Quality assessment of selected co-trimoxazole suspension brands marketed in Nairobi County, Kenya.

INTRODUCTION: Quality of medicines in both developed and developing countries is sometimes compromised due to infiltration of counterfeit, substandard or degraded medicines into the markets. It is a public health concern as poor quality medicines endanger public health where patients are exposed to chemical toxins and/or sub-therapeutic doses. This could lead to reduced treatment efficacy and promote development of drug resistance. Co-trimoxazole, a fixed dose combination of sulfamethoxazole and trimethoprim, is a broad spectrum for bacterial diseases and is also used as a prophylaxis for opportunistic infections in HIV infected individuals. This study evaluated quality of selected co-trimoxazole suspension brands marketed in Nairobi County, Kenya. METHODS: A total of 106 samples were collected, categorized into 15 brands and evaluated for active pharmaceutical ingredient content (API) and pH following United States Pharmacopeia. Assay for API was conducted using High Performance Liquid Chromatography. Results were compared with pharmacopeia references. Visual examination of labels and confirmation of retention status of the brands with Pharmacy and Poisons Board retention register was carried out. RESULTS: The samples were primarily of local origin (86.7%). On October 23, 2019, retention status of six of the fifteen brands documented were no longer listed in the Pharmacy and Poisons Board retention register. Of the 106 samples tested 70.6% and 86.8% were compliant with United States Pharmacopeia (USP) specifications for pH and API respectively while 84.0% adhered to packaging and labelling requirements. CONCLUSION: This study has demonstrated that majority of co-trimoxazole suspensions tested were compliant with USP requirements. Additionally, it has provided evidence of poor quality co-trimoxazole medicines that could compromise treatment of infectious diseases in children. This emphasizes the need for regular quality assurance tests to ensure only quality medicines are in the market.

Preparation, characterization and ex vivo-in vivo assessment of candesartan cilexetil nanocrystals via solid dispersion technique using an alkaline esterase activator carrier.

The objective of this study was to improve candesartan cilexetil (CC) efficacy by formulating nanocrystals via solid dispersion (SD) technique using tromethamine (Tris). SD was prepared by solvent evaporation at different drug carrier ratios, evaluated for particle size, vitro dissolution studies, TEM, FTIR, and X-ray powder diffraction. Ex vivo, in vivo pharmacokinetic parameters were conducted on selected formulae compared to drug suspension and marketed product. Size analysis demonstrated formation of particles in the nanorange lower than 300 nm. A burst drug release followed by an improved dissolution was observed indicating instant formation of nanocrystals along with amorphization as confirmed by X-ray diffraction. FTIR studies suggested the absence of chemical interaction between Tris and CC. TEM revealed formation of irregular oval nanoparticles. SD-1:5 has higher apparent permeability coefficient compared to CC suspension. Furthermore, the pharmacokinetic results proved the ability of the formed nanoparticles to enhance the efficacy of CC compared to drug suspension and marketed product. In conclusion, using of Tris as alkaline esterase activator carrier could be a promising tool to bypass the controversial effect of esterase enzymes that may be a source for inter-individual variations affecting ester prodrug candidates' efficacy.

QbD for pediatric oral lyophilisates development: risk assessment followed by screening and optimization.

OBJECTIVE: This study proposed the development of oral lyophilisates with respect to pediatric medicine development guidelines, by applying risk management strategies and DoE as an integrated QbD approach. METHODS: Product critical quality attributes were overviewed by generating Ishikawa diagrams for risk assessment purposes, considering process, formulation and methodology related parameters. Failure Mode Effect Analysis was applied to highlight critical formulation and process parameters with an increased probability of occurrence and with a high impact on the product performance. To investigate the effect of qualitative and quantitative formulation variables D-optimal designs were used for screening and optimization purposes. RESULTS: Process parameters related to suspension preparation and lyophilization were classified as significant factors, and were controlled by implementing risk mitigation strategies. Both quantitative and qualitative formulation variables introduced in the experimental design influenced the product's disintegration time, mechanical resistance and dissolution properties selected as CQAs. The optimum formulation selected through Design Space presented ultra-fast disintegration time (5 seconds), a good dissolution rate (above 90%) combined with a high mechanical resistance (above 600 g load). CONCLUSIONS: Combining FMEA and DoE allowed the science based development of a product with respect to the defined quality target profile by providing better insights on the relevant parameters throughout development process. The utility of risk management tools in pharmaceutical development was demonstrated.

A Method for Preparing Silver Nanoparticle Suspensions in Bulk for Ecotoxicity Testing and Ecological Risk Assessment.

Methods are needed to prepare stable suspensions of engineered nanoparticles in aqueous matrixes for ecotoxicity testing and ecological risk assessments. We developed a novel method of preparing large volumes of silver nanoparticles (AgNP) in suspension using a commercially available rotor-stator dispersion mill. AgNP in powder form (PVP capped, 30-50 nm) was suspended in deionized water and natural lake water at 1 g/L and the addition of 0.025% (w/v) gum arabic (GA) increased stability over 2 weeks after preparation. The concentrations of total and dissolved Ag in the suspensions did not change significantly over this period. Analysis of hydrodynamic diameters of the major peaks in suspension using dynamic light scattering showed that suspensions prepared with GA were stable, and this was confirmed by single-particle ICP-MS analysis. This method for dispersing AgNPs provides an inexpensive, yet reliable method for preparing suspensions for toxicity testing and ecosystem level studies of the fate and biological effects of AgNPs in aquatic ecosystems.

Assessment of simvastatin niosomes for pediatric transdermal drug delivery.

The prevalence of childhood dyslipidemia increases and is considered as an important risk factor for the incidence of cardiovascular disease in the adulthood. To improve dosing accuracy and facilitate the determination of dosing regimens in function of the body weight, the proposed study aims at preparing transdermal niosomal gels of simvastatin as possible transdermal drug delivery system for pediatric applications. Twelve formulations were prepared to screen the influence of formulation and processing variables on critical niosomal characteristics. Nano-sized niosomes with 0.31 µm number-weighted size displayed highest simvastatin release rate with 8.5% entrapment capacity. The niosomal surface coverage by negative charges was calculated according to Langmuir isotherm with n = 0.42 to suggest that the surface association was site-independent, probably producing surface rearrangements. Hypolipidemic activities after transdermal administration of niosomal gels to rats showed significant reduction in cholesterol and triglyceride levels while increasing plasma high-density lipoproteins concentration. Bioavailability estimation in rats revealed an augmentation in simvastatin bioavailability by 3.35 and 2.9 folds from formulation F3 and F10, respectively, compared with oral drug suspension. Hence, this transdermal simvastatin niosomes not only exhibited remarkable potential to enhance its bioavailability and hypolipidemic activity but also considered a promising pediatric antihyperlipidemic formulation.

Assessment of the characterization of nonabsorbing nanoparticles in suspension from effective optical properties.

We analyze a method recently proposed to retrieve the size, refractive index, and concentration of particles in nonabsorbing nanofluids from measurements of the complex effective refractive index of two dilutions of the nanofluid [Opt. Lett.39, 559 (2014)]. The method uses simple formulas to retrieve the particles' parameters. First, we discuss precautions needed with the new method when inferring the refractive index of the particles from measurements of the imaginary part of the effective refractive index of two dilutions of the original nanofluid. Then we analyze the use of this methodology to obtain some average radius in the size of polydisperse suspensions and in the case of suspensions of weakly absorbing particles. We also perform an error analysis considering fixed errors in measurements and calculating the errors in the retrieved size, refractive index, and concentration of particles. Finally, we characterize experimentally nanofluids of polymeric particles fabricated of poly(methyl-methacrylate) (PMMA) and polystyrene (PS) for which we achieved an uncertainty of 5×10(-3) and 1×10(-2) in the determination of the particle refractive index, respectively, and a precision better than 3% in the determination of their radii.

Entropic depletion in colloidal suspensions and polymer liquids: role of nanoparticle surface topography.

We employ a hybrid Monte Carlo plus integral equation theory approach to study how dense fluids of small nanoparticles or polymer chains mediate entropic depletion interactions between topographically rough particles where all interaction potentials are hard core repulsion. The corrugated particle surfaces are composed of densely packed beads which present variable degrees of controlled topographic roughness and free volume associated with their geometric crevices. This pure entropy problem is characterized by competing ideal translational and (favorable and unfavorable) excess entropic contributions. Surface roughness generically reduces particle depletion aggregation relative to the smooth hard sphere case. However, the competition between ideal and excess packing entropy effects in the bulk, near the particle surface and in the crevices, results in a non-monotonic variation of the particle-monomer packing correlation function as a function of the two dimensionless length scale ratios that quantify the effective surface roughness. As a result, the inter-particle potential of mean force (PMF), second virial coefficient, and spinodal miscibility volume fraction vary non-monotonically with the surface bead to monomer diameter and particle core to surface bead diameter ratios. A miscibility window is predicted corresponding to an optimum degree of surface roughness that completely destroys depletion attraction resulting in a repulsive PMF. Variation of the (dense) matrix packing fraction can enhance or suppress particle miscibility depending upon the amount of surface roughness. Connecting the monomers into polymer chains destabilizes the system via enhanced contact depletion attraction, but the non-monotonic variations with surface roughness metrics persist.

Design of a hybrid computational fluid dynamics-monte carlo radiation transport methodology for radioactive particulate resuspension studies.

There are numerous scenarios where radioactive particulates can be displaced by external forces. For example, the detonation of a radiological dispersal device in an urban environment will result in the release of radioactive particulates that in turn can be resuspended into the breathing space by external forces such as wind flow in the vicinity of the detonation. A need exists to quantify the internal (due to inhalation) and external radiation doses that are delivered to bystanders; however, current state-of-the-art codes are unable to calculate accurately radiation doses that arise from the resuspension of radioactive particulates in complex topographies. To address this gap, a coupled computational fluid dynamics and Monte Carlo radiation transport approach has been developed. With the aid of particulate injections, the computational fluid dynamics simulation models characterize the resuspension of particulates in a complex urban geometry due to air-flow. The spatial and temporal distributions of these particulates are then used by the Monte Carlo radiation transport simulation to calculate the radiation doses delivered to various points within the simulated domain. A particular resuspension scenario has been modeled using this coupled framework, and the calculated internal (due to inhalation) and external radiation doses have been deemed reasonable. GAMBIT and FLUENT comprise the software suite used to perform the Computational Fluid Dynamics simulations, and Monte Carlo N-Particle eXtended is used to perform the Monte Carlo Radiation Transport simulations.

Good manufacturing practice: manufacturing of a nerve agent antidote nanoparticle suspension.

We have established a current good manufacturing practice (GMP) manufacturing process to produce a nanoparticle suspension of 1,1'-methylenebis-4-[(hydroxyimino)methyl]pyridinium dimethanesulfonate (MMB4 DMS) in cottonseed oil (CSO) as a nerve agent antidote for a Phase 1 clinical trial. Bis-pyridinium oximes such as MMB4 were previously developed for emergency treatment of organophosphate nerve agent intoxication. Many of these compounds offer efficacy superior to monopyridinium oximes, but they have poor thermal stability due to hydrolytic cleavage in aqueous solution. We previously developed a nonaqueous nanoparticle suspension to improve the hydrothermal stability, termed Enhanced Formulation (EF). An example of this formulation technology is a suspension of MMB4 DMS nanoparticles in CSO. Due to the profound effect of particle size distribution on product quality and performance, particle size must be controlled during the manufacturing process. Therefore, a particle size analysis method for MMB4 DMS in CSO was developed and validated to use in support of good laboratory practice/GMP development and production activities. Manufacturing of EF was accomplished by milling MMB4 DMS with CSO and zirconia beads in an agitator bead mill. The resulting bulk material was filled into 5-mL glass vials at a sterile fill facility and terminally sterilized by gamma irradiation. The clinical lot was tested and released, a Certificate of Analysis was issued, and a 3-year International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) stability study started. The drug product was placed in storage for Phase 1 clinical trial distribution. A dose delivery uniformity study was undertaken to ensure that the correct doses were delivered to the patients in the clinic.

Phase behavior of colloids and proteins in aqueous suspensions: theory and computer simulations.

The fluid phase behavior of colloidal suspensions with short-range attractive interactions is studied by means of Monte Carlo computer simulations and two theoretical approximations, namely, the discrete perturbation theory and the so-called self-consistent Ornstein-Zernike approximation. The suspensions are modeled as hard-core attractive Yukawa (HCAY) and Asakura-Oosawa (AO) fluids. A detailed comparison of the liquid-vapor phase diagrams obtained through different routes is presented. We confirm Noro-Frenkel's extended law of scaling according to which the properties of a short-ranged fluid at a given temperature and density are independent of the detailed form of the interaction, but just depend on the value of the second virial coefficient. By mapping the HCAY and AO fluids onto an equivalent square-well fluid of appropriate range at the critical point we show that the critical temperature as a function of the effective range is independent of the interaction potential, i.e., all curves fall in a master curve. Our findings are corroborated with recent experimental data for lysozyme proteins.

Self-assembled biotransesterified cyclodextrins as Artemisinin nanocarriers - I: formulation, lyoavailability and in vitro antimalarial activity assessment.

We recently reported a one-step transesterification of cyclodextrins (CDs) by vinyl-acyl fatty esters catalyzed by thermolysin. By using the solvent displacement method and depending on the experimental conditions, the CD derivatives grafted with decanoic alkyl chains (CD-C(10)) yielded either nanosphere or nanoreservoir-type systems with a size ranging from 70 to 220 nm. Both types of nanostructures were able to associate artemisinin (ART), a well-known antimalarial lipophilic drug. The formulation parameters were optimized to reach stable and high ART dosage corresponding to drug levels of 0.3 and 1.6 mg mL(-1) in the colloidal suspension, for the spherical and reservoir-type nanosystems, respectively. PEG surface-decorated nanoparticles were also prepared by co-nanoprecipitation of PEG fatty acid esters and CD-C(10) molecules. The integration of the PEGylated amphiphiles within the CD-C(10) nanostructures did not influence the ART lyoavailability. Both types of ART-loaded nanosystems showed a sustained in vitro release profile over 96 (nanoreservoirs) and 240 h (nanospheres). Finally, the in vitro antimalarial activity was evaluated using the lactate dehydrogenase assay. ART-containing colloidal suspensions inhibited the growth of cultured Plasmodium falciparum, both multi-resistant K1 and susceptible 3D7 strains with IC(50) values (2.8 and 7.0 ng mL(-1)) close to those of reference ART solution. These colloidal nanosystems based on CD derivatives and containing ART may provide a promising alternative formulation for injectable use of ART.

Adhesion and cohesion in structures containing suspended microscopic polymeric films.

This paper presents a novel technique for the characterization of adhesion and cohesion in suspended micro-scale polymeric films. The technique involves push-out testing with probes that are fabricated using focused ion beam techniques. The underlying stresses associated with different probe tip sizes were computed using a finite element model. The critical force for failure of the film substrate interface is used to evaluate adhesion, while the critical force for penetration of the film determines cohesion. When testing a standard material, polycarbonate, a shear strength of approximately 70 MPa was calculated using the Mohr-Coulomb theory. This value was shown to be in agreement with the results in the literature. The technique was also applied to the measurement of adhesion and cohesion in a model drug-eluting stent (the Nevo™ Sirolimus Eluting Coronary Stent) containing suspended microscopic polymeric films in metallic Co-Cr alloy reservoirs. The cohesive strength of the formulation was found to be comparable with that of plastics such as those produced by reaction injection molding and high-density polyethylene.

Eudragit nanoparticles containing genistein: formulation, development, and bioavailability assessment.

BACKGROUND: Genistein, one of the major isoflavones, has received great attention as a phytoestrogen and potential cancer chemoprevention agent. However, the dissolution and bioavailability of genistein from solid oral preparations is low due to its poor water solubility. METHODS: In order to improve the oral bioavailability of genistein, genistein nanoparticles were prepared by the nanoprecipitation technique using Eudragit(®) E100 as carriers and an optimized formulation of mass ratio (genistein:Eudragit E100, 1:10). The mean particle size of genistein nanoparticles was approximately 120 nm when diluted 100 times with distilled water. The drug-loaded nanoparticles were spherical on observation by transmission electric microscopy. RESULTS: Encapsulation efficiency and drug loading of the genistein nanoparticles were approximately 50.61% and 5.02%, respectively. Release of drug from the genistein nanoparticles was two times greater than that from the conventional capsules. After administration of genistein suspension or genistein nanoparticles at a single dose of 100 mg/kg to fasted rats, the relative bioavailability of genistein from the nanoparticles compared with the reference suspension was 241.8%. CONCLUSION: These results suggested that a nanoparticle system is a potentially promising formulation for the efficient delivery of poorly water-soluble drugs by oral administration.

Nanosuspensions in drug delivery: recent advances, patent scenarios, and commercialization aspects.

The interest in the preparation and application of nanometer-sized materials is increasing due to their tremendous potential as a drug delivery system with wide range of applications. Recently, nanoscale systems have received much interest as a way to resolve solubility issues because of their cost-effectiveness and technical simplicity compared to liposomes and other colloidal drug carriers. Nanosuspensions have proven to be a better alternative over other approaches currently available for improving bioavailability of number of drugs with low solubility. Nanosuspensions have been extensively developed for a wide range of drugs and have been evaluated for in vitro and in vivo applications by various routes: parenteral, oral, pulmonary, topical. They have also been used for drug targeting. Different preparation methods for nanosuspensions and their application are being reported and patented. In fact, the number of products based on nanosuspension in the market and under clinical study is higher than that of other nanotechnology-based applications. This article reviews the research and recent advances in formulation, characterization, application of nanosuspensions as well as patents on nanosuspension methods.

Crystallization in suspensions of hard spheres: a Monte Carlo and molecular dynamics simulation study.

The crystallization of a metastable melt is one of the most important non-equilibrium phenomena in condensed matter physics, and hard sphere colloidal model systems have been used for several decades to investigate this process by experimental observation and computer simulation. Nevertheless, there is still an unexplained discrepancy between the simulation data and experimental nucleation rate densities. In this paper we examine the nucleation process in hard spheres using molecular dynamics and Monte Carlo simulation. We show that the crystallization process is mediated by precursors of low orientational bond-order and that our simulation data fairly match the experimental data sets.

Ultrasonic dispersion of nanoparticles for environmental, health and safety assessment--issues and recommendations.

Studies designed to investigate the environmental or biological interactions of nanoscale materials frequently rely on the use of ultrasound (sonication) to prepare test suspensions. However, the inconsistent application of ultrasonic treatment across laboratories, and the lack of process standardization can lead to significant variability in suspension characteristics. At present, there is widespread recognition that sonication must be applied judiciously and reported in a consistent manner that is quantifiable and reproducible; current reporting practices generally lack these attributes. The objectives of the present work were to: (i) Survey potential sonication effects that can alter the physicochemical or biological properties of dispersed nanomaterials (within the context of toxicity testing) and discuss methods to mitigate these effects, (ii) propose a method for standardizing the measurement of sonication power, and (iii) offer a set of reporting guidelines to facilitate the reproducibility of studies involving engineered nanoparticle suspensions obtained via sonication.

Structural and dynamical analysis of monodisperse and polydisperse colloidal systems.

We present a semigrand ensemble Monte Carlo and Brownian dynamics simulation study of structural and dynamical properties of polydisperse soft spheres interacting via purely repulsive power-law potentials with a varying degree of "softness." Comparisons focus on crystal and amorphous phases at their coexistence points. It is shown through detailed structural analysis that as potential interactions soften, the "quality of crystallinity" of both monodisperse and polydisperse systems deteriorates. In general, polydisperse crystalline phases are characterized by a more ordered structure than the corresponding monodisperse ones (i.e., for the same potential softness). This counter-intuitive feature originates partly from the fact that particles of different sizes may be accommodated more flexibly in a crystal structure and from the reality that coexistence (osmotic) pressure is substantially higher for polydisperse systems. These trends diminish for softer potentials. Potential softness eventually produces substitutionally disordered crystals. However, substitutional order is apparent for the hard-spherelike interactions. Diffusionwise, crystals appear quite robust with a slight difference in the vibrational amplitudes of small and large particles. This difference, again, diminishes with potential softness. Overcrowding in amorphous polydisperse suspensions causes "delayed" diffusion at intermediate times.

Study of magnetic nanovectors by Wet-STEM, a new ESEM mode in transmission.

Many nanovectors used for therapy (drug targeting, radiation therapy) or diagnostic such as Magnetic Resonance Imaging (MRI) have a composite structure consisting of an organic core or organic coverage encapsulating magnetic nanoparticles and they are commonly dispersed in liquid suspensions for intravenous injection. Here is presented the application of a new Environmental Scanning Electron Microscopy (ESEM) mode in transmission, so called Wet-STEM, for transmission imaging of droplets of such suspensions. This is illustrated by Wet-STEM images from PLLA/Re nanospheres (about 100-300 nm in diameter) loaded with magnetite nanoparticles (about 10 nm in diameter) and from iron oxide core (about 5 nm in size) MRI contrast agents, both examples in aqueous suspensions. It is shown that the Wet-STEM mode allows both the collective behavior of such nanovectors in suspension to be characterized and the inner composite structure of individual vectors to be revealed. Such experimental results are discussed by comparison with Monte Carlo computer simulations of the distribution of the electrons scattered through the samples in rather large solid angles (between 20° and 47°) corresponding to the detection conditions.

Characterization of fullerene colloidal suspension in a cell culture medium for in vitro toxicity assessment.

To elucidate important parameters for in vitro toxicity assessment of C(60) and C(70) fullerene colloidal particles, experiments were carried out in culture medium using pulsed field gradient nuclear magnetic resonance (PFG-NMR), asymmetrical flow field-flow fractionation (AFFFF), and dynamic light scattering (DLS) methods. First, the amounts of total and bulk bovine serum albumin (BSA) molecules in C(60) and C(70) fullerene colloidal suspensions were determined using the PFG-NMR and AFFFF methods. Because the amount of bulk BSA molecules in the cell culture medium is a significant factor in inducing cell growth and because BSA can strongly adsorb onto the fullerene particles, this value is an important parameter for toxicological assessment. It was found that most of the BSA molecules are freely diffusing for both fullerene colloidal suspensions, at least in the range of fullerene concentration from 0.0025-0.15 mg mL(-1). Second, structural analysis of the fullerene colloidal nanoparticles was successfully performed using AFFFF-multi angle light scattering (MALS) and DLS methods. Based on the observed light scattering profiles obtained from a narrow size distribution of colloidal particles collected after AFFFF separation, it was estimated that the fullerene colloidal nanoparticles of both C(60) and C(70) did not adopt a hard spherical structure in the culture medium. The results from combined analysis using the AFFFF-MALS and DLS methods also supported this conclusion and indicated that the fullerene colloidal particles adopted a more flexible structure in culture medium. Since carbon nanomaterials with different geometric structures exhibit quite different cytotoxicity and bioactivity, these results are important for in vitro toxicity assessment.

An assessment of beclomethasone dipropionate clathrate formation in a model suspension metered dose inhaler.

The aims of this study were to investigate and characterize the physico-chemical properties of beclomethasone dipropionate (BDP) crystallized from tricholoromonofluoromethane (CFC-11). Physical interactions in a model pressurised metered dose inhaler (pMDI) system and changes in surface energy after size reduction (micronization) were determined. Although CFC-11 has largely been phased out of use in pMDIs due to its ozone depletion potential, the BDP CFC-11 clathrate is a stable entity and thus suitable as a model for our initial investigations. In addition, although propellant clathrates have been known for sometime, as far as the authors are aware, their surface energies and adhesive interactions have not been reported. The structure of the clathrate was investigated using scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS) and X-ray powder diffraction (X-RPD). In addition, atomic force microscopy (AFM) was employed to determine the dispersive surface free energy (SE) and force of adhesion (F(adh)) of the BDP CFC-11 clathrate with different pMDI components in a model propellant (decafluoropentane). The dispersive surface free energies for anhydrous BDP (micronized), the CFC-11 clathrate and ball-milled BDP CFC-11 clathrate are (47.5+/-4.9) mJ m(-2), (11.3+/-4.1) mJ m(-2) and (15.2+/-1.3) mJ m(-2) respectively. Force of adhesion results shows that BDP CFC-11 clathrates, even after being ball-milled for 2.5h, have a lower F(adh) compared to micronized anhydrous BDP with different pMDI components. This shows that the formation of the crystalline CFC-11 clathrate is advantageous when compared to the micronized anhydrous form, in terms of its surface energy and potential interactions within a suspension MDI formulation. In the wider context, this work has implications for the future development of HFA formulations with APIs which are prone to the formation of propellant clathrates.