The Physical Stability of Felodipine and Its Recrystallization from an Amorphous Solid Dispersion Studied by NMR Relaxometry.

The 1H nuclear magnetic resonance (NMR) relaxometry method was applied to investigate the physical stability of an active pharmaceutical ingredient (API) and, for the first time, its recrystallization process in an amorphous solid dispersion system (ASD). The ASD of felodipine and polyvinylpyrrolidone (PVP) was prepared using the solvent evaporation method in a mass ratio of 50:50. In the first stage of the study (250 days), the sample was stored at 0% relative humidity (RH). The recovery of magnetization was described by one-exponential function. In the second stage (300 days in 75% relative humidity), the recrystallization process of felodipine was studied, showing in the sample three components of equilibrium magnetization related to (i) crystalline felodipine, (ii) water, and (iii) felodipine and PVP remaining in the ASD. The study shows that the 1H NMR relaxometry method is a very useful tool for analysing the composition of a three-phase system mixed at the molecular level and for the investigation of recrystallization process of API in amorphous solid dispersion system.

Exploring the molecular reorientations in amorphous rosuvastatin calcium.

Molecular reorientations in rosuvastatin calcium, a drug that is widely used to prevent cardiovascular disease, were explored thoroughly by means of solid state nuclear magnetic resonance (1H and 13C NMR) combined with calculations of steric hindrances. The experimental results reveal rich internal reorientational dynamics. All relaxation processes were tested in a broad range of temperatures and described in terms of their type and the associated energy barriers. The internal molecular mobility of rosuvastatin calcium can be associated with the reorientational dynamics of four methyl groups, accompanied by reorientation of the isopropyl group. The energy barriers of methyl and isopropyl group reorientation depended on the type of E/Z isomers, while the water content also had a strong influence on the dynamics of the isopropyl group. In the paper, a consistent picture of the molecular dynamics is provided, facilitating our understanding of molecular mobility in this important pharmaceutical solid.

Unusual cis-diprotonated forms and fluorescent aggregates of non-peripherally alkoxy-substituted metallophthalocyanines.

Protonation and aggregation of two metallophthalocyanines (zinc and magnesium) non-peripherally substituted with 1,4,7-trioxanonyl moieties were studied by steady-state and time-resolved optical spectroscopy. Both compounds are easily protonated in organic solvents, but the central metal ion strongly affects the character of this process. In particular, the magnesium derivative forms the cis-diprotonated isomer observed for the first time in phthalocyanines, in contrast to its zinc counterpart which forms the typical trans-diprotonated isomer. In addition, studies performed on phthalocyanines substituted with n-butoxy groups at their non-peripheral positions indicated that the formation of the cis-diprotonated forms is a more common feature of alkoxy-substituted magnesium metallophthalocyanines, in contrast to derivatives with other metal ions. The cis-diprotonated forms of the magnesium derivatives are formed at much lower proton concentrations than the trans-diprotonated forms of their zinc counterparts. The cis-isomers were also found to have more advantageous photophysical properties for photoactive applications than the trans-isomers. Aggregation studies of the trioxanonyl phthalocyanines revealed that the magnesium derivative aggregates much more easily in non-coordinating solvents than its zinc counterpart. Both the derivatives form fluorescent aggregates, which is typically attributed to the presence of oxygen-to-metal intermolecular coordination preventing the formation of non-fluorescent face-to-face stacks. The results indicate that the oxygen-to-metal coordination plays a significant role in the studied systems and the stronger oxygen-coordination ability of magnesium ions compared to zinc ions may underlie the observed differences between the phthalocyanines metallated with these two ions.

Estimating contamination monitor efficiency for beta radiation by means of PENELOPE-2008 Monte Carlo simulation.

Monte Carlo computer simulation of beta radiation transport within radioactively-contaminated food samples was studied and compared with experimental results. We used the Monte Carlo code PENELOPE-2008. The basic geometry of a hand-held contamination monitor and the geometry of beta-emitting food samples and surface sources were modeled, and the detection efficiency of the device was determined. Possibilities to improve the detection efficiency were tested by simulation.

Analysis of the Distribution of Energy Barriers in Amorphous Diazepam on the Basis of Computationally Supported NMR Relaxation Data.

Crystalline and amorphous diazepam, a psychoactive drug, were investigated by employing spin-lattice relaxation 1H NMR along with atom-atom calculations of the landscape of energy barriers. The activation barriers for reorientation of the methyl group in amorphous diazepam were found to be in the range of 1.9-12.7 kJ/mol. Atom-atom calculations permitted determination of the distribution of energy barriers for reorientations of methyl groups, which was in a good agreement with that obtained on the basis of experimental data. The NMR relaxation combined with calculations provided a quantitative description of the distribution of energy barriers including intra- and inter-molecular interactions.

Complex and mixture of ß-cyclodextrin with diazepam characterised by ¹H NMR and atom-atom potential methods.

Inclusion complex of ß-cyclodextrin with diazepam and a physical mixture of these components were studied by solid-state (1)H NMR. The activation barrier for reorientation of the methyl group in the diazepam molecule was found not changed by complex formation with ß-cyclodextrin. The complex formation resulted in a decrease in the number of water molecules and affected the relaxation time of ß-cyclodextrin. By the atom-atom potential method the most probable configuration of the diazepam molecule inside ß-cyclodextrin cavity was proposed.

Cellular changes, molecular pathways and the immune system following photodynamic treatment.

Photodynamic therapy (PDT) is a novel medical technique involving three key components: light, a photosensitizer molecule and molecular oxygen, which are essential to achieve the therapeutic effect. There has been great interest in the use of PDT in the treatment of many cancers and skin disorders. Upon irradiation with light of a specific wavelength, the photosensitizer undergoes several reactions resulting in the production of reactive oxygen species (ROS). ROS may react with different biomolecules, causing defects in many cellular structures and biochemical pathways. PDT-mediated tumor destruction in vivo involves cellular mechanisms with photodamage of mitochondria, lysosomes, nuclei, and cell membranes that activate apoptotic, necrotic and autophagic signals, leading to cell death. PDT is capable of changing the tumor microenvironment, thereby diminishing the supply of oxygen, which explains the antiangiogenic effect of PDT. Finally, inflammatory and immune responses play a crucial role in the long-lasting consequences of PDT treatment. This review is focused on the biochemical effects exerted by photodynamic treatment on cell death signaling pathways, destruction of the vasculature, and the activation of the immune system.

Ordered mesoporous silica material SBA-15: loading of new calcium channel blocker--lacidipine.

Mesoporous material SBA-15 of hexagonal structure was synthesised and its usefulness as a carrier for a poorly soluble drug--lacidipine (LA)--was tested. The source of silica was tetraethyl orthosilicate (TEOS) and the structure ordering agent was non-ionic surfactant Pluronic P123. SBA-15 with encapsulated LA was characterised by X-ray diffraction (XRD), infrared spectroscopy (FTIR), thermogravimetry (TG), differential scanning calorimetry (DSC) and transmission electron microscopy (TEM). Adsorption of the therapeutically active substance was performed in anhydrous environment (chloroform). The content of the therapeutic substance in SBA-15 estimated from TG measurements reached 9%. The properties of the compound obtained were compared with those of a physical mixture of the components.

Carbon nanotubes linked with pitavastatin: synthesis and characterisation.

The paper presents a study on functionalisation of multi-walled carbon nanotubes in the area of lattice defects and an attempt to bind the nanotubes with pitavastatin. Carbon nanotubes were synthesised by alcohol-chemical vapour deposition in the presence of the catalyst Fe-Co/MgO. The nanotubes were purified and the product was subjected to chemical functionalisation. Functional groups were introduced in the reaction of the purified nanotubes with thionyl chloride to obtain acidic chlorides linked to pitavastatin. The properties and structure of the nanotubes were analysed by FT-IR and Raman spectroscopies, transmission electron microscopy and liquid chromatography coupled with mass spectrometry. Photochemical stability of pitavastatin linked with carbon nanotubes has been found to be increased.

1H NMR study of rehydration/dehydration and water mobility in ß-cyclodextrin.

The processes of dehydration and rehydration of ß-cyclodextrin were studied by analysis of the (1)H NMR (nuclear magnetic resonance) line shape. Dehydration was carried in an open ampoule as a function of temperature and above 400 K total dehydration of ß-cyclodextrin was observed. This result was confirmed by the thermogravimetry (TG) measurements. Rehydration was studied as a function of time at room temperature. After 40 days, ß-cyclodextrin was found to absorb eight water molecules. The analysis of temperature changes in the shape of the (1)H NMR line of ß-cyclodextrin kept in a closed ampoule and its dielectric measurements provided information on the mobility of water molecules. The water molecules were found to perform complex molecular motions, that is, reorientational jumps below 200K and additionally, translational motion (diffusion) above 200K.

A hybrid method for estimation of molecular dynamics of diazepam-density functional theory combined with NMR and FT-IR spectroscopy.

Reorientation of the molecule of diazepam was investigated by calorimetric methods, IR absorption and NMR. The investigation of dynamics was complemented by density functional study (DFT) of vibrational frequencies and infrared intensities, calculations of steric hindrances and Monte Carlo simulations. The results indicated the occurrence of reorientation jumps of the CH(3) group and conformational motion of the benzodiazepine ring. The activation parameters of the methyl group reorientation were determined and the activation barrier obtained was in good agreement with the theoretically estimated value. The FT-IR spectra were assigned using results of DFT calculations.

The effect of beta-carotene on the photostability of nisoldipine.

The effect of beta-carotene on the photostability of nisoldipine (NS) has been investigated. Light stability studies were carried out following the recommendations of the International Conference on Harmonization (ICH), version I, using a high-pressure mercury lamp, type HBO-50, equipped with the interference filter and Wood's filter to isolate 365 nm wavelength. The photodegradation process was assayed by means of UV spectrophotometry and the reversed phase High-Performance Liquid Chromatography (HPLC). The quantum yields of photodegradation of NS and NS in the presence of beta-carotene were determined using the Reinecke salt as a chemical actinometer. The methanol solutions of NS degraded following apparent first-order kinetics. The degradation rate constant decreased as beta-carotene concentration increased. To verify the photostabilising role of the dye, a Stern-Volmer plot was constructed. The results have proved that beta-carotene does not act as a photosensitiser.

[Beta-radiation exposure at the finger tips during the radionuclide synovectomy]. / Beta-Ortsdosimetrie der Fingerkuppen bei der Radiosynoviorthese.

AIM: The radiation synovectomy is a widespread therapeutic option in rheumatoid arthritis. However, data for the beta-radiation exposure are rare. The aim of this study was to determine the personal dose equivalent H(P) (0.07) of the skin of the hands. METHODS: Thermo-luminescence detectors (TLDs) were attached at all fingertips of the therapist, the radiochemist and the nurse. In summary, the measurement of beta-exposure occurred in 155 joints at 6 days with different radio-nuclides ((169)Er, (186)Re, (90)Y). RESULTS: The greatest beta exposure were show at the forefinger (L-Ff) and thumb (L-Th) of the left hand, with which the therapist (right hander) fixed the injection needle. In 52 treated finger-joints (1204 MBq (169)Er), 29 treated large joints (2405 MBq (186)Re) and 15 treated knees (3100 MBq (90)Y) we found a cumulative beta exposure over all radionuclides of 190 mSv at L-Ff and 48 mSv at L-Th. The specific beta exposure for the individual radio-nuclides showed beta exposures of 0.56 mu Sv/MBq for (169)Er and 1.52 mu Sv/MBq for (186)Re-186 at the L-Ff. With using a manipulator the beta-exposure ((90)Y) could reduced from 22,09 to 0.42 mu Sv/MBq at the L-Ff. The greatest beta exposures for the radiochemist was 119 mSv at the L-Ff for all radionuclides. CONCLUSION: In usual techniques of radiation synovectomy the (90)Y produced the greatest part of radiation exposure. Especially at the L-Ff it might exceed the German limit for the official dosimetry service at the skin ( section sign 55 Strl-SchV). Using a holding forceps we can keep the legal rules and can reduce considerably the beta exposure.

Normal-phase TLC separation of enantiomers of 1.4-dihydropyridine derivatives.

A new TLC-based method was proposed for the separation of enantiomers and mixtures of racemic DHP derivatives differing in the kind of substituent in the phenyl ring. The conditions for the effective determination of the substances involved and the mechanism of their sorption were also studied. For the separation of felodipine, nilvadipine, and isradipine enantiomers, thin-layer chromatography was used, with a chiral stationary phase of the ligand exchange type, and developing phases of a different concentration of methanol (phi) as an organic modifier. The retention coefficient values k' were used to make the plots log k' = f(log phi) and log k' = f(phi). The processes taking place in the chromatographic systems were shown to be described by the Snyder-Soczewinski equation.

Spectroscopic and HPLC studies of photodegradation of nilvadipine.

Photochemical decomposition of nilvadipine (NV), a derivative of 1,4-dihydropyridine (DHP), was studied. Photodegradation was carried out in the conditions recommended in the first version of the document issued by the International Conference on Harmonization (ICH), currently in force in the studies of photochemical stability of drugs and therapeutic substances. Methanol solutions of NV were irradiated with a high-pressure mercury arc lamp, type HBO 200 (300-400 nm). The maximum absorption of radiation at 365 nm was achieved by applying the interference filter and Wood's filter. The assessment of NV photodegradation was made on the basis of the UV spectrophotometric and high-performance liquid chromatographic (HPLC) methods. Quantitatively, the process was described with the calculated rate constants of decomposition k, time of decomposition of 50% of the compound to 5, and time of decomposition of 10% of the compound t(0.1). The two methods applied allowed a determination of the kinetic parameters of NV photodegradation from the relationship ln c = f(t). Using the Reinecke salt as a chemical actinometer, apparent quantum yields of photodegradation were obtained; after extrapolation to the time of irradiation zero, these gave the actual quantum yield (phi = 7.3 10(-5)). The quantum yield of fluorescence at lambda(exc) = 375 nm was about 9.3 x 10(-4) The methods used for evaluation of NV photodegradation were subjected to validation, and results of the analytical methods were statistically assessed by Snedecor F and Student t tests. The former test revealed no statistically significant difference between the variances obtained by the HPLC and UV spectrophotometric methods. Also, verification of the zero hypothesis of the Student t test on equality of means of the results obtained gave no significant diferences between the two methods.

Identification of photodegradation products of nilvadipine using GC-MS.

Nilvadipine (NV) photodegradation products have been analysed with gas chromatography-mass spectrometry (GC-MS). The photodegradation was carried out in the conditions recommended in the first version of the document issued by the International Conference on Harmonization (ICH), currently in force in the studies of photochemical stability of drugs and therapeutic substances. Methanol solutions of NV were irradiated with a high-pressure UV lamp - type HBO 200. The maximum intensity at the wavelength lambda = 365 nm was achieved by applying the interference filter and Wood's filter. Using the Reinecke salt as a chemical actinometer, apparent quantum yields of photodegradation were obtained, which after extrapolation to the zero time of irradiation gave the actual quantum yield ((phi = 7.58 x 10(-5). The structure of three nilvadipine photodegradation products was established, after mass spectra analysis of compounds registered during GC-MS carried out of irradiated nilvadipine solutions. The quantitative results of GC-MS analyses enabled to determination of the kinetic parameters of NV photodegradation, calculated from the dependence In c =f(t). Quantitatively the process was described with the calculated rate constant of decomposition (k), decomposition time of 50% of the compound (t0.5) and decomposition time of 10% of the compound (t0.1). The exposure of nilvadipine to UV light was found to lead to aromatization of the DHP ring and elimination of the HCN molecule.

Photodegradation of inclusion complexes of isradipine with methyl-beta-cyclodextrin.

The paper presents results of the studies on photochemical decomposition of isradipine (IS) and its liquid inclusion complexes with methyl-beta-cyclodextrin (M-betaCD). The process of photodegradation was assessed by the methods of UV spectrophotometry, HPLC (reverse-phase) and HPTLC (normal phase) chromatographic methods. The process of photodegradation of IS was analysed in the conditions of version I of the document of International Chemical Harmonization (ICH)-HBO-200 lamp. Quantitative evaluation of the photochemical decomposition was performed on the basis of the calculated photodegradation rate constant (k), half-life period (t0.5) and time of degradation of 10% of the compound (t0.1). Formation of inclusion complexes of IS with M-betaCD was proved to increase twice the photostability of the drug. The analytical methods used were subjected to a validation procedure in which the limits of detectability and determinability as well as specificity, precision and sensitivity of the method were determined.

Analytical study of photodegradation of inclusion complexes of nimodipine with alpha-, gamma-cyclodextrin, methyl-beta-cyclodextrin, and hydroxypropyl-beta-Cyclodextrin.

The inclusion behavior of alpha-cyclodextrin (alpha-CD), gamma-cyclodextrin (gamma-CD), hydroxypropyl-beta-cyclodextrin (HP-betaCD), and methyl-beta-cyclodextrin (M-betaCD) with nimodipine (NM) in solution and in the solid state was investigated. Inclusion complexes of nimodipine with cyclodextrins (at a molar ratio of 1:1) in the solid state were obtained by the kneading method. Photochemical stability of NM in the solid inclusion complexes was assessed by IR spectrometry. The modified derivatives of beta-CD and alpha-CD were found to slow the photodegradation rate, whereas in the presence of gamma-CD the photodegradation of NM was a bit faster than in the corresponding physical mixture. Photochemical degradation of NM in liquid inclusion complexes was monitored by UV spectroscopy. According to the slowing effect on photodegradation of NM in the inclusion complexes, the studied cyclodextrins can be ordered as gamma-CD < alpha-CD < HP-betaCD < M-betaCD.

Photochemical stability of the inclusion complexes formed by modified 1,4-dihydropyridine derivatives with beta-cyclodextrin.

The results of studies of photochemical stability of the derivatives of 1,4-dihydropyridine (NR) are reported. The NR with various substituents (-NO2, -Cl, -F, CF3) at different positions in the phenyl ring were identified by UV spectrophotometry. Photodegradation of NR in the inclusion complexes with beta-cyclodextrin (beta-CD) was studied in the liquid phase. The rate of photodegradation of NR derivatives was dependent on the position of -NO2 group in the phenyl ring; for the ortho isomer it is ten times higher than for the meta one. The rate of photodegradation of 2-NO2-NR (ortho isomer) in inclusion complex with beta-CD was 200 times slower than that for this compound in the crystal phase. In the case of halogeno- and cyanoderivatives, the presence of beta-CD caused a 4-fold increase in the photodegradation rate.

Inclusion complexes of nifedipine and other 1.4-dihydropyridine derivatives with cyclodextrins. IV. The UV study on photochemical stability of the inclusion complexes of nisoldipine, nimodipine, nitrendipine and nicardipine with beta-cyclodextrin in the solution.

The results of measurements of photochemical stability of the inclusion complexes formed by nimodipine (NM), nisoldipine (NS), nitrendipine (NR) and nicardipine (NC) with beta-cyclodextrin (beta-CD) are reported. The inclusion complexes were obtained in solution. The formation of inclusion complexes in the liquid phase was estimated from a phase solubility diagram. The analysis of solubility curves in the phase diagram permitted calculation of stability constants of the inclusion complexes formed. Photochemical stability of 1.4-dihydropyridine derivatives obeyed the 1 order kinetic equation. The photodegradation of NM, NR and NC was found to be a single stage reaction. The photodegradation of NS occurred in two stages. In the inclusion complexes the photosensitivity of all studied DHP derivatives decreases. The complexation with beta-CD improved their photostability by 5-10 times. The greatest decrease in the photodegradation rate was observed for the most photosensitive compound NS whose photostability increased 100 times when in inclusion complex with beta-CD.