Physico-chemical and technological properties of sodium naproxen granules prepared in a high-shear mixer-granulator.

In the present work, authors produced tablets of anhydrous sodium naproxen by wet granulation using a high-shear mixer-granulator. Drug hydrated to the tetrahydrated form, as observed by X-ray powder diffractometry. After wet granulation, authors then performed two different drying procedures, obtaining granules of different water content and crystallographic characteristics.

Validation of an HPLC-MS method for rociverine tablet dissolution analysis.

The aim of this work was to develop and validate a method to assess the dissolution behaviour of rociverine sugar-coated tablets. In our laboratories, an HPLC-MS in reverse phase method of analysis was developed for the dosage of unknown rociverine solution. This analytical method was applied to determine the dissolution rate of rociverine tablets produced by the industrial procedure, because there is no official method description.

The role of several l-HPCs in preventing tablet capping during direct compression of metronidazole.

Several low-hydroxypropyl cellulose (l-HPC) derivatives (LH-11, 21, 22, 31, and 32) differing in granulometric particle size or in hydroxypropyl content were considered in the present study. The l-HPC grades were characterized as pure powders, in order to determine both compression and densification behavior, in presence or in absence of magnesium stearate as lubricant, and then, were physically mixed in different proportions with metronidazole, which was also previously characterized as pure powder. The tabletability and compressibility of these binary mixtures were then evaluated, in presence or in absence magnesium stearate as lubricant at two different compression speeds (20 and 70 mm/sec).

Characterization and compaction behaviour of nimesulide crystal forms.

Nimesulide is a typical nonsteroidal anti-inflammatory drug (NSAID), widely used in solid oral formulations. By crystallizing nimesulide from an ethanol solution a crystalline form was obtained, different from the reference sample, as confirmed by X-ray powder diffraction (XRPD), Differential Scanning Calorimetry (DSC) and solid cross polarization-magic angle spinning ((13)C-CPMAS) NMR. Moreover, when crystallized from dioxane nimesulide forms a solvate.

Influence of metronidazole particle properties on granules prepared in a high-shear mixer-granulator.

Metronidazole is a good example of high-dose drug substance with poor granulating and tableting properties. Tablets are generally produced by liquid granulation; however, the technological process failure is quite frequent. In order to verify how the metronidazole particle characteristics can influence granule properties, three metronidazole batches differing for crystal habit, mean particle size, BET surface area and wettability were selected, primarily designed according to their different elongation ratio: needle-shaped, stick-shaped, and isodimensional.

A new tetrahydrated form of sodium naproxen.

The anhydrous sodium naproxen (ASN) can form several hydrated phases if maintained at different relative humidities (RH). The water uptake can promote crystallographic modifications, according to the amount of water. In a previous work, the authors showed that a dihydrated form could be obtained either by crystallization in water or by exposure of the anhydrous form to a RH of 55%.

Evaluation of rapamycin chemical stability in volatile-organic solvents by HPLC.

Rapamycin or sirolimus is a carboxylic lactone-lactam macrolide with a potent immunosuppressive activity. It can be successfully used to impregnate stents inserted in coronary arteries during surgical applications, preventing fatal infection and rejection adverse effect. The chemical stability of rapamycin in several organic-volatile solvents (acetone, chloroform, dichloromethane, hexane, ethyl alcohol, ethyl acetate, methyl alcohol, pentane and tetrahydrofurane) was established by HPLC-DAD-MS in reverse phase analysis.

Synthesis of 7-oxo-7H-naphtho[1,2,3-de]quinoline derivatives as potential anticancer agents active on multidrug resistant cell lines.

Following our earlier finding that tetracyclic anthraquinone analogs with a fused pyridone ring exhibit cytotoxic activity toward multidrug resistant tumor cells, a series of new potential antitumor agents, 7-oxo-7H-naphtho[1,2,3-de]quinoline derivatives (3, 6-8, 10-12, 14, 15, and 18), bearing one or two basic side chains and various substituents at the pyridone ring, have been synthesized. The compounds have been obtained from 1-amino-4-chloroanthraquinone or 1-aminoanthraquinone by cyclization with diethyl malonate and the subsequent reactions of the key intermediates 2, 4, and 17. The compounds exhibited cytotoxic activity toward sensitive human leukemia cell line HL-60 and against its resistant sublines HL-60/VINC (MDR1 type) and HL-60/DX (MRP1 type).

2,7-Dihydro-3H-pyridazino[5,4,3-kl]acridin-3-one derivatives, novel type of cytotoxic agents active on multidrug-resistant cell lines. Synthesis and biological evaluation.

We have earlier postulated that the presence of a pyridazone ring fused with an anthracenedione moiety resulted in the analog's ability to overcome multidrug resistance of tumor cells [J. Med. Chem.

Evaluation of different fast melting disintegrants by means of a central composite design.

Fast-disintegration technologies have encountered increased interest from industries in the past decades. In order to orientate the formulators to the choice of the best disintegrating agent, the most common disintegrants were selected and their ability to quickly disintegrate direct compressed tablets was evaluated. For this study, a central composite design was used.

Rational design, synthesis, and biological evaluation of bis(pyrimido[5,6,1-de]acridines) and bis(pyrazolo[3,4,5-kl]acridine-5-carboxamides) as new anticancer agents.

The good results obtained with pyrimido[5,6,1-de]acridines 7 and with pyrazolo[3,4,5-kl]acridinecarboxamides 8 prompted us to the synthesis of two new series of bis acridine derivatives: the bis(pyrimidoacridines) 5 and the bis(pyrazoloacridinecarboxamides) 6. Compounds 5 can be regarded also as cyclized derivatives of bis(acridine-4-carboxamides) 3 and compounds 6 as cyclized derivatives of bis(acridine-4-carboxamides) 4. The noncovalent DNA-binding properties of these compounds have been examined using fluorometric techniques.

Particle interaction of lubricated or unlubricated binary mixtures according to their particle size and densification mechanism.

The aim of this study is to assess an experimental approach for technological development of a direct compression formulation. A simple formula was considered composed by an active ingredient, a diluent and a lubricant. The active ingredient and diluent were selected as an example according to their typical densification mechanism: the nitrofurantoine, a fragmenting material, and the cellulose microcrystalline (Vivapur), which is a typical visco-elastic material, equally displaying good bind and disintegrant properties.

Rheological, mucoadhesive and release properties of Carbopol gels in hydrophilic cosolvents.

Carbopol is one of the most common thickening agent for water phases. It is used after neutralisation and its rheological properties in the aqueous medium are well known. The aim of this work was to investigate the gelation properties of Carbopol 971 e 974 polymeric systems in water-miscible cosolvents such as glycerine and PEG 400.

Design, synthesis, and biological properties of new bis(acridine-4-carboxamides) as anticancer agents.

To enhance the outstanding biological response shown by the corresponding monomers 4 and 5, two classes of bis-acridine-4-carboxamides, 9, with a linker between the 4,4' positions, and 13, with a linker between the 1,1' positions, have been prepared as DNA-binding and potential antitumor agents. The noncovalent DNA-binding properties of these compounds have been examined using gel-electrophoresis and fluorometric techniques. The results indicate that (i).

Synthesis and biological evaluation of 2,7-Dihydro-3H-dibenzo[de,h]cinnoline-3,7-dione derivatives, a novel group of anticancer agents active on a multidrug resistant cell line.

A series of anthrapyridazone derivatives with one or two basic side chains at various positions in the tetracyclic chromophore have been synthesized. The key intermediates in the synthesis are 2,7-dihydro-3H-dibenzo[de,h]cinnoline-3,7-diones 1, 12 and 15 monosubstituted at position 2 (4d, 16a-e), or 6 (2a-f) or disubstituted at positions 2 and 6 (4a-c) or 2 and 8 (17a-e) with appropriate alkylaminoalkylamines. All analogues showed in vitro cytotoxic activity against murine leukemia (L1210) and human leukemia (K562) cell lines.

Rational design, synthesis and biological evaluation of thiadiazinoacridines: a new class of antitumor agents.

A series of potential DNA-binding antitumor agents, 3-[omega-(alkylamino)alkyl]-6-nitro-thiadiazino[3,4,5-kl]acridines 12 and 1,3-di[omega-(alkylamino)alkyl]-6-nitro-thiadiazino[3,4,5-kl]acridines 13, has been prepared by cyclization with SOCl(2) of 1-[[omega-(alkylamino)alkyl]amino]-9-imino-4-nitro-9,10-dihydroacridines 16 or 1-[[omega-(alkylamino)alkyl]amino]-9-[omega-(alkylamino)alkyl]imino-4-nitro-9,10-dihydroacridines 17, respectively. The non-covalent DNA-binding properties of 12, 13 have been examined using a fluorometric technique. In vitro cytotoxic potencies of these derivatives toward six tumor cell lines, including human colon adenocarcinoma (HT29) and human ovarian carcinoma (A2780 sensitive, A2780cisR cisplatin-resistant, CH1, CH1cisR cisplatin-resistant, and SKOV-3) cells, are described and compared to that of reference drugs.

Lonidamine solid dispersions: in vitro and in vivo evaluation.

Solid dispersions of lonidamine in PEG 4000 and PVP K 29/32 were prepared by the spray-drying method. Then, the binary systems were studied and characterized using differential scanning calorimetry, hot stage microscopy, and x-ray diffractometry. In vitro dissolution studies of the solid dispersed powders were performed to verify if any lonidamine dissolution rate or water solubility improvement occurred.

Microencapsulation of semisolid ketoprofen/polymer microspheres.

Ketoprofen controlled release microspheres were prepared, by emulsion/solvent evaporation, at 15 degrees C, in order to avoid the formation of semisolid particles. An identical procedure was carried out at 60 degrees C to speed up the solvent evaporation and the formed semisolid microspheres were directly microencapsulated by complex coacervation and spray-dried in order to recover them as free flowing powder. Microspheres and microcapsules were characterized by scanning electron microscopy, differential scanning calorimetry, X-ray diffractometry, in vitro dissolution studies, and then used for the preparation of tablets.

Binding free energy of selected anticancer compounds to DNA--theoretical calculations.

Many studies have elucidated structures and thermodynamics of complexes formed by different ligands with DNA. However, in most cases structural and free energy binding studies were not correlated with each other because of the problem of identifying which experimental free energy of binding corresponds to which experimental DNA-ligand structure. In the present work, Poisson-Boltzmann and solvent-accessible surface area methods were used to predict unknown modes of interaction between DNA and three different ligands: mitoxantrone and two pyrimidoacridine derivatives.

Effect of modification of 6-[(aminoalkyl)amino]-7H-benzo[e]-perimidin-7-ones on their cytotoxic activity toward sensitive and multidrug resistant tumor cell lines. Synthesis and biological evaluation.

Benzoperimidines, a novel group of antitumor anthracenedione analogues, are of interest due to their ability to overcome multidrug resistance of tumor cells (Stefańska, B., Dzieduszycka, M., Bontemps-Gracz, M.

2,6-Di(omega-aminoalkyl)-2,5,6,7-tetrahydropyrazolo[3,4,5-mn]pyrimido[5,6,1-de]acridine-5,7-diones: novel, potent, cytotoxic, and DNA-binding agents.

DNA-binding agents with potential antitumor activities bearing two cationic side chains, the 2,6-di(omega-aminoalkyl)-2,5,6,7-tetrahydropyrazolo[3,4,5-mn]pyrimido[5,6,1-de]acridine-5,7-diones (4a-r), have been prepared either by reaction of the appropriate 2-(omega-aminoalkyl)-6-chloro-2,3-dihydro-1H,7H-pyrimido[5,6,1-de]acridine-1,3,7-trione with the appropriate (omega-aminoalkyl)hydrazine or by cyclization of the requisite N-6,2-di(omega-aminoalkyl)-2,6-dihydropyrazolo[3,4,5-kl]acridine-6-carboxamide with phosgene. In vitro cytotoxic properties of these derivatives against three human colon adenocarcinoma cell lines (HT29, LoVo, and LoVo/Dx) and against some cell lines of the NCI panel are described and compared to that of reference drugs. Some of the new compounds showed outstanding potency while lacking cross-resistance with anthracyclines.