Isomeric Impurities Research Articles

Synthesis and Characterization of Chiral Impurities of Mirabegron, Used as an Overactive Bladder Drug

Mirabegron is used to treat overactive bladder that drug substance is the first β3-adrenoreceptor (AR) agonist. The mechanism of action of Mirabegron is as an adrenergic beta-3-Agonist and cytochrome P450 3A inhibitor, and p-Glycoprotein inhibitor. This molecule is optical active and having one chiral center and only (R)-Mirabegron presents pharmacological activity being (S)-Mirabegron an impurity which critical to control. During the process development of Mirabegron, the chiral impurity of drug substance is challenging and also challenging to all pharmaceutical industries too, the opposite isomeric impurity is introduced form its key starting material and it follows the same reaction mechanism path up to final drug substance, present work describe the synthesis of chiral impurities of each intermediate, including key starting material and its drug substance and their characterization by spectral data (MS,1H-NMR and 13C-NMR). This work will help quality control (QC) to identify and control these impurities in the Mirabegron drug substance as per ICH guideline.

Nebivolol hydrochloride and its impurities induce pseudo-allergic reactions via mast cell activation.

Nebivolol hydrochloride is a third-generation β-blocker commonly used to treat cardiovascular diseases. However, it has been reported to induce allergic reactions in clinical use which deserves much attention. Therefore, this study focused on the ability of two isomers of nebivolol and chiral isomer impurities to induce allergic reactions. Our findings demonstrate that both nebivolol and two isomeric impurities can activate mast cell degranulation in vitro and show significant retention on Mas-related G-protein-coupled receptor X2 (MRGPRX2)-HEK293 cell membrane chromatography. These effects were further validated in vivo, where nebivolol and impurity IP-3 were observed to cause toe swelling and mast cell degranulation in mice. Molecular docking studies revealed interactions between these compounds and key amino acids of MRGPRX2, suggesting a mechanism for the induced allergic reactions. This work lays the foundation for improving the clinical safety of nebivolol.

Tandem Mass Spectrometry Approaches for Differentiation and Quantification Pidotimod and Its Three Isomers in the Gas Phase.

Pidotimod is a chiral drug that possesses two chiral centers, resulting in three isomeric impurities (analytes, A). This study employs electrospray ionization ion trap mass spectrometry (ESI-MS) through collision-induced dissociation (CID) to investigate the chiral recognition of pidotimod and its three isomers to eliminate chromatographic separation. Three approaches were explored: (1) Protonated molecules in CID exhibited discriminative potential for diastereomers, with the ability to distinguish between S,S and R,R configurations, albeit with an Rchiral value of ~1.8. However, differentiation between R,S and S,R configurations was not achievable. (2) Alkali adductions (lithium and sodium) only discerned diastereomers. The Rchiral values of the diastereomers obtained from alkali adduct ions were significantly lower than those obtained from protonated ions. (3) Therefore, a third approach was used to address the challenge of distinguishing between R,S and S,R configurations, including the introduction of chiral references (ref) and transition metals (MII) to form metal-bound complexes [MII(A)(ref)-H]+. Additionally, we synthesized a novel ligand, 4-(N-tert-butoxycarbonyl [Boc]-L-prolinamido)phenol (denoted as ligand A), by modifying N-t-Boc-L-Pro with 2-aminophenol, which, in combination with CuII and NiII, enabled simultaneous differentiation of all four isomers. CuII complexes exhibited significant chiral selectivity between R,S and S,R configurations. Density functional theory calculations were performed to further elucidate the stereodynamic behavior and stoichiometry of these ions in the gas phase. These calculations revealed the interaction energy and coordination sites of the precursor ions in the gas phase, correlating well with MS/MS experiment results. Additionally, the logarithm of the CuII complexes' characteristic fragment ion abundance ratio demonstrated a strong linear relationship with enantiomeric excess (ee). This study presents a novel strategy for chiral drug quality control that eliminates chromatographic separation.

Synthesis and Characterization of Chiral Impurities of Rivaroxaban, Used as an Anticoagulant Drug

The mechanism of action of the anticoagulant medication rivaroxaban is the direct and specific suppression of activated coagulation factor X (FXa). With just (S)-Rivaroxaban exhibiting pharmacological activity and (R)-Rivaroxaban being an impurity that must be controlled, this molecule only has one chiral centre. The present work describes the synthesis of chiral impurities of each intermediate, including KSM and its drug substance, and their characterization by spectral data (IR, MS, 1H-NMR, and 13C-NMR). The chiral impurity of drug substance is challenging during the process development of Rivaroxaban, and it is challenging for all pharmaceutical industries as well. The opposite isomeric impurity is introduced form its key starting material and it follows the same reaction mechanism path up to final drug substance. This work will help quality control (QC) to identify and control these impurities in the Rivaroxban drug substance as per ICH guideline.

Development of HPLC method for isomeric impurities of key starting material of novel oral anticoagulant drug; Edoxaban Tosylate Monohydrate

Reverse-phase high-performance liquid chromatography method has been developed for the determination of EDO-S1 stereoisomeric impurities such as isomer 1, isomer 2, isomer 3, isomer 4, isomer 5, isomer 6 and isomer 7 with good resolution using the column, Bakerbond C18 (150 × 4.6 mm; 3 μm). The separation was achieved with mobile phase-A (10 mM dipotassium hydrogen phosphate pH-7.0 with 10% orthophosphoric acid solution in Milli-Q water) and mobile phase-B (n-Propanol: Acetonitrile ratio of 20:30 % V/V), which consisted of mobile phase mixture in the combination of moilephase-A: mobile phase-B (85:15). The total run time was 30 min at 0.8 mL/min flow rate, 20 µL injection volume and 30 ℃ column oven temperature. The column eluate was monitored at 210 nm to quantify the impurities The method showed adequate specificity, sensitivity, linearity, accuracy, precision, and robustness inline to ICH tripartite guidelines. The limit of detection and quantification limits were 0.1 and 0.3 μg mL−1, respectively, for all isomeric impurities and EDO-S1. The developed method was found to be linear over the concentration range of LOQ to 150% of specification range for isomeric impurities with a correlation coefficient >0.999. The method was precise (%RSD < 5.0), robust, and accurate (with 85%–115% recovery).

Identification and Synthesis of Oxidative-Degradation and Starting Materials-Attributed Impurities in Lisdexamfetamine Dimesylate

Abstract: Impurities are an integral part of drug substances, even though they have not been studied in the pharmacological evaluation of the Benefit-Risk (BR) profiles. Hence, understanding their origin and controlling them have prime importance during drug substance development. The structures of some of the impurities in lisdexamfetamine dimesylate, a central nervous system stimulant drug, have been confirmed based on literature and analytical data. The study has been undertaken to evaluate impurities arising from oxidative degradation and impurities due to material attributes. All the listed impurities have been identified, synthesized, and characterized by spectral tools. We have, herein, reported the synthesis of two oxidative degradant impurities, 2-hydroxylisdexamfetamine dimesylate and 4-hydroxylisdexafetamine dimesylate. In addition, chiral isomeric impurities of lisdexamfetamine dimesylate as (S,R), (R,S) and (R,R)-lisdexamfetamine dimesylate have also been reported. These impurities have been identified and synthesized, and a control strategy for mitigating risk in lisdexamfetamine dimesylate is provided.

Development of a sensitive immunoassay for detecting persistent contaminant dichlorodiphenyltrichloroethane (DDT) in food samples using a monoclonal antibody

Although gas chromatography is the gold standard for detecting the persistent organic pollutant dichlorodiphenyltrichloroethane (DDT), a quick and easy alternative is needed to detect this highly toxic pesticide in food and household products. Therefore, we developed a monoclonal antibody (mAb)-based assay for the sensitive detection of DDT. The mAb used in our assay demonstrated favourable binding affinity in the nanomolar range against 2,2-bis(4-chlorophenyl)acetic acid (DDA), a DDT analogue, which is considered higher than commercially developed antibodies. By optimizing the assay conditions, we were able to detect DDT and its closely related compounds, including dichlorodiphenyldichloroethylene (DDE), dichlorodiphenyldichloroethane (DDD), and isomeric impurities. Our dot blotting assay demonstrated a detection limit of 0.9 ng/mL for DDT. Using computational modelling, we predicted the structure of the mAb and its interaction with DDT. Overall, this study provides insights for engineering mAb with improved sensitivity, facilitates point-of-care detection of toxic chemicals, including DDT, and offers a vital method for food safety monitoring and environmental protection.

Hydroxyl-functionalized pillar[5]arene with high separation performance for gas chromatography.

Here we report the first example of employing hydroxyl-functionalized pillar[5]arene (P5A-C10-OH) as stationary phase for capillary gas chromatographic (GC) separations. The statically coated P5A-C10-OH capillary column possessed moderate polarity and column efficiency of 3233 plates per m determined by n-dodecane. As a result, the P5A-C10-OH column exhibited high-resolution capability for the mixture of 17 analytes from apolar to polar nature. Importantly, it exhibited advantageous performance for high resolution of the challenging isomers of bromonitrobenzene, chloroaniline, bromoaniline, iodoaniline and dimethylaniline with good peak shapes over the P5A-C10 and commercial HP-35 columns. In addition, eight cis-/trans-isomers with diverse types were baseline separated on the P5A-C10-OH column. And the application of detecting isomeric impurities in real samples gave strong evidence of its potential and feasibility for the viable GC analysis.

An unexpected side reaction in the transformation of an alcohol to an amine facilitated by triflic anhydride-pyridine

Two N-triflyl-4-vinyl-1,4-dihydropyridines 3 and 4 were identified as isomeric impurities in the mother liquor of a 3-step “telescopic” transformation of a secondary alcohol 1 to an amine 2 facilitated by triflic anhydride-pyridine. The vinyl ether moiety of impurities 3 and 4 was readily hydrolyzed under acidic condition to form a keto-alcohol product 5 where four chiral centers were established on a cyclopentane ring. Another keto-alcohol impurity 6 was also isolated from the same mother liquor and identified as a hydrolysis product of the putative vinyl ether intermediate V in support of postulating a plausible mechanism for such an unexpected side reaction. The unexpected finding of the vinyl ether intermediate V could be derivatized with electrophiles besides N-triflylpyridinium to form a variety of compounds with four chiral centers established on a cyclopentane ring.

Use of online sequential segmented heart cutting modulation and orthogonality approach for determination of isomeric impurity profile of a drug molecule using parallel 2-dimensional mass spectroscopy

Determination of impurity profile including chiral and achiral impurities is challenging as well as time consuming while analysis of the active moiety. With the recent evolution of 2-Dimensional separation modes, significant improvement can be made for simultaneous determination of both achiral and chiral impurities in a single set-up. Herein, the present work represents example of how both chiral and achiral impurities can be determined simultaneously. To represent the work, galantamine HBr was selected as the active moiety since it has achiral as well as many chiral impurities. Further, a 1D UPLC method with shorter runtime was developed to determine the achiral impurities and simultaneous heart cutting approach was used to cut the impurities and active compound and transfer to 2D chiral setup to separate out chiral impurities and perform its quantification. Both methods were proven to be orthogonal to each other with orthogonality factor of 0.241.

A Novel RP-Chiral Separation Technique for the Quantification of Brivaracetam and its process Related Isomeric Impurities using High Performance Liquid Chromatography

Reverse‐phase high‐performance liquid chromatography method has been developed for the determination of brivaracetam (BRV) with its stereoisomeric impurities (BRV-SS), (BRV-RR) and (BRV- RS). Brivaracetam with its impurities has been eluted with good resolution using the chiral column, chiralpakIG (250 × 4.6mm, 5µ) column at the detection wavelength of 210nm with the flow rate of 0.50ml/minute. The separation was achieved with the mobile phase consisted of methanol: acetonitrile and trifluoroacetic acid in the volume ratio of 90:10:0.1. The column temperature was maintained at 30°C and detection wavelength was maintained at 210 nm. Brivaracetum (BRV), and stereoisomeric impurities, BRV-SS, BRV-RR and BRV-RS, were eluted at 13.829, 11.810, 10.448 and 9.449 min, respectively. The method showed adequate specificity, sensitivity, linearity, accuracy, precision, and robustness inline to ICH tripartite guidelines. The limit of detections were 0.2 μg/mL for BRV-SS and BRV-RR, for BRV-RS it was found 0.1μg/mL.The limit of quantification limits were 0.5μg/mL for BRV-SS, BRV-RR and for BRV-RS as well.The developed method was found to be linear over the concentration range of 0.5-20µg/mL for BRV-RS, for BRV-RR and BRV-RS it was 0.5-3µg/mLfor stereoisomeric impurities with a correlation coefficient of 0.999. The developed method was found precise (%RSD = 0.5%, 0.6% and 0.5% for BRV-SS, BRV-RR and BRV-RS,) accurate (with 96%–107% recovery) and found robust. The validation parameters of the developed method were within the limits as per the regulation of ICH Q2(R1) guidelines. Therefore, in this present method a good separation was achieved specifically for the identification of brivaracetam and its processed related stereoisomeric impurities using high performance liquid chromatography and found suitable for the quantification of stereoisomeric impurities of brivaracetam in bulk scale as well.

A Robust and Scalable Process for the Synthesis of Substantially Pure Clarithromycin 9-(E)-Oxime with an Established Control of the (Z)-Isomer Impurity.

Controlling the isomeric impurity in a key raw material is always critical to achieve the corresponding pure isomer-free targeted active pharmaceutical ingredient (API) in downstream processing. Clarithromycin 9-(E)-oxime is the key raw material for the synthesis of the 9a-lactam macrolide, which is an interesting scaffold for the synthesis of several bioactive macrolides. Here demonstrated is a scalable process for the preparation of substantially pure clarithromycin 9-(E)-oxime, with less than 1.2% of the (Z)-isomer. The process does not involve a separate time-consuming purification by a crystallization operation to purge the undesired (Z)-oxime isomer. Further, the pure clarithromycin 9-(E)-oxime obtained was subjected to the Beckmann rearrangement, thereby converting it into the pure 9a-lactam scaffold. Additionally, a few other impurities were identified and controlled at each stage. The fine-tuned process was successfully up scaled to a multikilogram scale, enabling the large-scale manufacturing of potential APIs derived from this scaffold.

Identification and Characterization of the Isomeric Impurity of the Fungicide "Cyazofamid".

Identification and characterization of biproducts/ impurities present in agrochemicals are critical in view of their efficacy and safety towards public health. We herein present our study on identification and characterization of an impurity, 5-chloro-2-cyano-N,N-dimethyl-4-p-tolylimidazole-1-sulfonamide (2) present in the fungicide, "cyazofamid". Intermittent HPLC analysis of the reaction of substituted imidazole (1) with N,N-dimethylsulfamoyl chloride suggested that 2 is formed during the reaction. Isolation by preparative HPLC and characterization by NMR, LC/HRMS, MS/MS and single crystal XRD analysis confirmed 2 as an isomer of cyazofamid, wherein the N,N-dimethyl sulfonamide group was positioned on the other nitrogen of imidazole in close proximity to chloride group. Computational studies further supported the formation of 2 and ruled out the other possible isomeric structures.

Characterization of low-level D-amino acid isomeric impurities of Semaglutide using liquid chromatography-high resolution tandem mass spectrometry

Under the guideline issued by Food and Drug Administration (FDA), ANDAs for Certain Highly Purified Synthetic Peptide Drug Products That Refer to Listed Drugs of rDNA Origin Guidance for Industry, a synthetic Semaglutide that is intended to be a “generic” of the approved rDNA origin Semaglutide is under exploring. Thus, each peptide-related impurity that is 0.10% of the drug substance or greater need to be identified for Semaglutide covered by this guidance. Among others, characterization of the low-level D-amino acid (D form) isomeric impurities are always the most challenging ones. Reverse-phase high-performance liquid chromatography (RP-UPLC) was used to separate the impurities, followed by high resolution mass spectrometry (HRMS) to determine the molecular weight of the impurities that existed in both formulations. Following the targeted D form isomers off-line collection, the samples went through lyophilization, deuterated hydrochloric acid (D-HCl) hydrolyzation with low level D/L form shifting suppression substrates, chiral derivatization and RP-UPLC tandem mass spectrometry analysis of different amino acids by comparing with standards. Herein, we reported an accurate, straightforward characterization method with low limit of detection for the low-level D-Ser8, D-His1 and D-Asp9 Semaglutide impurities in Semaglutide formulations. The developed UPLC tandem HRMS method entails a valuable step forward in the detection of trace levels of the D-isomers of Semaglutide and other peptide products.

Validated quantitative 31P NMR spectroscopy for positional isomeric impurity determination in L-α-glycerylphosphorylcholine (L-α-GPC)

In this study a quantitative 31P nuclear magnetic resonance (31P NMR) spectroscopy method was described to determine positional isomeric impurity β-GPC in commercial products of L-α-GPC. The samples were dissolved in D2O and trimethyl phosphate (TMP) was selected as an internal calibrant. The measurements were performed on a Bruker 500 MHz spectrometer and the spectra were recorded under optimized process conditions. A good linear relationship was constructed for β-GPC in the range of 62.7–528.0 µg·mL−1, i.e. 0.03–0.25 % (w/w %, in relative to L-α-GPC) with a correlative coefficient of 0.9996. The limit of quantification (LOQ) and limit of detection (LOD) were 62.7 µg·mL−1 and 20.9 µg·mL−1 with signal to noise of 3 and 10, respectively. The spiked recoveries were in the range of 98.17–99.78 % with the relative standard deviation (RSD %) less than 1.0 %. Therefore, it could be supposed that the 31P NMR was a promising alternative method for sensitive determination of β-GPC for strict quality control of L-α-GPC.

Chiral LC method development: Stereo-selective separation, characterization, and determination of cabotegravir and related RS, RR, and SS isomeric impurities on coated cellulose-based chiral stationary phase by HILIC-LC and LC-MS

The first, sensitive, and rapid chiral method was developed for enatioseperations and determination of cabotegravir and its enantiomeric impurities by using HPLC and LC-MS. Cabotegravir is an antiretroviral medication used for the treatment of HIV/AIDS approved by the food and drugs administration (FDA) in the year 2021. The cabotegravir chiral separation was achieved on the coated cellulose-tris (4-chloro-3-methyl phenyl carbamate) (CHIRALCEL OX-3R) column in HILIC mode and the total run time is less than 15 min. The effects of mobile phase composition, elution mode, and percentage of organic modifier as well as the effect of mobile phase-additives and column temperature were investigated on selectivity, resolution, and peak symmetry. The mobile phase consisted of acetonitrile and water with 0.1% (v/v) addition of formic acid additive with the flow rate of 1 mLmin−1. UV detection was carried out at 220 nm. The calibration curves of cabotegravir and its enantiomers were linear over the concentration range of 0.04–1.125 µgmL−1. The limits of detection and quantification for cabotegravir and its enantiomer (RS isomer) were ≤ 0.02 and ≤ 0.06, and the RR and SS-isomers limits were ≤ 0.02 and 0.03 µgmL−1 respectively. It was demonstrated that the proposed method is selective, precise, and robust. Finally, the validated method was applied for the determination and identification of cabotegravir and its chiral enantiomers in the bulk drugs by using HPLC and LC-MS techniques.

Room-Temperature Phosphorescence of Pure Axially Chiral Bicarbazoles.

Ultralong room-temperature phosphorescence (RTP) is greatly important in a series of applications, but obtaining RTP from metal-free organic materials is still an enormous challenge due to the spin-forbidden nature of triplet excitons. Because of its electron-rich nature and easy derivatization, carbazole (Cz) is widely used to build organic RTP and thermally activated delayed fluorescence (TADF) materials. However, Liu et al. (Nat. Mater. 2021, 20, 175) recently demonstrated that the RTP of Cz is induced by charge traps of its isomeric impurity in commercial sources. Here, on the basis of the classical El-Sayed rule and the recently discovered intersystem crossing promotion principles (twisted structure and charge transfer), we designed and prepared highly pure (>99.9%) (R/S)-octahydro-binaphthyl-based bicarbazoles (BiCz) for high-performance RTP (ΦP = 23%; τp = 1.09 s). Interestingly, BiCz exhibited photoactivated TADF and RTP in isolated and aggregated states, respectively, and thus would be an efficient tool for rejuvenating Cz-based RTP.

Competition between ultralong organic phosphorescence and thermally activated delayed fluorescence in dichloro derivatives of 9-benzoylcarbazole.

Optoelectronic materials based on metal-free organic molecules represent a promising alternative to traditional inorganic devices. Significant attention has been devoted to the development of the third generation of OLEDs which are based on the temperature-activated delayed fluorescence (TADF) mechanism. In the last few years, several materials displaying ultra-long organic phosphorescence (UOP) have been designed using strategies such as crystal engineering and halogen functionalisation. Both TADF and UOP are controlled by the population of triplet states and the energy gaps between the singlet and triplet manifolds. In this paper, we explore the competition between TADF and UOP in the molecular crystals of three dichloro derivatives of 9H-carbazol-3-yl(phenyl)methanone. We investigate the excited state mechanisms in solution and the crystalline phase and address the effects of exciton transport and temperature on the rates of direct and reverse intersystem crossing under the Marcus-Levich-Jortner model. We also analyse how the presence of isomeric impurities and the stabilisation of charge transfer states affect these processes. Our simulations explain the different mechanisms observed for the three derivatives and highlight the role of intramolecular rotation and crystal packing in determining the energy gaps. This work contributes to a better understanding of the connection between chemical and crystalline structures that will enable the design of efficient materials.

Climate change risk to pheromone application in pest management.

Since of the first sex pheromone and the adoption of pheromone in pest management, the global pheromone market size has grown to reach USD 2.4 billion per year in 2019. This has enabled the development of environmentally friendly approaches that significantly reduce the application of pesticides. Recently, there have been reports of the failure of various commercial codlemone: (E,E)-8,10-dodecadien-1-ol formulations used for monitoring the apple pest codling moth, Cydia pomonella (L.). This work was initiated to investigate factors behind the lack of efficacy of codlemone lure in the Northern Hemisphere (Germany) and Southern Hemisphere (New Zealand). We hypothesised that the observed failure could be due to two main factors: (a) a shift in the response of male codling moth to codlemone and (b) degradation of codlemone under field conditions that renders the lure less attractive. Field trial tests of various doses and blends containing minor pheromone compounds suggested no change in response of male codling moth. The addition of an antioxidant and a UV stabiliser to codlemone resulted in a significant increase in the number of males caught in Germany, but not in New Zealand. Mean maximum temperatures during the growing season since 2004 indicate a 3°C increase to 35°C in Germany, but just a 1.5°C rise to 30°C in New Zealand. Chemical analysis of the lures used in the field trials in Germany and New Zealand indicated more degradation products and reduced half-life of the lures in Germany compared with those in New Zealand. Heating codlemone lures to 32°C significantly reduced the number of males caught in traps and increased the isomeric and chemical impurities of codlemone compared with unheated lures. Our data provide the first evidence that climate change affects pheromone molecule stability, thus reducing its biological efficacy. Our finding suggests that climate change could be a general problem for chemical communication and, therefore, could affect the integrity of natural ecosystems.

Extended porphyrinoid chromophores: heteroporphyrins fused to phenanthrene and acenaphthylene

Fusion of aromatic subunits onto porphyrin chromophores produces variable results and in some cases only minor bathochromic shifts are observed. In order to extend these observations, a series of oxa-, thia- and selenaporphyrins with fused acenaphthylene or phenanthrene units have been synthesized. Phenanthro[5,6-b]porphyrins were previously prepared via conventional ‘2 + 2’ MacDonald condensations, but a more versatile ‘3 + 1’ synthesis is now reported. Phenanthrotripyrranes reacted with a pyrrole dialdehyde in the presence of trifluoroacetic acid, followed by an oxidation step, to give phenanthroporphyrins. However, this chemistry initially gave products that were contaminated with isomeric impurities. Fortunately, good yields of isomerically pure phenanthroporphyrins were obtained when the reactions were carried out under relatively concentrated conditions, and a diphenanthroporphyrin was also obtained using this strategy. An alternative ‘3 + 1’ synthesis was performed where a phenanthropyrrole dialdehyde was condensed with a tripyrrane and this also afforded a phenanthroporphyrin in good yields. Furan, thiophene and selenophene dialdehydes similarly reacted with phenanthro- and acenaphthotripyrranes to give a series of heteroporphyrins with fused phenanthrene and acenaphthylene rings. All of these porphyrinoids retained highly diatropic characteristics. As is the case for tetrapyrrolic porphyrins, the presence of a fused acenaphthylene unit leads to highly modified UV–vis spectra with multiple Soret bands and relatively strong Q bands above 650 nm. However, the longest wavelength absorptions for the acenaphthylene series were only red shifted by 12–15 nm compared to the phenanthrene-fused heteroporphyrin series, which is a somewhat reduced effect compared to previously reported phenanthroporphyrins and acenaphthoporphyrins. Nevertheless, the combined effects of core modification and acenaphthylene ring fusion affords potentially valuable strongly red shifted absorption bands between 677 and 684 nm.