Modelling the Effect of Process Parameters on the Wet Extrusion and Spheronisation of High-Loaded Nicotinamide Pellets Using a Quality by Design Approach

Open access articleThe aim of the present study was to develop an alternative process to spray granulation in order to prepare high loaded spherical nicotinamide (NAM) pellets by wet extrusion and spheronisation. Therefore, a quality by design approach was implemented to model the effect of the process parameters of the extrusion-spheronisation process on the roundness, roughness and useable yield of the obtained pellets. The obtained results were compared to spray granulated NAM particles regarding their characteristics and their release profile in vitro after the application of an ileocolon targeted shellac coating. The wet extrusion-spheronisation process was able to form highly loaded NAM pellets (80%) with a spherical shape and a high useable yield of about 90%. However, the water content range was rather narrow between 24.7% and 21.3%. The design of experiments (DoE), showed that the spheronisation conditions speed, time and load had a greater impact on the quality attributes of the pellets than the extrusion conditions screw design, screw speed and solid feed rate (hopper speed). The best results were obtained using a low load (15 g) combined with a high rotation speed (900 m/min) and a low time (3–3.5 min). In comparison to spray granulated NAM pellets, the extruded NAM pellets resulted in a higher roughness and a higher useable yield (63% vs. 92%). Finally, the coating and dissolution test showed that the extruded and spheronised pellets are also suitable for a protective coating with an ileocolonic release profile. Due to its lower specific surface area, the required shellac concentration could be reduced while maintaining the release profil

Ultrasound-assisted surface engineering of pharmaceutical powders

Effective processing of powdered particles can facilitate powder handling and result in better drug product performance, which is of great importance in the pharmaceutical industry where the majority of active pharmaceutical ingredients (APIs) are delivered as solid dosage forms. The purpose of this work was to develop a new ultrasound-assisted method for particle surface modification and thin-coating of pharmaceutical powders. The ultrasound was used to produce an aqueous mist with or without a coating agent. By using the proposed technique, it was possible to decrease the interparticular interactions and improve rheological properties of poorly-flowing water-soluble powders by aqueous smoothing of the rough surfaces of irregular particles. In turn, hydrophilic polymer thin-coating of a hydrophobic substance diminished the triboelectrostatic charge transfer and improved the flowability of highly cohesive powder. To determine the coating efficiency of the technique, the bioactive molecule β-galactosidase was layered onto the surface of powdered lactose particles. Enzyme-treated materials were analysed by assaying the quantity of the reaction product generated during enzymatic cleavage of the milk sugar. A near-linear increase in the thickness of the drug layer was obtained during progressive treatment. Using the enzyme coating procedure, it was confirmed that the ultrasound-assisted technique is suitable for processing labile protein materials. In addition, this pre-treatment of milk sugar could be used to improve utilization of lactose-containing formulations for populations suffering from severe lactose intolerance. Furthermore, the applicability of the thin-coating technique for improving homogeneity of low-dose solid dosage forms was shown. The carrier particles coated with API gave rise to uniform distribution of the drug within the powder. The mixture remained homogeneous during further tabletting, whereas the reference physical powder mixture was subject to segregation. In conclusion, ultrasound-assisted surface engineering of pharmaceutical powders can be effective technology for improving formulation and performance of solid dosage forms such as dry powder inhalers (DPI) and direct compression products.Jauhepartikkelien pintakäsittelyn avulla voidaan parantaa lääkevalmistuksessa käytettävien kiinteiden lääke- ja apuaineiden käsiteltävyyttä, prosessoitavuutta ja vaikutusta lopputuottessa/ elimistössä. Tämän väitöskirjatutkimuksen tavoitteena oli kehittää uusi ultraääntä hyväksikäyttävä nesteen sumutusmenetelmä, jonka avulla olisi mahdollisuutta muokata/pinnoittaa erilaisia jauhemaisia lääke- ja apuaineita siten, että niiden jatkoprosessoitavuus ja viime kädessä myös lääkevalmisteen laatu paranisivat. Tutkimuksessa ultraääntä on käytetty muodostamaan vesi-höyrysumua joko päällystysaineen kanssa tai ilman sitä. Väitöskirjatyössä kehitetyn uuden jauheenkäsittelytekniikan avulla oli mahdollista muokata huonosti valuvien ja karkeapintaisten jauhepartikkelien (mm. tiamiinihydrokloridi ja laktoosi) pintoja suoraan veden avulla ja vähentää niiden välistä kontaktipinta-alaa. Tämä puolestaan vähensi jauhepartikkelien välistä vuorovaikutusta (koheesiota) ja paransi ko. jauhemassan valuvuutta. Lisäksi menetelmän avulla voitiin päällystää suoraan hienojakoista lääkeainetta (ibuprofeenia) hydroxypropyylimetyylselluloosa (HPMC) -polymeerin muodostamalla ohuella kalvolla. Tuloksena lääkeaineen jauhepartikkeleiden valuvuus parani. Yllä mainitulla ultraääniavusteisella sumutustekniikalla onnistuttiin pinnoittamaan myös laktoosijauhetta maitosokeria pilkkovalla bioaktiivisella β-galaktosidaasientsyymillä. Laktoosin nanopäällystyminen ja tutkitun ultraääniavusteisen tekniikan tehokkuus selvitettiin ensyymi-tuotteen konsentraatiomääritysten avulla. Ensyymipinnoituksella vahvistettiin, että työssä kehitetty menetelmä sopii myös labiilin proteinimateriaalin käsittelemiseksi. Lisäksi tämän tyyppisellä maitosokerin esikäsittelyllä voitaisiin lisätä laktoosia sisältävien lääkevalmisteiden käyttöä laktoosi-intoleransista kärsivillä ihmisillä. Ultraääniavusteista tekniikkaa käytettiin myös lääkeapuaineen jauhepartikkeleiden päällystämi-seen parantamaan pieniannoksisten tablettivalmisteiden annostarkkuutta. Tabletit valmistettiin mikrokiteisesta selluloosasta, jonka partikkelit oli ennen puristusprosessia päällystetty malliaineen (riboflaviininatriumfosfaatti) vesiliuoksella. Käsittelyn tuloksena tablettien paino ja annoksen jakelutarkkuus oli selkeästi parempi kuin fysikaalisesta binääriseoksesta puristetun referenssi-tabletin vastaavat laatuominaisuudet. Yhteenvetona jauheiden pintojen hallittu muokkaus ultraääniavusteisesti antaa lupaavan mahdollisuuden jatkossa parantaa kiinteiden lääkemuotojen (kuten esimerkiksi jauheinhalaatio-valmisteiden ja suorapuristeisten tablettien) prosessoitavuutta ja vaikutusta elimistössä

Positive region: An enhancement of partitioning attribute based rough set for categorical data

Datasets containing multi-value attributes are often involved in several domains, like pattern recognition, machine learning and data mining. Data partition is required in such cases. Partitioning attributes is the clustering process for the whole data set which is specified for further processing. Recently, there are already existing prominent rough set-based approaches available for group objects and for handling uncertainty data that use indiscernibility attribute and mean roughness measure to perform attribute partitioning. Nevertheless, most of the partitioning attribute methods for selecting partitioning attribute algorithm for categorical data in clustering datasets are incapable of optimal partitioning. This indiscernibility and mean roughness measures, however, require the calculation of the lower approximation, which has less accuracy and it is an expensive task to compute. This reduces the growth of the set of attributes and neglects the data found within the boundary region. This paper presents a new concept called the "Positive Region Based Mean Dependency (PRD)”, that calculates the attribute dependency. In order to determine the mean dependency of the attributes, that is acceptable for categorical datasets, using a positive region-based mean dependency measure, PRD defines the method. By avoiding the lower approximation, PRD is an optimal substitute for the conventional dependency measure in partitioning attribute selection. Contrary to traditional RST partitioning methods, the proposed method can be employed as a measure of data output uncertainty and as a tailback for larger and multiple data clustering. The performance of the method presented is evaluated and compared with the algorithmes of Information-Theoretical Dependence Roughness (ITDR) and Maximum Indiscernible Attribute (MIA)

Multipoint Spectroscopy and Stereoscopic Imaging of Pharmaceutical Particles

Particle and granule properties play a key role in the final product quality of pharmaceuticals. Thus the identification and monitoring of key chemical and physical parameters is essential in the production of pharmaceuticals. The existing off-line methods are generally slow and labour intensive. Near infra-red (NIR) multipoint spectroscopy and image analysis are an attractive alternative compared to the traditional methods because they are both nondestructive and non-interfering allowing the analysis in real time of particles physical and chemical properties. This research is a preliminary study performed at laboratory scale and aims at developing chemometric and imaging algorithms for real time measuring of pharmaceutical chemical and physical properties. These algorithms utilised real time NIR multipoint spectroscopy and a novel imaging system. NIR multipoint spectroscopy followed by a regression technique (such as PLS) was used to build calibration models to quantify a compound in a small size binary granule mixture under both static and dynamic conditions. The imaging technology provided key physical properties such as size, shape and texture. The Haralick correlation property and the variogram were used to analyse the surface texture of particles. These algorithms allowed the classification of particles by their morphological nature under both static and dynamic conditions

Influence of engineered particulate lactose on the performance of DPI formulations

Development of dry powder inhaler (DPI) formulations for respiratory diseases, such as Tuberculosis (TB), is challenging. The major limitation of current marketed DPIs is low delivery efficiency. In addition, delivered dose variation is also a challenging problem in the development and design of DPI formulations due to the poor flowability and dispersibility of the powder formulation. Furthermore, antibiotic drugs used in TB or other respiratory infectious diseases have to be administered in a relatively large dose for pulmonary delivery. However, currently there is no high dose conventional lactose based DPI formulations available. Therefore, I propose an innovative approach to solve these problems through the engineering of particulate lactose by wet granulation. Lactose is the commonly used carrier particle for DPI formulations. Although it was widely believed that carrier particles with smaller diameters were preferable to maximize aerosolization efficiency (the ability of the drugs to be delivered to the lung), it was found recently that lactose carriers with large size also can improve aerosol performance, especially when combined with greater surface roughness and an appropriately designed inhaler device. In the first study, after the engineered particulate lactose was manufactured, the relationship between the physico-chemical properties, e.g. size, of the granulated lactose and the DPI aerosol performance was investigated. It was concluded that poorer or enhanced dispersion performance is not an inherent property to the significantly large size of granulated lactose carriers as previously contended. Relatively large granulated lactose has improved flowability and increased surface roughness with increasing size fraction, which were properties for formulating high drug loaded DPI formulations. It was found that the aerosol performance of the high drug loaded DPI formulation depended significantly on the specific APIs and also the inhalation flow rate used in the cascade impactor study. DPI aerosol performance is the interplay of formulation, patient inhalation effort and device design. The device design was therefore modified and optimized to further improve the aerosol performance. In the end, with the optimized device and granulated lactose as the carrier, a high drug loaded rifampicin DPI formulation with improved aerosol performance (fine particle fraction around 70%), better blending uniformity and potential low systemic toxicity was achieved.Pharmaceutical Science

Interfacial Phenomena in Pharmaceutical Low Moisture Content Powder Processing

Powders are essential materials in the pharmaceutical industry, being involved in majority of all drug manufacturing. Powder flow and particle size are central particle properties addressed by means of particle engineering. The aim of the thesis was to gain knowledge on powder processing with restricted liquid addition, with a primary focus on particle coating and early granule growth. Furthermore, characterisation of this kind of processes was performed. A thin coating layer of hydroxypropyl methylcellulose was applied on individual particles of ibuprofen in a fluidised bed top-spray process. The polymeric coating improved the flow properties of the powder. The improvement was strongly related to relative humidity, which can be seen as an indicator of a change in surface hydrophilicity caused by the coating. The ibuprofen used in the present study had a d50 of 40 μm and thus belongs to the Geldart group C powders, which can be considered as challenging materials in top-spray coating processes. Ibuprofen was similarly coated using a novel ultrasound-assisted coating method. The results were in line with those obtained from powders coated in the fluidised bed process mentioned above. It was found that the ultrasound-assisted method was capable of coating single particles with a simple and robust setup. Granule growth in a fluidised bed process was inhibited by feeding the liquid in pulses. The results showed that the length of the pulsing cycles is of importance, and can be used to adjust granule growth. Moreover, pulsed liquid feed was found to be of greater significance to granule growth in high inlet air relative humidity. Liquid feed pulsing can thus be used as a tool in particle size targeting in fluidised bed processes and in compensating for changes in relative humidity of the inlet air. The nozzle function of a two-fluid external mixing pneumatic nozzle, typical for small scale pharmaceutical fluidised bed processes, was studied in situ in an ongoing fluidised bed process with particle tracking velocimetry. It was found that the liquid droplets undergo coalescence as they proceed away from the nozzle head. The coalescence was expected to increase droplet speed, which was confirmed in the study. The spray turbulence was studied, and the results showed turbulence caused by the event of atomisation and by the oppositely directed fluidising air. It was concluded that particle tracking velocimetry is a suitable tool for in situ spray characterisation. The light transmission through dense particulate systems was found to carry information on particle size and packing density as expected based on the theory of light scattering by solids. It was possible to differentiate binary blends consisting of components with differences in optical properties. Light transmission showed potential as a rapid, simple and inexpensive tool in characterisation of particulate systems giving information on changes in particle systems, which could be utilised in basic process diagnostics.Jauheet ovat tärkeä materiaali lääketeollisuudessa, sillä jauheita tavataan laajalti monissa lääkkeenvalmistusprosesseissa. Jauheen valumisominaisuudet ja hiukkaskoko ovat keskeisiä ominaisuuksia, joita pyritään muokkaamaan jauheteknologian keinoin. Tämän väitöstyön tavoitteena oli tutkia kuinka jauheita voi muokata rajoittamalla prosessiin lisättävän nesteen määrää. Pääasiallinen mielenkiinto kohdistui hiukkasten pinnan päällystämiseen ja rakeen varhaiseen kasvuun. Lisäksi tutkittiin menetelmiä, joiden avulla yllämainitun kaltaisia prosesseja voidaan karakterisoida. Ibuprofeenijauheen yksittäisten hiukkasten pinta päällystettiin polymeeripäällysteellä leijukerrosrakeistimessa. Kyseinen päällyste paransi jauheen valumisominaisuuksia. Muutos oli vahvasti riippuvainen ilmankosteudesta. Tämän voi tulkita osoituksena päällysteen aiheuttamasta pinnan hydrofilisuuden muutoksesta. Tutkimuksessa käytetyn ibuprofeenijauheen mediaanihiukkaskoko oli n. 40 µm ja se määritellään Geldart jauheenluokitusjärjestelmässä luokkaan C, eli jauhe luokitellaan haastavaksi materiaaliksi kuvaillunkaltaisissa leijukerrosprosesseissa. Ibuprofeenijauhetta päällystettiin myös uudella ultra-ääneen perustuvalla menetelmällä. Tulokset olivat johdonmukaisia yllämainitun leijukerrosprosessin tulosten kanssa. Todettiin että ultraääniavusteinen menetelmä on helppokäyttöinen ja varma menetelmä yksittäisten hiukkasten päällystämiseksi. Rakeen kasvua leijukerrosrakeistimessa rajoitettiin syöttämällä rakeistusneste pulssittain. Tulokset osoittavat että pulssitussyklin pituus on olennainen muuttuja rakeen kasvun säätelemiseksi. Lisäksi havaittiin pulssittaisen nesteensyötön vaikutuksen rakeen kasvuun korostuvan korkeassa suhteellisessa ilmankosteudessa. Pulssittaista nesteensyöttöä voi näin ollen käyttää hiukkaskoon säätelyyn, minkä lisäksi sillä voidaan kompensoida tuloilman ilmankosteuden vaihtelun aiheuttamia vaikutuksia prosessiin. Rakeistimissa yleisesti käytetyn nestesumuttimen toimintaa osana prosessia tutkittiin huippunopealla kameralla ja pisarantunnistusohjelmistolla. Pisaroiden todettiin yhdistyvän niiden liikkuessa suuttimesta poispäin. Pisaroiden yhdistymisen todettiin lisäävän niiden nopeutta. Nestesumun pyörteisyyttä tutkittaessa havaittiin pisaranmuodostuksen ja vastakkaiseen suuntaan liikkuvan ilmavirran aiheuttama pyörteisyys. Tulokset osoittivat että kyseinen menetelmä soveltuu nestesumun karakterisoimiseen osana prosessia. Hiukkaspedin läpi kulkevan valon, eli valotransmission, todettiin sisältävän informaatiota hiukkaskoosta ja hiukkasten pakkautumistiheydestä. Tutkimalla transmittoituvaa valoa oli mahdollista erottaa koostumukseltaan poikkeavia kahden komponentin seoksia. Valotransmissio todettiin nopeaksi, yksinkertaiseksi ja kustannustasoltaan alhaiseksi menetelmäksi karakterisoida hiukkassysteemejä. Parhaiten menetelmää voisi hyödyntää prosessiseurannassa hiukkassysteemeissä tapahtuvien muutosten havaitsemiseksi

Approximations from Anywhere and General Rough Sets

Not all approximations arise from information systems. The problem of fitting approximations, subjected to some rules (and related data), to information systems in a rough scheme of things is known as the \emph{inverse problem}. The inverse problem is more general than the duality (or abstract representation) problems and was introduced by the present author in her earlier papers. From the practical perspective, a few (as opposed to one) theoretical frameworks may be suitable for formulating the problem itself. \emph{Granular operator spaces} have been recently introduced and investigated by the present author in her recent work in the context of antichain based and dialectical semantics for general rough sets. The nature of the inverse problem is examined from number-theoretic and combinatorial perspectives in a higher order variant of granular operator spaces and some necessary conditions are proved. The results and the novel approach would be useful in a number of unsupervised and semi supervised learning contexts and algorithms.Comment: 20 Pages. Scheduled to appear in IJCRS'2017 LNCS Proceedings, Springe

Engineering human neural networks: controlling cell patterning and connectivity

Restorative treatments for diseases affecting the central nervous system (CNS) are difficult to develop, due to the complexity of CNS tissues and transferability issues with results from costly animal models. There is an urgent need to produce reliable, complex culture models to develop effective treatments. Such models require controlled interfaces and relevant dense neural cultures. In this thesis, techniques are developed to prepare and investigate scaffolds enabling complex structured neural model fabrication. To facilitate development of an interface layer, neural culture on polycarbonate track-etched membranes demonstrated that the growth of neural processes through pores required confluent cultures. To direct low density cultures, funnel-shaped pores were machined into glass coverslips, and neurite interaction with angled pore edges was analysed. Live-imaging results showed that neurites more often crossed shallower edges, and retreated from steeper edges. Concerning development of dense cultures, neural culture in non-granular hyaluronic acid (HA) hydrogels showed cell clustering and reduced neurite extension. A protocol adding secondary structure to the scaffold by granulating HA hydrogel was optimized, and cell viability and connectivity within the hydrogel were analysed. Cell viability in the granular hydrogel was comparable to the control, and there was improvement of network connectivity in granular hydrogels over non-granular counterparts. Potential application to improve nerve graft technology motivated the design of an extrusion device that generates tertiary structure by interspersing cell-seeded and unseeded granular HA hydrogel, facilitating control of cell distribution and alignment within the scaffold. Tertiary extruded and non-extruded hydrogels were analysed, and distribution was maintained within the tertiary extruded hydrogel scaffold, without detriment to the cell functionality. It is hypothesized that additional guidance cues could be added to the scaffolds to control cellular alignment. Findings demonstrate the fabrication of structured scaffolds optimized for neural network growth, and highlight strategies that can be used in the production of in vitro neural models for complex CNS study