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
Application of scaled‐up electrospinning in oral drug delivery.
Raman mapping and chemometrics are proposed to accurately characterize the composition of tablets. The most critical step of the state‐of‐art curve resolution methods (such as multivariate curve ...resolution‐alternating least squares MCR‐ALS) is the determination of the number of constituents, when chemical imaging is coupled with multivariate data analysis. However, it is usually performed in a considerably subjective way. We propose a variable clustering approach for the identification of the main dimensionality of vibrational spectral data. The method was tested on a Raman map of a complex pharmaceutical tablet that contained 4 major components with high spectral resemblance, and a low‐dose lubricant was also added for tableting purposes. Using a variable clustering algorithm called VARCLUS we were able to construct clusters from the Raman mapping data corresponding to the real constitution of the sample. The modeled clusters were analyzed by the “sum of ranking differences” method. All 4 major components could be identified. The potential of the clustering algorithm was further assessed by applying MCR‐ALS and spectral angle mapper‐orthogonal projection methods. We have shown that variable clustering corresponded with MCR‐ALS results and that it can be used to characterize the qualitative composition of an unknown pharmaceutical sample by combining the clustering algorithm with a pure component resolution method. Therefore, this method is well applicable to analyze and interpret the curve resolution of complex samples. Testing of the previously studied spectral angle mapper‐orthogonal projection method, which relies on spectral reference libraries and even the low‐dose lubricant (approximately 1% w/w), was identified through the chemical imaging.
A variable clustering can be identified the main dimensionality of vibrational spectral data. The method was further assessed by applying multivariate curve resolution‐alternating least squares (MCR‐ALS) and spectral angle mapper‐orthogonal projection methods. The variable clustering corresponded with MCR‐ALS results, and it can be used to characterize the qualitative composition of an unknown pharmaceutical sample by combining the clustering algorithm with a pure component resolution method. Therefore, this method is well applicable to analyze and interpret the curve resolution of complex samples.
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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.
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.
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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, pK
, 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)-β-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.
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.
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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.
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High speed electrospinning (HSES), compatible with pharmaceutical industry, was used to demonstrate the viability of the preparation of drug-loaded polymer nanofibers with radically ...higher productivity than the known single-needle electrospinning (SNES) setup. Poorly water-soluble itraconazole (ITRA) was formulated with PVPVA64 matrix polymer using four different solvent-based methods such as HSES, SNES, spray drying (SD) and film casting (FC). The formulations were assessed in terms of improvement in the dissolution rate of ITRA (using a “tapped basket” dissolution configuration) and analysed by SEM, DSC and XRPD. Despite the significantly increased productivity of HSES, the obtained morphology was very similar to the SNES nanofibrous material. ITRA transformed into an amorphous form, according to the DSC and XRPD results, in most cases except the FC samples. The limited dissolution of crystalline ITRA could be highly improved: fast dissolution occurred (>90% within 10min) in the cases of both (the scaled-up and the single-needle) types of electrospun fibers, while the improvement in the dissolution rate of the spray-dried microspheres was significantly lower. Production of amorphous solid dispersions (ASDs) with the HSES system proved to be flexibly scalable and easy to integrate into a continuous pharmaceutical manufacturing line, which opens new routes for the development of industrially relevant nanopharmaceuticals.
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.
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-β-cyclodextrin (SBE-β-CD). The freeze-dried, marketed product of this drug substance, Vfend® also contains SBE-β-CD as excipient. SBE-β-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.
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•Continuous collection of drug-loaded fibers by a cyclone attached to the high-speed electrospinning machine is performed•Viscous aqueous solution of sulfobutylether-β-cyclodextrin can be electrospun with high production rate at room temperature•Voriconazole becomes molecularly dispersed in the cyclodextrin matrix during electrospinning, the product dissolves in 30 s•Scaled-up electrospinning of aqueous solutions at room temperature can be a viable, continuous alternative to freeze drying
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