Abstract Background Diazepam, as one of the most frequent prescribed drug from 1,4-benzodiazepine group, has certain limitations in pharmaceutical technology due to its poor solubility in water. By forming inclusion complexes with 2-hydroxypropyl-β-cyclodextrin, diazepam's biopharmaceutical properties can be greatly improved. Aim Aim of this research was to in vitro evaluate genotoxicity of prepared novel complexes of diazepam and their influence on proliferation of human peripheral blood lymphocytes. Methods For identification of possible genotoxicity of diazepam inclusion complexes, cytokinesis-block micronucleus assay has been chosen. Evaluated concentrations of two diazepam inclusion complexes were 0.2 µg/mL, 0.5 µg/mL and 1.0 µg/mL in cell culture. For a reference, in vitro cytogenotoxicity evaluation of diazepam alone has been conducted as well. Results Neither one of the diazepam, complexed nor non-complexed, in given concentrations showed genotoxicity, induced genetic damage or loss of genetic material. Conclusions Nuclear division index values, as indicators of cytostaticity and cytotoxicity suggested that investigated inclusion diazepam complexes induced accelerated proliferation of human peripheral blood lymphocytes in vitro, therefore possibly shortening the duration and dynamics of the cell cycle.

Nanotechnology has a great potential for improving many areas of research and its applications, like nanoscale phenomena and processes, nanomaterials, nanoscale devices and instrumentation research. Nanoparticles, that are currently used, demonstrate many desirable properties for cancer management, considering their ability to accumulate in the specific parts of pathological areas and provide controlled drug release. Pharmaceutical nanocarriers can be used as a part of drug delivery systems for the purposes of therapy, diagnosis and imaging. Methods for nanoparticle manufacturing are: spray drying, aerosol flow reactor, mechanical methods (milling, homogenization under high pressure), precipitation techniques, techniques using supercritical fluids, methods for emulsion preparation and freezing (lyophilization). Future trends in the development of nanotechnology are expected to go towards additional decrease in dimensions of active and auxiliary compounds. The only way to achieve this is to combine methods used in medicine, engineering, materials studying, information technologies and physics. Keywords: nanoparticles, cancer, drug delivery

Suspension stability can be theoretically estimated prior to the beginning of the formulating process based on the solid phase particle size, liquid phase density, and viscosity. Stokes equation can be used to predict suspension stability in order to save time and resources. The examples of these calculations for the assessment of suspension physical characteristics are given in this article. One parameter that cannot be theoretically estimated with precision is flocculation/deflocculation. Flocculation can be experimentally determined using the "jar test," and it is a critical parameter for the substances showing inclination toward caking. Suspensions will sediment in time; however, it is their key feature to be able to redisperse in order to preserve the efficacy and proper dosage. Bismuth subnitrate is practically insoluble in water, which makes it convenient for oral pharmaceutical suspensions, rather than the other pharmaceutical forms. Like the other bismuth compounds, it tends to cake in aqueous medium. In order to prevent formation of the solid sediment, controlled flocculation of the suspended bismuth subnitrate particles is recommended. The effect of the excipients (sodium citrate, Tween 20, propylene glycol, microcrystalline cellulose) on the transmittance of the prepared suspensions and the quantity and characteristics of the formed sediment were evaluated. Suspensions containing sodium citrate, as well as the formulations with sodium citrate and microcrystalline cellulose, based on their transmittance characteristics, were determined to be flocculating suspensions, regardless of the sodium citrate concentration used. The highest affinity towards formation of flocculating suspensions, with the highest transmittance value had microcrystalline cellulose with 15% (w/w) sodium citrate.

Since the assay method for pantoprazole in pantoprazole pellets is not described in current pharmacopoeias (USP, BP), the aim of this work was to develop and validate a simple, precise and accurate method for determination of pantoprazole in pantoprazole pellets. Separation was achieved on a reversed-phase C8 column (250 x 4.6 mm i.d.; 5 a mixture of phosphate buffer pH 3.0 and acetonitrile as mobile phase, at a flow rate 2 ml/min and UV detection at 290 nm. The method was validated according to ICH Guidelines. Validation showed that developed method was valid and reliable for determination of active substance in pantoprazole

When the fast absorption of diazepam is needed in order to suppress febrile convulsions and epileptic seizures, the most suitable is intravenous application diazepam. To avoid inappropriate self administration of such diazepam dosage form, orodispersible tablets of diazepam would be the dosage form of choice. Poor solubility of diazepam in water is directly related to its dissolution rate after release from a solid dosage form. Inadequate dissolution rate of diazepam can be the limiting factor for its absorption rate. Inclusion complexation of diazepam with 2-hydroxypropyl-β-cyclodextrin was carried out to increase the solubility of diazepam at pH 6.8. Determination of the intrinsic dissolution rate of diazepam as well as complexated diazepam was carried out to predict the absorption rate of diazepam at given pH value. The solubility of micronized diazepam (particle size 5.4 µm) at pH 6.8, was 0.043 mg mL-1, while the solubility of non-micronized diazepam (particle size 414.8 µm) at the same pH was 0.036 mg mL-1. Inclusion complexation of diazepam with 2-hydroxypropyl-β-cyclodextrin resulted in increased solubility of diazepam. One mole of 2-hydroxypropyl-β-cyclodextrin increased the solubility of micronized diazepam 6.82 fold, while two moles of 2-hydroxypropyl-β-cyclodextrin increased the solubility of diazepam 12.55 fold. Given that the values of intrinsic dissolution rates (IDR) of micronized diazepam, non-micronized diazepam and inclusion complex D: 2-HP-β-CD 1:1 were less than 0.1 mg min-1 cm-2, the absorption of diazepam dissolution would be the rate limiting step to absorption, while the inclusion complex D: 2-HP-β-CD 1:2 where an IDR value was greater than 0.1 mg min-1 cm-2 at pH 6.8, suggested that its dissolution might be the rate-limiting step to absorption. Hydroxypropyl-β-cyclodextrin increased the solubility of diazepam at pH 6.8, thus increasing the dissolution rate and causing faster absorption of diazepam at pH 6.8.

The solubility enhancement of diazepam and nitrazepam in water was analyzed depending on temperature and amount of α-cyclodextrin ( α-CD), β-cyclodextrin (β-CD) and 2-hydroxypropyl-β-cyclodextrin (2-HP-β-CD). The interactions of drug-cyclodextrin in solution were investigated by the phase-solubility analysis. Diazepam (nitrazepam) content in aqueous complexation medium was analyzed UV spectrophotometrically. Classical solubility data were used to derive apparent stability constants (K1:1) which were used to derive thermodynamic parameters for the diazepam (nitrazepam)-cyclodextrin complexes. Since all phase solubility plots were of AL–types, and calculated Slopes after linear regression analysis were found to be less than 1, it could be assumed that stoichiometry of the formed binary systems was 1:1. According to the calculated K1:1 values, the stability of the complexes of diazepam and nitrazepam with a-CD, β-CD and 2-HP-β-CD varies as follows: 2-HP-β-CD > β-CD > β-CD. The a-CD has higher affinity for dissolving nitrazepam compared to diazepam. While all parameters lead to an improvement in solubility, the largest effect was obtained for guest-host complexation with 2-HP-β-CD. The solubility of diazepam and nitrazepam in water increased 93.02 times and 64.23 times, respectively, in the presence of 40% (w/w) 2-HP-β-CD, at 25°C. Solubility data for diazepam and nitrazepam in aqueous 2-HP-b-CD were used to derive thermodynamic parameters, ΔG° at 298 K = –14.43 kJ·mol–1, ΔH° = 0.79 kJ·mol–1, ΔS° at 298 K = 51.17 J·mol–1·K–1 and ΔG° at 298 K = –13.43 kJ·mol–1, ΔH° = 2.38 kJ·mol–1, ΔS° at 298 K = 53.01 J·mol–1·K–1, respectively. Formation of inclusion complexes substantially increases the water solubility of diazepam and nitrazepam. Diazepam and nitrazepam dissolution thermodynamics in aqueous 2-HP-β-CD were characterized by spontaneous and endothermic dissolution and hydrophobic interactions.

Lorazepam is an almost water insoluble substance. This study investigated the solubilization of lorazepam depending on media pH, cosolvents (ethanol, propylene glycol, polyethylene glycol 200 and 400), surfactants (Tween 80, Tween 20, Brij 35, sodium-cholate, sodium-deoxycholate, sodium-taurocholate) and cyclodextrins (α-cyclodextrin, -cyclodextrin and 2-hydroxypropyl-β-cyclodextrin). The main objective was to find the most suitable method for providing good solubility of this drug and thus its formulation in a liquid dosage form. Based on the results, the changes in the pH value of the media do not lead to a greater solubility of lorazepam. Of the cosolvents used, the greatest increase in solubility of lorazepam in water was achieved with ethanol. Of the bile salts used, sodium taurocholate showed the best solubilization ability, while Brij 35 was the best of the non-ionic surfactants. The solubility of lorazepam with the cyclodextrin derivative, 2-hydroxypropyl-β-cyclodextrin was better than natural cyclodextrin. Surfactants have the highest ability of solubilization of lorazepam in water.

Transdermal drug delivery systems are pharmaceutical preparations, intended to be applied to the unbroken skin in order to deliver the active ingredient(s) to the systemic circulation after passing through the skin barrier. Transdermal patches are formulated in different ways, but normally they consist of release liner, adhesive layer and backing layer. Active ingredient(s) can be incorporated in reservoir, matrix, adhesive, membrane-matrix and microreservoir. The releasing rate of active substances from patches is controlled by membrane, matrix and adhesive. Only several transdermal systems are available on the market today, because for the penetration of most substances skin represents a strong barrier. With transdermal systems it is possible to obtain a controllable and sustained plasma levels, to minimaze the risk of undesirable side effects and to avoid the hepatic first- pass metabolism. These devices are easy to apply and also to remove from the skin. Of a great pharmaceutical interest are also socalled cosmetic patches. They are applied with aim of cleaning and protecting the skin.