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.
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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.
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 Tg 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.
Microcharacterization of biominerals allows a better understanding of the pathophysiological events that occur in calcified tissues and synthetic biomaterials. Different methods have been extensively ...used to conduct such investigations. A new model for the intravital study of the composition and structure of membranous bone by Raman microspectroscopy is described. Titanium bone chambers equipped with a fused-silica optical window were implanted transcutaneously in the calvaria of New Zealand rabbits. The implanted optical windows were well tolerated, and spectral acquisitions were performed without any additional invasive procedure. Bone and implanted apatitic biomaterials were analyzed at different times after surgery. All Raman bands were unambiguously identified in the bone and biomaterial spectra. The main PO4 and CO3 Raman bands in bone spectra were consistent with those found in the carbonated apatite spectrum. The major collagen bands were always observed around 1200-1300 (amide III) and 1600-1700 (amide I) delta cm(-1) and, 1400-1470 and 2800-3100 delta cm(-1) (bending and stretching modes of CH groups, respectively). The phenylalanine (Phe) band was identified in all spectra at 1003 delta cm(-1) and overlapped that of the weak HPO4(2-) ion. The CH bands frequently overlapped the lipid bands. However a distinct protein and lipid bands were detected at 2950 and 2852 delta cm(-1), respectively. In bone areas close to blood vessels, the Raman signature of hemoglobin was detected with a characteristic band at 754 delta cm(-1). The changes observed in bone varied as a function of time and location. The composition and structure of all of the biomaterials studied--including those that were resorbable--seemed to remain stable over time and location. We report for the first time the complete intravital study of Raman spectra of bone and calcium phosphate biomaterials over a period of 8 months. This new approach does not require specimen preparation and allows simultaneous observation of mineral and organic bone constituents over time, which therefore should provide insightful information about their relationship.
The structural properties resulting from the reciprocal influence between water and three well-known homologous disaccharides, namely, trehalose, maltose, and sucrose, in aqueous solutions have been ...investigated in the 4−66 wt % concentration range by means of molecular dynamics computer simulations. Hydration numbers clearly show that trehalose binds to a larger number of water molecules than do maltose or sucrose, thus affecting the water structure to a deeper extent. Two-dimensional radial distribution functions of trehalose solutions definitely reveal that water is preferentially localized at the hydration sites found in the trehalose dihydrate crystal, this tendency being enhanced when increasing trehalose concentration. Over a rather wide concentration range (4−49 wt %), the fluctuations of the radius of gyration and of the glycosidic dihedral angles of trehalose indicate a higher flexibility with respect to maltose and sucrose. At sugar concentrations between 33 and 66 wt %, the mean sugar cluster size and the number of sugar−sugar hydrogen bonds formed within sugar clusters reveal that trehalose is able to form larger clusters than sucrose but smaller than maltose. These features suggest that trehalose−water mixtures would be more homogeneous than the two others, thus reducing both desiccation stresses and ice formation.
Objectives
This systematic literature review aims to summarize the existing scientific evidence about the association between a reduced salivary function and food consumption in elderly people.
...Methods
A validated search strategy in two databases (PubMed and ISI Web of Knowledge) was carried out and retrieved papers together with their reference lists were screened by two independent reviewers. The quality of the included studies was critically appraised via the Quality Assessment Criteria for Evaluating Primary Research Papers.
Results
From the originally identified studies (n=391), only 15 articles (all cross-sectional studies) met the pre-fixed inclusion/exclusion criteria. The methodological quality of the included studies was in general good, although only 3 from 15 obtained the maximum score. The control of confounding factors was the quality variable more poorly rated in the selected studies. Salivary hypofunction was associated with a decrease of the objective chewing and swallowing abilities and taste perception. Moreover, most of the selected studies showed a relationship between salivary hypofunction and food consumption (in terms of appetite loss, unbalanced dietary intake and malnutrition), although no causality could be established.
Conclusions
This study highlights the fact that salivary hypofunction definition and measurements are different across the studies. Therefore, future research efforts should focus on establishing a gold standard to define and identify salivary hypofunction throughout life and on performing longitudinal studies controlling for confounding factors to establish causality..
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.
•Mechanical activation gives amorphous states with specific DSC signatures.•Sub Tg peaks reveal specific relaxations in the activated glass.•Cryomilling of aged amorphous pharmaceuticals may induce fast rejuvenation.•Milling may modify the physical and chemical stability of pharmaceuticals.
The melting of glucose Willart, J.F.; Ouerghemmi, S.; Descamps, N. ...
International journal of pharmaceutics,
10/2022, Letnik:
626
Journal Article
Recenzirano
Odprti dostop
Several sugars are known to undergo a spontaneous liquefaction below their reputed melting point (Tm), but the origin of this apparent melting is not yet clearly understood. In this paper we address ...this puzzling behavior in the particular case of the crystalline forms of glucose: Gα and Gβ, involving respectively the glucose-α and glucose-β anomers. We show in particular that the spontaneous melting below their reputed melting point Tm (∼151 °C for Gα and ∼156 °C for Gβ) corresponds to a horizontal displacement of the system in the eutectic phase diagram of the anomeric mixture glucose-α / glucose-β. This displacement is associated with mutarotation in the liquid which, in turn, induces additional liquefaction of the remaining crystal. This feedback loop creates a vicious circle which stops when the mixture reaches the liquidus branch, i.e. when the liquefaction is total. It is also shown that this behavior becomes more complex on approaching the eutectic temperature Te (120 °C). Just above Te, the liquefaction process is followed by a recrystallization leading to the crystalline form Gβ. On the other hand, just below Te, the spontaneous liquefaction process stops as no melting is expected whatever the anomeric composition.
The influence of three well-known disaccharides, namely, trehalose, maltose, and sucrose, on some structural and dynamical properties of lysozyme has been investigated by means of molecular dynamics ...computer simulations in the 37−60 wt % concentration range. The effects of sugars on the protein conformation are found to be relatively weak, in agreement with the preferential hydration of lysozyme. Conversely, sugars seem to increase significantly the relaxation times of the protein. These effects are shown to be correlated to the fractional solvent accessibilities of lysozyme residues and further support the slaving of protein dynamics. Moreover, a significant increase in the relaxation times of lysozyme, sugars, and water molecules is observed within the studied concentration range and may result from the percolation of the hydrogen-bond network of sugar molecules. This percolation appears to be of primary importance to explain the influence of sugars on the dynamical properties of lysozyme and water.
1. Beak trimming is currently used in France to avoid the negative consequences of severe feather pecking (SFP). However, this practice is controversial in terms of animal welfare, and forbidden in ...some European countries.
2. This study aimed to assess the prevalence of SFP in French laying hen farms, to describe how farmers manage this behavioural disorder and to better understand the risk factors involved.
3. A study was carried out from April 2015 to June 2016. Visits were paid to 79 flocks kept in furnished cages (FC) and 80 flocks in a free-range (FR) system. All the hens had trimmed beaks and were genotypically brown. The information collected included feather cover, skin damage, beak condition, farm and poultry house characteristics, livestock performance and management.
4. The prevalence of SFP in FC flocks was estimated at 32.9% (IC = 95%, 22.5; 43.3) and the prevalence of cannibalism as 2.5% (IC = 95%, 0.7; 8.8) at 70 weeks of age. The prevalence of SFP in FR flocks was estimated to be 23.8% (IC = 95%, 14.5; 31.1) and the prevalence of cannibalism was 8.8% (IC = 95%, 4.3; 17.0) at 61 weeks of age.
5. In FC flocks, SFP was associated with the combination of genotype, type and length of perches, cage area per hen, type of lighting, number of hens per cage and farm location. In FR flocks, feather cover was associated with use of the outdoor run, lighting programme, genotype, farm location and date of house construction.
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