Search Results (181)

Background/Objectives: The aim of our research was to understand how excipients, unit operations, and process parameters impact processability and resulting properties, performance, and stability of tablets containing bovine lactoferrin, a cohesive biomacromolecule. Methods: Microcrystalline cellulose (MCC), croscarmellose (xCMC), lactose (LAC), hydroxypropyl methylcellulose (HPMC), and sodium stearyl fumarate (SSF) were used to produce various tablet formulations containing lactoferrin across a concentration range of 5 to 45%, targeting immediate- or controlled release performance. Tablets were made either by direct compression or via dry granulation followed by tableting. In addition to release performance, tablet attributes were characterized for tensile strength, friability, weight uniformity, and content uniformity. Results: Acceptable tablet tensile strength, friability, and performance were obtained for lactoferrin concentrations ranging from 15 to 45%, using a variety of excipients and manufacturing approaches. In several cases, dry granulation improved content uniformity. Excipient choice and tablet compression force impacted drug release, particularly when MCC alone was used as dry binder for immediate release. Dry granulation impacted tablet tensile properties, but did not significantly impact release performance. Lactoferrin–excipient compatibility was demonstrated for up to 2 years in ambient laboratory conditions. Conclusions: The study demonstrates that robust tablets can be produced using excipients and processes amenable to scale-up for industrial production. Consistent, stable, and suitably performing tablets were successfully produced using a variety of excipients, processing approaches, and across a broad concentration range with this cohesive biomacromolecule active pharmaceutical ingredient (API). Both immediate- and controlled release performance modes were possible. Full article

Vervain (Verbena officinalis L., Verbenaceae family) is a perennial plant which grows widely in Europe. It is rich in iridoids, phenolic acids, phenylpropanoid glycosides, flavonoids and terpenoids. Verbena has traditionally been used in folk medicine to calm the nervous system, but there is a lack of scientific data about it. The aim of this study was to explore and characterise the chemical profile and neurotropic effects of V. officinalis dry extracts and their amino acid-based preparations. We determined a total of eight main phenolic compounds and 17 amino acids in the V. officinalis dry extracts. To evaluate the neurotropic effects of the verbena extracts, the following behavioural pharmacology tests were used: Open Field Test, Elevated Plus Maze, Black-and-White Box Test and Tail Suspension Test. The dry aqueous–ethanolic extract (extractant 70% ethanol) demonstrated strong anxiolytic and antidepressant effects, while its dry modified extracts with valine and arginine consistently exhibited pronounced sedative activity across all studies. For example, the Tail Suspension Test demonstrated that the total immobility time in animals receiving the dry aqueous–ethanolic extract was the lowest, being 1.22-fold (p < 0.05) lower than in control animals and 2.25-fold (p < 0.05) lower than in the animals treated with the reference drug preparation (“Sedaphyton”). A novel aqueous-based gel formulation feasible for semi-solid extrusion (SSE) 3D printing was designed. This printing gel enables the fabrication of new oral dosage forms for V. officinalis dry extracts. The effects of pharmaceutical preparations on the human central nervous system require clinical studies. Full article

Background/Objectives: Smart Formulation is an artificial intelligence-based platform designed to predict the Beyond Use Dates (BUDs) of compounded oral solid dosage forms. The study aims to develop a decision-support tool for pharmacists by integrating molecular, formulation, and environmental parameters to assist in optimizing the stability of extemporaneous preparations. Methods: A tree ensemble regression model was trained using a curated dataset of 55 experimental BUD values collected from the Stabilis database. Each formulation was encoded with molecular descriptors, excipient composition, packaging type, and storage conditions. The model was implemented using the KNIME platform, allowing the integration of cheminformatics and machine learning workflows. After training, the model was used to predict BUDs for 3166 APIs under various formulation and storage scenarios. Results: The analysis revealed a significant impact of excipient type, number, and environmental conditions on API stability. APIs with lower LogP values generally exhibited greater stability, particularly when formulated with a single excipient. Excipients such as cellulose, silica, sucrose, and mannitol were associated with improved stability, whereas HPMC and lactose contributed to faster degradation. The use of two excipients instead of one frequently resulted in reduced BUDs, possibly due to moisture redistribution or phase separation effects. Conclusions: Smart Formulation represents a valuable contribution to computational pharmaceutics, bridging theoretical formulation design with practical compounding needs. The platform offers a scalable, cost-effective alternative to traditional stability testing and is already available for use by healthcare professionals. Its implementation in hospital and community pharmacies may help mitigate drug shortages, support formulation standardization, and improve patient care. Future developments will focus on real-time stability monitoring and adaptive learning for enhanced precision. Full article

Background/Objectives: In many parts of the world, pharmacists hold the primary responsibility for providing safe and effective pharmacotherapy. A key aspect is the availability of appropriate medicines for each individual patient. When industrially manufactured medicines are unsuitable or unavailable, pharmacists can prepare tailor-made medicines. While this principle applies globally, practices vary between countries. In the Netherlands, the preparation of medicines in pharmacies is well-established and integrated into routine healthcare. This narrative review explores the role and significance of extemporaneous compounding, pharmacy preparations and related product care in the Netherlands. Methods: Pharmacists involved in pharmacy preparations across various professional sectors, including community and hospital pharmacies, central compounding facilities, academia, and the professional pharmacists’ organisation, provided detailed and expert insights based on the literature and policy documents while also sharing their critical perspectives. Results: We present arguments supporting the need for pharmacy preparations and examine their position and role in community and hospital pharmacies in the Netherlands. Additional topics are discussed, including the regulatory and legal framework, outsourcing, quality assurance, standardisation, education, and international context. Specific pharmacy preparation topics, often with a research component and a strong focus on product care, are highlighted, including paediatric dosage forms, swallowing difficulties and feeding tubes, hospital-at-home care, reconstitution of oncolytic drugs and biologicals, total parenteral nutrition (TPN), advanced therapy medicinal products (ATMPs), radiopharmaceuticals and optical tracers, clinical trial medication, robotisation in reconstitution, and patient-centric solid oral dosage forms. Conclusions: The widespread acceptance of pharmacy preparations in the Netherlands is the result of a unique combination of strict adherence to tailored regulations that ensure quality and safety, and patient-oriented flexibility in design, formulation, and production. This approach is further reinforced by the standardisation of a broad range of formulations and procedures across primary, secondary and tertiary care, as well as by continuous research-driven innovation to develop new medicines, formulations, and production methods. Full article

Donepezil (DPZ) is an Alzheimer’s disease (AD) drug that promotes cholinergic neurotransmission and exhibits excellent acetylcholinesterase (AChE) selectivity. The current oral formulations of DPZ demonstrate decreased bioavailability, attributed to limited drug permeability across the blood–brain barrier (BBB). In order to overcome these limitations, various dosage forms aimed at delivering DPZ have been explored. This discussion will focus on the nose-to-brain (N2B) delivery system, which represents the most promising approach for brain drug delivery. Intranasal (IN) drug delivery is a suitable system for directly delivering drugs to the brain, as it bypasses the BBB and avoids the first-pass effect, thereby targeting the central nervous system (CNS). Currently developed formulations include lipid-based, solid particle-based, solution-based, gel-based, and film-based types, and a systematic review of the N2B research related to these formulations has been conducted. According to the in vivo results, the brain drug concentration 15 min after IN administration was more than twice as high those from other routes of administration, and the direct delivery ratio of the N2B system improved to 80.32%. The research findings collectively suggest low toxicity and high therapeutic efficacy for AD. This review examines drug formulations and delivery methods optimized for the N2B delivery of DPZ, focusing on technologies that enhance mucosal residence time and bioavailability while discussing recent advancements in the field. Full article

The number of newly developed substances with poor water solubility continually increases. Therefore, specialized formulation strategies are required to overcome the low bioavailability often associated with this property. This review provides an overview of novel physical modification strategies discussed in the literature over the past decades and focuses on oral dosage forms. A distinction is made between ‘brick-dust’ molecules, which are characterized by high melting points due to the solid-state properties of the substances, and ‘grease-ball’ molecules with high lipophilicity. In general, the discussed strategies are divided into the following three main categories: drug nanoparticles, solid dispersions, and lipid-based formulations. Full article

Background/Objectives: Although technology has progressed and novel dosage forms have been developed, tablets are still the most used form of medication. However, the present manufacturing methods of these oral solid dosage forms offer limited capacity for personalized treatment and adaptable dosing. Personalized therapy, with a few exceptions, is not yet a part of routine clinical practice. Drug printing could be a possible approach to increase the use of personalized therapy. The aim of this work was to investigate the role of surface tension and the viscosity of inks in the formation of the printing pattern and to investigate how the porosity of substrate tablets influences the behavior of inks on the surface. Methods: Spray-dried mannitol served as a binder and filler, while magnesium stearate functioned as a lubricant in the preparation of substrate tablets. Brilliant Blue dye was a model “drug”. The ink formulation was applied to the substrates in three varying quantities. Results: Increasing the viscosity enhanced the drug content, potentially improving printing speed and pattern accuracy. However, it negatively impacted the dosing accuracy due to nozzle clogging and prolonged drying time. Viscosity had a significantly higher impact on the ink behavior than surface tension. Lowering the surface tension improved the dosing accuracy and reduced the drying time but resulted in smaller drop sizes and decreases in pattern accuracy. Reducing the substrate porosity led to longer drying times and diminished pattern accuracy. Conclusions: A target surface tension of around 30 mN/m is suggested for inkjet printing. It is necessary to further investigate the applicability of the technology with solutions of inks with high viscosity and low surface tension, including the API. Full article

Background/Objectives: Controlling the critical quality attributes (CQAs), such as granule moisture level and particle size distribution, that impact product performance is essential for ensuring product quality in medicine manufacture. Oral solid dosage forms, such as tablets, often require appropriate powder flow for compaction and filling. Spray-dried fluidized bed granulation (FBG) is a key unit operation in the preparation of granulated powders. The determination of particle sizes in FBG using near-infrared spectroscopy (NIR) has been considered in the literature. Herein, for the first time, NIR is combined with process parameters to achieve improved prediction of the particle sizes in FBG. Methods: An inline model for particle size determination using both NIR and FBG process parameters was developed using the partial least square (PLS) method, or ‘merged-PLS model’. The particle size was predicted at the end point of the process, i.e., the last 10% of the particle-size data for each batch run. An additional two analyses included a merged-PLS model with 12 batches: (1) where nine batches were training and three batches were a test set; and (2) where 11 batches were training and one was a test batch. Results: For all considered particle size fractions, Dv10, Dv25, Dv50, Dv75, and Dv90, an improved root-mean-squared error of prediction (RMSEP) is obtained for the merged-PLS model compared to the NIR-only PLS model and compared to the process parameters alone model. Improved RMSEP is also achieved for the additional two analyses. Conclusions: The improved prediction performance of endpoint particle sizes by the merged-PLS model can help to enhance both the process understanding and the overall control of the FBG process. Full article

Improving the manufacturability of drug formulations via direct compression has been of great interest for the pharmaceutical industry. Selecting excipients plays a vital role in obtaining a high-quality product without the wet granulation processing step. In particular, for diluents which are usually present in a larger amount in a formulation, choosing the correct one is of utmost importance in the production of tablets via any method. In this work, we assessed the possibility of manufacturing a small-molecule drug product, omeprazole, which has been historically manufactured via a multi-step processes such as wet granulation and multiple-unit pellet system (MUPS). For this purpose, four prototypes were developed using several diluents: a co-processed excipient (Microcelac^®), two granulated forms of alpha-lactose monohydrate (Tablettose^® 70 and Tabletose^® 100), and a preparation of microcrystalline cellulose (Avicel^® PH102) and lactose (DuraLac^® H), both of which are common excipients without any enhancement. The tablets were produced using a single punch tablet press and thoroughly characterized physically and chemically in order to assess their functionality and adherence to drug product specifications. The direct compression process was used for the manufacturing of all proposed formulations, and the prototype formulated using Microcelac^® showed the best results and performance during the compression process. In addition, it remained stable over twelve months under 25 °C/60% RH conditions. Full article

Background/Objectives: Rivaroxaban, an oral anticoagulant, shows poor aqueous solubility, posing significant challenges to its bioavailability and therapeutic efficiency. The present study investigates the improvement of rivaroxaban’s solubility through the formation of different inclusion complexes with three cyclodextrin derivatives, such as β-cyclodextrin (β-CD), methyl-β-cyclodextrin (Me-β-CD), and hydroxypropyl-β-cyclodextrin (HP-β-CD) prepared by lyophilization in order to stabilize the complexes and improve dissolution characteristics of rivaroxaban. Methods: The physicochemical properties of the individual compounds and the three lyophilized complexes were analysed using Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), X-ray diffraction (XRD), and thermogravimetric analysis (TGA). Results: FTIR spectra confirmed the formation of non-covalent interactions between rivaroxaban and the cyclodextrins, suggesting successful encapsulation into cyclodextrin cavity. SEM images revealed a significant morphological transformation from the crystalline structure of pure rivaroxaban and cyclodextrins morphologies to a more porous and amorphous matrix in all lyophilized complexes. XRD patterns indicated a noticeable reduction in drug crystallinity, supporting enhanced potential of the drug solubility. TGA analysis demonstrated improved thermal stability in the inclusion complexes compared to the individual drug and cyclodextrins. Pharmacotechnical evaluation revealed that the obtained formulations (by comparison with physical mixtures formulations) possessed favorable bulk and tapped density values, suitable compressibility index, and good flow properties, making all suitable for direct compression into solid dosage forms. Conclusions: The improved cyclodextrins formulation characteristics, combined with enhanced dissolution profiles of rivaroxaban comparable to commercial Xarelto^® 10 mg, highlight the potential of both cyclodextrin inclusion and lyophilization technique as synergistic strategies for enhancing the solubility and drug release of rivaroxaban. Full article

Oral solid drug delivery continues to be the gold standard in pharmaceutical formulations, owing to its cost-effectiveness, ease of administration, and high patient compliance. Tablets, the most widely used dosage form, are favored for their precise dosing, simplicity, and economic advantages. Among these, controlled release (CR) tablets stand out for their ability to maintain consistent drug levels, enhance therapeutic efficacy, and reduce dosing frequency, thereby improving patient adherence and treatment outcomes. A well-designed CR system ensures a sustained and targeted drug supply, optimizing therapeutic performance while minimizing side effects. This review delves into the latest advancements in CR formulations, with a particular focus on hydrophilic matrix systems, which regulate drug release through mechanisms such as swelling, diffusion, and erosion. These systems rely on a variety of polymers as drug-retarding agents to achieve tailored release profiles. Recent breakthroughs in crystal engineering and polymer science have further enhanced drug solubility and bioavailability, addressing critical challenges associated with poorly soluble drugs. In terms of manufacturing, direct compression has emerged as the most efficient method for producing CR tablets, streamlining production while ensuring consistent drug release. The integration of the Quality by Design framework has been instrumental in optimizing product performance by systematically linking formulation and process variables to patient-centric quality attributes. The advent of cutting-edge technologies such as artificial intelligence and 3D printing is revolutionizing the field of CR formulations. AI enables predictive modeling and data-driven optimization of drug release profiles, while 3D printing facilitates the development of personalized medicines with highly customizable release kinetics. These innovations are paving the way for more precise and patient-specific therapies. However, challenges such as regulatory hurdles, patent constraints, and the need for robust in vivo validation remain significant barriers to the widespread adoption of these advanced technologies. This succinct review underscores the synergistic integration of traditional and emerging strategies in the development of CR matrix tablets. It highlights the potential of hydrophilic and co-crystal matrix systems, particularly those produced via direct compression, to enhance drug bioavailability, improve patient adherence, and deliver superior therapeutic outcomes. By bridging the gap between established practices and innovative approaches, this field is poised to address unmet clinical needs and advance the future of oral drug delivery. Full article

The solubility behavior of drugs is a critical factor in formulation development. Approximately 40–45% of new drugs face market entry challenges due to low water solubility. Enhancing drug bioavailability is thus essential in developing pharmaceutical dosage forms. Many biopharmaceutical class II and IV drugs are commonly prescribed to treat inflammations, infections, and pain from various pathologies. Their oral administration has several drawbacks, including significant first-pass liver effects, low bioavailability, and adverse gastrointestinal effects. Topical application has gained relevance due to its advantages in delivering drugs directly to the target site, avoiding gastrointestinal irritation, and increasing their effectiveness. However, topical hydrogel formulations with poorly water-soluble drugs face challenges related to the skin’s permeability. Therefore, preparing topical hydrogels using solid dispersions (SDs) is an effective strategy to enhance the dissolution rate of poorly soluble drugs, thereby improving their topical bioavailability. In this review, the concepts of SDs, topical delivery systems, and topical hydrogel formulations incorporating SDs, as well as their preparation methods, characterization, and applications, will be discussed. Full article

Background/Objectives: Tablet is the most popular oral solid dosage form, and high-shear wet granulation and tableting (HSWGT) is a versatile technique for manufacturing tablets. The conventional pharmaceutical development for HSWGT is carried out in a step-by-step mode, which is inefficient and may result in local optimal solutions. Inspired by the co-design philosophy, a formulation–process–product integrated design (FPPID) framework is innovatively brought forward to enable the target-oriented and simultaneous exploration of the formulation design space and the process design space. Methods: A combination of strategies, such as a material library, model-driven design (MDD), and simulation-supported solution generation, are used to manage the complexity of the multi-step development processes of HSWGT. The process model was developed at the intermediate level by incorporating dimensionless parameters from the wet granulation regime map approach into the process of the partial least square (PLS) model. The tablets tensile strength (TS) and solid fraction (SF) could be predicted from the starting materials’ properties and process parameters. The material library was used to diversify the model input and improve the model’s generalization ability. Furtherly, the mixture properties calculation model and the process model were interconnected. Results: A four-step FPPID methodology including the target definition, the formulation simulation, the process simulation, and the solution generation was implemented. The performance of FPPID was demonstrated through the efficient development of high-drug-loading tablets. Conclusions: As a holistic design method, the proposed FPPID offers great opportunity for designers to handle the complex interplay in the sequential development stages, facilitate instant decisions, and accelerate product development. Full article

The European Union, producing over 2.5 billion tons of waste annually, has prompted the European Parliament to implement legal measures and encourage the shift towards a circular economy. Millions of tons of biowaste from olive plant leaves are generated annually, resulting in environmental and economic challenges. To address this, the biowaste of olive leaves was valorized, resulting in the extraction of valuable components, triterpenes and polyphenols, which hold potential pharmaceutical, food, or cosmetic applications. Our research involved the formulation of a triterpene extract (TTP70, 70% triterpenes) as a solid dispersion using Poloxamer-188 (P188) and Poloxamer-407 (P407). The solid dispersions were prepared using a kneading method and various extract-to-polymer weight ratios, including 1:1, 1:2, and 1:5. The influence of hydrophilic carriers on the solubility, dissolution profile, and in vitro passive permeability of TTP70 was evaluated. Both carriers and all considered weight ratios significantly improved the solubility of hydrophobic extract and the dissolution of triterpenes. PAMPA experiments demonstrated the efficacy of the formulation in improving the passive permeation of triterpenes. Subsequently, the solid dispersions were physically mixed with a polyphenol-enriched extract (OPA40, 49% of polyphenols) also obtained from olive leaves, and they were used to fill hard gelatin capsules and produce an oral dosage form. The composite formulations improved the dissolution of both classes of constituents. Full article

Background/Objectives: Thickened waters are commonly used for dysphagic patients to ensure hydration, facilitate safer swallowing, and administer oral therapies, yet their impact on drug dissolution remains unclear. This study aims to investigate how thickening agents, viscosity, and solid oral dosage form (SODF) formulations influence drug release in gelled vehicles. Methods: Twelve commercially available thickened waters, including both ready-to-use products and powders for extemporaneous preparation, were used to disperse crushed sodium pravastatin tablets. The resulting preparations were evaluated for their rheological properties and dissolution performance. Results: Thickened water products vary in consistency, with starch-based thickeners providing more consistent results than gum-based ones. Pravastatin release profiles closely matched the original tablets with starch thickeners, while gum-based thickeners showed greater variability, primarily influenced by viscosity. Conclusions: These findings emphasize the importance of selecting the appropriate thickening agent for controlling drug release in thickened water products, highlighting the need to balance patient compliance with the potential impact on drug release during product development. Full article