Content uniformity is a critical attribute for potent and low-dosage formulations of active pharmaceutical ingredient (API) that, in addition to the formulation parameters, plays pivotal role during ...pharmaceutical development and production. However, when API content is low, implementing a vibrational spectroscopic analytical tool to monitor the content and blend uniformity remains a challenging task. The aim of this study was to showcase the potentials of mid-infrared (MIR), near-infrared (NIR), and Raman spectroscopy for quantitative analysis of alprazolam (ALZ) in a low-content powder blends with lactose, which is used as a common diluent for tablets produced by direct compression. The offered approach might be further scaled up and exploited for potential application in the process analytical technology (PAT). Partial least square and orthogonal PLS (OPLS) methodologies were employed to build the calibration models from raw and processed spectral data (standard normal variate, first and second derivatives). The models were further compared regarding their main statistical indicators: correlation coefficients, predictivity, root mean square error of estimation (RMSEE), and root mean square error of cross-validation (RMSEEcv). All statistical models presented high regression and predictivity coefficients. The RMSEEcv for the optimal models was 1.118, 0.08, and 0.059% for MIR, NIR, and Raman spectroscopy, respectively. The scarce information content extracted from the ALZ NIR spectra and the major band overlapping with those from lactose monohydrate was the main culprit of poor accuracy in the NIR model, whereas the subsampling instrumental setup (resulting in a non-representative spectral acquisition of the sample) was regarded as a main limitation for the MIR-based calibration model. The OPLS models of the Raman spectra of the powder blends manifested favorable statistical indicators for the accuracy of the calibration model, probably due to the distinctive ALZ Raman pattern resulting in the largest number of predictive spectral points that were used for the mathematical modeling. Furthermore, the Raman scattering calibration model was optimized in narrower scanning range (1700–700 cm−1) and its prediction power was evaluated (root mean square error of prediction, RMSEP = 0.03%). Thus, the Raman spectroscopy presented the most favorable statistical indicators in this comparative study and therefore should be further considered as a PAT for the quantitative determination of ALZ in low-content powder blends.
•Publicly available environmental risk assessment data for pharmaceuticals is limited.•Environmental hazard information is mainly based on standardized ecotoxicity tests.•Risk assessment of chronic ...effects outcomes is limited and challenging.•Nonstandardized ecotoxicity assays could inform of nonstandard modes of action.•Local environmental risks are largely impacted by drug consumption volumes.
Pharmaceutical residues are widely detected in aquatic environment worldwide mainly arising from human excretions in sewage systems. Presently, publicly available, high quality environmental risk assessment (ERA) data for pharmaceuticals are limited. However, databases like the Swedish Fass offer valuable resources aiding healthcare professionals and environmental scientists in identifying substances of significant concern. In this review, we provide a concise overview of the regulatory ERA process for medicinal products intended for human use. We explore its key assumptions and uncertainties using a subset of 37 pharmaceuticals. First, we compare the consistency of their predicted no-effect concentrations reported in the Fass database with those by marketing authorisation holders. Second, we compare the predicted environmental concentrations (PEC) calculated based on sales data between European and national drug consumption statistics as well as with measured environmental concentrations (MEC), to demonstrate their impact on the regional risk quotients. Finally, we briefly discuss the prevailing uncertainties and challenges of current ecotoxicity testing, especially outcomes of chronic and nonlethal effects.
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Abstract N -nitrosodimethylamine (NDMA) and N -nitrosodiethylamine (NDEA), group 2A carcinogens, were detected in finished drug products, including metformin, ranitidine, sartans and other drugs ...which caused multiple recalls in the USA and Europe. Important studies also reported the formation of NDMA when ranitidine and nitrite were added to simulated gastric fluid. Our objective was to screen finished drug products from Europe and USA for nitrosamine impurities and investigate the formation of NDMA in metformin finished drug products when added to simulated gastric fluid. One dosage unit of 30 different commercially available drugs, including metformin, sartans, and ranitidine were tested for NDMA, NDEA, and dimethylformamide (DMF) impurities, using a liquid chromatography-mass spectrometry (LC–MS) method. Then, 6 metformin finished drug products were tested in stomach conditions for 2 h at 37 °C in a 100 mL solution with a pH of 2.5 and different nitrite concentrations (40, 10, 1, 0.1 mM) and tested for NDMA, and DMF using LC–MS. We measured NDMA, NDEA, and DMF in 30 finished drug products. NDMA and DMF were quantified for metformin drug products in simulated gastric fluid with different nitrite concentrations. None of the 30 drugs showed concerning levels of NDMA, NDEA, or DMF when tested as single tablets. However, when metformin tablets are added to simulated gastric fluid solutions with high nitrite concentrations (40 mM and 10 mM), NDMA can reach amounts of thousands of nanograms per tablet. At the closest concentration to physiologic conditions we used, 1 mM, NDMA is still present in the hundreds of nanograms in some metformin products. In this in vitro study, nitrite concentration had a very important effect on NDMA quantification in metformin tablets added to simulated gastric fluid. 1 mM nitrite caused an increase above the acceptable daily intake set by the U.S. Food and Drug Administration (FDA) for some of the metformin drugs. 10 mM, 40 mM nitrite solutions generated NDMA amounts exceeding by more than a hundred times the acceptable daily intake set by the FDA of 96 nanograms. These findings suggest that metformin can react with nitrite in gastric-like conditions and generate NDMA. Thus, patients taking metformin could be exposed to NDMA when high nitrite levels are present in their stomach, and we recommend including a statement within the Patient Package Inserts/Instructions for use.
Nanotechnology ushered the field of medicine in to a new era. Miniaturization, increased surface area, and the unique physicochemical properties in the nano dimension were explored for new ...applications. Pharmaceutical industry picked up the technology and early success came fast for oral drug delivery through improvement in dissolution properties of the active molecules. Many products were launched using the nanocrystal technology on the oral side. Further development of polymeric nanoparticles led to wide spread research of nanocarriers for parenteral delivery. While considerable efforts have gone in the last two decades for testing nanoparticles for tumor targeting, delivery into tumors has remained challenging and suboptimal. Inadequate in vivo models that didn't accurately reflect the age and vascularity of human tumors, and inability to reproducibly target therapeutic drugs to the tissue of interest due to intrinsic biodistribution of the particles and hence side effects, limited the number of studies that advanced to the clinic. Our article addresses the questions commonly asked by scientific researchers in nanomedicine: “Has nanoparticle technology yielded on its initial promise that scientists predicted towards improving therapeutic index and avoid toxicity by delivering molecules to target tissues or was it more of wishful thinking that had several roadblocks?” We answer this question by linking the relevance of nanoparticles to cancer immunotherapy. The advent of immunotherapy has begun to show the potential applicability of nanoparticles in a different light, to target the immune system. In this approach, nanoparticles may positively influence the immune system rather than create the targeted “magic bullet”. Utilizing the intrinsic properties of nanoparticles for immune targeting as opposed to targeting the tumor can bring about a positive difference due to the underlying complex cancer mechanisms that can potentially overlap with the heterogeneous biodistribution of nanoparticles towards improving the acquired and innate immune responses. In this review, we have followed the progress of nanotechnology in pharmaceutical applications with key insights from oral and parenteral drug delivery, and how to modify our thinking to better utilize nanoparticles for immuno-oncology. In contrast to conventional “local” tumor targeting by nanoparticles, we propose a new mechanism whereby nanoparticles trigger priming of the T cells towards tumor destruction. The heterogenous biodistribution of nanoparticles lends itself to stimulating immune cells systemically in a “global” manner and with the right therapeutic combinations will be able to trigger tumor antigens to continually activate, retain memory effects and destroy tumor cells.
Schematic representation of nanotherapeutics in the nanorobot avatar. Cancer utilizes complex regulatory networks and nanorobots will seek out and interact with tumor cells using its unique surface functionalization and sensing capabilities for improving immune response. Circulating nanoparticles can interact with dentritic cells and macrophages to activate T cells for improving the immune response. Display omitted
Purpose
The aim of this study is to convert tretinoin (Tr), an active pharmaceutical ingredient (API), into ionic liquid for improving aqueous solubility and permeability of Tr in transdermal drug ...delivery applications.
Methods
Three ionic liquids of Tr (TrILs) were synthesized through neutralization reactions, which were characterized to confirm the compositions and ionic interactions. The
in vitro
drug release studies and skin penetration tests were carried out to assess the performance of formulations containing TrILs.
Results
The TrIL formed by choline and Tr at the molar ratio of 2:1 (2ChTr), was found to have prominent solubility, stability as well as permeability. In contrast with the insoluble Tr, 2ChTr presented as clear and transparent aqueous solution even after diluted to 14%. The aqueous solution of 2ChTr demonstrated better permeation effect, of which the solution with 20% of 2ChTr showed the optimal delivery efficiency in both epidermis (2.09 ± 0.18‰) and dermis (3.31 ± 0.48‰), realizing the improvement on the permeability of API. Meanwhile, TrILs can be easily fabricated as o/w emulsions as transdermal formulation. The emulsions are also able to improve the skin permeability of Tr, though the enhanced effect is inferior to TrILs solutions.
Conclusions
Ionic liquid technology can be used to improve solubility and permeability of Tr, providing a high potential strategy for the development of topical formulations and the desired transdermal application of drugs.
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•A novel d value model-based dynamic optimization of batch crystallization process.•Experiments with different targeted final crystal size distribution designed.•Cooling, stirring ...rate & seed amount simultaneously optimized.•The approach experimentally validated on different reactor vessel scales.•Sensitivity analysis emphasized the complex interplay of various kinetic phenomena.
Crystallization of active pharmaceutical ingredients (API) is one of the most important and complex multiphase engineering operations in pharmaceutical manufacturing industry. The desired physicochemical properties of solid crystalline product, such as crystal size distribution (CSD), are achieved by optimizing appropriate analyzed process operating conditions. In this application-derived study, an efficient straightforward mathematical modelling approach for the d value targeted CSD (characterized by 10th, 50th, and 90th centiles d10, d50, and d90) optimization of the API fesoterodine fumarate (FF) batches in different solvent mixtures on reactor dimension scales from 0.1 to 15 L is presented. The model is based on energy, mass, and population balance equations, the thermodynamic system equilibrium between solute/solution, and the kinetics of nucleation, crystal growth, and crystal agglomeration. In the first set of two experiments, the ability of the model to predict final CSD under chosen operating conditions was validated applying particular previously estimated kinetic parameters. An excellent statistical agreement between predicted and experimental CSD results was observed. Furthermore, the utility of the model to determine suitable operating conditions for the formation of FF crystals with d value defined CSD is presented. Two additional experiments were designed where stirring, cooling rate, and the amount of seed were optimally regressed. Good agreement between targeted and experimental CSD was shown and depending on the chosen vessel unit, mixing & cooling rates had the strongest relative impact on CSD. Algorithm may be beneficially utilized early during API industrial technological development, intensification, and scale-up, or transferred to continuous flow.
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•Standard analytical tools are used for the investigation of µm sized oral drug delivery systems.•Purpose-made sensors and experimental platforms are also needed for ...characterization.•Comprehensive efficacy, stability, and safety studies are needed to reach the clinical phase.
Complex and miniaturized oral drug delivery systems are being developed rapidly for targeted, controlled drug release and improved bioavailability. Standard analytical techniques are widely used to characterize i) drug carrier and active pharmaceutical ingredients before loading into a delivery device (to ensure the solid form), and ii) the entire drug delivery system during the development process. However, in light of the complexity and the size of some of these systems, standard techniques as well as novel sensing technologies and experimental platforms need to be used in tandem. These technologies and platforms are discussed in this review, with a special focus on passive delivery systems in size range from a few 100 µm to a few mm. Challenges associated with characterizing these systems and evaluating their effect on oral drug delivery in the preclinical phase are also discussed.
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