Drug Polymer Thermodynamic Phase Diagrams in the Selection of Optimal API-Polymer Compositions for Amorphous Solid Dispersions

Purpose The aim of this work was to examine, for amorphous solid dispersions, how the thermal analysis method selected impacts on the construction of thermodynamic phase diagrams, and to assess the predictive value of such phase diagrams in the selection of optimal, physically stable API-polymer compositions. Methods Thermodynamic phase diagrams for two API/polymer systems (naproxen/HPMC AS LF and naproxen/Kollidon 17 PF) were constructed from data collected using two different thermal analysis methods. The “dynamic” method involved heating the physical mixture at a rate of 1 &[deg]C/minute. In the "static" approach, samples were held at a temperature above the polymer Tg for prolonged periods, prior to scanning at 10 &[deg]C/minute. Subsequent to construction of phase diagrams, solid dispersions consisting of API-polymer compositions representative of different zones in the phase diagrams were spray dried and characterised using DSC, pXRD, TGA, FTIR, DVS and SEM. The stability of these systems was investigated under the following conditions: 25 &[deg]C, desiccated; 25 &[deg]C, 60 % RH; 40 &[deg]C, desiccated; 40 &[deg]C, 60 % RH. Results Endset depression occurred with increasing polymer volume fraction (Figure 1a). In conjunction with this data, Flory-Huggins and Gordon-Taylor theory were applied to construct thermodynamic phase diagrams (Figure 1b). The Flory-Huggins interaction parameter (&[chi]) for naproxen and HPMC AS LF was + 0.80 and + 0.72, for the dynamic and static methods respectively. For naproxen and Kollidon 17 PF, the dynamic data resulted in an interaction parameter of - 1.1 and the isothermal data produced a value of - 2.2. For both systems, the API appeared to be less soluble in the polymer when the dynamic approach was used. Stability studies of spray dried solid dispersions could be used as a means of validating the thermodynamic phase diagrams. Conclusion The thermal analysis method used to collate data has a deterministic effect on the phase diagram produced. This effect should be considered when constructing thermodynamic phase diagrams, as they can be a useful tool in predicting the stability of amorphous solid dispersions.

Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): results of a randomised, controlled, phase 3 trial

BACKGROUND: Acute promyelocytic leukaemia is a chemotherapy-sensitive subgroup of acute myeloid leukaemia characterised by the presence of the PML-RARA fusion transcript. The present standard of care, chemotherapy and all-trans retinoic acid (ATRA), results in a high proportion of patients being cured. In this study, we compare a chemotherapy-free ATRA and arsenic trioxide treatment regimen with the standard chemotherapy-based regimen (ATRA and idarubicin) in both high-risk and low-risk patients with acute promyelocytic leukaemia.

METHODS: In the randomised, controlled, multicentre, AML17 trial, eligible patients (aged ≥16 years) with acute promyelocytic leukaemia, confirmed by the presence of the PML-RARA transcript and without significant cardiac or pulmonary comorbidities or active malignancy, and who were not pregnant or breastfeeding, were enrolled from 81 UK hospitals and randomised 1:1 to receive treatment with ATRA and arsenic trioxide or ATRA and idarubicin. ATRA was given to participants in both groups in a daily divided oral dose of 45 mg/m(2) until remission, or until day 60, and then in a 2 weeks on-2 weeks off schedule. In the ATRA and idarubicin group, idarubicin was given intravenously at 12 mg/m(2) on days 2, 4, 6, and 8 of course 1, and then at 5 mg/m(2) on days 1-4 of course 2; mitoxantrone at 10 mg/m(2) on days 1-4 of course 3, and idarubicin at 12 mg/m(2) on day 1 of the final (fourth) course. In the ATRA and arsenic trioxide group, arsenic trioxide was given intravenously at 0·3 mg/kg on days 1-5 of each course, and at 0·25 mg/kg twice weekly in weeks 2-8 of course 1 and weeks 2-4 of courses 2-5. High-risk patients (those presenting with a white blood cell count >10 × 10(9) cells per L) could receive an initial dose of the immunoconjugate gemtuzumab ozogamicin (6 mg/m(2) intravenously). Neither maintenance treatment nor CNS prophylaxis was given to patients in either group. All patients were monitored by real-time quantitative PCR. Allocation was by central computer minimisation, stratified by age, performance status, and de-novo versus secondary disease. The primary endpoint was quality of life on the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 global health status. All analyses are by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN55675535.

FINDINGS: Between May 8, 2009, and Oct 3, 2013, 235 patients were enrolled and randomly assigned to ATRA and idarubicin (n=119) or ATRA and arsenic trioxide (n=116). Participants had a median age of 47 years (range 16-77; IQR 33-58) and included 57 high-risk patients. Quality of life did not differ significantly between the treatment groups (EORTC QLQ-C30 global functioning effect size 2·17 [95% CI -2·79 to 7·12; p=0·39]). Overall, 57 patients in the ATRA and idarubicin group and 40 patients in the ATRA and arsenic trioxide group reported grade 3-4 toxicities. After course 1 of treatment, grade 3-4 alopecia was reported in 23 (23%) of 98 patients in the ATRA and idarubicin group versus 5 (5%) of 95 in the ATRA and arsenic trioxide group, raised liver alanine transaminase in 11 (10%) of 108 versus 27 (25%) of 109, oral toxicity in 22 (19%) of 115 versus one (1%) of 109. After course 2 of treatment, grade 3-4 alopecia was reported in 25 (28%) of 89 patients in the ATRA and idarubicin group versus 2 (3%) of 77 in the ATRA and arsenic trioxide group; no other toxicities reached the 10% level. Patients in the ATRA and arsenic trioxide group had significantly less requirement for most aspects of supportive care than did those in the ATRA and idarubicin group.

INTERPRETATION: ATRA and arsenic trioxide is a feasible treatment in low-risk and high-risk patients with acute promyelocytic leukaemia, with a high cure rate and less relapse than, and survival not different to, ATRA and idarubicin, with a low incidence of liver toxicity. However, no improvement in quality of life was seen.

Shape stabilised phase change materials based on a high melt viscosity HDPE and paraffin waxes

Shape stabilised phase change materials (SSPCMs) based on a high density poly(ethylene)(hv-HDPE) with high (H-PW, Tm = 56–58 °C) and low (L-PW, Tm = 18–23 °C) melting point paraffin waxes were readily prepared using twin-screw extrusion. The thermo-physical properties of these materials were assessed using a combination of techniques and their suitability for latent heat thermal energy storage (LHTES) assessed. The melt processing temperature (160 °C) of the HDPE used was well below the onset of thermal decomposition of H-PW (220 °C), but above that for L-PW (130 °C), although the decomposition process extended over a range of 120 °C and the residence time of L-PW in the extruder was <30 s. The SSPCMs prepared had latent heats up to 89 J/g and the enthalpy values for H-PW in the respective blends decreased with increasing H-PW loading, as a consequence of co-crystallisation of H-PW and hv-HDPE. Static and dynamic mechanical analysis confirmed both waxes have a plasticisation effect on this HDPE. Irrespective of the mode of deformation (tension, flexural, compression) modulus and stress decreased with increased wax loading in the blend, but the H-PW blends were mechanically superior to those with L-PW.

Extent and mechanism of phase separation during the extrusion of calcium phosphate pastes

The aim of this study was to increase understanding of the mechanism and dominant drivers influencing phase separation during ram extrusion of calcium phosphate (CaP) paste for orthopaedic applications. The liquid content of extrudate was determined, and the flow of liquid and powder phases within the syringe barrel during extrusion were observed, subject to various extrusion parameters. Increasing the initial liquid-to-powder mass ratio, LPR, (0.4-0.45), plunger rate (5-20 mm/min), and tapering the barrel exit (45°-90°) significantly reduced the extent of phase separation. Phase separation values ranged from (6.22 ± 0.69 to 18.94 ± 0.69 %). However altering needle geometry had no significant effect on phase separation. From powder tracing and liquid content determination, static zones of powder and a non-uniform liquid distribution was observed within the barrel. Measurements of extrudate and paste LPR within the barrel indicated that extrudate LPR remained constant during extrusion, while LPR of paste within the barrel decreased steadily. These observations indicate the mechanism of phase separation was located within the syringe barrel. Therefore phase separation can be attributed to either; (1) the liquid being forced downstream by an increase in pore pressure as a result of powder consolidation due to the pressure exerted by the plunger or (2) the liquid being drawn from paste within the barrel, due to suction, driven by dilation of the solids matrix at the barrel exit. Differentiating between these two mechanisms is difficult; however results obtained suggest that suction is the dominant phase separation mechanism occurring during extrusion of CaP paste.

Placental antioxidant enzyme status and lipid peroxidation in pregnant women with type 1 diabetes: The effect of vitamin C and E supplementation

AIM: In view of the increased rates of pre-eclampsia observed in diabetic pregnancy and the lack of ex vivo data on placental biomarkers of oxidative stress in T1 diabetic pregnancy, the aim of the current investigation was to examine placental antioxidant enzyme status and lipid peroxidation in pregnant women with type 1 diabetes. A further objective of the study was to investigate the putative impact of vitamin C and E supplementation on antioxidant enzyme activity and lipid peroxidation in type 1 diabetic placentae.

METHODS: The current study measured levels of antioxidant enzyme [glutathione peroxidase (Gpx), glutathione reductase (Gred), superoxide dismutase (SOD) and catalase] activity and degree of lipid peroxidation (aqueous phase hydroperoxides and 8-iso-prostaglandin F2α) in matched central and peripheral samples from placentae of DAPIT (n=57) participants. Levels of vitamin C and E were assessed in placentae and cord blood.

RESULTS: Peripheral placentae demonstrated significant increases in Gpx and Gred activities in pre-eclamptic in comparison to non-pre-eclamptic women. Vitamin C and E supplementation had no significant effect on cord blood or placental levels of these vitamins, nor on placental antioxidant enzyme activity or degree of lipid peroxidation in comparison to placebo-supplementation.

CONCLUSION: The finding that maternal supplementation with vitamin C/E does not augment cord or placental levels of these vitamins is likely to explain the lack of effect of such supplementation on placental indices including antioxidant enzymes or markers of lipid peroxidation.

Effect of reinforcement and heat treatment on elevated temperature sliding of electroless Ni–P/SiC composite coatings

The investigation is focused on the wear behaviour at elevated test temperature of composite Ni–P/SiC deposit, with varying concentration of the reinforcing SiC particles. The phase evolution measured by X-ray diffraction suggests slight crystallisation during wear testing at 200 °C. In coating without reinforcing particles, adhesive wear is accompanied by microcracks. The thermal heat generated and the cyclic loading could have induced sub-surface microcracks. Owing to the effective matrix-ceramics system in composite coatings, fine grooves, abrasive polishing and uniform wearing are observed. Reinforcing particles in the matrix hinder microcrack formation and significantly reduce the wear rate. Triboxidation is confirmed from energy dispersive X-ray spectrometry.

Studies into the effect of temperature on the impact of model particles in co-melt granulation

In co-melt granulation, collisions occur between the particles to be agglomerated and the binder material. Depending on the stage of granulation, the binder material can be in the solid or liquid phase. The outcome of these collisions controls the dynamics of the granulation process and the fundamental physics of the impacts are of interest. This paper examines the impact of glass beads (model particles) and solid Poly Ethylene Glycol (PEG) flakes on a substrate of PEG as the temperature of the PEG layer is increased from below its melting point to above it. While the layer is in the solid state, the result of the impact can be quantified by the coefficient of restitution. When the layer is in the liquid state, the impact can be quantified by the immersion behaviour. The results obtained show that the coefficient of restitution between either glass beads and PEG flakes and the PEG layer is strongly affected by temperatures. As the PEG layer approaches its melting point, the coefficient of restitution falls to zero. Once the temperature of the PEG layer exceeds the melting point, the impact is characterised by a transient maximum indentation and then rebound to an equilibrium position. These too are strongly dependent on temperature.

Beneficial effect of a polyphenol-rich diet on cardiovascular risk: a randomised control trial

OBJECTIVES: There is previous epidemiological evidence that intake of polyphenol-rich foods has been associated with reduced cardiovascular disease risk. We aimed to investigate the effect of increasing dietary polyphenol intake on microvascular function in hypertensive participants.

METHODS: All participants completed a 4-week run-in phase, consuming <2 portions of fruit and vegetables (F&V) daily and avoiding berries and dark chocolate. Subjects were then randomised to continue with the low-polyphenol diet for 8 weeks or to consume a high-polyphenol diet of six portions F&V (including one portion of berries/day and 50 g of dark chocolate). Endothelium-dependent (acetylcholine, ACh) and endothelium-independent (sodium nitroprusside) vasodilator responses were assessed by venous occlusion plethysmography. Compliance with the intervention was measured using food diaries and biochemical markers.

RESULTS: Final analysis of the primary endpoint was conducted on 92 participants. Between-group comparison of change in maximum % response to ACh revealed a significant improvement in the high-polyphenol group (p=0.02). There was a significantly larger increase in vitamin C, carotenoids and epicatechin in the high-polyphenol group (between-group difference p<0.001; p<0.001; p=0.008, respectively).

CONCLUSIONS: This study has shown that increasing the polyphenol content of the diet via consumption of F&V, berries and dark chocolate results in a significant improvement in an established marker of cardiovascular risk in hypertensive participants.