Establishment of a continuous sonocrystallization process for lactose in an oscillatory baffled crystallizer

Crystallization at production scale (>10 kg) is typically a poorly understood unit operation with limited application of first-principles understanding of crystallization to routine design, optimization, and control. In this study, a systematic approach has been established to transfer an existing batch process enabling the implementation of a continuous process in an oscillatory baffled crystallizer (OBC) using ultrasound. Process analytical technology (PAT) was used to understand and monitor the process. Kinetic and thermodynamic parameters have been investigated for lactose sonocrystallization using focused beam reflectance measurement (FBRM) (Mettler Toledo) and mid-infrared spectroscopy (mid-IR) (ABB) in a multiorifice batch oscillatory baffled crystallizer (Batch-OBC). This platform provides an ideal mimic of the mixing, hydrodynamics and operating conditions of the continuous oscillatory flow crystallizer (COBC) while requiring only limited material. Full characterization of the hydrodynamics of the COBC was carried out to identify conditions that deliver plug-flow behavior with residence times of 1–5 h. The results show that continuous crystallization offers significant advantages in terms of process outcomes and operability, including particle size distribution (mean particle size <1500 μm) of alpha lactose monohydrate (ALM), as well as reduced cycle time (4 h compared to the 13–20 h in a batch process). Continuous sonocrystallization was performed for the first time at a throughput of 356 g·h–1 for 12–16 h. During the run at near plug flow, with supersaturation and controlled nucleation using sonication, no issues with fouling or agglomeration were observed. This approach has demonstrated the capability to provide close control of particle attributes at an industrially relevant scale

Sum frequency generation spectroscopy of the attachment disc of a spider

The pyriform silk of the attachment disc of a spider was studied using infrared-visible vibrational sum frequency generation (SFG) spectroscopy. The spider can attach dragline and radial lines to many kinds of substrates in nature (concrete, alloy, metal, glass, plant branches, leaves, etc.) with the attachment disc. The adhesion can bear the spider's own weight, and resist the wind on its orb web. From our SFG spectroscopy study, the NH group of arginine side chain and/or NH$_{2}$ group of arginine and glutamine side chain in the amino acid sequence of the attachment silk proteins are suggested to be oriented in the disc. It was inferred from the observed doublet SFG peaks at around 3300 cm$^{-1}$ that the oriented peptide contains two kinds of structures.Comment: 21 pages, 8 figure

Control over phase separation and nucleation using a laser-tweezing potential

Control over the nucleation of new phases is highly desirable but elusive. Even though there is a long history of crystallization engineering by varying physicochemical parameters, controlling which polymorph crystallizes or whether a molecule crystallizes or forms an amorphous precipitate is still a poorly understood practice. Although there are now numerous examples of control using laser-induced nucleation, the absence of physical understanding is preventing progress. Here we show that the proximity of a liquid–liquid critical point or the corresponding binodal line can be used by a laser-tweezing potential to induce concentration gradients. A simple theoretical model shows that the stored electromagnetic energy of the laser beam produces a free-energy potential that forces phase separation or triggers the nucleation of a new phase. Experiments in a liquid mixture using a low-power laser diode confirm the effect. Phase separation and nucleation using a laser-tweezing potential explains the physics behind non-photochemical laser-induced nucleation and suggests new ways of manipulating matter

Synthesis of Pure Aragonite by Sonochemical Mineral Carbonation.

The objective of this work was to promote the formation of the aragonite polymorph of calcium carbonate, which has some valuable applications in industry, via the mineral carbonation route. The combination of ultrasound with magnesium ions promoted the formation of pure aragonite crystals at optimum conditions. It was possible to synthesize high purity aragonite precipitates at temperatures ranging from 24 oC to 70 oC, with the resulting powders possessing varying particle size distributions (from sub-micron up to 20 μm) and crystal morphologies (from acicular needles to novel hubbard squash-like particles). Several process parameters were found to influence the produced calcium carbonate polymorph ratios (aragonite over calcite). Higher values of magnesium-to-calcium ratio, intermediate ultrasound amplitude (60%), continuous ultrasound application (100% cycle), introduction of ultrasound pre-breakage, lowering of the CO2 flow rate, and increase in the relative concentration (g/L Ca(OH)2), all promoted aragonite formation. A potential route for industrial production of this material has been identified via a fed-batch process, which effectively reutilizes magnesium chloride while maintaining high aragonite yield. The results presented herein are significantly superior to aragonite formation using only single promoting techniques, typically found in literature, and go beyond by focusing on pure (\u3e99%) aragonite formation

Study of the transformations of micro/nano-crystalline acetaminophen polymorphs in drug-polymer binary mixtures

This study elucidates the physical properties of sono-crystallised micro/nano-sized acetaminophen/paracetamol (PMOL) and monitors its possible transformation from polymorphic form I (monoclinic) to form II (orthorhombic). Hydrophilic Plasdone® S630 copovidone (S630), N-vinyl-2-pyrrolidone and vinyl acetate copolymer, and methacrylate-based cationic copolymer, Eudragit® EPO (EPO), were used as polymeric carriers to prepare drug/polymer binary mixtures. Commercially available PMOL was crystallised under ultra sound sonication to produce micro/nano-sized (0.2–10 microns) crystals in monoclinic form. Homogeneous binary blends of drug-polymer mixtures at various drug concentrations were obtained via a thorough mixing. The analysis conducted via the single X-ray crystallography determined the detailed structure of the crystallised PMOL in its monoclinic form. The solid state and the morphology analyses of the PMOL in the binary blends evaluated via differential scanning calorimetry (DSC), modulated temperature DSC (MTDSC), scanning electron microscopy (SEM) and hot stage microscopy (HSM) revealed the crystalline existence of the drug within the amorphous polymeric matrices. The application of temperature controlled X-ray diffraction (VTXRPD) to study the polymorphism of PMOL showed that the most stable form I (monoclinic) was altered to its less stable form II (orthorhombic) at high temperature (>112°C) in the binary blends regardless of the drug amount. Thus, VTXRD was used as a useful tool to monitor polymorphic transformations of crystalline drug (e.g. PMOL) to assess their thermal stability in terms of pharmaceutical product development and research

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

Design of Agglomerated Crystals of Ibuprofen During Crystallization: Influence of Surfactant

Objective(s)Ibuprofen is a problematic drug in tableting, and dissolution due to its poor solubility, hydrophobicity, and tendency to stick to surface. Because of the bad compaction behavior ibuprofen has to be granulated usually before tableting. However, it would be more satisfactory to obtain directly during the crystallization step crystalline particles that can be directly compressed and quickly dissolved. Materials and Methods Crystallization of ibuprofen was carried out using the quasi emulsion solvent diffusion method in presence of surfactant (sodium lauryl sulfate (SLS), Tween 80). The particles were characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (XRPD) and were evaluated for particle size, flowability, drug release and tableting behavior. ResultsIbuprofen particles obtained in the presence of surfactants consisted of numerous plate- shaped crystals which had agglomerated together as near spherical shape. The obtained agglomerates exhibited significantly improved micromeritic properties as well as tableting behavior than untreated drug crystals. The agglomerates size and size distribution was largely controlled by surfactant concentration, but there was no significant influence found on the tableting properties. The dissolution tests showed that the agglomerates obtained in presence of SLS exhibited enhanced dissolution rate while the agglomerates made in the presence of Tween 80 had no significant impact on dissolution rate of ibuprofen in comparison to untreated sample. The XRPD and DSC results showed that during the agglomeration process, ibuprofen did not undergo any polymorphic changes.Conclusion The study highlights the influence of surfactants on crystallization process leading to modified performance

Uso de microsistemas na precipitação em contínuo de hidroxiapatite

Neste trabalho é apresentado o estudo de dois microreatores ultrasónicos para a precipitação em contínuo de hidroxiapatite Ca5(PO4)3OH (HAp) a 37 º C. O primeiro reator consiste num microreator tubular imerso num banho ultrasónico, onde os fluxos laminar e segmentado (gás-líquido) foram ambos avaliados. De seguida, o estudo em regime laminar foi conduzido num novo dispositivo microfluídico desenvolvido no MIT. Este é constituído por uma pilha de placas de Teflon com um elemento piezoelétrico integrado, permitindo assim a transmissão direta de ultrassons para o reator. Para todos os microsistemas estudados foram obtidas nanopartículas de HAp, em condições próximas das condições fisiológicas de pH e temperatura. Além disso, as partículas produzidas apresentam-se sob a forma de bastonetes de aproximadamente 100 nm de comprimento e 20 a 50 nm de largura. Os microreatores utilizados produziram partículas de HAp num tempo muito curto e com maior cristalinidade, comparado com as partículas produzidas num reator batch. Também foi possível reduzir significativamente a agregação das partículas nos microsistemas, ao contrário do sistema batch, onde não foi possível evitar a formação de agregados.info:eu-repo/semantics/publishedVersio

Continuous-flow precipitation of hydroxyapatite in ultrasonic microsystems

This paper describes the continuous-flow precipitation of hydroxyapatite Ca5(PO4)3OH (HAp) in two ultrasonic microreactors using diluted aqueous solutions of calcium and phosphate at 37 °C. Precipitation of HAp was first carried out in a tubular microreactor immersed in an ultrasonic bath, where single-phase (laminar) flow and segmented gas-liquid flow were both evaluated. The single-phase flow study was then conducted in a novel microfluidic device developed at MIT. It consists of a Teflon stack microreactor with an integrated piezoelectric element (Teflon microreactor), thereby allowing the direct transmission of ultrasound to the reactor. Both microsystems produce single-phased calcium-deficient carbonated HAp under near-physiological conditions of temperature and pH. In addition, particle aggregation and primary particle size were significantly reduced in the segmented-flow tubular microreactor and in the Teflon microreactor. The as-prepared particles mostly consisted of rod-like shape nanoparticles with dimensions below 100 nm in length and around 20 nm in width. Further, the microreactors used yielded HAp particles with improved characteristics text was removed, namely higher crystallinity and less carbonate contamination, when compared to the HAp particles produced in a stirred tank batch reactor.This work was supported by the Portuguese Foundation for Science and Technology (SFRH/BD/42992/2008) through the MIT-Portugal Program, Bioengineering Systems Focus Area. The authors are thankful to Dr. Speakman for his help with the X-ray measurements and with the interpretation of the results. S.K. acknowledges funding from the Swiss National Science Foundation (SNF)

Process intensification and optimization for hydroxyapatite nanoparticles production

Precipitation processes are widely used in industry for the production of particulate solids. Efficient mixing of the reagents is of major importance for the chemical and physical nature of the synthesized particles. Recently, microreactors have been studied to overcome homogeneity problems found when using stirred tank batch reactors. The present work investigated an ultrasonic tubular microreactor for the continuous-flow precipitation of hydroxyapatite (HAp), both in single-phase flow (SPF) and in gas–liquid flow (GLF). HAp nanoparticles were yielded for both configurations under near-physiological conditions of pH and temperature. The as-prepared particles, especially those that were prepared under GLF, show improved characteristics compared to commercial powder or powder obtained in a stirred tank batch reactor. Primary particles are smaller, particle shape is more homogeneous, and the aggregation degree of the particles is lower