Investigating the Impact of Co-processed Excipients on the Formulation of Bromhexine Hydrochloride Orally Disintegrating Tablets (ODTs).

PURPOSE: Orodispersible tablets (orally disintegrating tablets, ODTs) have been used in pharmacotherapy for over 20 years since they overcome the problems with swallowing solid dosage forms. The successful formula manufactured by direct compression shall ensure acceptable mechanical strength and short disintegration time. Our research aimed to develop ODTs containing bromhexine hydrochloride suitable for registration in accordance with EMA requirements. METHODS: We examined the performance of five multifunctional co-processed excipients, i.e., F-Melt® C, F-Melt® M, Ludiflash®, Pharmaburst® 500 and Prosolv® ODT G2 as well as self-prepared physical blend of directly compressible excipients. We tested powder flow, true density, compaction characteristics and tableting speed sensitivity. RESULTS: The manufacturability studies confirmed that all the co-processed excipients are very effective as the ODT formula constituents. We noticed superior properties of both F-Melt's®, expressed by good mechanical strength of tablets and short disintegration time. Ludiflash® showed excellent performance due to low works of plastic deformation, elastic recovery and ejection. However, the tablets released less than 30% of the drug. Also, the self-prepared blend of excipients was found sufficient for ODT application and successfully transferred to production scale. Outcome of the scale-up trial revealed that the tablets complied with compendial requirements for orodispersible tablets. CONCLUSIONS: We proved that the active ingredient cannot be absorbed in oral cavity and its dissolution profiles in media representing upper part of gastrointestinal tract are similar to marketed immediate release drug product. In our opinion, the developed formula is suitable for registration within the well-established use procedure without necessity of bioequivalence testing.

Comparison of Amorphous Solid Dispersions of Spironolactone Prepared by Spray Drying and Electrospinning: The Influence of the Preparation Method on the Dissolution Properties.

This research aimed to compare two solvent-based methods for the preparation of amorphous solid dispersions (ASDs) made up of poorly soluble spironolactone and poly(vinylpyrrolidone-co-vinyl acetate). The same apparatus was used to produce, in continuous mode, drug-loaded electrospun (ES) and spray-dried (SD) materials from dichloromethane and ethanol-containing solutions. The main differences between the two preparation methods were the concentration of the solution and application of high voltage. During electrospinning, a solution with a higher concentration and high voltage was used to form a fibrous product. In contrast, a dilute solution and no electrostatic force were applied during spray drying. Both ASD products showed an amorphous structure according to differential scanning calorimetry and X-ray powder diffraction results. However, the dissolution of the SD sample was not complete, while the ES sample exhibited close to 100% dissolution. The polarized microscopy images and Raman microscopy mapping of the samples highlighted that the SD particles contained crystalline traces, which can initiate precipitation during dissolution. Investigation of the dissolution media with a borescope made the precipitated particles visible while Raman spectroscopy measurements confirmed the appearance of the crystalline active pharmaceutical ingredient. To explain the micro-morphological differences, the shape and size of the prepared samples, the evaporation rate of residual solvents, and the influence of the electrostatic field during the preparation of ASDs had to be considered. This study demonstrated that the investigated factors have a great influence on the dissolution of the ASDs. Consequently, it is worth focusing on the selection of the appropriate ASD preparation method to avoid the deterioration of dissolution properties due to the presence of crystalline traces.

How to Obtain the Maximum Properties Flexibility of 3D Printed Ketoprofen Tablets Using Only One Drug-Loaded Filament?

The flexibility of dose and dosage forms makes 3D printing a very interesting tool for personalized medicine, with fused deposition modeling being the most promising and intensively developed method. In our research, we analyzed how various types of disintegrants and drug loading in poly(vinyl alcohol)-based filaments affect their mechanical properties and printability. We also assessed the effect of drug dosage and tablet spatial structure on the dissolution profiles. Given that the development of a method that allows the production of dosage forms with different properties from a single drug-loaded filament is desirable, we developed a method of printing ketoprofen tablets with different dose and dissolution profiles from a single feedstock filament. We optimized the filament preparation by hot-melt extrusion and characterized them. Then, we printed single, bi-, and tri-layer tablets varying with dose, infill density, internal structure, and composition. We analyzed the reproducibility of a spatial structure, phase, and degree of molecular order of ketoprofen in the tablets, and the dissolution profiles. We have printed tablets with immediate- and sustained-release characteristics using one drug-loaded filament, which demonstrates that a single filament can serve as a versatile source for the manufacturing of tablets exhibiting various release characteristics.

Molecular Dynamics and Physical Stability of Ibuprofen in Binary Mixtures with an Acetylated Derivative of Maltose.

In this paper, we explore the strategy increasingly used to improve the bioavailability of poorly water-soluble crystalline drugs by formulating their amorphous solid dispersions. We focus on the potential application of a low molecular weight excipient octaacetyl-maltose (acMAL) to prepare physically stable amorphous solid dispersions with ibuprofen (IBU) aimed at enhancing water solubility of the drug compared to that of its crystalline counterpart. We thoroughly investigate global and local molecular dynamics, thermal properties, and physical stability of the IBU+acMAL binary systems by using broadband dielectric spectroscopy and differential scanning calorimetry as well as test their water solubility and dissolution rate. The obtained results are extensively discussed by analyzing several factors considered to affect the physical stability of amorphous systems, including those related to the global mobility, such as plasticization/antiplasticization effects, the activation energy, fragility parameter, and the number of dynamically correlated molecules as well as specific intermolecular interactions like hydrogen bonds, supporting the latter by density functional theory calculations. The observations made for the IBU+acMAL binary systems and drawn recommendations give a better insight into our understanding of molecular mechanisms governing the physical stability of amorphous solid dispersions.

Tabletting solid dispersions of bicalutamide prepared using ball-milling or supercritical carbon dioxide: the interrelationship between phase transition and in-vitro dissolution.

The studies were aimed at formulating tablets containing bicalutamide-PVP K-29/32 solid dispersions and accessing the interrelationships between the properties of obtained binary systems in the form of powder and compacts. The effect of the compression of the solid dispersions obtained by either milling or using the supercritical fluid method on the dissolution and phase transition of the drug was investigated. Mechanical stress induced the amorphization of the drug, while the treatment with supercritical carbon dioxide did not cause any phase transition as confirmed by X-ray diffractometry. Co-processing of the drug substance with the carrier resulted in even a 10-fold improvement of the bicalutamide dissolution from the solid dispersions. The release of the drug from tablets was lower than from the corresponding powder system.

Data-Driven Modeling of the Bicalutamide Dissolution from Powder Systems.

Low solubility of active pharmaceutical compounds (APIs) remains an important challenge in dosage form development process. In the manuscript, empirical models were developed and analyzed in order to predict dissolution of bicalutamide (BCL) from solid dispersion with various carriers. BCL was chosen as an example of a poor water-soluble API. Two separate datasets were created: one from literature data and another based on in-house experimental data. Computational experiments were conducted using artificial intelligence tools based on machine learning (AI/ML) with a plethora of techniques including artificial neural networks, decision trees, rule-based systems, and evolutionary computations. The latter resulting in classical mathematical equations provided models characterized by the lowest prediction error. In-house data turned out to be more homogeneous, as well as formulations were more extensively characterized than literature-based data. Thus, in-house data resulted in better models than literature-based data set. Among the other covariates, the best model uses for prediction of BCL dissolution profile the transmittance from IR spectrum at 1260 cm-1 wavenumber. Ab initio modeling-based in silico simulations were conducted to reveal potential BCL-excipients interaction. All crucial variables were selected automatically by AI/ML tools and resulted in reasonably simple and yet predictive models suitable for application in Quality by Design (QbD) approaches. Presented data-driven model development using AI/ML could be useful in various problems in the field of pharmaceutical technology, resulting in both predictive and investigational tools revealing new knowledge.

The Impact of the Preparation Method on the Properties of Orodispersible Films with Aripiprazole: Electrospinning vs. Casting and 3D Printing Methods.

Orodispersible films (ODFs) address the needs of pediatric and geriatric patients and people with swallowing difficulties due to fast disintegration in the mouth. Typically, they are obtained using the solvent casting method, but other techniques such as 3D printing and electrospinning have already been investigated. The decision on the manufacturing method is of crucial importance because it affects film properties. This study aimed to compare electrospun ODFs containing aripiprazole and polyvinyl alcohol with films prepared using casting and 3D printing methods. Characterization of films included DSC and XRD analysis, microscopic analysis, the assessment of mechanical parameters, disintegration, and dissolution tests. Simplified stability studies were performed after one month of storage. All prepared films met acceptance criteria for mechanical properties. Electrospun ODFs disintegrated in 1.0 s, which was much less than in the case of other films. Stability studies have shown the sensitivity of electrospun films to the storage condition resulting in partial recrystallization of ARP. These changes negatively affected the dissolution rate, but mechanical properties and disintegration time remained at a desirable level. The results demonstrated that electrospun fibers are promising solutions that can be used in the future for the treatment of patients with swallowing problems.

Hyaluronic Acid-Based Nanocapsules as Efficient Delivery Systems of Garlic Oil Active Components with Anticancer Activity.

Diallyl disulfide (DADS) and diallyl trisulfide (DATS) are garlic oil compounds exhibiting beneficial healthy properties including anticancer action. However, these compounds are sparingly water-soluble with a limited stability that may imply damage to blood vessels or cells after administration. Thus, their encapsulation in the oil-core nanocapsules based on a derivative of hyaluronic acid was investigated here as a way of protecting against oxidation and undesired interactions with blood and digestive track components. The nuclear magnetic resonance (1H NMR) technique was used to follow the oxidation processes. It was proved that the shell of the capsule acts as a barrier limiting the sulfur oxidation, enhancing the stability of C=C bonds in DADS and DATS. Moreover, it was shown that the encapsulation inhibited the lysis of the red blood cell membrane (mainly for DADS) and interactions with serum or digestive track components. Importantly, the biological functions and anticancer activity of DADS and DATS were preserved after encapsulation. Additionally, the nanocapsule formulations affected the migration of neoplastic cells-a desirable preliminary observation concerning the inhibition of migration. The proposed route of administration of these garlic extract components would enable reaching their higher concentrations in blood, longer circulation in a bloodstream, and thus, imply a better therapeutic effect.

Low Dose Curcumin Administered in Hyaluronic Acid-Based Nanocapsules Induces Hypotensive Effect in Hypertensive Rats.

BACKGROUND: Vascular drug delivery becomes a promising direction in the development of novel therapeutic strategies in the treatment of cardiovascular pathologies, such as hypertension. However, targeted delivery of hydrophobic substances, with poor bioavailability, remains a challenge. Here, we described the hypotensive effects of a low dose of curcumin delivered to the vascular wall using hyaluronic acid-based nanocapsules. METHODS: The group of hypertensive TGR(m-Ren2)27 rats, was administrated respectively with the vehicle, curcumin solution or curcumin delivered using hyaluronic acid-based nanocapsules (HyC12-Cur), for 7 days each, maintaining the wash-out period between treatments. Arterial blood pressure (systolic - SBP, diastolic - DBP) and heart rate (HR) were monitored continuously using a telemetry system (Data Science International), and Mean Arterial Pressure (MAP) was calculated from SBP and DBP. RESULTS: In hypertensive rats, a low dose of curcumin (4.5 mg/kg) administrated in HyC12-Cur for 7 days resulted in a gradual inhibition of SBP, DBP and MAP increase without an effect on HR. At the end of HyC12-Cur - based treatment changes in SBP, DBP and MAP amounted to -2.0±0.8 mmHg, -3.9±0.7 mmHg and -3.3±0.7 mmHg, respectively. In contrast, the administration of a curcumin solution (4.5 mg/kg) did not result in a significant hypotensive effect and the animals constantly developed hypertension. Vascular delivery of capsules with curcumin was confirmed using newly developed fluorine-rich nanocapsules (HyFC10-PFOB) with a shell based on a HA derivative and similar size as HyC12-Cur. HyFC10-PFOB gave fluorine signals in rat aortas analyzed ex vivo with a 19F NMR technique after a single intragastric administration. CONCLUSION: These results suggest that nanocapsules based on hyaluronic acid, the ubiquitous glycosaminoglycan of the extracellular matrix and an integral part of endothelial glycocalyx, may represent a suitable approach to deliver hydrophobic, poorly bioavailable compounds, to the vascular wall.

How Does the Addition of Kollidon®VA64 Inhibit the Recrystallization and Improve Ezetimibe Dissolution from Amorphous Solid Dispersions?

Amorphization serves as a strategy for the improvement of poor dissolution characteristics of many drug compounds. However, in many formulations the content of polymeric stabilizer is high, which is undesirable from the perspective of future applications. Thus, studying the composition-dependent stability of amorphous solid dispersions seems to be demanded. In this paper, we describe the amorphization of ezetimibe, a lipid-lowering drug, in the spray drying process and investigate the effect of polyvinylpyrrolidone-co-poly(vinyl acetate) (PVP/VA) content on the physical stability and dissolution characteristics of the drug. Fully amorphous systems were obtained when the concentration of the polymer in solid dispersion was as low as 20%. The amorphization led to the dissolution enhancement by even 70%, with a noticeable sudden increase at around 40% of PVP/VA content and very small variations for systems having 66-90% PVP/VA. It was also correlated to wettability characteristics of solid dispersions, which may suggest that in the vicinity of 40% of the polymer content, the behavior of the system becomes independent of the PVP/VA content.

Polymer Capsules with Hydrophobic Liquid Cores as Functional Nanocarriers.

Recent developments in the fabrication of core-shell polymer nanocapsules, as well as their current and future applications, are reported here. Special attention is paid to the newly introduced surfactant-free fabrication method of aqueous dispersions of nanocapsules with hydrophobic liquid cores stabilized by amphiphilic copolymers. Various approaches to the efficient stabilization of such vehicles, tailoring their cores and shells for the fabrication of multifunctional, navigable nanocarriers and/or nanoreactors useful in various fields, are discussed. The emphasis is placed on biomedical applications of polymer nanocapsules, including the delivery of poorly soluble active compounds and contrast agents, as well as their use as theranostic platforms. Other methods of fabrication of polymer-based nanocapsules are briefly presented and compared in the context of their biomedical applications.

Orodispersible films containing ball milled aripiprazole-poloxamer®407 solid dispersions.

This research aimed at developing ODFs containing an antipsychotic drug - aripiprazole (ARP). ARP, as a BCS II class molecule, requires enhancing its water solubility prior to formulating. Therefore, a solid dispersion of ARP - Poloxamer® 407 was prepared by ball milling, then incorporated into the films. It was found that co-processing led to an over 100-fold increase in drug solubility in comparison with pure drug. Moreover, ODFs with solid dispersion showed faster drug release (>95% below 15 min) and disintegration (<30 s), compared with raw ARP films. These results are believed to be due to the solubilization effect of poloxamer and enhanced wettability of the film. Films containing solid dispersions were found to possess smoother film surfaces and favorable mechanical properties - flexibility and strength. The ODF formulations, prepared by a casting method, were based on three different polymers (Kollicoat® IR, Kollicoat® Protect or PVA). It was found that not only the form of the incorporated drug, but also the type of film-forming polymer had an impact on the analyzed parameters. The use of PVA was beneficial in the film formulation with aripiprazole in comparison to other tested film-forming polymers.

Uptake and in vitro anticancer activity of oleic acid delivered in nanocapsules stabilized by amphiphilic derivatives of hyaluronic acid and chitosan.

The nanoemulsion-based delivery systems have gained particular attention due to effective encapsulation and protection of hydrophobic active compounds. However, several features like limited stability, cellular uptake or release of payloads still need to be addressed. We investigated the uptake of the nanocapsules based on the amphiphilic derivative of hyaluronate with oleic acid cores (oil-in-water nanoemulsion) and their anticancer activity in vitro. The core-shell nanocapsules exhibiting long term stability in dispersion showed an enhanced uptake by cancer cells and effectively killed them only if composed of hyaluronate-based shells and oleic acid cores - the anionic chitosan-based shells and/or corn oil cores were used for control experiments. We concluded that the nanocapsules stabilized by the amphiphilic derivative of hyaluronic acid may serve as very stable and efficient delivery systems for oil-soluble compounds without necessity of application of low molecular weight (co)surfactants. The in vitro studies indicated anticancer activity of such delivered oleic acid and crucial role of hyaluronate shell of the nanocapsules in its efficient delivery and enzyme-triggered disintegration inside cells. Corn oil was shown as a nutrient that can serve as an inert vehicle in the studied nanoemulsion that exhibit application potential in food, dietary supplement industry and medicine.

Multivariate Design of 3D Printed Immediate-Release Tablets with Liquid Crystal-Forming Drug-Itraconazole.

The simplicity of object shape and composition modification make additive manufacturing a great option for customized dosage form production. To achieve this goal, the correlation between structural and functional attributes of the printed objects needs to be analyzed. So far, it has not been deeply investigated in 3D printing-related papers. The aim of our study was to modify the functionalities of printed tablets containing liquid crystal-forming drug itraconazole by introducing polyvinylpyrrolidone-based polymers into the filament-forming matrices composed predominantly of poly(vinyl alcohol). The effect of the molecular reorganization of the drug and improved tablets' disintegration was analyzed in terms of itraconazole dissolution. Micro-computed tomography was applied to analyze how the design of a printed object (in this case, a degree of an infill) affects its reproducibility during printing. It was also used to analyze the structure of the printed dosage forms. The results indicated that the improved disintegration obtained due to the use of Kollidon®CL-M was more beneficial for the dissolution of itraconazole than the molecular rearrangement and liquid crystal phase transitions. The lower infill density favored faster dissolution of the drug from printed tablets. However, it negatively affected the reproducibility of the 3D printed object.

Compression-Induced Phase Transitions of Bicalutamide.

The formation of solid dispersions with the amorphous drug dispersed in the polymeric matrix improves the dissolution characteristics of poorly soluble drugs. Although they provide an improved absorption after oral administration, the recrystallization, which can occur upon absorption of moisture or during solidification and other formulation stages, serves as a major challenge. This work aims at understanding the amorphization-recrystallization changes of bicalutamide. Amorphous solid dispersions with poly(vinylpyrrolidone-co-vinyl acetate) (PVP/VA) were obtained by either ball milling or spray drying. The applied processes led to drug amorphization as confirmed using X-ray diffraction and differential scanning calorimetry. Due to a high propensity towards mechanical activation, the changes of the crystal structure of physical blends of active pharmaceutical ingredient (API) and polymer upon pressure were also examined. The compression led to drug amorphization or transition from form I to form II polymorph, depending on the composition and applied force. The formation of hydrogen bonds confirmed using infrared spectroscopy and high miscibility of drug and polymer determined using non-isothermal dielectric measurements contributed to the high stability of amorphous solid dispersions. They exhibited improved wettability and dissolution enhanced by 2.5- to 11-fold in comparison with the crystalline drug. The drug remained amorphous upon compression when the content of PVP/VA in solid dispersions exceeded 20% or 33%, in the case of spray-dried and milled systems, respectively.

How Does the CO2 in Supercritical State Affect the Properties of Drug-Polymer Systems, Dissolution Performance and Characteristics of Tablets Containing Bicalutamide?

The increasing demand for novel drug formulations has caused the introduction of the supercritical fluid technology, CO2 in particular, into pharmaceutical technology as a method enabling the reduction of particle size and the formation of inclusion complexes and solid dispersions. In this paper, we describe the application of scCO2 in the preparation of binary systems containing poorly soluble antiandrogenic drug bicalutamide and polymeric excipients, either Macrogol 6000 or Poloxamer®407. The changes in the particle size and morphology were followed using scanning electron microscopy and laser diffraction measurements. Differential scanning calorimetry was applied to assess thermal properties, while X-ray powder diffractometry was used to determine the changes in the crystal structure of the systems. The dissolution of bicalutamide was also considered. Binary solid dispersions were further compressed, and the attributes of tablets were assessed. Tablets were analyzed directly after manufacturing and storage in climate chambers. The obtained results indicate that the use of supercritical CO2 led to the morphological changes of particles and the improvement of drug dissolution. The flowability of blends containing processed binary systems was poor; however, they were successfully compressed into tablets exhibiting enhanced drug release.

Speed it up, slow it down An issue of bicalutamide release from 3D printed tablets.

The article describes the preparation and characterization of 3D-printed tablets with bicalutamide obtained using two-material co-extrusion-based fused deposition modeling (FDM). This method is a modification of typical two-material FDM where separate nozzles are used to print from two filaments. In this work we used a ZMorph® 3D printer with DualPro printhead which allows us to co-extrude two filaments through a single nozzle. This approach gives the opportunity to modify tablet properties in a wide range, especially the dissolution rate, by producing dosage forms with a complex design. The great advantage of this method is that switching between immediate dosage form and controlled release does not require any change in the 3D-printer set-up. We checked the accuracy of co-extrusion printing simply by weighing the amounts of soluble and insoluble material in the printed object as well as calculating the volumes of the printed objects from micro computed tomography (µ-CT) images. We printed several tablets with a different design including simple one-material tablets, two- and three-compartment tablets with various internal structure and composition of the printing path. The dissolution tests were conducted in sink and non-sink conditions. We obtained tablets with desired bicalutamide dissolution profiles, i.e. immediate, controlled, and combined. The formation of spatial matrix slows down the dissolution in controlled and combined release bicalutamide tablets what was confirmed by µ-CT analysis before and after dissolution.