Cryomilling for formulation

The pharmaceutical industry has experienced an increase in the amount of development candidates with low aqueous solubility and accordingly poor bioavailability. In order for this problem to be solved, amorphisation is thought to be the most favourable solution. The amorphous state is higher in free energy thus higher in solubility when compared to the crystalline form. Milling and specially cryomilling is a very unique technique for providing of the crystalline to amorphous transformation since there are no heat or solvents involved. Phthalic acid, isophthalic acid and terephthalic acid, individual and pair mixtures, are crystalline organic non medicinal compounds, which have been used for the first time as model compounds to investigate whether cryogenic milling can induce crystal to amorphous transformation and if the preparation of pair mixtures could affect the recrystallization rate of the subjected materials or not. The materials were cryomilled and analysed by DSC, XRPD, and FTIR. It was found that only terephthalic acid become amorphous after cryomilling, and even after the cryomilled sample been stored for three weeks DSC thermogram still detects recrystallization exothermic along with the XRPD pattern, which shows a very broad peaks indicative of particle size reduction. Pair mixtures were also studied and analysed by DSC and XRPD. Phthalic acid/isophthalic acid, isophthalic acid/terephthalic acid, phthalic acid/terephthalic acid were cryomilled together and mixed physically after been cryomilled separately. XRPD results show that unlike the cryomilled separately mixtures, phthalic acid/ isophthalic acid, isophthalic acid/terephthalic acid, terephthalic acid/phthalic acid cryomilled together samples produces a synergistic effect in which the Bragg peaks of both phthalic acid and isophthalic acid are suppressed. It appears that co cryomilling of these pair mixtures together resulted in the production of a new material that could potentially either be two-component single phase (nano-sized co-crystal), or a new polymorphic form of either phthalic acid, isophthalic acid or terephthalic acid. Single-component of aspirin (ASP), paracetamol (PCM) and caffeine (CAFF), along with multi-component systems of paracetamol/aspirin, paracetamol/caffeine and aspirin/caffeine were milled at room temperature and by a cryomill. The milled samples were analysed using DSC, XRPD and FTIR. It was noted that there are no clear indications of crystal to amorphous transformation in all three materials. When milling aspirin at room temperature a marked reduction in the melting point was observed. Generally, a reduction in the melting point is either attributed to particle size effects, polymorphism, impurities and decomposition. In this case, the decrease in the melting point was only noticed when aspirin was milled at room temperature, so it is possible that the heat generated during the milling process resulted in chemical decomposition of aspirin to salicylic acid. Anhydrous caffeine is acknowledged to have two polymorphic forms, Form II which is considered to be stable at room temperature until ~145 °C. Form I is stable from ~145 °C to its melting point ~ 236 °C. This polymorphic transformation was detected by DSC, XRPD and hot stage microscope and it was noticed only with the as received and the room temperature milled samples. Cryomilled caffeine data showed only the presence of Form I. On the other hand, for the cryomilled multi-component systems DSC and hot stage microscope images confirmed the eutectic formation with a composition of 45:55% w/w (PCM:ASP), 50:50% (ASP:CAFF) AND 50:50% (PCM:CAFF). The obtained data were compared with room temperature milled and the theoretical values resulted from Van Laar equation. Solid pharmaceuticals represent heterogeneous systems that typically consist of one or more active pharmaceutical ingredients (APIs) and a number of excipients. Multi-component systems from mixing aspirin, paracetamol and caffeine with different excipients, which included sucrose, lactose monohydrate, xylitol and trehalose dihydrate were prepared by the use of a cryomill and were analyesd by DSC and XRPD. It was found from the XRPD data that mixing both sucrose and lactose monohydrate respectively with ASP, PCM and CAFF would produce more of a synergistic effect than xylitol and trehalose dihydrate. Cryomilling caffeine/sucrose and caffeine/lactose resulted in a production of a new XRPD trace that cannot be described in terms of a linear combination of caffeine, sucrose and lactose monohydrate. A new material was therefore formed as a result of cryomilling which has not been reported before

Une cause rare d’exophtalmie

Une enfant de 3 ans, issue d’un mariage non consanguin, deuxième d’une fratrie de 3, et sans antécédents pathologiques particuliers. Le début de la symptomatologie remonte à un mois par la constatation par la maman d’une exophtalmie de l’œil gauche qui augmentait rapidement de volume sans autres signes associés. A l’examen clinique, on notait la présence d’une importante exophtalmie de l’œil gauche avec bombement du cavum sans déficits neurologiques, le fond d’œil a objectivé une atrophie optique temporale. Une tomodensitométrie orbitaire a objectivé un processus énorme intra-orbitaire iso dense infiltrant la base du crâne, le sinus caverneux, le sinus sphénoïdal gauche  avec extension vers le cavum sur une étendue de 40 mm

Economic integration and security in the Middle East and North Africa: what prospects for a liberal peace?

Since the late 1980s governments in the Middle East and North Africa (MENA) have created commercial institutions in order to promote regional economic integration. The primary aim of this policy has been regarded as the promotion of economic welfare gains at the national level. A second, albeit less-emphasized goal, has been to promote regional peace through economic interdependence. This study examines the prospects for a liberal peace in the MENA by analyzing two stages of the commercial institutional peace. Firstly, the study considers whether commercial institutions have promoted intra-regional trade in the MENA. Secondly, it examines if economic interaction has had an impact on promoting peace within the region. Twenty states are considered here and the unit of analysis is the dyad-year over a 25-year period from 1990-2014. This study finds that commercial institutions in the MENA have only a limited positive correlation with trade volume and while there is a direct positive correlation between economic integration and peace in the region, this is quite limited. These findings suggest that the conclusions made by previous studies that demonstrate a direct positive correlation between commercial institutions (and economic integration more generally) and peace, may be less applicable to some regions such as MENA

Quantification of myocardial blood flow with 82Rb positron emission tomography: clinical validation with 15O-water

PURPOSE: Quantification of myocardial blood flow (MBF) with generator-produced (82)Rb is an attractive alternative for centres without an on-site cyclotron. Our aim was to validate (82)Rb-measured MBF in relation to that measured using (15)O-water, as a tracer 100% of which can be extracted from the circulation even at high flow rates, in healthy control subject and patients with mild coronary artery disease (CAD). METHODS: MBF was measured at rest and during adenosine-induced hyperaemia with (82)Rb and (15)O-water PET in 33 participants (22 control subjects, aged 30 ± 13 years; 11 CAD patients without transmural infarction, aged 60 ± 13 years). A one-tissue compartment (82)Rb model with ventricular spillover correction was used. The (82)Rb flow-dependent extraction rate was derived from (15)O-water measurements in a subset of 11 control subjects. Myocardial flow reserve (MFR) was defined as the hyperaemic/rest MBF. Pearson's correlation r, Bland-Altman 95% limits of agreement (LoA), and Lin's concordance correlation ρ (c) (measuring both precision and accuracy) were used. RESULTS: Over the entire MBF range (0.66-4.7 ml/min/g), concordance was excellent for MBF (r = 0.90, [(82)Rb-(15)O-water] mean difference ± SD = 0.04 ± 0.66 ml/min/g, LoA = -1.26 to 1.33 ml/min/g, ρ(c) = 0.88) and MFR (range 1.79-5.81, r = 0.83, mean difference = 0.14 ± 0.58, LoA = -0.99 to 1.28, ρ(c) = 0.82). Hyperaemic MBF was reduced in CAD patients compared with the subset of 11 control subjects (2.53 ± 0.74 vs. 3.62 ± 0.68 ml/min/g, p = 0.002, for (15)O-water; 2.53 ± 1.01 vs. 3.82 ± 1.21 ml/min/g, p = 0.013, for (82)Rb) and this was paralleled by a lower MFR (2.65 ± 0.62 vs. 3.79 ± 0.98, p = 0.004, for (15)O-water; 2.85 ± 0.91 vs. 3.88 ± 0.91, p = 0.012, for (82)Rb). Myocardial perfusion was homogeneous in 1,114 of 1,122 segments (99.3%) and there were no differences in MBF among the coronary artery territories (p > 0.31). CONCLUSION: Quantification of MBF with (82)Rb with a newly derived correction for the nonlinear extraction function was validated against MBF measured using (15)O-water in control subjects and patients with mild CAD, where it was found to be accurate at high flow rates. (82)Rb-derived MBF estimates seem robust for clinical research, advancing a step further towards its implementation in clinical routine

Absolute quantitative total-body small-animal SPECT with focusing pinholes

Purpose: In pinhole SPECT, attenuation of the photon flux on trajectories between source and pinholes affects quantitative accuracy of reconstructed images. Previously we introduced iterative methods that compensate for image degrading effects of detector and pinhole blurring, pinhole sensitivity and scatter for multi-pinhole SPECT. The aim of this paper is (1) to investigate the accuracy of the Chang algorithm in rodents and (2) to present a practical Changbased method using body outline contours obtained with optical cameras. Methods: Here we develop and experimentally validate a practical method for attenuation correction based on a Chang first-order method. This approach has the advantage that it is employed after, and therefore independently from, iterative reconstruction. Therefore, no new system matrix has to be calculated for each specific animal. Experiments with phantoms and animals were performed with a highresolution focusing multi-pinhole SPECT system (USPECT-II, MILabs, The Netherlands). This SPECT system provides three additional optical camera images of the animal for each SPECT scan from which the animal contour can be estimated. Results: Phantom experiments demonstrated that an average quantification error of –18.7% was reduced to –1.7% when both window-based scatter correction and Chang correction based on the body outline from optical images were applied. Without scatter and attenuation correction, quantification errors in a sacrificed rat containing sources with known activity ranged from –23.6 to –9.3%. These errors were reduced to values between –6.3 and +4.3% (with an average magnitude of 2.1%) after applying scatter and Chang attenuation correction. Conclusion: We conclude that the modified Chang correction based on body contour combined with window-based scatter correction is a practical method for obtaining small-animal SPECT images with high quantitative accuracy.Radiation, Radionuclides and ReactorsApplied Science