Band flipping and bandgap closing in a photonic crystal ring and its applications.

The size of the bandgap in a photonic crystal ring is typically intuitively considered to monotonically grow as the modulation amplitude of the grating increases, causing increasingly large frequency splittings between the "dielectric" and "air" bands. In contrast, here we report that as the modulation amplitude in a photonic crystal ring increases, the bandgap does not simply increase monotonically. Instead, after the initial increase, the bandgap closes and then reopens again with the two bands flipped in energy. The air and dielectric band edges are degenerate at the bandgap closing point. We demonstrate this behavior experimentally in silicon nitride photonic crystal microrings, where we show that the bandgap is closed to within the linewidth of the optical cavity mode, whose intrinsic quality factor remains unperturbed with a value ≈ 1×106. Moreover, through finite-element simulations, we show that such bandgap closing and band flipping phenomena exist in a variety of photonic crystal rings with varying unit cell geometries and cladding layers. At the bandgap closing point, the two standing wave modes with a degenerate frequency are particularly promising for single-frequency lasing applications. Along this line, we propose a compact self-injection locking scheme that integrates many core functionalities in one photonic crystal ring. Additionally, the single-frequency lasing might be applicable to distributed-feedback (DFB) lasers to increase their manufacturing yield.

Traceable localization enables accurate integration of quantum emitters and photonic structures with high yield.

In a popular integration process for quantum information technologies, localization microscopy of quantum emitters guides lithographic placement of photonic structures. However, a complex coupling of microscopy and lithography errors degrades registration accuracy, severely limiting device performance and process yield. We introduce a methodology to solve this widespread but poorly understood problem. A new foundation of traceable localization enables rapid characterization of lithographic standards and comprehensive calibration of cryogenic microscopes, revealing and correcting latent systematic effects. Of particular concern, we discover that scale factor deviation and complex optical distortion couple to dominate registration errors. These novel results parameterize a process model for integrating quantum dots and bullseye resonators, predicting higher yield by orders of magnitude, depending on the Purcell factor threshold as a quantum performance metric. Our foundational methodology is a key enabler of the lab-to-fab transition of quantum information technologies and has broader implications to cryogenic and correlative microscopy.

Tramadol/Diclofenac Fixed-Dose Combination for Acute Pain Management: Bioavailability Assessment of a Generic Product.

The multimodal analgesia strategy for acute pain involves using 2 or more analgesic medications with distinct mechanisms of action. This study assessed the bioavailability and tolerability of 2 tramadol hydrochloride (50 mg)/diclofenac sodium (50 mg) fixed-dose combination formulations under fed conditions to attend the Brazilian regulatory requirements for generic product registration. An open-label, randomized, single-dose, 2-period, 2-way crossover trial was conducted, including healthy subjects of both sexes. Subjects received a single dose of either the test or reference formulation of tramadol/diclofenac fixed-dose combination tablets with a 7-day washout period. Blood samples were collected up to 36 hours after dosing for tramadol and 12 hours for diclofenac and quantified using a validated liquid chromatography-tandem mass spectrometry method. Of 56 subjects enrolled, 53 completed the study. The 90% confidence intervals for maximum plasma concentration and area under the concentration-time curve from time 0 to the last quantifiable concentration were within acceptable bioequivalence limits of 80%-125%. Considering the results presented in this study, the test formulation is bioequivalent to the reference formulation and could be interchangeable in medical practice.

Etoricoxib Coated Tablets: Bioequivalence Assessment between Two Formulations Administered under Fasting Conditions.

Etoricoxib is a non-steroidal anti-inflammatory drug with high selectivity for cyclooxygenase 2 (COX-2), exerting a pronounced anti-inflammatory effect with fewer adverse events when compared to COX-1 inhibitors. The present study aimed to evaluate the bioequivalence between two etoricoxib-coated tablet formulations to meet regulatory requirements for a branded generic product registration in Brazil. A crossover study with an open-label, randomized design and a single-dose regimen with two treatments and two periods was conducted on healthy Brazilians of both genders. Subjects randomly received a single dose of a 90 mg etoricoxib coated tablet of test product Xumer® 90 mg (Adium S.A.) and the reference product Arcoxia® 90 mg (Merck Sharp & Dohme Farmacêutica Ltda.) under fasting conditions separated by a 14-day period. Blood samples were collected sequentially for up to 96 h following drug administration, and the concentrations of etoricoxib in plasma were determined using a validated UPLC-MS/MS method. Pharmacokinetic parameters were computed utilizing non-compartmental analysis methods. A total of 32 healthy subjects were enrolled, and 25 subjects completed the study. Geometric mean ratios (90% confidence intervals) for Cmax, AUC0-t, and AUC0-inf were 103.98% (95.63-113.06), 96.82% (91.82-102.09), and 95.79% (90.70-101.16), respectively. In accordance with regulatory standards, the test formulation (Xumer® 90 mg) has been deemed bioequivalent to the reference product (Arcoxia® 90 mg). As a result, these formulations can be considered interchangeable in clinical practice, with both proving to be safe and well-tolerated. The need for in vivo testing for the Xumer® 60 mg strength was waived due to the proportional similarity of the formulations and the similar in vitro dissolution profiles observed across the various strengths.

Inverse design of a polarization demultiplexer for on-chip path-entangled photon-pair sources based on single quantum dots.

Epitaxial quantum dots can emit polarization-entangled photon pairs. If orthogonal polarizations are coupled to independent paths, then the photons will be path-entangled. Through inverse design with adjoint method optimization, we design a quantum dot polarization demultiplexer, a nanophotonic geometry that efficiently couples orthogonally polarized transition dipole moments of a single quantum dot to two independent waveguides. We predict 95% coupling efficiency, cross talk less than 0.1%, and Purcell radiative rate enhancement factors over 11.5 for both dipoles, with sensitivity to dipole misalignment and orientation comparable to that of conventional nanophotonic geometries. We anticipate our design will be valuable for the implementation of triggered, high-rate sources of path-entangled photon-pairs on chip.

Methylphenidate Multiphasic Release Tablet: Bioequivalence Assessment between Two Formulations Administered under Fasting and Fed Conditions.

Methylphenidate hydrochloride is used to treat children, adolescents, and adults with attention deficit/hyperactivity disorder (ADHD). Multiphasic release formulation has been used to control drug levels, mainly during children's school period. This study aimed to evaluate the bioequivalence between two methylphenidate hydrochloride extended-release tablets to meet regulatory requirements for registration in Brazil. Two independent studies (under fasting and fed conditions) designed as open-label, randomized, single-dose, two-period, two-way crossover trials were conducted in healthy subjects of both genders. Subjects were enrolled and randomly received a single dose of the test formulation methylphenidate hydrochloride 54 mg extended-release tablet (Consiv®, Adium S.A., São Paulo, Brazil) or the reference formulation (Concerta®, Janssen-Cilag Farmacêutica Ltd., São Paulo, Brazil), in each period, with a 7-day washout interval. Serial blood samples were collected up to 24 h post dose and methylphenidate plasma concentrations were obtained using a validated LC-MS/MS method. A total of 96 healthy subjects were enrolled in the fasting study, of which 80 completed the study. For the fed study, 52 healthy subjects were enrolled, and 46 subjects completed it. In both studies, 90% confidence intervals for Cmax, AUC0-t, AUC0-inf, and partial AUCs were within the acceptable limits of 80.00 to 125.00%. Thus, according to regulatory requirements, the test formulation (Consiv®) was considered to be bioequivalent to the reference formulation (Concerta®) in both conditions (fasting and fed) and, therefore, it can be considered interchangeable in clinical practice. Both formulations were safe and well tolerated in single-dose administration.

Multi-mode microcavity frequency engineering through a shifted grating in a photonic crystal ring.

Frequency engineering of whispering-gallery resonances is essential in microcavity nonlinear optics. The key is to control the frequencies of the cavity modes involved in the underlying nonlinear optical process to satisfy its energy conservation criterion. Compared to the conventional method that tailors dispersion by cross-sectional geometry, thereby impacting all cavity mode frequencies, grating-assisted microring cavities, often termed as photonic crystal microrings, provide more enabling capabilities through mode-selective frequency control. For example, a simple single period grating added to a microring has been used for single frequency engineering in Kerr optical parametric oscillation (OPO) and frequency combs. Recently, this approach has been extended to multi-frequency engineering by using multi-period grating functions, but at the cost of increasingly complex grating profiles that require challenging fabrication. Here, we demonstrate a simple approach, which we term as shifted grating multiple mode splitting (SGMMS), where spatial displacement of a single period grating imprinted on the inner boundary of the microring creates a rotational asymmetry that frequency splits multiple adjacent cavity modes. This approach is easy to implement and presents no additional fabrication challenges compared to an unshifted grating, and yet is very powerful in providing multi-frequency engineering functionality for nonlinear optics. We showcase an example where SGMMS enables OPO across a wide range of pump wavelengths in a normal-dispersion device that otherwise would not support OPO.

Ultra-low loss quantum photonic circuits integrated with single quantum emitters.

The scaling of many photonic quantum information processing systems is ultimately limited by the flux of quantum light throughout an integrated photonic circuit. Source brightness and waveguide loss set basic limits on the on-chip photon flux. While substantial progress has been made, separately, towards ultra-low loss chip-scale photonic circuits and high brightness single-photon sources, integration of these technologies has remained elusive. Here, we report the integration of a quantum emitter single-photon source with a wafer-scale, ultra-low loss silicon nitride photonic circuit. We demonstrate triggered and pure single-photon emission into a Si3N4 photonic circuit with ≈ 1 dB/m propagation loss at a wavelength of ≈ 930 nm. We also observe resonance fluorescence in the strong drive regime, showing promise towards coherent control of quantum emitters. These results are a step forward towards scaled chip-integrated photonic quantum information systems in which storing, time-demultiplexing or buffering of deterministically generated single-photons is critical.

Fractional Optical Angular Momentum and Multi-Defect-Mediated Mode Renormalization and Orientation Control in Photonic Crystal Microring Resonators.

Whispering gallery modes (WGMs) in circularly symmetric optical microresonators exhibit integer quantized angular momentum numbers due to the boundary condition imposed by the geometry. Here, we show that incorporating a photonic crystal pattern in an integrated microring can result in WGMs with fractional optical angular momentum. By choosing the photonic crystal periodicity to open a photonic band gap with a band-edge momentum lying between that of two WGMs of the unperturbed ring, we observe hybridized WGMs with half-integer quantized angular momentum numbers (m∈Z+1/2). Moreover, we show that these modes with fractional angular momenta exhibit high optical quality factors with good cavity-waveguide coupling and an order of magnitude reduced group velocity. Additionally, by introducing multiple artificial defects, multiple modes can be localized to small volumes within the ring, while the relative orientation of the delocalized band-edge states can be well controlled. Our Letter unveils the renormalization of WGMs by the photonic crystal, demonstrating novel fractional angular momentum states and nontrivial multimode orientation control arising from continuous rotational symmetry breaking. The findings are expected to be useful for sensing and metrology, nonlinear optics, and cavity quantum electrodynamics.

Kerr optical parametric oscillation in a photonic crystal microring for accessing the infrared.

Continuous wave optical parametric oscillation (OPO) provides a flexible approach for accessing mid-infrared wavelengths between 2 µm and 5 µm, but operation at these wavelengths has not yet been integrated into silicon nanophotonics. Typically, a Kerr OPO uses a single transverse mode family for pump, signal, and idler modes, and relies on a delicate balance to achieve normal (but close-to-zero) dispersion near the pump and the requisite higher-order dispersion needed for phase- and frequency-matching. Within integrated photonics platforms, this approach results in two major problems. First, the dispersion is very sensitive to geometry, so that small fabrication errors can have a large impact. Second, the device is susceptible to competing nonlinear processes near the pump. In this Letter, we propose a flexible solution to infrared OPO that addresses these two problems by using a silicon nitride photonic crystal microring (PhCR). The frequency shifts created by the PhCR bandgap enable OPO that would otherwise be forbidden. We report an intrinsic optical quality factor up to (1.2 ± 0.1)×106 in the 2-µm band, and use a PhC ring to demonstrated an OPO with a threshold dropped power in the cavity of (90 ± 20) mW, with the pump wavelength at 1998 nm, and the signal and idler wavelengths at 1937 nm and 2063 nm, respectively. We further discuss how to extend the OPO spectral coverage in the mid-infrared. These results establish the PhCR OPO as a promising route for integrated laser sources in the infrared.

Physiologically relevant dissolution conditions towards improved in vitro - in vivo relationship - A case study with enteric coated pantoprazole tablets.

There are many hurdles in the development of generic formulations. In vitro biopredictive dissolution conditions together with alternative in vitro - in vivo relationship (IVIVR) approaches can be a powerful tool to support the development of such formulations. In this study, we hypothesized that the release profile of enteric coated (EC) formulations of pantoprazole in physiologically relevant bicarbonate buffer (BCB) would detect possible performance differences between test and reference formulations resulting in more accurate IVIVR results and predictability when compared to a pharmacopeial dissolution test. We correlated the in vitro performance of test and reference formulations (both in BCB and pharmacopeial phosphate buffer) with the in vivo data from a failed bioequivalence study. Test and reference formulations of EC pantoprazole tablets passed the USP dissolution criteria. However, they failed statistical similarity in vitro both in compendial and BCB. Bicarbonate buffer was additionally more discriminative while being more physiologically relevant. Having BCB as an additional test to evaluate EC products in vitro might improve the comparison of formulations. This can de-risk the development of generic EC formulations.

Purcell-Enhanced Single Photon Source Based on a Deterministically Placed WSe2 Monolayer Quantum Dot in a Circular Bragg Grating Cavity.

We demonstrate a deterministic Purcell-enhanced single photon source realized by integrating an atomically thin WSe2 layer with a circular Bragg grating cavity. The cavity significantly enhances the photoluminescence from the atomically thin layer and supports single photon generation with g(2)(0) < 0.25. We observe a consistent increase of the spontaneous emission rate for WSe2 emitters located in the center of the Bragg grating cavity. These WSe2 emitters are self-aligned and deterministically coupled to such a broadband cavity, configuring a new generation of deterministic single photon sources, characterized by their simple and low-cost production and intrinsic scalability.

Sensitive LC-MS/MS method for quantification of rivaroxaban in plasma: Application to pharmacokinetic studies.

Rivaroxaban is an anticoagulant (orally active direct Xa inhibitor) considered to reduce the risk of stroke and systemic embolism and treat deep vein thrombosis, pulmonary embolism, and other cardiovascular complications. Bioanalytical methods for rivaroxaban quantification in plasma are necessary for application in pharmacokinetic studies, as well as in drug therapeutic monitoring. In this work, we developed and validated a sensitive bioanalytical method using LC-MS/MS for rivaroxaban quantification in human plasma using an one-step liquid-liquid extraction. The linear concentration range was 1-600 ng/mL. The bioanalytical method was also applied to pharmacokinetic studies in healthy volunteers under fasting and fed conditions. The results demonstrated that the method is rapid, sensitive, and adequate for application in pharmacokinetic studies.

Hyperspectral study of the coupling between trions in WSe2 monolayers to a circular Bragg grating cavity.

Circular Bragg gratings compose a very appealing photonic platform and nanophotonic interface for the controlled light-matter coupling of emitters in nanomaterials. Here, we discuss the integration of exfoliated monolayers of WSe2 with GaInP Bragg gratings. We apply hyperspectral imaging to our coupled system, and explore the spatio-spectral characteristics of our coupled monolayer-cavity system. Our work represents a valuable step towards the integration of atomically thin quantum emitters in semiconductor nanophotonic cavities.

High-Q dark hyperbolic phonon-polaritons in hexagonal boron nitride nanostructures.

The anisotropy of hexagonal boron nitride (hBN) gives rise to hyperbolic phonon-polaritons (HPhPs), notable for their volumetric frequency-dependent propagation and strong confinement. For frustum (truncated nanocone) structures, theory predicts five, high-order HPhPs, sets, but only one set was observed previously with far-field reflectance and scattering-type scanning near-field optical microscopy. In contrast, the photothermal induced resonance (PTIR) technique has recently permitted sampling of the full HPhP dispersion and observing such elusive predicted modes; however, the mechanism underlying PTIR sensitivity to these weakly-scattering modes, while critical to their understanding, has not yet been clarified. Here, by comparing conventional contact- and newly developed tapping-mode PTIR, we show that the PTIR sensitivity to those weakly-scattering, high-Q (up to ≈280) modes is, contrary to a previous hypothesis, unrelated to the probe operation (contact or tapping) and is instead linked to PTIR ability to detect tip-launched dark, volumetrically-confined polaritons, rather than nanostructure-launched HPhPs modes observed by other techniques. Furthermore, we show that in contrast with plasmons and surface phonon-polaritons, whose Q-factors and optical cross-sections are typically degraded by the proximity of other nanostructures, the high-Q HPhP resonances are preserved even in high-density hBN frustum arrays, which is useful in sensing and quantum emission applications.

In Vitro-In Vivo Correlation for Desvenlafaxine Succinate Monohydrate Extended Release Tablets.

The objective of this study was to develop a dissolution test in order to establish an in vitro-in vivo correlation (IVIVC) model for desvenlafaxine succinate monohydrate (DVSM) extended release (ER) tablets. The in vitro release characteristics of the drug were determined using USP apparatus 1 at 75 rpm, with volume of HCl pH 1.2, acetate buffer solution (ABS) pH 4.5, or phosphate buffer solution (PBS) pH 6.8. In vivo plasma concentrations and pharmacokinetic parameters in healthy volunteers were obtained from a bioequivalence study. The similarity factors f1 and f2 were used to compare the dissolution data. The IVIVC model was developed using fraction dissolved and fraction absorbed of the reference product. For predictability, the results showed that the percentage prediction error (%PE) value of Cmax was 7.63%. The observed low prediction error for Cmax demonstrated that the IVIVC model was valid for this parameter.

In Vivo Predictive Dissolution (IPD) for Carbamazepine Formulations: Additional Evidence Regarding a Biopredictive Dissolution Medium.

The aim of the present study was to bring additional evidence regarding a biopredictive dissolution medium containing 1% sodium lauryl sulphate (SLS) to predict the in vivo behavior of carbamazepine (CBZ) products. Twelve healthy volunteers took one immediate release (IR) dose of either test and reference formulations in a bioequivalence study (BE). Dissolution profiles were carried-out using the medium. Level A in vitro-in vivo correlations (IVIVC) were established using both one-step and two-step approaches as well as exploring the time-scaling approach to account for the differences in dissolution rate in vitro versus in vivo. A detailed step by step calculation was provided to clearly illustrate all the procedures. The results show additional evidence that the medium containing 1% SLS can be classified as a universal biopredictive dissolution tool, and that both of the approaches used to develop the IVIVC (one and two-steps) provide good in vivo predictability. Therefore, this biopredictive medium could be a highly relevant tool in Latin-American countries to ensure and check the quality of their CBZ marketed products for which BE studies were not requested by their regulatory health authorities.

In vitro - In vivo correlation in the development of oral drug formulation: A screenshot of the last two decades.

In vitro - in vivo correlation (IVIVC) allows prediction of the in vivo performance of a pharmaceutical product based on its in vitro drug release profiles and can be used to optimize formulations, set dissolution limits, reduce the number of bioequivalence studies during product development, and facilitate certain regulatory decisions. This review article aimed to assess papers published in the last two decades regarding the use of the IVIVC in the development of oral formulations, to demonstrate the scenario in this area, as well as to describe the main characteristics of the assessed studies. A systematic search of PubMed and Web of Science databases was conducted to retrieve articles reporting the use of the IVIVC in the oral formulation development in the period from 1998 to 2018. The qualified studies were abstracted regarding drug name, dosage form, BCS class, in vitro and in vivo data, level of IVIVC, number of formulations, presence of the validation and predictability. The discussion was supported by these data, which allowed to address broadly strengths and weaknesses in this area. Moreover, a large database has been described in this article containing different IVIVC models, with different substances, providing support to scientists interested in this area.

Advanced technologies for quantum photonic devices based on epitaxial quantum dots.

Quantum photonic devices are candidates for realizing practical quantum computers and networks. The development of integrated quantum photonic devices can greatly benefit from the ability to incorporate different types of materials with complementary, superior optical or electrical properties on a single chip. Semiconductor quantum dots (QDs) serve as a core element in the emerging modern photonic quantum technologies by allowing on-demand generation of single-photons and entangled photon pairs. During each excitation cycle, there is one and only one emitted photon or photon pair. QD photonic devices are on the verge of unfolding for advanced quantum technology applications. In this review, we focus on the latest significant progress of QD photonic devices. We first discuss advanced technologies in QD growth, with special attention to droplet epitaxy and site-controlled QDs. Then we overview the wavelength engineering of QDs via strain tuning and quantum frequency conversion techniques. We extend our discussion to advanced optical excitation techniques recently developed for achieving the desired emission properties of QDs. Finally, the advances in heterogeneous integration of active quantum light-emitting devices and passive integrated photonic circuits are reviewed, in the context of realizing scalable quantum information processing chips.

A randomized, single-dose, two-sequence, two-period, crossover study to assess the bioequivalence between two formulations of clonazepam tablet in healthy subjects.

Clonazepam is a benzodiazepine commonly prescribed to treat panic disorder, epilepsy, anxiety, depression and certain types of seizures. This study aimed to evaluate the bioequivalence between two formulations of clonazepam tablets in order to meet regulatory requirements for marketing in Colombia and other countries in Latin America. An open-label, randomized, single-dose, two-period, two-sequence, two-treatment crossover study was conducted in 36 healthy subjects of both genders. Subjects received a single dose of clonazepam 2 mg test tablet (Sanofi-Aventis de Colombia S.A.) and reference product (Rivotril®, Produtos Roche Químicos e Farmacêuticos S.A.) under fasting conditions according to a randomly assigned order with a 21-day washout period. Serial blood samples were collected up to 96 h post-dose. Plasma concentrations of clonazepam were obtained by a validated liquid chromatography-tandem mass spectrometry method. Pharmacokinetic parameters were calculated using non-compartmental methods. A total of 36 healthy subjects were enrolled and 31 of them completed the study. Twenty-nine adverse events were reported (11 events with test product versus 18 events with reference product). There were no serious adverse events during the study. Geometric mean ratios (90% confidence intervals) for Cmax and AUC0-96h were 103.28% (98.10-108.64) and 102.50% (99.87-105.19), respectively. The test formulation of clonazepam 2 mg tablet manufactured by Sanofi-Aventis de Colombia S.A. was considered bioequivalent to reference product Rivotril® (Produtos Roche Químicos e Farmacêuticos S.A.) according to regulatory requirements. Both formulations were safe and well-tolerated during the study.