Tuning the Physical State of Aripiprazole by Mesoporous Silica.

The main purpose of our studies is to demonstrate that commercially available mesoporous silica (MS) can be used to control the physical state of aripiprazole (ARP). The investigations performed utilizing differential scanning calorimetry and broadband dielectric spectroscopy reveal that silica can play different roles depending on its concentration in the system with amorphous ARP. At low MS content, it activates recrystallization of the active pharmaceutical ingredient and supports forming the III polymorphic form of ARP. At intermediate MS content (between ca. 27 and 65 wt %), MS works as a recrystallization inhibitor of ARP. At these concentrations, the formation of III polymorphic form is no longer favorable; therefore, it is possible to use this additive to obtain ARP in either IV or X polymorphic form. At the same time, employing MS in concentrations >65 wt % amorphous form of ARP with high physical stability can be obtained. Finally, regardless of the polymorphic form it crystallizes into, each composite is characterized by the same temperature dependence of relaxation times in the supercooled and glassy states.

Hot Melt Extruded Posaconazole-Based Amorphous Solid Dispersions-The Effect of Different Types of Polymers.

Four model polymers, representing (i) amorphous homopolymers (Kollidon K30, K30), (ii) amorphous heteropolymers (Kollidon VA64, KVA), (iii) semi-crystalline homopolymers (Parteck MXP, PXP), and (iv) semi-crystalline heteropolymers (Kollicoat IR, KIR), were examined for their effectiveness in creating posaconazole-based amorphous solid dispersions (ASDs). Posaconazole (POS) is a triazole antifungal drug that has activity against Candida and Aspergillus species, belonging to class II of the biopharmaceutics classification system (BCS). This means that this active pharmaceutical ingredient (API) is characterized by solubility-limited bioavailability. Thus, one of the aims of its formulation as an ASD was to improve its aqueous solubility. Investigations were performed into how polymers affected the following characteristics: melting point depression of the API, miscibility and homogeneity with POS, improvement of the amorphous API's physical stability, melt viscosity (and associated with it, drug loading), extrudability, API content in the extrudate, long term physical stability of the amorphous POS in the binary drug-polymer system (in the form of the extrudate), solubility, and dissolution rate of hot melt extrusion (HME) systems. The obtained results led us to conclude that the physical stability of the POS-based system increases with the increasing amorphousness of the employed excipient. Copolymers, compared to homopolymers, display greater homogeneity of the investigated composition. However, the enhancement in aqueous solubility was significantly higher after utilizing the homopolymeric, compared to the copolymeric, excipients. Considering all of the investigated parameters, the most effective additive in the formation of a POS-based ASD is an amorphous homopolymer-K30.

Effect of Shear Strain on the Supercooled Itraconazole.

This article investigated the effect of shear strain on the nematic itraconazole (ITR) from both elastic and plastic deformation regions. The rheo-dielectric technique was used for this purpose. It has been demonstrated that shear strain can change the sample color, liquid crystal alignment as well as its dielectric and thermal properties. The observed modifications depend on the shear strain value. One can distinguish four regions regarding the slope of ITR stress-strain dependence and caused changes. Proper alignment changes (obtained after the shearing procedure) can additionally affect the further recrystallization of ITR to other than the initial, i.e., second polymorphic form.

Inhibition of celecoxib crystallization by mesoporous silica - Molecular dynamics studies leading to the discovery of the stabilization origin.

In this article, the effect of mesoporous silica (MS) on the physical stability and molecular dynamics of the amorphous form of Celecoxib (CEL) is investigated. It has been proven that the recrystallization process of CEL slows down with increasing the MS content. Beside the elongation of stabilization time with the increase silica content leads to an increase in the amorphous drug fraction remaining after the finished crystallization. The conducted analyses show that the observed inhibition of CEL's recrystallization is associated with the formation of a monomolecular drug layer on the silica's surface. The performed non-isothermal dielectric studies of CEL + MS systems having both fully and partially amorphous CEL shows that the biggest impact of the drug's the temperature dependences of structural relaxation time τα(T) has a crystalline fraction of the API. Silica, even in high concentration, does not modify the temperature dependence of structural relaxation of CEL.

Ternary Eutectic Ezetimibe-Simvastatin-Fenofibrate System and the Physical Stability of Its Amorphous Form.

In this study, the phase diagram of the ternary system of ezetimibe-simvastatin-fenofibrate was established. It has been proven that the ternary composition recommended for the treatment of mixed hyperlipidemia forms a eutectic system. Since eutectic mixtures are characterized by greater solubility and dissolution rate, the obtained result can explain the marvelous medical effectiveness of combined therapy. Considering that another well-known method for improving the aqueous solubility is amorphization, the ternary system with eutectic concentration was converted into an amorphous form. Thermal properties, molecular dynamics, and physical stability of the obtained amorphous system were thoroughly investigated through various experimental techniques compared to both: neat amorphous active pharmaceutical ingredients (considered separately) and other representative concentrations of ternary mixture. The obtained results open up a new way of selecting the therapeutic concentrations for combined therapies, a path that considers one additional variable: eutecticity.

High-Pressure Dielectric Studies-a Way to Experimentally Determine the Solubility of a Drug in the Polymer Matrix at Low Temperatures.

In this work, we employed broad-band dielectric spectroscopy to determine the solubility limits of nimesulide in the Kollidon VA64 matrix at ambient and elevated pressure conditions. Our studies confirmed that the solubility of the drug in the polymer matrix decreases with increasing pressure, and molecular dynamics controls the process of recrystallization of the excess of amorphous nimesulide from the supersaturated drug-polymer solution. More precisely, recrystallization initiated at a certain structural relaxation time of the sample stops when a molecular mobility different from the initial one is reached, regardless of the temperature and pressure conditions. Finally, based on the presented results, one can conclude that by transposing vertically the results obtained at elevated pressures, one can obtain the solubility limit values corresponding to low temperatures. This approach was validated by the comparison of the experimentally determined points with the theoretically obtained values based on the Flory-Huggins theory.

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.

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.

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.

Isochronal Conditions-The Key To Maintain the Given Solubility Limit, of a Small Molecule within the Polymer Matrix, at Elevated Pressure.

In this work, we proposed the method to maintain the desired level of drug's solubility within the polymer matrix by adjusting conditions to uphold the same molecular dynamics of the system (e.g., temperature for set elevated pressure or vice versa). Namely, we observed, that recrystallization of the drug from the supersaturated drug-polymer system, initiated for the same structural relaxation time of the sample (τα-1) ceases when certain, different than the initial, molecular mobility of the systems is reached (τα-2)-regardless of a given combination of temperature and pressure conditions. Based on the presented results, one can conclude that the molecular dynamics seem to control the process of recrystallization of the excess amount of solute from the supersaturated solution (e.g., small molecules dissolved within the polymer). Therefore, it appears that the elevated pressure compensates the effect of solubility enhancement caused by the elevated temperature. Such information not only is of fundamental relevance in science but also, from a much broader perspective, could be potentially very useful considering extrusion-based manufacturing methods.

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.

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.

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.

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.

Enhancement of the Physical Stability of Amorphous Sildenafil in a Binary Mixture, with either a Plasticizing or Antiplasticizing Compound.

The main purpose of this paper was to evaluate the impact of both high- and low-Tg polymer additives on the physical stability of an amorphous drug, sildenafil (SIL). The molecular mobility of neat amorphous SIL was strongly affected by the polymeric excipients used (Kollidon VA64 (KVA) and poly(vinylacetate) (PVAc)). The addition of KVA slowed down the molecular dynamics of amorphous SIL (antiplasticizing effect), however, the addition of PVAc accelerated the molecular motions of the neat drug (plasticizing effect). Therefore, in order to properly assess the effect of the polymer on the physical stability of SIL, the amorphous samples at both: isothermal (at constant temperature-353 K) and isochronal (at constant relaxation time-τα = 1.5 ms) conditions were compared. Our studies showed that KVA suppressed the recrystallization of amorphous SIL more efficiently than PVAc. KVA improved the physical stability of the amorphous drug, regardless of the chosen concentration. On the other hand, in the case of PVAc, a low polymer content (i.e., 25 wt.%) destabilized amorphous SIL, when stored at 353 K. Nevertheless, at high concentrations of this excipient (i.e., 75 wt.%), its effect on the amorphous pharmaceutical seemed to be the opposite. Therefore, above a certain concentration, the PVAc presence no longer accelerates the SIL recrystallization process, but inhibits it.

Importance of Mesoporous Silica Particle Size in the Stabilization of Amorphous Pharmaceuticals-The Case of Simvastatin.

In this paper, the role of mesoporous silica (MS) particle size in the stabilization of amorphous simvastatin (SVT) is revealed. For inhibiting recrystallization of the supercooled drug, the two MS materials (Syloid® XDP 3050 and Syloid® 244 FP) were employed. The crystallization tendency of SVT alone and in mixture with the MS materials was investigated by Differential Scanning Calorimetry (DSC) and Broadband Dielectric Spectroscopy (BDS). Neither confinement of the SVT molecules inside the MS pores nor molecular interactions between functional groups of the SVT molecules and the surface of the stabilizing excipient could explain the observed stabilization effect. The stabilization effect might be correlated with diffusion length of the SVT molecules in the MS materials that depended on the particle size. Moreover, MS materials possessing different particle sizes could offer free spaces with different sizes, which might influence crystal growth of SVT. All of these factors must be considered when mesoporous materials are used for stabilizing pharmaceutical glasses.

Pressure-assisted solvent- and catalyst-free production of well-defined poly(1-vinyl-2-pyrrolidone) for biomedical applications.

In this work, we developed a fast, highly efficient, and environmentally friendly catalytic system for classical free-radical polymerization (FRP) utilizing a high-pressure (HP) approach. The application of HP for thermally-induced, bulk FRP of 1-vinyl-2-pyrrolidone (VP) allowed to eliminate the current limitation of ambient-pressure polymerization of 'less-activated' monomer (LAM), characterized by the lack of temporal control yielding polymers of unacceptably large disperisites and poor result reproducibility. By a simple manipulation of thermodynamic conditions (p = 125-500 MPa, T = 323-333 K) and reaction composition (two-component system: monomer and low content of thermoinitiator) well-defined poly(1-vinyl-2-pyrrolidone)s (PVP) in a wide range of molecular weights and low/moderate dispersities (M n = 16.2-280.5 kg mol-1, D = 1.27-1.45) have been produced. We have found that HP can act as an 'external' controlling factor that warrants the first-order polymerization kinetics for classical FRP, something that was possible so far only for reversible deactivation radical polymerization (RDRP) systems. Importantly, our synthetic strategy adopted for VP FRP enabled us to obtain polymers of very high M n in a very short time-frame (0.5 h). It has also been confirmed that VP bulk polymerization yields polymers with significantly lower glass transition temperatures (T g) and different solubility properties in comparison to macromolecules obtained during the solvent-assisted reaction.

Molecular dynamics, viscoelastic properties and physical stability studies of a new amorphous dihydropyridine derivative with T-type calcium channel blocking activity.

One of the greatest problems of pre-clinical development of new chemical entities is their poor aqueous solubility. Herein, we focus our attention on MD20 - a novel calcium channel blocker that selectively blocks T-type calcium channel (Cav3.2) over L-type calcium channel (Cav1.2). To avoid future problems with limited solubility of this compound, an amorphous form of MD20 was obtained and thoroughly investigated by various experimental techniques. The thermal properties of both crystalline and amorphous MD20 were examined by differential scanning calorimetry and thermogravimetry. Dielectric spectroscopy studies of MD20 at T < Tg revealed that this compound possesses as many as four secondary relaxation processes. The molecular dynamics of the supercooled sample was investigated by dielectric and mechanical spectroscopies. In this paper, a comparison of the relaxation dynamics of supercooled MD20 obtained from both of these experimental techniques is presented. On the basis of the dielectric studies, the time of physical stability of the investigated material (at T = 298 K) was predicted as 150 years. Finally, we have performed experimental long-term stability tests, which showed that amorphous MD20 did not reveal any signs of re-crystallization for at least 260 days.

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.

Glass Transition Dynamics and Physical Stability of Amorphous Griseofulvin in Binary Mixtures with Low-Tg Excipients.

Amorphization of drug formulations containing active pharmaceutical ingredients (APIs) and excipients has been proven to be an effective strategy to improve their poor aqueous solubility. The excipients can also impact the physical stability of the prepared amorphous forms. Generally, researchers are more apt to select excipients that have high values of glass transition temperature (Tg) because of the antiplasticization effect of the additives on APIs. In this article, we studied the glass transition dynamics as well as crystallization behavior in binary blends composed of griseofulvin (GSF) and two low-Tg additives, octaacetylmaltose (acMAL) and polyvinyl acetate (PVAc), with a particular focus on the plasticization effect. Effectively suppressed crystallization of GSF is observed in both systems when higher excipient contents are used. Our finding aims to encourage the use of specifically developed protocols in which suitable plasticizers are used as excipients for stabilizing the amorphous state of a drug.