Solid Dosage Forms Research Articles

Safety as a determining factor in the pharmaceutical drug development for patients of the pediatric population

Patients in the pediatric population are characterized by differences in the pharmacokinetics and pharmacodynamics of drugs and the range of acceptable dosage forms compared to adult patients. The development of safe drugs is designed to reduce the incidence of adverse reactions in this group. Aim. To highlight physiological features of the body of patients in the pediatric population, the corresponding differences in the pharmacological characteristics of drugs, and approaches to minimizing the risks of pharmacotherapy at the stage of pharmaceutical drug development. Materials and methods. Such general scientific theoretical methods as system analysis, generalization, and system approach, as well as the bibliographic method consisted in processing scientific sources of information on drug use in pediatrics and developing pediatric dosage forms were used. Results. When prescribing drugs to pediatric patients, the physiological features of the child’s body development should be considered, using a flexible approach to pharmacotherapy. Many drugs used in pediatrics have not been officially studied in pediatric clinical trials, and therefore, children often receive them off-label. The use of drugs in pediatrics requires special knowledge about the influence of age-related aspects of the child’s physiology on the absorption, distribution, metabolism and excretion of a drug, as well as on its interaction with receptors and organs. This article discusses approaches to the pharmaceutical development of drugs for use in the pediatric population. Conclusions. In pharmaceutical development of drugs for use in pediatric practice, it is necessary to keep in mind the features of drugs due to age and physiological factors in this category of patients, as well as to take into account the route of administration, the choice of the optimal dosage form, the safety profile of excipients, taste and ease of use of drugs. The development of new medicinal products, including multiparticulate solid dosage forms, is designed to improve the safety profile of drugs in children.

Recent Advances in Orally Disintegrating Tablet: Properties, Formulation and Production

: Healthcare practitioners, patients, and consumers widely recognize the convenience as-sociated with administering oral tablets. The emergence of orally disintegrating tablets (ODTs) represents a significant advancement in solid dosage forms, facilitating more convenient oral de-livery while maintaining medication safety, effectiveness, and quality. The ODTs market is ex-pected to experience continuous growth in the coming years despite the internal challenges faced by commercial manufacturers. This paper initiates a comprehensive discussion of the properties of ODTs, including palatability and taste, drug content, disintegration, mechanical strength, mois-ture content, safety, and efficacy. The formulation factors that affect each of these qualities are also discussed. Additionally, this review delves into the processes of the production of ODTs, en-compassing the approaches and technologies from the mixing of active ingredients and recipients to the formation and packaging of ODTs. This review provides valuable insights into the ad-vancement in ODTs technology, aiming to equip researchers with the knowledge necessary to improve quality and optimize efficiency, ultimately receiving high acceptance from patients or consumers.

Mapping active pharmaceutical ingredients Distributions in tablets using Time-of-Flight secondary ion mass spectrometry with multivariate curve resolution

This study introduces an advanced approach to identifying signals associated with indapamide, amlodipine, and perindopril in solid dosage form using time-of-flight secondary ion mass spectrometry (ToF-SIMS) combined with multivariate curve resolution (MCR). The primary objective was to obtain and characterize these signals through MCR factors, which then led to identifying unique signals specific to each active pharmaceutical ingredient (API). These unique signals were crucial for constructing detailed 2D and 3D images of the API distribution within the tablet. The results demonstrated that indapamide and amlodipine exhibited multiple unique peaks, while perindopril had only one. Additionally, the study revealed non-homogeneous distribution patterns of APIs and excipients, such as SiO2 and Mg stearate. This work highlights the significance of applying advanced analytical techniques such as ToF-SIMS and MCR in the pharmaceutical field to ensure consistent therapeutic efficacy through a better understanding of API distribution.

Leveraging solid solubility and miscibility of etoricoxib in Soluplus® towards manufacturing of 3D printed etoricoxib tablets by additive manufacturing

This research focuses on exploring the solid solubility and miscibility of Etoricoxib, a poorly water-soluble anti-inflammatory drug, within Soluplus®, a polymer used as a matrix for 3D-printed tablets. By utilizing hot-melt extrusion (HME), the drug was dispersed within Soluplus® to enhance its solubility. The extrudates were then employed in 3D printing to create customized solid oral dosage form. This study’s novelty lies in combining HME and 3D printing, aiming to improve drug incorporation, stability, and effectiveness in the final formulation. Comprehensive characterization techniques, including hot stage microscopy (HSM), scanning electron microscopy (SEM), micro-computed tomography (Micro-CT), florescence microscopy, optical microscopy, X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), solubility studies, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and aqueous solubility study were utilized to elucidate the physicochemical properties, thermal stability, and structural integrity for the extruded filaments (the printing ink), and 3D printed tablets made thereof. Furthermore, the in vitro drug release profile of the 3D printed tablet was systematically evaluated, revealing a controlled drug release pattern from the finished dosage form. The systematic investigation reported herein, starting from theoretical miscibility to the printing ink development through HME, detailed characterization of the extruded filaments, and further solid oral formulation development by additive manufacturing can be utilized as a platform technology or a pathway for the development of personalized medicine with drugs having similar physicochemical properties.

The Impact of Volume of Dissolution Medium for Biopredictive Dissolution/Permeation Studies of Enabling Formulations: A Comparison of Two Brands of Telmisartan / Amlodipine Tablets.

For compendial dissolution testing of solid dosage forms, media volumes of 500 to 900 mL are used in apparatus I and II to ensure sink conditions. However, these volumes are considerably larger than those in the gastrointestinal tract. Thus, the experiments are not biomimetic and possibly not suitable for biopredictive dissolution testing. The present study investigates the influence of volumes of dissolution media in non-compendial dissolution/permeation settings. Dissolution/permeation studies of two commercial bilayer tablets (Twynsta® and Arrow) containing the active pharmaceutical ingredients telmisartan (40 mg) and amlodipine (10 mg) were evaluated using the MacroFlux tool with various biomimetic media mimicking fasted and fed states as well as biological variability ("biorelevant"). Particularly, the two-stage dissolution process of telmisartan from the tablets is interesting because the compound has a pH-dependent solubility, and 2-stage dissolution leads to supersaturation and precipitation upon pH shift. For telmisartan, lower dissolution volumes significantly induced precipitation, leading to lower permeation, while no precipitation was observed in the larger volume. The permeation of telmisartan was overly sensitive to both pH and micelle concentrations in the biomimetic media. Amlodipine showed complete dissolution under any conditions, which correlates with its known complete absorption in vivo. In conclusion, volumes of dissolution media (and their compositions) are key parameters and play a significant role for designing relevant biomimetic experiments used to predict the bioavailability of supersaturating systems.

Virtual screening of drug materials for pharmaceutical tablet manufacturability with reference to sticking

The manufacturing of pharmaceutical solid dosage forms, such as tablets involves a large number of successive processing operations including crystallisation of the drug substance, granulation, drying, milling, mixing of the formulation, and compaction. Each step is fraught with manufacturing problems. Undesired adhesion of powders to the surface of the compaction tooling, known as sticking, is a frequent and highly disruptive problem that occurs at the very end of the process chain when the tablet is formed. As an alternative to the mechanistic approaches to address sticking, we introduce two different machine learning strategies to predict sticking directly from the chemical formula of the drug substance, represented by molecular descriptors. An empirical database for sticking behaviour was developed and used to train the machine learning (ML) algorithms to predict sticking properties from molecular descriptors. The ML model has successfully classified sticking/non-sticking behaviour of powders with 100% separation. Predictions were made for materials in the handbook of Pharmaceutical Excipients and a subset of molecules included in the ChemBL database, demonstrating the potential use of machine learning approaches to screen for sticking propensity early at drug discovery and development stages. This is the first-time molecular descriptors and machine learning were used to predict and screen for sticking behaviour. The method has potential to transform the development of medicines by providing manufacturability information at drug screening stage and is potentially applicable to other manufacturing problems controlled by the chemistry of the drug substance.

Mimosa pudica Mucilage as a Functional Polymer in Pharmaceutical Applications

Mimosa pudica mucilage has emerged as a versatile natural polymer with considerable potential for pharmaceutical applications due to its biocompatibility, biodegradability, and unique physicochemical properties. This study explores the extraction, characterization, and evaluation of Mimosa pudica mucilage, focusing on its use as a functional polymer in drug delivery systems. The mucilage was characterized for its organoleptic properties, swelling index, solubility, flow properties, and ash content. Results indicate that Mimosa pudica mucilage exhibits good swelling and gelling properties, making it ideal for use as a binder, disintegrant, and controlled-release agent in pharmaceutical formulations. Its high purity, as reflected by low ash values, and favorable flow properties further enhance its suitability for solid dosage forms. The findings of this study suggest that Mimosa pudica mucilage can serve as a promising alternative to synthetic polymers, offering advantages in terms of safety, cost, and environmental sustainability.

Structural Analysis and Processing Characterization of Chitins Extracted from Different Sources.

The characteristics of three different types of chitin extracted from commonly used seafood organisms; namely crabs, shrimps, and squids were investigated. X-ray powder diffraction (XRPD) and scanning electron microscopy (SEM) were employed to analyze these chitins' polymorphic structure and morphology. Bulk and tapped density measurements, along with Kawakita analysis, were used to assess the flowability and compression behaviour of the chitin powders. Chitin extracted from crabs and shrimp exhibited the α-polymorphic form, while chitin from squid showed the β-polymorphic form. SEM images of the two forms revealed distinct differences in chitin layer arrangement, with the α-form appearing more compact due to the anti-parallel alignment of its polymer chains. Both bulk and tapped density measurements and the calculated Hausner ratio (HR) and Carr Index (CI) indicated poor flowability for these chitins. However, Kawakita's analysis of compression and compaction properties demonstrated that both polymorphs are compressible, though they differ in their extent of compaction. Regardless of their source, chitin compacts exhibited high crushing strength. Based on the observed morphology, flowability, and compression characteristics, a blend of α- and β-polymorphic chitin could be an effective excipient for pharmaceutical solid dosage forms.

Advancements in Antiviral Therapy: Favipiravir Sodium in Nasal Formulation.

Favipiravir (FPV) is an Active Pharmaceutical Ingredient (API) known to have lower solubility in aqueous solvents. In the current study, efforts were made to generate a crystalline Favipiravir Sodium Salt (NaFPV) for enhanced solubility in aqueous media. The in-house generated NaFPV was characterized by NMR studies and its sodium content was determined by Flame Emission Spectroscopy (FES) as a confirmation of salt formation. Its solubility was determined where-in the solubility of NaFPV in water was about 100 times greater than FVP. FPV and NaFPV nasal spray formulations were prepared and its activity was determined against human coronavirus (hCoV) 229E strain. In the anti-hCoV assay as compared to FPV, NaFPV showed almost threefold higher anti-viral activity than its unmodified counterpart. Accelerated stability and spray pattern characteristics of both the formulations were studied. Interestingly, NaFPV showed higher physical stability during storage at conditions 40 ± 2°C/ 75% ± 5% RH. The nasal spray formulations of both FPV and NaFPV showed ideal plume geometry and spray pattern of acceptablespecifications. Due to its improvement in terms of solubility, NaFPV will have higher rate and extent of absorption, and faster onset of the therapeutic effect and may appear to be a feasible alternative to regular favipiravir for use in solid dosage forms.

Sparse-deconvolution terahertz near-field microprobe tomography enabling non-destructive inspection of small solid dosage forms

Terahertz (THz) pulsed imaging is a powerful tool for investigating solid dosage forms. However, traditional far-field systems struggle with physically small samples and strongly bent surfaces due to inherently limited lateral resolution. The present study introduces a novel approach using photo-conductive near-field microprobes (PC-NFMs) with a THz time-domain spectroscopy module to overcome the limitations of far-field setups concerning their achievable lateral resolution. In addition, a modified sparse deconvolution algorithm for advanced THz signal processing is presented, enabling the reconstruction of fainting interfaces in scattering media. This approach is particularly valuable for specialized dosage forms with extremely thick coatings, such as the investigated controlled-release dosage form, aiding as a worst-case scenario. While most pharmaceutical coatings are <100 µm thick, our method’s ability to analyze thicker coatings up to nearly 400 µm at an extraordinarily high spatial resolution of 87 µm in the x-direction and 175 µm in the y-direction sets it apart from approaches presented so far. This versatility makes the approach relevant for standard pharmaceutical products and niche, specialized dosage forms, including mini tablets.

Development of Solidified Self-microemulsifying Delivery Systems Containing Tacrolimus for Enhanced Dissolution and Pharmacokinetic Profile.

The use of tacrolimus (FK506) as an immunosuppressant is limited by its low aqueous solubility and bioavailability. The self-microemulsifying drug delivery system (SMEDDS) has successfully improved the solubility of FK506 in our previous study. This study focused on the solidification of liquid SMEDDS to capture the benefits of both liquid SMEDDS and solid dosage forms. Among several porous silica adsorbents evaluated, Aeroperl® 300 Pharma showed the best performance in terms of droplet size, in vitro dissolution, adsorbent-drug compatibility, and tabletabilities. And precoating the adsorbent with polyvinylpyrrolidone K30 resulted in complete drug release. Hydroxypropyl methylcellulose based matrix tablet was developed to achieve a sustained release of FK506. Differential scanning calorimetry and X-ray powder diffraction indicated that FK506 was present in a molecular or amorphous state in the solidified SMEDDS and tablets. In vivo pharmacokinetic studies showed that the self-prepared tablet had improved bioavailability (179.02%) compared to the marketed product Advagraf®. This study provided a promising candidate with improved dissolution and bioavailability for FK506 and a prospective platform for SMEDDS development.

Advances in Loading Techniques and Quality by Design for Fused Deposition Modeling in Pharmaceutical Production: A Systematic Review.

Three-dimensional printing technology has emerging interest in pharmaceutical manufacturing, offering new opportunities for personalized medicine and customized drug delivery systems. Fused deposition modeling (FDM) is highly regarded in the pharmaceutical industry because of its cost effectiveness, easy operation, and versatility in creating pharmaceutical dosage forms. This review investigates different methods of incorporating active pharmaceutical ingredients (APIs) into filament matrices for use in fused deposition modeling (FDM) 3D printing. Two electronic databases, the Web of Science and PubMed, were utilized to survey the literature. The selected keywords for this review were as follows: fused filament fabrication OR fused deposition modeling OR FDM OR FFF AND 3D printing AND loading techniques OR impregnation techniques AND solid dosage form. This paper evaluates various loading techniques such as soaking, supercritical impregnation, microwave impregnation, and hot-melt extrusion, focusing on their effectiveness and capacity for drug incorporation. Additionally, this review includes a thorough risk assessment of the extrusion process using Ishikawa and SWOT analyses. Overall, this review provides comprehensive insights into the latest advancements in 3D printing for pharmaceutical applications and identifies key areas for future research and development.

THERAPEUTIC USE OF ALPHA-LIPOIC ACID SUPPLEMENTATION: A REVIEW ON CURRENT USE AND FUTURE PROSPECTIVE

Alpha-lipoic acid (ALA, thioctic acid, 5-(1,2-dithiolan-3-yl) pentanoic acid) is an organosulfur compound produced by plants, humans, and animals. ALA plays a crucial role in mitochondrial bioenergetics reactions. It is a natural antioxidant and a dithiol compound. ALA is a coenzyme that plays a crucial role in the function of pyruvate and Alpha-ketoglutarate dehydrogenase complexes found in mitochondria. ALA has cytotoxic and antiproliferative effects on several cancers, including Polycystic Ovarian Syndrome (PCOS). Most of ALA's clinical applications come from its antioxidant properties, but it also shows potential in treating female and male infertility. Although ALA can potentially be a therapeutic agent, its pharmacokinetic profile limits its effectiveness. Research suggests that ALA has a short half-life and low bioavailability (around 30%) because it gets broken down in the liver, has reduced solubility, and is unstable in the stomach. Liquid formulations have higher bioavailability and plasma concentration than solid dose forms. This review covers the current clinical evidence on using ALA to prevent, manage, and cure numerous disorders, including diabetic neuropathy, obesity, central nervous system-related ailments, and pregnancy abnormalities.

Development of polymer-encapsulated microparticles of a lipophilic API-IL and its lipid based formulations for enhanced solubilisation

Active Pharmaceutical Ingredient-Ionic liquids (API-ILs) have the potential to improve the bioavailability of BCS Class IV Drugs. However, the problematic physical handling properties of room temperature API-ILs have impaired clinical and commercial exploitation to date. Lipid-based formulations (LBFs) are used to improve the absorption of drugs with limited bioavailability. Nonetheless, LBFs face limitations such as low drug loading capacity and sub-par physical stability. A platform for transforming API-ILs into solid forms at high loadings via spray encapsulation with polymers has been developed and previously demonstrated for hydrophilic API-ILs. The current work demonstrates that this platform technology can be applied to a lipophilic API-IL of the BCS Class IV API, chlorpromazine, and to multi-component solutions comprising API-IL and a LBF. Furthermore, solidification of a type IIIB, liquid LBF was achieved via spray encapsulation with cellulose- and methacrylate- based polymers for the first time. The spray-encapsulated formulations had excellent physical handling properties, and successfully eluted the API-IL in aqueous media. The chlorpromazine release profiles from the API-IL, the API-IL containing LBF, and the solidified formulations, were evaluated in vitro using phosphate buffer (pH 6.8) and fasted state simulated intestinal fluid (FaSSIF). Spray-encapsulated formulations exhibited improved release profiles compared to the liquid formulations. Overall, these findings indicate that phase-separated, polymeric, solid formulations of liquid API forms represent a promising platform technology for developing oral solid dosage forms of poorly bioavailable drugs.

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.

Formulation of minitablets with personalised dissolution profile by fluid-bed granulation of drug nanosuspensions

Transforming poorly soluble active pharmaceutical ingredients (APIs) into a nanoparticulate form is a proven way of improving their dissolution characteristics. The preparation of API nanosuspensions is commonly achieved by wet-stirred media milling. The challenge lies in converting the nanosuspension into a solid dosage form without compromising its re-dispersibility. In the present work, an API nanosuspension was combined with additional excipients and used as abinder in fluid-bed granulation to obtain granules with systematically varying dissolution properties. Specifically, polymeric excipients (hydroxypropyl methylcellulose grade E5 and polyvinylpyrrolidone grade K30) were used in the nanosuspension binder to granulate microcrystalline cellulose or Pearlitol CR-H substrate. The resulting granules were used as feed material to prepare minitablets whose combination enabled the formation of multi-unit dosage form (MUDF) capsules with tuneable drug release profiles, paving the way to rational design and manufacturing of precision medicines.

Continuous twin-screw melt granulation of drug-loaded electrospun fibers

Electrospinning (ES) is a promising continuous formulation strategy to produce amorphous solid dispersions (ASDs) and thereby improve the dissolution of poorly water-soluble drugs. However, processing the electrospun material into solid dosage forms (e.g. tablets) is challenging due to the poor flow properties. In this research, continuous twin-screw melt granulation was applied to improve the flowability of the fibers and therefore ease the further processing steps. During this work, two ASD compositions were investigated: one containing 60 % poly-vinylpyrrolidone-vinyl acetate 6:4 copolymer and 40 % itraconazole (ITR), and another one containing hydroxypropyl methylcellulose (HPMC) and ITR in the same ratio. Both fiber compositions were granulated with polyethene glycol as the binder material, while the effects of the process parameters were examined. The application of higher granulation temperature and screw configurations with increased shear forces compromised the fibrous structure, induced crystallization of the ASD, and decreased the dissolution. However, the stability of the ITR-HPMC fibers proved to be higher as their granulation at 60 °C led to granules with adequate flow properties and dissolution. Moreover, tablets with fewer excipients were pressed from them, resulting in a 34 % reduction in weight. Consequently, this process can complement ES technology and facilitate its industrial implementation.

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%.

Cosmic-Ray Radiation Effects on Ibuprofen Tablet Formulation Inside and Outside of the International Space Station.

In extreme environments people will have different needs for medicine(s), making it crucial to understand how such environments affect drug efficacy. Ibuprofen, commonly used in tablet formulation on Earth, could fail in space despite standard pharmaceutical packaging. We introduce the concept of 'space medicines', where solid-dosage forms protect the pharmaceutical from accelerated degradation in spaceflight. We simulate dose(s) in International Space Station (ISS) through radionuclide and photon experiments, and establish the impact of alpha, beta and gamma rays. We demonstrate that tablet formulation protects from impact of alpha and beta rays; however, gamma rays decompose ibuprofen even when 'masked'. We systematically analyse 19 tablet compositions inside and outside the ISS to determine the effect of compositional changes in the tablet matrix. We confirm that the iron oxide-shielded tablets show minimal degradation (〈10%) inside the ISS, compared to moderate reductions (〉10%) for other formulations, with one exception. The tablets exhibited significantly greater ibuprofen degradation (〉 30-50%) outside ISS, due to harsh conditions. Significantly, we found that flavour have shielding potential by scavenging free radicals. We conclude that ibuprofen efficacy is adversely affected in space, and these effects are expected to worsen on missions to deeper space destinations.