Utilizing Laser Activation of Photothermal Plasmonic Nanoparticles to Induce On-Demand Drug Amorphization inside a Tablet.

Poor aqueous drug solubility represents a major challenge in oral drug delivery. A novel approach to overcome this challenge is drug amorphization inside a tablet, that is, on-demand drug amorphization. The amorphous form is a thermodynamically instable, disordered solid-state with increased dissolution rate and solubility compared to its crystalline counterpart. During on-demand drug amorphization, the drug molecularly disperses into a polymer to form an amorphous solid at elevated temperatures inside a tablet. This study investigates, for the first time, the utilization of photothermal plasmonic nanoparticles for on-demand drug amorphization as a new pharmaceutical application. For this, near-IR photothermal plasmonic nanoparticles were tableted together with a crystalline drug (celecoxib) and a polymer (polyvinylpyrrolidone). The tablets were subjected to a near-IR laser at different intensities and durations to study the rate of drug amorphization under each condition. During laser irradiation, the plasmonic nanoparticles homogeneously heated the tablet. The temperature was directly related to the rate and degree of amorphization. Exposure times as low as 180 s at 1.12 W cm-2 laser intensity with only 0.25 wt % plasmonic nanoparticles and up to 50 wt % drug load resulted in complete drug amorphization. Therefore, near-IR photothermal plasmonic nanoparticles are promising excipients for on-demand drug amorphization with laser irradiation.

A Novel Photoreactive Excipient to Probe Peptide-Matrix Interactions in Lyophilized Solids.

Excipients used in lyophilized protein drug products are often selected by a trial-and-error method, in part, because the analytical methods used to detect protein-excipient interactions in lyophilized solids are limited. In this study, photolytic labeling was used to probe interactions between salmon calcitonin (sCT) and excipients in lyophilized solids. Two diazirine-derived photo-excipients, photo-leucine (pLeu) and photo-glucosamine (pGlcN), were incorporated into lyophilized solids containing sCT, together with an unlabeled excipient (sucrose or histidine) at prelyophilization pH values from 6 to 9.9. Commercially available pLeu was selected as an ionizable photo-excipient and amino acid analog, while pGlcN was synthesized as an analog of sugar-based excipients. Photolytic labeling was induced by exposing the solids to UV light (365 nm, 30-60 min), and the resulting products were identified and quantified with liquid-chromatography mass spectrometry. The distribution of photo-reaction products was affected by the photoreactive reagent used, the type of unlabeled excipient, and the solution pH before lyophilization. When other components of the solid were identical, the extent and sites of labeling on sCT were different for pGlcN and pLeu. The results suggest that ionizable and nonionizable excipients interact differently with sCT in lyophilized solids and that photo-excipients can be used to map these interactions.

Photostability Issues in Pharmaceutical Dosage Forms and Photostabilization.

Photodegradation is one of the major pathways of the degradation of drugs. Some therapeutic agents and excipients are highly sensitive to light and undergo significant degradation, challenging the quality and the stability of the final product. The adequate knowledge of photodegradation mechanisms and kinetics of photosensitive therapeutic entities or excipients is a pivotal aspect in the product development phase. Hence, various pharmaceutical regulatory agencies, across the world, mandated the industries to assess the photodegradation of pharmaceutical products from manufacturing stage till storage, as per the guidelines given in the International Conference on Harmonization (ICH). Recently, numerous formulation and/or manufacturing strategies has been investigated for preventing the photodegradation and enhancing the photostability of photolabile components in the pharmaceutical dosage forms. The primary focus of this review is to discuss various photodegradation mechanisms, rate kinetics, and the factors that influence the rate of photodegradation. We also discuss light-induced degradation of photosensitive lipids and polymers. We conclude with a brief note on different approaches to improve the photostability of photosensitive products.

An Electron Paramagnetic Resonance (EPR) spectroscopy study on the γ-irradiation sterilization of the pharmaceutical excipient l-histidine: Regeneration of the radicals in solution.

The effects of γ-radiation sterilization on the parenteral excipient l-histidine were analysed by means of EPR spectroscopy. The irradiation process was found to induce the formation of a deamination radical which was persistent in the solid state. The nature and reactivity of the radicals following dissolution in water was evaluated using spin-trapping EPR experiments. The deamination radical was found to regenerate in solution in the presence of trace metals, potentially leading to radical induced degradation reactions occurring up to an hour after the dissolution process. Understanding this process is significant for the improved design of parental pharmaceutical formulations in which unwanted radical reactions after γ-radiation sterilization could lead to degradation of active ingredients.

Surface Disinfection Enabled by a Layer-by-Layer Thin Film of Polyelectrolyte-Stabilized Reduced Graphene Oxide upon Solar Near-Infrared Irradiation.

We report an antibacterial surface that kills airborne bacteria on contact upon minutes of solar near-infrared (NIR) irradiation. This antibacterial surface employs reduced graphene oxide (rGO), a well-known near-infrared photothermal conversion agent, as the photosensitizer and is prepared by assembling oppositely charged polyelectrolyte-stabilized rGO sheets (PEL-rGO) on a quartz substrate with the layer-by-layer (LBL) technique. Upon solar irradiation, the resulting PEL-rGO LBL multilayer efficiently generates rapid localized heating and, within minutes, kills >90% airborne bacteria, including antibiotic-tolerant persisters, on contact, likely by permeabilizing their cellular membranes. The observed activity is retained even when the PEL-rGO LBL multilayer is placed underneath a piece of 3 mm thick pork tissue, indicating that solar light in the near-infrared region plays dominant roles in the observed activity. This work may pave the way toward NIR-light-activated antibacterial surfaces, and our PEL-rGO LBL multilayer may be a novel surface coating material for conveniently disinfecting biomedical implants and common objects touched by people in daily life in the looming postantibiotic era with only minutes of solar exposure.

Highly fluorescent, photostable, and ultrasmall silicon drug nanocarriers for long-term tumor cell tracking and in-vivo cancer therapy.

Silicon nanoparticle (SiNP) nanocarriers feature strong fluorescence, ultrasmall size, robust photostability, and tunable drug-loading capacity. Using SiNP nanocarriers, the first example of long-term cancer cell tracking is successfully demonstrated. Furthermore, in vivo experiments show that tumor-bearing mice treated with SiNP nanocarriers survive over 20 d without observable tumor growth, demonstrating the high-efficacy chemotherapy of the Si nanocarriers.

A study of photostability and compatibility of the anti-chagas drug Benznidazole with pharmaceutics excipients.

UNLABELLED: Abstract Context: Benznidazole (BNZ) is an antiparasitic with trypanocidal properties for the etiological treatment of Chagas disease since 1973. Monitoring the stability of this drug is one of the most effective methods of assessment, forecasting and prevention of problems related to quality product. OBJECTIVE: To investigate the direct and indirect photodegradation of BNZ and to evaluate the interference of the excipients used in the forms dosage solid as well as to shed light on the chemical structure of the degradation products obtained. MATERIALS AND METHODS: To perform this work we adopted the "ICH Harmonised Tripartite Guideline: Photostability Testing of New Drug Substances and Products Q1B" (Guideline Q1B). We used benzonidazole (BNZ) (N-benzil-2-(2-nitroimidazol-1-il) acetamide) (LAFEPE®, Recife, Brazil) and various excipients; beyond high-performance liquid chromatography (HPLC), differential scanning calorimetry (DSC), infrared spectroscopy (IR) and mass spectrometry/mass spectrometry (MS/MS). The indirect photodegradation of BNZ was carried out using physical mixtures with 13 pharmaceutical excipients commonly used in the preparation of solid dosage forms. RESULTS: HPLC and MS/MS techniques were selected for the identification of two photoproducts (PPs) and photoreactions found in direct and indirect tests with the microcrystalline cellulose, considered a critical excipient. DISCUSSION: Despite variations in the infrared spectrometry, differential scanning calorimetry and differential thermogravimetry curves, these techniques are not conclusive since the study of photodegradation of the drug caused decay of 30%, according to the ICH. CONCLUSIONS: The results show that BNZ only undergoes direct photodegradation, since no new PPs were found for a combination of the drug and excipients.

Gamma sterilization of pharmaceuticals--a review of the irradiation of excipients, active pharmaceutical ingredients, and final drug product formulations.

Sterilization by gamma irradiation has shown a strong applicability for a wide range of pharmaceutical products. Due to the requirement for terminal sterilization where possible in the pharmaceutical industry, gamma sterilization has proven itself to be an effective method as indicated by its acceptance in the European Pharmacopeia and the United States Pharmacopeia ( ). Some of the advantages of gamma over competitive procedures include high penetration power, isothermal character (small temperature rise), and no residues. It also provides a better assurance of product sterility than aseptic processing, as well as lower validation demands. Gamma irradiation is capable of killing microorganisms by breaking their chemical bonds, producing free radicals that attack the nucleic acid of the microorganism. Sterility by gamma irradiation is achieved mainly by the alteration of nucleic acid and preventing the cellular division. This review focuses on the extensive application of gamma sterilization to a wide range of pharmaceutical components including active pharmaceutical ingredients, excipients, final drug products, and combination drug-medical devices. A summary of the published literature for each class of pharmaceutical compound or product is presented. The irradiation conditions and various quality control characterization methodologies that were used to determine final product quality are included, in addition to a summary of the investigational outcomes. Based on this extensive literature review and in combination with regulatory guidelines and other published best practices, a decision tree for implementation of gamma irradiation for pharmaceutical products is established. This flow chart further facilitates the implementation of gamma irradiation in the pharmaceutical development process. The summary therefore provides a useful reference to the application and versatility of gamma irradiation for pharmaceutical sterilization. LAY ABSTRACT: Many pharmaceutical products require sterilization to ensure their safe and effective use. Sterility is therefore a critical quality attribute and is essential for direct injection products. Due to the requirement for terminal sterilization, where possible in the pharmaceutical industry sterilization by gamma irradiation has been commonly used as an effective method to sterilize pharmaceutical products as indicated by its acceptance in the European Pharmacopeia. Gamma sterilization is a very attractive terminal sterilization method in view of its ability to attain 10(-6) probability of microbial survival without excessive heating of the product or exposure to toxic chemicals. However, radiation compatibility of a product is one of the first aspects to evaluate when considering gamma sterilization. Gamma radiation consists of high-energy photons that result in the generation of free radicals and the subsequent ionization of chemical bonds, leading to cleavage of DNA in microorganisms and their subsequent inactivation. This can result in a loss of active pharmaceutical ingredient potency, the creation of radiolysis by-products, a reduction of the molecular weight of polymer excipients, and influence drug release from the final product. There are several strategies for mitigating degradation effects, including optimization of the irradiation dose and conditions. This review will serve to highlight the extensive application of gamma sterilization to a broad spectrum of pharmaceutical components including active pharmaceutical ingredients, excipients, final drug products, and combination drug-medical devices.

Solar energy assisted starch-stabilized palladium nanoparticles and their application in C-C coupling reactions.

Present work reports a novel one step, greener protocol for the synthesis of starch-stabilized palladium nanoparticles (PdNPs) with an average particle diameter of 30-40 nm. These particles were stable and uniform in size. In present protocol, the concentrated solar energy mediated reduction of palladium chloride was achieved by using citric acid as a reducing agent and starch as a capping agent. UV-Visible spectroscopy, Transmission Electron Microscopy, Field Emission Gun-Scanning Electron Microscopy, Selected Area Electron Diffraction and Electron dispersive X-ray Spectral analysis techniques were used to characterize this starch capped PdNPs. Herein; we are reporting such combination of starch and citric acid in the synthesis of PdNPs for the first time. The catalytic activity of synthesized nanoparticles has been checked for Suzuki and Heck cross coupling reactions. The product yield was confirmed by GC. The products were confirmed using GC-MS analysis and also using GC with the help of authentic standards. Solar energy assisted starch stabilized PdNPs showed excellent activity in the C-C bond formation between aryl halides (I, Br) with phenyl boronic acid and its derivatives. In addition, the catalyst showed good activity in the Heck coupling reaction of C-C bond formation of aryl halides with aromatic alkene. The use of starch, citric acid, water and solar energy makes present protocol greener.

Microwave modified non-crosslinked pectin films with modulated drug release.

The effects of microwave on drug release properties of pectin films carrying sulfanilamide (SN-P), sulfathiazole (ST-P) and sulfamerazine (SM-P) of high to low aqueous solubilities were investigated. These films were prepared by solvent evaporation technique and treated by microwave at 80 W for 5-40 min. Their profiles of drug dissolution, drug content, matrix interaction and matrix crystallinity were determined by drug dissolution testing, drug content assay, differential scanning calorimetry, X-ray diffractometry and scanning electron microscopy techniques. Microwave induced an increase in matrix amorphousness but lower drug release propensity with a greater retardation extent in SN-P films, following a rise in strength of matrix interaction. A gain in amorphous structure does not necessarily increase the drug release of film. Microwave can possibly retard drug release of pectin film carrying water-soluble drug through modulating its state of matrix interaction.

Hydrolytic degradation characteristics of irradiated multi-layered PLGA films.

Poly(lactide-co-glycolide) (PLGA) has been extensively investigated for controlled drug release. Because they undergo bulk degradation, they do not allow for a good controlled-release of drugs. The objective of this study is therefore to understand if a multi-layer-cum-irradiation technique would elicit surface erosion from PLGA polymers. A linear loss of mass and film thinning from PLGA films were observed. Also, the erosion of the top layer, of this multi-layered structure, accelerates degradation of the underlying layers. It is this effect that results in the observed pseudo-surface erosion for irradiated multi-layered PLGA.

Radiosterilization of drugs in aqueous solutions may be achieved by the use of radioprotective excipients.

The aim of this study was to assess the feasibility of radiosterilization of drugs aqueous solutions and to evaluate the effects of some additives, such as mannitol, nicotinamide and pyridoxine, which might protect the drug from degradation. Metoclopramide was selected as a model drug. The structures of the degradation products were determined to gain insight on the radiolysis mechanisms in aqueous solution in order to design strategies to lower the drug degradation. Metoclopramide hydrochloride aqueous solutions with and without excipients were irradiated either with gamma rays or high-energy electrons. HPLC-DAD was used to measure the loss of chemical potency and to quantify the degradation products which were also characterized by LC-APCI-MS-MS. Metoclopramide recovery for gamma and electron beam-irradiated solutions containing either mannitol, pyridoxine or nicotinamide meets the pharmacopoeial specifications for metoclopramide content up to a 15 kGy irradiation so that metoclopramide solutions containing these excipients might be radiosterilized at 15 kGy either with gamma rays or high-energy electrons. Structures are proposed for the majority of radiolysis products. Similar radiolysis products were detected for gamma and electron beam irradiations but the chromatographic profiles were different (differences in the distribution of radiolysis products).

Sustained release pellets based on poly(N-isopropyl acrylamide): matrix and in situ photopolymerization-coated systems.

The usefulness of poly(N-isopropyl acrylamide), PNIPA, for preparing sustained release matrix or photopolymerization-coated cellulosic pellets was evaluated. Theophylline pellets and granules were prepared using powdered cellulose (PC), poly(vinylpyrrolidone) (PVP), and PNIPA of Mw approximately 330 kDa, Mn approximately 93 kDa and low critical solubility temperature approximately 32 degrees C. The low consistency of wet mass, evaluated by torsion rheometry, due to hydrophilic character of PNIPA at room temperature, favored extrusion-spheronization. Theophylline (20%) pellets prepared with 15% PNIPA, 20% PVP and 45% PC, and granules obtained using 40% PNIPA and 40% PC showed an enhanced, although limited, ability to sustain the release. This effect was notably promoted after compression (which provides slowly eroding tablets) or coating of individualized pellets. A new coating technique consisting in forming the polymer film by photo-polymerization/cross-linking of NIPA monomers on pellets surface, using a photoinitiator and UV-irradiation at 366 nm, was developed. The composition of coating mixture and the time of irradiation were optimized using oscillatory rheometry. Coating did not significantly change the shape, size, or friability of the pellets but remarkably decreased the porosity and sustained drug release for several hours. In situ formation and cross-linking of PNIPA on the pellet appears as a feasible way for controlling drug release.

Stability studies on colloidal suspensions of polyurethane nanocapsules.

Generally nanocapsules suspensions are a colloidal system in a metastable state, there is aggregation due to attraction and repulsion forces between particles. The objective of this work was to bring the role of the polymeric membrane in the protection of the active drug against damaging caused by external agents and to select the monomer which leads to obtain stable formulation with the highest possible payload of the active drug. The stability testing involving visual aspect, particle size measurement, transmission electron microscopy (TEM) examination, and drug loss was conduced after 6 months of storage at different temperatures (4, 25, and 45 degrees C). The colloidal suspensions of nanocapsules were obtained using the combined interfacial polycondensation and spontaneous emulsification, the technique was used to encapsulate alpha-tocopherol using polyurethanes polymers. It is a one step procedure: An organic phase composed of a water miscible solvent (acetone), lipophilic monomer (Isophorone diisocyanate IPDI), oil, and a lipophilic surfactant, is injected in an aqueous phase containing hydrophilic monomer (diol with various molecular weight: 1,2-ethanediol (ED), 1,4-butanediol (BD), and 1,6-hexanediol (HD)) and hydrophilic emulsifying agent. The water miscible solvent diffuses to the aqueous phase, the oil precipitates as nano-droplets, and the two monomers react at the interface, forming a membrane around the nanoemulsion leading to nanocapsules. A good physical stability of suspensions corresponds to absence of symptoms such as sedimentation or agglomeration, significant size change and alpha-tocopherol degradation due to external agents such as oxygen, temperature, and ultraviolet (UV) irradiation. The size of nanocapsules before storage was about 232 +/- 3, 258 +/- 29, and 312 +/- 4 nm for ED, BD, and HD, respectively. After 6 months of storage, polyurethanes nanocapsules possess good stability against aggregation at 4 and 25 degrees C. Comparing results obtained using different monomers, it reveals that the polyurethane based on HD offers good protection of alpha-tocopherol against damaging caused by the temperature and UV irradiation.

Photosensitized degradation of losartan potassium in an extemporaneous suspension formulation.

During development of an extemporaneous suspension formulation for losartan potassium, previously unknown degradation products were observed in experimental suspensions prepared in a commercial cherry syrup vehicle. These degradates increased rapidly when analytical solutions prepared from that suspension were exposed to ambient light. The structures of the degradates were determined using a combination of preparative HPLC, LC/MS, (13)C and (1)H NMR (1D and 2D), and mechanistic chemistry. Each degradate results from destruction of the imidazole ring of losartan. Formation of the two major degradates required exposure to light (UV or visible) and the presence of oxygen. Experiments using Rose Bengal (a singlet oxygen photosensitizer) and 1,4-diazabicyclooctane (DABCO; a singlet oxygen quencher) established that the major photodegradates are formed via the intermediacy of singlet oxygen. The identity of the photosensitizer in the formulation was not unequivocally determined; however, the experiments implicated the artificial flavoring in fulfilling this role.

Novel method for studying photolability of topical formulations: a case study of titanium dioxide stabilization of ketoprofen.

Sunlight may decompose active substances and excipients in pharmaceuticals. This may cause formulation problems as well as induce adverse skin reactions. The photodecomposition of topical preparations may occur on the skin surface, but also deeper in the skin after penetration of light into the viable tissues. The aim of the present study was to investigate whether microparticles of titanium dioxide could protect against photodecomposition using ketoprofen as a photolabile model substance. The results showed quality differences between titanium dioxide, where surface-coated particles were superior to pharmaceutical grades in reducing the degradation in vitro. The protective effect was also studied in humans. The skin was treated for 3 h with the gels and then exposed to ultraviolet (UV) light (11.7 J/cm2 UVA and 5.4 mJ/cm2 UVB). Layers of the stratum corneum were then removed by consecutive tape strippings and assayed for content of ketoprofen. The remaining amount was higher in the different stratum corneum compartments after treatment with a gel containing 4% coated titanium dioxide compared with a transparent gel. Thus, surface-coated microparticles of titanium dioxide may well be of clinical benefit in protecting photolabile drug substances against sunlight.

Stabilization of nontoxic PVC formulation for gamma irradiation sterilization, II. Effect of antioxidants.

In order to investigate the fundamental data for the resistance of gamma radiation sterilization of polyvinylchloride (PVC), the formulations of the antioxidants such as commercial Irganox series and inorganic, processing aids, stabilizer aids, trans-stilbene oxide (StO) and so on have been carried out. The control and irradiated PVC samples with 1.5, 2.5 and 4.0 Mrad were characterized by mechanical tester, colorimetry, and extractant in water. Irganox 1010 was more effective than Irganox 1076 for color changes whereas Irganox 1076 was more effective than Irganox 1010 for the change of extractant. It was also observed the significant diminution of color changes for inorganic antioxidants as CaO and ZnO. Oxidized paraffin wax as lubricant, styrene-methylmetacrylate copolymers as processing aids, and nontoxic debenzoylmethane as secondary stabilizer did not show good stabilization for the irradiation. The new proposed radiation stabilizer in this study, StO, showed the significant improvement of gamma radiation resistance for the plasticized PVC. The possible mechanism could be explained that an epoxy functional group stabilizes effectively the processes of dehydrogenation, the formation of hydroperoxides, and the formation of oxygen containing groups, and the synergetic effects of an epoxy compound are more notable for the prevention of radiation oxidation in the presence of an aromatic group.

Behavior of uptake of moisture by drugs and excipients under accelerated conditions of temperature and humidity in the absence and the presence of light. 1. Pure anti-tuberculosis drugs and their combinations.

An investigation was carried out to determine the behavior of moisture gain by four anti-tuberculosis drugs, viz. rifampicin, isoniazid, pyrazinamide and ethambutol, when exposed in pure form and in combinations to accelerated conditions of 40 degrees C and 75% RH, in the absence and the presence of light. Weight gain was seen only in those samples that contained ethambutol, and this behavior was observed both in dark and lighted chambers. There was a decrease in moisture uptake with an increase in the number of drugs in the mixture. Another observation was a higher weight gain by the mixture of ethambutol and isoniazid in a dark chamber, than either pure ethambutol or drug combinations containing ethambutol. The most interesting finding was an overall acceleration of weight gain in the presence of light as compared with dark conditions, which is a hitherto unknown phenomenon.

The effect of gamma-irradiation on drug release from bioerodible microparticles: a quantitative treatment.

The two major objectives of this study were: (i) to monitor the effect of different gamma-irradiation doses (4-33 kGy) on the release kinetics from 5-fluorouracil (5-FU)-loaded poly(D,L-lactide-co-glycolide) (PLGA)-based microparticles, and (ii) to analyze the obtained experimental data with a new mathematical model giving insight into the occurring mass transport phenomena. Drug release was found to depend significantly on the applied gamma-irradiation dose. Interestingly, the obtained release profiles were all biphasic: a rapid initial drug release phase ("burst") was followed by a slower, approximately constant drug release phase. Surprisingly, only the initial rapid drug release was accelerated by gamma-irradiation; the subsequent zero-order phase was almost unaffected. Importantly, the new mathematical model which is based on Fick's second law of diffusion and which considers polymer degradation was applicable to all the investigated systems. In addition, the gamma-irradiation dose could be quantitatively related to the resulting drug release rate. In conclusion, diffusion seems to be the dominating release rate controlling mechanism in all cases, with a significant contribution of the polymer degradation process.

Formulation and stability testing of photolabile drugs.

Exposure of a drug to irradiation can influence the stability of the formulation, leading to changes in the physicochemical properties of the product. The influence of excipients of frequently used stabilizers is often difficult to predict and, therefore, stability testing of the final preparation is important. The selection of a protective packaging must be based on knowledge about the wavelength causing the instability. Details on drug photoreactivity will also be helpful in order to minimize side-effects and/or optimize drug targeting by developing photoresponsive drug delivery systems. This review focuses on practical problems related to formulation and stability testing of photolabile drugs.