Development of novel antimicrobials with engineered endolysin LysECD7-SMAP to combat Gram-negative bacterial infections.

BACKGROUND: Among the non-traditional antibacterial agents in development, only a few targets critical Gram-negative bacteria such as carbapenem-resistant Pseudomonas aeruginosa, Acinetobacter baumannii or cephalosporin-resistant Enterobacteriaceae. Endolysins and their genetically modified versions meet the World Health Organization criteria for innovation, have a novel mode of antibacterial action, no known bacterial cross-resistance, and are being intensively studied for application against Gram-negative pathogens. METHODS: The study presents a multidisciplinary approach, including genetic engineering of LysECD7-SMAP and production of recombinant endolysin, its analysis by crystal structure solution following molecular dynamics simulations and evaluation of antibacterial properties. Two types of antimicrobial dosage forms were formulated, resulting in lyophilized powder for injection and hydroxyethylcellulose gel for topical administration. Their efficacy was estimated in the treatment of sepsis, and pneumonia models in BALB/c mice, diabetes-associated wound infection in the leptin receptor-deficient db/db mice and infected burn wounds in rats. RESULTS: In this work, we investigate the application strategies of the engineered endolysin LysECD7-SMAP and its dosage forms evaluated in preclinical studies. The catalytic domain of the enzyme shares the conserved structure of endopeptidases containing a putative antimicrobial peptide at the C-terminus of polypeptide chain. The activity of endolysins has been demonstrated against a range of pathogens, such as Klebsiella pneumoniae, A. baumannii, P. aeruginosa, Staphylococcus haemolyticus, Achromobacter spp, Burkholderia cepacia complex and Haemophylus influenzae, including those with multidrug resistance. The efficacy of candidate dosage forms has been confirmed in in vivo studies. Some aspects of the interaction of LysECD7-SMAP with cell wall molecular targets are also discussed. CONCLUSIONS: Our studies demonstrate the potential of LysECD7-SMAP therapeutics for the systemic or topical treatment of infectious diseases caused by susceptible Gram-negative bacterial species and are critical to proceed LysECD7-SMAP-based antimicrobials trials to advanced stages.

Use of Magnetic Resonance Imaging for Visualization of Oral Dosage Forms in the Human Stomach: A Scoping Review.

Oral dosage forms are the most widely and frequently used formulations to deliver active pharmaceutical ingredients (APIs), due to their ease of administration and noninvasiveness. Knowledge of intragastric release rates and gastric mixing is crucial for predicting the API release profile, especially for immediate release formulations. However, knowledge of the intragastric fate of oral dosage forms in vivo to date is limited, particularly for dosage forms administered when the stomach is in the fed state. An improved understanding of gastric food processing, dosage form location, disintegration times, and food effects is essential for greater understanding for effective API formulation design. In vitro standard and controlled modeling has played a significant role in predicting the behavior of dosage forms in vivo. However, discrepancies are reported between in vitro and in vivo disintegration times, with these discrepancies being greatest in the fed state. Studying the fate of a dosage form in vivo is a challenging process, usually requiring the use of invasive methods, such as intubation. Noninvasive, whole body imaging techniques can however provide unique insights into this process. A scoping review was performed systematically to identify and critically appraise published studies using MRI to visualize oral solid dosage forms in vivo in healthy human subjects. The review identifies that so far, an all-purpose robust contrast agent or dosage form type has not been established for dosage form visualization and disintegration studies in the gastrointestinal system. Opportunities have been identified for future studies, with particular focus on characterizing dosage form disintegration for development after the consumption food, as exemplified by the standard Food and Drug Administration (FDA) high fat meal.

Importance of Considering Fed-State Gastrointestinal Physiology in Predicting the Reabsorption of Enterohepatic Circulation of Drugs.

PURPOSE: The purpose of this study was to develop a simulation model for the pharmacokinetics (PK) of drugs undergoing enterohepatic circulation (EHC) with consideration to the environment in the gastrointestinal tract in the fed state in humans. The investigation particularly focused on the necessity of compensating for the permeability rate constant in the reabsorption process in consideration of drug entrapment in bile micelles. METHODS: Meloxicam and ezetimibe were used as model drugs. The extent of the entrapment of drugs inside bile micelles was evaluated using the solubility ratio of Fed State Simulated Intestinal Fluid version 2 (FeSSIF-V2) to Fasted State Simulated Intestinal Fluid version 2 (FaSSIF-V2). Prediction accuracy was evaluated using the Mean Absolute Percentage Error (MAPE) value, calculated from the observed and predicted oral PK profiles. RESULTS: The solubilization of ezetimibe by bile micelles was clearly observed while that of meloxicam was not. Assuming that only drugs in the free fraction of micelles permeate through the intestinal membrane, PK simulation for ezetimibe was performed in both scenarios with and without compensation by the permeation rate constant. The MAPE value of Zetia® tablet, containing ezetimibe, was lower with compensation than without compensation. By contrast, Mobic® tablet, containing meloxicam, showed a relatively low MAPE value even without compensation. CONCLUSION: For drugs which undergo EHC and can be solubilized by bile micelles, compensating for the permeation rate constant in the reabsorption process based on the free fraction ratio appears an important factor in increasing the accuracy of PK profile prediction.

Untapped options to reduce waste from blister packaging for tablets and capsules.

PURPOSE: In Europe, most medicines are taken orally and primarily packaged as single solid oral dosage forms (SODF) in blister chambers (alveoli) arranged on blister cards. Blister cards are constructed as multilayer laminates of aluminum (Al) foils and/or various plastic polymers bonded together, forming the alveoli, which are separated by more or less large gaps. We calculated the amount of packaging material (and thus waste) generated annually for the packaging of the most commonly prescribed SODF in Germany and estimated how much waste could be saved by rearranging the alveoli. METHODS: For this purpose, we analysed the SODF of the 50 most frequently prescribed medicines that were packaged in alveoli (N = 45; 13 of aluminum-aluminum blisters, 32 of mixed materials), measured and weighed their packaging material and content, calculated the annual amount of waste produced from them, and estimated how much waste could be saved if the alveoli were optimally positioned on the blister cards. In addition, we examined the variability of the blister packaging of eight groups of commonly prescribed generics of the same strength. RESULTS: Detailed analysis of the blister cards revealed that most of the material (69%) was used for the space between blisters and that aluminum-aluminum alveoli were more than four times larger than the packaged SODF. The (conservatively) estimated annual amount of composite waste generated for the primary packaging of these SODF was 3868 t (and extrapolated to the entire German pharmaceutical market 8533 t), of which an optimized arrangement of the blister chambers, i.e., a 2-mm sealing area around each alveolus and the arrangement of the SODF in 2 rows, would save approximately 37%. CONCLUSION: Considering that other ecological strategies are not yet mature, the optimal arrangement of blister chambers would be a captivatingly simple and, above all, immediately implementable strategy to avoid large amounts of avoidable waste.

Manipulation of solid dosage forms for oral administration to paediatric patients for drug-resistant tuberculosis in South Africa: an observation study.

BACKGROUND: Children represent a particularly vulnerable demographic in the context of drug-resistant (DR) tuberculosis (TB) due to their increased likelihood of close contact with adults diagnosed with the disease. Approximately 25 000-30 000 children develop DR-TB annually. While treatment success rates for DR-TB in children surpass those in adults, children and adolescents encounter distinct challenges throughout the diagnosis and treatment of DR-TB (including MDR-TB, Pre-XDR TB, and XDR-TB). AIM: To identify current practices in drug administration to children diagnosed with DR-TB where appropriate dosage forms are not available in South Africa. METHOD: An observational study was carried out at the study site to determine how medication prescribed was manipulated and administered by nursing staff to paediatric patients in the wards. RESULTS: The observational study identified 8 drugs used in DR-TB at the study site, where some manipulation to the formulation was necessary to enable administration to paediatric patients. Linezolid and para-aminosalicylic acid are the only drugs available and registered in the South Africa in a formulation that is suitable for administration to paediatric patients. Activities carried out by nursing staff to enable the administration of DR-TB medication included cutting capsules and tablets and dissolving the tablet or capsule contents in distilled water to obtain the required suitable dose. DISCUSSION: Lack of availability of suitable dosage forms for paediatrics patients results in several challenges, such as additional time required for drug preparation, increased time duration of medication administration, and unpalatability of drugs. These challenges may subsequently affect compliance and therapeutic outcomes of the treatment of paediatric patients, especially as outpatients. CONCLUSION: Research needs to focus on the development of appropriate dosage forms for the paediatric population and focus on identifying cases of DR-TB in children. This will assist in building evidence to advocate for registration of child-friendly dosage forms thereby ensuring a sustainable supply of medication.

A review of the physiological effects of microgravity and innovative formulation for space travelers.

During the space travel mission, astronauts' physiological and psychological behavior will alter, and they will start consuming terrestrial drug products. However, factors such as microgravity, radiation exposure, temperature, humidity, strong vibrations, space debris, and other issues encountered, the drug product undergo instability This instability combined with physiological changes will affect the shelf life and diminish the pharmacokinetic and pharmacodynamic profile of the drug product. Consequently, the physicochemical changes will produce a toxic degradation product and a lesser potency dosage form which may result in reduced or no therapeutic action, so the astronaut consumes an additional dose to remain healthy. On long-duration missions like Mars, the drug product cannot be replaced, and the astronaut may relay on the available medications. Sometimes, radiation-induced impurities in the drug product will cause severe problems for the astronaut. So, this review article highlights the current state of various space-related factors affecting the drug product and provides a comprehensive summary of the physiological changes which primarly focus on absorption, distribution, metabolism, and excretion (ADME). Along with that, we insist some of the strategies like novel formulations, space medicine manufacturing from plants, and 3D printed medicine for astronauts in longer-duration missions. Such developments are anticipated to significantly contribute to new developments with applications in both human space exploration and on terrestrial healthcare.

Selective detection of azelnidipine in pharmaceuticals via carbon dot mediated spectrofluorimetric method: A green approach.

A spectrofluorimetric method using fluorescent carbon dots (CDs) was developed for the selective detection of azelnidipine (AZEL) pharmaceutical in the presence of other drugs. In this study, N-doped CDs (N-CDs) were synthesized through a single-step hydrothermal process, using citric acid and urea as precursor materials. The prepared N-CDs showed a highly intense blue fluorescence emission at 447 nm, with a photoluminescence quantum yield of ~21.15% and a fluorescence lifetime of 0.47 ns. The N-CDs showed selective fluorescence quenching in the presence of all three antihypertensive drugs, which was used as a successful detection platform for the analysis of AZEL. The photophysical properties, UV-vis light absorbance, fluorescence emission, and lifetime measurements support the interaction between N-CDs and AZEL, leading to fluorescence quenching of N-CDs as a result of ground-state complex formation followed by a static fluorescence quenching phenomenon. The detection platform showed linearity in the range 10-200 µg/ml (R2 = 0.9837). The developed method was effectively utilized for the quantitative analysis of AZEL in commercially available pharmaceutical tablets, yielding results that closely align with those obtained from the standard method (UV spectroscopy). With a score of 0.76 on the 'Analytical GREEnness (AGREE)' scale, the developed analytical method, incorporating 12 distinct green analytical chemistry components, stands out as an important technique for estimating AZEL.

Optimization of solid oral dosage form administration to patients with swallowing difficulties: An integrative review.

AIM: To appraise and synthesize research investigating optimizing the administration of solid oral dosage forms (SODFs) to adults with swallowing difficulties. DESIGN: An integrative review. METHODS: An electronic search was conducted on Medical Literature Analysis and Retrieval System Online (Public Medline interface), Elsevier SciVerse Scopus and Scientific Electronic Library Online (updated February 2023). Restriction regarding the publication date was not considered for the inclusion of records. Studies addressing risks, general aspects, recommendations about patient postural adjustments, swallowing techniques, swallowing aids and aspects of concealment of SODFs were included. RESULTS: Fifty-three records published between 2002 and 2021 were included. The main administration risks were aspiration, asphyxia and solid oral dosage form-induced oral/oesophageal mucosal lesions. The most frequent general aspect reported was administering one oral dosage form at a time. The sitting position was the most patient postural adjustment mentioned. The most frequently reported solid oral dosage form swallowing technique was the lean-forward method for capsules. Solid oral dosage form swallowing aids cited: tongue and throat lubricant and solid oral dosage form coating device, swallowing cup and swallowing straw. CONCLUSION: The literature data on administering SODFs for adults with swallowing difficulties were appraised and synthesized. Some aspects, for example, not administering SODFs simultaneously, can make swallowing safer. Postural adjustments and solid oral dosage form swallowing aids are important to avoid administration risks. Swallowing SODFs can be easier if learned by techniques. Liquid and food are helpful as vehicles, and several of these have been listed. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: By optimizing the contributing factors of administering oral pharmacotherapy, the nurse can use appropriate practices to improve patient safety. Additionally, knowing and establishing the administration aspects are reasonable steps for standardizing care for patients with swallowing oral dosage form difficulties. IMPACT: This study addressed administering SODFs to adult patients with swallowing difficulties. The administration of SODFs to adult patients with swallowing difficulties can be optimized if only one oral dosage form at a time is administrated and if patient postural adjustments, swallowing techniques and swallowing aids are used. This investigation will impact the care of patients with swallowing difficulties. REPORTING METHOD: The authors declare they adhered to the relevant EQUATOR guidelines and report following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 Statement. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution.

Quantitative analysis of solid dosage forms of Atenolol by Raman spectroscopy.

OBJECTIVE: To develop a Raman spectroscopy-based analytical model for quantification of solid dosage forms of active pharmaceutical ingredient (API) of Atenolol.Significance: For the quantitative analysis of pharmaceutical drugs, Raman Spectroscopy is a reliable and fast detection method. As part of this study, Raman Spectroscopy is explored for the quantitative analysis of different concentrations of Atenolol. METHODS: Various solid-dosage forms of Atenolol were prepared by mixing API with excipients to form different solid-dosage formulations of Atenolol. Multivariate data analysis techniques, such as Principal Component Analysis (PCA) and Partial least square regression (PLSR) were used for the qualitative and quantitative analysis, respectively. RESULTS: As the concentration of the drug increased in formulation, the peak intensities of the distinctive Raman spectral characteristics associated with the API (Atenolol) gradually increased. Raman spectral data sets were classified using PCA due to their distinctive spectral characteristics. Additionally, a prediction model was built using PLSR analysis to assess the quantitative relationship between various API (Atenolol) concentrations and spectral features. With a goodness of fit value of 0.99, the root mean square errors of calibration (RMSEC) and prediction (RMSEP) were determined to be 1.0036 and 2.83 mg, respectively. The API content in the blind/unknown Atenolol formulation was determined as well using the PLSR model. CONCLUSIONS: Based on these results, Raman spectroscopy may be used to quickly and accurately analyze pharmaceutical samples and for their quantitative determination.

Excipients for Novel Inhaled Dosage Forms: An Overview.

Pulmonary drug delivery is a form of local targeting to the lungs in patients with respiratory disorders like cystic fibrosis, pulmonary arterial hypertension (PAH), asthma, chronic pulmonary infections, and lung cancer. In addition, noninvasive pulmonary delivery also presents an attractive alternative to systemically administered therapeutics, not only for localized respiratory disorders but also for systemic absorption. Pulmonary delivery offers the advantages of a relatively low dose, low incidence of systemic side effects, and rapid onset of action for some drugs compared to other systemic administration routes. While promising, inhaled delivery of therapeutics is often complex owing to factors encompassing mechanical barriers, chemical barriers, selection of inhalation device, and limited choice of dosage form excipients. There are very few excipients that are approved by the FDA for use in developing inhaled drug products. Depending upon the dosage form, and inhalation devices such as pMDIs, DPIs, and nebulizers, different excipients can be used to provide physical and chemical stability and to deliver the dose efficiently to the lungs. This review article focuses on discussing a variety of excipients that have been used in novel inhaled dosage forms as well as inhalation devices.

Utility of a xanthene-based dye for determination of nilotinib using two spectroscopic approaches. Applications to bulk powder, capsules, and spiked human plasma.

Novel, selective, facile, and precise spectroscopic approaches were validated to determine nilotinib hydrochloride, a tyrosine kinase inhibitor used to treat patients with chronic myeloid leukemia. These approaches depend on the reaction of the tertiary amine group of nilotinib with erythrosine B in the Britton-Robinson buffer at pH 4. Method I, depends on measuring the absorbance of the formed complex at 551 nm. The absorbance concentration plot showed linearity over the concentration range of 1.0 to 9.0 µg/ml. Method II, involved the measurement of the quenching of the native fluorescence of erythrosine B by adding nilotinib in an acidic medium. The fluorescence quenching of erythrosine B was measured at 549 nm after excitation at 528 nm. This approach showed excellent linearity in the concentration range of 0.04 to 0.7 µg/ml. The limit of detection values for Method I and Method II were 0.225 and 0.008 µg/ml, respectively, while the limit of quantitation values for Method I and Method II were 0.68 and 0.026 µg/ml, respectively. To get the optimal conditions, factors that may affect the formation of the ion-pairing complex were thoroughly examined. The two approaches were carefully validated following the International Conference of Harmonization (ICH Q2R1) guidelines. Statistical assessment of the results achieved using the suggested and previously published comparison approaches showed no significant difference. The approaches were successful in determining nilotinib in a pharmaceutical dosage form as well as spiked human plasma samples. The eco-friendly properties of the methods were evaluated by three different tools.

Advances in ATR-FTIR Spectroscopic Imaging for the Analysis of Tablet Dissolution and Drug Release.

One of the major challenges in the development of effective pharmaceutical formulations for oral administration is the poor solubility of active pharmaceutical ingredients. For this reason, the dissolution process and drug release from solid oral dosage forms, such as tablets, is usually thoroughly studied in order to understand the dissolution behaviour under various conditions and optimize the formulation accordingly. Standard dissolution tests used in the pharmaceutical industry provide information on the amount of drug released over time; however, these do not allow for a detailed analysis of the underlying chemical and physical mechanisms of tablet dissolution. FTIR spectroscopic imaging, by contrast, does offer the ability to study these processes with high spatial and chemical specificity. As such, the method allows us to see the chemical and physical processes which occur inside the tablet as it dissolves. In this review, the power of ATR-FTIR spectroscopic imaging is demonstrated by presenting a number of successful applications of this chemical imaging technique to dissolution and drug release studies for a range of different pharmaceutical formulations and study conditions. Understanding these processes is essential for the development of effective oral dosage forms and optimization of pharmaceutical formulations.

Vanadium-Containing Anionic Chelate for Spectrophotometric Determination of Hydroxyzine Hydrochloride in Pharmaceuticals.

Four azo dyes known to form anionic complexes with V(V) were investigated as potential liquid-liquid extraction-spectrophotometric reagents for the antihistamine medication hydroxyzine hydrochloride (HZH). A stable ion-association complex suitable for analytical purposes was obtained with 6-hexyl-4-(2-thiazolylazo)resorcinol (HTAR). The molar absorption coefficient, limit of detection, linear working range, and relative standard deviation in the analysis of real pharmaceutical samples (tablets and syrup) were 3.50 × 104 L mol-1 cm-1, 0.13 µg mL-1, 0.43-12.2 µg mL-1, and ≤2.7%, respectively. After elucidating the molar ratio in the extracted ion-association complex (HZH:V = 1:1), the ground-state equilibrium geometries of the two constituent ions-HZH+ and [VO2(HTAR)]--were optimized at the B3LYP level of theory using 6-311++G** basis functions. The cation and anion were then paired in four different ways to find the most likely structure of the extracted species. In the lowest-energy structure, the VO2 group interacts predominantly with the heterochain of the cation. A hydrogen bond is present (V-O···H-O; 1.714 Å) involving the terminal oxygen of this chain.

Preliminary Study on the Development of Caffeine Oral Solid Form 3D Printed by Semi-Solid Extrusion for Application in Neonates.

Apnea of prematurity can be treated with a body-weight-adjusted dosage of caffeine. Semi-solid extrusion (SSE) 3D printing represents an interesting approach to finely tailor personalized doses of active ingredients. To improve compliance and ensure the right dose in infants, drug delivery systems such as oral solid forms (orodispersible film, dispersive form, and mucoadhesive form) can be considered. The aim of this work was to obtain a flexible-dose system of caffeine by SSE 3D printing by testing different excipients and printing parameters. Gelling agents (sodium alginate (SA) and hydroxypropylmethyl cellulose (HPMC)) were used to obtain a drug-loaded hydrogel matrix. Disintegrants (sodium croscarmellose (SC) and crospovidone (CP)) were tested for get rapid release of caffeine. The 3D models were patterned by computer-aided design with variable thickness, diameter, infill densities, and infill patterns. The oral forms produced from the formulation containing 35% caffeine, 8.2% SA, 4.8% HPMC, and 52% SC (w/w) were found to have good printability, achieving doses approaching to those used in neonatology (between 3 and 10 mg of caffeine for infants weighing approximately between 1 and 4 kg). However, disintegrants, especially SC, acted more as binder/filler, showing interesting properties to maintain the shape after extrusion and enhance printability without a significant effect on caffeine release.

Recent Advances in the Applications of Additive Manufacturing (3D Printing) in Drug Delivery: A Comprehensive Review.

There has been a tremendous increase in the investigations of three-dimensional (3D) printing for biomedical and pharmaceutical applications, and drug delivery in particular, ever since the US FDA approved the first 3D printed medicine, SPRITAM® (levetiracetam) in 2015. Three-dimensional printing, also known as additive manufacturing, involves various manufacturing techniques like fused-deposition modeling, 3D inkjet, stereolithography, direct powder extrusion, and selective laser sintering, among other 3D printing techniques, which are based on the digitally controlled layer-by-layer deposition of materials to form various geometries of printlets. In contrast to conventional manufacturing methods, 3D printing technologies provide the unique and important opportunity for the fabrication of personalized dosage forms, which is an important aspect in addressing diverse patient medical needs. There is however the need to speed up the use of 3D printing in the biopharmaceutical industry and clinical settings, and this can be made possible through the integration of modern technologies like artificial intelligence, machine learning, and Internet of Things, into additive manufacturing. This will lead to less human involvement and expertise, independent, streamlined, and intelligent production of personalized medicines. Four-dimensional (4D) printing is another important additive manufacturing technique similar to 3D printing, but adds a 4th dimension defined as time, to the printing. This paper aims to give a detailed review of the applications and principles of operation of various 3D printing technologies in drug delivery, and the materials used in 3D printing, and highlight the challenges and opportunities of additive manufacturing, while introducing the concept of 4D printing and its pharmaceutical applications.

Nutraceuticals in Bulk and Dosage Forms: Analysis by 35Cl and 14N Solid-State NMR and DFT Calculations.

This study uses 35Cl and 14N solid-state NMR (SSNMR) spectroscopy and dispersion-corrected plane-wave density functional theory (DFT) calculations for the structural characterization of chloride salts of nutraceuticals in their bulk and dosage forms. For eight nutraceuticals, we measure the 35Cl EFG tensor parameters of the chloride ions and use plane-wave DFT calculations to elucidate relationships between NMR parameters and molecular-level structure, which provide rapid NMR crystallographic assessments of structural features. We employ both 35Cl direct excitation and 1H→35Cl cross-polarization methods to characterize a dosage form containing α-d-glucosamine HCl, observe possible impurity and/or adulterant phases, and quantify the weight percent of the active ingredient. To complement this, we also investigate 14N SSNMR spectroscopy and DFT calculations to characterize nitrogen atoms in the nutraceuticals. This includes a discussion of targeted acquisition experimental protocols (i.e., acquiring a select region of the overall pattern that features key discontinuities) that allow ultrawideline spectra to be acquired rapidly, even for unreceptive samples (i.e., those with long values of T1(14N), short values of T2eff(14N), or very broad patterns). It is hoped that these experimental and computational protocols will be useful for the characterization of various solid forms of nutraceuticals (i.e., salts, polymorphs, hydrates, solvates, cocrystals, amorphous solid dispersions, etc.), help detect impurity and counterfeit solid phases in dosage forms, and serve as a foundation for future NMR crystallographic studies of nutraceutical solid forms, including studies using ab initio crystal structure prediction algorithms.

Evaluating Spatially Offset Low-Frequency Anti-Stokes Raman Spectroscopy (SOLFARS) for Detecting Subsurface Composition below an Emissive Layer: A Proof of Principle Study Using a Model Bilayer System.

This work explores the potential use of spatially offset low-frequency anti-Stokes Raman spectroscopy (SOLFARS) to detect subsurface composition below an emissive surface. A range of bilayer tablets were used to evaluate this approach. Bilayer tablets differed in both the underlying layer composition (active pharmaceutical ingredient to excipient ratio, celecoxib: α-lactose monohydrate) and the upper layer thickness of the fluorescent coating (polyvinylpyrrolidone mixture with sunset yellow FCF dye). Two low- (<300 cm-1) plus mid- (300 to 1800 cm-1) frequency Raman instrumental setups, with lateral displacements for spatial analysis of solid dosage forms, using different excitation wavelengths were explored. The 532 nm system was used to illustrate how the low-frequency anti-Stokes Raman approach works with samples exhibiting extreme fluorescence/background emission interference, and the 785 nm system was used to demonstrate the performance when less extreme fluorescence/emission is present. Qualitative and quantitative chemometric analyses were performed to evaluate the performance of individual spectral domains and their combinations for the determination of the composition of the subsurface layer as well as the coating layer thickness. Overall, the commonly used midfrequency region (300-1800 cm-1) proved superior when using 785 nm incident laser for quantifying the coating thickness (amorphous materials), whereas a combined Stokes and anti-Stokes low-frequency region was found to be superior for quantifying underlying crystalline materials. When exploring individual spectral regions for subsurface composition using spatially offset measurements, the anti-Stokes LFR spectral window performed best. The anti-Stokes low-frequency range also demonstrated an advantage for models composed of data exhibiting high levels of fluorescence (e.g., data collected using 532 nm incident laser), as the Stokes scattering was masked by fluorescence. Transmission measurements were also explored for comparison and showed the best applicability for both upper and lower layer analysis, attributed to the inherently larger bulk sampling volume of this setup. From a practical perspective, these results highlight the potential adjustments that can be made to already existing (in-line) Raman setups to facilitate similar analysis in pharmaceutical industry-based settings.

Seeing Is Believing: Time-Lapse Macro-Imaging of Morphological Changes of Solid Dosages as a Teaching and Research Tool.

PURPOSE: Disintegration kinetics and behaviors are critical for the quality and performance of oral solid dosages. Instead of performing standard disintegration tests, herein, we aim to visualize these kinetic processes in real time. METHOD: A visual acquisition system is developed to capture the morphological changes of tablets under static conditions via time-lapse macro-imaging. The system consists of: i) a customized quartz chamber, ii) a metal sieve with pore sizes ranging from 1 to 2 mm in diameter to allow rapid settling of the disintegrated particles, and iii) a temperature-controlled water bath. A typical workflow consists of the following steps: i) planning of the experiment to consider the type of the active pharmaceutical ingredient and drug release mechanism; ii) acquisition of photo-imaging data from at least two cameras arranged at different angles over a predetermined time period; iii) post-processing of the image data; iv) production of video clips and image analysis. RESULTS: Representative works are shown to demonstrate the disintegration phenomenon or the morphological changes of solid drug products of various controlled- and extended-release mechanisms. CONCLUSION: These video clips are used as teaching materials for students majoring in pharmacy or pharmaceutical chemistry, which also provide an insightful unique perspective of the microprocess during tablet fragmentation, disintegration or drug release.

Novel 3D Printed Modular Tablets Containing Multiple Anti-Viral Drugs: a Case of High Precision Drop-on-Demand Drug Deposition.

3D printed drug delivery systems have gained tremendous attention in pharmaceutical research due to their inherent benefits over conventional systems, such as provisions for customized design and personalized dosing. The present study demonstrates a novel approach of drop-on-demand (DoD) droplet deposition to dispense drug solutions precisely on binder jetting-based 3D printed multi-compartment tablets containing 3 model anti-viral drugs (hydroxychloroquine sulfate - HCS, ritonavir and favipiravir). The printing pressure affected the printing quality whereas the printing speed and infill density significantly impacted the volume dispersed on the tablets. Additionally, the DoD parameters such as nozzle valve open time and cycle time affected both dispersing volume and the uniformity of the tablets. The solid-state characterization, including DSC, XRD, and PLM, revealed that all drugs remained in their crystalline forms. Advanced surface analysis conducted by microCT imaging as well as Artificial Intelligence (AI)/Deep Learning (DL) model validation showed a homogenous drug distribution in the printed tablets even at ultra-low doses. For a four-hour in vitro drug release study, the drug loaded in the outer layer was released over 90%, and the drug incorporated in the middle layer was released over 70%. In contrast, drug encapsulated in the core was only released about 40%, indicating that outer and middle layers were suitable for immediate release while the core could be applied for delayed release. Overall, this study demonstrates a great potential for tailoring drug release rates from a customized modular dosage form and developing personalized drug delivery systems coupling different 3D printing techniques.

Direct Granule Feeding of Thermal Droplet Deposition 3D Printing of Porous Pharmaceutical Solid Dosage Forms Free of Plasticisers.

PURPOSE: To develop a new direct granule fed 3D printing method for manufacturing pharmaceutical solid dosage forms with porous structures using a thermal droplet deposition technology. METHODS: Eudragit® E PO was used as the model polymer, which is well-known to be not FDM printable without additives. Wet granulation was used to produce drug loaded granules as the feedstock. The flow and feedability of the granules were evaluated. The physicochemical properties and in vitro drug release performance of the granules and the printed tablets were fully characterised. RESULTS: Using the method developed by this study, Eudragit E PO was printed with a model drug into tablets with infills ranging from 30-100%, without additives. The drug was confirmed to be molecularly dispersed in the printed tablets. The printing quality and performances of the porous tablets were confirmed to be highly compliant with the pharmacopeia requirement. The level of infill density of the porous tablets had a significant effect on their in vitro drug release performance. CONCLUSION: This is the first report of thermal droplet deposition printing via direct granule feeding. The results of this study demonstrated that this new printing method can be used as a potentially valuable alternative for decentralised pharmaceutical solid dosage form manufacturing.