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In the pharmaceutical industry, in vitro dissolution testing ofsolid oral dosage forms is a very important tool for drug development and quality control. However, ion-pairing ...interaction between the ionic drugand surfactants in dissolution medium often occurs, resulting in inconsistent and incomplete drug release. The aim of this study is toevaluate the effects ofsodium dodecyl sulfate (SDS) mediated medium onthe dissolution behaviors of a poorly soluble cationic drug (Drug B). The study was carried out by measuring solubility of Drug B substance and dissolution rate of Drug B product in media containing SDS.Desolubilization of Drug B substance was observed at pH 4.5 in the presence of SDS at concentrations below critical micelle concentration (CMC) which is attributed to the formation of an insoluble di-dodecyl sulfate salt between SDS and Drug B. This ion-pairing effect is less significant with increasing medium pH where Drug B is less ionized and CMC of SDS is lower. In medium at pH 4.5, dissolution of Drug B product was found incomplete with SDS concentration below CMC due to the desolubilization of Drug B substance. In media with SDS level above CMC, the dissolution rate is rather slower with higher inter-vessel variations compared to that obtained in pH 4.5 medium without SDS. The dissolution results demonstrate that the presence of SDS in medium generates unexpected irregular dissolution profiles for Drug B which are attributed to incompatible dissolution medium for this particular drug. Therefore, non-ionic surfactant was selected for Drug B product dissolution method and ion-pairing effect in SDS mediated medium should be evaluated when developing a dissolution method for any poorly soluble cationic drugs.
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•Simple HPLC methods developed for siRNA determination in lipid nanoparticle formulation.•A practical approach to the traditionally used size exclusion chromatography methodology with ...greater sensitivity.•The method demonstrated adequate accuracy, precision, sensitivity and robustness.
This paper describes the development of simple and user-friendly HPLC methods that can quantitate the amount of small interfering RNA (siRNA) in lipid-based nanoparticle (LNP) formulations. The methods have been used as alternative chromatographic approaches to the size exclusion chromatography in order to perform “fit for purpose” analysis such as determining the amount of released siRNA from LNP formulations as a part of in-vitro release testing. Two HPLC conditions were optimized using reversed phase (a 250 × 4.6 mm Waters XSelect CSH column) and cation exchange columns (a 250 × 4.6 mm Zorbax SCX-300 column) maintained at 30 °C with a mobile phase of 0.1 M ammonium bicarbonate aqueous solution containing 20–30% acetonitrile. All the siRNA variants were excluded from pores in stationary phase and led to a single peak eluted earlier than the solvent front. The impact of chromatographic conditions and column configurations on method specificity, accuracy, and sensitivity have been investigated. Validation data for both methods in terms of precision, linearity, accuracy and sensitivity are also presented.
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•A simple RPLC method was developed for a polymeric impurity in drug substance and product.•Overcome several challenges of polymer quantitation such as band broadening, peak coeluting ...and low sensitivity.•The method demonstrated adequate accuracy, precision, sensitivity and robustness.
This paper describes the development of a simple reversed-phase HPLC method that can quantitate trace amounts of a polymeric degradants (BMT-041910) in asunaprevir drug substance and formulated drug product with quantitation limits of ∼0.05% w/w. The method has overcome several challenges of polymer quantitation such as band broadening, peak coeluting and low sensitivity. The hydrophobic function group (BOC) of BMT-041910 is removed to increase its aqueous solubility by a simple sample treatment procedure (des-BOC). The des-BOC polymer (BMT-052076) is excluded from stationary phase pores and eluted as a single peak before solvent front, and then its peak area response can be used to determine BMT-041910 amount. The HPLC conditions were optimized using a 250 × 4.6 mm Waters XSelect CSH column maintained at 30 °C with a mobile phase of water-acetonitrile-trifluoroacetic acid (20:80:0.1 v/v/v). The feasibility of other HPLC approaches including size exclusion chromatography and normal phase chromatography were also investigated and found to be less suitable for this particular application. Validation data for this method in terms of precision, linearity, accuracy and sensitivity are also presented.
In the pharmaceutical industry, the analysis of atropisomers is of considerable interest from both scientific and regulatory perspectives. The compound of interest contains two stereogenic axes due ...to the hindered rotation around the single bonds connecting the aryl groups, which results in four potential configurational isomers(atropisomers). The separation of the four atropisomers was achieved on a derivatized β-cyclodextrin bonded stationary phase. Further investigation showed that low temperature conditions, including sample preparation(?70 °C), sample storage (?70 °C), and chromatographic separation (6 °C), were critical to preventing interconversion. LC-UV-laser polarimetric analysis identified peaks 1 and 2 as a pair of enantiomers and peaks3 and 4 as another. Thermodynamic analysis of the retention data indicated that the separation of the pairs of enantiomers is primarily enthalpy controlled as indicated by the positive slope of the van’t Huff plot. The difference in absolute Δ (Δ H), ranged from 2.20 kJ/mol to 2.42 kJ/mol.
In this paper, I begin to explore what a naïve realist might say about the phenomenology of episodic memory. I start by arguing that, when it comes to accounting for the phenomenology of memory ...experiences, there are two primary options available to the naïve realist: to treat memory phenomenology along the same lines as perceptual phenomenology – as involving phenomenal character that is grounded in acquaintance with the external environment – or to treat memory as lacking such acquaintance-based phenomenal character, and then attempting to account for there being something it is like to remember as being somehow inherited from cases that do have phenomenal character. I then explore the prospects of providing an account of the phenomenology of episodic memory in both ways, before tentatively coming down in favour of the latter approach
In this paper, I begin to explore what a naive realist might say about the phenomenology of episodic memory. I start by arguing that, when it comes to accounting for the phenomenology of memory ...experiences, there are two primary options available to the naive realist: to treat memory phenomenology along the same lines as perceptual phenomenology--as involving phenomenal character that is grounded in acquaintance with the external environment--or to treat memory as lacking such acquaintance-based phenomenal character, and then attempting to account for there being something it is like to remember as being somehow inherited from cases that do have phenomenal character. I then explore the prospects of providing an account of the phenomenology of episodic memory in both ways, before tentatively coming down in favour of the latter approach. Keywords: naive realism; phenomenology; acquaintance; episodic memory; imagination; mental time travel. Neste artigo, comeco a explorar o que um realista ingenuo pode dizer sobre a fenomenologia da memoria episodica. Inicio argumentando que, no que concerne aexplicacao da fenomenologia das experiencias mnemicas, existem duas opcoes principais disponiveis para o realista ingenuo: tratar a fenomenologia da memoria de modo similar a fenomenologia da percepcao--como envolvendo carater fenomenico que esta baseado em 'acquaintance' com o ambiente externo--ou tratar a memoria como nao tendo carater fenomenico baseado em 'acquaintance' e entao tentar explicar como e ter a experiencia do lembrar como sendo derivada de casos que 'possuem' carater fenomenico. Exploro entao as perspectivas de se oferecer uma explicacao da fenomenologia da memoria episodica dos dois modos, antes de favorecer, de modo provisorio, a ultima abordagem. Palavras-chave: realismo ingenuo; fenomenologia; acquaintance; memoria episodica; imaginacao; viagem no tempo mental.
In this paper, I begin to explore what a naive realist might say about the phenomenology of episodic memory. I start by arguing that, when it comes to accounting for the phenomenology of memory ...experiences, there are two primary options available to the naive realist: to treat memory phenomenology along the same lines as perceptual phenomenology--as involving phenomenal character that is grounded in acquaintance with the external environment--or to treat memory as lacking such acquaintance-based phenomenal character, and then attempting to account for there being something it is like to remember as being somehow inherited from cases that do have phenomenal character. I then explore the prospects of providing an account of the phenomenology of episodic memory in both ways, before tentatively coming down in favour of the latter approach.
Fish argues that we have no good reason to think that the properties that appear in the sensory, presentational element are restricted to basic properties, such as color, shape, and motion. In part ...1, I begin by clarifying the nature of the taxonomic question under investigation before moving, in part 2, to investigate the prospects for using a phenomenological methodology for answering this question. As we shall see, although some have claimed this methodology demonstrates that the sensory, presentational component is limited to basic properties, the methodology yields different answers in the hands of different theorists. With this in mind, I suggest that the deliverances of this methodology should not be relied upon. In part 3, I then consider potential alternative methodologies that appeal to empirical findings, and show that not one of these methodologies can be used to deliver the verdict that the presentational element is restricted to basic properties. I conclude, in part 4, with the suggestion that there are no compelling reasons to think that higher-level properties do not feature in the sensory, presentational component of visual experiences.
Lipid nanoparticle (LNP) formulations have been used to encapsulate and deliver small interfering RNAs (siRNAs) to the in-vivo targets for gene silencing through an intravenous (IV) administration. ...Diethylhexyl phthalate (DEHP), a commonly used plasticizer, is often present in IV bag materials and could be potentially leached into parental drug products. In this study, we investigated the extent of DEHP leaching in IV bags with LNP saline solution over a use time of administration for 24 h. The data showed that the amount of DEHP in LNP saline solution increased with increasing time in contact with IV bag materials and exceeded the safety limit set by FDA (3 mg per day or 30 ppm according to proposed dose) after 8 h. DEHP amount in the bagged LNP saline solution was also found increased with increasing concentration of LNP in the IV bag, suggesting that DEHP leaching is primarily attributed to the presence of lipophilic LNP formulation. The effect of leached DEHP on encapsulation efficiency was also examined and no impact was observed. The results demonstrated that LNP drug product should be administrated using DEHP-free IV bags.
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•Leachability of diethylhexyl phthalate (DEHP) from IV bags in the presence of lipid nanoparticle (LNP) formulation has been investigated.•DEHP amount in LNP saline solution exceeded the safety limit set by FDA (3 mg per day) after 8 h in contact with IV bag materials.•Although LNP integrity was not impacted by increasing DEHP level in LNP saline solution, standard IV bags (containing DEHP) is not recommended for administrating lipid containing formulations.
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