The context of 3D printing in the pharmaceutical sector and its significance [...]

PEGs are often used as plasticizers in filaments formulated for FDM 3D printing. Here, we present the behavior of paracetamol in solid dispersions based on PEG 4000 and 6000 via the determination of binary phase diagrams. It is shown, as was already the case with PEG 1500, that paracetamol is present, almost obviously, in its polymorphic Form II during the second heating. This metastable form remains stable in the presence of PEG, and its solubility appears to be independent of the molar mass of PEG, as is the case for Form I. This work aims to mimic the behavior of paracetamol in the presence of PEG during an extrusion process by HME then coupled with 3D printing by FDM.

This Special Issue aims to highlight the interest of characterizing the structural aspects of an API before its formulation, as much work is required between the discovery of a molecule with a therapeutic effect and its formulation [...]

Three-dimensional printing (3DP) technology in pharmaceutical areas is leading to a significant change in controlled drug delivery and pharmaceutical product development. Pharmaceutical industries and academics are becoming increasingly interested in this innovative technology due to its inherent inexpensiveness and rapid prototyping. The 3DP process could be established in the pharmaceutical industry to replace conventional large-scale manufacturing processes, particularly useful for personalizing pediatric drugs. For instance, shape, size, dosage, drug release and multi-drug combinations can be tailored according to the patient’s needs. Pediatric drug development has a significant global impact due to the growing needs for accessible age-appropriate pediatric medicines and for acceptable drug products to ensure adherence to the prescribed treatment. Three-dimensional printing offers several significant advantages for clinical pharmaceutical drug development, such as the ability to personalize medicines, speed up drug manufacturing timelines and provide on-demand drugs in hospitals and pharmacies. The aim of this article is to highlight the benefits of extrusion-based 3D printing technology. The future potential of 3DP in pharmaceuticals has been widely shown in the last few years. This article summarizes the discoveries about pediatric pharmaceutical formulations which have been developed with extrusion-based technologies.

Lung cancer is a highly vascularized tumor for which a combination between an antitumor agent, cisplatin, and an antiangiogenic molecule, fisetin, appears a promising therapeutic approach. In order to deliver both chemotherapies within the tumor, to enhance fisetin solubility and decrease cisplatin toxicity, an encapsulation of both drugs into liposomes was developed. Purification and freeze-drying protocols were optimized to improve both the encapsulation and liposome storage. The cytotoxicity of the encapsulated chemotherapies was evaluated on Lewis lung carcinoma (3LL) cell lines. The antitumor effect of the combination was evaluated in vivo on an ectopic mouse model of Lewis Lung carcinoma. The results showed that fisetin and cisplatin co-loaded liposomes were successfully prepared. Freeze-drying allowed a 30 days storage limiting the release of both drugs. The combination index between liposomal fisetin and liposomal cisplatin on 3LL cell line after 24 h of exposure showed a clear synergism: CI = 0.7 for the co loaded liposomes and CI = 0.9 for the mixture of cisplatin loaded and fisetin loaded liposomes. The co-encapsulating formulation showed in vivo efficacy against an ectopic murine model of Lewis Lung carcinoma with a probable reduction in the toxicity of cisplatin through co-encapsulation with fisetin.

This study describes the preparation, characterization, and influence of the enantiopure vs. racemic coformer on the physico-chemical properties of a pharmaceutical cocrystal. For that purpose, two new 1:1 cocrystals, namely lidocaine:dl-menthol and lidocaine:d-menthol, were prepared. The menthol racemate-based cocrystal was evaluated by means of X-ray diffraction, infrared spectroscopy, Raman, thermal analysis, and solubility experiments. The results were exhaustively compared with the first menthol-based pharmaceutical cocrystal, i.e., lidocaine:l-menthol, discovered in our group 12 years ago. Furthermore, the stable lidocaine/dl-menthol phase diagram has been screened, thoroughly evaluated, and compared to the enantiopure phase diagram. Thus, it has been proven that the racemic vs. enantiopure coformer leads to increased solubility and improved dissolution of lidocaine due to the low stable form induced by menthol molecular disorder in the lidocaine:dl-menthol cocrystal. To date, the 1:1 lidocaine:dl-menthol cocrystal is the third menthol-based pharmaceutical cocrystal, after the 1:1 lidocaine:l-menthol and the 1:2 lopinavir:l-menthol cocrystals reported in 2010 and 2022, respectively. Overall, this study shows promising potential for designing new materials with both improved characteristics and functional properties in the fields of pharmaceutical sciences and crystal engineering.

Genus Kermadecia (Proteaceae) showed interesting biological activities related to their macrocyclic derivatives (kermadecin). Nevertheless, chemistry of Kermadecia sinuata was not studied until now. Phytochemical investigation of the bark of K. sinuata led to the isolation of two previously undescribed compounds: 4-(hydroxymethyl)-3,5-diphenyldihydrofuran-2(3H)-one, kermafuranone (1) and (+)-(5S,8R,9R,10S,5’S,8’S,9’R,10’S)-onocerane-8,8’-diol (2), along with four known compounds: methyl haematommate (3), atranorine (4), β-sitosterol (5) and docosyl ferulate (6). The structures of these compounds were elucidated by HRESIMS and NMR spectroscopic data analysis, and the absolute configuration of compound 2 was determined by single-crystal X-ray diffraction analysis. This compound is the first non-symmetrical onocerane-8,8’-diol. Hypothesised biosynthesis pathway was suggested for kermafuranone (1).

Studies of the interactions between paracetamol, chosen as model active ingredient, and PEG 1500, a pharmaceutical carrier, are conducted in the solid state. Solid dispersions of PEG 1500 and paracetamol were prepared in different mass ratios. Two temperature cycles are then applied and the characterization is carried out by DSC and X-ray powder diffraction. Following this, a phase diagram is established for each cycle. On second heating, the metastable Form II of paracetamol is obtained within the PEG-based matrix. However, on the second heating, for paracetamol contents higher than 65%, Form I or form II is obtained randomly.

The dehydration of prednisolone sesquihydrate is studied and characterized by different physico-chemical analysis methods. The meticulous study of this dehydration led to the highlighting of a new solid form (form 3), metastable, never identified before. In a second step, the rehydration of anhydrous forms 1 and 2 of prednisolone is studied, in particular by Dynamic Vapor Sorption. It is then demonstrated that neither of the two forms is sensitive to humidity. By means of solid-gas equilibria, the sesquihydrate can only be obtainable from the isomorphic anhydrous form. Finally, a classification of the sesquihydrate is made, taking into account, in particular, the activation energy determined during dehydration.

Amiodarone hydrochloride, an antiarrhythmic and vasodilatory drug, was characterized from a thermodynamic point of view. Its XRPD profile was found to be in agreement with the single crystal structure previously reported. When the DSC heating rates are not high enough, the compound starts to degrade before melting. This phenomenon is emphasized during melting and also in the liquid state. The degradation products were identified by coupling TGA/FTIR experiments. When increasing the DSC scan rates, the onset of melting as well as the endothermic value of the signal increase to reach plateau values. This clearly indicates that the degradation processes have been pushed back to higher temperatures than the melting temperature. This allowed determining accurately the melting characteristics of the compound. The so-obtained melting temperature was then confirmed by Fast Scanning Calorimetry.

Self-emulsifying microbubbles, especially designed to increase the contrast of ultrasound images by the inclusion of perfluorocarbon molecules, have been studied by thermal analysis techniques. The microbubbles were made of a blend of gas (20%), surfactants (50%) and water (30%). The surfactants were mixtures of polysorbate-85, Span-80, poloxamer 188, glycerol and fluorinated surfactant (Zonyl®). Microbubbles have been characterized by means of diffusion light scattering and optical imaging. The effect of Zonyl® on encapsulation rate, as well as gas vaporization temperature and gas release temperature, has been assessed by means of Differential Scanning Calorimetry (DSC) and Thermogravimetric Analyses (TGA). Microscopy and laser granulometry techniques have been also carried out for each formulation in order to determine the number of microbubbles and their size, respectively. Moreover, stability of the emulsions has been evaluated by DSC and confronted with the results obtained from the ultrasound experiments. Average microbubble concentrations of 7.2 × 107 and 8.9 × 107 per mL were obtained for perfluorohexane and perfluoropentane based emulsions, respectively. The present study demonstrates that the amount of encapsulated perfluorocarbon increases and the gas evaporation temperature decreases with the concentration of Zonyl®. Furthermore, the best ultrasound contrast images have been obtained in vitro with the samples containing the lowest Zonyl® concentration. An explication regarding the role of Zonyl® in the emulsion/microbubbles preparations is proposed here in order to optimize self-emulsifying microbubble formulation for pharmaceutical development.

The dehydration of prednisolone sesquihydrate is studied by differential scanning calorimetry at different scan rates. This study then made it possible, using the Kissinger model, to determine a reaction order of 1.4 and an activation energy of 96.5 ± 3.3 kJ.mol -1 . Prior to this study, the crystalline structure of the study compound, determined from the powder diffraction pattern obtained at room temperature, was compared with that obtained on single crystal at -50°C.

The stable and metastable phase diagrams between the sinister and the rectus ibuprofen enantiomers were established by means of thermal analysis and X-ray powder diffraction experiments as a function of temperature. The results obtained allow proving for the first time the existence, for the stable system, of a solid solution by mixing the racemic ibuprofen with one of its enantiomers for low concentration of the enantiomer. Since the rectus ibuprofen is a non-active pharmaceutical agent which can be partially bio-converted into the sinister enantiomer, the present work offers a new approach for scalemic mixtures preparation in order to improve the benefit/risk ratio related to ibuprofen solid dosage form administration.

(1) Background: Glioblastoma (GBM) is the most frequent cerebral tumor. It almost always relapses and there is no validated treatment for second-line GBM. We proposed the coencapsulation of fisetin and cisplatin into liposomes, aiming to (i) obtain a synergistic effect by combining the anti-angiogenic effect of fisetin with the cytotoxic effect of cisplatin, and (ii) administrate fisetin, highly insoluble in water. The design of a liposomal formulation able to encapsulate, retain and deliver both drugs appeared a challenge. (2) Methods: Liposomes with increasing ratios of cholesterol/DOPC were prepared and characterized in term of size, PDI and stability. The incorporation of fisetin was explored using DSC. The antiangiogneic and cytotoxic activities of the selected formulation were assayed in vitro. (3) Results: We successfully developed an optimized liposomal formulation incorporating both drugs, composed by DOPC/cholesterol/DODA-GLY-PEG2000 at a molar ratio of 75.3/20.8/3.9, with a diameter of 173 ± 8 nm (PDI = 0.12 ± 0.01) and a fisetin and cisplatin drug loading of 1.7 ± 0.3% and 0.8 ± 0.1%, respectively, with a relative stability over time. The maximum incorporation of fisetin into the bilayer was determined at 3.2% w/w. Then, the antiangiogenic activity of fisetin was maintained after encapsulation. The formulation showed an additive effect of cisplatin and fisetin on GBM cells; (4) Conclusions: The developed co-loaded formulation was able to retain the activity of fisetin, was effective against GBM cells and is promising for further in vivo experimentations.

Crystal structure and kinetic stability of a conglomerateversusthe racemic compound ofp-synephrine.

The phase diagrams between thymol and racemic ibuprofen, on the one hand, and between l -menthol and this same ibuprofen, on the other hand, were reviewed and corrected using thermal analysis and thermodynamic approach. The Tammann diagrams constructed from thermal analysis data coupled with the thermodynamic assessments allowed to conclude that the two systems present a eutectic behavior with complete immiscibility in the solid state between the components. For l -menthol–ibuprofen system, this is in contradiction with what it was previously mentioned. Indeed, no eutectic reaction was observed on the l -menthol rich side. This result was previously observed for samples melted before being cooled. Indeed, it happens that one of the two components does not recrystallize once cooled down, preventing at this time from observing the eutectic reaction. In the present case, racemic ibuprofen does not regularly recrystallize once melted, as previously reported for other systems involving this component. In the present study, the samples were prepared and homogenized in a solid state without passing through a pre-melting. Owing to thermodynamic assessment and Gibbs energy calculations, one can conclude that repulsive interactions or attractive interactions take place in the liquid state depending on the system. A packing coefficient is introduced to assess the similarity of the molecules, allowing to discuss the possible formation of solid solution within both systems.

A complete solid-state study of the drug quinacrine dihydrochloride has highlighted the existence of two anhydrous phases and a tetrahydrate form, using water sorption experiments, thermal analysis techniques, and crystallographic studies. The tetrahydrate crystal obtained by crystal growth from a water/dioxane (80:20, v/v) solution has been characterized by singlecrystal X-ray diffraction at 123 K. This phase is a complex three-dimensional hydrogen bonding network, including four water molecules and two free chloride ions, and crystallizes in the P (1) over bar space group. Because no filiation between the two hydrates has been evidenced yet, the dehydration-rehydration mechanism has been evaluated for the present study as a destructive- reconstructive process. Two related anhydrous phases were also characterized by X-ray powder diffraction and thermal analysis.

Adrenaline, in its enantiomeric form l-, is the drug of choice for the treatment of cardiac arrest or certain serious shock conditions. However, although its crystal structure is known, there are no thermodynamic data on this molecule. Regarding the racemic form of this molecule, the latter has never been characterized either from a thermodynamic or crystallographic point of view. The melting characteristics, temperature and enthalpy of both the enantiomer and the racemate of adrenaline were determined using the plateau values obtained at high DSC scan rates. The refinement of the RX diffraction pattern of the racemate revealed that this equimolar mixture was a conglomerate with partial solid solutions. This conclusion was supported by the phase diagram between the two enantiomers established from the l-enantiomer and the racemate where the results presented in this paper show that a lower solid-state miscibility exists between the two enantiomers. The equimolar compound is therefore part of the very limited series of conglomerate with partial miscibility.