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L'etat solide amorphe est devenu un incontournable de la formulation des composes pharmaceutiques. Cet article s'interesse a ses applications et a ce qui le differencie de l'etat cristallin. Il fait le point sur les avantages et problemes de sa mise en œuvre. L'essentiel de l'article porte sur son interet du point de vue de la solubilite et discute tous les aspects lies a sa stabilite physique et chimique, ainsi qu'a sa capacite a stabiliser des biomolecules fragiles. Les systemes amorphes complexes associant plusieurs composes (dispersions solides amorphes dans les polymeres, co-amorphes, agents plastifiants et antiplastifiants, etc.) font l'objet d'une attention particuliere.

In this paper we have investigated the recrystallization properties of amorphous griseofulvin obtained by melt quenching. We have shown that the maximum nucleation rates of crystalline forms 2 and 3 are located around the glass transition temperature. However, it appears that these nucleation rates are strongly increased by the sudden formation of cracks into the amorphous solid during deep quenches below Tg. Suitable thermal treatments have revealed that these cracks strongly promote the development of crystalline nuclei, but do not produce the nuclei themselves. The investigations have been performed by differential scanning calorimetry and by thermal microscopy.

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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.

This paper presents an overview of recent advances in understanding the role of the amorphous state in the physical and chemical transformations of pharmaceutical materials induced by mechanical milling. The following points are addressed: (1) Is milling really able to amorphise crystals?, (2) Conditions for obtaining an amorphisation, (3) Milling of hydrates, (4) Producing amorphous state without changing the chemical nature, (5) Milling induced crystal to crystal transformations: mediation by an amorphous state, (6) Nature of the amorphous state obtained by milling, (7) Milling of amorphous compounds: accelerated aging or rejuvenation, (8) Specific recrystallisation behaviour, and (9) Toward a rationalisation and conceptual framework.

Polymeric fenofibrate-loaded films and particles aiming at improved dissolution of this poorly water-soluble drug were prepared by solvent evaporation or co-grinding. HPMC, PVP and PEG of various molecular weights were studied. In the case of HPMC, thin films were obtained when using the solvent evaporation method, whereas in all other cases particles were obtained. Interestingly, not only the type of polymer, but also the preparation method had a substantial impact on system performance and this in a not straightforward manner: For HPMC and PVP, solvent evaporation was much more efficient than co-grinding, whereas the opposite was observed with PEG. Fenofibrate was molecularly dispersed in HPMC and PVP, whereas it was partially dissolved and partially dispersed in the form of small crystals in PEG, irrespective of the type of preparation technique. Differences in the particle size could explain why drug release was faster from PVP-based systems prepared by solvent evaporation compared to co-grinding, and why the opposite was true in the case of PEG. For HPMC, differences in system homogeneity could explain the effects of the type of preparation method. Importantly, the drug dissolution rate and extent could be substantially increased, while assuring stability during at least 3 months open storage.

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 groupP212121) and the asymmetric unit contains two molecules.

International audience; This study aims to investigate the polymorphism, physical stability, and amorphization possibilities of dexamethasone (DEX) drug. Milling was found to be an advantageous mean to prepare amorphous DEX nonchemically degraded. It appears to be a very useful process that allowed generating crystalline polymorphic transformation, either from the milling induced amorphous sample or from a mechanically damaged polymorphic form. The paper illustrates the interest of milling as a complementary tool to screen crystal polymorphism and to determine the relative stability of polymorphs when the decision is difficult. Physical characterizations were mainly carried out using X-ray diffraction and differential scanning calorimetry.

International audience; 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.

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.

The industrial formulation processes used to prepare drugs impose high energy mechanical constraints which involve dynamic aspects in addition to temperature or pressure variations. Materials which are driven by dynamic stresses undergo modifications of their physical state which affect solubility and bioavailability. In the present paper we are concerned with the very nature of the amorphous end products resulting from a high energy milling. Information is obtained by investigating with (DSC) the relaxation behavior of the glass when heating it over the glass transition at Tg. Two different situations are considered: 1) That of a crystalline compound—trehalose (TRE)—amorphized by milling. In that case further characterization is achieved by looking at the effects of temperature and duration of subsequent aging steps. 2) That of high energy cryomilling on a long aged quench cooled amorphous indomethacine (IDM). The specificities of the activated glass are revealed by Tg and sub-Tg events. Milling induces some relaxation capabilities within the glass. An interesting result is that cryomilling is able to fastly rejuvenate an aged amorphous sample and to modify its local structure. Impacts on recrystallization are demonstrated. Such mechanically induced modifications of the physical state can induce physical and chemical instabilities.

We have investigated the solid-state transformation of anhydrous β-d-mannitol upon milling using synchrotron X-ray powder diffraction. The 1720 diffraction patterns, collected in real time during the operation of the mill (6 h), have been analyzed by sequential Rietveld refinements. From this analysis we confirm that a polymorphic conversion has occurred from the form β toward the form α. Moreover, the quantification and the microstructural analysis of both polymorphs have allowed obtaining new results: (i) the kinetic of the transformation is characterized by a sigmoidal shape, (ii) little microstructural evolution occurs during the solid-state transformation, (iii) no intermediate amorphous phase, preceding the transformation toward the metastable crystalline α phase, can be detected. A comparison in depth of the two crystal structures is given, and two models are proposed in order to explain this direct conversion β → α.

L'etat solide amorphe, plutot que cristallin, est d'un interet croissant dans de nombreux domaines. Sa formation peut etre accidentelle et nefaste, ou intentionnelle. En pharmacie, il permet d'accroitre la solubilite des composes peu solubles ou de stabiliser les macromolecules fragiles. Cependant, il est difficile a maitriser du fait de son instabilite. Il presente aussi des difficultes propres de caracterisation physique. Cet article fait le point sur les proprietes physiques des solides moleculaires amorphes, ainsi que sur l'alternative cristal/amorphe. Il prend en compte les avancees recentes dans les domaines de la structure, de la thermodynamique et de la mobilite moleculaire.

International audience; This work establishes that the plasticization effect of a classical petrochemical plasticizer, dimethyl phthalate (DMP), on a polymer matrix, cellulose acetate (CA), is due to the development of intermolecular interactions of dipolar type. Plasticized cellulose acetate films are studied with regard to the interactions between the polymer and plasticizer at the macroscopic scale by thermogravimetric analysis and differential scanning calorimetry. At the molecular level, Fourier transform infrared spectroscopy and dielectric relaxation spectroscopy are used to elucidate the nature of interactions that are responsible for the plasticizing effects. These static and dynamic complementary analyses evidenced that DMP does not establish H-bonding interactions with the polymer chains of cellulose acetate but rather weaker interactions of dipolar type. These dipole–dipole interactions that develop between acetyl side groups of CA and the ester phthalate moieties of DMP increase the overall mobility of CA chains and also locally influence the molecular mobility and the water uptake tendency.

Fenofibrate-loaded microparticles based on PVP/Eudragit E or HPMC/Eudragit E blends were prepared by spray-drying. The composition of the systems (in particular the polymer/polymer blend ratio and the drug loading) was varied and the resulting key properties were determined (including drug release measurements in 0.1 M HCl, X-ray diffraction studies, solubility measurements and particle size analysis). For reasons of comparison, also the respective physical drug/polymer/polymer mixtures, microparticles based on binary drug/PVP and drug/HPMC blends, the fenofibrate powder as received and a commercially available drug product were investigated. Importantly, highly supersaturated fenofibrate solutions were created upon exposure of the different types of microparticles to the release medium, in contrast to any reference formulation. Also, the presence of co-dissolved Eudragit E led to a significant increase in fenofibrate solubility. At 10 % drug loading, all microparticles were amorphous and drug release stable during one month open storage. However, at 30 % loading, HPMC containing microparticles showed storage instability, due to drug re-crystallization.

Polymeric matrices loaded with 10–50% ketoprofen were prepared by hot-melt extrusion or spray-drying. Eudragit® E, PVP, PVPVA and HPMC were studied as matrix formers. Binary “drug–Eudragit® E” as well as ternary “drug–Eudragit® E-PVP”, “drug–Eudragit® E-PVPVA” and “drug–Eudragit® E-HPMC” combinations were investigated and characterized by optical macro/microscopy, SEM, particle size measurements, mDSC, X-ray diffraction and in vitro drug release studies in 0.1 M HCl. In all cases ketoprofen release was much faster compared to a commercially available product and the dissolution of the drug powder (as received). Super-saturated solutions were obtained, which were stable during at least 2 h. Importantly, not only the composition of the systems, but also their inner structure potentially significantly affected the resulting ketoprofen release kinetics: For instance, spray-drying ternary ketoprofen:Eudragit® E:HPMC combinations led to a more homogenous HPMC distribution within the systems than hot-melt extrusion, as revealed by mDSC and X-ray diffraction. This more homogenous HPMC distribution resulted in more pronounced hindrance for water and drug diffusion and, thus, slower drug release from spray-dried powder compared to hot-melt extrudates of identical composition. This “homogeneity/heterogeneity effect” even overcompensated the “system size effect”: the surface exposed to the release medium was much larger in the case of the spray-dried powder. All formulations were stable during storage at ambient conditions in open vials.

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. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:2214–2220, 2013

Novel PLGA derivatives bearing carboxylated side chains have been synthesized and used to encapsulate the fragile drug apomorphine HCl with a solid-in-oil-in-water solvent extraction/evaporation method. Blends of d,l-lactide and l-3-(2-Benzyloxycarbonyl)Ethyl-1,4-Dioxane-2,5-dione (BED) were co-polymerized at different ratios via ring-opening using benzyl alcohol as initiator. Optionally, the ester groups in the side chains as well as the terminal ester groups were hydrogenolyzed (leading to free COOH groups). For reasons of comparison, different types of "conventional" PLGAs were also synthesized and used for apomorphine HCl encapsulation. The polymers and microparticles were thoroughly characterized using SEC, (1)H NMR, DSC, SEM, X-ray and laser diffraction, Headspace-GC as well as in vitro drug release measurements in flow-through cells and agitated flasks. Importantly, microparticles based on the new polymers bearing carboxylic groups in the polymeric side chains: (i) allowed a significant reduction of the amount of residual solvent (dichloromethane), and (ii) provided different types of drug release patterns compared to microparticles based on "conventional" PLGAs (at least partially due to altered polymer degradation kinetics). Thus, they offer an interesting potential as novel matrix formers in controlled drug delivery systems, overcoming potential shortcomings of standard PLGAs.

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.

International audience; We have investigated the amorphization of β-trehalose by high energy milling using in situ and ex situ synchrotron powder diffraction and PDF analysis. From this analysis we show that amorphization takes place through a two-phase process involving an amorphous and a long-range ordered phase. The proportion and coherent domain size of the latter rapidly decrease with milling time until the whole sample appears amorphized. The PDF describing the local structure of the amorphous phase after two hours of milling is very close to that of a sample quenched from the liquid, and seems to continue to evolve for longer milling times. Their differences with the PDF expected for a rigid THL molecule confirm the existence of a conformational disorder of the torsion angles from the glycosidic linkage between the two cycles forming the molecule.

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The aim of this work was to determine the main physical characteristics of β-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 β-cyclodextrin (polyβ-CD) and a polymer of partially methylated (DS=0.57) β-cyclodextrin (polyMe-β-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-β-CD)=317°C±5°C and Tg (polyβ-CD)=418°C±6°C.

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 (T-g) 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 T-g determined for amorphous formulations, ranging from 70 to 147 degrees 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.

Tadalafil (TD) is a crystalline drug of a high melting point (Tm=299°C) and limited solubility in water (

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 β relaxations typical of glasses in the milled compound.

We show in this paper the contribution of the whole Raman spectrum including the phonon spectrum, to detect, identify and characterize polymorphic forms of molecular compounds, and study their stability and transformation. Obtaining these kinds of information is important in the area of pharmaceutical compounds. Two different polymorphic systems are analyzed through investigations in indomethacin and caffeine exposed to variable environmental conditions and various stresses, as possibly throughout the production cycle of the active pharmaceutical ingredient. It is shown the capability of the low-frequency Raman spectroscopy to reveal disorder in the crystalline state, to detect small amorphous or crystalline material, and to elucidate ambiguous polymorphic or polyamorphic situations.

Lipid implants prepared by melting and casting offer a great potential for advanced drug delivery. However, care must be taken with respect to the solid state of the lipid(s) and potential changes thereof during storage. Generally, a thermal aftertreatment is required. However, little is known about the impact of the curing time and temperature on drug release. The aim of this study was to better understand the importance of these parameters for different types of implants containing propranolol hydrochloride. Hydrogenated cottonseed oil and hydrogenated soybean oil were used as matrix formers. The implants were characterized with respect to their in vitro release kinetics, water uptake, thermal properties, and morphology. On the basis of these experimental results, a mechanistic mathematical model was used to gain further insight into the underlying mass transport mechanisms. Both the curing time and the temperature strongly affected the resulting drug release patterns. Importantly, in most cases, these effects could not be attributed to polymorph transformations but to changes in the implants' microstructure. The size of the lipid particles depended on both the curing time and the temperature, and determined the size of the pores/channels through which water and drug diffuse. The importance of this aspect is often underestimated.

It has been recently shown that mechanical milling can amorphize D-glucose without any mutarotation, giving rise to an anomerically pure amorphous sample. We have taken advantage of this exceptional possibility to study the kinetic of mutarotation in the amorphous solid state. The investigations have been performed in situ by time-resolved Raman spectroscopy. The results reveal an unexpected coupling between the mutarotation process and the structural relaxations involved in the glassy state.

The aim of this study was to better understand the importance of the "microparticle mass:bulk fluid volume" ratio during in vitro drug release measurements from PLGA microparticles. Initially porous/non-porous, ibuprofen/lidocaine/propranolol HCl-loaded systems were exposed to phosphate buffer pH 7.4 in agitated test tubes, varying the microparticle concentration from 5:1 to 20:1mg:mL. Interestingly, drug release was virtually unaffected by the "microparticle mass:bulk fluid volume" ratio in the case of initially porous, ibuprofen-loaded microparticles, exhibiting complete drug release within about 1 week. Optical microscopy, SEM, DSC and pH measurements of the bulk fluid revealed no major impact of the microparticle concentration on the systems' properties within the first couple of days. However, a more rapid and pronounced decrease in the pH of the release medium occurred after 10-14 d at elevated "microparticle mass:bulk fluid volume" ratios. This resulted in an accelerated: (i) decrease in the glass transition temperature, (ii) microparticle agglomeration, and (iii) increase in the internal and external microparticle porosity. Importantly, this phenomenon did not significantly affect drug release from initially porous, lidocaine-loaded microparticles, exhibiting complete release within about 18 d. In contrast, drug release became significantly faster at higher "microparticle mass:bulk fluid volume" ratios in the case of initially non-porous, lidocaine-loaded microparticles and initially porous, propranolol HCl-loaded systems, exhibiting complete release after 1 and 2 months, respectively. Thus, depending on the type of system, the "microparticle mass:bulk fluid volume" ratio may or may not affect the observed release kinetics in vitro. This should be carefully taken into account when defining the experimental conditions for drug release measurements from this type of advanced drug delivery systems.

Using time-resolved dielectric relaxation spectroscopy, we have studied the kinetics of the first-order phase transformation of caffeine from its high temperature rotational solid form to the room temperature phase. The results indicate that the kinetics can be fitted by a highly stretched exponential law. The kinetics, thus, differ from that of a ‘typical’ nucleation and growth process. This unusual non-sigmoidal evolution can be understood as being dominated by slow nucleation in grains with a dispersion of their size ranging below the characteristic dimension of the nucleation and growth process. The relaxation times of polarization are characterized by an activation energy closely correlated with that of the nucleation process.

Amorphous solids are conventionally formed by supercooling liquids or by concentrating noncrystallizing solutes (spray-drying and freeze-drying). However, a lot of pharmaceutical processes may also directly convert compounds from crystal to noncrystal which may have desired or undesired consequences for their stability. The purpose of this short review paper is (i) to illustrate the possibility to amorphize one compound by several different routes (supercooling, dehydration of hydrate, milling, annealing of metastable crystalline forms), (ii) to examine factors that favor crystal to glass rather than crystal to crystal transformations, (iii) to discuss the role of possible amorphous intermediates in solid-solid conversions induced by milling, (iv) to address the issue of chemical stability in the course of solid state amorphization, (v) to discuss the nature of the amorphous state obtained by the nonconventional routes, (vi) to show the effect of milling conditions on glasses properties, and (vii) to attempt to rationalize the observed transformations using the concepts of effective temperature introduced in nonequilibrium physics.

The structural and thermodynamic changes in the organic molecular crystals of α -D-glucose and β -D-glucose upon high energy ball milling at room temperature and −15 ∘C have been studied. The investigations have been performed by X-ray diffraction, differential scanning calorimetry and Raman spectroscopy. The results show the possibility to reach the glassy amorphous state of both forms of glucose, if mechanical milling is performed far enough below the glass transition temperature of the corresponding liquid ( T g ≈ 38 ∘ C ) . This route to the glassy state is found to be free of mutarotation whatever the starting glucose variety, while this mutarotation is unavoidable using the usual thermal quench of the liquid.

The aim of this work is to search for the existence of crystalline polymorphism for racemic Ibuprofen. The pharmaceutical material was studied by X-ray diffraction to identify crystalline phases, and by Differential Scanning Calorimetry to follow the thermodynamic evolution of these forms versus temperature. Results presented here show that, in addition to the already known conventional crystalline phase, whose nucleation domain extends between 233 K and 263 K and which melts at 349 K, racemic Ibuprofen can crystallize in another polymorphic phase. The nucleation of this new polymorphic variety is triggered by a stay at least 60 degrees below the glass transition temperature Tg of Ibuprofen (Tg = 228 K). This nucleation is probably of heterogeneous type. The new phase melts well below the conventional one, i.e. at 290 K. A schematic free energy diagram is provided allowing establishing the relative thermodynamic stability of the two polymorphs. These results establish, for the first time, that Ibuprofen can exist under two different crystalline phases which constitute a monotropic system, the new form being metastable.

In this paper, we show the possibility of forming amorphous molecular trehalose/mannitol alloys by two independent routes: the usual thermal quenching of the mixed melts, and the co-milling of the stable crystalline forms at room temperature. However, by quenching the melt, molecular alloys can be obtained for the whole range of mannitol concentration, while by co-milling the possibility of forming the alloy ceases when the glass transition temperature of the alloy approaches the milling temperature. The fraction of mannitol not involved in the alloy then undergoes a polymorphic transformation toward a metastable polymorph which coexists with the alloy. The detailed analysis of all these transformations indicates clearly that the glass transition temperature is a key parameter which drives the “amorphization/polymorphic transformation” duality often detected during the milling of molecular materials.

International audience; The correlations between some macroscopic and microscopic properties of model glass-forming materials are investigated using molecular dynamics simulations. Dynamics of three different binary mixtures of Lennard-Jones atoms, which differ only in the curvature of their particle-particle interaction potentials are reported. In the framework of the Coupling Model, we show that the capacity for interparticle coupling and anharmonicity of the potential are responsible for the behavior of the fragility and fast dynamics using both the diffusion coefficient and the non-ergodicity parameter. © 2007 Elsevier B.V. All rights reserved.

In this paper we compare the solid-state transformations upon room temperature milling of four sugars: lactose, trehalose, mannitol and sorbitol. The two disaccharides (lactose and trehalose) are found to undergo a direct transformation from crystal to glass while the two sugar alcohols (mannitol and sorbitol) are found to undergo polymorphic transformations. The origin of these different behaviors is discussed and ascribed to the relative position of the glass transition temperature (T g) of the amorphous states with respect to the milling temperature. This point was also finely studied through co-milling experiments of lactose and mannitol. These two compounds having their glass transition respectively above and below room temperature the T g of the mixture can be conveniently tuned on either side of the milling temperature by varying the concentrations.

The effect of cryogenic grinding on the piroxicam and its mixtures with polyvinylpyrrolidone (PVP) was studied by powder X-ray diffraction and differential scanning calorimetry (DSC). The crystallization of the amorphous piroxicam obtained during cryogrinding showed two events in a DSC curve (noticeable for pure piroxicam, and much more pronounced for the PVP-piroxicam mixtures). For the same measurement conditions, the intensity ratio of the peaks corresponding to the two events differed for the PVP-piroxicam mixtures of different drug-excipient ratios. The temperatures, at which these events were observed, increased with the increase in the PVP-concentration in the mixture. For the mixtures with a high relative content of PVP (≥60%), crystallization was not observed at all. Only one glass transition was revealed for the mixture containing 80% PVP suggesting that a molecular alloy was formed.

Milling is a usual process used in the course of drug formulation, which however may change the physical nature of the end product. The diversity of the transformations of organic compounds upon milling has been widely demonstrated in the pharmaceutical literature. However, no effort has still been devoted to study the correlation between the nature of the transformation and the milling conditions. Results clarifying such transformations are shortly reviewed with special attention paid to the temperature of milling. The importance of the position of the glass transition temperature compared with that of milling is demonstrated. It is shown that decreasing the milling temperature leads to an increase of the amorphization tendency whereas milling above T(g) can produce a crystal-to-crystal transformation between polymorphic varieties. These observations contradict the usual suggestion that milling transforms the physical state only by a heating effect which induces a local melting. Equilibrium thermodynamics does not seem appropriate for describing the process. The driven alloys concept offers a more rational framework to interpret the effect of the milling temperature. Other results are also presented, which demonstrate the possibility for milling to form low temperature solid-state alloys that offer new promising ways to stabilize amorphous molecular solids.

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In this work, we investigate the effect of milling on the glassy state of the molecular glass former indomethacin. Milling of this model pharmaceutical compound was performed at room temperature. The effects of the milling intensity and duration on the physical state of the glass were investigated by X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). Depending on the milling parameters, either we observed crystallization under milling or a modification of the physical state of the glass itself. The results are confronted with previous investigations of the effects of both the cooling rate of the melt and the physical ageing of the glass. The possibilities for milling to change the configurational state of the glassy state and the local molecular organization are discussed.

In this paper, we report the possibility to form glassy amorphous molecular alloys α-lactose/mannitol and α-lactose/budesonide by milling together pure crystalline powders of α-lactose and mannitol on the one hand, and pure crystalline powders of α-lactose and budesonide on the other hand. It is also shown that upon milling, pure mannitol undergoes a polymorphic transformation from the stable form β towards the metastable form α, while pure budesonide undergoes a complete amorphization. The results have been established by differential scanning calorimetry and by powder X-ray diffraction.

A detailed structural description of the glacial state in triphenyl phosphite, based on Raman microspectroscopy investigations and a complementary structural analysis by X-ray diffraction, of a nano-structured glacial state, is reported in this paper. The optical images obtained for the glacial state, isothermally prepared at 214 K and 220 K, display contrasting effects typical of an heterogeneous system. Very large clusters of hexagonal shape are distinguished, and Raman microspectroscopy gives the opportunity to describe the structural organization inside these clusters. The diffraction pattern of a glacial state formed in a low-temperature range [210 K, 216 K], was calculated from the consideration of an isotropic crystallite size of 50 A. The good agreement between the calculated and experimental diffraction patterns confirms that the glacial state is composed of crystallites of the stable crystalline phase coexisting with the non-transformed supercooled liquid according to the micro-structural analysis of a glacial state prepared at higher temperature (222 K). Raman spectroscopy and X-ray diffraction investigations provide the description of two structural organizations corresponding to the liquid and the crystalline states. No other structural organization was detected in TPP using (direct and indirect) structural probes.

International audience; Dynamical properties of three glassforming binary Lennard-Jones systems with different anharmonicities of the interaction potential have been studied by molecular dynamics simulations. The onset temperature of slow dynamics TA, the Mode Coupling theory critical temperature TC and the Vogel-Fulcher-Tamman temperature TVFT have been determined for the three models. A good agreement is found with most of the predictions of the Mode Coupling Theory. However, a detailed analysis of the master curve obtained from the superposition of the intermediate scattering functions reveals a significative temperature dependence of the stretched exponent β over a wide temperature range from the liquid state to the glass transition. It is shown that both fragility and stretched exponent β unambigously correlate with anharmonicity of the interaction potential. © 2006 Elsevier B.V. All rights reserved.

In this paper, we report the possibility to form glassy molecular alloys (α-lactose)1−x(mannitol)x for x

This study was conducted to characterize the molecular mobility of supercooled fananserine and derive from this analysis the non-Arrhenius and nonexponential properties of the primary alpha-relaxation.The use of three investigation techniques of the molecular mobility, namely, dielectric relaxation, modulated differential scanning calorimetry, and proton nuclear magnetic resonance, allowed us to describe the dynamic properties of supercooled fananserine on a wide range of frequencies and temperatures, ranging from the melting temperature T(m) = 372 K down to the glass transition temperature T(g) = 292 K.We emphasized the capacity of these three techniques to give a coherent set of information. We used the coupling-model theory to interpret the dielectric results. It allowed us to identify two relaxation processes (alpha and beta), corresponding to different molecular motions. The temperature evolution of the alpha-relaxation indicates that fananserine is a fragile glass former, as reflected by the steepness index value, m = 77. The temperature T(o) where the relaxation times diverge was also determined.The description of the dielectric relaxation data in terms of the Kohlrausch-Williams-Watt relaxation function has shown the existence of an additional low-amplitude relaxation process assigned to the so-called Johari-Goldstein process. Mainly concerned by the primary alpha-process directly involved in the glass formation, we derived from this analysis the characteristic features of this process and showed that supercooled fananserine is characterized by a strongly non-Arrhenius and nonexponential behavior.