Sudheer Jawla

High Frequency Dynamic Nuclear Polarization

During the three decades 1980-2010, magic angle spinning (MAS) NMR developed into the method of choice to examine many chemical, physical, and biological problems. In particular, a variety of dipolar recoupling methods to measure distances and torsion angles can now constrain molecular structures to high resolution. However, applications are often limited by the low sensitivity of the experiments, due in large part to the necessity of observing spectra of low-γ nuclei such as the I = 1/2 species (13)C or (15)N. The difficulty is still greater when quadrupolar nuclei, such as (17)O or (27)Al, are involved. This problem has stimulated efforts to increase the sensitivity of MAS experiments. A particularly powerful approach is dynamic nuclear polarization (DNP) which takes advantage of the higher equilibrium polarization of electrons (which conventionally manifests in the great sensitivity advantage of EPR over NMR). In DNP, the sample is doped with a stable paramagnetic polarizing agent and irradiated with microwaves to transfer the high polarization in the electron spin reservoir to the nuclei of interest. The idea was first explored by Overhauser and Slichter in 1953. However, these experiments were carried out on static samples, at magnetic fields that are low by current standards. To be implemented in contemporary MAS NMR experiments, DNP requires microwave sources operating in the subterahertz regime, roughly 150-660 GHz, and cryogenic MAS probes. In addition, improvements were required in the polarizing agents, because the high concentrations of conventional radicals that are required to produce significant enhancements compromise spectral resolution. In the last two decades, scientific and technical advances have addressed these problems and brought DNP to the point where it is achieving wide applicability. These advances include the development of high frequency gyrotron microwave sources operating in the subterahertz frequency range. In addition, low temperature MAS probes were developed that permit in situ microwave irradiation of the samples. And, finally, biradical polarizing agents were developed that increased the efficiency of DNP experiments by factors of ∼4 at considerably lower paramagnet concentrations. Collectively, these developments have made it possible to apply DNP on a routine basis to a number of different scientific endeavors, most prominently in the biological and material sciences. This Account reviews these developments, including the primary mechanisms used to transfer polarization in high frequency DNP, and the current choice of microwave sources and biradical polarizing agents. In addition, we illustrate the utility of the technique with a description of applications to membrane and amyloid proteins that emphasizes the unique structural information that is available in these two cases.

Dynamic nuclear polarization at 700 MHz/460 GHz

We describe the design and implementation of the instrumentation required to perform DNP-NMR at higher field strengths than previously demonstrated, and report the first magic-angle spinning (MAS) DNP-NMR experiments performed at (1)H/e(-) frequencies of 700 MHz/460 GHz. The extension of DNP-NMR to 16.4 T has required the development of probe technology, cryogenics, gyrotrons, and microwave transmission lines. The probe contains a 460 GHz microwave channel, with corrugated waveguide, tapers, and miter-bends that couple microwave power to the sample. Experimental efficiency is increased by a cryogenic exchange system for 3.2 mm rotors within the 89 mm bore. Sample temperatures ≤85 K, resulting in improved DNP enhancements, are achieved by a novel heat exchanger design, stainless steel and brass vacuum jacketed transfer lines, and a bronze probe dewar. In addition, the heat exchanger is preceded with a nitrogen drying and generation system in series with a pre-cooling refrigerator. This reduces liquid nitrogen usage from >700 l per day to <200 l per day and allows for continuous (>7 days) cryogenic spinning without detrimental frost or ice formation. Initial enhancements, ε=-40, and a strong microwave power dependence suggests the possibility for considerable improvement. Finally, two-dimensional spectra of a model system demonstrate that the higher field provides excellent resolution, even in a glassy, cryoprotecting matrix.

Mode Content Determination of Terahertz Corrugated Waveguides Using Experimentally Measured Radiated Field Patterns

This work focuses on the accuracy of the mode content measurements in an overmoded corrugated waveguide using measured radiated field patterns. Experimental results were obtained at 250 GHz using a vector network analyzer with over 70 dB of dynamic range. The intensity and phase profiles of the fields radiated from the end of the 19 mm diameter helically tapped brass waveguide were measured on planes at 7, 10, and 13 cm from the waveguide end. The measured fields were back propagated to the waveguide aperture to provide three independent estimates of the field at the waveguide exit aperture. Projecting that field onto the modes of the guide determined the waveguide mode content. The three independent mode content estimates were found to agree with one another to an accuracy of better than 0.3%. These direct determinations of the mode content were compared with indirect measurements using the experimentally measured amplitude in three planes, with the phase determined by a phase retrieval algorithm. The phase retrieval technique using the planes at 7, 10, and 13 cm yielded a mode content estimate in excellent agreement, within 0.3%, of the direct measurements. Phase retrieval results using planes at 10, 20, and 30 cm were less accurate due to truncation of the measurement in the transverse plane. The reported measurements benefited greatly from a precise mechanical alignment of the scanner with respect to the waveguide axis. These results will help to understand the accuracy of mode content measurements made directly in cold test and indirectly in hot test using the phase retrieval technique.

In-Situ Characterization of Pharmaceutical Formulations by Dynamic Nuclear Polarization Enhanced MAS NMR

A principal advantage of magic angle spinning (MAS) NMR spectroscopy lies in its ability to determine molecular structure in a noninvasive and quantitative manner. Accordingly, MAS should be widely applicable to studies of the structure of active pharmaceutical ingredients (API) and formulations. However, the low sensitivity encountered in spectroscopy of natural abundance APIs present at low concentration has limited the success of MAS experiments. Dynamic nuclear polarization (DNP) enhances NMR sensitivity and can be used to circumvent this problem provided that suitable paramagnetic polarizing agent can be incorporated into the system without altering the integrity of solid dosages. Here, we demonstrate that DNP polarizing agents can be added in situ during the preparation of amorphous solid dispersions (ASDs) via spray drying and hot-melt extrusion so that ASDs can be examined during drug development. Specifically, the dependence of DNP enhancement on sample composition, radical concentration, relaxation properties of the API and excipients, types of polarizing agents and proton density, has been thoroughly investigated. Optimal enhancement values are obtained from ASDs containing 1% w/w radical concentration. Both polarizing agents TOTAPOL and AMUPol provided reasonable enhancements. Partial deuteration of the excipient produced 3× higher enhancement values. With these parameters, an ASD containing posaconazole and vinyl acetate yields a 32-fold enhancement which presumably results in a reduction of NMR measurement time by ∼1000. This boost in signal intensity enables the full assignment of the natural abundance pharmaceutical formulation through multidimensional correlation experiments.

Design and test of an internal coupler to corrugated waveguide for high power gyrotrons

Gyrotrons produce power in high-order TE modes that are converted to a Gaussian beam inside the tube and then matched to the HE11 mode in an external waveguide. A design for coupling to the HE11 mode inside the gyrotron has been developed. Test results show high HE11 output mode purity.

Experimental Results for a Pulsed 110/124.5-GHz Megawatt Gyrotron

We report experimental results on a two frequency gyrotron, operating in the TE22,6 mode at 110 GHz and the TE24,7 mode at 124.5 GHz. The gyrotron uses the same electron gun as a previous single frequency 110-GHz gyrotron, with a new cavity and internal mode converter designed for optimized performance at the two frequencies. For a 98 kV, 42-A electron beam operating in 3-μs pulses, an output power of 1.25 MW was obtained at 110 GHz (30% efficiency) and 1.0 MW at 124.5 GHz (24% efficiency). The highest power obtained was 1.4 MW with a 96 kV, 45-A beam (32% efficiency) at 110 GHz. In both modes, mode competition was minimal around the high-power operating point and operation was extremely stable. The output power and efficiency in the TE24,7 mode were limited by the electron beam quality. At both frequencies, excellent Gaussian beam content was found: 1) 99% for the TE22,6 mode and 2) 97% for the TE24,7 mode. Both output beams had waist radii of 2.65 cm, in very good agreement with theory.

Operation of a 140-GHz Gyro-Amplifier Using a Dielectric-Loaded, Severless Confocal Waveguide

The design and experimental results of a 140-GHz gyro-amplifier that uses a dielectric-loaded, severless confocal waveguide are presented. The gyro-traveling wave amplifier uses the HE06 mode of a confocal geometry with power coupled in and out of the structure with Vlasov-type, quasi-optical couplers. Dielectric loading attached to the side of the confocal structure suppresses unwanted modes allowing zero-drive stable operation at 48 kV and 3 A of beam current. The confocal gyro-amplifier demonstrated a peak circuit gain of 35 dB, a bandwidth of 1.2 GHz, and a peak output power of 550 W at 140.0 GHz.

Photonic-band-gap gyrotron amplifier with picosecond pulses

We report the amplification of 250 GHz pulses as short as 260 ps without observation of pulse broadening using a photonic-band-gap circuit gyrotron traveling-wave-amplifier. The gyrotron amplifier operates with a device gain of 38 dB and an instantaneous bandwidth of 8 GHz. The operational bandwidth of the amplifier can be tuned over 16 GHz by adjusting the operating voltage of the electron beam and the magnetic field. The amplifier uses a 30 cm long photonic-band-gap interaction circuit to confine the desired TE03-like operating mode while suppressing lower order modes which can result in undesired oscillations. The circuit gain is >55 dB for a beam voltage of 23 kV and a current of 700 mA. These results demonstrate the wide bandwidths and a high gain achievable with gyrotron amplifiers. The amplification of picosecond pulses of variable lengths, 260-800 ps, shows good agreement with the theory using the coupled dispersion relation and the gain-spectrum of the amplifier as measured with quasi-CW input pulses.

Amplification of picosecond pulses with a photonic-band-gap gyro-TWT

We report the amplification of 250 GHz pulses as short as 150 ps without observation of pulse broadening using a photonic-band-gap (PBG) gyrotron traveling-wave-amplifier. The gyrotron amplifier operates with 38 dB of device gain and 8 GHz of instantaneous bandwidth. The operational bandwidth of the amplifier can be tuned over 16 GHz by adjusting the operating voltage of the electron beam and the magnetic field. The amplifier uses a 30 cm PBG interaction circuit to confine the desired TE03 operating mode while suppressing lower order modes which can result in undesired oscillations. The circuit gain is >55 dB for a beam voltage of 23 kV and a current of 700 mA. These results demonstrate the wide bandwidths and high gain achievable with gyrotron amplifiers.

330 GHz / 500 MHz Dynamic Nuclear Polarization-NMR spectrometer

We describe the implementation of a 330 GHz gyrotron and microwave transmission line system for Dynamic Nuclear Polarization - NMR experiments performed at 1H frequencies of 500 MHz. Overall microwave transmission efficiency of 72% was achieved by careful alignment of the corrugated waveguides. Initial DNP signal enhancement of 120 was observed.