Evaluation of the printability of agar and hydroxypropyl methylcellulose gels as gummy formulations: Insights from rheological properties.

The trial-and-error method currently used to create formulations with excellent printability demands considerable time and resources, primarily due to the increasing number of variables involved. Rheology serves as a relatively rapid and highly beneficial method for assessing materials and evaluating their effectiveness as 3D constructs. However, the data obtained can be overwhelming, especially for users lacking experience in this field. This study examined the rheological properties of formulations of agar, hydroxypropyl methylcellulose, and the model drug caffeine, alongside exploring their printability as gummy formulations. The gels' rheological properties were characterized using oscillatory and rotational experiments. The correlation between these gels' rheological properties and their printability was established, and three clusters were formed based on the rheological properties and printability of the samples using principal component analysis. Furthermore, the printability was predicted using the sample's rheological property that correlated most with printability, the phase angle δ, and the regression models resulted in an accuracy of over 80%. Although these relationships merit confirmation in later studies, this study suggests a quantitative definition of the relationship between printability and one rheological property and can be used for the development of formulations destined for extrusion 3D printing.

Fused Deposition Modelling 3D printing and solubility improvement of BCS II and IV active ingredients - A narrative review.

In the field of pharmaceutical research and development, Fused Deposition Modelling (FDM) 3D printing (3DP) has aroused growing interest within the last ten years. The use of thermoplastic polymers, combined with the melting process of the raw materials, offers the possibility of manufacturing amorphous solid dispersions (ASDs). In the pharmaceutical industry, the formulation of an ASD is a widely used strategy to improve the solubility of poorly soluble drugs (classified by the Biopharmaceutical Classification System (BCS) as class II and IV). In this review, an analysis of studies that have developed a FDM printed form containing a BCS class II or IV active substance was performed. The focus has been placed on the evaluation of the solid state of the active molecules (crystalline or amorphous) and on the study of their dissolution profile. Thus, the aim of this work is to highlight the interest of FDM 3DP to induce the amorphisation phenomenon of Class II and IV active substances by forming an ASD, and as result improving their solubility.

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.

Decellularized Spinach Biomaterials Support Physiologically Relevant Mechanical Cyclic Strain and Prompt a Stretch-Induced Cellular Response.

Recently, decellularized plant biomaterials have been explored for their use as tissue engineered substitutes. Herein, we expanded upon the investigation of the mechanical properties of these materials to explore their elasticity as many anatomical areas of the body require biomechanical dynamism. We first constructed a device to secure the scaffold and induce a strain within the physiological range of the normal human adult lung during breathing (12-20 movements/min; 10-20% elongation). Results showed that decellularized spinach leaves can support cyclic strain for 24 h and displayed heterogeneous local strain values (7.76-15.88%) as well as a Poisson's ratio (0.12) similar to that of mammalian lungs (10.67-19.67%; 0.01), as opposed to an incompressible homogeneous standard polymer (such as PDMS (10.85-12.71%; 0.4)). Imaging and mechanical testing showed that the vegetal scaffold exhibited strain hardening but maintained its structural architecture and water retention capacity, suggesting an unaltered porosity. Interestingly, we also showed that cells seeded on the scaffold can also sense the mechanical strain as demonstrated by a nuclear reorientation perpendicular to strain direction (63.3° compared to 41.2° for nonstretched cells), a nuclear location of YAP and increased expression of YAP target genes, a high cytoplasmic calcium level, and an elevated expression level of collagen genes (COL1A1, COL3A1, COL4A1, and COL6A) with an increased collagen secretion at the protein level. Taken together, these data demonstrated that decellularized plant leaf tissues have an inherent elastic property similar to that found in the mammalian system to which cells can sense and respond.

Alginate ester: New moisture-scavenging excipients for direct compressible pharmaceutical tableting.

The objective of this work is to evaluate methyl ester alginates and alginic acid (AA) as moisture-scavenging excipients for the formulation of aspirin tablets obtained by direct compression. The tablets were stored at accelerated conditions (40 °C/75 % RH) and assessed for changes in tensile strength, mass, thickness and disintegration time. While moisture caused a reduction in the hardness of MCC and AA tablets, hardness of the tablets made from methylated materials was virtually unaffected. The physical stability of alginate ester tablets was found to be related to their increased plastic deformation leading to extended interparticle contact with less impact on tablet porosity. Finally, the combination of higher moisture affinity and lower water dissociation exhibited by alginates esters resulted in tablets with the lowest aspirin degradation. These findings suggest that excipients with high water retention can act as moisture-scavengers without losing their functional properties and reducing the degradation of moisture-sensitive drugs.

Weak Polyelectrolytes as Nanoarchitectonic Design Tools for Functional Materials: A Review of Recent Achievements.

The ionization degree, charge density, and conformation of weak polyelectrolytes can be adjusted through adjusting the pH and ionic strength stimuli. Such polymers thus offer a range of reversible interactions, including electrostatic complexation, H-bonding, and hydrophobic interactions, which position weak polyelectrolytes as key nano-units for the design of dynamic systems with precise structures, compositions, and responses to stimuli. The purpose of this review article is to discuss recent examples of nanoarchitectonic systems and applications that use weak polyelectrolytes as smart components. Surface platforms (electrodeposited films, brushes), multilayers (coatings and capsules), processed polyelectrolyte complexes (gels and membranes), and pharmaceutical vectors from both synthetic or natural-type weak polyelectrolytes are discussed. Finally, the increasing significance of block copolymers with weak polyion blocks is discussed with respect to the design of nanovectors by micellization and film/membrane nanopatterning via phase separation.

Healthy Zerumbone: From Natural Sources to Strategies to Improve Its Bioavailability and Oral Administration.

Zerumbone is a multifunctional compound with antimicrobial, antitumor, hyperalgesic, antioxidant and anti-inflammatory applications, and constitutes a point molecule for the future synthesis of derivatives with improved efficiency. This monocyclic sesquiterpenoid is found in high content in wild ginger (Zingiber zerumbet Smith), a perennial herb with economic importance as an ornamental as well as a medicinal plant. The presence of zerumbone is a distinctive feature that allows identification and differentiation from other species, not only in Zingiber, but also in Curcuma, Alpinia, Boesenbergia, Ethlingera and Ammomum spp., as well as related families (Costaceaee). To successfully use zerumbone in areas such as medicine, food and agriculture, further research on improving its low solubility and bioavailability, as well as its preservation, is a major current priority. In addition, despite its promising pharmacological activities, preclinical and clinical studies are required to demonstrate and evaluate the in vivo efficacy of zerumbone.

Low-Dimensional Architectures in Isomeric cis-PtCl2{Ph2PCH2N(Ar)CH2PPh2} Complexes Using Regioselective-N(Aryl)-Group Manipulation.

The solid-state behaviour of two series of isomeric, phenol-substituted, aminomethylphosphines, as the free ligands and bound to PtII, have been extensively studied using single crystal X-ray crystallography. In the first library, isomeric diphosphines of the type Ph2PCH2N(Ar)CH2PPh2 [1a-e; Ar = C6H3(Me)(OH)] and, in the second library, amide-functionalised, isomeric ligands Ph2PCH2N{CH2C(O)NH(Ar)}CH2PPh2 [2a-e; Ar = C6H3(Me)(OH)], were synthesised by reaction of Ph2PCH2OH and the appropriate amine in CH3OH, and isolated as colourless solids or oils in good yield. The non-methyl, substituted diphosphines Ph2PCH2N{CH2C(O)NH(Ar)}CH2PPh2 [2f, Ar = 3-C6H4(OH); 2g, Ar = 4-C6H4(OH)] and Ph2PCH2N(Ar)CH2PPh2 [3, Ar = 3-C6H4(OH)] were also prepared for comparative purposes. Reactions of 1a-e, 2a-g, or 3 with PtCl2(η4-cod) afforded the corresponding square-planar complexes 4a-e, 5a-g, and 6 in good to high isolated yields. All new compounds were characterised using a range of spectroscopic (1H, 31P{1H}, FT-IR) and analytical techniques. Single crystal X-ray structures have been determined for 1a, 1b∙CH3OH, 2f∙CH3OH, 2g, 3, 4b∙(CH3)2SO, 4c∙CHCl3, 4d∙½Et2O, 4e∙½CHCl3∙½CH3OH, 5a∙½Et2O, 5b, 5c∙»H2O, 5d∙Et2O, and 6∙(CH3)2SO. The free phenolic group in 1b∙CH3OH, 2f∙CH3OH,2g, 4b∙(CH3)2SO, 5a∙½Et2O, 5c∙»H2O, and 6∙(CH3)2SO exhibits various intra- or intermolecular O-H∙∙∙X (X = O, N, P, Cl) hydrogen contacts leading to different packing arrangements.

Investigating the Potential Plasticizing Effect of Di-Carboxylic Acids for the Manufacturing of Solid Oral Forms with Copovidone and Ibuprofen by Selective Laser Sintering.

In selective laser sintering (SLS), the heating temperature is a critical parameter for printability but can also be deleterious for the stability of active ingredients. This work aims to explore the plasticizing effect of di-carboxylic acids on reducing the optimal heating temperature (OHT) of polymer powder during SLS. First, mixtures of copovidone and di-carboxylic acids (succinic, fumaric, maleic, malic and tartaric acids) as well as formulations with two forms of ibuprofen (acid and sodium salt) were prepared to sinter solid oral forms (SOFs), and their respective OHT was determined. Plasticization was further studied by differential scanning calorimetry (DSC) and Fourier-transform infrared spectroscopy (FTIR). Following this, the printed SOFs were characterized (solid state, weight, hardness, disintegration time, drug content and release). It was found that all acids (except tartaric acid) reduced the OHT, with succinic acid being the most efficient. In the case of ibuprofen, only the acid form demonstrated a plasticizing effect. DSC and FTIR corroborated these observations showing a decrease in the glass transition temperature and the presence of interactions, respectively. Furthermore, the properties of the sintered SOFs were not affected by plasticization and the API was not degraded in all formulations. In conclusion, this study is a proof-of-concept that processability in SLS can improve with the use of di-carboxylic acids.

A QbD Approach for Evaluating the Effect of Selective Laser Sintering Parameters on Printability and Properties of Solid Oral Forms.

The aim of this work was to investigate the effect of process parameters on the printability of a formulation containing copovidone and paracetamol, and on the properties of solid oral forms 3D-printed through selective laser sintering. Firstly, the influence of the heating temperature was evaluated individually, and it was revealed that this parameter was critical for printability, as a sufficiently high temperature (100 °C) is necessary to avoid curling. Secondly, the effects of laser power, scan speed, and layer thickness were determined using a Box-Behnken design. The measured responses, printing yield, height, weight, hardness, disintegration time, and percentage of drug release at 10 min showed the following ranges of values: 55.6-100%, 2.92-3.96 mm, 98.2-187.2 mg, 9.2-83.4 N, 9.7-997.7 s, and 25.8-99.9%, respectively. Analysis of variance (ANOVA) proved that the generated quadratic models and the effect of the three-process parameters were significant (p < 0.05). Yield improved at high laser power, low scan speed, and increased layer thickness. Height was proportional to laser power, and inversely proportional to scan speed and layer thickness. Variations in the other responses were related to the porosity of the SOFs, which were dependent on the value of energy density. Low laser power, fast scan speed, and high layer thickness values favored a lower energy density, resulting in low weight and hardness, rapid disintegration, and a high percentage of drug release at 10 min. Finally, an optimization was performed, and an additional experiment validated the model. In conclusion, by applying a Quality by Design approach, this study demonstrates that process parameters are critical for printability, but also offer a way to personalize the properties of the SOFs.

Selective Laser Sintering (SLS), a New Chapter in the Production of Solid Oral Forms (SOFs) by 3D Printing.

3D printing is a new emerging technology in the pharmaceutical manufacturing landscape. Its potential advantages for personalized medicine have been widely explored and commented on in the literature over recent years. More recently, the selective laser sintering (SLS) technique has been investigated for oral drug-delivery applications. Thus, this article reviews the work that has been conducted on SLS 3D printing for the preparation of solid oral forms (SOFs) from 2017 to 2020 and discusses the opportunities and challenges for this state-of-the-art technology in precision medicine. Overall, the 14 research articles reviewed report the use of SLS printers equipped with a blue diode laser (445-450 nm). The review highlights that the printability of pharmaceutical materials, although an important aspect for understanding the sintering process has only been properly explored in one article. The modulation of the porosity of printed materials appears to be the most interesting outcome of this technology for pharmaceutical applications. Generally, SLS shows great potential to improve compliance within fragile populations. The inclusion of "Quality by Design" tools in studies could facilitate the deployment of SLS in clinical practice, particularly where Good Manufacturing Practices (GMPs) for 3D-printing processes do not currently exist. Nevertheless, drug stability and powder recycling remain particularly challenging in SLS. These hurdles could be overcome by collaboration between pharmaceutical industries and compounding pharmacies.

Sodium alginate and alginic acid as pharmaceutical excipients for tablet formulation: Structure-function relationship.

Alginic acid and its sodium salt are well-accepted pharmaceutical excipients fulfilling several roles in the development of solid oral dosage forms. Although they have attractive advantages as safety, abundance, relatively low cost and biodegradability, these natural polysaccharides possess a high variability that may limit their use as excipients for tablet formulation. Thus, to obtain robust formulations and high-quality drug products with consistent performance a complete understanding of the structure-property relationship becomes necessary as the structure of alginates affects both, technological and biopharmaceutical properties. This review compiles the compaction studies carried out that relate the structure of alginates to their mechanical and dissolution performances. The different analytical methods used to determine the chemical composition, primary structure and molecular weight distribution, major factors affecting the behavior of alginates in direct compression, are also exposed. Finally, different strategies reported to improve the properties of alginic acid as direct compression excipient are discussed.

Performance Evaluation of a Novel Biosourced Co-Processed Excipient in Direct Compression and Drug Release.

This study exposes the potential usefulness of a new co-processed excipient, composed of alginic acid and microcrystalline cellulose (Cop AA-MCC), for the preparation of immediate drug release tablets by direct compression. Evaluation of the physical and mechanical properties as well as the disintegration behavior of Cop AA-MCC in comparison to commercial co-processed excipients (Cellactose®, Ludipress®, Prosolv® SMCC HD90 and Prosolv® ODT) and to the physical mixture of the native excipients (MCC and AA), was carried out. The obtained results illustrate the good performance of Cop AA-MCC in terms of powder flowability, tablet tensile strength, compressibility, and disintegration time. Although, this new co-processed excipient showed a slightly high lubricant sensitivity, which was explained by its more plastic than fragmentary deformation behavior, it presented a low lubricant requirement due to the remarkably low ejection force observed during compression. Compression speed and dwell time seemed not to affect significantly the tabletability of Cop AA-MCC. The study exposed evenly the performance of Cop AA-MCC compared to Prosolv® ODT, in terms of tabletability and dissolution rate of Melatonin. Cop AA-MCC presented comparable hardness, lower dilution potential, higher lubricant sensitivity, lower ejection force, and faster Melatonin's release time than Prosolv® ODT. In summary, Cop AA-MCC exhibited interesting physical, mechanical, and biopharmaceutical properties, which demonstrate its concurrence to commercially available co-processed excipients. Furthermore, the simplicity of its composition and the scalability of its elaboration makes this multifunctional excipient highly recommended for direct compression.

Selective Laser Sintering of Solid Oral Dosage Forms with Copovidone and Paracetamol Using a CO2 Laser.

Material suitability needs to be considered for the 3D printing of solid oral dosage forms (SODFs). This work aims to assess the suitability of a CO2 laser (λ = 10.6 µm) for selective laser sintering of SODFs containing copovidone and paracetamol. First, physicochemical characterization of powders (two grades of copovidone, two grades of paracetamol and their mixtures at various proportions) was conducted: particle size distribution, morphology, infrared absorbance, flowability, and compactness. Then, printing was launched, and printability of the powders was linked to their physicochemical characteristics. The properties of the sintered SODFs were evaluated (solid state, general aspect, porosity, hardness, drug content and release). Hence, it was found that as copovidone absorbs at the laser's wavelength, sintering was feasible without using an absorbance enhancer. Also, flowability, which mainly depends on the particle size, represents the first control line for "sinterability" as a fair flow is at least required. Low compactness of copovidone and mixtures reduces the mechanical properties of the SODFs but also increases porosity, which can modulate drug release. Moreover, the drug did not undergo degradation and demonstrated a plasticizer effect by lowering the heating temperature. In conclusion, this work proves the applicability of CO2 laser SLS printer to produce SODFs.

Fused Deposition Modeling (FDM), the new asset for the production of tailored medicines.

Over the last few years, conventional medicine has been increasingly moving towards precision medicine. Today, the production of oral pharmaceutical forms tailored to patients is not achievable by traditional industrial means. A promising solution to customize oral drug delivery has been found in the utilization of 3D Printing and in particular Fused Deposition Modeling (FDM). Thus, the aim of this systematic literature review is to provide a synthesis on the production of pharmaceutical solid oral forms using FDM technology. In total, 72 relevant articles have been identified via two well-known scientific databases (PubMed and ScienceDirect). Overall, three different FDM methods have been reported: "Impregnation-FDM", "Hot Melt Extrusion coupled with FDM" and "Print-fill", which yielded to the formulation of thermoplastic polymers used as main component, five families of other excipients playing different functional roles and 47 active ingredients. Solutions are underway to overcome the high printing temperatures, which was the initial brake on to use thermosensitive ingredients with this technology. Also, the moisture sensitivity shown by a large number of prints in preliminary storage studies is highlighted. FDM seems to be especially fitted for the treatment of rare diseases, and particular populations requiring tailored doses or release kinetics. For future use of FDM in clinical trials, an implication of health regulatory agencies would be necessary. Hence, further efforts would likely be oriented to the use of a quality approach such as "Quality by Design" which could facilitate its approval by the authorities, and also be an aid to the development of this technology for manufacturers.

Structure-Property Relationship of Amorphous Maltitol as Tableting Excipient.

Maltitol shows interesting properties compared with mannitol or sorbitol, two other polyols, which are widely used as a pharmaceutical excipients for tablet compaction. For this study, the properties of an amorphous polyol, maltitol, were investigated using a tablet press simulator. The aim of this study was to evaluate the behavior of amorphous maltitol compared to SweetPearl® P 200, a pure product, and SweetPearl® P 300 DC, a textured crystalline maltitol excipient for direct compression. The physicochemical and pharmacotechnical properties were compared, revealing a major change in properties after amorphization. The study of the tabletability, mean yield pressure, elastic properties, etc. shows that the compression behavior of amorphous powders has been significantly altered. The results showed specific properties of amorphous maltitol with good tabletability at low compaction pressure. The stability of the amorphous and the evolution of its behavior in compression were then studied, showing a direct link between its recrystallization and the change in its properties. The use of a stabilizing agent, maltotriitol, slowed down the recrystallization, maintaining the specific properties of the amorphous material in compression for a longer period of time.

Encapsulated Limonene: A Pleasant Lemon-Like Aroma with Promising Application in the Agri-Food Industry. A Review.

Limonene, mainly found as a major component in Citrus spp., has been proven to possess a valuable potential as sustainable replacement to synthetic pesticides and food preservatives. This review intends to give a clear overview of the principal emerging applications of limonene in the agri-food industry as antimicrobial, herbicidal and antioxidant agent. To successfully use limonene in a greener agri-food industry, its preservation had become a top concern for manufacturers. In order to elucidate the most efficient and sustainable manner to encapsulate limonene, the different techniques and materials tested up to the present are also reviewed. In general, encapsulation conserves and protects limonene from outside aggressions, but also allows its controlled release as well as enhances its low water solubility, which can be critical for the discussed applications. Other parameters such as scalability, low cost and availability of equipment will need to be taken into account. Further efforts would likely be oriented to the elucidation of encapsulating sustainable systems obtained by cost-efficient elaboration processes, which can deliver effective concentrations of limonene without affecting crops and food products.

Development of alginate esters as novel multifunctional excipients for direct compression.

Methyl ester derivatives of alginic acid have been evaluated as potential multifunctional excipients for pharmaceutical direct compression. The use of alginic acid as an excipient in tablet formulation is limited because of certain drawbacks such as low tablet hardness and poor compressibility. The objective of this work is to improve these properties through esterification of alginic acid, chemical modification commonly used for enhancing the functionality of tableting excipients. It has been observed that the degree of methylation (DM) has a profitable impact in the physico-chemical and mechanical properties of the obtained materials. In general, an increase in the degree of methylation yielded tablets with higher tensile strength and better compressibility. Furthermore, modified alginates exhibited extended disintegration times compared to native alginic acid due to the introduced hydrophobicity. Finally, the functional versatility of the modified alginates as disintegrating and filling/binding agents was tested by formulating them with microcrystalline cellulose and lactose.

Structure-Properties Relationship in the Evaluation of Alginic Acid Functionality for Tableting.

The aim of this study is to investigate the relationship between the structural, molecular, and particulate properties of alginic acid and its functional characteristics in direct compression (tabletability, compressibility, elasticity, deformation mechanism, and disintegration ability). Therefore, accurate characterization of two different batches of alginic acid was executed (X-ray powder diffraction, Fourier-transform infrared spectroscopy, thermogravimetric analysis, scanning electronic microscopy, 1H nuclear magnetic resonance, size exclusion chromatography - multi angle light scattering, viscosimetry, carboxylic acid titration, powder flowability, true density, laser granulometry). Results showed that molecular weight seems to affect tablet properties and that the alginic acid with the lowest molecular weight provides the hardest tablets with the lowest elastic recovery. Furthermore, these results show the potential interest of exploiting alginic acid as filler excipient in tablet formulation. Finally, disintegration properties of tested materials were found to be close to that of commercial superdisintegrants (Glycolys® and Kollidon Cl®) but not correlated to their swelling force. It can be concluded, for the first time, that the determination of alginic acid molecular weight seems key for applications in direct compression and in particular for obtaining tablets with reproducible strength.

Flexible heteroionic calcium-magnesium alginate beads for controlled drug release.

In the present work heteroionic calcium-magnesium alginate beads have been prepared by ionotropic gelation using different Ca:Mg ratios. This simple and straightforward approach allowed the obtention of CaMg-alginate beads presenting different mechanical performance depending on the Mg:Ca ratio. The dynamic swelling behavior of the beads was investigated. Increase in the quantity of Mg2+ incorporated in the beads increased the rate of swelling at pH 1.2 and pH 7.2. Finally, the release of ibuprofen was investigated. It was found that increasing the Mg2+ present in the beads raised the drug release rate.