Influence of Aqueous Solubility-Enhancing Excipients on the Microstructural Characteristics of Furosemide-Loaded Electrospun Nanofibers.

Electrospun nanofibers were prepared from furosemide-containing hydroxypropyl cellulose and poly(vinylpyrrolidone) aqueous solutions using different solubility enhancers. In one case, a solubilizer, triethanolamine, was applied, while in the other case a pH-modifier, sodium hydroxide, was applied. Scanning electron microscopy (SEM) was carried out for morphological characterization of the fibers. The SEM images indicated similar mean diameter size of the two fibrous formulations. However, in contrast to the NaOH-containing fibers of normal diameter distribution, the triethanolamine-containing fibers showed approximately normal diameter distribution, possibly due to their plasticizing effect and the consequent slightly ribbon-like morphology. Attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR), powder X-ray diffraction (XRD) and positron annihilation lifetime spectroscopy (PALS) were applied for microstructural characterization. The FTIR measurements confirmed that furosemide salt was formed in both cases. There was no sign of any crystallinity based on the XRD measurements. However, the PALS highlighted the differences in the average o-Ps lifetime values and distributions of the furosemide-loaded fibrous formulations. The two types of electrospun nanofibrous formulations containing amorphous furosemide salt showed similar macrostructures but different microstructural characteristics depending on the type of solubility enhancers, which lead to altered storage stability.

Scale-up of electrospinning technology: Applications in the pharmaceutical industry.

Recently, electrospinning (ES) of fibers has been shown to be an attractive strategy for drug delivery. One of the main features of ES is that a wide variety of drugs can be loaded into the fibers to improve their bioavailability, to enhance dissolution, or to achieve controlled release. Besides, ES is a continuous technology with low energy consumption, which can make it a very economic production alternative to the widely used freeze drying and spray drying. However, the low production rate of laboratory-scaled ES has limited the industrial application of the technology so far. This article covers the various ES technologies developed for scaled-up fiber production with an emphasis on pharmaceutically relevant examples. The methods used for increasing the productivity are complied, which is followed by a review of specific examples from literature where these technologies are utilized to produce oral drug delivery systems. The different technologies are compared in terms of their basic principles, advantages, and limitations. Finally, the different downstream processing options to prepare tablets or capsules containing the electrospun drug are covered as well. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies.

Continuous drying of a protein-type drug using scaled-up fiber formation with HP-ß-CD matrix resulting in a directly compressible powder for tableting.

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 (ß-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.

Continuous Formulation Approaches of Amorphous Solid Dispersions: Significance of Powder Flow Properties and Feeding Performance.

Preparation and formulation of amorphous solid dispersions (ASDs) are becoming more and more popular in the pharmaceutical field because the dissolution of poorly water-soluble drugs can be effectively improved this way, which can lead to increased bioavailability in many cases. During downstream processing of ASDs, technologists need to keep in mind both traditional challenges and the newest trends. In the last decade, the pharmaceutical industry began to display considerable interest in continuous processing, which can be explained with their potential advantages such as smaller footprint, easier scale-up, and more consistent product, better quality and quality assurance. Continuous downstream processing of drug-loaded ASDs opens new ways for automatic operation. Therefore, the formulation of poorly water-soluble drugs may be more effective and safe. However, developments can be challenging due to the poor flowability and feeding properties of ASDs. Consequently, this review pays special attention to these characteristics since the feeding of the components greatly influences the content uniformity in the final dosage form. The main purpose of this paper is to summarize the most important steps of the possible ASD-based continuous downstream processes in order to give a clear overview of current course lines and future perspectives.

Electrospun amorphous solid dispersions of meloxicam: Influence of polymer type and downstream processing to orodispersible dosage forms.

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 ±â€¯2 °C and 50%RH ±â€¯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 HPßCD 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.

Scaled-Up Production and Tableting of Grindable Electrospun Fibers Containing a Protein-Type Drug.

The aims of this work were to develop a processable, electrospun formulation of a model biopharmaceutical drug, ß-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% ß-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 ß-galactosidase were in an amorphous state in the fibers, whereas mannitol was crystalline (δ-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. ß-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.

Application of artificial neural networks for Process Analytical Technology-based dissolution testing.

This work proposes the application of artificial neural networks (ANN) to non-destructively predict the in vitro dissolution of pharmaceutical tablets from Process Analytical Technology (PAT) data. An extended release tablet formulation was studied, where the dissolution was influenced by the composition of the tablets and the tableting compression force. NIR and Raman spectra of the intact tablets were measured, and the dissolution of the tablets was modeled directly from the spectral data. Partial Least Square (PLS) regression and ANN models were developed for the different spectroscopic measurements individually as well as by combining them together. ANN provided up to 3% lower root mean square error for prediction (RMSEP) than the PLS models, due to its capability of modeling non-linearity between the process parameters and dissolution curves. The ANN model using reflection NIR spectra provided the most accurate predictions with 6.5 and 63 mean f1 and f2 values between the computed and measured dissolution curves, respectively. Furthermore, ANN served as a straightforward data fusion method without the need for additional preprocessing steps. The method could significantly advance data processing in the PAT environment, contribute to an enhanced real-time release testing procedure and hence the increased efficacy of dissolution testing.

Data fusion strategies for performance improvement of a Process Analytical Technology platform consisting of four instruments: An electrospinning case study.

The aim of this work was to develop a PAT platform consisting of four complementary instruments for the characterization of electrospun amorphous solid dispersions with meloxicam. The investigated methods, namely NIR spectroscopy, Raman spectroscopy, Colorimetry and Image analysis were tested and compared considering the ability to quantify the active pharmaceutical ingredient and to detect production errors reflected in inhomogeneous deposition of fibers. Based on individual performance the calculated RMSEP values ranged between 0.654% and 2.292%. Mid-level data fusion consisting of data compression through latent variables and application of ANN for regression purposes proved efficient, yielding an RMSEP value of 0.153%. Under these conditions the model could be validated accordingly on the full calibration range. The complementarity of the PAT tools, demonstrated from the perspective of captured variability and outlier detection ability, contributed to model performance enhancement through data fusion. To the best of the author's knowledge, this is the first application of data fusion in the field of PAT for efficient handling of big-analytical-data provided by high-throughput instruments.

Continuous alternative to freeze drying: Manufacturing of cyclodextrin-based reconstitution powder from aqueous solution using scaled-up electrospinning.

The aims of this study were to evaluate electrospinning as a continuous alternative to freeze drying in the production of a reconstitution injection dosage form, and to prove that aqueous electrospinning can be realized with a high production rate at room temperature. High-speed electrospinning with a novel continuous cyclone collection was used to manufacture a formulation of the poorly water-soluble antifungal voriconazole (VOR) with sulfobutylether-ß-cyclodextrin (SBE-ß-CD). The freeze-dried, marketed product of this drug substance, Vfend® also contains SBE-ß-CD as excipient. SBE-ß-CD acted as a 'quasi-polymer', and it could be electrospun despite its low molecular mass (2163 Da). According to X-ray diffraction and differential scanning calorimetry, no traces of crystalline VOR were detectable in the fibers. Furthermore, Raman mapping and energy dispersive spectroscopy measurements showed a uniform distribution of amorphous VOR in the fibers. Reconstitution tests carried out with ground fibrous powder showed complete dissolution resulting in a clear solution after 30 s (similarly to Vfend®). The high productivity rate (~240 g/h) achieved using high-speed electrospinning makes this scaled-up, continuous and flexible manufacturing process capable of fulfilling the technological and capacity requirements of the pharmaceutical industry. This work shows that aqueous high-speed electrospinning, being a continuous and high-throughput process, is an economically viable production alternative to freeze drying.

Drying technology strategies for colon-targeted oral delivery of biopharmaceuticals.

In chronic intestinal diseases like inflammatory bowel disease, parenteral administration of biopharmaceuticals is associated with numerous disadvantages including immune reactions, infections, low patient compliance, and toxicity caused by high systemic bioavailability. One alternative that can potentially overcome these limitations is oral administration of biopharmaceuticals, where the local delivery will reduce the systemic exposure and furthermore the manufacturing costs will be lower. However, the development of oral dosage forms that deliver the biologically active form to the intestines is one of the greatest challenges for pharmaceutical technologists due to the sensitive nature of biopharmaceuticals. The present article discusses the various drug delivery technologies used to produce orally administered solid dosage forms of biopharmaceuticals with an emphasis on colon-targeted delivery. Solid oral dosage compositions containing different types of colon-targeting biopharmaceuticals are compiled followed by a review of currently applied and emerging drying technologies for biopharmaceuticals. The different drying technologies are compared in terms of their advantages, limitations, costs and their effect on product stability.

Homogenization of Amorphous Solid Dispersions Prepared by Electrospinning in Low-Dose Tablet Formulation.

Low-dose tablet formulations were produced with excellent homogeneity based on drug-loaded electrospun fibers prepared by single-needle as well as scaled-up electrospinning (SNES and HSES). Carvedilol (CAR), a BCS II class compound, served as the model drug while poly (vinylpyrrolidone-co-vinyl acetate) (PVPVA64) was adopted as the fiber-forming polymer. Scanning electron microscopy (SEM) imaging was used to study the morphology of HSES and SNES samples. Different homogenization techniques were compared to maximize homogeneity: mixing in plastic bags and in a high-shear granulator resulting in low-shear mixing (LSM) and high-shear mixing (HSM). Drug content and homogeneity of the tablets were measured by UV-Vis spectrometry, the results revealed acceptably low-dose fluctuations especially with formulations homogenized with HSM. Sieve analysis was used on the final LSM and HSM powder mixtures in order to elucidate the observed differences between tablet homogeneity. Tablets containing drug-loaded electrospun fibers were also studied by Raman mapping demonstrating evenly distributed CAR within the corpus.

Spectroscopic characterization of tablet properties in a continuous powder blending and tableting process.

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.

Real-time feedback control of twin-screw wet granulation based on image analysis.

The present paper reports the first dynamic image analysis-based feedback control of continuous twin-screw wet granulation process. Granulation of the blend of lactose and starch was selected as a model process. The size and size distribution of the obtained particles were successfully monitored by a process camera coupled with an image analysis software developed by the authors. The validation of the developed system showed that the particle size analysis tool can determine the size of the granules with an error of less than 5 µm. The next step was to implement real-time feedback control of the process by controlling the liquid feeding rate of the pump through a PC, based on the real-time determined particle size results. After the establishment of the feedback control, the system could correct different real-life disturbances, creating a Process Analytically Controlled Technology (PACT), which guarantees the real-time monitoring and controlling of the quality of the granules. In the event of changes or bad tendencies in the particle size, the system can automatically compensate the effect of disturbances, ensuring proper product quality. This kind of quality assurance approach is especially important in the case of continuous pharmaceutical technologies.

In-line Raman spectroscopic monitoring and feedback control of a continuous twin-screw pharmaceutical powder blending and tableting process.

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.

Oral bioavailability enhancement of flubendazole by developing nanofibrous solid dosage forms.

The bioavailability of the anthelminthic flubendazole was remarkably enhanced in comparison with the pure crystalline drug by developing completely amorphous electrospun nanofibres with a matrix consisting of hydroxypropyl-ß-cyclodextrin and polyvinylpyrrolidone. The thus produced formulations can potentially be active against macrofilariae parasites causing tropical diseases, for example, river blindness and elephantiasis, which affect altogether more than a hundred million people worldwide. The bioavailability enhancement was based on the considerably improved dissolution. The release of a dose of 40 mg could be achieved within 15 min. Accordingly, administration of the nanofibrous system ensured an increased plasma concentration profile in rats in contrast to the practically non-absorbable crystalline flubendazole. Furthermore, easy-to-grind fibers could be developed, which enabled compression of easily administrable immediate release tablets.

Novel Alternating Current Electrospinning of Hydroxypropylmethylcellulose Acetate Succinate (HPMCAS) Nanofibers for Dissolution Enhancement: The Importance of Solution Conductivity.

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.

Preformulation Studies of Furosemide-Loaded Electrospun Nanofibrous Systems for Buccal Administration.

Furosemide loaded electrospun fibers were prepared for buccal administration, with the aim of improving the oral bioavailability of the poorly soluble and permeable crystalline drug, which can be achieved by the increased solubility and by the circumvention of the intensive first pass metabolism. The water soluble hydroxypropyl cellulose (HPC) was chosen as a mucoadhesive polymer. In order to improve the electrospinnability of HPC, poly (vinylpyrrolidone) (PVP) was used. During the experiments, the total polymer concentration was kept constant at 15% (w/w), and only the ratio of the two polymers (HPC-PVP = 5:5, 6:4, 7:3, 8:2, 9:1) was changed. A combination of rheological measurements with scanning electron microscopic morphological images of electrospun samples was applied for the determination of the optimum composition of the gels for fiber formation. The crystalline⁻amorphous transition of furosemide was tracked by Fourier transform infrared spectroscopy. A correlation was found between the rheological properties of the polymer solutions and their electrospinnability, and the consequent morphology of the resultant samples. With decreasing HPC ratio of the system, a transition from the spray-dried droplets to the randomly oriented fibrous structures was observed. The results enable the determination of the polymer ratio for the formation of applicable quality of electrospun fibers.

Investigation and Mathematical Description of the Real Driving Force of Passive Transport of Drug Molecules from Supersaturated Solutions.

The aim of this study was to investigate the impact of formulation excipients and solubilizing additives on dissolution, supersaturation, and membrane transport of an active pharmaceutical ingredient (API). When a poorly water-soluble API is formulated to enhance its dissolution, additives, such as surfactants, polymers, and cyclodextrins, have an effect not only on dissolution profile but also on the measured physicochemical properties (solubility, pKa, permeability) of the drug while the excipient is present, therefore also affecting the driving force of membrane transport. Meloxicam, a nonsteroidal anti-inflammatory drug, was chosen as a poorly water-soluble model drug and formulated in order to enhance its dissolution using solvent-based electrospinning. Three polyvinylpyrrolidone (PVP) derivatives (K30, K90, and VA 64), Soluplus, and (2-hydroxypropyl)-ß-cyclodextrin were used to create five different amorphous solid dispersions of meloxicam. Through experimental design, the various formulation additives that could influence the characteristics of dissolution and permeation through artificial membrane were observed by carrying out a simultaneous dissolution-permeation study with a side-by-side diffusion cell, µFLUX. Although the dissolution profiles of the formulations were found to be very similar, in the case of Soluplus containing formulation the flux was superior, showing that the driving force of membrane transport cannot be simplified to the concentration gradient. Supersaturation gradient, the difference in degree of supersaturation (defined as the ratio of dissolved amount of the drug to its thermodynamic solubility) between the donor and acceptor side, was found to be the driving force of membrane transport. It was mathematically derived from Fick's first law, and experimentally proved to be universal on several meloxicam containing ASDs and DMSO stock solution.

Lubricant-Induced Crystallization of Itraconazole From Tablets Made of Electrospun Amorphous Solid Dispersion.

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.