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[Display omitted] Aptamers have shown significant potential in treating diverse diseases. However, challenges such as stability and drug delivery limited their clinical application. In this paper, the development of AS1411 prodrug-type aptamers for tumor treatment was introduced. A Short oligonucleotide was introduced at the end of the AS1411 sequence with a disulfide bond as responsive switch. The results indicated that the aptamer prodrugs not only enhanced the stability of the aptamer against nuclease activity but also facilitated binding to serum albumin. Furthermore, in the reducing microenvironment of tumor cells, disulfide bonds triggered drug release, resulting in superior therapeutic effects in vitro and in vivo compared to original drugs. This paper proposes a novel approach for optimizing the structure of nucleic acid drugs, that promises to protect other oligonucleotides or secondary structures, thus opening up new possibilities for nucleic acid drug design. [ABSTRACT FROM AUTHOR]

Actively targeted nanomedicines though conceptually attractive for tumor therapy are extremely hard to realize due to problems of premature drug leakage, excessive liver accretion, inadequate tumor uptake, and/or retarded drug release inside tumor cells. Here, we systemically studied the influence of disulfide crosslinking on the in vitro and in vivo performance of integrin-targeting micellar docetaxel (t-MDTX). Of note, t-M5DTX with a high disulfide content was clearly advantageous in terms of stability, intracellular drug release, anti-tumor activity toward α V β 3 -overexpressing A549 cells, blood circulation and therapeutic efficacy in orthotopic A549-luc lung tumor-bearing mice. t-MDTX induced extraordinary tumor targetability with tumor-to-normal tissue ratios of 1.7–8.3. Further studies indicated that t-M5DTX could effectively eradicate α V β 3 -overexpressing lung and prostate cancer patient-derived xenografts (PDX), in which ca. 80% mice became tumor-free. This integrin-targeting disulfide-crosslinked micellar docetaxel emerges as a promising actively targeted nanoformulation for tumor therapy. Nanomedicines have a great potential in treating advanced tumor patients; however, their tumor-targeting ability and therapeutic efficacy remain unsatisfactory. In addition to PEGylation and ligand selection, particle size, stability and drug release behavior are also critical to their performance in vivo. In this paper, we find that small and cRGD-guided disulfide-crosslinked micellar docetaxel (t-MDTX) induces superior tumor uptake and retention but without increasing liver burden, leading to extraordinary selectivity and inhibition of α v β 3 overexpressing lung tumors. t-MDTX is further shown to effectively treat α v β 3 -positive patient-derived tumor models, lending it a high potential for clinical translation. [Display omitted] [ABSTRACT FROM AUTHOR]

High inter-laboratory reproducibility is required for conducting collaborative experiments among several laboratories. The primary aim of our evaluation of the physical stability of amorphous drugs, conducted in co-operation with eight laboratories, was to establish a protocol for isothermal storage tests to obtain data of the same quality from all the participating laboratories. Sharing a protocol that contained the same level of detail as the experimental section of general papers was insufficient for high inter-laboratory reproducibility. We investigated the causes of variations in the data from the various laboratories and restricted the protocol step-by-step to achieve high inter-laboratory reproducibility. The various experimentalists had very different levels of awareness regarding how to control the temperature of a sample as the samples were transferred into and out of thermostatic chambers. Specific instructions on how to conduct this operation, such as regarding the time required for the transfer and thermal protection of the container during the transfer, helped to reduce variation. Improved inter-laboratory reproducibility revealed that the physical stabilities of amorphous drugs differed when samples were prepared in differently shaped aluminum pans designed for various differential scanning calorimeters. [ABSTRACT FROM AUTHOR]

Prefilled syringes (PFS) as a primary container for parenteral drug products offer significant advantages, such as fast delivery time, ease of self-administration and fewer dosing errors. Despite the benefits that PFS can provide to patients, the silicone oil pre-coated on the glass barrels has shown migration into the drug product, which can impact particle formation and syringe functionality. Health authorities have urged product developers to better understand the susceptibility of drug products to particle formation in PFS due to silicone oil. In the market, there are multiple syringe sources provided by various PFS suppliers. Due to current supply chain shortages and procurement preferences for commercial products, the PFS source may change in the middle of development. Additionally, health authorities require establishing source duality. Therefore, it is crucial to understand how different syringe sources and formulation compositions impact the drug product quality. Here, several design of experiments (DOE) are executed that focus on the risk of silicone oil migration induced by syringe sources, surfactants, protein types, stress, etc. We utilized Resonant Mass Measurement (RMM) and Micro Flow Imaging (MFI) to characterize silicone oil and proteinaceous particle distribution in both micron and submicron size ranges, as well as ICP-MS to quantify silicon content. The protein aggregation and PFS functionality were also monitored in the stability study. The results show that silicone oil migration is impacted more by syringe source, siliconization process and surfactant (type & concentration). The break loose force and extrusion force across all syringe sources increase significantly as protein concentration and storage temperature increase. Protein stability is found to be impacted by its molecular properties and is less impacted by the presence of silicone oil, which is the same inference drawn in other literatures. A detailed evaluation described in this paper enables a thorough and optimal selection of primary container closure and de-risks the impact of silicone oil on drug product stability. [ABSTRACT FROM AUTHOR]

Recently, concerns have been raised about the safety of titanium dioxide (TiO 2), a commonly used component of pharmaceutical film coatings. The European Union has recently prohibited the application of this material in the food industry, and it is anticipated that the same will happen in the pharmaceutical industry. For this reason, pharmaceutical manufacturers have to consider the possible impact of removing TiO 2 from the film coating of tablets. In this paper, we present a case study of a commercially produced tablet where the film coating containing TiO 2 was replaced with a coating using calcium carbonate (CaCO 3) or with a transparent coating. The performance of the coatings was compared by measuring the moisture absorption rate and the dissolution profile of the tablets. In these regards, there were negligible differences between the coating types. The tablets contained a highly photosensitive drug, the ability of the coatings to protect the drug was evaluated through environmental stability and photostability measurements. The HPLC results showed that the inclusion of TiO 2 does not provide additional benefits, when humidity and thermal stress is applied, however its role was vital in protecting the drug from external light. There were several decomposition products which appeared in large quantities when TiO 2 was missing from the coating. These results imply that photosensitivity is an issue, replacing TiO 2 will be challenging, though its absence can be tolerated when the drug does not need to be protected from light. [Display omitted] [ABSTRACT FROM AUTHOR]

Long-term space missions must be prepared to provide means to treat astronauts' illnesses that could occur at take-off, during flights or arriving on other planets. This could be achieved using multipurpose medicines. Phenothiazine derivatives, normally used to treat mental and emotional disorders, are photosensitive drugs and in solutions undergo molecular modifications by exposure to UV laser radiation, which leads to transformation of a parent-compound into photoproducts with increased antimicrobial activity when compared to unirradiated solutions. Since space missions involve, even if only for short durations, hypergravity environment transitions, their effects on unirradiated and laser irradiated chlorpromazine and promazine aqueous solutions were studied in this paper. The experiment was performed at the European Space Agency's Large Diameter Centrifuge, subjecting solutions at 20 times Earth's gravitational acceleration. Since, generally, little is known about medicines exposed to high-g levels, this research brings an insight into the impact of hypergravity on phenothiazines. To evaluate drug stability, samples were assessed pre- and post-hypergravity treatment by pH measurements, UV-Vis-NIR/FTIR spectroscopy and thin layer chromatography. No significant changes between uncentrifuged and centrifuged samples were evidenced subsequent to hypergravity exposure, emphasising the stability of unirradiated and laser irradiated phenothiazines, which may allow their use during future space missions. [Display omitted] • Aqueous phenothiazine solutions irradiated at 266 nm by a Nd:YAG pulsed laser. • Unexposed and laser exposed phenothiazines subjected to hypergravity conditions. • Drugs studied by: pH, UV-Vis-NIR/FTIR spectroscopy and thin layer chromatography. • Drug stability in function of gravitational conditions: terrestrial vs hypergravity. • Research dedicated to future implementation of phenothiazines in space missions. [ABSTRACT FROM AUTHOR]

The stability of self-assembled drug nanocarriers during blood circulation and the controlled intracellular drug delivery are two challenges in cancer therapy. In this paper, we constructed an adenosine triphosphate (ATP)/hyaluronidase(Hyals) dually responsive core-shell hyaluronan/chitosan-based drug nanocarrier for breast cancer therapy, using SNX-loaded 3-fluoro-4-carboxyphenylboronic acid-conjugated quaternary ammonium chitosan nanoparticles (SNX@HTCC-FPBA NPs) as the core and crosslinked polyethylene glycol-/methacrylate-modified hyaluronic acid (mHA-PEG) as the shell. The formed SNX@HTCC-FPBA/mHA-PEG NPs were stable against salt ion strength, pH values and human plasma mimicking the bloodstream, but ATP/Hyals dually sensitive with a drug delivery of 85% within 48 h in the mimicking intracellular environment of breast cancer cells. These nanoparticles showed a low hemolysis of less than 3%, a high resistance to bovine serum albumin adsorption of 0.06 mg/mg, and an efficient internalization by two breast cancer cell lines (MCF-7 and MDA-MB-453). The cell culture indicated that they were friendly to human skin fibroblasts, but presented a close IC 50 value to SNX for MCF-7 (0.14 μg mL−1) and MDA-MB-453 (0.05 μg mL−1) at 48 h, respectively. Thus, SNX@HTCC-FPBA/mHA-PEG NPs were potential drug nanocarriers for breast tumor therapy. [ABSTRACT FROM AUTHOR]

Problems of stability were found for biomarkers of alcohol consumption: ethyl glucuronide (EtG), ethyl sulfate (EtS), phosphatidylethanols (PEths), and fatty acid ethyl esters (FAEEs) in whole blood. The purpose of this study was to establish a method for the determination of these four kinds of ethanol's non-oxidative metabolites in dried blood spots (DBS) by liquid chromatography tandem mass spectrometry (LC-MS/MS), and to evaluate their stability. In this method, 50 μL of human blood was spotted onto a filter paper for DBS analysis. Samples were extracted by methanol, reconstituted by 2-propanol, and injected into the LC-MS/MS system. Limits of detection were among 0.5-50 ng/mL, and deviations in accuracy and precision were all lower than 15% at three quality control levels. The stability of the four kinds of ethanol non-oxidative metabolites in DBS was investigated during a 90-day range under three temperatures, -20 °C, 4 °C, and 25 °C. EtG and EtS showed a high level of stability in DBS in the 90-day range, regardless of the temperature. FAEEs were unstable after three days. PEths showed stability within 15 days in postmortem DBS and 60 days in antemortem DBS, respectively, at all temperatures. [ABSTRACT FROM AUTHOR]

Abstract: Bioactive food peptides are encrypted within the sequence of food proteins but can be released during food processing (by enzymatic hydrolysis or fermentation) or during gastrointestinal transit. Among bioactive food peptides, those with antihypertensive activity are receiving special attention due to the high prevalence of hypertension in the Western countries and its role in cardiovascular diseases. This paper reviews the current literature on antihypertensive food peptides, focusing on the main methodologies for their production, such as enzymatic hydrolysis, fermentation and the use of recombinant bacteria. This paper also describes the structure/activity relationship of angiotensin-converting enzyme (ACE)-inhibitory peptides, as well as their bioavailability, physiological effects demonstrated by both in vitro and in vivo assays, and the contribution of mechanisms of action other than ACE inhibition. Finally, current reported strategies for incorporation of antihypertensive peptides into foods and their effects on both availability and activity are revised in this manuscript. [Copyright &y& Elsevier]

Abstract: This Part I paper describes the qualification of a new high performance hypromellose (hydroxypropyl methylcellulose, HPMC) capsule shell which contains no gelling agent and is dissolution friendly. The development history and the test results for a series of quality attributes including scanning electron microscopy, hygroscopicity, machineability, weight variation, powder leakage, mechanical strength, stability, cross-linking, animal and human pharmacokinetic results are reported. Comparisons to gelatin and HPMC capsule containing carrageenan showed the new HPMC capsule is superior in terms of mechanical strength, hygroscopicity and compatibility with a wide range of drugs. Specifically, the new HPMC capsule demonstrated improved weight variation, machineability and powder leakage than the HPMC capsule containing carrageenan. And the new capsule demonstrated a broader applicability than gelatin capsule for new drug development due to its inertness and compatibility for a wide range of excipients including those used for liquid fill formulations. In the second phase of qualification, disintegration and dissolution properties of the new HPMC were evaluated and reported in a Part II paper for 10 new clinical compounds with a variety of formulations optimized based on the biopharmaceutical classification system of solubility and permeability. Based on the superior performance, the new HPMC capsule is satisfactorily qualified and has since been used successfully for nearly 20 investigational new drug (IND) compounds. [Copyright &y& Elsevier]

[Display omitted] • Relatively small PHT based-nanomicelles stabilized with different polymers were obtained. • PTH was largely encapsulated inside the nanomicelles and sustainably released. • PHT established strong hydrogen bonding with polymeric stabilizers inside the micelles. • The present drug-loaded nanoformulation showed a high cell bioactivity and specificity in vitro. Many drugs currently used in clinics to treat different diseases show low solubilities in aqueous solutions and must be then administered with the aid of organic solvents within the designed formulations leading to harmful health effects. For such reason, drug delivery using nanocarriers appears as an excellent alternative since it improves the solubilization and controlled release of many different pharmaceuticals, favoring the decrease of the overall administered therapeutic doses and by diminishing the risk of potential associated adverse side effects. Among the different types of nanocarriers, those based on polymeric micelles are an excellent option since the polymer structure and composition may be tuned in order to regulate the characteristics and properties of the resulting nanoassemblies to maximize drug solubilization and release profiles. For this reason, in this paper a drug delivery nanosystem based on oil-in-water polymeric-based microemulsion used to load the anti-epileptic phenytoin drug (PHT) was developed in the oily phase. Two different biocompatible polymers were evaluated to form the nanomicelles and maximize encapsulation efficiencies and colloidal stability: The amphiphilic triblock copolymer Pluronic F127, which poses the ability to cross the blood brain barrier (BBB), and the natural lipophilic lignin, which bears antipathogenic properties. Density functional theory (DFT) calculations were performed with the 6-31G(d) basis set to elucidate the interactions of PHT with F127 and lignin monomers. Simulation data showed that hydrogen bonding (HB) interactions between PHT, F127 and lignin are the predominant force to allow for drug solubilization and stability. Atoms in molecules (AIM) and natural bond orbital (NBO) analyses were performed to evaluate the strength of such HB. and their drug encapsulation efficiency, release profiles, and antibacterial susceptibility were determined. Moreover, the cytotoxicity of the developed nanoformulations together with a morphological examination of PC12 and NIH cells after drug-loaded nanocarrier administration and subsequent uptake were also investigated. In this manner, the obtained nanocarriers were also characterized by dynamic light scattering (DLS) and zeta potential, showing a nanometer size (between ca. 16 and 22 nm) and surface negative charge. PHT loading into F127 and lignin nanomicelles were ca. 96.7 ± 1.5% and 68.2 ± 3.5%, respectively, and the drug release profile kinetics of F127/PHT-loaded nanomicelles was rather slower compared to that of lignin/PHT-loaded ones. On the other hand, in vitro cytotoxicity data confirmed the lack of any significant cytotoxicity of PHT-loaded nanomicelles in both NIH/3T3 and PC12 cell lines, but a slightly higher cell viability and well-preserved cell morphology was observed for PC12 cells compared to NIH/3T3 ones. After culturing in chocolate blood agar medium inoculated with F127/PHT-loaded and lignin/ PHT-loaded nanomicelles, pathogenic bacteria did not grow despite confirming certain antimicrobial character of the encapsulated drug. Hence, thanks to their excellent encapsulation and biocompatibility properties, these nanocarriers appear as an excellent option to configure new drug delivery nanocarriers of hydrophobic drugs. [ABSTRACT FROM AUTHOR]

[Display omitted] This paper aimed to prepare a Mabuterol (MAB) patch for treating asthma by ion-pair strategy to overcome the drug's thermal instability and elucidate the molecular mechanisms of the stabilization effect. The formulation factor, including counter-ion and pressure-sensitive adhesive (PSA), was optimized by the stability and in vitro skin permeation studies. The molecular mechanism of ion-pair stability was characterized using TGA, Raman, FT-IR, NMR, XPS, and molecular modeling. The optimized patch comprised MAB-Lactic acid (MAB-LA) and hydroxyl adhesive (AAOH) as the matrix, with Q = 126.47 ± 9.75 μg/cm2 and F abs = 75.27%. The increased TGA (213.11 °C), disproportionation energy (Δ G = 97.44 KJ), and ion-pair lifetime (T life = 2.21 × 103) indicated that the counter-ion improved MAB stability through strong ionic and hydrogen bonds with LA. The remaining drug content in the MAB-LA patch was 15% higher than that of the pure MAB patch after storage for 12 months at room temperature, which was visualized by Raman imaging. The interaction between MAB-LA and AAOH PSA via hydrogen bond decreased the diffusion rate and increased the drug stability further. This study successfully developed the MAB patch, which provided a reference for applying ion-pairing strategies to improve the stability of transdermal patches. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract In recent years, the preparation of valuable drug delivery systems (DDS) from self-assembled amphiphilic copolymers has attracted much attention since these nanomaterials provide new opportunities to solve problems such as the lack of solubility in water of lipophilic drugs, improve their bioavailability, prolong their circulation time and decrease the side effects associated with their administration. In the current study two types of biocompatible pH-responsive nanoparticles derived from poly(2-hydroxyethyl methacrylate) (pHEMA) have been used as drug nano-carriers, being one of them core cross-linked to circumvent their instability upon dilution in human fluids. The present paper deals with the optimization of the loading process of the labile, hydrophobic and highly active anticancer drug, Camptothecin (CPT) into the nanoparticles with regard to four independent variables: CPT/polymer ratio, sonication, temperature and loading time. Forty experiments were carried out and a Box–Behnken experimental design was used to evaluate the significance of the independent variables related to encapsulation efficiency and drug retention capacity. The enhanced drug loading and encapsulation efficiency values (58% and >92%, respectively) of CPT were achieved by the core cross-linked NPs in 2 h at 32 °C at CPT/polymer ratio 1.5:1 w/w and 14 min of sonication. The optimized CPT-loaded NPs were studied by dynamic light scattering and scanning electron microscopy, and an increase in size of the loaded-NP compared to the unloaded counterparts was found. Other twenty experiments were conducted to study the enability to retain CPT into the conjugates at different ionic strength values and times. The stability studies demonstrated that the core cross-linked nanocarriers displayed an excellent drug retention capacity (>90%) at 25 °C for 15 days in every ionic-strength environments whereas the non-cross-linked ones were more stable at physiological ionic strength. The optimized systems proved to be a major step forward to encapsulate and retain CPT in the NP nuclei, what makes them ideal devices to control the delivery of CPT upon the triggered acidic conditions of solid tumors. [ABSTRACT FROM AUTHOR]

Functional coatings on Active Pharmaceutical Ingredients (API) are used in the pharmaceutical industry to enhance mechanical strength, enable controlled release, taste masking, reduce formulation complexity and/or to improve drug product stability. Current API coating technologies have many challenges related to coating uniformity and defects, leading to variations in drug performance. This paper discusses using an ultra-thin API coating technology adapted from the semiconductor industry that can address many of the shortcomings of current coating technologies commonly used in the pharmaceutical industry. We show that this technique can achieve uniform and conformal nano-coating on multiple APIs without impacting their specific surface area and particle size distribution. We demonstrate the processability enhancements achieved using these coatings. The improvement in the processability of coated API was compared against uncoated API in commercially relevant unit operations used in the pharmaceutical industry, such as a loss in weight screw feeder and rotary tablet press. [Display omitted] • Atomic layer coating of API for processibility enhancement. • Different Metal Oxide Based Coatings applied on micronized APIs. • Processability enhancement demonstrated in pharmaceutical unit operations. [ABSTRACT FROM AUTHOR]

Polyethylene glycol (PEG) is widely used to sterically stabilize liposomes and improve the pharmacokinetic profile of drugs, peptides and nanoparticles. Here we report that ammonium sulfate (AS) can evoke the aggregation of PEGylated vesicles in a concentration-dependent manner. Liposomes with 5 mol% PEG were colloidally stable at AS concentrations up to 0.7 mM, above which they precipitated and formed micron-size aggregates with irregular shape. While aggregation was reversible up to 0.9 M of AS, above 1 M fusion occurred, which irreversibly distorted the size distribution. Zeta potential of liposomes markedly increased from −71 ± 2.5 mV to 2 ± 0.5 mV upon raising the AS concentration from 0 to 0.1 M, but no considerable increase was seen during further AS addition, showing that the aggregation is independent of surface charge. There was no aggregation in the absence of the PEG chains, and increasing PEG molar% shifted the aggregation threshold to lower AS concentrations. Changes in the FTIR spectral features of PEGylated vesicles suggest that AS dehydrates PEG chains. Other kosmotropic salts also led to aggregation, while chaotropic salts did not, which indicates a general kosmotropic phenomenon. The driving force behind aggregation is likely to be the hydrophobic effect due to salting out the polymer similarly to what happens during protein purification or Hydrophobic Interaction Chromatography. Since liposome aggregation and fusion may result in difficulties during formulation and adverse reaction upon application, the phenomena detailed in this paper may have both technological and therapeutical consequences. [ABSTRACT FROM AUTHOR]

The main goal of this review is to provide a comprehensive overview on the methods used for analysis of cyclodextrins (CDs) and CD-derivatives. The paper intends to act as a guide for the readers in looking around the classical and modern instrumental analytical methods suitable for identification, characterization and determination of CDs themselves, CDs in finished products or even in biological samples. At present, in the European and United States Pharmacopoeias, the three parent CDs and two synthetic derivatives, namely the (2-hydroxypropyl)-beta-CD and sulfobutylether-beta-CD Na salt are official. Besides these modified CDs, two other derivatives are approved as excipients in human pharmaceutical products: the (2-hydroxypropyl)-gamma-CD and the randomly methylated-beta-CD. Although most of the official analysis methods in the pharmacopoeias have been well used for decades, new aspects of the functional excipient CD characterization suggest a need to revisit compendial methods. Comparison of strengths and weaknesses of current official methods with new improved techniques intends to help analysts to decide on changing traditional analytical methods with improved new ones. This review also deals with the analytical aspects of the first single isomer CD derivative approved as a drug active (Sugammadex/Bridion ® ) as well as analytical considerations of using CDs themselves as active pharmaceutical ingredients. Stability-indicating instrumental methods suitable to adequately follow chemical- and enzymatic degradation of CDs will also be discussed. Challenges in the determination of CDs in different biological matrices will be illustrated on real pharmaco- and toxicokinetic studies of CD-enabled drug formulations. [ABSTRACT FROM AUTHOR]

Large molecules, such as biopharmaceuticals, are considered the key driver of growth for the pharmaceutical industry. Freeze-drying is the preferred way to stabilise these products when needed. However, it is an expensive, inefficient, time- and energy-consuming process. During freeze-drying, there are only two main process variables to be set, i.e. the shelf temperature and the chamber pressure, however preferably in a dynamic way. This manuscript focuses on the essential use of uncertainty analysis for the determination and experimental verification of the dynamic primary drying Design Space for pharmaceutical freeze-drying. Traditionally, the chamber pressure and shelf temperature are kept constant during primary drying, leading to less optimal process conditions. In this paper it is demonstrated how a mechanistic model of the primary drying step gives the opportunity to determine the optimal dynamic values for both process variables during processing, resulting in a dynamic Design Space with a well-known risk of failure. This allows running the primary drying process step as time efficient as possible, hereby guaranteeing that the temperature at the sublimation front does not exceed the collapse temperature. The Design Space is the multidimensional combination and interaction of input variables and process parameters leading to the expected product specifications with a controlled (i.e., high) probability. Therefore, inclusion of parameter uncertainty is an essential part in the definition of the Design Space, although it is often neglected. To quantitatively assess the inherent uncertainty on the parameters of the mechanistic model, an uncertainty analysis was performed to establish the borders of the dynamic Design Space, i.e. a time-varying shelf temperature and chamber pressure, associated with a specific risk of failure. A risk of failure acceptance level of 0.01%, i.e. a ‘zero-failure’ situation, results in an increased primary drying process time compared to the deterministic dynamic Design Space; however, the risk of failure is under control. Experimental verification revealed that only a risk of failure acceptance level of 0.01% yielded a guaranteed zero-defect quality end-product. The computed process settings with a risk of failure acceptance level of 0.01% resulted in a decrease of more than half of the primary drying time in comparison with a regular, conservative cycle with fixed settings. [ABSTRACT FROM AUTHOR]

Amorphous solid dispersion formulations have been widely used to enhance bioavailability of poorly soluble drugs. In these formulations, polymer is included to physically stabilize the amorphous drug by dispersing it in the polymeric carrier and thus forming a solid solution. The polymer can also maintain supersaturation and promote speciation during dissolution, thus enabling better absorption as compared to crystalline drug substance. In this paper, we report the use of hot melt extrusion (HME) to develop amorphous formulations of a poorly soluble compound (FaSSIF solubility = 1 μg/mL). The poor solubility of the compound and high dose (300 mg) necessitated the use of amorphous formulation to achieve adequate bioperformance. The effect of using three different polymers (HPMCAS-HF, HPMCAS-LF and copovidone), on the dissolution, physical stability, and bioperformance of the formulations was demonstrated. In this particular case, HPMCAS-HF containing HME provided the highest bioavailability and also had better physical stability as compared to extrudates using HPMCAS-LF and copovidone. The data demonstrated that the polymer type can have significant impact on the formulation bioperformance and physical stability. Thus a thorough understanding of the polymer choice is imperative when designing an amorphous solid dispersion formulation, such that the formulation provides robust bioperformance and has adequate shelf life. [ABSTRACT FROM AUTHOR]

1,4-dihydropyridine antihypertensives (DHPs) are almost all dispensed in solid pharmaceutical formulations for their easy lability when exposed to light. This paper reports a study on the photoprotective effect of containers in different glassy or polymeric matrices with regard to four known DHPs when in solutions. The samples were subjected to forced degradation by means of a Xenon lamp, in accordance with the international rules on drug stability evaluation. The simultaneous determination of the drugs and their photoproducts was carried out by applying the multivariate curve resolution (MCR) methodology to the spectral data recorded along the irradiation test. This technique was able to determine the kinetic parameters and resolve the spectra of the photoproducts. The time required to reduce by 10% the concentration of the drug ( t 0.1 ) was adopted as a criterion to compare the protective ability of the containers. A significant photoprotection for all drugs tested was obtained by the use of polyethylene terephthalate (PET) containers. The best result was achieved for the felodipine solution in blue PET transparent bottle of 0.6 mm thickness, reaching an almost complete stabilization up to six hours under stressing irradiation. In contrast, the glass containers, whether or not coloured, did not provide a satisfactory photoprotection of the drugs, showing in any case t 0.1 values under 24 min. These results can be a good opportunity to design new photoprotective pharmaceutical packaging for DHPs in liquid dosage form. [ABSTRACT FROM AUTHOR]

Practically all medications contain excipients, which are added for the purpose of production enhancement, patient acceptability, improving stability, controlling release etc. Typically excipients are the major components of a drug product, with the active molecule only present in relatively small amounts. Historically, excipients were termed inactive components. However, as highlighted in the present paper; excipients can have an impact on the absorption, distribution, metabolism and elimination (ADME) processes of the co-administered drug, which is important information when selecting excipients for any new formulation. Further, this review also provides a description of the regulatory processes to get new excipients approved in different regions and a discussion of the recent regulatory initiatives, e.g. excipients for paediatric formulations, thereby providing points to consider for the pharmaceutical scientist when selecting excipients for a new drug formulation. [ABSTRACT FROM AUTHOR]

Purpose This paper discussed the influence of microstructure of emulsion membrane on O/W emulsion stability. Methods O/W emulsions were emulsified with equal dosage of egg yolk lecithin and increasing dosage of co-emulsifier (oleic acid or HS15). The average particle size and centrifugal stability constant of emulsion, as well as interfacial tension between oil and water phase were determined. The microstructure of emulsion membrane had been studied by 1 H/ 13 C NMR, meanwhile the emulsion droplets were visually presented with TEM and IFM. Results With increasing dosage of co-emulsifier, emulsions showed two stable states, under which the signal intensity of characteristic group (orient to lipophilic core) of egg yolk lecithin disappeared in NMR of emulsions, but that (orient to aqueous phase) of co-emulsifiers only had some reduction at the second stable state. At the two stable states, the emulsion membranes were neater in TEM and emulsion droplets were rounder in IFM. Furthermore, the average particle size of emulsions at the second stable state was bigger than that at the first stable state. Conclusions Egg yolk lecithin and co-emulsifier respectively arranged into monolayer and bilayer emulsion membrane at the two stable states. The microstructure of emulsion membrane was related to the stability of emulsion. [ABSTRACT FROM AUTHOR]

Stability studies under stress conditions or forced degradation studies play an important role in different phases of development and production of biopharmaceuticals and biological products. These studies are mostly applicable to selection of suitable candidates and formulation developments, comparability studies, elucidation of possible degradation pathways and identification of degradation products, as well as, development of stability indicating methods. Despite the integral part of these studies in biopharmaceutical industry, there is no well-established protocol for the selection of stress conditions, timing of stress testing and required extent of degradation. Therefore, due to the present gap in the stability studies guidelines, it is the responsibility of researchers working in academia and biopharmaceutical industry to set up forced degradation experiments that could fulfill all the expectations from the stability studies of biopharmaceuticals under stress conditions. Concerning the importance of the function of desired stress conditions in forced degradation studies, the present review aims to provide a practical summary of the applicable stress conditions in forced degradation studies of biopharmaceuticals according to the papers published in a time period of 1992–2015 giving detailed information about the experimental conditions utilized to induce required stresses. [ABSTRACT FROM AUTHOR]

The aim of this paper was to evaluate physical stability of solid dispersions in respect to the drug, tadalafil (Td), in vinylpyrrolidone and vinyl acetate block copolymer (PVP-VA). Nine solid dispersions of Td in PVP-VA (Td/PVP-VA) varied in terms of quantitative composition (1:9–9:1, w/w) were successfully produced by spray-drying. Their amorphous nature, supersaturated character and molecular level of mixing (a solid solution structure) were subsequently confirmed using DSC, PXRD, SEM and calculation of Hansen total solubility parameters. Due to thermal degradation of both components before the melting point of Td (302.3 °C), an approach based on the drug crystallization from the supersaturated solid dispersion was selected to calculate the solubility of Td in the polymer. Annealing of the Td/PVP-VA solid dispersion (1:1, w/w) at selected temperatures above its T g resulted in different stable solid dispersions. According to the Gordon–Taylor equation their new T g s gave the information about the quantitative composition which corresponded to the thermodynamic solubility of Td in PVP-VA at given temperatures of annealing. The obtained relationship was fitted to the exponential function, with the calculated solubility of Td of 20.5% at 25 °C. This value was in accordance with the results of hot stage polarizing light microscopy as well as stability tests carried out at 80 °C and 0% RH, in which Td solid dispersions containing 10–20% of the drug were the only systems that did not crystallize within two months. A thermal analysis protocol utilizing a fast heating rate was shown to generate Td solubility data complementing the solid dispersion method. The Flory–Huggins model applied for the Td/PVP-VA system yielded the solubility value of 0.1% at 25 °C, showing the lack of applicability in this case. [ABSTRACT FROM AUTHOR]

Drug nanoparticles in suspensions can form aggregates leading to physical instability, which is traditionally mitigated using soluble polymers and surfactants. The aim of this paper was to explore common superdisintegrants, i.e., sodium starch glycolate (SSG), croscarmellose sodium (CCS), and crospovidone (CP), as novel class of dispersants for enhanced stabilization of fenofibrate (FNB), a model BCS Class II drug, suspensions. FNB was wet-milled with superdisintegrants along with hydroxypropyl methylcellulose (HPMC), a soluble adsorbing polymer, in a stirred media mill. For comparison, FNB was also milled in the presence of HPMC and/or SDS (sodium dodecyl sulfate) without superdisintegrants. Laser diffraction, scanning electron microscopy, viscometry, differential scanning calorimetry, and powder X-ray diffraction were used to characterize the suspensions. The results show that 2% HPMC along with 1% SSG or 1% CCS mitigated the aggregation of FNB nanoparticles significantly similar to the use of either 5% HPMC or 1% HPMC–0.075% SDS, whereas CP was not effective due to its low swelling capacity. CCS/SSG enhanced steric–kinetic stabilization of the FNB suspensions owing to their high swelling capacity, viscosity enhancement, and physical barrier action. Overall, this study provides a mechanistic basis for a novel method of formulating surfactant-free drug nanosuspensions with co-milled superdisintegrants. [ABSTRACT FROM AUTHOR]

Flexible plastic bags are the container of choice for most intravenous (i.v.) infusions. Under certain circumstances, however, the air-liquid interface present in these i.v. bags can lead to physical instability of protein biopharmaceuticals, resulting in product aggregation. In principle, the air headspace present in the bags can be removed to increase drug stability, but experiments described here show that this can result in incomplete draining of solution from the bag using gravity delivery, or generation of negative pressure in the bag when an infusion pump is used. It is expected that these issues could lead to incomplete delivery of medication to patients or pump-related problems, respectively. However, here it is shown that contrary to the standard pharmacy practice of using nonvented spikes with i.v. bags, the use of vented spikes with i.v. bags that lack air headspace allows complete delivery of the dose solution without impacting the physical stability of a protein-based drug. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:2397-2400, 2015 [ABSTRACT FROM AUTHOR]

Collagen, the most abundant protein in mammals, is able to form fibrils, which have central role in tissue repair, fibrosis, and tumor invasion. As a component of skin, tendons, and cartilages, this protein contacts with any implanted materials. An inherent problem associated with implanted prostheses is their propensity to be coated with host proteins shortly after implantation. Also, silicone implants undergoing relatively long periods of contact with blood can lead to formation of thrombi and emboli. In this paper, we demonstrate the existence of interactions between siloxanes and collagen. Low-molecular-weight cyclic siloxane (hexamethylcyclotrisiloxane-D3) and polydimethylsiloxanes ( PDMS) forming linear chains, ranging in viscosity from 20 to 12,000 cSt, were analyzed. We show that D3 as well as short-chain PDMS interact with collagen, resulting in a decrease in fibrillogenesis. However, loss of collagen native structure does not occur because of these interactions. Rather, collagen seems to be sequestered in its native form in an interlayer formed by collagen-siloxane complexes. On the other hand, silicone molecules with longer chains (i.e., PDMS with viscosity of 1000 and 12,000 cSt, the highest viscosity analyzed here) demonstrate little interaction with this protein and do not seem to affect collagen activity. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:1275-1281, 2015 [ABSTRACT FROM AUTHOR]

Formulation scientists are recognizing nanoengineered drug delivery systems as an effective strategy to overcome limitations associated with antibiotic drug therapy. Antibiotics encapsulated into nanodelivery systems will contribute to improved management of patients with various infectious diseases and to overcoming the serious global burden of antibiotic resistance. An extensive review of several antibiotic-loaded nanocarriers that have been formulated to target drugs to infectious sites, achieve controlled drug release profiles, and address formulation challenges, such as low-drug entrapment efficiencies, poor solubility and stability is presented in this paper. The physicochemical properties and the in vitro/ in vivo performances of various antibiotic-loaded delivery systems, such as polymeric nanoparticles, micelles, dendrimers, liposomes, solid lipid nanoparticles, lipid-polymer hybrid nanoparticles, nanohybirds, nanofibers/scaffolds, nanosheets, nanoplexes, and nanotubes/horn/rods and nanoemulsions, are highlighted and evaluated. Future studies that will be essential to optimize formulation and commercialization of these antibiotic-loaded nanosystems are also identified. The review presented emphasizes the significant formulation progress achieved and potential that novel nanoengineered antibiotic drug delivery systems have for enhancing the treatment of patients with a range of infections. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:872-905, 2015 [ABSTRACT FROM AUTHOR]

In this paper the stability of the arsenic sulfide (As 4 S 4 ) nanosuspension prepared by wet milling in a circulation mill in the environment of copolymer Poloxamer 407 was studied. The obtained As 4 S 4 particles in nanosuspension were of ∼100 nm in size. The influence of temperature and UV irradiation on the changes in physical and/or chemical properties was followed. Long-term stability was observed via particle size distribution and zeta potential measurements. Influence of UV irradiation was studied via UV–vis spectroscopy (UV–vis), photoluminicsence (PL) technique and Fourier transform infrared spectroscopy (FTIR) measurements. The best stability of the nanosuspension (24 weeks) was achieved when stored at 4 °C and in the dark. [ABSTRACT FROM AUTHOR]

This paper describes a rational method of characterizing the biopharmaceutical stability of two oral suspensions of ursodeoxycholic acid (UDCA) used in pediatrics. Because there is no commercial presentation of UDCA that can administer appropriate doses for infants and children, an active pharmaceutical ingredient (API) formulation is required. Due to its very low solubility and low dose in the formula (1.5%), two different suspensions with minimal use of excipients were studied, avoiding the use of complex additives and those not recommended by the European Medicines Agency (EMA). Adherence to Standard Operating Procedure (SOP) allows the preparation of formulations with appropriately sized and stable particles, and suitable rheological behavior in withdrawing the dose after stirring. Dose uniformity, expressed as mass and content variability, was determined using the criteria of the European and the United States Pharmacopoeia. Additionally, dose content variation of every mass determined was studied. A rational method was developed for determining the dose uniformity of UDCA in suspensions, whether freshly prepared or after storage under different conditions for 30 and 60 days. This method permits detection of differences between doses taken at different heights in the vessel at various times and storage conditions. UDCA was stable under all conditions studied, requiring the presence of glycerol in the formulation to obtain the declared API value after stirring. Storage of UDCA suspensions in a refrigerator increased variability between doses. [ABSTRACT FROM AUTHOR]

Since more than 40% of today’s drugs have low stability, poor solubility and/or limited ability to cross certain biological barriers, new platform technologies are required to address these challenges. This paper describes a novel continuous process that converts a stabilized aqueous nano-suspension into a solid oral formulation in a single step (i.e., the NANEX process) in order to improve the solubility of a model drug (phenytoin). Phenytoin nano-suspensions were prepared via media milling using different stabilizers. A stable nano-suspension was obtained using Tween ® 80 as a stabilizer. The matrix material (Soluplus ® ) was gravimetrically fed into the hot melt extruder. The suspension was introduced through a side feeding device and mixed with the molten polymer to immediately devolatilize the water in the nano-suspension. Phenytoin nano-crystals were dispersed and embedded in the molten polymer. Investigation of the nano-extrudates via transmission electron microscopy and atomic force microscopy showed that the nano-crystals were embedded de-aggregated in the extrudates. Furthermore, no changes in the crystallinity (due to the mechanical and thermal stress) occurred. The dissolution studies confirmed that the prepared nano-extrudates increased the solubility of nano-crystalline phenytoin, regardless of the polymer. Our work demonstrates that NANEX represents a promising new platform technology in the design of novel drug delivery systems to improve drug performance. [ABSTRACT FROM AUTHOR]

This paper describes a systematic approach to select optimum stabilizer for the preparation of nano-crystalline suspensions of an active pharmaceutical ingredient (API). The stabilizer can be either a dispersant or a combination of dispersant and wetting agent. The proposed screening method is a quick and efficient way to investigate a large number of stabilizers based on the principles of physical-chemistry and employs a stepwise approach. The methodology has been divided in two main parts; the first part being focused on the qualitative screening with the objective of selecting the best candidate(s) for further investigation, the second part has been focused on quantitative screening with the objective to optimize the ratio and amount of wetting and dispersing agents, based on wettability, surface charges measurement, adsorption evaluation, process-ability evaluation and storage stability. The results showed clearly that SDS/PVP 40/60% (w/w) (sodium dodecyl sulfate/poly(vinyl pyrrolidone)) at a total concentration of 1.2% was the optimum stabilizer composition, at which the resulting nanosuspensions were stable for more than 50 days at room temperature. [ABSTRACT FROM AUTHOR]

This paper describes a stability study performed for 56 antibiotics belonging to 9 different groups – macrolides, tetracyclines, fluoroquinolones, quinolones, penicillins, cephalosporines, lincosamides, sulfonamides and nitroimidazole antibiotics – in purified water samples fortified with the selected compounds at 10 ng/ml. For this purpose, three different sample preservation modes were tested with the aim of avoiding biotic and abiotic degradation: (i) storage at −20 °C, (ii) storage at −20 °C with 0.1% of EDTA and (iii) pre-concentration in a solid phase extraction cartridge (SPE), which was afterwards stored at −20 °C. Concentrations of antibiotics in the samples preserved using the different protocols were monitored after 0, 1, 2 and 12 weeks. The results showed that, for the accurate determination of all compounds they should be analyzed right after sampling. However, if this is not possible, most of the antibiotics can be analyzed within the 1st week after sampling and preservation at −20 °C (with or without EDTA) or in a SPE cartridges at −20 °C. Nonetheless, some antibiotics found extensively in the environment, such as sulfamethoxazole, ciprofloxacin, ofloxacin, erythromycin, azithromycin and clarithromycin exhibited low stability after 1 week preservation and, therefore, they should be analyzed within this time. [ABSTRACT FROM AUTHOR]

Epigallocatechin gallate (EGCG) is a green tea catechin with potential health benefits, such as anti-oxidant, anti-carcinogenic and anti-inflammatory effects. In general, EGCG is highly susceptible to degradation, therefore presenting stability problems. The present paper was focused on the study of EGCG stability in HEPES ( N -2-hydroxyethylpiperazine- N ′-2-ethanesulfonic acid) medium regarding the pH dependency, storage temperature and in the presence of ascorbic acid a reducing agent. The evaluation of EGCG in HEPES buffer has demonstrated that this molecule is not able of maintaining its physicochemical properties and potential beneficial effects, since it is partially or completely degraded, depending on the EGCG concentration. The storage temperature of EGCG most suitable to maintain its structure was shown to be the lower values (4 or −20 °C). The pH 3.5 was able to provide greater stability than pH 7.4. However, the presence of a reducing agent (i.e., ascorbic acid) was shown to provide greater protection against degradation of EGCG. A validation method based on RP-HPLC with UV–vis detection was carried out for two media: water and a biocompatible physiological medium composed of Transcutol ® P, ethanol and ascorbic acid. The quantification of EGCG for purposes, using pure EGCG, requires a validated HPLC method which could be possible to apply in pharmacokinetic and pharmacodynamics studies. [ABSTRACT FROM AUTHOR]

Amorphous materials, although lacking the long-range translational and rotational order of crystalline and liquid crystalline materials, possess certain local (short-range) structure. This paper reviews the distribution of one particular component present in all amorphous pharmaceuticals, that is, water. Based on the current understanding of the structure of water, water molecules can exist in either unclustered form or as aggregates (clusters) of different sizes and geometries. Water clusters are reported in a range of amorphous systems including carbohydrates and their aqueous solutions, synthetic polymers, and proteins. Evidence of water clustering is obtained by various methods that include neutron and X-ray scattering, molecular dynamics simulation, water sorption isotherm, concentration dependence of the calorimetric Tg, dielectric relaxation, and nuclear magnetic resonance. A review of the published data suggests that clustering depends on water concentration, with unclustered water molecules existing at low water contents, whereas clusters form at intermediate water contents. The transition from water clusters to unclustered water molecules can be expected to change water dependence of pharmaceutical properties, such as rates of degradation. We conclude that a mechanistic understanding of the impact of water on the stability of amorphous pharmaceuticals would require systematic studies of water distribution and clustering, while such investigations are lacking. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2663-2672, 2014 [ABSTRACT FROM AUTHOR]

Abstract: Background: Drug photodegradation data are usually treated by zero-, first- or second-order kinetic equations. Such treatments would lack reliability since the aforementioned equations have been originally developed for pure thermal reactions. In this respect, it has recently been shown that unimolecular photodegradations obey Ф-order kinetics (Maafi and Maafi, 2013). However, no similar information is, thus far, available for other reactions including photoreversible AB(2Ф) systems. This paper aims at filling this gap for AB(2Ф) kinetics. Methods: Runge–Kutta numerical integration data for photoreversible reactions traces were combined with a template equation in order to derive an optimized (semi-empirical) integrated rate-law equation for AB(2Ф) reactions. The proposed model equation was test by examining its ability to fit synthetic Runge–Kutta data that have not been used for the optimization. The obtained fitting parameters are then compared to their theoretical counterparts. Results: Both an integrated rate-law and an analytical equation for the overall reaction rate-constant were set for photoreversible drug reactions. The values of overall reaction rate-constant and initial velocity obtained theoretically correlated well with those obtained by fitting the kinetic traces of reactions with the derived integrated rate-law. AB(2Ф) photodegradation reactions have been proven to obey Ф-order kinetics. The equation proposed describes faithfully their kinetic behaviour in solution. The formula of the overall rate-constant involves both reagents' characteristics and experimental parameters. These equations facilitated the rationalisation and prediction of the individual effects of each reaction parameter. Specially, our results proved a self-photostabilisation with increasing initial drug-concentration and demonstrated the potential for actinometry of drugs obeying AB(2Ф) mechanism. [Copyright &y& Elsevier]

Resveratrol is a polyphenol from the stilbens family that has been reported to have various benefits for human health, including antioxidant, anti-inflammatory, anti-carcinogenic, anti-obesity, and heart/brain protective effects. However, the utilization of resveratrol as a nutraceutical in the food industry is currently limited due to its poor water solubility, high chemical instability, and low oral bioavailability. Encapsulation of resveratrol can be used to improve its water-dispersibility, chemical stability, and bioavailability. This paper reviews delivery systems available to encapsulate, protect and release resveratrol, and highlights their potential applications within the food industry. [ABSTRACT FROM AUTHOR]

Abstract: Translation of micelles from the laboratory to the clinic is limited by a poor understanding of their in vivo fate following administration. In this paper, we establish a robust approach to real-time monitoring of the in vivo stability of micelles using Förster Resonance Energy Transfer (FRET). This characterization method allows for exquisite insight into the fate of micellar constituents, affording the capabilities to rapidly and efficiently evaluate a library of synthetically derived micellar systems as new therapeutic platforms in vivo. FRET-enabled biological characterization further holds potential to tailor material systems being uniquely investigated across the delivery community towards the next generation of stable therapeutics for disease management. [Copyright &y& Elsevier]

[Display omitted] In this paper, we describe a modular post-printing loading protocol for a 3D printed gastro-retentive drug delivery system. Fused Deposition Modelling (FDM) 3D printing was exploited for the rapid prototyping of a modular floating system (caps-in-cap). Optimized models were produced as blank PVA scaffolds, and a morphological analysis of the FDM printed models was conducted to develop a straightforward protocol for drug-loading. The 3D printed gastro-retentive systems were then subjected to microwave irradiation in oversaturated solutions of anhydrous caffeine for drug loading, and research focused on an analysis of the impact of microwave irradiation on the chemical and physical properties of the polymer and the drug. The drug-loading efficiency, thermal and chemical characteristics of components, the stability of the drug and the morphology of processed printouts are characterised and described. Parameters of this unexplored microwave-assisted post-printing loading technique were evaluated and adequately set up, and the process resulted in the preservation of the polymeric matrix and enhancement of drug loading. Hence, microwave impregnation confirmed its potential in superseding the traditional pre- and post-printing loading methods, such as soaking techniques, being faster and more efficient and providing a new paradigm approach to personalised drug delivery. [ABSTRACT FROM AUTHOR]

During the autopsy of forensic cases, when there is no suspicion of drug use or chemical exposure, biological fluids may not be obtained for toxicological analysis, while specimens of tissues may be collected and preserved in a formalin solution for histological examination. When specific questions arise after the burial, the only possible options are the exhumation of an embalmed body or the toxicological analysis of the formalin-fixed specimens. The drug concentrations in these specimens can be altered due to the extraction efficiency and/or the chemical activity of the formalin solutions used during chemical fixation or embalming process. The aim of this paper is to review the published studies about the determination of specific groups of drugs in formalin-fixed or embalmed specimens and their stability after chemical fixation or embalming process. The analytical aspects of this determination are also discussed. The stability of drugs in formalin environment and the possible reaction of the drugs with formaldehyde, which is a highly reactive chemical substance, should always be considered during postmortem/post-embalming forensic analysis. The additional analysis of the formalin solution in which the tissue was preserved is considered necessary. The identification and the evaluation of the possible degradation products or chemical derivatives are extremely useful during the interpretation of the results. [ABSTRACT FROM AUTHOR]

To predict the stability of pharmaceutical preparations under uncontrolled temperature conditions accurately, a method to compute the average reaction rate constant taking into account the heat transfer from the atmosphere to the product was developed. The average reaction rate constants computed with taken into consideration heat transfer ( κre) were then compared with those computed without taking heat transfer into consideration ( κin). The apparent thermal diffusivity ( κa) exerted some influence on the average reaction rate constant ratio ( R, R = κre/ κin). In the regions where the κa was large (above 1 h−1) or very small, the value of R was close to 1. On the contrary, in the middle region (0.001-1 h−1), the value of R was less than 1.The κa of the central part of a large-size container and that of the central part of a paper case of 10 bottles of liquid medicine (100 mL) fell within this middle region. On the basis of the above-mentioned considerations, heat transfer may need to be taken into consideration to enable a more accurate prediction of the stability of actual pharmaceutical preparations under nonisothermal atmospheres. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:1495-1503, 2013 [ABSTRACT FROM AUTHOR]

Abstract: Arctiin, an important lignan compound in Fructus Arctii, has been reported to possess various kinds of bioactivities. Previous studies on the pharmacokinetic of arctiin after oral administration showed that it had a rapid absorption phase followed by a sharp but lasting disappearance. To gain deep insight into the action mechanism of arctiin, the excretion and metabolism of arctiin in vivo should be further studied. In this paper, three metabolites were isolated and identified in rat feces as (−)-enterolactone (M-1), (−)-arctigenin (M-2) and [(2R,3R)-2-(3′-hydroxybenzyl)-3-(3″,4″-dimethoxybenzyl)-butyrolactone] (M-3). Based on the structures of three metabolites, possible metabolic pathways of arctiin in rats are proposed. At the same time, the cumulative excretion rate of arctiin and its metabolites in rat urine and feces were determined, indicating that arctiin was excreted 19.84% in urine and 1.80% in feces, respectively, enterolactone, the most main metabolite, was excreted 35.80% in feces. These results provide very important information for understanding the metabolism and excretion of arctiin in vivo and speculating its action mechanism, they can provide useful information and reference for further metabolic investigations on arctiin in humans. [Copyright &y& Elsevier]

Abstract: The paper presents an HPLC method for cefazolin determination in human serum. The preparation step was based on serum protein precipitation with acetonitrile followed by supernatant evaporation and sample reconstitution in water before injection. The separation of cefazolin and internal standard cefamandole was performed at ambient temperature under isocratic conditions on LiChrosorb RP8-5 column (250mm×4.6mm) using the mixture: CH3CN:H2O:0.5M KH2PO4 (100:894:6, v/v) as a mobile phase with a flow rate of 1.5mL/min. UV detection was performed at 272nm with LLOQ of 0.2μg/mL. The precision was satisfactory in the whole range tested with RSD of 2.3–12.5% (accuracy: from −2.3% to +3.6%) and of 1.7–7.1% (accuracy: from −3.5% to +1.1%) for intra- and inter-assay, respectively. The method stability was confirmed in a series of experiments including: freeze–thaw and short- and long-term stability testing. Finally, the procedure described was found resistant to potential human errors. [Copyright &y& Elsevier]

Abstract: Solid lipid nanoparticles (SLN) have attracted increasing attention during recent years. This paper presents an overview about the selection of the ingredients, different ways of SLN production and SLN applications. Aspects of SLN stability and possibilities of SLN stabilization by lyophilization and spray drying are discussed. Special attention is paid to the relation between drug incorporation and the complexity of SLN dispersions, which includes the presence of alternative colloidal structures (liposomes, micelles, drug nanosuspensions, mixed micelles, liquid crystals) and the physical state of the lipid (supercooled melts, different lipid modifications). Appropriate analytical methods are needed for the characterization of SLN. The use of several analytical techniques is a necessity. Alternative structures and dynamic phenomena on the molecular level have to be considered. Aspects of SLN administration and the in vivo fate of the carrier are discussed. [Copyright &y& Elsevier]

Abstract: Two new degradation products for Anastrozole active pharmaceutical ingredient (ANZ) have been identified and reported in this paper. The ANZ was subjected to thermal, photolytic, oxidative and base stress conditions prescribed by ICH guidelines. Separation of ANZ from its existing impurities and the two new impurities was achieved by using on Oyster ODS-3 (100mm×4.6mm×3.0μm) column with an isocratic mixture of 10mM ammonium formate and acetonitrile in the ratio 60:40 (v/v). The flow rate was 0.5mlmin−1. The elution was monitored at 215nm. An isocratic stability indicating reverse phase liquid chromatographic (RP-LC) and LC–MS/MS method was developed for the determination of purity and assay of ANZ through forced degradation studies. The two new impurities detected were further subjected to spectroscopic studies. Based on the results obtained from the different spectroscopic studies, these impurities have been characterized as 2,2′-(5-((1H-1,2,4-triazol-1-yl)methyl)-1,3-phenylene)bis(2-methylpropanoicacid) (Diacid) and 2-(3-((1H-1,2,4-triazol-1-yl)methyl)-5-(2-cyanopropan-2-yl)phenyl)-2-methylpropanoicacid (Monoacid). ANZ was found to degrade in base, slightly in oxidative degradation conditions. The degradation products were well resolved from main peak and its impurities thus proved the stability, indicating power of the method. The developed method was validated as per International Conference on Harmonization (ICH) guidelines with respect to specificity, limit of detection, limit of quantitation, precision, linearity, accuracy, robustness and system suitability. [Copyright &y& Elsevier]

Abstract: The goal of this paper is to demonstrate the separation and detection capability of eco-friendly micro-TLC technique for the classification of spirulina and selected herbs from pharmaceutical and food products. Target compounds were extracted using relatively low-parachor liquids. A number of the spirulina samples which originated from pharmaceutical formulations and food products, were isolated using a simple one step extraction with small volume of methanol, acetone or tetrahydrofuran. Herb samples rich in chlorophyll dyes were analyzed as reference materials. Quantitative data derived from micro-plates under visible light conditions and after iodine staining were explored using chemometrics tools including cluster analysis and principal components analysis. Using this method we could easily distinguish genuine spirulina and non-spirulina samples as well as fresh from expired commercial products and furthermore, we could identify some biodegradation peaks appearing on micro-TLC profiles. This methodology can be applied as a fast screening or fingerprinting tool for the classification of genuine spirulina and herb samples and in particular may be used commercially for the rapid quality control screening of products. Furthermore, this approach allows low-cost fractionation of target substances including cyanobacteria pigments in raw biological or environmental samples for preliminary chemotaxonomic investigations. Due to the low consumption of the mobile phase (usually less than 1mL per run), this method can be considered as environmentally friendly analytical tool, which may be an alternative for fingerprinting protocols based on HPLC machines and simple separation systems involving planar micro-fluidic or micro-chip devices. [Copyright &y& Elsevier]

In this paper, we explore the use of Neusilin, an inorganic magnesium aluminometasilicate, to stabilize the amorphous form of an acidic drug Sulindac. Both cryomilling and ball milling of the drug with Neusilin were found to produce the amorphous phase. However, the ball-milled (BM) material exhibited superior physical stability when compared with the cryomilled material at 40°C/75% relative humidity. C solid-state nuclear magnetic resonance investigation of the BM material revealed an acid-base reaction between Sulindac and Neusilin. Optimal milling conditions and the kinetics of salt formation were also established. As benchtop milling is a laboratory-scale process, a scalable process was developed to make Sulindac-Neusilin amorphous drug complex using hot-melt extrusion (HME). The dissolution properties of the resulting HME material was found to have been improved over the material made by benchtop milling while maintaining similar physical stability. The HME material was used to make tablets using a direct compression method. The HME tablets were found to have better dissolution properties than tablets made from crystalline Sulindac. For the broad class of acidic drugs containing the carboxyl moiety, inorganic silicates such as Neusilin would offer a better choice than organic polymers to stabilize the amorphous phase. © 2011 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:3332-3344, 2011 [ABSTRACT FROM AUTHOR]

Oxidation, particularly of methionine residues, is one of the major chemical degradations of proteins. In a previous publication we studied the conformation of recombinant human growth hormone (r-hGH) selectively oxidized at Met and Met. Conformation of oxidized r-hGH was found not different from that of nonoxidized r-hGH. In this paper, the effect of methionine oxidation on the thermal stability of r-hGH folding was investigated. The thermally induced unfolding process of the oxidized and nonoxidized protein was measured by monitoring the circular dichroism signal at 220 nm. The melting temperatures ( T) of the oxidized and nonoxidized r-hGH forms were determined at different pHs and in the presence of salts often used in pharmaceutical formulations. The effect of the location of the oxidized Met residue in the protein and the percentage of oxidation were investigated. Our findings indicate that the monoxidation of the two most accessible methionine residues of r-hGH-Met and Met-has no effect on the protein conformation. However, oxidation of these residues to form sulfoxides does influence the thermal stability of the protein folding. The presence of the polar oxygen atom on the methionine sulfoxide group thermally destabilizes r-hGH folding. The effect ( T) depends upon pH, ionic strength, and the location of the oxidized methionine residues in the protein. The thermal melting of r-hGH and its oxidized products is a highly cooperative process. Methionine oxidation leads to a thermal destabilization of the whole protein folding and is not just a local destabilization. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:451-463, 2011 [ABSTRACT FROM AUTHOR]

Abstract: Nonionic polyethylene glycol-derived surfactants are today’s choice as surfactants in protein formulations. Different groups discovered that although surface-induced stresses are reduced by these excipients, the long-term stability of different proteins decreased due to polyethylene glycol-related induction of oxidation processes under static storage conditions. In this paper, the potential of polyoxyethylene-free surfactants for protein formulation was evaluated. Three different sugar-based surfactants, 6-O-monocaprinoyl-α,α-trehalose, 6-O-monolauroyl-α,α-trehalose and 6-O-monopalmitoyl-α,α-trehalose, were synthesized in four reaction steps. These substances lack polyethylene glycol residues and can be produced from renewable resources. The chemical and physical properties of these three surfactants were investigated and compared with polysorbate 20 and 80. 6-O-Monopalmitoyl-α,α-trehalose was insoluble in water at room temperature and was hence excluded from some of the further tests. The critical micellar concentration of all surfactants is in a comparable range of approximately 0.001–0.01% (m/V). The sugar-based surfactants showed slightly higher hemolytic activity than the polysorbate references. The surfactants with shorter chain length proved to be comparable to polysorbates in regard to physicochemical properties. Finally for human growth hormone, the protein-stabilizing properties against shaking-induced stress were tested and compared to polysorbate-containing formulations. Whereas in the absence of surfactant, dramatic monomer loss and aggregate formation occurred, it was found that 100% monomer content was maintained when 0.1% (m/V) 6-O-monocaprinoyl-α,α-trehalose or 6-O-monolauroyl-α,α-trehalose was added to the formulation. Polysorbate 80 at a concentration of 0.1% (m/V) also significantly stabilized the protein. Lower amounts of surfactants result in only partial stabilization. Furthermore, adsorption of human growth hormone to the container surface is reduced in the presence of the surfactants. Thus, the new sugar-based surfactants offer a promising alternative and have potential for application in protein formulations. [Copyright &y& Elsevier]

Abstract: Trace analysis of unstable and reactive pharmaceutical genotoxic impurities (GTIs) is a challenging task in pharmaceutical analysis. Many method issues such as insufficient sensitivity, poor precision, and unusual (too high/low) spiking recovery are often directly related to analytes’ instability. We report herein a matrix deactivation approach that chemically stabilizes these analytes for analytical method development. In contrast to the conventional chemical derivatization approach where the analytes are transformed into stable detectable species, the matrix deactivation approach chemically deactivates the hypothetical reactive species in the sample matrix. The matrix deactivation approach was developed on the premise that the instability of certain analytes at trace level is caused by reactions between the analytes and low level reactive species in the sample matrix. Thus, quenching the reactivity of the reactive species would be a key to stabilizing the unstable and reactive analytes. For example, electrophilic alkylators could be destabilized by nucleophiles or bases through either nucleophilic substitution or elimination reactions. One way to mask those reactive species is via protonation by adding acids to the diluent. Alternatively, one can use nucleophile scavengers to deplete reactive unknown species in the sample matrix completely, in analogy to the use of antioxidants and metal chelators to prevent oxidation in the analysis of compounds liable to oxidation. This paper reports the application of the matrix deactivation to the analyses of unstable and reactive pharmaceutical genotoxic impurities. Some of the methods have been used to support development of manufacturing processes for drug substances and a recent regulatory filing. [Copyright &y& Elsevier]

Abstract: Angiotensin-converting enzyme (ACE) inhibitors are a group of active substances binding to an active site of ACE. Many authors who studied the structure activity relationship suggested the structural elements needed for a potent ACE inhibitor. While many authors studied the activity of ACE inhibitor substances only a few structure stability studies have been presented. In this paper the stability properties of molecule xPRIL were studied by determination of degradation path and rate of degradation in aqueous solutions with different pH (2.0, 6.8 and 12.0) and temperatures (40, 60 and 80°C). The degradation of molecule through two main degradation paths was identified and confirmed by liquid chromatography and mass spectroscopy (LC–MS). Stability properties of xPRIL were determined in a stability study evaluated by high-performance liquid chromatography (HPLC). The first order kinetics of degradation reaction of xPRIL and Arrhenius equations for each pH were determined at observed conditions. xPRIL showed the highest stability at pH 2 solution. The degradation kinetics of xPRIL was compared to the degradation kinetics of enalapril maleate (EM) and perindopril (PER) in bio relevant solutions with pH 2.0 and 6.8. In addition to the stability study of xPRIL the forced degradation study of all three molecules at rigorous conditions was conducted. From the obtained results the structural element having the highest influence on stability properties of the studied molecules was identified. The fragmentation paths of xPRIL, its cyclization degradation product and its hydrolysis degradation product were identified and confirmed by MS/MS method. [Copyright &y& Elsevier]