High-Energy Ball Milling as Green Process To Vitrify Tadalafil and Improve Bioavailability.

In this study, the suitability of high-energy ball milling was investigated with the aim to vitrify tadalafil (TD) and improve its bioavailability. To achieve this goal, pure TD as well as binary mixtures composed of the drug and Soluplus (SL) were coprocessed by high-energy ball milling. Modulated differential scanning calorimetry (MDSC) and X-ray powder diffraction (XRD) demonstrated that after such coprocessing, the crystalline form of TD was transformed into an amorphous form. The presence of a single glass transition (Tg) for all the comilled formulations indicated that TD was dispersed into SL at the molecular level, forming amorphous molecular alloys, regardless of the drug concentration. The high values of Tg determined for amorphous formulations, ranging from 70 to 147 °C, foreshow their high stability during storage at room temperature, which was verified by XRD and MDSC studies. The stabilizing effect of SL on the amorphous form of TD in comilled formulations was confirmed. Dissolution tests showed immediate drug release with sustained supersaturation in either simulated gastric fluid of pH 1.2 or in phosphate buffer of pH 7.2. The beneficial effect of both amorphization and coamorphization on the bioavailability of TD was found. In comparison to aqueous suspension, the relative bioavailability of TD was only 11% for its crystalline form and 53% for the crystalline physical mixture, whereas the bioavailability of milled amorphous TD and the comilled solid dispersion was 128% and 289%, respectively. Thus, the results provide evidence that not only the presence of polymeric surfactant but also the vitrification of TD is necessary to improve bioavailability.

Accelerated ketoprofen release from spray-dried polymeric particles: importance of phase transitions and excipient distribution.

HPMC-, PVPVA- and PVP-based microparticles loaded with 30% ketoprofen were prepared by spray drying suspensions or solutions in various water:ethanol blends. The inlet temperature, drying gas and feed flow rates were varied. The resulting differences in the ketoprofen release rates in 0.1 M HCl could be explained based on X-ray diffraction, mDSC, SEM and particle size analysis. Importantly, long term stable drug release could be provided, being much faster than: (i) drug release from a commercial reference product, (ii) the respective physical drug:polymer mixtures, as well as (iii) the dissolution of ketoprofen powder as received. In addition, highly supersaturated release media were obtained, which did not show any sign for re-crystallization during the observation period. Surprisingly, spraying suspensions resulted in larger microparticles exhibiting faster drug release compared to spraying solutions, which resulted in smaller particles exhibiting slower drug release. These effects could be explained based on the physico-chemical characteristics of the systems.

A new protocol to determine the solubility of drugs into polymer matrixes.

In this paper we present a new protocol to determine faster the solubility of drugs into polymer matrixes. The originality of the method lies in the fact that the equilibrium saturated states are reached by demixing of supersaturated amorphous solid solutions and not by dissolution of crystalline drug into the amorphous polymer matrix as for usual methods. The equilibrium saturated states are thus much faster to reach due to the extra molecular mobility resulting from the strong plasticizing effect associated with the supersaturation conditions. The method is validated using the indomethacin/polyvinylpyrrolidone mixture whose solubility diagram was previously determined by usual techniques. The supersaturated states have been directly obtained in the solid state by comilling, and the investigations have been performed by differential scanning calorimetry and powder X-ray diffraction.

Solid-solid transformation in racemic Ibuprofen.

PURPOSE: To clarify the polymorphism of racemic Ibuprofen and to determine the kinetic of the phase transformation that follows crystallisation of phase II. METHODS: Differential Scanning Calorimetry (DSC), X-ray powder diffraction and Hot Stage Microscopy are complementarily used to perform a kinetic investigation of the particular temperature range where competition between the occurrence of phases I and II is suspected. RESULTS: Experiments performed with the three techniques reveal that at 273 K the crystallisation to phase II is then followed by a solid-solid transition towards phase I. This transformation is exothermic (conversion enthalpy of 8.0 ± 0.5 kJ/mol), which proves that the two phases form a monotropic set. The kinetics of conversion deduced from X-Ray experiments follows a Johnson-Mehl-Avrami equation and the Hot Stage Microscopy allows us to establish that the transformation proceeds by the growth of some nuclei of phase I probably formed at lower temperature. CONCLUSIONS: These results allow us to precise the stability pattern of racemic Ibuprofen and to establish the kinetic conditions of appearance and interconversion of the different phases. Therefore such real time resolved investigations would help if applied in the screening of polymorphs when competitive crystallisations occur.

Ab initio structure determination of phase II of racemic ibuprofen by X-ray powder diffraction.

Annealing of the quenched ibuprofen at 258 K yielded a new crystalline form, called phase II. Powder X-ray diffraction patterns of this phase II were recorded with a laboratory diffractometer equipped with an INEL G3000 goniometer and a curved position-sensitive detector CPS120. The starting structural model was found by a Monte-Carlo simulated annealing method. The final structure was obtained through Rietveld refinements with rigid-body constraints for the phenyl group and soft restraints on the other interatomic bond lengths and bond angles. The cell volume is 5% larger than that of the conventional phase I at 258 K. It is also shown that the orientation of the propanoic acid group is drastically changed with respect to phase I, leading to strong modifications of the orientation of the O-H...O hydrogen bonds with respect to the chains of dimers. These structural considerations could explain the metastable character of this phase II.

Thermostabilization mechanism of bovine serum albumin by trehalose.

Thermal denaturation of bovine serum albumin (BSA) is analyzed from differential scanning calorimetry (DSC) and Raman spectroscopy investigations. DSC curves exhibit a marked dependence on protein concentration. BSA thermal denaturation becomes broader and bimodal, and the temperature of denaturation increases with increasing protein concentration. Raman scattering investigations simultaneously carried out in the low-frequency range (10-350 cm(-1)) and in the amide I band region (1500-1800 cm(-1)) indicate that the denaturation process is described as a biphasic process independent of protein concentration. The dependence of the protein stability upon the protein concentration can be interpreted from the coupling of protein and solvent dynamics. The confrontation of previous results obtained from Raman investigations on lysozyme (LYS) and the present study of BSA brings out significant information on protein dynamics and the coupling of protein and hydration-water dynamics in relation with the solvent accessible surface area. Contrary to LYS, the modification of the dynamics of hydration water by the protein is clearly observed on BSA. The influence of trehalose on the protein dynamics was analyzed. We found that trehalose reduces the dynamic fluctuations of polar side chains at the protein-solvent interface. The mechanism of thermostabilization by trehalose is related to the reduction of the exposure of hydrophobic groups of BSA to the water molecules, and to a strengthening of intermolecular O-H interactions in the hydrogen-bond network of water, leading to the stabilization of the tertiary structure.

Comparison of physical and inhalation properties of spray-dried and micronized terbutaline sulphate.

Terbutaline sulphate particles, for use in dry powder inhaler formulations, were prepared by spray-drying, using a Büchi 190 mini spray dryer. Spray-drying conditions were chosen to allow the production of spray-dried terbutaline sulphate with a size similar to micronized terbutaline sulphate, that is to say about 2.9 microm of volume mean diameter. The physical properties and in vitro inhalation behaviour of micronized and spray-dried terbutaline sulphate were compared. X-ray diffraction, DSC, SEM and laser size analysis were investigated. Spray-dying produced spherically shaped particles with amorphous structure. After blending with different lactoses, adhesion and aerodynamic properties were investigated. Evaluation of adhesion was carried out with a mechanical sieve and an Alpine air-jet sieve. The adhesion of terbutaline sulphate on the lactoses tested was lower in the case of the spray-dried drug. Aerodynamic evaluation of fine particle dose and emitted dose was conducted using a twin stage impactor. The emitted doses and the fine particle doses were higher with the spray-dried terbutaline sulphate. The Alpine air-jet sieve assays showed that there was a correlation between drug separation from a carrier by sieving and that obtained from longer in vitro deposition studies. There was a linear relationship between the adhesion characteristics and the fine particle dose.

Scaling laws and size effects for amorphous crystallization kinetics: Constraints imposed by nucleation and growth specificities.

In the present paper we review different aspects of the crystallization of amorphous compounds in relation to specificities of the nucleation and growth rates. Its main purpose is: i) to underline the interest of a scaling analysis of recrystallization kinetics to identify similarities or disparities of experimental kinetic regimes. ii) to highlight the intrinsic link between the nucleation rate and growth rate with a temperature dependent characteristic transformation time τ(T), and a characteristic size ξ(T). The consequences on the influence of the sample size on kinetics of crystallization is considered. The significance of size effect and confinement for amorphous stabilization in the pharmaceutical sciences is discussed.

Structure determination of phase II of the antifungal drug griseofulvin by powder X-ray diffraction.

Two new crystalline polymorphs of the widely used antifungal drug griseofulvin (phases II and III), which originate from the crystallization of the melt, have been detected recently. The crystal structure of phase II of griseofulvin {systematic name: (2S,6'R)-7-chloro-2',4,6-trimethoxy-6'-methyl-3H,4'H-spiro[1-benzofuran-2,1'-cyclohex-2-ene]-3,4'-dione}, C17H17ClO6, has been solved by powder X-ray diffraction (PXRD). The PXRD pattern of this new phase was recorded at room temperature using synchrotron radiation. The starting structural model was generated by a Monte Carlo simulated annealing method. The final structure was obtained through Rietveld refinement with soft restraints for interatomic bond lengths and angles, except for the aromatic ring, where a rigid-body constraint was applied. The symmetry is orthorhombic (space group P212121) and the asymmetric unit contains two molecules.

Crystalline Polymorphism Emerging From a Milling-Induced Amorphous Form: The Case of Chlorhexidine Dihydrochloride.

In this paper, solid-state amorphization induced by mechanical milling is shown to be a useful tool to explore the polymorphism of drugs and their mechanism of devitrification. We show in particular how the recrystallization of amorphous chlorhexidine dihydrochloride obtained by milling reveals a complex polymorphism that involves several polymorphic forms. Two new crystalline forms are identified, one of them appearing as a highly disordered precursor state which however clearly differs from the amorphous one. Several interpretations are here proposed to describe the puzzling nature of this phase. In addition, the possibility to amorphize chlorhexidine dihydrochloride by milling allowed to determine the main physical characters of the amorphous state which cannot be obtained through the usual thermal quench of the liquid because of a strong chemical degradation occurring on melting.

Dielectric study of the slow motional processes in the polymorphic States of anhydrous caffeine.

Molecular mobility in crystalline anhydrous caffeine was studied by the dielectric technique of thermally stimulated depolarization currents (TSDC). Two relaxational processes were found, one appearing at approximately -10 degrees C that is ascribed to a reorientational glass transition, and a higher temperature one that probably arises from local molecular motions that are precursors of diffusion and sublimation. The experimental results suggest that both crystalline phases II and I of caffeine, that have distinct crystal structures, are solid rotator phases. Furthermore, this dynamic reorientational disorder shows a reorientational glass transition at the same temperature in phase II and in metastable phase I.

High energy ball milling and supercritical carbon dioxide impregnation as co-processing methods to improve dissolution of tadalafil.

Tadalafil (TD) is a crystalline drug of a high melting point (Tm=299°C) and limited solubility in water (<5µg/mL). These properties may result in reduced and variable bioavailability after oral administration. Since the melting of TD is followed by its decomposition, the drug processing at high temperatures is limited. The aim of the research is, therefore, to improve the dissolution of TD by its co-processing with the hydrophilic polymer Soluplus® (SL) at temperatures below 40°C. In this study, two methods, i.e. high energy ball-milling and supercritical carbon dioxide impregnation (scCO2) are compared, with the aim to predict their suitability for the vitrification of TD. The influence of the amount of SL and the kind of co-processing method on TD thermal properties is analyzed. The results show that only the high energy ball milling process makes it possible to obtain a completely amorphous form of TD, with the characteristic X-ray 'halo' pattern. The intensity of the Bragg peaks diminishes for all the formulations treated with scCO2, but these samples remain crystalline. The MDSC results show that high energy ball milling is capable of forcing the mixing of TD and SL at a molecular level, providing a homogeneous amorphous solid solution. The glass transition temperatures (Tg), determined for the co-milled formulations, range from 79°C to 139°C and they are higher than Tg of pure SL (ca. 70°C) and lower than Tg of pure TD (ca. 149°C). In contrast to the co-milled formulations which are in the form of powder, all the formulations after scCO2 impregnation form a hard residue, sticking to the reaction vessel, which needs to be ground before analysis or further processing. Finally, the dissolution studies show that not only has SL a beneficial effect on the amount of TD dissolved, but also both co-processing methods make the dissolution enhancement of TD possible. After co-processing by scCO2, the amount of TD dissolved increases with the decreasing amount of SL, whereas in the case of the co-milled formulations, the higher the amount of SL in the glassy solution is, the higher the amount of TD dissolved.

Crystalline mesophases: Structure, mobility, and pharmaceutical properties.

Crystalline mesophases, which are commonly classified according to their translational, orientational, and conformational order as liquid crystals, plastic crystals, and conformationally disordered crystals, represent a common state of condensed matter. As an intermediate state between crystalline and amorphous materials, crystalline mesophases resemble amorphous materials in relation to their molecular mobility, with the glass transition being their common property, and at the same time possessing a certain degree of translational periodicity (with the exception of nematic phase), with corresponding narrow peaks in X-ray diffraction patterns. For example, plastic crystals, which can be formed both by near-spherical molecules and molecules of lower symmetry, such as planar or chain molecules, can have both extremely sharp X-ray diffraction lines and exhibit glass transition. Fundamentals of structural arrangements in mesophases are compared with several types of disorder in crystalline materials, as well as with short-range ordering in amorphous solids. Main features of the molecular mobility in crystalline mesophases are found to be generally similar to amorphous materials, although some important differences do exist, depending on a particular type of mobility modes involved in relaxation processes. In several case studies reviewed, chemical stability appears to follow the extent of disorder, with the stability of crystalline mesophase found to be intermediate between amorphous (least stable) and crystalline (most stable) materials. Finally, detection of crystalline mesophases during manufacturing of two different types of dosage forms is discussed.

Determination of the glass transition temperature of cyclodextrin polymers.

The aim of this work was to determine the main physical characteristics of ß-cyclodextrin polymers, well known for improving complexation capacities and providing enhanced and sustained release of a large panel of drugs. Two polymers were investigated: a polymer of ß-cyclodextrin (polyß-CD) and a polymer of partially methylated (DS=0.57) ß-cyclodextrin (polyMe-ß-CD). The physical characterizations were performed by powder X-ray diffraction and differential scanning calorimetry. The results indicate that these polymers are amorphous and that their glass transition is located above the thermal degradation point of the materials preventing their direct observation and thus their full characterization. We could however estimate the virtual glass transition temperatures by mixing the polymers with different plasticizers (trehalose and mannitol) which decreases Tg sufficiently to make the glass transition observable. Extrapolation to zero plasticizer concentration then yield the following Tg values: Tg (polyMe-ß-CD)=317°C±5°C and Tg (polyß-CD)=418°C±6°C.

Plastic and glassy crystal states of caffeine.

The present paper focuses on the high temperature form I of caffeine and on its low temperature metastable form. Structural, dynamic, and kinetic information has been obtained by X-ray, dielectric, and calorimetric investigations. This study shows the following features: (1) The high temperature phase (I) of caffeine is in a state of dynamically orientationally disordered crystalline state (so-called "plastic, or rotator, phase"). (2) This high-symmetry hexagonal phase can be maintained at low temperature in a metastable situation. (3) Under deep undercooling of form I a glass transition occurs in the disordered crystalline state near room temperature. It is associated with the orientational freezing in of the molecular motions. Otherwise stated, the metastable state I enters into a nonergodic unstable state, so-called "glassy crystal" state. These findings rationalize the difficulties seen with caffeine in pharmaceutical science.

Influence of homologous disaccharides on the hydrogen-bond network of water: complementary Raman scattering experiments and molecular dynamics simulations.

A comparative investigation of trehalose, sucrose, and maltose in water solution has been performed using Raman scattering experiments and Molecular Dynamics simulations. From the analysis of the O-H stretching region in the [2500,4000] cm(-1) Raman spectral range, which includes for the first time the contribution of 'free' water, and the statistical distribution of water HB probabilities from MD simulations, this study confirms the privileged interaction of trehalose with water above a peculiar threshold weight concentration of about 30%. The role of the hydration number of sugars--found higher for trehalose--on the destructuring effect of the water hydrogen bond network is also addressed. The analysis of the water O-H-O bending spectral range [1500,1800] cm(-1) reveals a change of the homogeneity of water molecules influenced by sugars, but the three investigated sugars are found to behave similarly.

Crystallization from the amorphous state: nucleation-growth decoupling, polymorphism interplay, and the role of interfaces.

The physical stability of the amorphous state is governed by crystallization, which results from the complex interplay of nucleation and growth processes. These processes can be further complicated by the preferred initial nucleation of less-stable phases, and interpretation requires the evaluation of the relative roles of structure, dynamics, and thermodynamics on the kinetics of the recrystallization. As a contribution to this issue, we reanalyze data sets concerning recrystallization of two pharmaceutical compounds: L-arabitol and RS ibuprofen. These compounds share the property of being good glass formers and present monotropic polymorphism. In the present analysis, we are mainly focusing on the localization of nucleation and growth zones and the role of a transient crystallization of the metastable phase. On the basis of the elementary theories, the results offer the opportunity to discuss the impact of interfacial energies, molecular mobility, crystal disorder, liquid short-range order, and crack formation in the glass.

Solid-state amorphization of linaprazan by mechanical milling and evidence of polymorphism.

In this paper, we study the thermodynamic and structural changes of crystalline linaprazan (a proton pump inhibitor) upon high-energy ball milling at room temperature. The investigations have been performed by differential scanning calorimetry and powder X-ray diffraction. The results indicate that this drug undergoes a direct crystal-to-glass transformation upon milling. Moreover, upon heating, the amorphous material obtained by milling is shown to recrystallize toward two different polymorphs that appear to form a monotropic set.

On the polymorphism of griseofulvin: identification of two additional polymorphs.

In this paper, we present an investigation of the polymorphism of griseofulvin. In addition to the only reported crystalline form (form I), two new polymorphic forms (II and III) have been identified and characterized by differential scanning calorimetry and powder X-ray diffraction. Reasons why these two polymorphs were isolated during the present study, but not detected during the numerous previous studies on this drug, are also discussed.

Solid-state vitrification of crystalline griseofulvin by mechanical milling.

The thermodynamic, dynamic, and structural changes of crystalline griseofulvin upon high-energy ball milling at room temperature have been studied. The investigations have been performed by differential scanning calorimetry (DSC), dielectric relaxation spectroscopy, and powder X-ray diffraction. The results indicate that this compound undergoes a direct crystal-to-glass transformation upon milling, whereas no glass transition can be clearly detected upon heating because of the exceptional sub-glass transition temperature (T(g) ) recrystallization of the milled sample. This intrinsic difficulty for characterizing the glassy state has been overcome using three independent strategies: (i) comparison of the evolutions upon milling of both the crystalline powder and the quenched liquid, (ii) use of fast DSC to delay the recrystallization event, and (iii) search for dielectric ß relaxations typical of glasses in the milled compound.