Performance Of Tablets Research Articles

Preparation of tenofovir amibufenamide fumarate spherical particles to improve tableting performance and sticking propensity by designing a spherical crystallization process

Tenofovir amibufenamide fumarate (TMF) is the first oral drug developed in Asia for the treatment of adult patients with chronic viral hepatitis B, however, further applications are limited by poor tableting performance and high sticking propensity. In this work, the spherulitic growth process of TMF has been designed and explored with the help of molecular dynamics simulation and process analysis technologies (ATR-FTIR, FBRM and EasyViewer). The spherical particles with high bulk density, good flowability and uniform particle size distribution are prepared by a simple quenching process. More importantly, experimental results show that spherical particles have higher average tensile strength (100.8% increase), higher plastic deformability and lower amount of punch sticking (87.4% decrease in 30 tablets) compared to the commercial powder products. These contributions not only shed light on the design principle of drug spherulitic growth processes, but also provide guidance for the manufacture of high-quality tablet products.

Optimization of green spherical agglomeration process based on response surface methodology for preparation of high-performance spherical particles

Spherical agglomeration (SA) is a processing technique that enhances the physical properties of particles, reduces the number of unit operations in pharmaceutical manufacturing, and improves process efficiency. However, one of the limitations of SA is its high nonlinearity, which makes scalability a challenge. This prospective study was designed to realize the optimization of SA process parameters of aspirin, the world’s first and most widely used nonsteroidal anti-inflammatory drug, by developing a green SA model through response surface methodology. First, Plackett-Burman experiments were conducted to identify the key operating variables affecting SA, and Sustainability Index (STI) was defined to evaluate the effects of these operating variables on the SA and the energy input to the environment during the post-processing process. Furthermore, the effects of three independent variables on mean size, yield, and STI were investigated based on Box-Behnken design. A second-order regression equation with response values was developed to optimize the above three objectives. As a result, the spherical products were obtained with excellent powder properties, including anti-caking property, filtration property, and tableting performance compared to the raw materials. This work provides an experimental and modelling basis for the further application of this environmentally-friendly SA technology.

Investigation of Groundnut Shell Powder as Potential Super Disintegrant in Chronotherapeutic Delivery of Sacubitril–valsartan

ABSTRACT Context: Chronotherapeutic delivery of antihypertensives plays a potential role in the treatment by providing a therapeutic amount of drug at the target site in the body. Sacubitril–valsartan (SV), an angiotensin receptor neprilysin inhibitor, has been indicated for the treatment of hypertension. The study explores the formulation and evaluation of compression-coated tablets (CCTs) of SV using a natural super disintegrant in the core tablet for chronotherapeutic drug delivery. Aim and Objective: The main objective of the current investigation is to study the applicability of groundnut shell powder (GSP) as super disintegrant and its role in chronotherapeutic drug delivery. Materials and Methods: Core tablets of SV were prepared using different concentrations of natural excipient (GSP) and compression coated. The CCT was evaluated for the postcompression tableting properties, in vitro drug release, Fourier transform infra red spectroscopy (FTIR), and stability studies and compared the disintegrating property with a synthetic excipient (crospovidone). Results: The results of the in vitro dissolution performance of core tablets indicated that the incorporation of GSP as a super disintegrant significantly reduced the disintegration time. Optimized core tablets were subjected to compression coating using a graded concentration of cellulose acetate phthalate as coating polymer and evaluated tableting properties and dissolution performance. Among all the formulations, CCT5 with 8% GSP in the core, coated with 300 mg coating polymer shown 6 h lag time followed by the rapid release of the drug within 1 h. Accelerated stability studies on optimized formulation revealed that there were no significant changes in the tableting parameters after storage indicating the stability of the formulation. Conclusion: The use of natural disintegrant in the core tablet offers a promising approach for rapid release of drug from CCT after a lag time of 6 h to achieve chronotherapy of SV.

Design and preparation of spherical particles in water via thermal-induced liquid-liquid phase separation and a molecular mechanism study

In the pharmaceutical and fine chemical industries, spherical particles are highly valuable due to their numerous applications; however, they are hindered by traditional methods requiring intricate devices, high energy consumption, and biohazardous solvents. In this study, we constructed a strategy for the design of spherical particles based on thermal-induced liquid–liquid phase separation at the microscopic molecular level. Based on this strategy, high-performance spherical particles were successfully prepared in water by a simple heating-quenching operation. Moreover, this strategy could also control the solid structure of particles by utilizing intermolecular interactions to meet the requirements of various application scenarios. In the case of fenofibrate, the equipment was simplified, the use of organic solvents was avoided, and the powder properties, filtration properties, and tableting performance of the product were significantly enhanced compared to those reported literature. This work elucidated the design and green production of new crystalline/amorphous materials with versatile functions.

Compound Danshen Tablets ameliorate myocardial ischemia/reperfusion injury-induced ventricular remodeling by regulating autophagy via AMPK/mTOR signaling pathway

ObjectiveLeft ventricular remodeling induced by myocardial ischemia/reperfusion injury (MI/RI) is a common cardiac dysfunction. Accumulating evidence has demonstrated that autophagy plays a vital role in protecting against ventricular remodeling. This study aims to investigate the performance of compound Danshen Tablets (CDT) in rescuing ventricular remodeling and whether autophagy as the potential mechanism. MethodsThe left anterior descending arteries of rats were temporarily ligated for 30 min to construct the MI/RI model. Ventricular remodeling was induced by reperfusion for 28 d, during which the MI/RI rats were administered CDT (300 mg/kg and 600 mg/kg), atorvastatin (2 mg/kg), and diltiazem (16 mg/kg). Cardiac function and structure were examined by echocardiography. Immunohistochemistry, Masson's trichrome staining, and hematoxylin-eosin (H & E) staining were utilized to assess the fibrosis and histological alterations in the heart tissue. The expression of autophagy-related proteins was detected using Western blotting. ResultsCDT attenuated the cardiac dysfunction, structural changes, histopathological changes and fibrosis induced by MI/RI. CDT significantly enhanced the level of Beclin1 and microtubule-associated protein 1 light chain 3 beta (LC3β), and reduced p62 levels in MI/RI rats. Moreover, CDT significantly increased the phosphorylation of AMP-activated protein kinase (AMPK) and inhibited mammalian target of rapamycin (mTOR) phosphorylation. ConclusionCDT ameliorated MI/RI-induced ventricular remodeling by activating autophagy and improving autophagic flux via the AMPK/mTOR signaling pathway.

The impact of diluents on the compaction, dissolution, and physical stability of amorphous solid dispersion tablets

Amorphous solid dispersion (ASD) is an effective approach for enhancing the solubility, dissolution, and bioavailability of poorly water-soluble drugs. However, these metastable forms can transform into more thermodynamically stable but less soluble crystalline forms. Despite this challenge, research on processing ASDs into solid dosage forms, such as tablets, is lacking. This work aims to fill this gap by investigating the impact of common diluents on the tableting behavior, dissolution, and physical stability of ASDs composed of itraconazole and hypromellose acetate succinate. Four widely used diluents found in commercially available ASD tablets were selected for the study: microcrystalline cellulose (MCC), anhydrous lactose, starch, and mannitol. The performance of ASD tablets varied significantly depending on the diluent used. Tablets prepared with MCC exhibited higher mechanical strength than those formulated using other diluents. ASD tablets containing mannitol and lactose revealed a faster release rate than those composed of MCC or starch. Notably, the study highlighted that the physical stability of ASDs within a tablet is not solely dependent on the amount of sorbed water; crystalline diluents like lactose and mannitol were found to facilitate ASD recrystallization within a tablet. In summary, the study underscores the importance of excipient selection, considering factors such as mechanical strength, dissolution rate, and physical stability of ASD tablets. These findings offer valuable insights into the selection of excipients for downstream ASD tablet development, leading to improved manufacturability, physical stability, and the overall quality of ASD drug products.

The internal structure of handwriting proficiency in beginning writers.

Fluent and automatized handwriting frees cognitive resources for more complex elements of writing (i.e., spelling or text generation) or even math tasks (i.e., operating) and is therefore a central objective in primary school years. Most previous research has focused on the development of handwriting automaticity across the school years and characteristics of handwriting difficulties in advanced writers. However, the relative and absolute predictive power of the different kinematic aspects for typically developing beginning handwriting remains unclear. The purpose of the present study was to investigate whether and to what extent different kinematic aspects contribute to handwriting proficiency in typically developing beginning handwriters. Further, we investigated whether gender, socioeconomic background, or interindividual differences in executive functions and visuomotor integration contribute to children's acquisition of handwriting. Therefore, 853 first-grade children aged seven copied words on a digitized tablet and completed cognitive performance tasks. We used a confirmatory factor analysis to investigate how predefined kinematic aspects of handwriting, specifically the number of inversions in velocity (NIV), pen stops, pen lifts, and pressure on the paper, are linked to an underlying handwriting factor. NIV, pen stops, and pen lifts showed the highest factor loadings and therefore appear to best explain handwriting proficiency in beginning writers. Handwriting proficiency was superior in girls than boys but, surprisingly, did not differ between children from low versus high socioeconomic backgrounds. Handwriting proficiency was related to working memory but unrelated to inhibition, shifting, and visuomotor integration. Overall, these findings highlight the importance of considering different kinematic aspects in children who have not yet automatized pen movements. Results are also important from an applied perspective, as the early detection of handwriting difficulties has not yet received much research attention, although it is the base for tailoring early interventions for children at risk for handwriting difficulties.

Designing an effective dissolution test for bilayer tablets tailored for optimal melatonin release in sleep disorder management.

This project aims to investigate the release performance of bilayer tablet (BL-Tablet) designed with both fast and slow-release technology, targeting sleep disorders. The tablet incorporates Melatonin, extracts of Eschscholzia californica and Melissa officinalis. In order to validate the effectiveness of the extended-release profile, an advanced dissolution test was herein proposed. This new method utilizes biorelevant intestinal fluid media and incorporates a stomach-to-intestine fluid changing (SIFC) system. To demonstrate the advantages of employing this method for assessing the controlled release profile of active ingredients, the dissolution results were compared with those obtained using the conventional EU Pharmacopoeia approach. Furthermore, the comparative analysis was extended to include a monolayer tablet version (ML-Tablet) lacking the slow-release technology. Technological characterization and bioaccessibility studies, including intestinal permeability test, were conducted as well to assess the pharmacological performance and bioavailability of active ingredients. The dissolution data recovered revealed that the two dissolution methods did not exhibit any significant differences in the release of ML-Tablet's. However, the dissolution profile of the BL-Tablet exhibited notable differences between the two methods particularly when assessing the behavior of the slow-release layer. In this scenario, both methods initially exhibited a similar release pattern within the first approximately 0.5 h, driven by the fast-release layer of the tablet. Following this, distinct gradual and sustained releases were observed, spanning 2.5 h for the EU Pharmacopoeia method and 8 h for the new SIFC-biorelevant dissolution method, respectively. Overall, the novel method demonstrated a substantial improvement compared to conventional EU Pharmacopoeia test in evaluating the performance of a controlled slow-release technology. Remarkably, the prolonged release technology did not have an adverse impact on melatonin intestinal absorption, and, consequently, maintaining its potential bioavailability of around 78%. Concluding, this research provides valuable insights into how the innovative dissolution test can assist formulators in developing controlled release formulations.

Formulation and Drug Release Study of Rivaroxaban Oral Disintegrating Tablets Using Various Super-Disintegrants

This study aims to improve Rivaroxaban's solubility, dissolution, and bioavailability. Orally disintegrating tablets (ODTs) made with super-disintegrants like crospovidone, sodium starch glycolate, and cross-carmellose sodium will do this. Tablet preparation used direct compression and formulation optimization with design expert software. After a thorough factorial design and evaluation of pre- and post-compression parameters, the F3 batch, which contained Rivaroxaban (7.97%), Crospovidone (3.59%), Croscarmellose sodium (5.18%), Sodium Starch Glycolate (5.18%), Lactose Anhydrous (31.08%), Mannitol (15.94%), MCC (27.89%), SSF (1.59%), and Talc (1.59%), was the best. The enhanced tablet formulation (F3) showed positive qualities, including 3.3 kg/cm² hardness, 23 seconds disintegration time, and 99% drug release after 30 minutes. The innovative Rivaroxaban orally disintegrating tablet (ODT) method disintegrated and dissolved faster than market forms. Rivaroxaban's physical and chemical properties were assessed before formulation. The medication was colorless, scentless, crystalline, and melted at 227°C-229°C, as described in published research. The pharmaceutical was found to be a BCS Class II drug with low water solubility and high solubility in acetate buffer pH 4.5 and 0.1 N Hydrochloric acid. Fourier-transform infrared spectroscopy (FTIR) confirmed no drug-polymer-excipient interactions. Every batch of tablets exhibited uniform thickness (3.5 mm to 3.8 mm) and diameter (10.31 mm to 10.36 mm), indicating good compression without adhering to shaping tools. All samples had a 3-5 kg cm-² hardness, indicating strong mechanical properties. The Roche friability method showed that all batches had good abrasion resistance, ranging from 0.1% to 0.5%. Variations in croscarmellose sodium and crospovidone on tablet disintegration time and hardness were examined using design expert software. The ANOVA showed important factors affecting these attributes. Data-driven polynomial equations predict tablet disintegration time and hardness. These models reveal formulation parameters that affect tablet performance. Thus, the improved F3 batch of rivaroxaban orally disintegrating tablets (ODTs) improves solubility, dissolving, and bioavailability. This may improve treatment outcomes.

Development of Effervescent Tablets Containing Elderberry Vine Tea Compound and Evaluation of Their Antioxidant Activity

Elderberry and vine tea, renowned for their wealth of bioactive constituents and potent antioxidant prowess, hold remarkable promise within a wide array of culinary contexts. This study presents a pioneering advancement in the realm of compound effervescent tablet formulation. Employing the response surface design optimization, this work develops a formulation comprising a total disintegrant (acid-to-base ratio 1.3 : 1) at 50%, elderberry extracts at 31.7%, ultra-micro vine tea powder at 8.3%, stevioside at 3.4%, PEG-6000 at 2.7%, mannitol at 2.9%, and PVP at 1%. Under these carefully optimized conditions, the resultant tablet exhibits remarkable attributes including an average disintegration time of 184.50 ± 4.65 s , foaming quantity of 30.64 ± 2.10 mg / g , and tablet hardness measuring 54.59 ± 3.41 N , with a weight uniformity well within the ±5%. Regarding the antioxidant efficacy, the total flavonoid content attains 76.79 ± 3.76 mg RE/g, and phenolic content reaches 94.84 ± 4.95 mg GAE / g . Moreover, the E C 50 values for scavenging 1,1-diphenyl-2-picrohydrazine (DPPH), hydroxyl (OH), and 2, 2 ′ -azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)(ABTS) radicals are determined at 0.4667 mg/mL, 0.9772 mg/mL, and 0.5014 mg/mL, respectively. This investigation underscores the performance of the effervescent tablet in satisfying stringent physicochemical standards, while also showcasing outstanding antioxidant potency, paving the way for the advancement of antioxidant-functional foods and sustainable exploitation of natural resources.

Development of an Image-based Method for Tablet Microstructure Description and Its Correlation with API Release Rate

The performance of a pharmaceutical formulation, such as the drug (API) release rate, is significantly influenced by the properties of the materials used, the composition of the final product and the tablet compression process parameters. However, in some cases, the knowledge of these input parameters does not necessarily provide a reliable description or prediction of tablet performance. Therefore, the knowledge of tablet microstructure is desirable to understand such formulations. Commonly used analytical techniques, such as X-ray tomography and intrusion mercury porosimetry, are not widely used in pharmaceutical companies due to their price and/or toxicity, and therefore, efforts are made to develop a tool for fast and easy microstructure description. In this work, we have developed an image-based method for microstructure description and applied it to a model system consisting of ibuprofen and CaHPO4∙2H2O (API and excipient with different deformability). The obtained parameter, the quadratic mean of the equivalent diameter of the non-deformable, brittle excipient CaHPO4∙2H2O, was correlated with tablet composition, compression pressure and API release rate. The obtained results demonstrate the possibility of describing the tablet dissolution performance in the presented model system based on the microstructural parameter, providing a possible model system for compressed solid dosage forms in which a plastic component is present and specific API release is required.Graphical

Effect of drug loading and relative humidity on the mechanical properties and tableting performance of Celecoxib–PVP/VA 64 amorphous solid dispersions

The mechanical properties of polymer-based amorphous solid dispersions (ASDs) are susceptible to changes in relative humidity (RH) conditions. The purpose of this study is to understand the impact of RH on both the mechanical properties and tableting performance of Celecoxib-polyvinyl pyrrolidone vinyl acetate co-polymer (PVP/VA 64) ASDs. The ASDs were prepared by solvent evaporation technique to obtain films for nanoindentation, which were also pulverized to obtain powder for compaction. Our results show that higher RH corresponds to lower Hardness, H, and Elastic Modulus, E. At a given RH, both the E and H increase with drug loading to a maximum and decrease with further drug loading. Using ASD powders with a narrow particle size range (d50 = 9–14 µm), we have demonstrated that increasing RH from 11% to 67% leads to improved tablet tensile strength for pure PVP/VA 64 and the ASDs. However, the extent of the increase in tablet tensile strength depends on their mechanical properties, H and E, and drug loading. At a higher compaction pressure and a higher RH, the effect of ASD mechanical properties on tabletability is less because the particles are nearly fully deformed so that bonding areas are approximately the same. Thus, difference in tablet strength is mainly contributed by the inter-particulate forces of attraction. Understanding the impact of these key processing conditions, i.e., RH and compaction pressure, will guide the design of an ASD tablet formulation with robust manufacturability.

Nicotinamide-based agglomerates of ibuprofen: formulation, solid state characterization and evaluation of tableting performance with in-silico investigation

BackgroundThe objective of the present investigation was to obtain directly compressible agglomerates of ibuprofen with nicotinamide by a quasi-emulsification solvent diffusion technique. Ibuprofen-nicotinamide agglomerates were prepared by quasi-emulsification solvent diffusion technique using ethanol (good solvent), water (poor solvent), and chloroform (bridging liquid). The prepared agglomerates were characterized by ATR-FTIR, powder X-ray diffraction, differential scanning calorimetry, and scanning electron microscopy and were evaluated for tableting performance and in vitro drug release. To appropriately identify the hydrogen bonding sites, a thorough understanding of the structures of API and coformer is necessary, hence molecular docking approach was implemented to depict the interaction between the proposed coformer and COX-2 protein (PDB Id:4PH9).ResultsThe percent yield of agglomerates was in the range of 85–98 w/w%, and drug content for all batches was in the range of 96–99%. The microphotographs showed irregular circularly shaped agglomerates. ATR-FTIR study showed a strong possibility of hydrogen bonding between ibuprofen and nicotinamide. The crystallinity of ibuprofen was slightly reduced and confirmed by P-XRD and DSC. Crushing strength and friability studies showed good handling qualities of ibuprofen agglomerates. Heckel plot studies showed low mean yield pressure and high tensile strength, indicating excellent compressibility and compactibility of ibuprofen agglomerates. More than 90% drug release was obtained within 60 min in PBS (pH 7.4). The docking studies revealed that nicotinamide individually has –CDOCKER energy 16.8109 where coformer showed 29.0584, which indicates coformer has a better binding affinity to target as compared to nicotinamide individual.ConclusionsIt can be concluded that the agglomerates improved the dissolution, tableting performance, and solid-state properties of ibuprofen and hence can be useful to improve the therapeutic performance of ibuprofen.Graphic

Formulation and characterization of metformin hydrochloride orodispersible tablets with super disintegrants

Metformin hydrochloride's fast onset of action is very desirable, making it a prime candidate for the preparation of orodispersible tablets in the present study. This medication is prescribed for the management of type 2 diabetes, which does not respond to insulin. The tablets were made using direct compression and a mixture of the super disintegrants sodium starch glycolate (SSG) and croscarmellose sodium (CCS). Mannitol is a sugar-based excipient that serves as a binding agent, dissolves well in water, and provides a pleasant mouth feel. The blend's pre-compression results show that the medication excipients work well together and have desirable compression characteristics. Eight distinct formulations with varying amounts of SSG, CCS, and Mannitol were made. The properties of the tablets' drug release were measured, including their in vitro disintegration time, water absorption ratio, mechanical stability, wetting time, and so on. When using a greater concentration of SSG, CCS, and Mannitol, formulations F4 and F8 showed shorter in vitro disintegration times of 10.2 and 7.8 ​s, respectively, and formulation F8 showed 99.65% in vitro drug release at the end of 30 ​min. The orodispersible tablet performance can be enhanced through direct compression using the super disintegrants inclusion methodology.

Tabletability and compactibility of α-lactose monohydrate powders of different particle size. II: predicted relationships

This study aimed to evaluate a material sparing method to predict tabletability and compactibility relationships. Seven α-lactose monohydrate powders with varying particle size were used as test materials. The compressibility of the powders was determined experimentally, whereas tabletability and compactibility profiles were derived both experimentally and predicted. In the prediction method, two experimental compression parameters (Kawakita and Heckel plastic stiffness) and a single tensile strength reference value were used, all necessary data obtained from a single compression experiment. For both predicted and experimental relationships, compaction and tableting parameters (performance indicators) were calculated. The correction for viscoelastic recovery was successful in generating compressibility profiles that corresponded to the series of experimental out-of-die tablet porosities. For both the tabletability and compactibility, the experimental and predicted profiles showed a high degree of similarity. Good correlations were obtained between the predicted and experimental compaction and tableting parameters. It is concluded that the hybrid prediction method is a material sparing method, which can give good approximations of tabletability and compactibility relationships. The prediction method has the potential to be included as a part of a protocol for the characterisation of the tableting performance of particulate solids.

Manufacturing classification system for oral solid dosage forms of traditional Chinese medicines (Ⅱ): classification of tablets disintegration behavior

In this paper, 50 batches of representative traditional Chinese medicine tablets were selected and the disintegration time was examined with the method in Chinese Pharmacopoeia. The disintegration time and disintegration phenomenon were recorded, and the dissolution behaviors of water-soluble and ultraviolet-absorbent components during the disintegration process of tablets were characterized by self-control method. The results revealed that coating type and raw material type influenced the disintegration time of tablets. It was found that only 4% of traditional Chinese medicine tablets had obvious fragmentation during the disintegration process, while 96% of traditional Chinese medicine tablets showed gradual dissolution or dispersion. Furthermore, according to the disintegration speed, disintegration phenomenon, and whether the cumulative dissolution of measured components was > 90% at complete disintegration, a disintegration behavior classification system(DBCS) was created for the regular-release traditional Chinese medicine tablets. As a result, the disintegration behaviors of 50 batches of traditional Chinese medicine tablets were classified into four categories, i.e. ⅠA_2, ⅠB_1, ⅡB_1, and ⅡB_2. traditional Chinese medicine tablets(Class I) with disintegration time ≤ 30 min were defined to be rapid in disintegration, which can be the objective of optimization or improvement of Chinese herbal extract(semi extract) tablets. Different drug release models were used to fit the dissolution curve of traditional Chinese medicine tablets with gradual dissolution or dispersion phenomenon(i.e. Type B tablets). The results showed that the dissolution curves of water-soluble components in the disintegration process conformed to the zero order kinetics and the Ritger-Peppas model. It could be inferred that the disintegration mechanisms of type B tablets were a combination of dissolution controlled and swelling controlled mechanisms. This study contributes to understanding the disintegration behavior of traditional Chinese medicine tablets, and provides a reference for the design and improvement of disintegration performance of traditional Chinese medicine tablets.

Impact of material properties and process parameters on tablet quality in a continuous direct compression line

The current paper shows how excipient properties impact the process parameters and the final tablet properties in a fully integrated continuous direct compression line. Blend properties of low-dose (1% w/w) and high-dose (40% w/w) paracetamol formulations were evaluated and linked to the blending and tableting performance via multivariate models (Partial Least Squares analysis, PLS). Feeding behavior was analyzed separately, as the amount of active pharmaceutical ingredient (API) that ended into tablets was driven by random fluctuations in the API feeding behavior. The developed PLS models elucidated that formulation behavior was mainly driven by the concentration of the active pharmaceutical ingredient (API), explained by the distinct API properties. Excipient properties also had a substantial impact on formulation behavior. Generally, formulations with microcrystalline cellulose as a filler showed better compactability, lower hold-up mass, lower flowability and higher cohesion than formulations with different lactose grades. The relative performance of a formulation with different fillers differed for 1% w/w and 40% w/w drug loading. Granular and spray dried lactose grades increased in compactability ranking compared to anhydrous lactose when evaluating higher drug loading, due to the difference in morphology. It was shown that besides understanding the impact of excipients on the formulation performance, processability of ingredients is crucial for formulation design.

Influence of formulation variables on the processability and properties of tablets manufactured by fused deposition modelling

The present work studied the influence of different formulation variables (defined also as factors), namely, different polymers (HPC EF, PVA and HPMC-AS LG), drugs with different water solubilities (paracetamol, hydrochlorothiazide and celecoxib) and drug loads (10 or 30 %) on their processability by HME and FDM. Both filaments and tablets were characterized for physic and chemical properties (DSC, XRPD, FTIR) and performance properties (drug content, in vitro drug release). Experiments were designed to highlight relationships between the 3 factors selected and the mechanical properties of filaments, tablet mass and dissolution profiles of the model drugs from printed tablets. While the combination of hydrochlorothiazide and HPMC-AS LG could not be extruded, the combination of paracetamol with HPC EF turned the filaments too ductile and not stiff enough hampering the process of printing. All other polymer and drug combinations could be successfully extruded and printed. Models reflected the influence of the solubility of the drug considered but not the drug load in formulations. The ranking of the drug release rates was in good agreement with their solubilities. Furthermore, PVA presenting the fastest swelling rate, promoted the fastest drugs’ releases in comparison with the other polymers studied. Overall, the study enabled the identification of the key factors affecting the properties of printed tablets, with the proposal of a model that has valued the relative contribution of each factor to the overall performance of tablets.

Establishing the Safe Space via Physiologically Based Biopharmaceutics Modeling. Case Study: Fevipiprant/QAW039.

Physiologically based pharmacokinetic and absorption modeling has increasingly been implemented for biopharmaceutics applications to define the safe space for drug product quality attributes such as dissolution. For fevipiprant/QAW039, simulations were performed to assess the impact of in vitro dissolution on the in vivo performance of immediate-release film-coated tablets during development and scaling up to commercial scale. A fevipiprant dissolution safe space was established using observed clinical intravenous and oral PK data from bioequivalent and non-bioequivalent formulations. Quality control dissolution profiles with tablets were used as GastroPlus™ model inputs to estimate the in vivo dissolution in the gastrointestinal tract and to simulate human exposure. The model was used to evaluate the intraluminal performance of the dosage forms and to predict the absorption rate limits for the 450mg dose. The predictive model performance was demonstrated for various oral dosage forms (150‒500mg), including the non-bioequivalent batches in fasted healthy adults. To define the safe space at 450mg, simulations were performed using theoretical dissolution profiles. A specification of Q = 80% dissolved in 60 min or less for an immediate-release oral solid dosage form reflected the boundaries of the safe space. The dissolution profile of the 450mg commercial scale batch was within a dissolution region where bioequivalence is anticipated, not near an edge of failure for dissolution, providing additional confidence to the proposed acceptance criteria. Thus, the safe space allowed for a wider than 10% dissolution difference for bioequivalent batches, superseding f2 similarity analyses.

Modelling the Evolution of Pore Structure during the Disintegration of Pharmaceutical Tablets

Pharmaceutical tablet disintegration is a critical process for dissolving and enabling the absorption of the drug substance into the blood stream. The tablet disintegration process consists of multiple connected and interdependent mechanisms: liquid penetration, swelling, dissolution, and break-up. One key dependence is the dynamic change of the pore space in a tablet caused by the swelling of particles while the tablet takes up liquid. This study analysed the changes in the pore structure during disintegration by coupling the discrete element method (DEM) with a single-particle swelling model and experimental liquid penetration data from terahertz-pulsed imaging (TPI). The coupled model is demonstrated and validated for pure microcrystalline cellulose (MCC) tablets across three porosities (10, 15, and 22%) and MCC with three different concentrations of croscarmellose sodium (CCS) (2, 5, and 8% w/w). The model was validated using experimental tablet swelling from TPI. The model captured the difference in the swelling behaviour of tablets with different porosities and formulations well. Both the experimental and modelling results showed that the swelling was lowest (i.e., time to reach the maximum normalised swelling capacity) for tablets with the highest CCS concentration, cCCS = 8%. The simulations revealed that this was caused by the closure of the pores in both the wetted volume and dry volume of the tablet. The closure of the pores hinders the liquid from accessing other particles and slows down the overall swelling process. This study provides new insights into the changes in the pore space during disintegration, which is crucial to better understand the impact of porosity and formulations on the performance of tablets.