Drug-plasticizer interactions causing solid state transitions of rifaximin.

Solid phase interactions are often the reason for incompatibilities in solid dosage forms. A special situation occurs, if the incompatible compounds are able to migrate within the solid matrix. This study describes for the first time the migration of a plasticizer from the coating into the core and its interaction with the active ingredient located there. This behavior was observed in rifaximin gastro-resistant granules and resulted in the formation of solvates with altered dissolution behavior. For a detailed study, rifaximin was incubated with five plasticizers of different solubility and miscibility as well as different molecular geometry (linear vs branched), (dibutyl sebacate, tributyl citrate, triacetin, polyethylene glycol 400, and propylene glycol). The resulting solid states were analyzed by means of PXRD, supported by thermogravimetric analysis, infrared spectroscopy, and quantitative H NMR. No direct correlation could be demonstrated between the resulting type of solvate/hydrate and the affinity of rifaximin with the respective plasticizers. Interestingly all plasticizers that are able to form type I solvates/hydrates have linear structures. This common feature, which distinguishes them from the more bulky TAC and TBC, seems to be a key characteristic. Rifaximin-PG-solvate formation was not only detected after direct incubation trials, but also observed in enteric coated granules.

Application of species-specific primers to estimate the in situ diet of Bythotrephes [Cladocera, Onychopoda] in its native European range via molecular gut content analysis.

The study of invasive species often focuses on regions of recent introduction rather than native habitats. Understanding an invasive species in its natural environment, however, can provide important insights regarding the long-term outcome of invasions. In this study we investigated the diet of the invasive spiny water flea, Bythotrephes longimanus, in two Austrian perialpine lakes, where it is native. The gut contents of wild-caught Bythotrephes individuals were estimated by quantitative polymerase chain reaction, targeting species-specific fragments of the barcoding region of the cytochrome c oxidase I gene of potential prey. The observed prey spectrum of Bythotrephes in the study lakes consisted primarily of Eudiaptomus gracilis and Diaphanosoma brachyurum. The Daphnia longispina complex, Leptodora kindtii and Mesocyclops leuckarti also contributed to the diet. Results indicate that Bythotrephes is a generalist feeder with a preference for epilimnetic prey.

Revision of the Garra species of the Hajar Mountains in Oman and the United Arab Emirates with the description of two new species (Teleostei: Cyprinidae).

The Garra species inhabiting the Hajar Mountains are revised and five species are recognised, two of which are newly species described herein. Garra barreimiae, from the United Arab Emirates (UAE) and Northern Oman, is distinguished from other Garra species in the Hajar Mountains by a strongly mottled flank pattern with individual or series of midlateral orange scales, a white dorsal-fin tip, an orange spot at the upper operculum, and more gill rakers on the lower limb of the first gill arch. Garra barreimiae shawkahensis is a synonym of G. barreimiae. Garra gallagheri, from the Wadi Bani Khalid drainage in Oman, is distinguished by flank-scale margins the same colour or slightly darker than the centre of the scales. Garra longipinnis, from the interior wadis in the Central Hajar Mountains in Oman, is distinguished by flank-scale margins being clearly darker than the centre of scales. The original description of G. longipinnis was based on a few individuals with very large fins, which are here considered aberrant. Garra shamal, new species, from the coastal drainages around Muscat in Oman, is distinguished by a strongly mottled flank pattern usually without orange midlateral scales, a white dorsal-fin tip, no orange spot at the upper operculum, and middle caudal-fin rays and membranes the same colour or slightly darker than the rest of the fins in colouration. Garra sharq, new species, from the Wadi Kabbah drainage and a few interior springs in Oman, is distinguished by a strongly mottled flank pattern with individual or series of orange midlateral scales, no orange spot at the upper opercle, and dorsal-fin tip and membranes between central caudal-fin rays the same colour as the rest of the fins. All five species are well differentiated genetically and form distinct mitochondrial clades with between 2.1 and 9.2% differences (p-distances) in the mitochondrial COI.

Co-crystals, Salts or Mixtures of Both? The Case of Tenofovir Alafenamide Fumarates.

Tenofovir alafenamide fumarate (TAF) is the newest prodrug of tenofovir that constitutes several drug products used for the treatment of HIV/AIDS. Although the solid-state properties of its predecessor tenofovir disoproxil fumarate have been investigated and described in the literature, there are no data in the scientific literature on the solid state properties of TAF. In our report, we describe the preparation of two novel polymorphs II and III of tenofovir alafenamide monofumarate (TA MF2 and TA MF3). The solid-state structure of these compounds was investigated in parallel to the previously known tenofovir alafenamide monofumarate form I (TA MF1) and tenofovir alafenamide hemifumarate (TA HF). Interestingly, the single-crystal X-ray diffraction of TA HF revealed that this derivative exists as a co-crystal form. In addition, we prepared a crystalline tenofovir alafenamide free base (TA) and its hydrochloride salt (TA HCl), which enabled us to determine the structure of TA MF derivatives using 15N-ssNMR (15N-solid state nuclear magnetic resonance). Surprisingly, we observed that TA MF1 exists as a mixed ionization state complex or pure salt, while TA MF2 and TA MF3 can be obtained as pure co-crystal forms.

Population data analysis of dissolution time profiles: Assessment of physicochemical properties of the drug, drug particles and the pharmaceutical formulation.

Disintegration of finished dosage forms (FDF) and drug dissolution are fundamentally important processes that affect bioavailability. Established theories do not account for disintegration and usually assume sink conditions for drug dissolution that often do not apply. We present the theory to describe the disintegration of FDF with subsequent dissolution of liberated particles containing the active pharmaceutical ingredient (API) and its application using population data analysis. Population modeling, using dissolution profiles of 400mg cefditoren pivoxil tablets manufactured under various tableting pressures, characterized the intrinsic lifetime distribution of the particles and identified the presence of crystalline API in the formulation that was proven by X-ray diffraction. Modeling further estimated the disintegration time of FDF, the solubility of the amorphous API and its chemical instability in the medium that were in agreement with the experimentally determined values. This novel approach provides a quantitative understanding of the manufacturing process of FDF and can substantially contribute to the targeted development of finished dosage forms.

Z-DNA's conformer substates revealed by FT-IR difference spectroscopy of nonoriented left-handed double helical poly(dG-dC).

Nonoriented hydrated films of double helical poly(dG-dC) in the Z-form were studied by Fourier transform infrared (FT-IR) spectroscopy either as equilibrated slow-cooled samples between 290 and 220 K or, after quenching into the glassy state, as nonequilibrated film isothermally at 200, 220, and 240 K. IR spectral changes on isothermal relaxation at 200 and 220 K toward equilibrium, caused by interconversion of two conformer substates (CS) called Z1 and Z2, are revealed by IR difference spectra. Pronounced spectral changes on Z1-to-Z2 interconversion occur between approximately 750-1250 cm(-1) and these are attributed to structural changes of the phosphodiester-sugar backbone caused by changes of torsion angles, and to decreasing hydrogen-bonding of the ionic phosphate group with water molecules. These spectral changes on Z1-to-Z2 transition can be related to structural differences between ZI and ZII CS observed in single crystals. ZI/ZII CS occurs only at (dGpdC) base steps, and similar behavior is assumed for Z1/Z2. The Z1/Z2 population ratio was determined via curve resolution of marker bands for Z1 and Z2 centered at 785 and 779 cm(-1). This ratio is 0.64 at 290 K, corresponding to 39% of the phosphates of the (dGpdC) base steps in Z1 and 61% in Z2, and it increases to 1.24 on cooling to 220 K. For the Z2<=>Z1 equilibrium, an enthalpy change of -4.9 +/- 0.2 kJ mol(dGpdC)(-1) is obtained from the temperature dependence of the equilibrium constant. Z1 interconverts into Z2 at isothermal relaxation at 200 and 220 K, whereas on slow cooling from ambient temperature, Z2 interconverts into Z1. This unexpected reversal of CS interconversion is attributed to slow restructuring of hydration shells of the CS on quenching, in the same manner reported by Pichler et al. for the BI and BII CS of B-DNA (J. Phys. Chem. B 106, 3263-3274 (2002)). IR difference curves demonstrate two time scales on isothermal relaxation of Z1-->Z2 interconversion, a fast one for structural relaxation of the sugar-phosphate backbone, and a slow one for relaxation of the hydration shells. This slowing down of restructuring of CS hydration shells at approximately 220-240 K could be the cause for the suppression of biological functions at low temperatures.

Blind source separation of photoacoustic depth profiles into independent components.

Step-scan photoacoustic spectroscopy is a powerful tool to nondestructively retrieve depth related information from a sample. Through digital signal processing a series of spectra with effectively different modulation frequencies, probing different thermal diffusion lengths within a sample, can be collected simultaneously. For layered samples spectra of the constituent layers can then be obtained by calculating spectra at specific phase angles from the in-phase and quadrature data through phase projection. However, without prior knowledge of the spectra of the constituent layers, this approach can be difficult. In this report we present an alternate possibility for evaluating step scan photoacoustic data, namely independent component analysis (ICA), which allows for ''blind separation'' of the mixed photoacoustic spectra without prior knowledge of the constituent spectra. Phase projection and ICA are applied to photoacoustic data acquired from a multilayer sample in an attempt to isolate the spectra of the constituent layers. The results for the two methods are comparable, with ICA offering the advantage that no prior information about the pure spectra of the sample layers is needed.

Using the linearization approach for synchronizing the phase of photoacoustic reference and sample data.

Linearization of photoacoustic spectra is a technique that allows for detection of surface layers and the compensation of saturation effects in photoacoustic spectra by combining amplitude and phase information. The objective of this report is a thorough description of the linearization procedure. The influence of interferogram rotation on the real and imaginary parts of the complex Fourier transformation and on spectral phase angles is shown. The possibility of using the linearization approach to correct for phase differences between reference and sample data is discussed. The method can be used to calculate phase spectra from photoacoustic spectra taken with rapid scan spectrometers.

The conformer substates of nonoriented B-type DNA in double helical poly(dG-dC).

A nonoriented hydrated film of poly(dG-dC) with ?20 water molecules per nucleotide (called B* by Loprete and Hartman (Biochem. 32, 4077-4082 (1993)) was studied by Fourier transform infrared (FT-IR) spectroscopy either as equilibrated sample between 290 and 270 K or, after quenching into the glassy state, as nonequilibrated film isothermally at 200 and 220 K. IR spectral changes on isothermal relaxation at 200 and 220 K, caused by interconversion of two conformer substates, are revealed by difference spectra. Comparison with difference curves obtained in the same manner from two classical B-DNA forms, namely the d(CGCGAATTCGCG)(2) dodecamer and polymeric NaDNA from salmon testes, revealed that the spectral changes on B(I)-to-B(II) interconversion in the classical B-DNA forms are very similar to those in the B*-form, and that the spectroscopic differences between the B(I) and B(II) features from classical B-DNA and those from the modified B*-form are minor. Nonexponential kinetics of the B(I)-->B(II) transition in the B*-form of poly(dG-dC) at 200 K showed that the structural relaxation time is about three times of that in the classical B-DNA forms (approximately equal to 30 versus approximately equal to 10 min at 200 K). The unexpected reversal of conformer substates interconversion (that is B(II)-->B(I) transition on cooling from 290 K and B(I)-->B(II) transition on isothermal relaxation at 200 K) observed for classical B-DNA occurs also in the modified B*-form. We therefore conclude that restructuring of hydration shells rules the low-temperature dynamics of the B*-form via its two conformer substates in the same manner reported for classical B-DNA by Pichler et al. (J. Phys. Chem. B 106, 3263-3274 (2002)).