Dry powder inhaler (DPI) products have traditionally comprised a simple formulation of micronised drug mixed with a carrier excipient, typically lactose monohydrate. The presence of the carrier is ...aimed at overcoming issues of poor flowability and dispersibility, associated with the cohesive nature of small, micronised active pharmaceutical ingredient (API) particles. Both the powder blend and the DPI device must be carefully designed so as to ensure detachment of the micronised drug from the carrier excipient on inhalation.
Over the last two decades there has been a significant body of research undertaken on the design of carrier-free formulations for DPI products. Many of these formulations are based on sophisticated particle engineering techniques; a common aim in formulation design of carrier-free products being to reduce the intrinsic cohesion of the particles, while maximising dispersion and delivery from the inhaler. In tandem with the development of alternative formulations has been the development of devices designed to ensure the efficient delivery and dispersion of carrier-free powder on inhalation. In this review we examine approaches to both the powder formulation and inhaler design for carrier-free DPI products.
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It has been postulated that synaptic potentiation during waking is offset by a homoeostatic reduction in net synaptic strength during sleep. However, molecular mechanisms to support such a process ...are lacking. Here we demonstrate that deficiencies in the RNA-editing gene Adar increase sleep due to synaptic dysfunction in glutamatergic neurons in Drosophila. Specifically, the vesicular glutamate transporter is upregulated, leading to over-activation of NMDA receptors, and the reserve pool of glutamatergic synaptic vesicles is selectively expanded in Adar mutants. Collectively these changes lead to sustained neurotransmitter release under conditions that would otherwise result in synaptic depression. We propose that a shift in the balance from synaptic depression towards synaptic potentiation in sleep-promoting neurons underlies the increased sleep pressure of Adar-deficient animals. Our findings provide a plausible molecular mechanism linking sleep and synaptic plasticity.
Ciprofloxacin (CIP) is a poorly soluble drug that also displays poor permeability. Attempts to improve the solubility of this drug to date have largely focused on the formation of crystalline salts ...and metal complexes. The aim of this study was to prepare amorphous solid dispersions (ASDs) by ball milling CIP with various polymers. Following examination of their solid state characteristics and physical stability, the solubility advantage of these ASDs was studied, and their permeability was investigated via parallel artificial membrane permeability assay (PAMPA). Finally, the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of the ASDs were compared to those of CIP. It was discovered that acidic polymers, such as Eudragit L100, Eudragit L100-55, Carbopol, and HPMCAS, were necessary for the amorphization of CIP. In each case, the positively charged secondary amine of CIP was found to interact with carboxylate groups in the polymers, forming amorphous polymeric drug salts. Although the ASDs began to crystallize within days under accelerated stability conditions, they remained fully X-ray amorphous following exposure to 90% RH at 25 °C, and demonstrated higher than predicted glass transition temperatures. The solubility of CIP in water and simulated intestinal fluid was also increased by all of the ASDs studied. Unlike a number of other solubility enhancing formulations, the ASDs did not decrease the permeability of the drug. Similarly, no decrease in antibiotic efficacy was observed, and significant improvements in the MIC and MBC of CIP were obtained with ASDs containing HPMCAS-LG and HPMCAS-MG. Therefore, ASDs may be a viable alternative for formulating CIP with improved solubility, bioavailability, and antimicrobial activity.
Fish samples initially collected by local veterinarians on the common and koi carp farms in Poland between 2013 and 2015 as part of a KHV surveillance programme, when the water temperature was ...between 16 and 26 °C, and were also tested for CEV by qPCR. A partial 478 nucleotide fragment of the 4a gene was subsequently generated from 17 qPCR‐positive common carp Cyprinus carpio samples from 36 farm sites tested during the period. Sequence alignments and analysis revealed the presence of CEV in Poland both in common carp as well as in koi carp farms, and phylogenetic analysis assigned the Polish CEV sequences into three distinct genogroups. A lineage which includes the original sequences obtained from koi carp in Japan (genogroup II) included sequences from both koi carp and common carp, and the second lineage (genogroup I) contained sequences from common carp only. A third lineage (genogroup III) which was more closely related to the genogroup II also consisted of sequences from common carp only. The latter represents a lineage of CEV not previously described in the literature.
In this article we study the effectiveness of three well-known polymers: inulin, Soluplus, and PVP in stabilizing the amorphous form of nimesulide (NMS) drug. The recrystallization tendency of pure ...drug as well as measured drug–polymer systems were examined at isothermal conditions by broadband dielectric spectroscopy (BDS) and at nonisothermal conditions by differential scanning calorimetry (DSC). Our investigation has shown that the crystallization half-life time of pure NMS at 328 K is equal to 33 min. We found that this time can be prolonged to 40 years after adding 20% w/w PVP to NMS. This polymer proved to be the best NMS stabilizer, while the worst stabilization effect was exhibited by inulin. Additionally, our DSC, BDS, and FTIR studies indicate that for suppression of NMS recrystallization in the NMS–PVP system, the two mechanisms are responsible: the polymeric steric hindrances and the antiplastization effect exerted by the excipient.
Objectives
Cocrystallization of sulfadimidine (SDM) with suitable coformers, such as 4‐aminosalicylic acid (4‐ASA), combined with changes in the crystal habit can favourably alter its physicochemical ...properties. The aim of this work was to engineer SDM : 4‐ASA cocrystals with different habits to investigate the effect on dissolution, and the derived powder properties of flow and compaction.
Methods
Cocrystals were prepared in a 1 : 1 molar ratio by solvent evaporation using ethanol (habit I) or acetone (habit II), solvent evaporation followed by grinding (habit III) and spray drying (habit IV).
Key findings
Powder X‐ray diffraction showed Bragg peak position was the same in all the solid products. The peak intensity varied, indicating different preferred crystal orientation confirmed by SEM micrographs: large prismatic crystals (habit I), large plate‐like crystals (habit II), small cube‐like crystals (habit III) and microspheres (habit IV). The habit III exhibited the fasted dissolution rate; however, it underwent a polymorphic transition during dissolution. Habits I and IV exhibited the highest Carr's compressibility index, indicating poor flowability. However, habits II and III demonstrated improved flow. Spray drying resulted in cocrystals with improved compaction properties.
Conclusions
Even for cocrystals with poor pharmaceutical characteristics, a habit can be engineered to alter the dissolution, flowability and compaction behaviour.
Ionic liquids (ILs) are key materials for the development of a wide range of emerging technologies. Protic ionic liquids, an important class of ILs, have long been envisioned as promising anhydrous ...electrolytes for fuel cells. It is well known that in comparison to all other cations, protons exhibit abnormally high conductivity in water. Such superprotonic dynamics was expected in protic ionic conductors as well. However, many years of extensive studies led to the disappointing conclusion that this is not the case and most protic ionic liquids display subionic behavior. Therefore, the relatively low conductivity seems to be the main obstacle for the application of protic ionic liquids in fuel cells. Using dielectric spectroscopy, herein we report the observation of highly decoupled conductivity in a newly synthesized protic ionic conductor. We show that its proton transport is strongly decoupled from the structural relaxation, in terms of both temperature dependence and characteristic rates. This finding offers a fresh look on the charge transport mechanism in PILs and also provides new ideas for design of anhydrous materials with exceptionally high proton conductivity.
Using dielectric spectroscopy, we report the observation of highly decoupled conductivity in a newly synthesized protic ionic conductor, lidocaine di-(dihydrogen phosphate).
This study for the first time investigates physicochemical properties of amorphous indapamide drug (IND), which is a known diuretic agent commonly used in the treatment of hypertension. The ...solid-state properties of the vitrified, cryomilled and ball-milled IND samples were analyzed using X-ray powder diffraction (XRD), mass spectrometry, nuclear magnetic resonance (NMR), infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC) and broadband dielectric spectroscopy (BDS). These analytical techniques enabled us (i) to confirm the purity of obtained amorphous samples, (ii) to describe the molecular mobility of IND in the liquid and glassy state, (iii) to determine the parameters describing the liquid-glass transition i.e. T g and dynamic fragility, (iv) to test the chemical stability of amorphous IND in various temperature conditions and finally (v) to confirm the long-term physical stability of the amorphous samples. These studies were supplemented by density functional theory (DFT) calculations and apparent solubility studies of the amorphous IND in 0.1 M HCl, phosphate buffer (pH = 6.8), and water (25 and 37 °C).
The proposed approach to two-component speciation analysis relies on simultaneous application of two calibration methods to determination of two different forms of an analyte. One form is determined ...in extrapolative way, whereas the second form is determined in interpolative way, with the use of the same calibration graph, after appropriate chemical treatment, e.g. oxidation or reduction. The applicability of the approach has been verified on the examples of spectrophotometric determinations of Fe(II)/Fe(III) and Cr(VI)/Cr(III) using 1,10-phenanthroline and 1,5-diphenylcarbazide methods, respectively. In the above methods, ascorbic acid and Ce(IV) have been used to reduce Fe(III) to Fe(II) and to oxidize Cr(III) to Cr(VI), respectively. Lab-In-Syringe and SIA systems (for determination of iron and chromium species, respectively) have been applied to make the implementation of the proposed approach more convenient. The approach was verified on the example of determination of the analytes in synthetic and certified reference materials of ground and waste water samples. Using the developed methods, Fe(II)/Fe(III) and Cr(VI)/Cr(III) were determined within the concentration ranges of 0.06–4.0/0.06–3.0 and 0.03–0.5/0.05–7.0mgL−1, with precision (RSD, %) less than 3.8/2.0 and 2.2/6.0, and accuracy (RE, %) better than 2.9/4.3 and 6.8/5.2, respectively. The detection limits (mgL−1) are 0.02/0.02 and 0.01/0.02 for determination of both forms of iron and chromium, respectively. The applicability of the approach has been checked by analysis of artesian water (Fe(II)/Fe(III)) and post-production waste samples (Cr(III)/Cr(VI)).
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•Novel approach to two-component speciation analysis is proposed.•Two calibration methods have been applied to the determinations.•One form of the analyte is determined in extrapolative way.•Second form is determined in interpolative way using the same calibration graph. Fe(II)/Fe(III) and Cr(III)/Cr(VI) were determined in Lab-In-Syringe and SIA systems.
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