Solid Form Research Articles

Production sustained release dosage forms from deliquescent substances by solid dispersion systems

Introduction. The production of solid dosage forms from hygroscopic substances is a complex technological task. The addition of hygroscopic substances into a polymer matrix allows to reduce their moisture absorption capacity.Aim. Reducing the hygroscopicity of deliquescent substances and obtaining sustained release solid dosage forms by using solid dispersion systems.Materials and methods. Substance: DEAE; excipients: Kollidon® VA 64, Soluplus®, PEG 1500, PEG 6000, PEG 8000, Poloxamer Kolliphor® P 188 and Kolliphor® P 407; reagents: hydrochloric acid, sodium dihydrogen phosphate, potassium hydrogen phosphate. The melt of the components was obtained on a twin-screw laboratory extruder and cast into silicone molds. The resulting solid dosage forms were studied for disintegration in three environments corresponding to the sections of the human gastrointestinal tract.Results and discussion. The active pharmaceutical substance DEAE is characterized as deliquescent substance. The introduction of DEAE into PEG-polymer matrices made it possible to reduce the hygroscopicity of solid dosage forms in the form of bars. The introduction of solubilizers into the melt made it possible to obtain bars with the appropriate organoleptic properties. The release of DEAE from bear- or toroid-shaped bars occurs on average 29–47 % faster than from heart-shaped bars.Conclusion. Compositions based on Soluplus® and Kolliphor® P 407 have proven promising for further development of tiles containing DEAE. In order to create tiles with a slow release, it is recommended to use heart-shaped forms, as they have a smaller surface area.

Development of 3D-Printed Two-Compartment Capsular Devices for Pulsatile Release of Peptide and Permeation Enhancer.

The oral absorption of a peptide is driven by a high local concentration of a permeation enhancer (PE) in the gastrointestinal tract. We hypothesized that a controlled release of both PE and peptide from a solid formulation, capable of maintaining an effective co-localized concentration of PE and peptide could enhance oral peptide absorption. In this study, we aimed to develop a 3D-printed two-compartment capsular device with controlled pulsatile release of peptide and sodium caprate (C10). 3D-printed two-compartment capsular device was fabricated using a fused deposition modeling method. This device was then filled with LY peptide and C10. The release profile was modulated by changing the thickness and polymer type of the capsular device. USP apparatus II dissolution test was used to evaluate the impacts of device thickness and polymer selection on release profile in vitro. An optimal device was then enteric coated with HPMCAS. A strong linear relationship between the thickness of capsular devices and the delay in the release onset time was observed. An increase in the device thickness or the use of PLA decreased the release rate. The capsular device with compartment 1, compartment 2 and fence thickness of 0.4; 0.95 and 0.5mm, respectively, and the use of PVA achieved desired pulsatile release profiles of both peptide and C10. Furthermore, enteric-coated capsular devices with HPMCAS had similar pulsatile release profiles compared to non-enteric coated devices. These findings suggest potential application of 3D-printing techniques in the formulation development for complex modified drug release products.

Pemberdayaan Masyarakat di Bidang Pertanian melalui Pembuatan Pupuk Organik

Organic fertilizer is defined as fertilizer that is partly or wholly derived from plants and/or animals that has gone through an engineering process, can be in solid or liquid form which is used to supply organic material to improve the physical, chemical and biological properties of the soil. The aim of this activity is to empower the community through making organic fertilizer in the agricultural sector. The activity steps include: 1) Preparation stage. The preparation stage is very important as a form of more mature planning to achieve better things. This preparation stage includes observations and interviews with partners and the community, checking the implementation location, in this case I used Sumbek Hamlet, Wajageseng Village, Kopang District, Central Lombok Regency, establishing collaboration with youth and the entire community, preparing tools and materials for the main program which includes everything needed in this training; and 2) Program implementation stage. The program implementation stages are described as follows: the process of collecting cow dung which is processed into fertilizer, the process of mixing cow dung with straw, and the fermentation process for up to ± 30 days to make it into soil to be used as fertilizer. The results achieved in this training activity were the acquisition of knowledge by the community and youth about how to make organic fertilizer using existing materials. The community is able to minimize expenditure on purchasing fertilizer and reduce the use of chemical fertilizers. Through this activity, the public also understands more about the negative impacts caused by the use of chemical or inorganic fertilizers if used over a long period of time. This community empowerment can also support various village activities in organizing training in the agricultural sector, because the community is able to create their own fertilizer from materials that are easily obtained.

Various drugs used in oral disintegration tablet formulation

Oral drug administration is more widely accepted because it is used to provide between 50 and 60 percent of medications. The solid dosage forms are commonly utilized since they are simple to administer, precise in their dosage forms, beneficial for self-medication, and preventive of discomfort, and last but not least, the excellent level of patient adherence. The capsules and tablets are the most widely used solid dose form administered orally. Aside from ingesting it does not possess any noteworthy drawbacks. Water plays a crucial function in this swallowing process. Even following this, some people had difficulty swallowing. In order to prevent these issues, mouth dissolving tablets were developed. They have the benefit of not requiring water and don't require swallowing because they dissolve or disintegrate in saliva. In light of the design it began to behave in two ways: first, some tablets disintegrated quickly, taking just a few moments in saliva. Another kind of tablet is known as a "first disintegration tablet" since it contains some substances that slowed down the tablet's rate of breakdown. Review attention was drawn to the concise talk about mouth dissolving tablets and the most recent versions available.

Ultrasound-assisted extraction of itraconazole from pellets: an efficient approach for the recovery of active pharmaceutical compounds from solid dosage forms

IntroductionItraconazole is a widely used broad-spectrum antifungal drug on a global scale. However, its poor water solubility necessitates the development of advanced formulations for its effective use. Currently, itraconazole is available commercially in capsule form, with pellets containing the active drug. The extraction of itraconazole from these granules is often required when developing new formulations. Extracting active pharmaceutical ingredients (APIs) from pellets is crucial in ensuring precise and consistent dosing when producing pharmaceutical dosage forms. Surprisingly, no existing methods for extracting itraconazole from pellets have been reported thus far.ObjectiveTherefore, this study aimed to develop and evaluate an efficient method for extracting this API from pellets.MethodsTwo extraction methods were assessed: conventional Soxhlet extraction and ultrasound-assisted extraction.Results and DiscussionThe results demonstrated that ultrasound-assisted extraction significantly outperformed the conventional method, yielding higher amounts of itraconazole with a high purity level of 96.8%.

Assessing Drug Product Shelf Life Using the Accelerated Stability Assessment Program: A Case Study of a GLPG4399 Capsule Formulation

Objective: To evaluate and project the shelf life of GLPG4399, an early-phase clinical drug formulation by applying the Accelerated Stability Assessment Program (ASAP) approach. Methods: Forced degradation conditions were implemented to identify the stability-limiting degradation product. The drug and its degradation products were separated using a validated liquid chromatography method. Then, the selected clinical capsule formulation was placed in a glass vial and exposed to accelerated short-term conditions of combinations of high- and low-level heat and humidity in an open state for 5 weeks. The liquid chromatography results were evaluated using the ASAP, which is based on the moisture-modified Arrhenius principle. The resulting data were fitted using a suitable diffusion kinetics method. Results: The developed model was applied to predict the shelf life of the drug product when using clinically appropriate primary packaging (high-density polyethylene container). The derived stability parameters of the moisture-modified Arrhenius equation were the Arrhenius collision frequency, activation energy, and humidity sensitivity constant. The goodness of fit parameters R2 (>0.95) and goodness of prediction Q2 (>0.80) parameters for the selected model were acceptable. The results of the accelerated, short-term stability study were verified against real-time, long-term 12-month data. Conclusions: We demonstrated the application of the ASAP approach to evaluate the shelf life of a GLPG4399 solid capsule formulation. The studied ASAP approach can be extended to evaluate the stability and shelf-life estimations of other early-phase clinical formulations.

Activity of protegrin-1 against mouse Ehrlich ascites carcinoma <i>in vitro</i> and <i>in vivo</i>

BACKGROUND: The problem of multidrug resistance in cancer treatment creates an urgent demand for developing new effective antitumor agents. Due to the unusual mechanism of recognizing and damaging tumor cells, antimicrobial peptides are considered as possible prototypes for designing such therapeutics. AIM: This work was aimed to compare the antitumor potential of the promising membranolytic antimicrobial peptide protegrin-1 in vitro and in vivo in Ehrlich ascites carcinoma mice model. MATERIALS AND METHODS: We used two variants of the model by inducing a tumor in solid or ascites form. In the first case, the mice were injected with the peptide twice a week for three weeks, and in the second injections were provided every other day for six days. The activity of antimicrobial peptides against isolated Ehrlich ascites carcinoma cells in vitro was analyzed using MTT-test. RESULTS: Protegrin-1 demonstrated high activity against Ehrlich ascites carcinoma cells in vitro, but had no significant effect on the lifespan of mice bearing solid or ascites form of Ehrlich tumor at the dosing and administration regimens we used. However, treatment with protegrin-1 caused a decrease in the ascites volume and in the number of cells in the ascites fluid. CONCLUSIONS: Protegrin-1 retains its antitumor properties in vivo, but it may be presumed, that to effectively suppress tumor growth it requires a more frequent and prolonged administration compared with conventional antitumor antibiotics, of which we adopted the administration regimen for protegrin-1 in this study.

Enhancing the In vivo Bioavailability and Absorption of Niclosamide with Amorphous Solid Dispersion via Solvent Method

Abstract Objective This research aims to prepare a superior amorphous solid dispersion (ASD) formulation via solvent method for the oral delivery of Niclosamide to enhance oral bioavailability and absorption. Methods Phase solubility tests were conducted to select an optimal carrier combination for Niclosamide solid dispersion (SD). The Niclosamide amorphous solid dispersion was synthesized using a solvent rotary evaporation method and characterized through in vitro dissolution tests, differential scanning calorimetry (DSC), modulated DSC, powder X-ray diffraction, and scanning electron microscopy. In vivo oral pharmacokinetic studies were conducted in in Sprague Dawley rats at a dose of 50 mg/kg. Key findings PEG6000 and poloxamer 188 combination was selected as optimal carrier. ASD named ASD-5 was successfully prepared, encompassing a 25% drug loading, Niclosamide within ASD-5 remains amorphous and stable. 75% of Niclosamide in ASD-5 rapidly dissolved in 5 min, while below 5% of pure Niclosamide and physical mixture dissolved in longer time. Amorphization of Niclosamide in ASD-5 notably contributes to its dissolution rate and extent. Furthermore, among reported Niclosamide solid dispersion formulations with drug loading above 25%, ASD-5 demonstrated the highest bioavailability, showing a 2.33-fold increase in plasma exposure and bioavailability compared to pure Niclosamide. Conclusion Amorphous ASD-5 prepared by solvent method has higher drug loading and be scalable in pre-clinical stage preparation. Due to using PEG6000 and poloxamer 188 combination, ASD-5 had the highest bioavailability among reported Niclosamide solid dispersions with a drug load exceeding 25%. Also, ASD-5 presented simplified preparation procedure compared to other reported Niclosamide solid dispersion.

Using the Cocrystal Approach as a Promising Drug Delivery System to Enhance the Dissolution and Bioavailability of Formononetin Using an Imidazole Coformer

Background: Natural isoflavones are recognized for their diverse pharmacological activities; however, their low aqueous solubility presents a significant challenge for further development. Here, we aimed to develop a cocrystal of formononetin (FMN) to improve its solubility. Methods: The formononetin-imidazole (FMN-IMD) cocrystal was prepared using liquid-assisted grinding method. The prepared cocrystal was identified through a thermal analysis of physical mixtures with various coformers. FTIR and solid-state NMR confirmed the presence of hydrogen bonds and π-π interactions in the FMN-IMD cocrystal. Results: The solubility of FMN-IMD was two to three times higher than that of crystalline FMN. The FMN-IMD cocrystal showed a 4.93-fold increase in the Cmax value and a 3.58-fold increase in the AUC compared to FMN after oral administration in rats. There were no changes in the PXRD of the FMN-IMD cocrystal after six months of storage at 40 °C. Conclusions: Thus, the FMN-IMD cocrystal is proposed as an effective solid form for oral delivery, offering enhanced solubility and physical stability.

Flame temperature and emissivity distribution measurement of solid propellant based on clustering analysis of multispectral radiation images.

To measure the combustion parameters of a solid propellant, this Letter researches the fitting method for flame temperature and emissivity based on multispectral images and proposes the particle swarm optimization-K-means (PSO-K-means) clustering optimization algorithm of a flame multispectral image. Considering the difference in flame radiation characteristics in different regions, the flame multispectral image is clustered, and spectra in different regions are analyzed and selected in different fitting bands to inverse temperature and emissivity. On this basis, the method is applied to measure solid propellant combustion parameters with different formulations. The measurement shows that the flame temperature is between 1700 and 2100 K, and the emissivity is concentrated in 0.1-0.5. Compared with temperature measurements obtained from tungsten-rhenium thermocouples, the relative deviation of multispectral imaging thermometry is less than 5%. The distribution characteristics of solid propellant combustion parameters with different formulations were analyzed, which provided important data support for evaluating combustion conditions and optimizing solid propellant formulations.

Pediatric Orally Disintegrating Tablets (ODTs) with Enhanced Palatability Based on Propranolol HCl Coground with Hydroxypropyl-β-Cyclodextrin

Background: Propranolol, largely prescribed as an antihypertensive and antiarrhythmic drug in pediatrics, is characterized by a bitter taste and an astringent aftertaste. Currently, the therapy requires crushing of tablets for adults and their dispersion in water many times a day, leading to loss of dosing accuracy, low palatability, and poor compliance for both patients and caregivers. Objectives: This work aimed to exploit cyclodextrin complexation by cogrinding to develop orally disintegrating tablets (ODTs) endowed with reliable dosing accuracy, good palatability and safety, ease of swallowability, and ultimately better compliance for both pediatric patients and caregivers. Results: Different formulation variables and process parameters were evaluated in preparing ODTs. The technological and morphological characterization and disintegration tests were performed according to official and alternative tests to select the ODT formulation based on the drug Hydroxypropyl-β-cyclodextrin (HPβCD) coground complex form containing Pearlitol® Flash as the diluent and 8% Explotab® as the superdisintegrant, which demonstrated the highest % drug dissolution in simulated saliva and acceptable in vitro palatability assessed by the electronic tongue, confirming the good taste-masking power of HPβCD towards propranolol. Conclusions: Such a new dosage form of propranolol could represent a valid alternative to the common extemporaneous preparations, overcoming the lack of solid formulations of propranolol intended for pediatric use.

Solid Forms of Bio-Based Monomer Salts for Polyamide 512 and Their Effect on Polymer Properties

Polyamides’ properties are greatly influenced by the polymerization process and the type of feedstock used. The solid forms of nylon salts play a significant role in determining the final characteristics of the material. This study focuses on the long-chain bio-nylon 512. Firstly, we systematically investigated the possible solid forms of the nylon 512 salt, including crystal forms and morphologies, by massive experimental screening, single-crystal X-ray diffraction, Hirshfeld surface analysis, and TG-DSC measurements. The regulation and control of the various solid forms were achieved through solid-state transformations (SSTs) and solution-mediated phase transformations (SMPTs). Our findings shows that the nylon 512 salt exists in two crystal forms (anhydrate and dihydrate) and four morphologies (needle-like, plate-like, rod-like, and massive block crystal). Many factors will influence the formation of these solid forms, such as water activity, temperature, solvent, and ultrasonic physical fields. We can choose the right factors to regulate this as needed. On this basis, we studied the effects of different solid forms (crystal forms and morphologies) on the properties of the resulting polyamides prepared using direct solid-state polymerization (DSSP). The solid form of the salt had many effects on the polymer, including its structure, melting point, and mechanical properties. The polyamide obtained through DSSP of the anhydrate salt exhibited a higher melting point (204.22 °C) and greater elastic modulus (3.366 GPa) compared to that of the dihydrate salt, especially for the anhydrate salt of plate-like crystals.

Two Forms of Thick Filament in the Flight Muscle of Drosophila melanogaster.

Invertebrate striated muscle myosin filaments are highly variable in structure. The best characterized myosin filaments are those found in insect indirect flight muscle (IFM) in which the flight-powering muscles are not attached directly to the wings. Four insect orders, Hemiptera, Diptera, Hymenoptera, and Coleoptera, have evolved IFM. IFM thick filaments from the first three orders have highly similar myosin arrangements but differ significantly among their non-myosin proteins. The cryo-electron microscopy of isolated IFM myosin filaments from the Dipteran Drosophila melanogaster described here revealed the coexistence of two distinct filament types, one presenting a tubular backbone like in previous work and the other a solid backbone. Inside an annulus of myosin tails, tubular filaments show no noticeable densities; solid filaments show four paired paramyosin densities. Both myosin heads of the tubular filaments are disordered; solid filaments have one completely and one partially immobilized head. Tubular filaments have the protein stretchin-klp on their surface; solid filaments do not. Two proteins, flightin and myofilin, are identifiable in all the IFM filaments previously determined. In Drosophila, flightin assumes two conformations, being compact in solid filaments and extended in tubular filaments. Nearly identical solid filaments occur in the large water bug Lethocerus indicus, which flies infrequently. The Drosophila tubular filaments occur in younger flies, and the solid filaments appear in older flies, which fly less frequently if at all, suggesting that the solid filament form is correlated with infrequent muscle use. We suggest that the solid form is designed to conserve ATP when the muscle is not in active use.

Lignin: An Adaptable Biodegradable Polymer Used in Different Formulation Processes.

LIG is a biopolymer found in vascular plant cell walls that is created by networks of hydroxylated and methoxylated phenylpropane that are randomly crosslinked. Plant cell walls contain LIG, a biopolymer with significant potential for usage in modern industrial and pharmaceutical applications. It is a renewable raw resource. The plant is mechanically protected by this substance, which may increase its durability. Because it has antibacterial and antioxidant qualities, LIG also shields plants from biological and chemical challenges from the outside world. Researchers have done a great deal of work to create new materials and substances based on LIG. Numerous applications, including those involving antibacterial agents, antioxidant additives, UV protection agents, hydrogel-forming molecules, nanoparticles, and solid dosage forms, have been made with this biopolymer. For this review, a consistent literature screening using the Pubmed database from 2019-2024 has been performed. The results showed that there is an increase in interest in lignin as an adaptable biomolecule. The most recent studies are focused on the biosynthesis and antimicrobial properties of lignin-derived molecules. Also, the use of lignin in conjunction with nanostructures is actively explored. Overall, lignin is a versatile molecule with multiple uses in industry and medical science.

The Design of Novel 3D-Printed, Moulded, and Oral Viscous Budesonide Formulations for Paediatrics: A Comparative Evaluation of Their Mucoadhesive Properties.

Paediatric eosinophilic oesophagitis (EoE) treatment is challenging due to the limited number of age-appropriate formulations. This study aims to develop and evaluate oral viscous suspensions and solid formulations of budesonide (BUD), focusing on their in vitro mucoadhesive properties, to enhance drug delivery and therapeutic outcomes in paediatric EoE. This study encompasses the development of oral viscous suspensions and orodispersible solid formulations (moulded tablets and 3D-printed dosage forms) containing BUD. The formulations underwent quality control tests as per the European Pharmacopoeia, chemical stability assessments, and an in vitro evaluation of their mucoadhesiveness properties. A validated analytical method enabled accurate BUD quantification and efficient extraction, and all developed formulations demonstrated chemical stability for 30 days, meeting Ph. Eur. quality standards. Three-dimensional printing using SSE successfully produced 1 mg and 0.5 mg BUD printlets, complying with quality tests for conventional tablets. Formulations containing xanthan gum (L2-XG and P1-0.5-XG) exhibited superior mucoadhesive properties. L2-XG showed significantly higher mucoadhesion than L1-MC. Among the solid formulations, P1-0.5-XG demonstrated the highest mucoadhesive properties. This is the first study to develop solid oral dosage forms of BUD at a very low dose, specifically for paediatric use. The results highlight the potential of 3D printing for developing individualised orodispersible BUD formulations with improved bioadhesion for paediatric EoE treatment. The L2-XG formulation and the XG-containing printlets are the most promising formulations in terms of increasing contact time with the oesophageal mucosa, which could translate into improved therapeutic efficacy in this patient population.

Phase-separated polymer blends for controlled drug delivery by tuning morphology

Controlling drug release rate and providing physical and chemical stability to the active pharmaceutical ingredient are key properties of oral solid dosage forms. Here, we demonstrate a formulation strategy using phase-separated polymer blends where the morphology provides a route for tuning the drug release profile. By utilising phase separation of a hydrophobic and a hydrophilic polymer, the hydrophilic component will act as a channelling agent, creating a porous network upon dissolution that will dictate the release characteristics. With ptychographic X-ray tomography and scanning transmission X-ray microscopy we reveal how the morphology depends on both polymer fraction and presence of drug, and how the drug is distributed over the polymer domains. Combining X-ray imaging results with dissolution studies reveal how the morphologies are correlated with the drug release and showcase how tuning the morphology of a polymer matrix in oral formulations can be utilised as a method for controlled drug release.

Therapeutic potential of phytocompounds of Bacopa monnieri (L.) Wettst (literature review)

The aim of the work was to evaluate the pharmacological effects and therapeutic potential of individual compounds and extracts of B. monnieri based on the analysis of data from scientific periodicals regarding chemical composition and biological action. Theoretically significant were the studies of the materials of the scientific-metric database PubMed and Google Scholar over the last five years regarding the chemical composition and biological action of extracts based on B. monnieri and their individual components. The search query was carried out by the Latin name of the plant, with the exception of publications related to botanical research. In separate PubChem searches, names of individual phytocompounds were used to establish structure and distribution in plants. The SuperPred web server was used to predict therapeutic potential. The authors analyzed the chemical composition of the extracts, presented the structural and pharmacological characteristics of bacosides and their aglycones: bacosin and juubogenin, cucurbitacin E, loliolide, betulinic and asiatic acids and the flavonoid oroxindin. The mechanism of action of bacoside on β-amyloid is characterized and illustrated. Using machine learning, the prospects for using the main compounds of bacopa to create drugs were calculated taking into account the ATC classification, their biological effects and alternative plant sources were given. Experimental animal studies of whole aqueous or ethanolic extracts of B. monnieri have been found to support a cognitive enhancement effect. The extract was not toxic to humans. Numerous clinical trials show the effectiveness of the use of extracts in the treatment of anhedonia, depression, Alzheimer's disease, Parkinson's disease, dementia and hyperactivity. An analysis of clinical studies in Ukraine shows that drugs based on B. monnieri can be used in the complex treatment of cognitive impairment associated with dyscirculatory encephalopathy in adults and perinatal CNS damage in children. Considering the amphiphilicity of bacosides and the non-toxicity of extracts, they can be involved in the development of various dosage forms with a wide range of therapeutic applications. Further study of the pharmacological action of B. monnieri and the development of drug technology for solid and liquid dosage forms based on it are promising.

Review article on self emulsifying system

The solubility challenges faced by the pharmaceutical industry, particularly with orally administered drugs, are indeed significant. Low aqueous solubility often leads to poor dissolution and subsequently, low bioavailability, which can result in inconsistent drug effects among patients. Various methods have been explored to address this issue, including salt formation, solid dispersion, and complex formation.Among these approaches, Self-Emulsifying Drug Delivery Systems (SEDDS) have emerged as a promising solution for enhancing the solubility of lipophilic drugs. SEDDS consist of isotropic mixtures of hydrophilic solvents, co-solvents, and surfactants. They possess the unique ability to form fine oil-in-water micro emulsions upon mild agitation and dilution in aqueous media, such as gastrointestinal fluids.The advancement in SEDDS technology encompasses improvements in composition, evaluation methods, development of different dosage forms, and techniques for converting liquid SEDDS into solid forms. These advancements not only enhance solubility but also offer versatility in administration routes and dosage forms, thereby expanding the potential applications of SEDDS in pharmaceutical formulations.This comprehensive review provides valuable insights into the latest developments in SEDDS, offering a detailed account of its composition, evaluation parameters, diverse dosage forms, and innovative techniques for solidification. Moreover, it highlights the diverse applications of SEDDS across various therapeutic areas, underscoring its growing significance in modern pharmaceutical research and development.

Moisture‐Driven Actuators

AbstractWater constitutes a huge circulation network in solid, liquid and gaseous forms that contains inestimable recyclable energy. Obtaining energy from gaseous moisture is challenging but of great significance to promote the energy upgrading. The emergence of moisture‐driven actuator (MDA) provides an effective way in converting moisture energy to mechanical energy. The MDA can combine with water molecules through hygroscopicity and swell to produce macroscopic deformation. Due to the wide distribution of humidity and the wireless driving mode, MDA shows great application potential in the fields of environmental monitoring, remote control and energy harvesting. This paper comprehensively reviews the research progress of MDA from aspects of hydrophilic materials, structures, preparing methods, multi‐response integration and applications, aiming at providing guidance for the design, preparation and application of MDA. Besides, the challenges faced by MDA are analyzed and corresponding solutions are proposed, which points out the next stage developing direction of MDA.

Sublethal Damage Caused by Cold Plasma on Bacillus cereus Cells: Impact on Cell Viability and Biofilm-Forming Capacity.

The Bacillus cereus group represents a serious risk in powdered and amylaceous foodstuffs. Cold plasma (the fourth state of matter) is emerging as an alternative effective nonthermal technology for pasteurizing a wide range of matrices in solid, liquid, and powder form. The present study aims to evaluate the mechanisms involved in Bacillus cereus inactivation via cold plasma, focusing on (i) the technology's ability to generate damage in cells (at the morphological and molecular levels) and (ii) studying the effectiveness of cold plasma in biofilm mitigation through the direct effect and inhibition of the biofilm-forming capacity of sublethally damaged cells post-treatment. Dielectric barrier discharge cold plasma (DBD-CP) technology was used to inactivate B. cereus, B. thuringiensis, and B. mycoides under plasma power settings of 100, 200, and 300 W and treatment times ranging from 1 to 10 min. Inactivation levels were achieved in 2-7 log10 cycles under the studied conditions. Percentages of sublethally damaged cells were observed in a range of 45-98%, specifically at treatment times below 7 min. The sublethally damaged cells showed poration, erosion, and loss of integrity at the superficial level. At the molecular level, proteins and DNA leakage were also observed for B. cereus but were minimal for B. mycoides. Biofilms formed by B. cereus were progressively disintegrated under the DBD-CP treatment. The greater the CP treatment intensity, the greater the tearing of the bacteria's biofilm network. Additionally, cells sublethally damaged by DBD-CP were evaluated in terms of their biofilm-forming capacity. Significant losses in the damaged cells' biofilm network density and aggregation capacity were observed when B. cereus was recovered after inactivation at 300 W for 7.5 min, compared with the untreated cells. These results provide new insights into the future of tailored DBD-CP design conditions for both the inactivation and biofilm reduction capacity of B. cereus sensu lato species, demonstrating the effectiveness of cold plasma and the risks associated with sublethal damage generation.