Jamie Barras

Nitrogen-14 Nuclear Quadrupole Resonance Spectroscopy: A Promising Analytical Methodology for Medicines Authentication and Counterfeit Antimalarial Analysis

We report the detection and analysis of a suspected counterfeit sample of the antimalarial medicine Metakelfin through developing nitrogen-14 nuclear quadrupole resonance ((14)N NQR) spectroscopy at a quantitative level. The sensitivity of quadrupolar parameters to the solid-state chemical environment of the molecule enables development of a technique capable of discrimination between the same pharmaceutical preparations made by different manufacturers. The (14)N NQR signal returned by a tablet (or tablets) from a Metakelfin batch suspected to be counterfeit was compared with that acquired from a tablet(s) from a known-to-be-genuine batch from the same named manufacturer. Metakelfin contains two active pharmaceutical ingredients, sulfalene and pyrimethamine, and NQR analysis revealed spectral differences for the sulfalene component indicative of differences in the processing history of the two batches. Furthermore, the NQR analysis provided quantitative information that the suspected counterfeit tablets contained only 43 ± 3%, as much sulfalene as the genuine Metakelfin tablets. Conversely, conventional nondestructive analysis by Fourier transform (FT)-Raman and FT-near infrared (NIR) spectroscopies only achieved differentiation between batches but no ascription. High performance liquid chromatography (HPLC)-UV analysis of the suspect tablets revealed a sulfalene content of 42 ± 2% of the labeled claim. The degree of agreement shows the promise of NQR as a means of the nondestructive identification and content-indicating first-stage analysis of counterfeit pharmaceuticals.

Magnetic field-cycling NMR and 14N, 17O quadrupole resonance in the explosive pentaerythritol tetranitrate (PETN)☆

The explosive pentaerythritol tetranitrate (PETN) C(CH(2)-O-NO(2))(4) has been studied by (1)H NMR and (14)N NQR. The (14)N NQR frequency and spin-lattice relaxation time T(1Q) for the nu(+) line have been measured at temperatures from 255 to 325K. The (1)H NMR spin-lattice relaxation time T(1) has been measured at frequencies from 1.8kHz to 40MHz and at temperatures from 250 to 390K. The observed variations are interpreted as due to hindered rotation of the NO(2) group about the bond to the oxygen atom of the CH(2)-O group, which produces a transient change in the dipolar coupling of the CH(2) protons, generating a step in the (1)H T(1) at frequencies between 2 and 100kHz. The same mechanism could also explain the two minima observed in the temperature variation of the (14)N NQR T(1Q) near 284 and 316K, due in this case to the transient change in the (14)N...(1)H dipolar interaction, the first attributed to hindered rotation of the NO(2) group and the second to an increase in torsional amplitude of the NO(2) group due to molecular distortion of the flexible CH(2)-O-NO(2) chain which produces a 15% increase in the oscillational amplitude of the CH(2) group. The correlation times governing the (1)H T(1) values are approximately 25 times longer than those governing the (14)N NQR T(1Q), explained by the slow spin-lattice cross-coupling between the two spin systems. At higher frequencies, the (1)H T(1) dispersion results show well-resolved dips between 200 and 904kHz assigned to level crossing with (14)N and weaker features between 3 and 5MHz tentatively assigned to level crossing with (17)O.

Authentication of medicines using nuclear quadrupole resonance spectroscopy

The production and sale of counterfeit and substandard pharmaceutical products, such as essential medicines, is an important global public health problem. We describe a chemometric passport-based approach to improve the security of the pharmaceutical supply chain. Our method is based on applying nuclear quadrupole resonance (NQR) spectroscopy to authenticate the contents of medicine packets. NQR is a non-invasive, non-destructive, and quantitative radio frequency (RF) spectroscopic technique. It is sensitive to subtle features of the solid-state chemical environment and thus generates unique chemical fingerprints that are intrinsically difficult to replicate. We describe several advanced NQR techniques, including two-dimensional measurements, polarization enhancement, and spin density imaging, that further improve the security of our authentication approach. We also present experimental results that confirm the specificity and sensitivity of NQR and its ability to detect counterfeit medicines.

Quantitative 35Cl nuclear quadrupole resonance in tablets of the antidiabetic medicine Diabinese.

Pulsed (35)Cl nuclear quadrupole resonance (NQR) experiments have been performed on 250-mg tablets of the antidiabetic medicine Diabinese to establish the conditions needed for noninvasive quantitative analysis of the medicine in standard bottles. One important condition is the generation of a uniform radio-frequency (RF) field over the sample, which has been achieved by two designs of sample coil: one of variable pitch, and the other a resonator that has been fabricated from a single turn of copper sheet with a longitudinal gap bridged by tuning capacitors. The results from blind tests show that the number of tablets in a bottle could be predicted to within +/-3%.

Batch-Specific Discrimination Using Nuclear Quadrupole Resonance Spectroscopy

In this paper, we report on the identification of batches of analgesic paracetamol (acetaminophen) tablets using nitrogen-14 nuclear quadrupole resonance spectroscopy ((14)N NQR). The high sensitivity of NQR to the electron charge distribution surrounding the quadrupolar nucleus enables the unique characterization of the crystal structure of the material. Two hypothesis were tested on batches of the same brand: the within the same batch variability and the difference between batches that varied in terms of their batch number and expiry date. The multivariate analysis of variance (MANOVA) did not provide any within-batches variations, indicating the natural deviation of a medicine manufactured under the same conditions. Alternatively, the statistical analysis revealed a significant discrimination between the different batches of paracetamol tablets. Therefore, the NQR signal is an indicator of factors that influence the physical and chemical integrity of the material. Those factors might be the aging of the medicine, the manufacturing, or storage conditions. The results of this study illustrate the potential of NQR as promising technique in applications such as detection and authentication of counterfeit medicines.

Variable-pitch rectangular cross-section radiofrequency coils for the nitrogen-14 nuclear quadrupole resonance investigation of sealed medicines packets.

The performance of rectangular radio frequency (RF) coils capable of being used to detect nuclear quadrupole resonance (NQR) signals from blister packs of medicines has been compared. The performance of a fixed-pitch RF coil was compared with that from two variable-pitch coils, one based on a design in the literature and the other optimized to obtain the most homogeneous RF field over the whole volume of the coil. It has been shown from 14N NQR measurements with two medicines, the antibiotic ampicillin (as trihydrate) and the analgesic medicine Paracetamol, that the latter design gives NQR signal intensities almost independent of the distribution of the capsules or pills within the RF coil and is therefore more suitable for quantitative analysis.

Detecting NQR signals severely polluted by interference

The proposed method effectively cancels complicated interference which can be strong, nonstationary, and have frequencies close to that of signal of interest.The proposed method facilitates a valid detection of the NQR signal severely polluted by interference.The proposed method performs better than general frequency selective methods of interference cancellation. Nuclear Quadrupole Resonance (NQR) signal detection can be severely obstructed by interference in real life settings, especially when the interference is strong, nonstationary, and its frequencies are close to that of the NQR signal. A novel algorithm is proposed to effectively remove (or reduce) interference components in the data and facilitate a valid detection of the NQR signal. The proposed method exhibits better performance compared to the previously proposed ETAML and FETAML algorithms, when applied to both simulated and measured data. Importantly, the present algorithm directly operates on the original primary data, without requiring any secondary data (NQR signal-free data) for acquiring prior knowledge of the interference.

Detection of extremely weak NQR signals using stochastic resonance and neural network theories

Abstract Nuclear Quadrupole Resonance (NQR) signal detection is widely used for searching related substances of interest, such as explosives, petroleum, drugs, etc. NQR responses from these substances are usually very weak compared to background noise. Moreover, in some applications such as landmine detection, NQR responses decay with time quickly, and the required scanning times are usually prohibitively long. This paper presents a novel approach which can detect NQR signals of very low SNRs in such scenarios, by combining a stochastic resonance framework and neural network theory. Firstly, the approach relies on the design of a stochastic resonance (SR) system which can transform the original data into a nonlinear waveform with special SR features. Secondly, a (feedforward) robust neural network is trained to discern this nonlinear waveform accurately, in order to identify the NQR signal. Our results demonstrate that the neural network approach outer-performs traditional signal processing detection and estimation methods. Moreover, this stochastic resonance neural network approach (SRNN) can be designed to detect a variety of NQR signals which have similar NQR parameters. The SRNN approach can also be effective in cases where both noise and radio frequency interference are strong relative to the NQR response.

(14)N NQR, relaxation and molecular dynamics of the explosive TNT.

Multiple pulse sequences are widely used for signal enhancement in NQR detection applications. Since the various (14)N NQR relaxation times, signal decay times and frequency of each NQR line have a major influence on detection sequence performance, it is important to characterise these parameters and their temperature variation, as fully as possible. In this paper we discuss such measurements for a number of the ν+ and ν- NQR lines of monoclinic and orthorhombic TNT and relate the temperature variation results to molecular dynamics. The temperature variation of the (14)N spin-lattice relaxation times T1 is interpreted as due to hindered rotation of the NO2 group about the C-NO2 bond with an activation energy of 89 kJ mol(-1) for the ortho and para groups of monoclinic TNT and 70 kJ mol(-1) for the para group of orthorhombic TNT.

Off-resonance effects in 14N NQR signals from the pulsed spin-locking (PSL) and three-pulse echo sequence; a study for monoclinic TNT ☆

In NQR detection applications signal averaging by the summation of rapidly regenerated signals from multiple pulse sequences of the pulsed spin-locking (PSL) type is often used to improve sensitivity. It is important to characterise and if possible minimise PSL sequence off-resonance effects since they can make it difficult to optimise detection performance. We illustrate this with measurements of the variation of the decay time T2e and the amplitude of PSL signal trains with pulse spacing and excitation offset frequency for the 870 kHz ν+(14)N NQR line of monoclinic TNT under carefully stabilised temperature conditions. We have also carried out a similar study of signals from monoclinic TNT and 1H-1,2,3-triazole generated by a three-pulse echo sequence and the results are shown to agree well with a theoretical treatment appropriate to polycrystalline NQR samples such as TNT for which spin I=1, asymmetry parameter η≠0 and T1≫T2. Based on this theory we derive simple models for calculating TNT PSL signal trains and hence the pulse spacing and off-resonance dependence of signal amplitude and T2e which we compare to our experimental data. We discuss the influence of PSL echo summation on off-resonance effects in detected signal intensity and show how a phase-alternated multiple pulse sequence can be used in combination with the PSL sequence to eliminate variation in detection performance due to off-resonance effects.