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To utilize the effect of probiotics in the oral cavity, an easily applicable, orally dissolving dosage form of Lactobacillus paracasei was prepared by high-speed electrospinning. The scaled-up electrostatic drying technology resulted in high productivity of submicronic, fast-dissolving fibers. To minimize the viability loss of the bacteria, polyvinyl alcohol-polyethylene oxide (PVA-PEO) based polymer systems combined with different stabilizing excipients (glucose, lactose, mannitol, saccharose, trehalose, inulin, and skim milk) were developed. The use of excipients was successful to decrease osmotic and dehydration stress while increasing bacterial survival during electrospinning and long-term storage. The application of trehalose, saccharose, and skim milk as stabilizing excipient, gave 80% or higher bacterial survival during electrospinning; furthermore, in skim milk and mannitol containing formulations 0.5 log unit and 0.2 log unit viability loss was detected after one year. Skim milk showed the best results considering survival rate and long-term stability: after 1 year of storage, a cell count of 7.4 109 CFU/g was measured at 7 °C and 1.56 1010 CFU/g at −20 °C (initial loading was 2.7 1010 CFU/g). Thus, electrospinning using well-selected excipients provides an adequate system that can sustain high-viability of probiotic cells during long-term storage.

Flame retardancy and mechanical performance of multi-layered biocomposites, consisting of polylactic acid (PLA) matrix films and plain-woven flax fabrics as reinforcement, were investigated. Full factorial design (32) was applied to evaluate the effects of the distribution of P and N containing compounds between the matrix and the fibrous carrier. Composition property correlations of the composite constituents (i.e. flax fabrics treated in aqueous solutions of diammonium phosphate and urea with differing ratio and concentrations and matrix films with 0 to 20 wt% ammonium polyphosphate based intumescent flame retardant content) were determined by thermogravimetric analyses and open flame tests. Positive interaction between the composite constituents was revealed for green composites consisting of various combinations of treated fabrics and intumescent PLA systems. The biocomposites flame retarded with a combined approach, i.e. with a balanced distribution of P containing additives between the phases, were found to gain improved mechanical performance and fire retardancy. It was confirmed by tensile testing and electron microscopy as well as by UL-94, limiting oxygen index and cone calorimeter tests. As a conclusion, interpretation is given for the optimum found.

Curcuminoids (CUs) of antitumor and various other potential biological activities have extremely low water solubility therefore special formulation was elaborated. New fast dissolving reconstitution dosage forms of four CUs were prepared as fibrous form of 2-hydroxypropyl-β-cyclodextin (HP-β-CD). In the electrospinning process HP-β-CD could act both as solubilizer and fiber-forming agent. The solubilization efficiency of the CU-HP-β-CD systems was determined with phase-solubility measurements. The electrospun CUs were amorphous and uniformly distributed in the fibers according to XRD analysis and Raman mappings. The fibrous final products had fast (5 min) and complete dissolution. In typical iv. infusion reconstitution volume (20 mL) fibers containing 40-80 mg of CU could be dissolved, which is similar to the currently proposed dose (120 mg/m

In a continuous powder blending process machine vision is utilized as a Process Analytical Technology (PAT) tool. While near-infrared (NIR) and Raman spectroscopy are reliable methods in this field, measurements become challenging when concentrations below 2 w/w% are quantified. However, an active pharmaceutical ingredient (API) with an intense color might be quantified in even lower quantities by images recorded with a digital camera. Riboflavin (RI) was used as a model API with orange color, its Limit of Detection was found to be 0.015 w/w% and the Limit of Quantification was 0.046 w/w% using a calibration based on the pixel value of images. A calibration for in-line measurement of RI concentration was prepared in the range of 0.2−0.45 w/w%, validation with UV/VIS spectrometry showed great accuracy with a relative error of 2.53 %. The developed method was then utilized for a residence time distribution (RTD) measurement in order to characterize the dynamics of the blending process. Lastly, the technique was applied in real-time feedback control of a continuous powder blending process. Machine vision based direct or indirect API concentration determination is a promising and fast method with a great potential for monitoring and control of continuous pharmaceutical processes.

A model anaerobic bacterium strain from the gut microbiome (Clostridium butyricum) producing anti-inflammatory molecules was incorporated into polymer-free fibers of a water-soluble cyclodextrin matrix (HP-β-CD) using a promising scaled-up nanotechnology, high-speed electrospinning. A long-term stability study was also carried out on the bacteria in the fibers. Effect of storage conditions (temperature, presence of oxygen) and growth conditions on the bacterial viability in the fibers was investigated. The viability of the sporulated anaerobic bacteria in the fibers was maintained during 12 months of room temperature storage in the presence of oxygen. Direct compression was used to prepare tablets from the produced bacteria-containing fibers after milling (using an oscillating mill) and mixing with tableting excipients, making easy oral administration of the bacteria possible. No significant decrease was observed in bacterial viability following the processing of the fibers (milling and tableting).

The use of Process Analytical Technology tools coupled with chemometrics has been shown great potential for better understanding and control of mammalian cell cultivations through real-time process monitoring. In-line Raman spectroscopy was utilized to determine the glucose concentration of the complex bioreactor culture medium ensuring real-time information for our process control system. This work demonstrates a simple and fast method to achieve a robust partial least squares calibration model under laboratory conditions in an early phase of the development utilizing shake flask and bioreactor cultures. Two types of dynamic feeding strategies were accomplished where the multi-component feed medium additions were controlled manually and automatically based on the Raman monitored glucose concentration. The impact of these dynamic feedings was also investigated and compared to the traditional bolus feeding strategy on cellular metabolism, cell growth, productivity, and binding activity of the antibody product. Both manual and automated dynamic feeding strategies were successfully applied to maintain the glucose concentration within a narrower and lower concentration range. Thus, besides glucose, the glutamate was also limited at low level leading to reduced production of inhibitory metabolites, such as lactate and ammonia. Consequently, these feeding control strategies enabled to provide beneficial cultivation environment for the cells. In both experiments, higher cell growth and prolonged viable cell cultivation were achieved which in turn led to increased antibody product concentration compared to the reference bolus feeding cultivation.

The effect of different frequencies and waveforms was investigated for the first time on alternating current electrospinning (ACES). PVPVA64, a polyvinylpyrrolidone-vinyl acetate copolymer was selected for the experiments as an important matrix for amorphous solid dispersions but never processed with ACES. It has been proved that ACES could be operated in a wide range of frequencies (40–250 Hz) and using different waveforms (sinusoidal, square, triangle, saw tooth) without significant changes in fiber morphology. Nevertheless, deterioration of the fiber formation process could be also observed especially at high frequencies. The developed PVPVA64-based fibers containing small amounts of additives (polyethylene oxide (PEO) and sodium dodecyl sulfate (SDS)) served as an excellent carrier for spironolactone (SPIR), a poorly soluble antihypertensive drug. As a result of the amorphously dispersed SPIR and the large surface area of the AC electrospun fibers immediate drug release could be achieved.

The flame retardancy of sorbitol-based epoxy resin is targeted. From the bioepoxy 3% phosphorus-containing matrix samples were prepared. Surprisingly, only HB classification of UL-94 test was reach...

Itraconazole is a fungicide drug which has low bioavailability due to its poor water solubility. Amorphous solid dispersion (ASD) is a tool that has the potential to greatly increase the dissolution rate and extent of compounds. In this work, the dissolution of tablets containing the ASD of itraconazole with either hydroxypropyl methylcellulose (HPMC) or vinylpyrrolidone-vinyl acetate copolymer (PVPVA) was compared in order to find a formulation which can prevent the drug from the precipitation caused by magnesium stearate. Formulations containing the PVPVA-based ASD with HPMC included in various forms could reach 90% dissolution in 2 h, while HPMC-based ASDs could release 100% of the drug. However, HPMC-based ASD had remarkably poor grindability and low bulk density, which limited its processability and applicability. The latter issue could be resolved by roller compacting the ASD, which significantly increases the bulk density and the flowability of the powder blends used for tableting. This roller compaction step might be a base for the industrial application of HPMC-based, electrospun ASDs.

Flame-retardant-treated cellulose (FR-cell) was used as bio-based charring agent in combination with ammonium polyphosphate (APP) based intumescent flame retardant (IFR) system to reduce the flammability of poly(lactic acid) (PLA) foams produced by supercritical carbon dioxide (sc-CO2) assisted extrusion. FR-cell was obtained by surface treatment of cellulose with diammonium phosphate (DAP) and boric acid (BA). To enhance foamability, the inherently low melt strength and slow crystallization rate of PLA was increased by adding epoxy-based chain extender (CE) and montmorillonite (MMT) nanoclay, respectively. The morphology of the foams was examined using water displacement method, scanning electron microscopy (SEM) and energy dispersive X-ray spectrometry (EDS). Thermal properties were assessed using differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). Flammability was evaluated by limiting oxygen index (LOI) measurements, UL-94 tests and pyrolysis combustion flow calorimetry (PCFC). The continuous extrusion foaming technique allowed the preparation of low density PLA foams with uniform microcellular structure and void fractions higher than 90% accompanied with increased crystallinity of up to 19%. Despite the high expansion ratios (i.e. high surface area), the PLA foams showed excellent flame retardancy, UL-94 V-0 rate and LOI value of 31.5 vol% was achieved with an additive content as small as 19.5%. However, the flame retardant synergism evinced between IFR and MMT proved to be less pronounced in the expanded foams compared to bulk materials with identical additive contents.

2-hydroxypropyl-β-cyclodextrin (HP-β-CD) microfibres with diameters ranging between 3 and 7 µm were prepared by aqueous solution based high-speed electrospinning (HSES) technique and then used as carbonising agent at 3 wt% loading besides 15 wt% ammonium polyphosphate (APP) to obtain flame-retarded poly(lactic acid) (PLA) composites. The high specific surface area of the microfibrous HP-β-CD was found to have a crucial role in its flame retardant efficiency. Compared to the effect of the same amount of conventional HP-β-CD powder additive, microfibrous HP-β-CD resulted in higher char yields both during thermogravimetric analysis and cone calorimeter test accompanied with significantly increased mechanical resistance and consequently with improved flame retarding efficacy. The Limiting Oxygen Index (LOI) of the intumescent flame-retarded PLA composite increased noticeably, from 29.0% to 32.5%, while the Flame Retardancy Index (FRI), determined from cone calorimetry data, increased from 1.9 (with powder HP-β-CD) to 2.6 (with microfibrous HP-β-CD) only by changing the physical form i.e. the specific surface area of the used HP-β-CD. The advantage of the special microfibrous structure of the oligosaccharide type charring agent lies in the efficient interaction with APP and the attribution of the intumescent char layer with improved thermal and mechanical resistance without compromising its swelling ability. Besides, the microfibrous structure of the HP-β-CD also contributed to the improvement of the mechanical performance of the flame retarded PLA composites.

Disadvantageous crystallization phenomenon of amorphous itraconazole (ITR) occurring in the course of dissolution process was investigated in this work. A perfectly amorphous form (solid dispersion) of the drug was generated by the electroblowing method (with vinylpyrrolidone-vinyl acetate copolymer), and the obtained fibers were formulated into tablets. Incomplete dissolution of the tablets was noticed under the circumstances of the standard dissolution test, after which a precipitated material could be filtered. The filtrate consisted of ITR and stearic acid since no magnesium content was detectable in it. In parallel with dissolution, ITR forms an insoluble associate, stabilized by hydrogen bonding, with stearic acid deriving from magnesium stearate. This is why dissolution curves do not have the plateaus at 100%. Two ways are viable to tackle this issue: change the lubricant (with sodium stearyl fumarate95% dissolution can be accomplished) or alter the polymer in the solid dispersion to a type being able to form hydrogen bonds with ITR (e.g., hydroxypropyl methylcellulose). This work draws attention to one possible phenomenon that can lead to a deterioration of originally good dissolution of an amorphous solid dispersion.

Eudragit® FS (EudFS), a novel anionic metachrylate terpolymer with pH dependent solubility was processed using electrospinning (ES) for the first time and melt extrusion (EX) for controlled delivery of a poorly water-soluble model drug, spironolactone (SPIR). Optimization of ES showed good spinnability of EudFS. Nanofibrous products could be obtained using fairly polar solvents (acetone, dichloromethane-ethanol (1:1), dimethylformamide). Drug-loaded nanofibers were prepared using novel alternating current electrospinning at multiple times higher throughput than direct current electrospinning. Melt extrusion proved to be also a feasible technique to prepare EudFS-based solid dispersions above 100 °C. The viscoelasticity of EudFS melts was characterized in terms of temperature, frequency and heating time dependence. Solid state analyses revealed amorphous SPIR content in the electrospun fibers, however, signs of residual crystallinity could be detected in the extruded sample with 20% SPIR according to XRPD and EDS mapping. In vitro dissolution of the EudFS-based solid dispersions showed superior control of drug release compared to the physical mixture of crystalline SPIR and EudFS. At gastric pH where the polymer is insoluble the drug was more restrained in the ground extrudates than in the electrospun fibers. This state was followed by a quick burst as the pH rose to 7.4. EudFS, well-processed by electrospinning or melt extrusion, proved to be a promising matrix for oral drug delivery applications especially targeting the colon.

A method was elaborated to prepare flame retarded self-reinforced polypropylene composites by injection moulding. The effect of intumescent flame retardant (FR) loading was comprehensively investigated on the morphology, flammability, and mechanical properties of the self-reinforced polypropylene composites and compared with non-reinforced counterparts of identical additive contents. Homogeneous distribution of both the reinforcing polypropylene fibres and the FR additive was achieved endowing significantly improved strength and stiffness accompanied with increased fire resistance. At 10% FR content, 37% reduction of peak of heat release rate, UL94 V-2 rating, and LOI of 24.5 vol% were achieved without compromising the improved mechanical performance of the injection moulded self-reinforced composites, ie, a 4-fold increase of tensile strength and a 7-fold increase of tensile modulus were reached compared with the non-reinforced counterpart. At higher loading (15% FR), the FR properties improved further (LOI of 29.5 vol% was reached); however, due to the abrasive effect of the FR particles in the matrix, the structure of the reinforcing fibres tends to get damaged during the thermo-mechanical processing, and thus their reinforcing efficacy deteriorated. It is demonstrated that the combination of polymer fibre reinforcement with other fillers (such as FRs) is advantageous and feasible even by injection moulding, but the balance between the individual attributed properties needs to be found.

This work was carried out to explore the unknown area of converting non-woven fibres, prepared by high speed electrospinning, into a directly compressible blend by mixing with excipients. An experimental design, with independent variables of compression force and fillers fraction, was realized to investigate tabletability of electrospun material (EM) and to produce hard tablets with appropriate disintegration time. The models proved to be adequate; fitted to the results and predicted values well for the optimal tablet, which was found to be at 76.25% fillers fraction and 6 kN compression force. Besides standard characterizations, distribution of EM was investigated by Raman mapping and scanning electron microscopy revealing the propensity of EM to cover the surface of microcrystalline cellulose and not of mannitol. These analytical tools were also found to be useful at investigating the possible formation of the so-called gelling polymer network in tablets. Scanning electron microscopic pictures of tablets confirmed the maintenance of fibrous structure after compression. The moisture absorption of EM under increasing humidity was studied by dynamic vapour sorption measurement, which suggested good physical stability at 25 °C and 60% relative humidity (corroborated by modulated DSC). These results demonstrate the feasibility of a pharmaceutically acceptable downstream processing for EMs.

Novel, high-yield alternating current electrospinning (ACES) and direct current electrospinning methods were investigated to prepare high-quality hydroxypropylmethylcellulose acetate succinate (HPMCAS) fibers for the dissolution enhancement of poorly soluble spironolactone. Although HPMCAS is of great pharmaceutical importance as a carrier of marketed solid dispersion-based products, it was found to be unprocessable using electrospinning. Addition of small amounts of polyethylene oxide as aid polymer provided smooth fibers with direct current electrospinning but strongly beaded products with ACES. Solution characteristics were thus modified by introducing further excipients. In the presence of sodium dodecyl sulfate, high-quality, HPMCAS-based fibers were obtained even at higher throughput rates of ACES owing to the change in conductivity (rather than surface tension). Replacement of sodium dodecyl sulfate with non-surface-active salts (calcium chloride and ammonium acetate) maintained the fine quality of nanofibers, confirming the importance of conductivity in ACES process. The HPMCAS-based fibers contained spironolactone in an amorphous form according to differential scanning calorimetry and X-ray powder diffraction. In vitro dissolution tests revealed fast drug release rates depending on the salt used to adjust conductivity. The presented results signify that ACES can be a prospective process for high-scale production of fibrous solid dispersions in which conductivity of solution has a fundamental role.

Ammonium-polyphosphate (APP) was modified by microencapsulation with a bio-based sorbitol polyglycidyl ether (SPE)-type epoxy resin and used as a flame retardant additive in polylactic acid (PLA) matrix. The bioresin-encapsulated APP (MCAPP) particles were characterized using Fourier transform infrared (FTIR) spectroscopy and Raman mapping, particle size distribution was determined by processing of scanning electron microscopic (SEM) images. Interaction between the APP core and the bioresin shell was revealed by combined thermogravimetric analysis (TGA)‑FTIR spectroscopy. The APP to SPE mass ratio of 10 to 2 was found to be optimal in terms of thermal, flammability, and mechanical properties of 15 wt% additive containing biocomposites. The bioresin shell effectively promotes the charring of the APP-loaded PLA composites, as found using TGA and cone calorimetry, and eliminates the flammable dripping of the specimens during the UL-94 vertical burning tests. Thus, the V-0 rating, the increased limiting oxygen index, and the 20% reduced peak of the heat release rate was reached compared to the effects of neat APP. Furthermore, better interfacial interaction of the MCAPP with PLA was indicated by differential scanning calorimetry and SEM observation. The stiff interphase resulted in increased modulus of these composites. Besides, microencapsulation provided improved water resistance to the flame retardant biopolymer system.

Raman spectroscopy as a process analytical technology tool was implemented for the monitoring and control of ethanol fermentation carried out with Saccharomyces cerevisiae. The need for the optimization of bioprocesses such as ethanol production, to increase product yield, enhanced the development of control strategies. The control system developed by the authors utilized noninvasive Raman measurements to avoid possible sterilization problems. Real-time data analysis was applied using partial least squares regression (PLS) method. With the aid of spectral pretreatment and multivariate data analysis, the monitoring of glucose and ethanol concentration was successful during yeast fermentation with the prediction error of 4.42 g/L for glucose and 2.40 g/L for ethanol. By Raman spectroscopy-based feedback control, the glucose concentration was maintained at 100 g/L by the automatic feeding of concentrated glucose solution. The control of glucose concentration during fed-batch fermentation resulted in increased ethanol production. Ethanol yield of 86% was achieved compared to the batch fermentation when 75% yield was obtained. The results show that the use of Raman spectroscopy for the monitoring and control of yeast fermentation is a promising way to enhance process understanding and achieve consistently high production yield.

The goals of this work were to evaluate if high-speed electrospinning can be used as a gentle and continuous drying technology to produce protein-containing cyclodextrin-based fibers from an aqueous solution and to convert the produced protein-cyclodextrin fibers into a directly compressible powder. A 400 mL/h feeding rate was used during the electrospinning experiments, corresponding to a ~270 g/h production rate of the dried material. The produced fibers were collected in a cyclone. The fibers were found grindable without secondary drying, and the ground powder was mixed with tableting excipients and was successfully tableted by direct compression. The model protein-type drug (β-galactosidase) remained stable during each of the processing steps (electrospinning, grinding, tableting) and after 6 months of storage at room temperature in the tablets. The obtained results demonstrate that high speed electrospinning can be a gentle alternative to traditional drying methods used for protein-type drugs, and that tablet formulation is achievable from the electrospun material prepared this way.

The aims of this work were to develop a processable, electrospun formulation of a model biopharmaceutical drug, &beta, galactosidase, and to demonstrate that higher production rates of biopharmaceutical-containing fibers can be achieved by using high-speed electrospinning compared to traditional electrospinning techniques. An aqueous solution of 7.6 w/w% polyvinyl alcohol, 0.6 w/w% polyethylene oxide, 9.9 w/w% mannitol, and 5.4 w/w% &beta, galactosidase was successfully electrospun with a 30 mL/h feeding rate, which is about 30 times higher than the feeding rate usually attained with single-needle electrospinning. According to X-ray diffraction measurements, polyvinyl alcohol, polyethylene oxide, and &beta, galactosidase were in an amorphous state in the fibers, whereas mannitol was crystalline (&delta, polymorph). The presence of crystalline mannitol and the low water content enabled appropriate grinding of the fibrous sample without secondary drying. The ground powder was mixed with excipients commonly used during the preparation of pharmaceutical tablets and was successfully compressed into tablets. &beta, galactosidase remained stable during each of the processing steps (electrospinning, grinding, and tableting) and after one year of storage at room temperature in the tablets. The obtained results demonstrate that high-speed electrospinning is a viable alternative to traditional biopharmaceutical drying methods, especially for heat sensitive molecules, and tablet formulation is achievable from the electrospun material prepared this way.

The objectives of this work were to develop meloxicam based amorphous solid dispersion through electrospinning technique and evaluate the effect of the polymeric matrix on the physicochemical properties of the fibers and the downstream processing ability to orodispersible dosage forms. Drug – polymer interactions formed between Eudragit E and meloxicam, confirmed through Raman and 1HNMR spectra, enabled the development of fibers from ethanol, thus allowing an increased production rate compared to PVPk30 where a DMF:THF solvent system was suitable. Microflux dissolution-permeation studies showed a significantly higher diffusion from amorphous solid dispersions compared to crystalline meloxicam. The flux through the membrane was influenced by the polymers only under basic conditions, where the precipitation of Eudragit E limited the complete resolubilization of the active ingredient. This phenomenon was not observed during large volume conventional dissolution testing. The effect of formulation on long term stability could not be highlighted as all products were stable up to 15 months, stored in closed holders at 25 °C ± 2 °C and 50%RH ± 10%. The increased surface area of fibers enabled tablet preparation with low pressures due to favorable bonding between particles during compression. PVPk30 formulation presented higher tabletability and compactability, as higher tensile strength compacts could be prepared. Eudragit E formulation had lower detachment and ejection stress, suggesting a lower sticking tendency during tableting. The presence of HPsCD in PVPk30 formulation offered improved morphological features of the fibers, however no significant effect was observed on dissolution, permeation or mechanical properties. Downstream processing was guided by polymer mechanical properties and solubility, thus PVPk30 fibers could be delivered in the form of orodispersible webs and conventional tablets, whereas Eudragit E fibers as orodispersible tablets.

This paper presents a new recognition in reactive toughening of poly(ethylene terephthalate) (PET), namely the major effect of the molecular weight of PET on the evolution of the compatibilization and crosslinking reactions with ethylene‑butyl acrylate-glycidyl methacrylate (EBA-GMA) type reactive terpolymer, and thus indirectly on its toughening efficiency. It was found that the use of highly degraded recycled PET (rPET) grades, due to the available larger number of reactive functional end groups and increased mobility of the decreased-molecular-weight chains, multiplies the impact strength of the product compared to that of original PET (oPET) with identical EBA-GMA contents. The evinced noticeable difference between the toughening behaviour of rPET and oPET is explained by morphological and interfacial factors and connected to differences in rheological behaviour as well. The reactive oligomeric rPET macromolecules form a Toughening Enhancer Interphase (TEI) around the dispersed particles. Based on systematic analyses, conclusions were drawn regarding the quality, i.e. optimal intrinsic viscosity (IV) range, and quantity of rPET to be used to obtain high-impact-strength PET blends (notched Izod impact strength higher than 40 kJ/m2) with optimised mechanical properties, being suitable even for injection moulding applications, at significantly lower terpolymer contents (10.0–12.5 wt%) than expected. Besides, the proposed new way of utilisation of PET recyclates, especially the unmarketable highly degraded fractions, is believed to give a new driving force in PET recycling.

An immobilization engineering approach using bioinformatics and experimental design tools was applied to improve the sol–gel enzyme entrapment methodology. This strategy was used for the immobilization of lipase B from Candida antarctica (CaLB), a versatile enzyme widely used even on the industrial scale. The optimized entrapment of CaLB in sol–gel matrices is reported by the response-surface methodology enabling efficient process development. The immobilized CaLBs characterized by functional efficiency and enhanced recovery provided economical and green options for flow chemistry. Various ternary mixtures of sol–gel precursors allowed the creation of tailored entrapment matrices best suited for the enzyme and its targeted substrate. The sol–gel-entrapped forms of CaLB were excellent biocatalysts in the kinetic resolutions of secondary alcohols and secondary amines with aromatic or aliphatic substituents both in batch and continuous-flow biotransformations.

Immobilization of lipases from Pseudomonas fluorescens (Lipase AK), Burkholderia (Pseudomonas) cepacia (Lipase PS) and lipase B from Pseudozyma (Candida) antarctica (CaLB) was investigated by entrapment in electrospun poly(vinyl alcohol) (PVA) nanofibers. The activity and selectivity of the lipases entrapped in PVA nanofibers were characterized in kinetic resolution of racemic secondary alcohols using acylation in organic media. Potential bioimprinting effect of eight substrate-mimicking additives [polyethylene glycols (PEGs), non-ionic detergents (NIDs) and various organosilanes] was tested with the fiber-entrapped lipases. The nanofibrous lipase biocatalyst entrapped in the presence of the additives were also characterized by rheology, differential scanning calorimetry and scanning electron microscopy. In addition to the known lipase-bioimprinting agents (PEGs, NIDs), phenyl- and octyltriethoxysilane also enhanced substantially the biocatalytic properties of lipases in their electrospun PVA fiber-entrapped forms. The reasons of bioimprinting effect of several additives were rationalized by docking studies in the open and closed form of CaLB.

The development of real-time monitoring and an improved control system was performed according to a process analytical technology initiative focusing on the benefits of the pharmaceutical industry. As an extension of the results of pioneering Raman-based closed-loop feedback control of crystallization and synthesis, a bioprocess, namely, the enzymatic hydrolysis of lactose, was investigated in this work. For this purpose, an effective control system was developed to maintain the lactose concentration at a level of 20 g/L. Real-time evaluation of Raman spectra was accomplished using classical least-squares (CLS) and partial least-squares (PLS) multivariate data analysis methods. Formation of oligosaccharides during the hydrolysis of lactose causes inaccuracy in the CLS evaluation, and thus, optimization of lactose hydrolysis was needed to decrease oligosaccharide formation. After optimization, control of lactose hydrolysis could be achieved. To improve real-time evaluation, the PLS method was used, resulti...

Investigation of downstream processing of nanofibrous amorphous solid dispersions to generate tablet formulation is in a quite early phase. Development of high speed electrospinning opened up the possibility to study tableting of electrospun solid dispersions (containing polyvinylpyrrolidone-vinyl acetate and itraconazole [ITR] in this case). This work was conducted to investigate the influence of excipients on dissolution properties and the feasibility of scaled-up rotary press tableting. The dissolution rates from tablets proved to be mainly composition dependent. Magnesium stearate acted as a nucleation promoting agent (providing an active hydrophobic environment for crystallization of ITR) hindering the total dissolution of ITR. This crystallization process proved to be temperature dependent as well. However, the extent of dissolution of more than 95% was realizable when a less hydrophobic lubricant, sodium stearyl fumarate (soluble in the medium), was applied. Magnesium stearate induced crystallization even if it was put in the dissolution medium next to proper tablets. After optimization of the composition, scaled-up tableting on a rotary press was carried out. Appropriate dissolution of ITR from tablets was maintained for 3 months at 25°C/60% relative humidity. HPLC measurements confirmed that ITR was chemically stable both in the course of downstream processing and storage.

This work demonstrates how nonlinearity in Raman spectrometry of pharmaceuticals can be handled and accurate quantification can be achieved by applying certain chemometric methods including variable selection. Such approach proved to be successful even if the component spectra are very similar or spectral intensities of the constituents are strongly different. The relevant examples are: blends of two crystalline forms of carvedilol ("CRYST-PM" blend) and a three-component pharmaceutical model system ("PHARM-TM" blend). The widely used classical least squares regression (CLS) and partial least squares regression (PLS) quantification methods provided relatively poor root mean squared error of prediction (RMSEP) values: approximately 2-4% and 4-10% for CRYST-PM and PHARM-TM respectively. The residual plots of these models indicated the nonlinearity of the preprocessed data sets. More accurate quantitative results could be achieved with properly applied variable selection methods. It was observed that variable selection methods discarded the most intensive bands while less intensive ones were retained as the most informative spectral ranges. As a result not only the accuracy of concentration determination was enhanced, but the linearity of models was improved as well. This indicated that nonlinearity occurred especially at the intensive spectral bands. Other methods developed for handling nonlinearity were also capable of adapting to the spectral nature of both data sets. The RMSEP could be decreased this way to 1% in CRYST-PM and 3-6% in PHARM-TM. Raman maps with accurate real concentrations could be prepared this way. All quantitative models were compared by the non-parametric sum of ranking differences (SRD) method, which also proved that models based on variable selection or nonlinear methods provide better quantification.

The diastereomeric salt resolution of racemic tetramisole was studied using ultrasound irradiation. We examined the effect of power and duration of ultrasonic irradiation on the properties of the crystalline phase formed by ultrasound-assisted crystallization and the result of the whole optical resolution. The results were compared with reference experiment without using ultrasound. The US time (5-30min) caused higher enantiomeric excess. Although yield was lower continuously high resolving efficiency could have been reached through ultrasound. We had the best results with 4.3W ultrasound power when resolvability was even higher than the best of reference. Furthermore, we accomplished a deep and thorough examination of the salts that possibly could form in this resolution. One of the four diastereomeric salts, which have been identified by powder X-ray diffraction, FTIR-spectroscopy, and differential scanning calorimetry (DSC) in the ternary system of the two tetramisole enantiomers and the resolving agent, namely the bis[(S)-tetramisole]-dibenzoyl-(R,R)-tartrate salt have been proven the key compound in the resolution process, and presented the highest melting point of 166°C (dec.) among the four salts. The originally expected diastereomeric bitartrate salts with 1:1M base:acid ratio [(S)-tetramisole-dibenzoyl-(R,R)-hydrogen-tartrate salt and (R)-tetramisole-dibenzoyl-(R,R)-hydrogen-tartrate salt] and their 'racemic' co-crystal [(RS)-tetramisole-dibenzoyl-(R,R)-hydrogen-tartrate salt] showed somewhat lower melting points (152, 145, and 150°C, respectively) and their crystallization was also prevented by application of ultrasound. Based on the melting points and enthalpies of fusion measured by DSC, all the binary and ternary phase diagrams have been newly established and calculated in the system with help of classical modelling equations of liquidus curves.

Alternating current electrospinning (ACES) capable to reach multiple times higher specific productivities than widely used direct current electrospinning (DCES) was investigated and compared with DCES to prepare drug-loaded formulations based on one of the most widespread polymeric matrix used for commercialized pharmaceutical solid dispersions, hydroxypropylmethylcellulose 2910 (HPMC). In order to improve the insufficient spinnability of HPMC (both with ACES and DCES) polyethylene oxide (PEO) as secondary polymer with intense ACES activity was introduced into the electrospinning solution. Different grades of this polymer used at as low concentrations in the fibers as 0.1% or less enabled the production of high quality HPMC-based fibrous mats without altering its physicochemical properties remarkably. Increasing concentrations of higher molecular weight PEOs led to the thickening of fibers from submicronic diameters to several microns of thickness. ACES fibers loaded with the poorly water-soluble model drug spironolactone were several times thinner than drug-loaded fibers prepared with DCES in spite of the higher feeding rates applied. The amorphous HPMC-based fibers with large surface area enhanced the dissolution of spironolactone significantly, the presence of small amounts of PEO did not affect the dissolution rate. The presented results confirm the diverse applicability of ACES, a novel technique to prepare fibrous drug delivery systems.

The self-assembling gold nanoparticle (GNP)-supported l -proline derivative, which was readily synthesized in four steps from 4-hydroxy- l -proline and chloroauric acid, was used for enamine-based aldol reactions. The modified Brust-Schiffrin (BS) synthesis was favored over the ligand exchange reaction in order to develop a new and simple synthetic pathway for nanoparticle-supported catalyst. Use of immobilized organocatalyst on nanoscale solid carrier led to excellent selectivities (up to 94:6 dr and 94% ee) in asymmetric reactions of ketones and benzaldehydes. GNPs operate under pseudo-homogeneous conditions which are easily recycled and reused at least five times without significant loss of weight, activity, diastereo- and enantioselectivities.

In this study a new intravenous (i.v.) bolus dosage form of doxycycline was prepared by electrospinning. A tetracycline-type antibiotic with low water solubility (doxycycline (DOX)) was used with 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) as solubilizer. The new solid formulation could be produced with high (~80 g/h) productivity rate using high-speed electrospinning (HSES) from a water-based precursor solution. Freeze-dried DOX-HP-β-CD was also prepared from the same precursor solution as HSES for comparison. Raman mapping showed that the amorphous DOX was uniformly distributed in the fibrous powder making precise dosing of the API possible. The new formulation’s viability as an i.v. bolus product was examined with reconstitution test. The samples contained 100 mg of pure DOX (similarly to the products currently on the market). To ensure i.v. bolus applicability, the dissolution was carried out in 1.5 mL water. The final DOX concentration was 66.7 mg/(mL solvent), which is 7 times higher than the currently marketed formulation. The drug release was followed by UV–VIS spectrophotometry. The results confirmed that the reconstitution solution could be applied as an i.v. bolus dosage form. Moreover, the work confirmed that the continuous high-speed electrospinning process can be a viable high productivity alternative to freeze-drying.

An end-to-end continuous pharmaceutical manufacturing process was developed for the production of conventional direct compressed tablets on a proof-of-concept level for the first time. The output reaction mixture of the flow synthesis of acetylsalicylic acid was crystallized continuously in a mixed suspension mixed product removal crystallizer. The crystallizer was directly connected to a continuous filtration carousel device, thus the crystallization, filtration and drying of acetylsalicylic acid (ASA) was carried out in an integrated 2-step process. Steady state was reached during longer operations and the interaction of process parameters was evaluated in a series of experiments. The filtered crystals were ready for further processing in a following continuous blending and tableting experiment due to the good flowability of the material. The ASA collected during the crystallization-filtration experiments was fed into a continuous twin-screw blender along with microcrystalline cellulose as tableting excipient. After continuous blending Near-Infrared spectroscopy was applied to in-line analyze the drug content of the powder mixture. A belt conveyor carried the mixture towards an eccentric lab-scale tablet press, which continuously produced 500 mg ASA-loaded compressed tablets of 100 mg dose strength. Thus, starting from raw materials, the final drug product was obtained by continuous manufacturing steps with appropriate quality.

Corona alternating current electrospinning (C-ACES), a scaled-up productivity electrospinning method was developed by combining the intense forces of the alternating electrostatic field and a sharp-edged spinneret design with increased free surface. C-ACES reached two orders of magnitude higher productivity (up to 1200 mL/h) than the classical single needle direct current electrospinning (DCES) without any alteration of fiber properties. Polyvinylpyrrolidone K90 (PVPK90), a water soluble high molecular weight nonionic polymer was processed for the first time with single needle alternating current electrospinning (ACES) and C-ACES in order to prepare fast dissolving amorphous solid dispersions of spironolactone (SPIR), a poorly water-soluble antihypertensive model drug. The limited spinnability of PVPK90 with AC high voltage could only be resolved by optimizing the solution conductivity with organophilic salts such as sodium dodecyl sulfate (SDS) demonstrating the importance of conductivity during ACES. The effects of varied solution properties (composition and conductivity) and scaling-up were investigated by SEM imaging. Solid state analyses revealed that SPIR was dispersed in an amorphous form in the fibrous mats. In vitro dissolution tests showed ultrafast drug release in case of the amorphous formulations even when prepared with scaled-up C-ACES. Besides the enhancement of conductivity SDS also prevents SPIR from precipitation from the dissolution media due to its solubilization ability.

The three dimensional printing (3DP) in the pharmaceutical domain constitutes an alternative, innovative approach compared to the conventional production methods. Fused deposition modelling (FDM), is a simple, cost-effective 3DP technique, however the range of pharmaceutical excipients that can be applied for this methodology is restricted. The study set to define the requirements of the FDM printability, using as technical support custom made, pharmaceutical polymer based filaments and to evaluate if these new dosage forms can live up to the current GMP/GCP quality standards. Formulation rationale was assessed in accordance to the apparatus functionality. Blends were pre-screened based on the processability under the API (carvedilol) thermogravimetric analysis determined critical limit. The technological process implied the use of FDM coupled with hot melt extrusion (HME), while printability was defined by means of thermal, rheological and mechanical measurements. From the pharmaceutical standpoint, the consistency of the in vitro dissolution kinetics was monitored ‘at release’ and ‘in stability’, while the print process impact was evaluated based on the previously determined processability potential. Results showed that FDM printability is multifactorial, with brittleness and melt viscosity as primary limitation factors. The increase in shear-thinning and flexural modulus can enable broader processability intervals, which in turn proved to be essential in limiting degradation product formation. The 3DP tablets released the API in an extended rate, however the temperature and humidity along production and storage should be carefully considered as it may affect the final product quality in time. In conclusion, HME + FDM can be considered as an alternative production methodology, with prospects of applicability in the clinical sector, however for some formulations extensive packaging development will be necessary before confirming their suitability.

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.

By the advent of continuous pharmaceutical manufacturing, fast and accurate characterization of product quality has become of a major interest. Although it also promotes the real-time release testing approach, so far mainly content uniformity studies were performed by near-infrared (NIR) spectroscopy. This paper proposes the simultaneous application of NIR and Raman spectroscopy to nondestructively analyze the critical quality attributes of continuously produced tablets in a real-time release testing procedure. A face-centered composite design was applied to determine the impact of lubrication and compression force on the properties of a tablet formulation containing caffeine, glucose-monohydrate and magnesium stearate and to provide a systematic comparison of the applicability of spectroscopic methods. Quantitative methods were developed to evaluate different lubrication approaches in a continuous blending and tableting line. The simultaneous application of NIR and Raman spectroscopy revealed that NIR spectroscopy is more suitable to follow the changes of compression force, while Raman spectroscopy could be successfully applied for the detection of overlubrication. The presented approach can be a part of a comprehensive real-time release strategy, where NIR and Raman spectroscopy provide complementary information about multiple critical quality attributes, such as content uniformity, tablet hardness, friability and dissolution.

Electrospinning was applied to create easy-to-handle and high-surface-area membranes from continuous nanofibers of polyvinyl alcohol (PVA) or polylactic acid (PLA). Lipase PS from Burkholderia cepacia and Lipase B from Candida antarctica (CaLB) could be immobilized effectively by adsorption onto the fibrous material as well as by entrapment within the electrospun nanofibers. The biocatalytic performance of the resulting membrane biocatalysts was evaluated in the kinetic resolution of racemic 1-phenylethanol (rac-1) and 1-phenylethyl acetate (rac-2). Fine dispersion of the enzymes in the polymer matrix and large surface area of the nanofibers resulted in an enormous increase in the activity of the membrane biocatalyst compared to the non-immobilized crude powder forms of the lipases. PLA as fiber-forming polymer for lipase immobilization performed better than PVA in all aspects. Recycling studies with the various forms of electrospun membrane biocatalysts in ten cycles of the acylation and hydrolysis reactions indicated excellent stability of this forms of immobilized lipases. PLA-entrapped lipases could preserve lipase activity and enantiomer selectivity much better than the PVA-entrapped forms. The electrospun membrane forms of CaLB showed high mechanical stability in the repeated acylations and hydrolyses than commercial forms of CaLB immobilized on polyacrylamide beads (Novozyme 435 and IMMCALB-T2-150).

Natural hemp fabric reinforced epoxy resin composites were prepared in flame retarded form. Fabrics were treated in three ways: the first method involved the immersion of preheated fabric into cold phosphoric acid solution (allowing penetration into the capillaries of the fibres) and subsequent neutralization, the second way was a reactive modification carried out with an aminosilane-type coupling agent, while the third treatment combined the sol–gel surface coating with the first method. The introduction of phosphorus into the reinforcing fibres decreased the flammability not only of the hemp fabrics, but also of the epoxy composites made thereof. By applying amine-type phosphorus-containing curing agent (TEDAP) in combination with the treated fabrics, V-0 UL-94 rating was achieved. Composites of unexpectedly improved static and dynamic mechanical properties could be prepared only when the simple phosphorous fibre treatment and reactive flame retardancy was combined.

Suitability of electrospinning for biodrug formulation was investigated in order to develop an electrospinning-based method for producing oral dosage form of β-galactosidase. β-Galactosidase-loaded polymeric (polyvinyl alcohol, polyvinylpyrrolidones with two different molar masses, and polyethylene glycol) nanofibers were prepared by electrospinning in order to lengthen the shelf life of the enzyme (providing an alternative technology to drying). Based on the activity of the encapsulated β-galactosidase, the most suitable polymer was polyvinylpyrrolidone with higher molecular weight (1,200,000 Da), because 97% of the original activity remained in this case. Kinetic behavior of β-galactosidase did not show any alteration after encapsulation, and the pH and temperature profiles were not changed either. Time course of viability testing showed that the nanofibrous formulation can provide long-term stability for β-galactosidase; the activity of the enzyme decreased only 4% after a year. Furthermore, scaling-up and tableting had no influence on activity and long-term stability; thus, the developed drying technology and tablets, containing enzyme-loaded nanofibers, can provide a new promising way of oral biodrug delivery. Copyright © 2015 John Wiley & Sons, Ltd.

Two continuous processes, the spray drying method, producing microparticles in presence of hot gas flow, and the electrospinning technology, producing continuous polymer nanofibers at low temperature under high electric fields, were investigated and compared the first time. Both techniques were used to prepare slow release caffeine (as a model of rapidly water-soluble drug) using water-insoluble, biocompatible and bioresorbable PLGA and PLA as polymeric matrix. The structural characterization of the obtained samples was performed using SEM, XRD, DSC and at-line Raman mapping, while in vitro dissolution was detected by UV spectrophotometer. We found that the release profile of a highly water soluble drug can be adjusted to the requirements through the investigated continuous technologies. Solid molecular dispersion of caffeine at colloidal level could be prepared in PLA matrix using electrostatic spinning. Furthermore the continuous nonwoven structure of ultrafine fibers, produced this way, allows easer handling than that of independent fine particle’s. On the other hand continuous production of drug loaded microspheres with slightly less performance can be performed with the conventional technology of spray drying which is well known in the pharmaceutical industry.

Summary The synthesis of phosphorylated di- and triallyl glucopyranosides was elaborated that may be regarded as precursors of bio-based monomers having potential flame-retardant properties. In a separate series of experiments, the phosphorylation of methyl-α-d-glucopyranoside was also investigated.

This paper reports the preparation of newly synthesized sugar-based epoxy monomers, suitable for replacing petrochemical-derived epoxy resins of high thermal stability. Several bi- tri- and tetrafunctional epoxy components were prepared from d -glucose, among them the glucopyranoside- and glucofuranoside-based trifunctional ones proved to be the most promising for high-tech applications. The applicability of the synthesized compounds as epoxy monomers was investigated by curing probes with a model aromatic amine-type hardener. The curing enthalpy of the bioepoxy resins were examined, and compared to theoretical values, as well as the glass transition temperature, which is a crucial parameter when determining the potential fields of application of the bioresins. Tg values up to 175 °C were reached, while the thermal degradation of the cured resins start at around 300 °C.

Melt blowing (MB) was investigated to prepare a fast dissolving fibrous drug-loaded solid dispersion and compared with solvent-based electrospinning (SES) and melt electrospinning (MES). As a conventional solvent-free technique coupled with melt extrusion and using a high-speed gas stream, MB can provide high-quality micro- and nanofibers at industrial throughput levels. Carvedilol, a weak-base model drug with poor water solubility, was processed using a common composition optimized for the fiber spinning and blowing methods based on a hydrophilic vinylpyrrolidone-vinyl acetate copolymer (PVPVA64) and PEG 3000 plasticizer. Scanning electron microscopy combined with fiber diameter analysis showed diameter distributions characteristic to each prepared fibrous fabrics (the mean value increased toward SES

Electrospinning, electroblowing and freeze-drying were investigated to prepare fast dissolving cyclodextrin-based drug-loaded solid complexes. Combining the huge surface area of fibrous mats with the capabilities of cyclodextrins to prepare a reconstitution injection was tested to overcome the instability of liquid-based products. Diclofenac sodium was used as drug with limited water solubility and 2-hydroxypropyl-β-cyclodextrin (HPβCD) as carrier and solubilizer. The applied composition of the complex was determined based on phase solubility measurements. In order to resolve the frequent unavoidable interruption of the fiber formation during electrospinning from the HPβCD solution, high-speed blowing air was coupled with the electrostatic force (electroblowing) to draw polymer-free HPβCD fibers steadily, moreover, at increased flow rates. According to the scanning electron microscopic images, X-ray diffraction, differential scanning calorimetry no traces of crystallinity of the drug were detectable in the fibers as opposed to the freeze-dried product. Reconstitution tests of the fibers showed fast dissolution obtaining clear solutions equivalent to a marketed liquid-based bolus injection. The results demonstrate the first time the viability of electroblowing for preparing drug delivery systems.

Impact resistant all-poly(lactic acid) composites were prepared by film-stacking of highly crystalline poly(lactic acid) (PLA) fibres with fully amorphous PLA films. The flammability of the self-reinforced PLA composites (PLA-SRCs) was effectively reduced by incorporating ammonium polyphosphate based flame retardant (FR) additive and montmorillonite clays in a weight ratio of 10 to 1 into the matrix layers. As low as 16 wt% FR content proved to be sufficient for achieving self-extinguishing behaviour, i.e. UL94 V-0 rating, and to achieve 50% and 40% reduction of peak of heat release rate and total heat emission, respectively. The introduction of FR additives improved also important mechanical properties compared to the FR-free all-PLA composite. The stiffness of the PLA-SRCs increased steadily with the FR contents of their matrix layers, furthermore, owing to the improved fibre–matrix bonding, prominent energy absorption capacity (impact perforation energy as high as 16 J/mm) was determined for the effectively flame retarded PLA-SRC.

This work presents a study of film coating with the vaginal strain of Lactobacillus acidophilus, the aim of which was to manufacture administrable probiotic tablets in one step and to enhance the survival rate of bacteria and their viability during storage. The results show that the film coated lactose-based tablets contained viable bacteria and the survival rate after the process was 21%, which could be enhanced up to 59% by applying protective media (trehalose, sucrose, reconstituted skim milk (RSM) during dehydration. Additionally, protective agents improved the viability of bacteria during storage too. After one year, 20% of the embedded bacteria were active when stored at –20°C, and viability dropped only one order of magnitude when stored at 7°C. It was verified that the bacteria in film coated tablets were not sensitive to higher levels of humidity owing to the moisture-moderating PVA-based coating composite.

The integration of Process Analytical Technology (PAT) initiative into the continuous production of pharmaceuticals is indispensable for reliable production. The present paper reports the implementation of in-line Raman spectroscopy in a continuous blending and tableting process of a three-component model pharmaceutical system, containing caffeine as model active pharmaceutical ingredient (API), glucose as model excipient and magnesium stearate as lubricant. The real-time analysis of API content, blend homogeneity, and tablet content uniformity was performed using a Partial Least Squares (PLS) quantitative method. The in-line Raman spectroscopic monitoring showed that the continuous blender was capable of producing blends with high homogeneity, and technological malfunctions can be detected by the proposed PAT method. The Raman spectroscopy-based feedback control of the API feeder was also established, creating a ‘Process Analytically Controlled Technology’ (PACT), which guarantees the required API content in the produced blend. This is, to the best of the authors’ knowledge, the first ever application of Raman-spectroscopy in continuous blending and the first Raman-based feedback control in the formulation technology of solid pharmaceuticals.

Carbon fibre reinforced flame-retarded bioepoxy composites were prepared from commercially available sorbitol polyglycidyl ether (SPE) cured with cycloaliphatic amine hardener. Samples containing 1, 2, and 3% phosphorus (P) were prepared using additive type flame retardants (FRs) resorcinol bis(diphenyl phosphate) (RDP), ammonium polyphosphate (APP), and their combinations. The fire performance of the composites was investigated by limiting oxygen index (LOI), UL-94 tests, and mass loss calorimetry. The effect of FRs on the glass transition temperature, and storage modulus was evaluated by dynamic mechanical analysis (DMA), while the mechanical performance was investigated by tensile, bending, and interlaminar shear measurements, as well as by Charpy impact test. In formulations containing both FRs, the presence of RDP, acting mainly in gas phase, ensured balanced gas and solid-phase mechanism leading to best overall fire performance. APP advantageously compensated the plasticizing (storage modulus and glass transition temperature decreasing) effect of RDP in combined formulations; furthermore, it led to increased tensile strength and Charpy impact energy.