Preparation of respirable nanoparticle agglomerates of the low melting and ductile drug ibuprofen: impact of formulation parameters

Ductile and low melting point drugs exhibit challenging behaviour during both particle size reduction and spray drying as considerable amount of heat is involved in both processes. In this study, a systematic approach was employed to understand the preparation and in-vitro performance of respirable nanoparticle agglomerates by coupling wet milling and spray drying for ibuprofen, which is a drug with a low melting point and challenging mechanical properties. Wet milling in the presence of two stabilizers differing in their thermal properties and subsequent spray drying of the suspensions were employed after the addition of mannitol and/or leucine. The effects of the stabilizer type and the amounts of mannitol (matrix former) and leucine (dispersibility enhancer), on the yield of the process, the particle size, the redispersibility (i.e. reformation of nanoparticles upon rehydration) and the aerosolization (fine particle fraction, FPF%) of the nanoparticle agglomerates were evaluated using standard least squares model and a 23 full factorial design (3 factors at 2 levels plus four centre points). All factors investigated were found to have a significant effect on the yield of nanoparticle agglomerates (p < 0.05). The size of the nanoparticle agglomerates was mainly dependent on the leucine to drug ratio and the type of stabilizer (p < 0.05), while mannitol to drug ratio was the only significant factor affecting the redispersibility of the formulations (p < 0.05). The FPF%, determined using a fast screening impactor, was found to be dependent on both the leucine and mannitol to drug ratio (p < 0.05). This study demonstrates the successful preparation of respirable nanoparticle agglomerates of low melting point and ductile ibuprofen and the usefulness of the design of experiments as a tool to understand the impact of the formulation parameters on their fabrication and in-vitro performance

Insight into the formation of glimepiride nanocrystals by wet media milling

Nanocrystal formation for the dissolution enhancement of glimepiride was attempted by wet media milling. Di erent stabilizers were tested and the obtained nanosuspensions were solidified by spray drying in presence of mannitol, and characterized regarding their redispersibility by dynamic light scattering, physicochemical properties by di erential scanning calorimetry (DSC), FT-IR spectroscopy, powder X-ray di raction (PXRD), and scanning electron microcopy (SEM), as well as dissolution rate. Lattice energy frameworks combined with topology analysis were used in order to gain insight into the mechanisms of particle fracture. It was found that nanosuspensions with narrow size distribution can be obtained in presence of poloxamer 188, HPC-SL and Pharmacoat® 603 stabilizers, with poloxamer giving poor redispersibility due to melting and sticking of nanocrystals during spray drying. DSC and FT-IR studies showed that glimepiride does not undergo polymorphic transformations during processing, and that the milling process induces changes in the hydrogen bonding patterns of glimepiride crystals. Lattice energy framework and topology analysis revealed the existence of a possible slip plane on the (101) surface, which was experimentally verified by PXRD analysis. Dissolution testing proved the superior performance of nanocrystals, and emphasized the important influence of the stabilizer on the dissolution rate of the nanocrystals

Preparation of theophylline inhalable microcomposite particles by wet milling and spray drying: the influence of mannitol as a co-milling agent

Inhalable theophylline particles with various amounts of mannitol were prepared by combining wet milling in isopropanol followed by spray drying. The effect of mannitol as a co-milling agent on the micromeritic properties, solid state and aerosol performance of the engineered particles was investigated. Crystal morphology modelling and geometric lattice matching calculations were employed to gain insight into the intermolecular interaction that may influence the mechanical properties of theophylline and mannitol. The addition of mannitol facilitated the size reduction of the needle-like crystals of theophylline and also their assembly in microcomposites by forming a porous structure of mannitol nanocrystals wherein theophylline particles are embedded. The microcomposites were found to be in the same crystalline state as the starting material(s) ensuring their long-term physical stability on storage. Incorporation of mannitol resulted in microcomposite particles with smaller size, more spherical shape and increased porosity. The aerosol performance of the microcomposites was markedly enhanced compared to the spray-dried suspension of theophylline wet milled without mannitol. Overall, wet co-milling with mannitol in an organic solvent followed by spray drying may be used as a formulation approach for producing respirable particles of water-soluble drugs or drugs that are prone to crystal transformation in an aqueous environment (i.e. formation of hydrates)

Pseudomyxoma Peritonei Presenting as Acute Appendicitis: Clinical and Imaging Findings

A 30-year old man presented with symptoms and signs of acute appendicitis. Abdominal imaging via ultrasound and computed tomography detected a mass in the right iliac fossa. Exploratory laparotomy revealed an appendiceal mass and gelatinous peritoneal fluid, while histopathology confirmed the diagnosis of pseudomyxoma peritonei arising from a mucocele of the appendix and attributed to an appendiceal cystadenocarcinoma. The clinical and imaging findings of this rare case are herein presented

Neural network: an instrument to study flow and packing properties of pharmaceutical powders

In the present study five brands of microcrystalline cellulose (Ph101, Vivapur, Ph 301, Emcocel and Prosolv), three brands of Crospovidone (XL, XL-10 and INF) and pregelatinized Starch were mixed with 2% w/w of Aerosil 200, Aerosil R972 (two different kinds of colloidal silicon dioxide) or Mg stearate, to obtain 27 distinct mixtures. Flow rate, bulk and tapped density of mixtures were measured and tablets were prepared

Pharmaceutical nanocrystals: production by wet milling and applications

Nanocrystals are regarded as an important nanoformulation approach exhibiting advantages of increased dissolution and saturation solubility with chemical stability and low toxicity. Nanocrystals are produced in the form of nanosuspensions using top-down (e.g., wet milling or high pressure homogenization) and bottom-up methods (e.g., antisolvent precipitation). Wet milling is a scalable method applicable to drugs with different physicochemical and mechanical properties. Nanocrystalline-based formulations, either as liquid nanosuspensions or after downstream processing to solid dosage forms, have been developed as drug delivery systems for various routes of administration (i.e., oral, parenteral, pulmonary, ocular, and dermal). In this review, we summarize and discuss the features, preparation methods, and therapeutic applications of pharmaceutical nanocrystals, highlighting their universality as a formulation approach for poorly soluble drugs

Improvement of Aripiprazole Solubility by Complexation with (2-Hydroxy)propyl-beta-cyclodextrin Using Spray Drying Technique

Due to the fact that the number of new poorly soluble active pharmaceutical ingredients is increasing, it is important to investigate the possibilities of improvement of their solubility in order to obtain a final pharmaceutical formulation with enhanced bioavailability. One of the strategies to increase drug solubility is the inclusion of the APIs in cyclodextrins. The aim of this study was to investigate the possibility of aripiprazole solubility improvement by inclusion in (2-hydroxy)propyl-beta-cyclodextrin (HPBCD) and simultaneous manipulation of pH of the medium and addition of polyvinylpyrrolidone. Aripiprazole-HPBCD complexes were prepared by spray drying aqueous drug-HPBCD solutions, and their properties were compared with those prepared by solvent-drop co-grinding and physical mixing. The obtained powders were characterized by thermoanalytical methods (TGA and DSC), FTIR spectroscopy, their dissolution properties were assessed, while the binding of aripiprazole into the cavity of HPBCD was studied by molecular docking simulations. The solubilization capacity was found to be dependent on pH as well as the buffer solution's ionic composition. The presence of PVP in the formulation could affect the solubilization capacity significantly, but further experimentation is required before its effect is fully understood. On the basis of solubility studies, the drug/HPBCD stoichiometry was found to be 1:3. The spray-dried products were free of crystalline aripiprazole, they possessed higher solubility and dissolution rate, and were stable enough over a prolonged period of storage. Spray drying of cyclodextrin solutions proved to be an appropriate and efficient technique for the preparation of highly soluble inclusion compounds of aripiprazole and HPBCD

A quantitative study of the influence of coprocessing of binders on the mechanical properties of paracetamol tablets

A 2³ factorial experimental design has been used to quantitatively study individual and interaction effects of the nature of binder (N), concentration of binder (C) and the applied pressure (P) on two mechanical properties, namely, tensile strength (TS) and brittle fracture index (BFI), of paracetamol tablets. The factorial design was also used to study the quantitative effects of coprocessing of binders on the mechanical properties. The results obtained from this study suggest that the nature (i.e. plastic/elastic) and ratio of binders coprocessed together alter the influence of C and P on TS and BFI.Utilizou-se planejamento experimental fatorial 2³ para estudar, quantitativamente, os efeitos individuais e de interação da natureza do ligante (N), concentração do ligante (C) e a pressão aplicada (P) em duas propriedades mecânicas, como forças de ruptura (TS) e índice de fragilidade (BFI) de comprimidos de paracetamol. O planejamento fatorial foi, também, empregado para estudar os efeitos quantitativos do coprocessamento de ligantes nas propriedades mecânicas. Os resultados obtidos desse trabalho sugerem que a natureza (plástica/elástica) e a proporção de ligantes coprocessados, juntas, alteram a influência de C e P em TS e em BFI

eine Elektronische Speckle Pattern-Korrelation Interferometrie Untersuchung

The high qualities of dental composite resins have established them as first choice materials for direct filling restorations. However their longevity is highly dependent on the integrity of the adhesive interface between the restoration and the tooth. This interface is in turn influenced by the dimensional behavior of the material and its response to the various conditions in the mouth. The composite fillings have to operate in a wet environment under constant thermal fluctuations. Phenomena like water absorption and elution of chemical species from the material, post- polymerization and changes in temperature strongly influence the dimensional behavior of the material, posing a challenge to the adhesive interface. In order to be able to investigate the impact of these phenomena on the dimensions of the material, and since the magnitude of these deformations is very small, a very sensitive method should be applied. Electronic speckle pattern- correlation interferomentry (ESPI) is a non-contact, non-destructive optical method for measuring small deformations of surfaces taking place in a range of 20 nm to 2 μm, being therefore suitable for performing this kind of measurements. The aim of this study was to measure the actual deformations of the composite when heated up to 37°C and to investigate the different impact of the factors influencing the dimensional behavior of the material. Accordingly, through these measurements the potential of ESPI for conducting small scale recordings of the deformations taking place in composite materials should be determined and a measurement protocol should be established in order to standardize this procedure. Within this framework, two materials were chosen, Admira (VOCO, Cuxhaven) for the preliminary measurements and Grandio (VOCO, Cuxhaven) for the main deformation measurements. Each specimen was stored dry (ambient conditions) or wet (water) for particular durations before measurement. The deformations taking place as the specimen was heated from 26°C to 37°C were recorded, with each recording lasting 27 min, corresponding to 400 measurements over the surface. Comparisons were made between the deformations recorded for the various groups. The impact of water absorption and post-polymerization over the dimensional behavior of the material was investigated with ESPI, as well as the time frame in which these phenomena exert their influence. Additional measurements in this direction included microindentation tests and measurements of the weight. The possibility of water pre-existing in the dry specimens was also examined. Through the measurements with the ESPI it was demonstrated that as temperature rose from 26°C up to 37°C, following an initial expansion all specimens shrank for the duration of the measurement (-0.05%≤deformation≤-0.011%). The largest and most dramatic dimensional response of the material was exerted at the first 24 hours after polymerization, regardless of the storage medium. 72 hours after polymerization the material showed the greatest stability. For storages longer than 72 hours and up to 1 month, the shrinkage values started rising again. Evidently, the first 24 hours are overall the most important period for the dimensional behavior of the material. The shrinkage exhibited as a result of the rise in temperature is the most statistically significant, even when this rise is only up to mouth temperature. During this time, post-polymerization exerts the greatest influence. By contrast, 72 hours after polymerization, the impact of water absorption is greater than that of post-polymerization. Through all these measurements it was demonstrated that ESPI is capable of measuring nanometer deformations and minute strains related to the molecular dynamics of the composites, relevant to the clinical conditions where these materials are used. Through the measurements with the ESPI, a measurement protocol was established standardizing the method for future investigations.Die hohe Qualität der zahnärztlichen Komposite hat sich als erste Wahl für direkte Restaurationen etabliert. Doch ihre Langlebigkeit ist stark abhängig von der Integrität des adhäsiven Verbunds zwischen Restauration und Zahn. Diese Grenzfläche ist wiederum durch das dimensionale Verhalten des Materials und seine Reaktion auf die verschiedenen Bedingungen im Mund beeinflusst. Die Kompositfüllungen müssen einer feuchten Umgebung und konstanten thermischen Fluktuationen widerstehen. Phänomene wie Wasseraufnahme und Löslichkeit von chemischen Substanzen aus dem Material, Post-Polymerisation und Änderungen der Temperatur beeinflussen das dimensionale Verhalten des Materials und stellen eine Herausforderung an die Adhäsive Grenzfläche. Um in der Lage zu sein die Auswirkungen dieser Phänomene auf die Dimensionen des Materials zu untersuchen, insbesondere da die Größe dieser Verformungen sehr klein ist, sollte entsprechend eine sehr empfindliche Methode angewendet werden. Elektronische Speckle-Korrelation Interferometrie (ESPI) ist eine berührungslose, zerstörungsfreie, optische Methode zur Messung von kleinen Verformungen der Oberfläche, in einem Bereich von 20nm bis 2μm und ist deshalb geeignet für die Durchführung dieser Art von Messungen. Das Ziel dieser Studie war es, die tatsächlichen Verformungen des Kunststoffes zu messen, wenn er bis zu 37 ° C erhitzt ist und die unterschiedlichen Auswirkungen der Faktoren zu untersuchen, die das dimensionale Verhalten des Materials beeinflussen. Durch diese Messungen wird die Möglichkeit kleinste Deformationen im Kunststoff mit ESPI aufzunehmen untersucht. Zur Standardisierung wurde ein Messprotokoll eingerichtet. Im Rahmen dessen wurden zwei Materialien gewählt: Admira (VOCO, Cuxhaven) für den vorläufigen Messungen und Grandio (VOCO, Cuxhaven) für die Hauptdeformationsmessungen. Für bestimmte Zeiträume vor der Messung wurde jede Probe trocken (Umgebungsbedingungen) bzw. feucht (Wasser) gelagert. Verformungen während des Verfahrens, zwischen dem Heizen von 26°C bis 37°C, wurden gemessen und aufgenommen. Jede Aufnahme dauerte 27 min, bzw. entspricht 400 Messungen auf der Oberfläche. Vergleiche zwischen den Verformungen der verschiedenen Gruppen wurden durchgeführt. Die Auswirkungen der Wasseraufnahme und Polymerisation über dem dreidimensionalen Verhalten des Materials wurde mit ESPI untersucht, sowie der Zeitraum, in dem diese Phänomene ihren Einfluss ausüben. Zusätzliche Messungen in diese Richtung enthalten die Mikroindentation- Tests und Messungen des Gewichts. Die Möglichkeit von Wassereinlagerung in den trockenen Proben wurde ebenfalls untersucht. Durch die Messungen mit dem ESPI wurde gezeigt, dass während des Temperaturanstiegs von 26°C auf 37°C nach einer ersten Expansion alle Proben schrumpften. Für die Dauer der Messung entsprach dies -0,05%≤Verformung≤-0,011%. Die größte und dramatischste dimensionale Reaktion des Materials findet innerhalb der ersten 24 Stunden nach der Polymerisation statt, unabhängig von dem Lagerungsmedium. 72 Stunden nach der Polymerisation zeigt das Material die größte Stabilität. Für Lagerungszeiträume zwischen 72 Stunden und 1 Monat, zeigte sich wieder ein Anstieg der Schrumpfung. Offensichtlich sind die ersten 24 Stunden insgesamt die wichtigsten für die Dimensionen des Materials. Die Schrumpfung als Folge des Anstiegs der Temperatur ist statistisch signifikant, auch wenn dieser Temperaturanstieg nur auf Niveau der Mundtemperatur ist. Während dieser Zeit übt die Post-Polymerisation den stärksten Einfluss aus. Im Gegensatz dazu sind 72 Stunden nach der Polymerisation die Auswirkungen der Wasseraufnahme größer als die der Polymerisation. Außerdem wurde durch diese Experimente gezeigt, dass die Messung mit ESPI Nanometerverformungen und Spannungen der Kunststoffe, unter klinisch relevanten Bedingungen, möglich ist. Durch die Messungen mit ESPI wurde ein Messprotokoll zur Standardisierung für zukünftige Untersuchungen hergestellt