Residual Solvent Content Research Articles

Detection of Residual Solvent in Solvent-Extracted Unconventional Oil Ore Gangues

The solvent extraction technology is a promising method for recovery of unconventional oil resources because of its high efficiency, low energy consumption, and high compatibility. Solvent selection and solvent loss are the main limitations in terms of industrialization of the technology. To evaluate the solvent, efficient detection of the residual solvent content in the extracted-oil gangue is also a problem. A solvent extraction-gas chromatography (GC) combined method is proposed for fast determination of residual organic solvent in extracted-oil ore gangues (mixed with process water). To improve the precision, a combination of the external standard method and the internal standard method (ES&IS method) was applied. This analytical method shows a relative standard deviation (RSD) of less than 2%. The recovery of residual solvent was in the range of 95.4 ~ 102.0 wt% (for a spiked organic solvent content of 0.5 to 25.0 wt%). It is also found that whatever types of solvent (ethanol, tetrahydrofuran, cyclohexane, n-heptane, acetone, ethyl acetate, or toluene) are used, the method detection limit (MDL) can be less than 0.023 mg/mg. The whole procedure of this method, including the pretreatment and instrumental detection, can be finished in-situ in a relatively short time (less than 1.5 hours). On the other hand, due to the simple application of solvent extraction pretreatment and GC detection, this measurement can be a low-cost one. Therefore, it can be applied to solvent selection and solvent recovery method evaluation and propel the industrialization of the solvent extraction technology.

Nonspecific Impurities in Pharmaceutical Substances: Characteristics of Test Methods

One of the prerequisites of efficacy and safety of finished pharmaceutical products is the quality of pharmaceutical substances used in their production. Criteria of assessment of pharmaceutical substance purity are determined by the substance composition and production technology, as well as by specific aspects of the finished pharmaceutical product production and use. It is necessary to control the content of nonspecific organic and inorganic impurities, impurities of microbial origin, and residual solvents. The aim of the study was to analyse characteristics of test methods used to determine nonspecific impurities in pharmaceutical substances. The State Pharmacopoeia of the Russian Federation describes various chemical, physical, physicochemical and biological tests for the analysis of nonspecific impurities. Determination of inorganic cations and anions usually includes comparison of test solutions with solutions of the corresponding reference standards, or checking the absence of a positive reaction in the test solution. Quantitative analysis of trace impurities largely relies on highly specific and sensitive test methods, such as atomic absorption spectrometry, atomic emission spectrometry and inductively coupled plasma mass spectrometry. The content of residual organic solvents is determined by gas chromatography or high-performance liquid chromatography. The purity and safety of pharmaceutical substances are ensured by biological tests: “Microbial quality”, “Sterility”, “Pyrogenicity”, “Bacterial endotoxins”. Specific characteristics of test methods used for determination of the content of nonspecific impurities in various pharmaceutical substances depend on physicochemical properties of the tested substances, toxicity of the analysed impurities, and content limits. The results of the study make it possible to formulate a methodological approach to the development of criteria for assessing the quality of pharmaceutical substances. This approach includes mandatory compliance with the basic principles of substance standardisation, as well as case-by-case selection of quality parameters, specific test conditions and content limits for impurities.

Merits of sponge-like PLGA microspheres as long-acting injectables of hydrophobic drug

Our study was initiated to challenge the preconception that nonporous PLGA microspheres with compact matrices should be used to develop long-acting depot injectables of hydrophobic drugs. A simple, new oil-in-water emulsion technique was utilized to produce porous PLGA microspheres with a sponge-like skeleton. Then, their applicability to developing sustained-release depots of hydrophobic drugs was explored in this study. As control, nonporous microspheres with a compact matrix were produced following a typical solvent evaporation process. Both microsphere manufacturing processes used non-halogenated isopropyl formate and progesterone as a dispersed solvent and a model hydrophobic drug, respectively. Various attempts were made to evaluate critical quality attributes of the porous microspheres and the nonporous ones. Surprisingly, the former displayed interesting features from the viewpoints of manufacturability and microsphere quality. For example, the spongy microspheres improved drug encapsulation efficiency and particle size uniformity, inhibited drug crystallization during microencapsulation, and minimized the residual solvent content in microspheres. Furthermore, the porous microspheres provided continual drug release kinetics without a lag time and much faster drug release than the non-porous microspheres did. In summary, the porous and sponge-like PLGA microspheres might find lucrative applications in developing sustained release dosage forms of hydrophobic drugs.

Dry powder inhaler of colistimethate sodium for lung infections in cystic fibrosis: optimization of powder construction

Colistimethate sodium (CMS) for treatment of lung infections in cystic fibrosis patient was transformed into a dry powder for inhalation by spray drying. Design of Experiment was applied for understanding the role of the spray-drying process parameters on the critical quality attributes of the CMS spray-dried (SD) powders and agglomerates thereof. Eleven experimental SD microparticle powders were constructed under different process conditions according to a central composite design. The SD microparticles were then agglomerated in soft pellets. Eleven physico-chemical characteristics of SD CMS microparticle powders or agglomerates thereof were selected as critical quality attributes. The yield of SD process was higher than 75%. The emitted fraction of agglomerates from RS01 inhaler was 75–84%, and the fine particle fraction (particles <5 µm) was between 58% and 62%. The quality attributes of CMS SD powders and respective agglomerates that were significantly influenced by spray-drying process parameters were residual solvent and drug content of the SD microparticles as well as bulk density and respirable dose of the agglomerates. These attributes were also affected by the combination of the process variables. The air aspiration rate was found as the most positively influential on drug and solvent content and respirable dose. The residual solvent content significantly influenced the powder bulk properties and aerodynamic behavior of the agglomerates, i.e. quality attributes that govern drug metering in the device and the particles lungs deposition. Agglomerates of CMS SD microparticles, in combination with RS01 DPI, showed satisfactory results in terms of dose emitted and fine particle fraction.

Effect of relative-stoichiometry on the shape and catalytic properties of cobalt antimonide (CoSb)

This article presents a report regarding the low cost synthesis of highly crystalline single phase CoSb nanoparticles of different morphology. Shape control without the presence of any reducing/capping agent makes the work interesting, as it was only the variation in stoichiometry which played the game. It was observed that off-stoichiometry makes the conditions favorable for the growth of one dimensional structure. A hypothetical explanation regarding the diffusion based growth mechanism is also proposed in the discussions. However, the catalytic performance observed for the dimensional structures was not much impressive, which was understood in terms of the residual solvent content that remained adsorbed on the surface of the nanoparticles. The approach employed here is also expected to yield similar control over the morphology of other intermetallic compounds also.

Reprocessing of Irradiated [18O]H2O under the Conditions of a PET Center

The possibility of reprocessing of irradiated [18O]H2O after isolation of [18F]fluoride ion from it (regenerate) under the conditions of the cyclotron-radiochemical laboratory of an operating PET center was examined. The radionuclide and chemical composition of [18O]H2O and the degree of its enrichment in 18O before and after distillation at atmospheric pressure were studied comprehensively. The suggested method allows efficient removal of long-lived γ-emitting radionuclides (56Co, 57Co, 58Co, 65Zn, 54Mn, 51Cr) from the [18O]H2O regenerate. The distillation reduces the content of residual solvents (acetaldehyde, acetone, isopropanol, ethanol, acetonitrile), whereas the content of 3H and 18O in [18O]H2O changes within the measurement uncertainty. The distillation residues and decontamination solutions after neutralization can be jointly cemented to incorporate the γ-emitters into a compact matrix with the aim of its subsequent delivery to specialized organizations performing long-term storage and disposal of solid radioactive waste.

Stability test of novel combined formulated dry powder inhalation system containing antibiotic: physical characterization and in vitro–in silico lung deposition results

Objective: The aim was to study the stability of dry powder inhaler (DPI) formulations containing antibiotic with different preparation ways – carrier-based, carrier-free, and novel combined formulation – and thereby to compare their physicochemical and in vitro–in silico aerodynamical properties before and after storage. Presenting a novel combined technology in the field of DPI formulation including the carrier-based and carrier-free methods, it is the most important reason to introduce this stable formulation for the further development of DPIs.Methods: The structure, the residual solvent content, the interparticle interactions, the particle size distribution and the morphology of the samples were studied. The aerodynamic values were determined based on the cascade impactor in vitro lung model. We tested the in silico behavior of the novel combined formulated samples before and during storage.Results: The physical measurements showed that the novel combined formulated sample was the most favorable. It was found that thanks to the formulation technique and the use of magnesium stearate (MgSt) has a beneficial effect on the stability compared with the carrier-based formulation without MgSt and carrier-free formulations. The results of in vitro and in silico lung models were consistent with the physical results, so the highest deposition was found for the novel combined formulated sample during the storage.Conclusions: It can be established that after the storage a novel combined formulated DPI contained amorphous drug to have around 2.5 μm mass median aerodynamic diameter and nearly 50% fine particle fraction predicted high lung deposition in silico also.

Drying of cellulose nanocrystal gel beads using supercritical carbon dioxide

AbstractBACKGROUNDThe effects of the conditions for the supercritical carbon dioxide (scCO2) drying of cellulose nanocrystal (CNC) wet gel were investigated on the residual solvent content, the shrinkage and the microstructure of the ensuing aerogel.RESULTSThe scCO2 drying of CNC wet gel could be divided into a spillage phase and an extraction phase. In the first phase, just a very short time after the beginning of drying, shrinkage occurred and more than half of the solvent was removed. No further shrinkage was observed thereafter, but the solvent continued to be exponentially removed. Increasing pressure, temperature and time were favorable for solvent removal and the reduction of aerogel shrinking. The shrinkage increased the pore size inside the aerogel and made the outer surface of the CNC aerogel much denser than its interior. To preserve the original microstructure of the wet gel, the optimal drying was performed at 11.04 MPa and 40 °C for 120 min. At these conditions, the shrinkage ratio was only inversely proportional to the CNC content in the wet gel.CONCLUSIONCNC aerogel was obtained with a shrinkage ratio of 3.1%, a surface area of 387 m2 g−1 and an average pore size of 7.2 nm using 3.0% (w/w) CNC wet gel. © 2019 Society of Chemical Industry

Continuous manufacturing of orally dissolving webs containing a poorly soluble drug via electrospinning

An orally dissolving web (ODW) formulation of poorly soluble carvedilol (CAR) was developed and manufactured continuously using electrospinning (ES) as a key technology. Phase solubility tests revealed that hydroxypropyl-β-cyclodextrin (HPβCD) solubilizer alone cannot ensure sufficient solubility (6.25 mg CAR in 20 mL) in the oral cavity even if citric acid was present to ionize the basic drug. In turn, electrospun amorphous nanofibers of polyvinylpyrrolidone K30 (PVPK30) and CAR exhibited notable supersaturation of the drug in the presence of citric acid. Differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD) confirmed the amorphous state of CAR. The final ODW was prepared by layering the nanofibers onto pullulan, a well-soluble polysaccharide film carrying citric acid. The double-layered formulation showed ultrafast disintegration and dissolution modeling the oral cavity meeting regulatory requirements (<30 s). The continuous production was accomplished using our recently developed continuous model system by controlled deposition of the nanofibers onto the carrier film strained to a wheel collector and followed by cutting into final dosage units. Performance tests of the continuous system revealed satisfactory content uniformity over time (average acceptance value = 9.45), while residual solvent content measurements showed trace amounts of ethanol (EtOH) after production and acceptable dimethyl-formamide (DMF) content with secondary drying at room temperature. The presented work demonstrates how ES can be part of a continuous manufacturing system as an advanced drying tool during the formulation of challenging drugs.

Size Reduction of HNS to Nanoscale by in Tandem Application of Chemo‐mechanical methods

AbstractThe present study was undertaken to evaluate and compare the extent of particle size reduction of HNS and its characterization by applying sequentially the solvent based crystallization, ultrasonication, and ball‐milling. It was found that submicron ultrafine HNS (UF‐HNS) of mean diameter ∼0.5 μm with a size range extending to micron scale (∼3 μm) was produced by the solvent‐antisolvent crystallization process. This HNS was subsequently subjected to long duration ultrasonication up to 28 h and planetary ball milling up to 8 h. The HNS particles were characterized for morphology and particle size by scanning electron microscope (SEM), laser diffraction‐based and dynamic light scattering based particle size analyzer (PSA). The structural analysis was done by FTIR and thermal stability by the thermo‐gravimetric analyzer (TGA). The residual solvent content was estimated by headspace GC‐MS. Impact and friction sensitivity were evaluated by BAM fall hammer and friction sensitivity tester. Compared to ultrasonication varying from 4 h to 28 h, planetary ball milling of the micron‐sized HNS caused the size reduction to maximum extent and resulted in production of nano‐scale HNS (∼300 nm average diameter) with a very narrow size distribution of less than 1 μm which had lower impact sensitivity, thermal stability and lesser residual solvent content compared to micron‐sized HNS (UF‐HNS). Thus, nanoscale HNS with a very narrow size distribution was produced by application of the mechanical method of ball milling sequentially to the solvent based crystallization process.

KARAKTERISTIK DAN SKRINING FITOKIMIA EKSTRAK ETANOL 70% BATANG KEPUH (Sterculia foetida L.)

Kepuh (Sterculia foetida L) is a type of kapok plant that has been scientifically proven to have activity as an anti-inflammatory and analgesic. 70% ethanol extract of stem stem is obtained by maceration using 70% ethanol. Examination of the characteristics of 70% ethanol extract of kepuh stem included organoleptic, of moisture content and determination of residual solvent content. Phytochemical screening of 70% ethanol extract of kepuh bark includes: alkaloid, flavonoid, saponin, tannin , polyphenol, and examination of glycosides. The results of the examination of the characteristics of 70% ethanol extract of kepuh stem obtained water content of 8.66 ± 0.748%, the residual content of the solvent had a 0 (zero) ethanol level. The results of phytochemical screening showed 70% ethanol extract of stem stem containing steroid compounds, triterpenoids, flavonoids, saponins, tannins and polyphenols. The identification using UV-Vis spectrophotometry produced ? 212, the absorbance was 1.8601 and ? 284, the absorbance was 0.42186.

Lysozyme-Based Composite Drug Preparations for Inhalation Administration

Inhalation delivery is a promising route for drug administration. The particles of drug aerosol must have a diameter between 1 and 3 μm. The use of microspherical particles based on protein matrix allows for enhanced bioavailability of poorly water-soluble drugs and improved biocompatibility. In the present work, spray drying method was employed for the preparation of the microspherical particles of lysozyme with a model drug compound phenacetin. The average aerodynamic radius of the prepared particle is 1 μm. We show that the spray drying regime produces microparticles with low residual solvent content. The release time of phenacetin from the microspherical particles is much lower than that of the pure drug. These results allow developing a strategy for the production of the protein matrix-based systems for the inhalation delivery of poorly water-soluble drugs.

Pilot evaluation of an aqueous/nonaqueous hybrid bitumen extraction process for mineable oil sands

An aqueous/nonaqueous hybrid bitumen extraction (HBE) process for mined oil sand has the potential to reduce thermal energy demand and greenhouse gas emissions while integrating the productivity and robustness of the current commercial process. The process involves the application of a small amount of solvent to pre-soak the mined ore prior to slurry conditioning, followed by the currently used water-based process, albeit at a lower temperature (e.g. 20 °C) and with no need for caustic addition. In this work, the HBE technology is advanced to the testing of a pilot continuous flow system of 100 kg per hour. This communication describes the extraction outcomes of a series of pilot HBE flotation tests conducted at various extraction conditions, and determination of the respective residual solvent contents in the extraction tailings. Results showed that bitumen recoveries and froth qualities from the pilot HBE process depended on the type and dosage of solvent used to soak the ore prior to slurry conditioning, as well as on the slurry conditioning and residence time. Importantly, lower-temperature HBE could produce comparable or higher bitumen recoveries than those achieved using standard Clark hot water extraction; bitumen froth generated from ambient HBE contained lower fines or water contents. The amount of residual solvent in the tailings produced from the pilot hybrid extractions largely correlated to the unrecovered bitumen percentage. For good-processing ores, for which over 90% bitumen recoveries were achieved, the amount of solvent lost to the tailings was below the regulatory limit even without the use of a tailings solvent recovery unit.

CHROMATOGRAPHIC DETERMINATION OF RESIDUAL ORGANIC SOLVENTS IN (2R,4R,4aR,7R,8aR)-4,7-DIMETHYL-2-(THIOPHEN-2-YL)OCTAHYDRO-2H- CHROMEN-4-OL WHICH EXHIBITS HIGH ANALGESIC ACTIVITY

Introduction of a substance into medical practice requires the indispensable evidence of the substance purity as early as the stage of preclinical testing. The content of residual organic solvents, which can affect the pharmacological activity of the drug, is one of the indicators of the substance quality control. Four solvents are used during synthesis and isolation of the substance: dichloromethane, ethyl acetate, methyl tert -butyl ether (MTBE), and n -hexane. Two methods of determining residual organic solvents in (2 R ,4 R ,4 aR ,7 R ,8 aR )-4,7-dimethyl-2-(thiophen-2-yl)octahydro-2 H -chromen-4-ol using gas chromatography are offered: i) introduction of a gas sample and separation of the components on a commercial HP-5ms capillary column (30 m × 0.35 mm × 0.25 im); ii) introduction of a liquid sample and separation on a capillary column (30 m × 0.32 mm × 0.30 im) filled with a modified poly(1-trimethylsilyl-1- propyne) (PTMS). Since the first method provides only determination of n -hexane and ethyl acetate, the procedure was developed and validated for determination of four residual solvents, i.e., dichloromethane, ethyl acetate, methyl n -butyl ether, and n -hexane in test substance using gas chromatography on the column with a modified PTMSP-based phase. We detected trace amounts of ethyl acetate and methyl n -butyl ether; the content of dichloromethane and n -hexane in the substance appeared below the detection limits. The average content of ethyl acetate and MTBE in the substance for 9 parallel determinations (0.10 and 0.20 ppm) appeared 5 and 2.5 × 104 times lower than maximum permissible content (5000 ppm), respectively. The developed technique was assessed for: specificity, linearity of the calibration curve, correctness, precision at the level of the repeatability and intralaboratory precision, and stability of the chromatographic system. Standard deviations in the determination of ethyl acetate and MTBE in the substance do not exceed 0.03 and 0.09, respectively. The procedure is specific, accurate and reliable for determination of the residual organic solvents in the substance.

Reverse Engineering the 1-Month Lupron Depot®.

The 1-month Lupron Depot® (LD) encapsulating water-soluble leuprolide in poly(lactic-co-glycolic acid) (PLGA) microspheres is a benchmark product upon which modern long-acting release products are often compared. Despite expiration of patent coverage, no generic product for the LD has been approved in the USA, likely due to the complexity of components and manufacturing processes involved in the product. Here, we describe the reverse engineering of the LD composition and important product attributes. Specific attributes analyzed for microspheres were as follows: leuprolide content by three methods; gelatin content, type, and molecular weight distribution; PLGA content, lactic acid/glycolic acid ratio, and molecular weight distribution; mannitol content; in vitro drug release; residual solvent and moisture content; particle size distribution and morphology; and glass transition temperature. For the diluent, composition, viscosity, and specific gravity were analyzed. Analyzed contents of the formulation and the determined PLGA characteristics matched well with the official numbers stated in the package insert and those found in literature, respectively. The gelatin was identified as type B consistent with ~ 300 bloom. The 11-μm volume-median microspheres in the LD slowly released the drug in vitro in a zero-order manner after ~ 23% initial burst release. Very low content of residual moisture (< 0.5%) and methylene chloride (< 1ppm) in the product indicates in-water drying is capable of removing solvents to extremely low levels during manufacturing. The rigorous approach of reverse engineering described here may be useful for development of generic leuprolide-PLGA microspheres as well as other new and generic PLGA microsphere formulations.

Amorphous Fluoropolymer Membrane for Gas Separation Applications.

Amorphous fluoropolymers have been studied in the past few decades and received extensive attention due to their unique and useful properties. One of the remarkable properties of amorphous fluoropolymers is high fractional free volume (FFV), and they tend to retain large amounts of solvent inside their polymer chains. In this study, amorphous flouoropolymer membranes were employed to examine the influences of the residual solvent and drying condition on the thermal properties, gas permeation behavior, and structure change by the polymer chains. Thermal properties of the produced membranes were characterized by differential scanning calorimetry (DSC) and a thermogravimetric analysis (TGA) to verify the effects of residual solvent. The residual solvent content and the glass transition temperature (Tg) of amorphous fluoropolymer membranes prepared with both solvents decrease with increasing drying temperature. The effect of the thermal treatment method on the d-spacing between the polymer chains of the prepared membranes was investigated using X-ray diffraction (XRD). The d-spacing decreased with drying below the Tg whereas it drastically increased near the Tg because of chain relaxation. From these phenomena, the helium permeability of the membranes treated at 120 °C radically increased. However, the oxygen and nitrogen permeability decreased with decreasing residual solvent content. The glass transition range shifted to higher temperature, from 75 °C to 133 °C, depending on the reduced amount of residual solvent.

Development of a new formulation of roflumilast for pulmonary drug delivery to treat inflammatory lung conditions

The aim of this study was to develop roflumilast dry powder inhaler (DPI) formulations by spray drying using hydroxypropyl-β-cyclodextrin (HPβCD) and to determine their suitability for pulmonary delivery. Different feed solution concentrations, solvent systems and spray drying parameters were used to obtain the formulations which were characterized using X-ray powder diffraction, thermal analysis, scanning electron microscopy, particle size distribution, bulk and tapped density, specific surface area, dynamic vapour sorption, in vitro deposition properties using a Next Generation Impactor (NGI) and transepithelial permeability. Microparticles spray dried from ethanol were wrinkled and amorphous, exhibiting high glass transition temperatures while those from methanol:n-butyl acetate consisted of irregularly shaped porous particles partially crystalline. All formulations presented low density, particle size and residual solvent content exhibiting high depositon in the lower stages of the NGI. Mass median aerodynamic diameters (MMADs) were in the range of 3.32–4.49 μm, with high fine particle fractions (FPF < 5 μm). Stability studies demonstrated no significant modifications in the solid-state nature and in the aerolisation performance of the selected formulation which presented a Papp of 8.73 × 10−6 ± 4.70 × 10−7 cm/s. The developed roflumilast DPI formulations have potential therapeutic applications in the treatment of lung diseases.

Amorphous Enzalutamide – Non-isothermal recrystallization kinetics and thermal stability

Recrystallization kinetics of amorphous Enzalutamide (two batches prepared by hot-melt extrusion and thermal evaporation of the solvent) was studied by differential scanning calorimetry. The preparation route was found to have significant effect on material thermal stability and initial degree of crystallinity – solvent evaporation led to formation of partially crystalline matrix with residual solvent content causing plasticization and the ongoing thermally induced crystallization was largely accelerated. Thermal recrystallization of both Enzalutamide batches led to a similar polymorphic form. The recrystallization kinetics was evaluated by means of modified multivariate kinetic analysis and described in terms of the autocatalytic Šesták-Berggren and the nth order autocatalytic reaction models. The recrystallization kinetics were found to be dependent on applied heating rate, gradually shifting from the nucleation-growth kinetics to the autocatalyzed 0th order kinetics (with the effective order of reaction changing from 1 to 0.2). The autocatalytic Šesták-Berggren model appears to be more suitable for predictions of the Enzalutamide recrystallization behavior due to the constancy of the autocatalytic term (M = 0.55) with regard to the experimental conditions. In addition, the kinetic predictions of crystallization in pharmaceuticals were discussed in general based on theoretical simulations – importance of the aspects influencing the kinetic predictions was demonstrated.

KARAKTERISTIK FISIKOKIMIA ANTOSIANIN EKSTRAK KULIT BUAH NAGA MERAH MENGGUNAKAN METODE UAE (Physicochemical Characteristics of Red Dragon Fruit Skin Anthocyanin Extracts using UAE Method)

Red dragon fruit skin (Hylocereus polyrhizus) contains naturally pigment as anthocyanin. Anthocyanins can be extracted using conventionally or other method. Ultrasound Assisted Extraction (UAE) is a prospective extraction method because resulting higher yield and shorten time process. The aim of this study was to identify the effect of extraction time and amplitude to the physicochemical characteristic of extract red dragon fruit’s skin. The maceration method was used as control treatment. The parameters observed were total extraction yield, residual solvent content, anthocyanin content, pH, specific gravity and colour. The method used was laboratory experiment by using descriptive analysis. The research showed extraction time at 45 minutes and amplitude number 65% was a best variables extraction which resulted total yield 10.62%, residual solvent content 37.50%, specific gravity 1.2198, total anthocyanin content 29.640 ppm, pH 2.80, respectively. Based on hue angle (23.42o) indicated that the dragon fruit peel extract was red colour. Meanwhile, control treatment resulted a total yield was 9.44%, residual solvent content was 52.67%, specific gravity 1.0609, total anthocyanin content 24.074 ppm, pH 3.06, and hue angle 33.16o. The UAE method revealed a better extraction method than maceration to produce a higher red dragon fruit’s skin extracts and anthocyanin concentration.&#x0D; Keywords: anthocyanin, extract, physicochemical characteristic, red dragon fruit skin, UAE&#x0D; &#x0D; ABSTRAKKulit buah naga merah (Hylocereus polyrhizus) mengandung pigmen alami sebagai antosianin. Antosianin dapat diekstraksi dengan cara konvensional atau metode lainnya. Ultrasound Assisted Extraction (UAE) merupakan metode ekstraksi prospektif karena menghasilkan rendemen lebih tinggi dan waktu proses lebih singkat. Penelitian ini bertujuan untuk mengkaji lama waktu ekstraksi dan amplitudo terhadap karakteristik fisikokimia ekstrak kulit buah naga merah. Metode maserasi dilakukan sebagai kontrol. Karakteristik ekstrak yang diamati meliputi rendemen, kadar sisa pelarut, total antosianin, pH, bobot jenis dan warna. Metode penelitian yang digunakan adalah penelitian eksperimental laboratorium dengan analisis deskriptif. Hasil penelitian menunjukkan bahwa kulit buah naga merah dengan amplitudo 65% dan lama ekstraksi 45 menit merupakan perlakuan terbaik dengan rendemen total 10,62%, kadar sisa pelarut 37,50%, bobot jenis 1,2198, kadar total antosianin sebesar 29,640 ppm, pH 2,80. Berdasarkan nilai hue (23,42o) ekstrak tersebut berwarna merah. Sedangkan perlakuan kontrol menghasilkan rendemen total 9,44%, kadar sisa pelarut 52,67%, bobot jenis 1,0609, kadar total antosianin sebesar 24,074 ppm, pH 3,06 dan hue 33,16o. Pada penelitian ini dibuktikan bahwa metode UAE menghasilkan lebih banyak ekstrak kulit buah naga merah dan konsentrasi antosianin lebih tinggi dibandingkan metode maserasi.&#x0D; Kata kunci: antosianin, ekstrak, karakteristik fisikokimia, kulit buah naga merah, UAE

Continuous manufacturing and analytical characterization of fixed-dose, multilayer orodispersible films

Various drug therapies require more than one active pharmaceutical ingredient (API) for an effective treatment. There are many advantages, e.g. to improve the compliance or pharmacodynamic response in comparison to a monotherapy or to increase the therapy safety. Until now, there are only a few products available for the paediatric population due to the lack of age appropriate dosage forms or studies proving the efficacy and safety of these products. This study aims to develop orodispersible films (ODFs) in a continuous solvent casting process as child appropriate dosage form containing both enalapril maleate (EM) and hydrochlorothiazide (HCT) separated in different film layers. Furthermore, they should be characterised and the API migration analysed by confocal Raman microscopy (CRM).ODFs were successfully produced in a continuous manufacturing process in form of double- and triple-layer formulations based on hydroxypropylcellulose (HPC) or a combination of HPC and polyvinyl alcohol (PVA). CRM revealed that both APIs migrate within the film layers shortly after manufacturing. PVA inhibits the migration inside the double-layer film, but is not able to prevent the API migration as an interlayer inside a triple-layer ODF. With increasing film layers, the content of residual solvents and the disintegration time increases (mono-layer films: <10 s, triple-layer films: 37 s). In conclusion, it was feasible to produce fixed-dose combinations in therapeutic doses up to 9 mg HCT and 3.5 mg EM for the double-layer film with adequate mechanical properties, which enable coiling up onto jumbo rolls directly after production. The best separation of the two APIs was achieved by casting a double-layer ODF consisting of different film forming polymers, which can be beneficial when processing two incompatible APIs.