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.

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.

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.

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.

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.

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.

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.

Influence of Polymeric Additive on the Physical Stability and Viscoelastic Properties of Aripiprazole.

In this article, we investigated aripiprazole + Kollidon VA64 (ARP/KVA) and aripiprazole + Soluplus (ARP/SOP) amorphous solid dispersions. Thermal properties of all prepared systems have been examined by means of differential scanning calorimetry (DSC). Compositions revealing the recrystallization tendency were subsequently investigated by means of broadband dielectric spectroscopy (BDS). On the basis of dielectric data, the physically stable drug-polymer concentrations have been found. Finally, these systems have been investigated by rheology, which enables us to determine the minimal temperature required for dissolving the drug in the polymeric matrix, as well as the temperature dependence of the sample viscosity. Our investigations have shown that the amorphous form of the investigated antipsychotic drug might be effectively stabilized by both employed polymers. However, due to the better stabilization effect and the more favorable rheological properties, KVA proved to be a better polymeric excipient for extrusion of amorphous aripiprazole.

Theoretical Model for the Structural Relaxation Time in Coamorphous Drugs.

We propose a simple approach to investigate the structural relaxation time and glass transition of amorphous drugs. Amorphous materials are modeled as a set of equal sized hard spheres. The structural relaxation time over many decades in hard-sphere fluids is theoretically calculated using the elastically collective nonlinear Langevin equation theory associated with Kramer's theory. Then, new thermal mapping from a real material to an effective hard-sphere fluid provides temperature-dependent relaxation time, which can be compared to experiments. Numerical results quantitatively agree with previous experiments for pharmaceutical binary mixtures having different weight ratios. We carry out experiments to test our calculations for an ezetimibe-simvastatin-Kollidon VA64 mixture. Our approach would provide a simple but comprehensive description of glassy dynamics in amorphous composites.

Can Storage Time Improve the Physical Stability of Amorphous Pharmaceuticals with Tautomerization Ability Exposed to Compression? The Case of a Chloramphenicol Drug.

In this article we thoroughly investigated the physical stability of the amorphous form of a chloramphenicol drug. The tendency toward recrystallization of this drug has been examined (i) at nonisothermal conditions by means of a DSC technique; (ii) at isothermal conditions and temperature close to Troom by means of dielectric spectroscopy; (iii) at isothermal conditions and elevated temperatures of T = 323 K and 338 K by dielectric spectroscopy; and (iv) at conditions imitating the manufacturing procedure (i.e., elevated temperature and compression procedure). Our investigations have shown that amorphous chloramphenicol, stored at both standard storage and elevated temperature conditions, does not reveal a tendency toward recrystallization. However, compression significantly changes this behavior and destabilizes the examined compound. We found that due to chemical equilibration of the sample, the elongation of the storage time before compression might improve the physical stability of the examined pharmaceutical exposed to compression 34-times.

Changes in Physical Stability of Supercooled Etoricoxib after Compression.

In the case of formulations with amorphous active pharmaceutical ingredients the risk of pressure-induced recrystallization should be carefully considered. We reported here that supercooled etoricoxib (ETB), which was found as a relatively stable system with low crystallization tendency at atmospheric pressure, crystallized quickly after compression. The observed strong pressure-dependence of the induction period suggests that during compression the first step of crystallization that is nucleation may be accelerated. To overcome the experimental challenge associated with studies at elevated temperatures and high pressures we applied broadband dielectric spectroscopy. Dielectric measurements gave us detailed insight into crystallization kinetics of ETB at varying ( T, p) conditions corresponding to the supercooled liquid state of a drug. We found that pressure-induced recrystallization of supercooled ETB, constituting a serious impediment from a technological point of view, can be efficiently inhibited when amorphous solid dispersion containing ETB and polymer polyvinylpyrrolidone PVP (10% w/w) was prepared. Besides, we performed the comprehensive analysis of molecular dynamics of both systems at elevated pressure to address some fundamental issues related to the pressure sensitivity of their supercooled dynamics.

Co-Stabilization of Amorphous Pharmaceuticals-The Case of Nifedipine and Nimodipine.

Currently, a research hotspot in amorphous active pharmaceutical ingredients (APIs) is to understand the key factors that dominate recrystallization and to develop effective methods for stabilizing amorphous forms. Consequently, we investigated the influence of the global molecular mobility and structural properties on the crystallization tendency of three 1,4-dihydropyridine derivatives (nifedipine, nisoldipine, and nimodipine) in their supercooled states using differential scanning calorimetry (DSC) and broadband dielectric spectroscopy (BDS) techniques. The BDS is also employed to monitor the isothermal crystallization kinetics of supercooled nifedipine and nimodipine at T = 333 K under ambient pressure. As a result, we found that nimodipine exhibits much slower crystallization in comparison to nifedipine. However, nimodipine crystallizes much faster when as little as 10 MPa of pressure is exerted on sample. Such compression-induced crystallization of nimodipine as well as the inherent instability of nifedipine can be solved effectively by preparing coamorphous nifedipine/nimodipine combinations. Interestingly, the high physical stability of nifedipine/nimodipine mixtures is achieved despite the fact that the nimodipine acts as a plasticizer.

Molecular Dynamics, Recrystallization Behavior, and Water Solubility of the Amorphous Anticancer Agent Bicalutamide and Its Polyvinylpyrrolidone Mixtures.

In this paper, we investigated the molecular mobility and physical stability of amorphous bicalutamide, a poorly water-soluble drug widely used in prostate cancer treatment. Our broadband dielectric spectroscopy measurements and differential scanning calorimetry studies revealed that amorphous BIC is a moderately fragile material with a strong tendency to recrystallize from the amorphous state. However, mixing the drug with polymer polyvinylpyrrolidone results in a substantial improvement of physical stability attributed to the antiplasticizing effect governed by the polymer additive. Furthermore, IR study demonstrated the existence of specific interactions between the drug and excipient. We found out that preparation of bicalutamide-polyvinylpyrrolidone mixture in a 2-1 weight ratio completely hinder material recrystallization. Moreover, we determined the time-scale of structural relaxation in the glassy state for investigated materials. Because molecular mobility is considered an important factor governing crystallization behavior, such information was used to approximate the long-term physical stability of an amorphous drug and drug-polymer systems upon their storage at room temperature. Moreover, we found that such systems have distinctly higher water solubility and dissolution rate in comparison to the pure amorphous form, indicating the genuine formulation potential of the proposed approach.

Crystallization of supercooled fenofibrate studied at ambient and elevated pressures.

In this work, we have performed a detailed investigation on the crystallization tendency of the modeled glass-forming pharmaceutical compound, fenofibrate. To do this, we have employed four different experimental techniques allowing following of the crystallization process. This has included dielectric spectroscopy, optical microscopy, X-ray diffraction and differential scanning calorimetry. From the crystallization kinetic studies carried out at atmospheric pressure, we have determined the temperature dependence of the crystal growth rate and the overall crystallization rate. It was found that the time scale of the molecular motions responsible for α-relaxation correlates much better with the crystal growth rate than with the overall crystallization rate. Experiments carried out under varying thermodynamic conditions while remaining on the same timescale of α-relaxation have demonstrated that the crystallization tendency of the supercooled fenofibrate significantly slows down with increasing pressure. Lastly, we have also shown that the thermodynamic history of reaching crystallization conditions has a substantial impact on its overall progress.

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.

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.

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.

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.

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.