Continuous integrated production of glucose granules with enhanced flowability and tabletability.

Glucose is widely used in both the food and pharmaceutical industry. However, the application of industrially crystallized glucose in solid dosage forms is challenged by its poor flowability and tabletability. To improve these characteristics continuous twin-screw granulation was tested, which has the potential to be integrated into the continuous production of solid glucose from corn starch. A completely continuous manufacturing line (including drying and milling) was developed and the different production steps were examined and synchronized. Our line was supplemented with an in-line applicable near-infrared spectroscopic probe to monitor the moisture content of the milled granules in real-time. The flowability and tabletability of the powder improved significantly, and tablets with acceptable breaking force (greater than 100 N) could be prepared from the granules. The developed continuous line can be easily installed into the industrial solid glucose production process resulting in pure glucose granules with adequate flow properties and tabletability in a simple, continuous and efficient way.

Soft sensor for content prediction in an integrated continuous pharmaceutical formulation line based on the residence time distribution of unit operations.

In this study, a concentration predicting soft sensor was achieved based on the Residence Time Distribution (RTD) of an integrated, three-step pharmaceutical formulation line. The RTD was investigated with color-based tracer experiments using image analysis. Twin-screw wet granulation (TSWG) was directly coupled with a horizontal fluid bed dryer and an oscillating mill. Based on integrated measurement, we proved that it is also possible to couple the unit operations in silico. Three surrogate tracers were produced with a coloring agent to investigate the separated unit operations and the solid and liquid inputs of the TSWG. The soft sensor's prediction was compared to validating experiments of a 0.05 mg/g (15% of the nominal) concentration change with High-Performance Liquid Chromatography (HPLC) reference measurements of the active ingredient proving the adequacy of the soft sensor (RMSE < 4%).

In-line particle size measurement based on image analysis in a fully continuous granule manufacturing line for rapid process understanding and development.

The present paper serves as a demonstration how an in-line PAT tool can be used for rapid and efficient process development in a fully continuous powder to granule line consisting of an interconnected twin-screw wet granulator, vibrational fluid bed dryer, and a regranulating mill. A new method was investigated for the periodic in-line particle size measurement of high mass flow materials to obtain real-time particle size data of the regranulated product. The system utilises a vibratory feeder with periodically altered feeding intensity in order to temporarily reduce the mass flow of the material passing in front of the camera. This results in the drastic reduction of particle overlapping in the images, making image analysis a viable tool for the in-line particle size measurement of high mass-flow materials. To evaluate the performance of the imaging system, the effect of several milling settings and the liquid-to-solid ratio was investigated on the product's particle size in the span of a few hours. The particle sizes measured with the in-line system were in accordance with the expected trends as well as with the results of the off-line reference particle size measurements. Based on the results, the in-line imaging system can serve as a PAT tool to obtain valuable real-time information for rapid process development or quality assurance.

Transformable amyloid-beta mimetic peptide amphiphiles for lysosomal disruption in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is the largest contributor to cancer mortality in the United States. Traditional chemotherapies are toxic and prone to the development of drug-resistance. Recently, several drug candidates were shown to induce lysosomal membrane permeabilization (LMP) in aggressive cancers. This has led to increased interest in lysosome dysregulation as a therapeutic target. However, approaches are needed to overcome two limitations of current lysosomal inhibitors: low specificity and potency. Here, we report the development of a transformable nanomaterial which is triggered to induce LMP of lysosomes in NSCLC. The nanomaterial consists of peptide amphiphiles, which self-assemble into nanoparticles, colocalize with the lysosome, and change conformation to nanofibrils due to lysosomal pH shift, which leads to the disruption of the lysosome, cell death, and cisplatin sensitization. We have found that this cell-penetrating transformable peptide nanoparticle (CPTNP) was cytotoxic to NSCLC cells in the low-micromolar range and it synergized cisplatin cytotoxicity four-fold. Moreover, we demonstrate CPTNP's promising antitumor effect in mouse xenograft models with limited toxicity when given in combination with low dose cisplatin chemotherapy. This is the first example of enhanced LMP via transformable peptide nanomaterial and offers a promising new strategy for cancer therapy.

Continuous blending monitored and feedback controlled by machine vision-based PAT tool.

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.

Process Design of Continuous Powder Blending Using Residence Time Distribution and Feeding Models.

The present paper reports a thorough continuous powder blending process design of acetylsalicylic acid (ASA) and microcrystalline cellulose (MCC) based on the Process Analytical Technology (PAT) guideline. A NIR-based method was applied using multivariate data analysis to achieve in-line process monitoring. The process dynamics were described with residence time distribution (RTD) models to achieve deep process understanding. The RTD was determined using the active pharmaceutical ingredient (API) as a tracer with multiple designs of experiment (DoE) studies to determine the effect of critical process parameters (CPPs) on the process dynamics. To achieve quality control through material diversion from feeding data, soft sensor-based process control tools were designed using the RTD model. The operation block model of the system was designed to select feasible experimental setups using the RTD model, and feeder characterizations as digital twins, therefore visualizing the output of theoretical setups. The concept significantly reduces the material and instrumental costs of process design and implementation.

Electrospun Solid Formulation of Anaerobic Gut Microbiome Bacteria.

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-ß-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).

End-to-end continuous manufacturing of conventional compressed tablets: From flow synthesis to tableting through integrated crystallization and filtration.

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.

Digital UV/VIS imaging: A rapid PAT tool for crushing strength, drug content and particle size distribution determination in tablets.

The Process Analytical Technology (PAT) and the Quality-by-Design (QbD) approaches can efficiently facilitate the shift to the desired continuous manufacturing and real time release testing (RTRT). By this, it is vital to develop new, in-line analytical methods which fulfil the pharmaceutical requirements. The fast-developing digital imaging-based machine vision systems can provide revolutionary solutions not just in the automotive industry but in the pharmaceutical technology, as well. This study aimed to explore the capabilities of UV/VIS-based machine vision in tablet inspection as a PAT tool for the determination of compression force and crushing strength, drug content and drug distribution in tablets using meloxicam a yellow model drug. In the case of determining the compression force and crushing strength, the application of multivariate wavelet texture analysis (MWTA) based models provided relatively low prediction errors. To predict the drug content of meloxicam tablets CIELAB or RGB colorspace based algorithms were successfully developed and validated. UV/VIS imaging was also used to map the particle size distribution and spatial distribution of meloxicam, the results were compared to chemical maps obtained by Raman microscopy. Digital imaging combined with multivariate data analysis might be a valuable, high throughput, in-line PAT tool for automated inspection of pharmaceutical tablets.

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.

Synthesis and Optoelectronic Properties of New Methoxy-Substituted Diketopyrrolopyrrole Polymers.

The introduction of functional groups with varying electron-donating/-withdrawing properties at the ß-position of diketopyrrolopyrrole (DPP) has been shown to affect the optoelectronic properties of the polymers. We report the synthesis of a new diketopyrrolopyrrole monomer wherein a strong electron-donating substituent, a methoxy group, was incorporated at the ß-position in an effort to modulate polymer properties. Homopolymers and co-polymers of the new ß-methoxy DPP and nonderivatized DPP were synthesized, and their properties were measured by cyclic voltammetry and UV-vis-near-infrared. Density functional theory computations also were employed to predict the degree of planarity of ß-methoxy oligomers to probe the significance of the newly introduced S-O conformational lock. The combined experimental and computational results showed a reduction in the gap between highest occupied molecular orbital/lowest unoccupied molecular orbital levels, a redshift toward the near-infrared region, and an increased planarity in the ß-methoxy polymers.

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

An orally dissolving web (ODW) formulation of poorly soluble carvedilol (CAR) was developed and manufactured continuously using electrospinning (ES) as a key technology. Phase solubility tests revealed that hydroxypropyl-ß-cyclodextrin (HPßCD) 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.

Cyclodextrins: Assessing the Impact of Cavity Size, Occupancy, and Substitutions on Cytotoxicity and Cholesterol Homeostasis.

Cyclodextrins (CDs) are cyclic oligosaccharides; the most common CDs contain six, seven, or eight glucose units called α-CDs, ß-CDs, and γ-CDs, respectively. The use of CDs in biomedical research is increasing due to their ability to interact with membrane lipids as well as a wide variety of poorly water-soluble molecules. We assessed the impact of CD cavity size, occupancy, and substitutions on cytotoxicity and cholesterol homeostasis. The potency of CD-mediated cytotoxicity was in the order of ß-CDs, α-CDs, and γ-CDs. Substitutions with hydroxypropyl or carboxymethyl group attenuated cytotoxicity compared with the native CDs, whereas CDs substituted with methyl groups exhibited cytotoxicity that was similar to that of the native CDs. The lipid components in blood exerted remarkable hemolysis-alleviating effects in methyl-ß-CD-induced hemolysis. Occupancy of the CD cavity with cholesterol or a structurally related lipid molecule abrogated the cytotoxic capacity of the CDs. Interestingly, hydroxypropyl-γ-CD (HPγCD) was able to reduce intracellular cholesterol accumulation in Niemann⁻Pick disease type C (NPC) patient-derived fibroblasts as efficiently as HPßCD. Proteomic study indicated that HPßCD and HPγCD treatments altered the expression pattern of cellular proteins, suggesting that some of the CD-induced cellular proteins may play an important function in modulating intracellular cholesterol homeostasis.

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.

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.