Assessment of the origin and stability of Nifedipine polymorph IV by differential scanning calorimetry (DSC)

Purpose. To examine the thermal transition(s) between different polymorphic forms of Nifedipine and to define experimental conditions that lead to the generation of polymorph IV. Methods. Experiments were performed using a DSC 823e (Mettler Toledo). Nifedipine exists in four polymorphic forms, as well as an amorphous state. Examination of Nifedipine was conducted using the following method(s): cycle 1: 25ºC to 190ºC, 190ºC to 25ºC (formation of amorphous Nifedipine); cycle 2: 25ºC to X (60,70,80...150ºC), X to 25ºC; cycle 3: 25ºC to 190ºC and holding isothermally for 5 min between cycles (heating/cooling rate of 10ºC/min). Results. The amorphous state Nifedipine can sustain heating up to 90ºC without significant changes in its composition. Cycle 2 of amorphous material heated up to 90ºC shows only the glass transition at ~44ºC. In cycle 3 of the same material, a glass transition has been recorded at ~44ºC, followed by two exotherms (~100 and ~115ºC (crystallisation of polymorph III and II, respectively) and an endotherm (169ºC (melting of polymorphs I/II)). Samples that have been heated to temperatures between 100ºC and 120ºC in the second cycle showed a glass transition at ~44ºC and an additional exotherm at ~95ºC (crystallisation of polymorph III) on cooling a exotherm was observed at ~40ºC (crystallisation of polymorph IV). The same material showed no glass transition in cycle 3 but an endotherm at around 62ºC (melting of polymorph IV) an exotherm (~98ºC) and an endotherm (169ºC) melting of polymorph I/II. Heating the sample to a temperatures greater than 130ºC in cycle two results in a glass transition at ~44ºC, and two exotherms at ~102 and 125ºC (crystallisation of polymorphs III and I, respectively). Conclusions. DSC data suggests that polymorph IV can only be produced from amorphous or polymorph III samples. The presence of polymorph I or II drives the conversion of the less stable polymorphic form IV into the most stable form, I. Although form IV of Nifedipine can easily be created, following defined experimental conditions, it may only coexist with amorphous or polymorph III states. When polymorphs I and II are present in the sample polymorph IV cannot be etected.

Differential cytotoxic and prooxidnant activity of knipholone and knipholone anthrone

Knipholone (KP) and knipholone anthrone (KA) are natural 4-phenylanthraquinone structural analogues with established differential biological effects including in vitro antioxidant [1] and antimicrobial properties [2]. The present study was designed to investigate the comparative in vitro cytotoxic activity and the possible mechanism of action of these two compounds. We demonstrated that KA is by order of magnitude more cytotoxic to mammalian cells than KP. In parallel with the demonstrated cytotoxic effect, KA but not KP induces prooxidative DNA damage in the presence of copper ions. In order to establish the possible involvement of reactive oxygen species in the KA-mediated prooxidative effect, we investigated the protective effect of several metal chelators and reactive oxygen species scavengers. Our data suggest that reactive oxygen species such as hydrogen peroxide are involved and a good correlation between prooxidative action, antioxidant effect and cytotoxicity is established for these two structural analogues. The chemistry, pharmacology and potential medicinal/toxicological potential of these compounds are discussed.

Modelling of dosator operation for improved manufacturing performance

Purpose: To develop an improved mathematical model for the prediction of dose accuracy of Dosators - based upon the geometry of the machine in conjunction with measured flow properties of the powder. Methods: A mathematical model has been created, based on a analytical method of differential slices - incorporating measured flow properties. The key flow properties of interest in this investigation were: flow function, effective angle of wall friction, wall adhesion, bulk density, stress ratio K and permeability. To simulate the real process and (very importantly) validate the model, a Dosator test-rig has been used to measure the forces acting on the Dosator during the filling stage, the force required to eject the dose and the dose weight. Results: Preliminary results were obtained from the Dosator test-rig. Figure 1 [Omitted] shows the dose weight for different depths to the bottom of the powder bed at the end of the stroke and different levels of pre-compaction of the powder bed. A strong influence over dose weight arising from the proximity between the Dosator and the bottom of the powder bed at the end of the stroke and the conditions of the powder bed has been established. Conclusions: The model will provide a useful tool to predict dosing accuracy and, thus, optimise the future design of Dosator based equipment technology – based on measured bulk properties of the powder to be handled. Another important factor (with a significant influence) on Dosator processes, is the condition of the powder bed and the clearance between the Dosator and the bottom of the powder bed.

Assessment of the degradation of Aspirin by Differential Scanning Calorimetry (DSC)

Purpose. To study thermal stability of Aspirin and define thermal events that are associated with the thermal degradation of aspirin. Methods. Experiments were performed using a DSC 823e (Mettler Toledo, Swiss). Aspirin is prone to thermal degradation upon exposure to high temperatures. The melting point of aspirin is 140.1±0.4ºC (DSC). Aspirin has been examined by heating samples to 120ºC, 155ºC and 185ºC with subsequent cooling to -55ºC and a final heating to 155ºC. Although different heating and cooling ranges have been used, only results obtained at a rate of 10ºC/min will be presented. All runs where conducted in hermetically sealed pans. Results. Upon heating the sample to 120ºC no significant thermal event can be detected. After cooling the sample and reheating a glass transition can be observed at ~-8ºC, followed by the melting of aspirin at ~139ºC. By heating the sample to 155ºC melting of aspirin has been detected at ~139ºC. On cooling and subsequent heating a glass transition occurs at ~-32ºC, together with a broad crystallisation (onset at ~38ºC and peak maximum at ~57ºC) followed by a broad melting with an onset at 94ºC and peak maximum at ~112ºC. Finally, by heating the sample to 185ºC melting at ~ 139ºC was observed, and upon cooling and reheating a glass transition was detected at ~-26ºC and no further events could be recorded. Conclusions. This research demonstrates that the degradation steps of Aspirin depend on the thermal treatment. The main degradation products of different thermal treatments are currently unknown it is clear that acetic acid, which is one of the degradation products, acts as an antiplasticiser by lowering the glass transition temperature. In addition, due to the presence of the degradation products in liquid form (observed by hot stage microscopy), Aspirin is still present in the sample and recrystallises during the second heating step and melts at much lower temperatures.

Communication system model for information rate evaluation of differential detection over time-varying channels

A communication system model for mutual information performance analysis of multiple-symbol differential M-phase shift keying over time-correlated, time-varying flat-fading communication channels is developed. This model is a finite-state Markov (FSM) equivalent channel representing the cascade of the differential encoder, FSM channel model and differential decoder. A state-space approach is used to model channel phase time correlations. The equivalent model falls in a class that facilitates the use of the forward backward algorithm, enabling the important information theoretic results to be evaluated. Using such a model, one is able to calculate mutual information for differential detection over time-varying fading channels with an essentially finite time set of correlations, including the Clarke fading channel. Using the equivalent channel, it is proved and corroborated by simulations that multiple-symbol differential detection preserves the channel information capacity when the observation interval approaches infinity.

Mutual information performance of differential MPSK detection over time-varying channels

This paper provides mutual information performance analysis of multiple-symbol differential WSK (M-phase shift keying) over time-correlated, time-varying flat-fading communication channels. A state space approach is used to model time correlation of time varying channel phase. This approach captures the dynamics of time correlated, time-varying channels and enables exploitation of the forward-backward algorithm for mutual information performance analysis. It is shown that the differential decoding implicitly uses a sequence of innovations of the channel process time correlation and this sequence is essentially uncorrelated. It enables utilization of multiple-symbol differential detection, as a form of block-by-block maximum likelihood sequence detection for capacity achieving mutual information performance. It is shown that multiple-symbol differential ML detection of BPSK and QPSK practically achieves the channel information capacity with observation times only on the order of a few symbol intervals

Design of differential amplifier with negative impedance compensation

Design of differential amplifier with high gain accuracy and high linearity is presented in the paper. The amplifier design is based on the negative impedance compensation technique reported by the authors in [1]. A negative impedance with high precision, low sensitivity, wide input signal range and simple structure is used for the compensation of differential amplifier. Analysis and simulation results show that gain accuracy and linearity can be improved significantly with the negative impedance compensation

Differential contribution of diatoms and dinoflagellates to phytoplankton biomass in the NE Atlantic Ocean and the North Sea

Sampling by the continuous plankton recorder (CPR) survey over the North Atlantic Ocean and the North Sea has enabled long-term studies of phytoplankton biomass. Analysis of an index of phytoplankton biomass, the phytoplankton colour index (PCI), has previously shown an increase in phytoplankton biomass in the NE Atlantic. In the current study, further investigations were conducted to determine the contribution of diatom and dinoflagellate cell counts to the PCI, their fluctuations over the last 45 yr and their geographical variations in the eastern North Atlantic and the North Sea. An increased contribution of dinoflagellates to the PCI was revealed over the south NE Atlantic and the northern North Sea. In contrast, the contribution of diatoms decreased in the north NE Atlantic and the northern North Sea. No discernible trends were found in the other regions of the North Sea. The relative contributions of diatoms and dinoflagellates to the PCI led to the identification of 3 geographically distinct dynamic regimes in the diatom/dinoflagellate dynamics in the NE Atlantic and the North Sea. Finally, it is stressed that the discrepancy observed in the patterns of PCI and diatom and dinoflagellate cell counts suggests that changes in PCI do not reflect changes in the community structure and that the exclusive use of PCI is not adequate to investigate the long-term trends in the trophic link between phytoplankton and herbivorous zooplankton.