Alena Komersová

The use of hot melt extrusion combined with fused deposition modeling 3D printing was explored to enhance the solubility and bioavailability of poorly water‐soluble compounds intended for Alzheimer's disease (AD) therapy. AD, a neurodegenerative disorder with no definitive treatment, affects millions worldwide, underscoring the urgent need for effective and personalized therapeutic strategies. Four sulfonamide‐derived compounds, identified as potential AD therapeutics, were synthesized and successfully incorporated (loads between 10 and 50 wt.%) into customized, 3D‐printed oral dosage forms. These 3D‐printed tablets were evaluated for properties such as hardness, thermo‐analytical characterization, dissolution, cytotoxicity, and stability. Notably, successful amorphization of the incorporated APIs was observed in most 3D‐printed tablets, which may be critical for improving solubility. In vitro dissolution testing revealed multiple favorable release profiles, with several formulations demonstrating sustained or enhanced drug release suitable for the therapeutic requirements of AD. When compared to the dissolution data of the corresponding conventional matrix tablets, the present 3D‐printed tablets offered superior or comparable dissolution characteristics, demonstrating the potential of personalized medicine and remote digital control for optimizing patient‐specific treatments.

This study introduces a novel approach to prepare an intestine‐targeting transport system with a controlled drug release profile, combining two 3D printing techniques: selective laser sintering (SLS) and fused deposition modeling (FDM). Material evaluations indicate that a mixture of Kollidon^® VA64 with 20% of Kollicoat^® IR and 0.2% of Aeroperl^® has the best flow behavior and exhibits optimal printability at a laser speed of 90 mm s⁻¹. The formulation is subsequently drug‐loaded and the printed cores are coated using the FDM technique. The core serves as a drug carrier and the FDM coating shell, consisting of 95% HPMC and 5% pectin, provides modified drug release and enhanced mechanical resistance of the tablet. The coating exhibits acid‐resistant properties, with no drug release in the pH of 1.2 during the first 120 min of dissolution testing. In the pH of 6.8, the release profile shows zero‐order kinetics with a constant release rate of 0.249% min⁻¹ (in the time interval from 255 to 480 min). At the time point of 720 min, 92% of the drug is released. Dissolution testing thus demonstrates delayed and prolonged drug release. Combining both 3D printing methods shows great potential for personalized treatment of intestinal inflammatory diseases.

Differential scanning calorimetry and Raman spectroscopy were used to study the nonisothermal and isothermal crystallization behavior of amorphous indomethacin powders (with particle sizes ranging from 50 to 1000 µm) and their dependence on long-term storage conditions, either 0–100 days stored freely at laboratory ambient temperatures and humidity or placed in a desiccator at 10 °C. Whereas the γ-form polymorph always dominated, the accelerated formation of the α-form was observed in situations of heightened mobility (higher temperature and heating rate), increased amounts of mechanically induced defects, and prolonged free-surface nucleation. A complex crystallization behavior with two separated crystal growth modes (originating from either the mechanical defects or the free surface) was identified both isothermally and nonisothermally. The diffusionless glass–crystal (GC) crystal growth was found to proceed during the long-term storage at 10 °C and zero humidity, at the rate of ~100 µm of the γ-form surface crystalline layer being formed in 100 days. Storage at the laboratory temperature (still below the glass transition temperature) and humidity led only to a negligible/nondetectable GC growth for the fine indomethacin powders (particle size below ~150 µm), indicating a marked suppression of GC growth by the high density of mechanical defects under these conditions. The freely stored bulk material with no mechanical damage and a smooth surface exhibited zero traces of GC growth (as confirmed by microscopy) after >150 days of storage. The accuracy of the kinetic predictions of the indomethacin crystallization behavior was rather poor due to the combined influences of the mechanical defects, competing nucleation, and crystal growth processes of the two polymorphic phases as well as the GC growth complex dependence on the storage conditions within the vicinity of the glass transition temperature. Performing paired isothermal and nonisothermal kinetic measurements is thus highly recommended in macroscopic crystallization studies of drugs with similarly complicated crystal growth behaviors.

Non-isothermal differential scanning calorimetry (DSC) was used to study the influences of particle size (d_aver) and heating rate (q⁺) on the structural relaxation, crystal growth and decomposition kinetics of amorphous indomethacin. The structural relaxation and decomposition processes exhibited d_aver-independent kinetics, with the q⁺ dependences based on the apparent activation energies of 342 and 106 kJ·mol⁻¹, respectively. The DSC-measured crystal growth kinetics played a dominant role in the nucleation throughout the total macroscopic amorphous-to-crystalline transformation: the change from the zero-order to the autocatalytic mechanism with increasing q⁺, the significant alteration of kinetics, with the storage below the glass transition temperature, and the accelerated crystallization due to mechanically induced defects. Whereas slow q⁺ led to the formation of the thermodynamically stable γ polymorph, fast q⁺ produced a significant amount of the metastable α polymorph. Mutual correlations between the macroscopic and microscopic crystal growth processes, and between the viscous flow and structural relaxation motions, were discussed based on the values of the corresponding activation energies. Notably, this approach helped us to distinguish between particular crystal growth modes in the case of the powdered indomethacin materials. Ediger’s decoupling parameter was used to quantify the relationship between the viscosity and crystal growth. The link between the cooperativity of structural domains, parameters of the Tool-Narayanaswamy-Moynihan relaxation model and microscopic crystal growth was proposed.

The present study focused on the more detailed characterization of chitosan–carrageenan-based matrix tablets with respect to their potential utilization for drug targeting in the intestine. The study systematically dealt with the particular stages of the dissolution process, as well as with different views of the physico-chemical processes involved in these stages. The initial swelling of the tablets in the acidic medium based on the combined microscopy–calorimetry point of view, the pH-induced differences in the erosion and swelling of the tested tablets, and the morphological characterization of the tablets are discussed. The dissolution kinetics correlated with the rheological properties and mucoadhesive behavior of the tablets are also reported, and, correspondingly, the formulations with suitable properties were identified. It was confirmed that the formation of the chitosan–carrageenan polyelectrolyte complex may be an elegant and beneficial alternative solution for the drug targeting to the intestine by the matrix tablet.

Tablets used for extended drug release commonly contain large amounts of drugs. The corresponding drug release mechanism thus has to be well-known and invariable under numerous conditions in order to prevent any uncontrolled drug release. Particularly important is the stability and invariability of the release mechanism in the presence of alcohol due to the possible occurrence of the dose dumping effect. The effect of 3D printing (3DP) coating on the drug release mechanism and the drug release rate was studied as a possible tool for the prevention of the alcohol-induced dose dumping effect. Three types of matrix tablets (hydrophilic, lipophilic, and hydrophilic-lipophilic) were prepared by the direct compression method and coated using 3DP. The commercial filament of polyvinyl alcohol (PVA) and the filament prepared from hypromellose by hot melt extrusion (HME) were used as coating materials. Both coating materials were characterized by SEM, DSC, Raman spectroscopy, and PXRD during particular stages of the processing/coating procedure. The dissolution behavior of the uncoated and coated tablets was studied in the strongly acidic (pH 1.2) and alcoholic (40% of ethanol) dissolution media. The dissolution tests in the alcoholic medium showed that the Affinisol coating was effective in preventing the dose dumping incidence. The dissolution tests in the acidic dissolution media showed that the Affinisol coating can also be useful for the delayed release of active substances.

A drug dissolution profile is one of the most critical dosage form characteristics with immediate and controlled drug release. Comparing the dissolution profiles of different pharmaceutical products plays a key role before starting the bioequivalence or stability studies. General recommendations for dissolution profile comparison are mentioned by the EMA and FDA guidelines. However, neither the EMA nor the FDA provides unambiguous instructions for comparing the dissolution curves, except for calculating the similarity factor f₂. In agreement with the EMA and FDA strategy for comparing the dissolution profiles, this manuscript provides an overview of suitable statistical methods (CI derivation for f₂ based on bootstrap, CI derivation for the difference between reference and test samples, Mahalanobis distance, model-dependent approach and maximum deviation method), their procedures and limitations. However, usage of statistical approaches for the above-described methods can be met with difficulties, especially when combined with the requirement of practice for robust and straightforward techniques for data evaluation. Therefore, the bootstrap to derive the CI for f₂ or CI derivation for the difference between reference and test samples was selected as the method of choice.

The catalytic effect of copper in Devarda’s Al-Cu-Zn alloy (Dev. alloy) and sole metallic copper, copper salts and copper oxides in the coaction of NaBH₄ within the hydrodehalogenation (HDH) of polybrominated phenols, such as the herbicide Bromoxynil in alkaline aqueous solution has been investigated. Namely, the hydrodebromination (HDB) activity of Dev. alloy/NaOH system has been compared to heterogeneous Cu-based catalysts using NaBH₄ as a reductant. Differences in the solid-state structures of used Cu-based heterogeneous catalysts after the mentioned HDB process have been studied using the powder XRD and SEM techniques. It was found that some of the used copper-based catalysts are reusable and reasonably effective even at room temperature. Efficiency of the most promising copper-based reduction systems (Dev. alloy/NaOH and Cu-based catalysts/NaBH₄) have been successfully tested within the HDB of industrially important brominated flame retardant tetrabromobisphenol A (TBBPA). Dev. alloy/NaOH and Cu-based catalyst generated in-situ within the CuSO₄/NaBH₄ produced were recognized as the most active HDB agents for complete debromination of both BRX and TBBPA.