Improving the Solubility, Stability, and Bioavailability of Albendazole through Synthetic Salts.

Albendazole (ABZ) is a highly effective yet poorly water-soluble antiparasitic drug known to form salts (ABZ-FMA, ABZ-DTA, and ABZ-HCl) with fumaric acid (FMA), D-tartaric acid (DTA), and hydrochloric acid (HCl). This research utilized a range of analytical techniques, including Fourier transform infrared spectroscopy (FT-IR), nuclear magnetic resonance hydrogen spectroscopy (1H NMR), powder X-ray diffraction (PXRD), dynamic vapor sorption (DVS), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and scanning electron microscopy (SEM), to validate and characterize the solid-state properties of these drug salts. This study also assessed the solubility and intrinsic dissolution rate (IDR) of these salts under different pH conditions compared to the active pharmaceutical ingredient (API) and conducted stability studies. Moreover, the in vivo pharmacokinetic performance of ABZ salt was evaluated. The results of this study reveal that the new solid form of ABZ is primarily associated with amino acid esters and benzimidazole groups, forming intermolecular interactions. All three ABZ salts significantly improved the solubility and dissolution rate of ABZ, with ABZ-HCl demonstrating the optimal performance. Importantly, the drug salt exhibited robust physical stability when exposed to adverse conditions, including strong light irradiation (4500 ± 500 lux), high humidity (92.5 ± 5% relative humidity), elevated temperatures (50 ± 2 °C), and accelerated test conditions (40 °C/75 ± 5% relative humidity). Lastly, the in vivo pharmacokinetic analysis demonstrated that ABZ salt led to a substantial increase in AUC(0-24) and Cmax compared to ABZ. This elevation in solubility in aqueous solvents signifies that ABZ salt exhibits characteristics that can enhance oral bioavailability and pharmacokinetics. These findings provide potential solutions for the development of more effective and innovative drug formulations.

Lessons to Learn for 3D Printing of Drug Products by Semisolid Extrusion (SSE).

Semisolid extrusion (SSE) 3D printing (3DP) technology is emerging due to its simplicity and potential for on-site manufacturing of personalized drug products with tailored functionality (dose, release profile), as well as recognizability (size, shape, color). However, even a minor change in the composition of the ink (the feedstock material) and the printing process parameters can largely influence the outcome of printing. This paper summarizes the recent SSE 3DP studies, where the important factors affecting the quality of the printed drug products are discussed. Further challenges are showcased by introducing a case study focusing on the design of oral theophylline immediate-release drug products. The identified crucial factors, such as the printing hardware and connected software, printing parameters, and composition of the ink are discussed. Especially, the rheological properties of the ink during the printing process, together with solidification, mechanical properties, and morphology studies of already printed products are deliberated to gain more understanding of the printability of drug products by SSE. This work aims to provide an overview of design aspects related to SSE-based fabrication of personalized drug products.

Formulation factors affecting foam properties during vacuum foam-drying.

This paper explores how vacuum foam-drying of a protein is influenced by formulation parameters by investigating the foam structure, physical properties of the foam, and the stability of the protein. Recombinant human bile salt-stimulated lipase was used as a model of a protein drug. The stability of the lipase was evaluated through activity measurements. Two disaccharides (sucrose and trehalose), strongly tending to an amorphous form, were used as matrix formers, and the physical properties were assessed through residual water content, glass transition temperature, and crystalline state. Moreover, some formulations included surfactants with different sizes and structures of the head group. The alkyl chain length was kept constant to only investigate the impact of the surfactant head group, in the presence of the lipase, on the foamability and surface coverage of the lipase. The study demonstrated that the lipase allowed for a dry, solid foam with a foam overrun of up to 2600 %. The wall thickness of the dry, solid foam was estimated to be 20-50 µm. Clear differences between sucrose and trehalose as matrix former were identified. The lipase showed no tendency to lose activity because of the drying and rehydration, despite a proportion of the lipase covering the surfaces of the dry material.

Solid-state analysis for pharmaceuticals: Pathways to feasible and meaningful analysis.

The solid state of matter is the preferred starting point for designing a pharmaceutical product. This is driven by both patient preferences and the relative ease of supplying a solid pharmaceutical product with desired quality and performance. Solid form diversity is increasingly prevalent as a crucial element in designing these products, which underpins the importance of solid-state analytical methods. This paper provides a critical analysis of challenges related to solid-state analytics, as well as considerations and suggestions for feasible and meaningful pharmaceutical analysis.

Impact of Solid-State Properties on the Aerosolization Performance of Spray-Dried Curcumin Powders.

Amorphous and crystalline active pharmaceutical ingredients (APIs) are both widely studied for pulmonary delivery. The past research mainly studied the impact of solid-state properties on pharmacokinetic attributes; however, the influence of solid-state properties on aerosolization performance was much less studied. This study aimed to investigate the different aerosolization performances of amorphous and crystalline curcumin (Cur) stabilized with L-leucine. Cur was spray-dried with different concentrations of L-leucine (0, 5, 20, 35, and 50%, w/w) as both solution-based and suspension-based formulations to acquire amorphous and crystalline Cur powders. The physicochemical properties of the spray-dried powders, including particle size, morphology, and solid-state characteristics, were studied. The aerosolization performance as well as dissolution properties were evaluated. It was found that 35% (w/w) L-leucine or above led to the formation of amorphous Cur in the spray-dried powders, and the amorphous Cur powders exhibited higher FPF (70.8%, with 50% L-leucine, w/w) than the crystalline Cur formulations with an FPF at 56.3% (with 50% L-leucine, w/w). In conclusion, with a high concentration of L-leucine (35% or above) in the formulations, amorphous Cur would exhibit higher aerosolization efficiency than crystalline Cur. However, with a low concentration of L-leucine (20% or less) in the formulations, crystalline Cur would be preferred for more enhanced consideration.

Berberine-loaded liposomes for oral delivery: Preparation, physicochemical characterization and in-vivo evaluation in an endogenous hyperlipidemic animal model.

Berberine (BBR) is a plant-origin quaternary isoquinoline alkaloid presenting exogenous cholesterol lowering and anti-hyperlipidemia therapeutic effects. The aim of this study was to design and generate BBR-loaded proliposomes (PLs) as solid templates for high-dose liposomes and consequently, to enhance the oral bioavailability and therapeutic effect of BBR. An air-suspension coating (layering) method was used for generating BBR-loaded PLs. The size, distribution size, morphology, and entrapment efficiency (EE) of the final reconstituted liposomes were assessed. The oral bioavailability and endogenous cholesterol lowering effects of BBR loaded in liposomes were investigated in rats and mice, respectively. The BBR-loaded PLs showed a smooth BBR-embedded film around micron-scale carrier particles (mannitol). The reconstituted BBR-loaded liposomes had a nano-scale average size (116.6 ± 5.8 nm), narrow size distribution (polydispersity index, PDI 0.269 ± 0.038), and high EE (87.8 ± 1.0%). The oral bioavailability of reconstituted BBR-loaded liposomes at a dose of 100 mg/kg in rats was increased even 628% compared to that obtained with pure BBR (according to 90% confidence interval). The BBR-loaded liposomes at the daily oral dose 100 mg/kg in P-407- reduced total cholesterol, triglycerides and low-density lipoprotein cholesterol (LDL-C) in hyperlipidemic mice by 15.8%, 38.2%, and 57.0%, respectively.

Topologically directed confocal Raman imaging (TD-CRI): Advanced Raman imaging towards compositional and micromeritic profiling of a commercial tablet components.

Particle size distribution (PSD), spatial location and particle cluster size of ingredients, polymorphism, compositional distribution of a pharmaceutical product are few of the most important attributes in establishing the drug release-controlling microstructural and solid state properties that would be used to (re)design or reproduce similar products. There are numerous solid-state techniques available for PSD analysis. Laser diffraction (LD) is mostly used to study PSD of raw materials. However, a constraint of LD is the interference between the active pharmaceutical ingredients (API) and excipients, where it is very challenging to measure API size in a tablet. X-ray powder diffraction (XRPD) is widely employed in establishing the polymorphism of API and excipients. This research examined a commercial osmotic tablet in terms of extracting solid state properties of API and functional excipient by Raman Imaging. Establishing repeatability, reproducibility, and sample representativeness when the samples are non-uniform and inhomogeneous necessitates multiple measurements. In such scenarios, when employing imaging-based techniques, it can be time-consuming and tedious. Advanced statistical methodologies are used to overcome these disadvantages and expedite the characterization process. Overall, this study demonstrates that Raman imaging can be employed as a non-invasive and effective offline method for assessing the solid-state characteristics of API and functional excipients in complex dosage forms like osmotic tablets.

Applications of Supercritical Anti-Solvent Process in Preparation of Solid Multicomponent Systems.

Solid multicomponent systems (SMS) are gaining an increasingly important role in the pharmaceutical industry, to improve the physicochemical properties of active pharmaceutical ingredients (APIs). In recent years, various processes have been employed for SMS manufacturing. Control of the particle solid-state properties, such as size, morphology, and crystal form is required to optimize the SMS formulation. By utilizing the unique and tunable properties of supercritical fluids, supercritical anti-solvent (SAS) process holds great promise for the manipulation of the solid-state properties of APIs. The SAS techniques have been developed from batch to continuous mode. Their applications in SMS preparation are summarized in this review. Many pharmaceutical co-crystals and solid dispersions have been successfully produced via the SAS process, where the solid-state properties of APIs can be well designed by controlling the operating parameters. The underlying mechanisms on the manipulation of solid-state properties are discussed, with the help of on-line monitoring and computational techniques. With continuous researching, SAS process will give a large contribution to the scalable and continuous manufacturing of desired SMS in the near future.

Preformulation Study of Electrospun Haemanthamine-Loaded Amphiphilic Nanofibers Intended for a Solid Template for Self-Assembled Liposomes.

Haemanthamine (HAE) has been proven as a potential anticancer agent. However, the therapeutic use of this plant-origin alkaloid to date is limited due to the chemical instability and poorly water-soluble characteristics of the agent. To overcome these challenges, we developed novel amphiphilic electrospun nanofibers (NFs) loaded with HAE, phosphatidylcholine (PC) and polyvinylpyrrolidone (PVP), and intended for a stabilizing platform (template) of self-assembled liposomes of the active agent. The NFs were fabricated with a solvent-based electrospinning method. The chemical structure of HAE and the geometric properties, molecular interactions and physical solid-state properties of the NFs were investigated using nuclear magnetic resonance (NMR) spectroscopy, scanning electron microscopy (SEM), photon correlation spectroscopy (PCS), Fourier transform infrared (FTIR) spectroscopy, X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC), respectively. An in-house dialysis-based dissolution method was used to investigate the drug release in vitro. The HAE-loaded fibers showed a nanoscale size ranging from 197 nm to 534 nm. The liposomes with a diameter between 63 nm and 401 nm were spontaneously formed as the NFs were exposed to water. HAE dispersed inside liposomes showed a tri-modal dissolution behavior. In conclusion, the present amphiphilic NFs loaded with HAE are an alternative approach for the formulation of a liposomal drug delivery system and stabilization of the liposomes of the present alkaloid.

Prediction of Phase Behavior of Spray-Dried Amorphous Solid Dispersions: Assessment of Thermodynamic Models, Standard Screening Methods and a Novel Atomization Screening Device with Regard to Prediction Accuracy.

The evaluation of drug-polymer miscibility in the early phase of drug development is essential to ensure successful amorphous solid dispersion (ASD) manufacturing. This work investigates the comparison of thermodynamic models, conventional experimental screening methods (solvent casting, quench cooling), and a novel atomization screening device based on their ability to predict drug-polymer miscibility, solid state properties (Tg value and width), and adequate polymer selection during the development of spray-dried amorphous solid dispersions (SDASDs). Binary ASDs of four drugs and seven polymers were produced at 20:80, 40:60, 60:40, and 80:20 (w/w). Samples were systematically analyzed using modulated differential scanning calorimetry (mDSC) and X-ray powder diffraction (XRPD). Principal component analysis (PCA) was used to qualitatively assess the predictability of screening methods with regards to SDASD development. Poor correlation was found between theoretical models and experimentally-obtained results. Additionally, the limited ability of usual screening methods to predict the miscibility of SDASDs did not guarantee the appropriate selection of lead excipient for the manufacturing of robust SDASDs. Contrary to standard approaches, our novel screening device allowed the selection of optimal polymer and drug loading and established insight into the final properties and performance of SDASDs at an early stage, therefore enabling the optimization of the scaled-up late-stage development.

Pharmaceutical Cocrystals: New Solid Phase Modification Approaches for the Formulation of APIs.

Cocrystals can be used as an alternative approach based on crystal engineering to enhance specific physicochemical and biopharmaceutical properties of active pharmaceutical ingredients (APIs) when the approaches to salt or polymorph formation do not meet the expected targets. In this article, an overview of pharmaceutical cocrystals will be presented, with an emphasis on the intermolecular interactions in cocrystals and the methods for their preparation. Furthermore, cocrystals of direct pharmaceutical interest, along with their in vitro properties and available in vivo data and characterization techniques are discussed, highlighting the potential of cocrystals as an attractive route for drug development.

Very fast dissolving acid carboxymethylcellulose-rifampicin matrix: Development and solid-state characterization.

One of the main obstacles to the successful treatment of tuberculosis is the poor and variable oral bioavailability of rifampicin (RIF), which is mainly due to its low hydrophilicity and dissolution rate. The aim of this work was to obtain a hydrophilic new material that allows a very fast dissolution rate of RIF and therefore is potentially useful in the development of oral solid dosage forms. The acid form of carboxymethylcellulose (CMC) was co-processed with RIF by solvent impregnation to obtain CMC-RIF powder, which was characterized by polarized optical microscopy, powder x-ray diffraction, DSC-TGA, hot stage microscopy, 13C and 15N solid-state NMR and FT-IR spectroscopy. In addition, the CMC-RIF matrices were subjected to water uptake and dissolution studies to assess hydrophilicity and release kinetics. CMC-RIF is a crystalline solid dispersion. Solid-state characterization indicated that no ionic interaction occurred between the components, but RIF crystallized as a zwitterion over the surface of CMC, which drastically increased the hydrophilicity of the solid. The CMC-RIF matrices significantly improved the water uptake of RIF and disintegrated in a very short period immediately releasing RIF. As CMC improves the hydrophilicity and delivery properties of RIF, CMC-RIF is very useful in the design of oral solid dosage forms with very fast dissolution of RIF, either alone or in combination with other antitubercular drugs.

In-depth investigation on physicochemical and thermal properties of magnesium (II) gluconate using spectroscopic and thermoanalytical techniques.

Magnesium gluconate is a classical organometallic pharmaceutical compound used for the prevention and treatment of hypomagnesemia as a source of magnesium ion. The present research described the in-depth study on solid state properties viz. physicochemical and thermal properties of magnesium gluconate using sophisticated analytical techniques like PXRD, PSA, FT-IR, UV-Vis spectroscopy, TGA/DTG, and DSC. Magnesium gluconate was found to be crystalline in nature along with the crystallite size ranging from 14.10 to 47.35 nm. The particle size distribution was at d(0.1)=6.552 µm, d(0.5)=38.299 µm, d(0.9)=173.712 µm and D(4,3)=67.122 µm along with the specific surface area of 0.372 m2/g. The wavelength for the maximum absorbance was at 198.0 nm. Magnesium gluconate exhibited 88.51% weight loss with three stages of thermal degradation process up to 895.18 °C from room temperature. The TGA/DTG thermograms of the analyte indicated that magnesium gluconate was thermally stable up to around 165 °C. Consequently, the melting temperature of magnesium gluconate was found to be 169.90 °C along with the enthalpy of fusion of 308.7 J/g. Thus, the authors conclude that the achieved results from this study are very useful in pharmaceutical and nutraceutical industries for the identification, characterization and qualitative analysis of magnesium gluconate for preformulation studies and also for developing magnesium gluconate based novel formulation.

Towards J/mol Accuracy for the Cohesive Energy of Solid Argon.

The cohesive energies of argon in its cubic and hexagonal closed packed structures are computed with an unprecedented accuracy of about 5 J mol(-1) (corresponding to 0.05 % of the total cohesive energy). The same relative accuracy with respect to experimental data is also found for the face-centered cubic lattice constant deviating by ca. 0.003 Å. This level of accuracy was enabled by using high-level theoretical, wave-function-based methods within a many-body decomposition of the interaction energy. Static contributions of two-, three-, and four-body fragments of the crystal are all individually converged to sub-J mol(-1) accuracy and complemented by harmonic and anharmonic vibrational corrections. Computational chemistry is thus achieving or even surpassing experimental accuracy for the solid-state rare gases.

Spray-dried amorphous isomalt and melibiose, two potential protein-stabilizing excipients.

The possibility of producing amorphous isomalt and melibiose by spray drying was studied. The impact of process parameters on yield and solid-state stability was compared to sucrose and trehalose. All powders remained amorphous during 2-3 weeks. Processing was challenging due to powder stickiness. Low-temperature and low-humidity drying processes generally performed best. Most isomalt and sucrose powder was retrieved when using 60°C inlet temperature, 800L/h atomizing rate, 1.4ml/min feed rate, 15% concentration and 100% aspirator rate, giving 42-43°C outlet temperature. Isomalt was the most problematic, because it had the lowest Tg and became sticky very easily, therefore process parameters needed to be precisely balanced. There was more freedom in designing processes for melibiose but best yields were obtained with low-temperature (50°C inlet temperature, 800L/h atomizing rate, 4.9ml/min feed rate, 10% concentration and 100% aspirator, 39°C outlet temperature). Trehalose was different in that higher temperatures resulted in better yields. Yet, trehalose generally contained the highest moisture contents. The possibility to produce amorphous isomalt and melibiose at low-temperature process conditions makes them promising considering spray drying applications for heat-sensitive proteins. Melibiose is a better candidate than isomalt because of easier processability and superior solid-state stability.

Novel ether-linkages containing aliphatic copolyesters of poly(butylene 1,4-cyclohexanedicarboxylate) as promising candidates for biomedical applications.

A new class of biodegradable and biocompatible poly(butylene 1,4-cyclohexanedicarboxylate) based random copolymers are proposed for biomedical applications. The introduction of ether-oxygen containing BDG sequences along the PBCE macromolecular chain is expected to remarkably improve chain flexibility and surface hydrophilicity due to the presence of highly electronegative oxygen atoms. P(BCExBDGy) copolymers were synthesized by polycondensation. The homopolymer PBCE and three copolymers, namely (P(BCE70BDG30), P(BCE55BDG45) and P(BCE40BDG60)) were characterized from the molecular, thermal, structural and mechanical point of view. Hydrolytic degradation studies in the presence and absence of hog-pancreas lipase were performed under physiological conditions. To evaluate the diffusion profile of small molecules through the polymer matrix, the release behaviour of fluorescein isothiocyanate (FITC) was investigated. For biocompatibility studies, cell adhesion and proliferation of murine fibroblast (L929) and endocrine pancreatic (INS-1) cells were performed on each polymeric film. Results showed that solid-state properties can be tailored by simply varying copolymers' composition. Crystallinity degree and hydrophobicity significantly decreased with the increase of BDG co-unit mol%. Moreover, mechanical properties and biodegradability of PBCE, both depending on crystallinity degree, were remarkably improved: P(BCE40BDG60) showed an elastomeric behaviour with εb over 600% and, as regard to biodegradability, after 98days it lost over 60% of its initial weight if incubated in the presence of the pancreatic lipase. Lastly, the newly developed biomaterials resulted not cytotoxic with both types of cells and could be properly tailored for biomedical applications varying the content of BDG co-unit mol%.

Effect of Moisture on Powder Flow Properties of Theophylline.

Powder flow is influenced by environmental factors, such as moisture and static electricity, as well as powder related factors, such as morphology, size, size distribution, density, and surface area. Pharmaceutical solids may be exposed to water during storage in an atmosphere containing water vapor, or in a dosage form consisting of materials (e.g., excipients) that contain water and are capable of transferring in to other ingredients. The effect of moisture on powder flowability depends on the amount of water and its distribution. The aim of this work was to examine the effect of humidity on the flow properties of theophylline using information derived from solid-state analysis of the systems investigated.