out of favor as a quantitative tool. As a result, the emphasis switched to qualitative analysis. This was a natural role for infrared spectroscopy because of the significant amount of unique structural and chemical/physical information that is intrinsically available from the spectrum. The resultant increase in the use of infrared spectroscopy, as a qualitative tool, was aided by the influx of new, commercial instrumentation introduced during the 1950s - including lower priced, easy to use instruments for routine analysis. Much of the published work for the next two decades focused on the identification and characterization of materials and the development of correlations between the measured spectrum and molecular structure and chemical functionality.
Summary The aim of this study was to formulate and characterize pDNA adsorbed chitosan-TPP-PEG nanoparticles for dispersion in aerosol propellants. Chitosan-TPP-PEG nanoparticles were formed using an ionic gelation process. The particles were spherically shaped with a mean diameter of 150-210 ηm and a surface charge of +22 to +36 mV. These nanoparticles were freeze-dried and dispersed in a model propellant (DFP). The particle diameter was analyzed to be
The thermodynamics of dissolution in water of a set of substances has been studied calorimetrically. The examined substances were: potassium chloride, (glycyl-glycyl)diketopiperazine, (alanyl-alanyl)diketopiperazine, (leucyl-glycyl)diketopiperazine. They were chosen on the basis of their solubilities, going from a highly soluble electrolyte to the sparingly soluble diketopiperazines. It is shown that, using a commercially available calorimeter, it is possible to perform in a single calorimetric experiment the simultaneous determination of all thermodynamic parameters characterizing dissolution of a substance in a given solvent, i.e. solubility, dissolution enthalpy and dilution enthalpy. The solubility values in water obtained through the proposed method are in good agreement with those reported in the literature and obtained by other techniques.
The purpose of this study was to prepare ultrafine beclomethasone dipropionate (BDP) powder via antisolvent precipitation without any surfactants. Various solvents were screened to determine the suitable system for optimum processing while deionized water was kept as the antisolvent. Methanol was selected as the solvent, because a higher degree of supersaturation could be achieved. Several experimental parameters, such as the volume ratio of solution to antisolvent, the concentration of BDP−methanol solution, the temperature, and the stirring speed and time, were investigated in the methanol−deionized water system. The results showed that the yielded powder had a mean particle length of 850 nm and 85% of the particles were distributed in the range of 0.2−1.2 μm, whereas the raw particle size was 2.13 μm, ranging in size from 0.2 μm to 12 μm. Fourier transform infrared spectroscopy (FT-IR) and X-ray diffraction (XRD) analysis indicated no change in chemical group structure and crystal structure during the process. In addition, a process recovery rate of >99.99% was obtained.
In situ elucidation of kinetics of solution-mediated phase transformations using direct structural determination has been achieved using synchrotron SAXS/WAXS radiation. Using theophylline as a model drug with known phase transformation from anhydrate to monohydrate form in aqueous conditions within a few minutes, the kinetics of the structural transition were resolved at the second scale, and the results achieved agreed well with those determined using indirect approaches such as Raman spectroscopy. The recrystallization of the monohydrate in situ (due to its lower solubility) from dissolved anhydrate solution (higher solubility) is demonstrated directly, highlighting a major issue for such compounds in application. The technique has the additional benefit of having the potential to identify intermediate structures which are not readily achievable with in situ spectroscopic techniques, as well as being amenable to high throughput approaches.
Beclomethasone dipropionate (BDP), which is a member in the inhaled glucocorticosteroid class, is commonly used in the treatment of asthma by pulmonary delivery. The purpose of this study is to prepare ultrafine BDP particles for dry powder inhalation (DPI) administration by combining microfluidic antisolvent precipitation without surfactant, high-pressure homogenization (HPH) and spray drying. T-junction microchannel was adopted for the preparation of needle-like BDP particles. The needle-like particles could be easily broken down into smaller particles during HPH, which were assembled into uniform low-density spherical BDP aggregates by spray drying. The effects of the operation parameters, such as the flow rates of BDP methanol solution and antisolvent, the overall flow rate, the BDP concentration, and the change of the injection phase on BDP particle size were explored. The results indicated that the BDP particle size greatly decreased with the reduction of BDP solution flow rate and the increase of antisolvent flow rate. However, the BDP particle size firstly decreased and then increased with the increase of the overall flow rate and the increase of BDP concentration. Also, BDP solution as the injection phase could form the smaller BDP particles. 10 HPH cycles are enough to forming short rod-like particles. After spray drying, the BDP spherical aggregates with a 2-3 μm size could be achieved. They have an excellent aerosol performance, 2.8 and 1.4 times as many as raw BDP and vacuum-dried BDP particles, respectively.
Freeze drying is a process whereby solutions are frozen in a cold bath and then the frozen solvents are removed via sublimation under vacuum, leading to formation of porous structures. Pore size, pore volume and pore morphology are dependent on variables such as freeze temperature, solution concentration, nature of solvent and solute, and the control of the freeze direction. Aqueous solutions, organic solutions, colloidal suspensions, and supercritical CO2 solutions have been investigated to produce a wide range of porous and particulate structures. Emulsions have recently been employed in the freeze drying process, which can exert a systematic control on pore morphology and pore volume and can also lead to the preparation of organic micro- and nano-particles. Spray freezing and directional freezing have been developed to form porous particles and aligned porous materials. This review describes the principles, latest progress and applications of materials prepared by controlled freezing and freeze drying. First of all the basics of freeze drying and the theory of freezing are discussed. Then the materials fabricated by controlled freezing and freeze drying are reviewed based on their morphologies: porous structures, microwires and nanowires, and microparticles and nanoparticles. The review concludes with new developments in this area and a brief look into the future. Copyright © 2010 Society of Chemical Industry
A solution calorimetry method was developed to quantitatively examine mixtures of amorphous and crystalline sucrose or warfarin sodium based on the energy differences between their solid forms. The heats of solution of crystalline sucrose, amorphous sucrose, clathrate warfarin sodium and amorphous warfarin sodium were 1474.08±37.78 cal/mol, −3550.47±51.04 cal/mol, −1.701±0.041 cal/g and −7.386±0.226 cal/g, respectively. The observed linear relationship between the heat of solution and the percent of the crystalline form present in the sample provided a rapid and convenient way to quantitatively determine the crystallinity of a common drug excipient (sucrose) and/or a complex system, such as the clathrate warfarin sodium (a complex of warfarin sodium, isopropyl alcohol and water). The solid state conversion process could also be monitored by measuring the energy changes associated with changes in crystallinity.
Salbutamol sulphate particles, for use in dry powder aerosol formulation, were prepared by spray drying, using a Büchi 190 mini spray dryer. The spray drying parameters were investigated in relation to particle size and yield of the resultant powder. Important factors were determined using a 24 factorial statistical design. The four factors investigated were pump speed, aspirator level (the rate at which the drying air is pulled through the dryer), inlet temperature and the concentration of the aqueous salbutamol sulphate solution dried. Spray drying conditions were chosen based on results from the experimental design and working knowledge of the spray dryer, to produce a batch of salbutamol sulphate powder on which further studies were performed. The physicochemical properties of spray dried salbutamol sulphate were compared to those of the micronised drug. Infrared spectroscopy, X-ray diffraction, appearance, particle size analysis (including aerodynamic diameter) and powder flow were investigated. It was found that spray drying produced spherically shaped particles of salbutamol sulphate having a mass median diameter of 4.5 μm (laser diffraction), mean Feret's diameter (image analysis) of 1.58 μm and a mass median aerodynamic diameter of 9.7 μm (cascade impaction), i.e., particles sufficiently small in diameter for use in inhalation formulation. The spray dried material was seen to perform as well as the micronised material in most cases with the exception of powder flow properties, where performance was slightly poorer.
The crystallinity of a hydrophobic drug (L-365,260) has been investigated by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and isothermal microcalorimetry. The crystallinity was assessed in the isothermal microcalorimeter by taking a ratio of the responses seen when an unknown sample and an amorphous standard were exposed to ethanol vapour. It was found that large amounts of the material (up to 75%) became amorphous with protracted micronisation. The XRPD, DSC and isothermal microcalorimetry methods could all be used to characterise the amorphous content for these highly disordered samples. When the drug was milled in a ball mill, considerably less of the sample mass became amorphous (less than 10% even for reasonably long milling times) and for such samples, only isothermal microcalorimetry was a suitable technique for quantifying the degree of disorder as no difference was observed by use of DSC or XRPD for materials with up to 10% amorphous content. Microcalorimetry is a suitable approach for crystallinity studies on hydrophobic powders, giving a lower limit of detection for amorphous content that is in the order of 1% or less, which is well below that seen for XRPD.
Many processing steps can result in generation of partially amorphous materials. While the fraction of disorder may be low (typically up to 5% w/w) its location primarily on particle surfaces means its effects might be significant, especially in regard to powder flow and force of adhesion. Quantification of small amorphous contents is thus becoming an important part of product development. Isothermal microcalorimetry can be used as an assay for amorphous content by controlling the relative humidity or relative vapour pressure in the sample ampoule. The technique is very sensitive (typically detecting less than 1% w/w amorphous content) and universally applicable to pharmaceutical powders. However method design and data interpretation are critical factors in successful assay design. This article discusses methods and techniques and reviews current pharmaceutical applications to aid assay design.
The drug-drug interaction of two pMDI (pressure metered dose inhaler) combination products budesonide-formoterol fumarate dihydrate and salmeterol xinafoate-fluticasone propionate were investigated using in situ atomic force microscopy (AFM), equipped with a liquid cell filled with model a propellant, and Raman spectroscopy. Electron microscopy images of the budesonide-formoterol formulation suggested discrete particulates while the salmeterol-fluticasone formulation appeared agglomerated. Based on the analysis of the AFM curves, it is proposed that interactions in the budesonide-formoterol system (cohesion and adhesion) are dominated by van der Waals forces while interactions between salmeterol and fluticasone are of a chemical nature. Such observations are further substantiated by analysis of the Raman maps produced from pMDI actuations deposited on Andersen cascade impactor plates. The relevance of such synergy between particulates of different chemical nature is discussed. In particular, it is anticipated that strong interactions between particles could lead to heteroflocculation, increase aerosol particle size and consequently reduction of the respirable fine particle fraction.
The understanding of deposition of particles in the respiratory tract is of great value to risk assessment of inhalation toxicology and to improve efficiency in drug delivery of inhalation therapies. There are three main basic mechanisms of particle deposition based primarily on particle size: inertial impaction, sedimentation and diffusion. The regional deposition in the lungs can be evaluated in regards to the aerodynamic particle size, in which particle density plays a significant role. In this review paper, we first introduce the available imaging techniques to confirm regional deposition of particles in the human respiratory tract, such as planar scintigraphy, single photon emission computed tomography (SPECT) and positron emission tomography (PET). These technologies have widely advanced and consequently benefited the understanding of deposition pattern, although there is a lack of lung dosimetry techniques to evaluate the deposition of nanoparticles. Subsequently, we present a comprehensive review summarizing the evidence available in the literature that confirms the deposition of smaller particles in the smaller airways as opposed to the larger airways.
Molecular dynamic simulations have been successfully utilised with molecular modelling to estimate the glass transition temperature (T(g)) of polymers. In this paper, we use a similar approach to predict the T(g) of a small pharmaceutical molecule, beclomethasone dipropionate (BDP). Amorphous beclomethasone dipropionate was prepared by spray-drying. The amorphous nature of the spray-dried material was confirmed with scanning electron microscopy, differential scanning calorimetry (DSC) and X-ray powder diffraction (XRD). Molecular models for amorphous BDP were constructed using the amorphous cell module in Discovery studio™. These models were used in a series of molecular dynamic simulations to predict the glass transition temperature. The T(g) of BDP was determined by isothermal-isobaric molecular dynamic simulations, and different thermodynamic parameters were obtained in the temperature range of -150 to 400°C. The discontinuity at a specific temperature in the plot of temperature versus amorphous cell volume (V) and density (ρ) was considered to be the simulated T(g.) The predicted T(g) from four different simulation runs was 63.8°C ± 2.7°C. The thermal properties of amorphous BDP were experimentally determined by DSC and the experimental T(g) was found to be ∼ 65°C, in good agreement with computational simulations.
The aims of this study were to investigate and characterize the physico-chemical properties of beclomethasone dipropionate (BDP) crystallized from tricholoromonofluoromethane (CFC-11). Physical interactions in a model pressurised metered dose inhaler (pMDI) system and changes in surface energy after size reduction (micronization) were determined. Although CFC-11 has largely been phased out of use in pMDIs due to its ozone depletion potential, the BDP CFC-11 clathrate is a stable entity and thus suitable as a model for our initial investigations. In addition, although propellant clathrates have been known for sometime, as far as the authors are aware, their surface energies and adhesive interactions have not been reported. The structure of the clathrate was investigated using scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS) and X-ray powder diffraction (X-RPD). In addition, atomic force microscopy (AFM) was employed to determine the dispersive surface free energy (SE) and force of adhesion (F(adh)) of the BDP CFC-11 clathrate with different pMDI components in a model propellant (decafluoropentane). The dispersive surface free energies for anhydrous BDP (micronized), the CFC-11 clathrate and ball-milled BDP CFC-11 clathrate are (47.5+/-4.9) mJ m(-2), (11.3+/-4.1) mJ m(-2) and (15.2+/-1.3) mJ m(-2) respectively. Force of adhesion results shows that BDP CFC-11 clathrates, even after being ball-milled for 2.5h, have a lower F(adh) compared to micronized anhydrous BDP with different pMDI components. This shows that the formation of the crystalline CFC-11 clathrate is advantageous when compared to the micronized anhydrous form, in terms of its surface energy and potential interactions within a suspension MDI formulation. In the wider context, this work has implications for the future development of HFA formulations with APIs which are prone to the formation of propellant clathrates.
Pressurized metered dose inhaler (MDI) output from three different albuterol formulations was characterized using three inertial separation devices. Results were compared for the Delron six-stage cascade impactor (DC16), the Andersen Mark II eight-stage impactor (AC18), and Copley's twin-stage liquid impinger (LI). None of the devices tested in this study was ideal in all respects. All devices could differentiate between formulations in terms of respirable doses (albuterol amount with aerodynamic diameters less than 5.5 through 6.4 microns). Only the high-flow rate LI could differentiate among all three formulations when data were presented in terms of respirable percentage (RP) of drug collected. Values for RP were in excellent agreement for the independently calibrated impactors when the same evaporation chamber was used atop the impactors. The LI appeared to overestimate values for RP in vivo. Results are discussed in light of the debate surrounding the revision of USP aerosol testing requirements. Rigorous specifications for evaporation chambers and methodologies are necessary for meaningful inter- and intra-laboratory comparison of results when any of these devices are used.
New albuterol-containing metered-dose inhaler (MDI) formulations were under development to replace chlorofluorocarbon (CFC) propellants with more environmentally friendly hydrofluoroalkane (HFA) propellants. To achieve good chemical and physical stability of MDI formulations with HFA propellants, different drug forms were evaluated in model formulations (drug, oleic acid, and one of the following: P12/P11, P12/ethanol, P12, P134a/ethanol, P134a). The effects of drug form (base versus sulfate), propellant type (P12 versus P134a), and cosolvent type (P11 or ethanol versus none) on the chemical and physical stability were examined. The chemical stability of the formulations was determined by monitoring the percent drug remaining in the formulations using HPLC. The physical stability of the formulations was followed by visually assessing the suspension appearance, and by determining the mass median diameter (MMD) of the suspended particles using laser diffraction analysis. The drug form has a great impact on the chemical and physical stability of the formulations. The sulfate formulations were chemically stable up to 12 months when stored at 30 degrees C and 40 degrees C/85% relative humidity (RH). Poor chemical stability was observed for the base formulations, except for ethanol-free formulations (P12/P11, P12, and P134a) at 30 degrees C and a P134a formulation at 40 degrees C/85% RH. The chemical instability of albuterol base formulations at 30 degrees C correlates with its solubility. The presence of a cosolvent greatly improved the dispersion characteristics of both sulfate and base formulations. The sulfate formulations in the presence of a cosolvent (P12/P11, P12/ethanol, and P134a/ethanol) showed good physical stability when stored for up to 12 months at 30 degrees C and 40 degrees C/85% RH. The physical stability of the base formulations was not acceptable due to crystal growth/agglomeration in all formulations, except for the P12/P11 formulation. The physical instability of both sulfate and base formulations not only correlates with the drug solubility, but also with particle agglomeration. In conclusion, good chemical and physical stability of albuterol-containing suspension formulations can be achieved with the appropriate choice of drug form and formulation constituents.
The solubility, heat of solution and dissolution rate of paracetamol and polyethyelene glycol 4000 (PEG 4000) systems have been studied in order to clarify the nature of the interaction between the two components during dissolution of solid dispersions. The logarithmic solubility of paracetamol demonstrated a non-linear increase with concentration of PEG 4000, while linear relationships between heat of solution in water and concentration were seen for both individual components. However, the heat of solution of paracetamol was found to decrease with increasing concentrations of PEG 4000. Similarly, the heats of solution in water of physical mixes and solid dispersions prepared using two manufacturing protocols were found to be lower than the theoretical values calculated from those corresponding to the individual components. Drug release studies showed a marked increase in paracetamol dissolution rate when prepared as a solid dispersion, with behaviour consistent with carrier controlled dissolution observed at low drug contents which was ascribed to enhanced dissolution of the drug into the diffusion layer of the PEG 4000. The implications of the understanding of this mechanism for the choice of carrier and manufacturing protocol for solid dispersion products is discussed.
A sensitive and selective microcalorimetric technique has been used to determine the enthalpy of solution of diclofenac sodium (DS), paracetamol (PC) and their binary mixtures over a wide range of composition in the pH range 4-12. The systems showed endothermic behavior. The molar enthalpies of solutions of DS vary between 42.26+/-0.16 and 50.48+/-0.03 kJ mol(-1) at pH 4-9 and for PC from 24.28+/-0.05 to 36.03+/-0.01 kJ mol(-1) at pH 5-12. The excess molar enthalpy of their mixtures has also been determined. The values of excess molar enthalpy of solutions are negative and very low in magnitude indicating no specific interaction between DS and PC in solution.
There were three aims of this work: (1). to study the suitability of spray drying to prepare surface modified microparticles coated with alkylpolyglycoside surfactants (for potential use in metered dose inhalation systems, although their use is not reported here); (2). to assess the utility of inverse phase gas chromatography (IGC) as a means of assessing the surface properties of modified microparticles; and (3). to attempt to relate dynamic surface tension measurements with the ability for a molecule to diffuse to a surface during spray drying. Microparticles of salbutamol sulphate-alkylpolyglycosides were prepared by spray drying from solution and then characterised using scanning electron microscopy, particle size analysis (laser diffraction) and inverse gas chromatography. Further to this, the critical micelle concentration (CMC) and the dynamic surface tension of alkylpolyglycosides were measured. Spray drying a solution of salbutamol sulphate with alkylpolyglycosides produced spherical amorphous microparticles with a diameter of less than 10 microm. The analysis of the surface energies of spray dried salbutamol sulphate showed that the addition of alkylpolyglycosides, at concentrations below and above their CMC, decreases substantially the basic component of the surface energy. This demonstrates that it is possible to sequentially modify the surface energy of the particles. Dynamic surface tension measurements of the alkylpolyglycosides above their CMC showed that the surfactant that has the least effect on the surface energy of the particles, presents the slowest diffusion in water. This may indicate that the diffusion of this particular molecule in water may be too slow to allow the surfactant to migrate to the surface of the microparticle during the drying process. IGC can be useful to analyse the surface energy of the particles after spray drying in order to assess the presence of the surfactant on the surface of the microparticles.
A novel model propellant for the study of the properties of pMDIs (pressurized metered-dose inhalers) at atmospheric pressure is proposed and extensively characterized. The reasons for the choice of this liquid, with its advantages and drawbacks, are explained and justified. Comparison with existing fluorinated propellants is also documented.
To compare experimental measurements of particle cohesion and adhesion forces in a model propellant with theoretical measurements of the interfacial free energy of particulate interactions; with the aim of characterizing suspension stability of pressurized metered dose inhalers (pMDIs).
Interparticulate forces of salbutamol sulfate, budesonide, and formoterol fumarate dihydrate were investigated by in situ atomic force microscopy (AFM) in a model propellant 2H,3H perfluoropentane. The surface thermodynamic properties were determined by contact angle (CA) and inverse gas chromatography (IGC). Experimental data were compared with theoretical work of adhesion/cohesion using a surface component approach (SCA), taking into account both dispersive and polar contributions of the surface free energy.
Results indicated that the measured forces of interaction between particles in model propellant could not be accounted for by theoretical treatment of the dispersive surface free energies via CA and IGC. A correlation between theoretical work of adhesion/cohesion and AFM measurements was observed upon the introduction of the polar interfacial interactions within the SCA model.
It is suggested that the polar contributions of the surface free energy measurements of particles may play a crucial role in particle interaction within propellant-based systems. Together with the application of a SCA model, this approach may be capable of predicting suspension stability of pMDI formulations.
Calorimetric methods (isothermal or solution calorimetry) offer the ability to detect amorphous contents to 0.5% (w/w) or better in processed pharmaceuticals and calorimetric data are becoming more widely accepted in regulatory submissions. However, both methods require the construction of calibration curves, prepared using quantitative physical mixtures of entirely amorphous and entirely crystalline material. If the sample under investigation exists in two or more isomers or polymorphs, and the enthalpy of solution (solution calorimetry) or the enthalpy of crystallisation (isothermal calorimetry) are different for the isomers or polymorphs, then it must be ensured that the batch of material used to prepare the calibration samples has the same isomeric or polymorphic composition as the (processed) material to be tested. Here, we demonstrate the problems that may arise using lactose as a pharmaceutically important model substance. Calibration curves were prepared from solution calorimetry and isothermal gas perfusion calorimetry data using two batches of lactose (one predominantly anhydrous alpha-lactose and one predominantly beta-lactose). The calibration curves are shown to be significantly different for the two batches, and it is shown that quantification of the amorphous content of a processed sample of unknown isomeric composition is impossible, unless the calibration curve is prepared from the same batch of material as the processed sample. In addition, some of the other problems inherent in using isothermal gas perfusion calorimetry for amorphous content determination, such as wetting issues and the preparation of calibration standards that mimic processes samples, are discussed.
In this study, a novel laser diffraction particle size analysis dispersion system, capable of sizing particles in situ within suspension hydrofluoroalkane (HFA) pressurised metered dose inhalers (pMDIs), was developed and tested. The technique was compared to four indirect particle sizing methods commonly used to determine the size of particles suspended in HFA pMDIs. The median volume diameter obtained using laser diffraction of both the salbutamol sulphate and fluticasone propionate suspended either in 2H, 3H-decafluoropentane or perfluoropentane (employed as surrogate propellants) was over one-order of magnitude larger than the particle sizes of the drugs suspended in HFA 134a. In contrast, the "in-flight" particle size using the Sympatec inhaler 2000 laser diffraction equipment undersized the particles, predicting higher delivery efficacy compared to the other sizing methods. However, the size of particles suspended in HFAs derived using the novel pressurised dispersion system, showed a linear correlation with the impaction results, r2=0.8894 (n=10). The novel pressure cell sizing technique proved to be simple to use, has the ability to be automated and was accurate, suggesting it could be an essential tool in the development of new suspension-based pMDI formulations.
Colloid probe atomic force microscopy (AFM) was utilised to quantify the cohesive forces of salbutamol sulphate in a model non-pressurised fluorinated liquid (mHFA), in the presence of increasing concentrations of poly(ethylene glycol) (PEG; molecular weight (MW) 200, 400 and 600). In addition, samples of PEG 400 (0.05-0.5%, v/w), were analysed in the presence of 0.001% (w/w) of poly(vinyl pyrrolidone) (PVP). In the absence of any stabilizing agents, strong attractive forces were present between particles. Increasing the concentration of the different MW PEG solutions in the mHFA system (up to 0.5%, v/w), significantly decreased the force of interaction (ANOVA, p<0.05). The decrease in cohesion was particularly evident at very low concentrations of PEG (0.05-0.1%, v/w). Further data analysis (p<0.05) suggested that the reduction in the force of cohesion was dependent on the concentration and molecular weight of PEG. The addition of low concentration of PVP to the PEG 400-mHFA system had the most significant influence on drug particle cohesion. In the presence of PVP, increasing addition of PEG 400 (0.05-0.5%, v/w) to the mHFA, resulted in no significant reduction in the force of cohesion (p>0.05). Clearly, an understanding of the conformation of polymer molecules at interfaces is of vital importance when controlling the stability/flocculation behaviour of sterically stabilized pMDI suspensions. In this context, the use of the colloid probe AFM technique has provided a quantitative insight into the interactions of these complex systems and may be an invaluable asset during the early phase of formulation product development.
The physicochemical and aerodynamic properties of spray dried powders of the drug/drug mixture salbutamol sulphate/ipratropium bromide were investigated. The in vitro deposition properties of spray dried salbutamol sulphate and the spray dried drug/excipient mixtures salbutamol sulphate/lactose and salbutamol sulphate/PEG were also determined. Spray drying ipratropium bromide monohydrate resulted in a crystalline material from both aqueous and ethanolic solution. The product spray dried from aqueous solution consisted mainly of ipratropium bromide anhydrous. There was evidence of the presence of another polymorphic form of ipratropium bromide. When spray dried from ethanolic solution the physicochemical characterisation suggested the presence of an ipratropium bromide solvate with some anhydrous ipratropium bromide. Co-spray drying salbutamol sulphate with ipratropium bromide resulted in amorphous composites, regardless of solvent used. Particles were spherical and of a size suitable for inhalation. Twin impinger studies showed an increase in the fine particle fraction (FPF) of spray dried salbutamol sulphate compared to micronised salbutamol sulphate. Co-spray dried salbutamol sulphate:ipratropium bromide 10:1 and 5:1 systems also showed an increase in FPF compared to micronised salbutamol sulphate. Most co-spray dried salbutamol sulphate/excipient systems investigated demonstrated FPFs greater than that of micronised drug alone. The exceptions to this were systems containing PEG 4000 20% or PEG 20,000 40% both of which had FPFs not significantly different from micronised salbutamol sulphate. These two systems were crystalline unlike most of the other spray dried composites examined which were amorphous in nature.
The accurate solubility of salbutamol sulfate, budesonide, and formoterol fumarate dihydrate in hydrofluoroalkane propellant 134a at 25 degrees C for 24 h, are reported. The authors describe a novel reusable in-line pressurized solubility apparatus containing an integral filter holder and a continuous decrimpable valve for the determination of drug/excipients solubility in pressurized metered dose inhalers. The solubility was determined by high-performance liquid chromatography. Solubility of salbutamol sulfate was determined as being below the detection limits while budesonide and formoterol fumarate dihydrate solubility were 23.136 +/- 2.951 microg x g(-1) and 0.776 +/- 1.023 microg x g(-1), respectively (n = 3). This novel solubility apparatus offers an improved ease of use and potential higher analytical throughput.
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.
Demonstrate the applicability of a novel particle-based technology for the development of suspensions of small polar drugs and biomolecules in hydrofluoroalkane (HFA) propellants for pressurized metered-dose inhalers (pMDIs).
Emulsification diffusion was used to prepare core-shell particles. The shell consisted of oligo(lactide) grafts attached onto a short chitosan backbone. The active drug was arrested within the particle core. Colloidal Probe Microscopy (CPM) was used to determine the cohesive forces between particles in a model HFA propellant. The aerosol characteristics of the formulations were determined using an Anderson Cascade Impactor (ACI). Cytotoxicity studies were performed on lung epithelial and alveolar type II cells.
CPM results indicate that particle cohesive forces in liquid HFA are significantly screened in the presence of the polymeric shell and correlate well with the physical stability of suspensions in propellant HFA. The proposed formulation showed little or no cytotoxic effects on both Calu-3 and A549 cells.
Core-shell particles with a shell containing the lactide moiety as the HFA-phile showed excellent dispersion stability and aerosol characteristics in HFA-based pMDIs. This is a general strategy that can be used for developing novel suspension pMDIs of both small polar drugs and large therapeutic molecules.
Safety assessment of the HFA propellant and the new inhaler
- C L Leach
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PEG-based positively charged nanoparticles for pulmonary delivery of nucleic acids. In: Drug Delivery to the Lung Simultaneous determination of solubility, dissolution and dilution enthalpies of a substance from a single calorimetric experiment
- K Sharma
- S Somavarapu
- K Taylor
- N Govind
Sharma, K., Somavarapu, S., Taylor, K., Govind, N., 2008. PEG-based positively charged nanoparticles for pulmonary delivery of nucleic acids. In: Drug Delivery to the Lung, Edinburgh. Castronuovo, G., Elia, V., Niccoli, M., Velleca, F., 1998. Simultaneous determination of solubility, dissolution and dilution enthalpies of a substance from a single calorimetric experiment. Thermochim. Acta 320, 13–22.