The entire pharmaceutical sector is in an urgent need of both innovative technological solutions and fundamental scientific work, enabling the production of highly engineered drug products. ...Commercial-scale manufacturing of complex drug delivery systems (DDSs) using the existing technologies is challenging. This review covers important elements of manufacturing sciences, beginning with risk management strategies and design of experiments (DoE) techniques. Experimental techniques should, where possible, be supported by computational approaches. With that regard, state-of-art mechanistic process modeling techniques are described in detail. Implementation of materials science tools paves the way to molecular-based processing of future DDSs. A snapshot of some of the existing tools is presented. Additionally, general engineering principles are discussed covering process measurement and process control solutions. Last part of the review addresses future manufacturing solutions, covering continuous processing and, specifically, hot-melt processing and printing-based technologies. Finally, challenges related to implementing these technologies as a part of future health care systems are discussed.
There is an increasing demand for new approaches to understand the chemical and physical phenomena that occur during pharmaceutical unit operations. Obtaining real‐time information from processes ...opens new perspectives for safer and more efficient manufacture of pharmaceuticals. Raman spectroscopy provides a molecular level insight into processing, and therefore it is a future process analytical tool. In this review, different applications of Raman spectroscopy in the field of process analysis of pharmaceutical solid dosage forms are summarized. In addition, pitfalls associated with interfacing to the process environment and challenges within data management are discussed.
Application of additive manufacturing techniques (3D printing) for mass-customized products has boomed in the recent years. In pharmaceutical industry and research, the interest has grown ...particularly with the future scenario of more personalized medicinal products. Understanding a broad range of material properties and process behavior of the drug-excipient combinations is necessary for successful 3D printing of dosage forms. This commentary reviews recent 3D-printing studies by fused deposition modeling (FDM) technique in pharmaceutical sciences, extending into the fields of polymer processing and rapid prototyping, where more in-depth studies on the feedstock material properties, modeling, and simulation of the FDM process have been performed. A case study of a model oral dosage form from custom-prepared indomethacin-polycaprolactone feedstock filament was used as an example in the pharmaceutical context. The printability was assessed in the different process steps: preparation of customized filaments for FDM, filament feeding, deposition, and solidification. These were linked with the rheological, thermal, and mechanical properties and their characterization, relevant for understanding the printability of drug products by FDM.
Nanopharmaceuticals aim at translating the unique features of nano-scale materials into therapeutic products and consequently their development relies critically on the progression in manufacturing ...technology to allow scalable processes complying with process economy and quality assurance. The relatively high failure rate in translational nanopharmaceutical research and development, with respect to new products on the market, is at least partly due to immature bottom-up manufacturing development and resulting sub-optimal control of quality attributes in nanopharmaceuticals. Recently, quality-oriented manufacturing of pharmaceuticals has undergone an unprecedented change toward process and product development interaction. In this context, Quality by Design (QbD) aims to integrate product and process development resulting in an increased number of product applications to regulatory agencies and stronger proprietary defense strategies of process-based products. Although QbD can be applied to essentially any production approach, microfluidic production offers particular opportunities for QbD-based manufacturing of nanopharmaceuticals. Microfluidics provides unique design flexibility, process control and parameter predictability, and also offers ample opportunities for modular production setups, allowing process feedback for continuously operating production and process control. The present review aims at outlining emerging opportunities in the synergistic implementation of QbD strategies and microfluidic production in contemporary development and manufacturing of nanopharmaceuticals. In doing so, aspects of design and development, but also technology management, are reviewed, as is the strategic role of these tools for aligning nanopharmaceutical innovation, development, and advanced industrialization in the broader pharmaceutical field.
Display omitted
Display omitted
The use of amino acids as excipients is a promising approach to improve the physical stability and powder dispersibility of spray-dried powders for inhalation.
The aim of this study ...was to investigate the stabilizing effect of different amino acids on spray-dried amorphous powders for inhalation using simvastatin (SV) as a model compound.
Two hydrophobic amino acids (leucine, LEU and tryptophan, TRP), and one hydrophilic amino acid (lysine, LYS) were spray dried from 1% (w/v) solutions with SV at a molar ratio of 1:1 into dry powders for inhalation. Scanning electron microscopy (SEM), X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) were used to characterize the morphology, solid form and potential intermolecular interactions of the spray-dried powders. X-ray photoelectron spectroscopy (XPS) was used to analyse the chemical composition of the surface of the particles. The physical stability of the dry powders was examined upon storage in controlled conditions. A Next generation impactor (NGI) was applied to assess the in vitro aerosol performance of the powders.
XRPD and DSC results confirmed that the spray-dried SV-LEU was composed of crystalline LEU and amorphous SV, the spray-dried SV-LYS was co-amorphous, and the spray-dried SV-TRP was an amorphous system with two phases. XPS analyses revealed that the surface of the spray-dried SV-LEU particles were LEU rich, indicating surface-enrichment of LEU in these particles. In contrast, an almost even distribution of TRP and SV at the surface of spray-dried SV-TRP was observed. FTIR results indicated no intermolecular interaction between SV and the amino acids used in the present study. The three spray-dried samples were physically stable after eight months storage in a desiccator (12% RH, ca. 22 °C). Nevertheless, spray-dried SV-LEU exhibited the best storage stability as compared to the other two spray-dried samples when the samples were stored at 60% RH, 25 °C. Both, the spray-dried SV-LEU and SV-TRP exhibited higher fine particle fractions than the spray-dried SV-LYS.
Both the spray-dried SV-LEU and SV-TRP exhibited better aerosol performance and storage stability compared to the spray-dried SV-LYS. Compared to TRP, LEU exhibited better protection of spray-dried amorphous SV from re-crystallization, which could be attributed to the formation of a LEU crystalline shell covering SV upon the spray drying process.
Display omitted
Oromucosal delivery of active pharmaceutical ingredients provides an attractive alternative route of administration, due to avoidance of the first pass effect and improved patient ...compliance. In the current work, fused deposition modelling (FDM) 3D printing was investigated as an additive manufacturing approach for poly(vinyl alcohol)-based mucoadhesive films, enabling unidirectional drug release. For this purpose, chitosan was incorporated as a permeation and mucoadhesion enhancer whereas ethylcellulose and commercial wafer sheets were evaluated as backing layers. The formulated films were initially assessed for structural integrity and dose uniformity. Solid-state characterization of the films, including thermal methods (DSC, TGA), diffraction (XRPD) and Raman spectroscopy, was implemented to characterize the physicochemical properties of the produced polymeric filaments and buccal films. The mechanical properties of the products were investigated by instrumented indentation and tensile tests. Evaluation of buccal films was assessed in vitro, to study the effect of backing-layer type on hydration capacity of the films, diffusion of the drug throughout the restricting layer and release profiles in simulated saliva. The ex vivo performance of the manufactured products, associated with the presence of chitosan, was investigated by textural analysis for mucoadhesion properties, whereas permeation studies and histological studies were performed across porcine buccal epithelium. The results demonstrated that FDM printing is a timesaving and versatile approach in the context of manufacturing multi-layered mucoadhesive buccal films, providing unidirectional release properties.
In this study, the influence of drug load on the microwave-induced amorphization of celecoxib (CCX) in polyvinylpyrrolidone (PVP) tablets was investigated using quantitative transmission Raman ...spectroscopy. A design of experiments (DoE) setup was applied for developing the quantitative model using two factors: drug load (10, 30, and 50% w/w) and amorphous fraction (0, 25, 50, 75 and 100%). The data was modeled using partial least-squares (PLS) regression and resulted in a robust model with a root mean-square error of prediction of 2.5%. The PLS model was used to study the amorphization kinetics of CCX-PVP tablets with different drug content (10, 20, 30, 40 and 50% w/w). For this purpose, transition Raman spectra were collected in 60 s intervals over a total microwave time of 10 min with an energy input of 1000 W. Using the quantitative model it was possible to measure the amorphous fraction of the tablets and follow the amorphization as a function of microwaving time. The relative amorphous fraction of CCX increased with increasing microwaving time and decreasing drug load, hence 90 ± 7% of the drug was amorphized in the tablets with 10% drug load whereas only 31 ± 7% of the drug was amorphized in the 50% CCX tablets. It is suggested that the degree of amorphization depends on drug loading. The likelihood of drug particles being in direct contact with the polymer PVP is a requirement for the dissolution of the drug into the polymer upon microwaving, and this is reduced with increasing drug load. This was further supported by polarized light microscopy that revealed evidence of crystalline particles and clusters in all the microwaved tablets.
Display omitted
The increasing interest in protein- and peptide-based oral pharmaceuticals has culminated in the first protein-based products for oral delivery becoming commercially available. This study ...investigates the compaction properties of proteins in binary mixtures with common excipients up to 30% (
/
) of particulate protein. Two model proteins, lysozyme and bovine serum albumin, were compacted with either microcrystalline cellulose, spray-dried lactose monohydrate, or calcium hydrogen phosphate dihydrate at two different compaction pressures. Compared to the compacted pure materials, a significant increase in the tensile strength of the compacts was observed for the binary blends containing lysozyme together with the brittle excipients. This could be attributed to the increased bonding forces between the particles in the blend compared to the pure materials. The use of bovine serum albumin with a larger particle size resulted in a decrease in tensile strength for all the compacts. The change in the tensile strength with an increasing protein content was non-linear for both proteins. This work highlights the importance of considering the particulate properties of protein powders and that protein-based compacts can be designed with similar principles as small-molecules in terms of their mechanical tablet properties.
Thermal methods are indispensable for the characterization of most materials. However, the existing methods require bulk amounts for analysis and give an averaged response of a material. This can be ...especially challenging in a biomedical setting, where only very limited amounts of material are initially available. Nano- and microelectromechanical systems (NEMS/MEMS) offer the possibility of conducting thermal analysis on small amounts of materials in the nano-microgram range, but cleanroom fabricated resonators are required. Here, we report the use of single drug and collagen particles as micro mechanical resonators, thereby eliminating the need for cleanroom fabrication. Furthermore, the proposed method reveals additional thermal transitions that are undetected by standard thermal methods and provide the possibility of understanding fundamental changes in the mechanical properties of the materials during thermal cycling. This method is applicable to a variety of different materials and opens the door to fundamental mechanistic insights.
Display omitted
Commonly used methods for analyzing tablet disintegration are based on visual observations and can thus be user-dependent. To address this, a generally applicable image analytical ...algorithm has been developed for machine vision-based quantification of tablet disintegration. The algorithm has been tested with a conventional immediate release tablet, as well as model compacts disintegrating mainly through erosion, and finally, with a polymeric slow-release system. Despite differences in disintegration mechanisms between these compacts, the developed image analytical algorithm demonstrated its general applicability through quantifying the extent of disintegration without adaptation of image analytical parameters. The reproducibility of the approach was estimated with commercial tablets, and further, it could differentiate a range of different model compacts. The developed image analytical algorithm mimics the human decision-making processes and the current experience-based visual evaluation of disintegration time. In doing so the algorithmic method allows a user-independent approach for development of the optimal tablet formulation as well as gaining an understanding on how the selection of excipients and manufacturing processes ultimately influences tablet disintegration.
PDF
