Towards the development of analytical monograph specifications for the quality assessment of the medicinal plant Phyllanthus urinaria.

Many people in developing countries rely on herbal remedies for their primary healthcare needs. The challenge however is that several of these products lack proper documentation of quality and safety. To ensure consistent quality, validated methods are needed to establish and control quality attributes associated with identity, purity, and levels of bioactive constituents of the respective herbal materials. The present study focused on Phyllanthus urinaria (PU), a widely used medicinal plant in Ghana and West Africa that lacks the necessary quality control standards. The study aimed to develop an HPTLC identification method, which together with UPLC-ESI-Q-TOF-MS/MS analysis established the identity of PU samples and differentiated PU from other closely related Phyllanthus species. Quantitative UPLC and HPTLC methods were developed to assess the contents of selected active markers in the PU samples, which invariably led to the proposal of acceptance criteria for the active markers. Prior to the content analyses, the sample extraction procedure was optimized through the use of Design of Experiment method. The effects of harvest time and geographic origin on the content of active compounds were demonstrated in the investigations. PU samples were also found to be contaminated with higher levels of pesticides like chlorpyrifos and folpet. Essentially, this study provides analytical protocols, insights into the quality status of PU samples in Ghana, and analytical specifications contained in a drafted monograph for future consideration in regional and subregional African pharmacopoeias.

Libkrylov: A modular open-source software library for extremely large on-the-fly matrix computations.

We present the design and implementation of libkrylov, an open-source library for solving matrix-free eigenvalue, linear, and shifted linear equations using Krylov subspace methods. The primary objectives of libkrylov are flexible API design and modular structure, which enables integration with specialized matrix-vector evaluation "engines." Libkrylov features pluggable preconditioning, orthonormalization, and tunable convergence control. Diagonal (conjugate gradient, CG), Davidson, and Jacobi-Davidson preconditioners are available, along with orthonormal and nonorthonormal (nKs) schemes. All functionality of libkrylov is exposed via Fortran and C application programming interfaces (APIs). We illustrate the performance of libkrylov for eigenvalue calculations arising in time-dependent density functional theory (TDDFT) in the Tamm-Dancoff approximation (TDA) and discuss the convergence behavior as a function of preconditioning and orthonormalization methods.

Bioequivalence studies of cetirizine tablets using the urine excretion data of healthy Ghanaian male volunteers.

Background: In the wake of economic challenges, the role of generic medicines has become crucial in meeting the healthcare needs of people. Their use, however, can only be guaranteed if established to be bioequivalent to their corresponding innovator products. Aim: In this study, we assess the suitability of a generic brand of cetirizine hydrochloride tablet to be used in place of the innovator brand on the Ghanaian market through bioequivalence assessment. Method: An HPLC bioanalytical method was developed and validated for the detection and quantitation of cetirizine in a urine matrix. This was then used to quantify the amount of cetirizine excreted unchanged in urine samples of 12 healthy male volunteers collected over a 24-h period using a two-way crossover design approach. Results: Chromatographic separation was successfully achieved with an isocratic elution on a reverse-phase column. The mean retention time for cetirizine was 2.890 ± 0.243 min. The mean cumulative amounts of cetirizine in the reference and test drugs excreted were 5.69 ± 0.98 mg and 5.82 ± 1.96 mg respectively. Other pharmacokinetic parameters including mean relative Areas Under Curve (AUC0-24) of 13.32 and 13.05 µg/mL, and peak Concentration (Cmax) of 3.378 and 3.043 µg/mL at the times at which Cmax was observed (Tmax) being 7.25 and 7.42 min were established respectively for the reference and test drugs. The relative bioavailability was determined to be 102.28, making the locally manufactured brand bioequivalent to the innovator brand. Conclusion: The locally manufactured test Cetirizine drug was found to be bioequivalent with the innovator brand and could serve as a suitable alternative to the latter. Additionally, relevant pharmacokinetic parameters for cetirizine has been established using urinary excretion data.

Development of an Analytical Workflow to Support the Establishment of Monographs in African Pharmacopoeias - Combretum mucronatum Leaves as Example.

Herbal medicines are invaluable in African medicine, but quality and safety are not documented in many cases. Besides controlled farming, validated quality control methods are needed to ensure identity, purity, and content. Analytical specifications within modern monographs are needed for consistent batch quality. Combretum mucronatum leaves are widely used in West Africa, but state-of-the-art quality control methods and specifications are non-existent. The aim of the following study was the development of ICH-validated chromatographic protocols for identity, purity, content assay, and analytical specifications for consideration into pharmacopoeial monographs. UPLC-ESI-Q-TOF-MS/MS was used for untargeted phytochemical information on composition. Optimisation of extraction was based on phytochemical profiling. HPTLC was used for differentiation of C. mucronatum from other Combretum species and UPLC for simultaneous determination of 7 marker compounds. C. mucronatum batch analyses (n = 49) investigated the influence of harvest time and geographical origin. Pesticides screening from a 349-compound panel were carried out. 30 compounds, identified by LC-MS, were used for characterization of the plant material. Orietin, isoorientin, vitexin and isovitexin were used as specific marker compounds for qualitative and quantitative HPTLC purposes, while UPLC quantified additionally epicatechin, procyanidins B2 and C1. Influence of harvest time and geographic origin on the content of marker compounds was observed. Differences in the metabolite profiles of C. mucronatum compared to related Combretum species were established for quality control purposes. Contamination with high amoounts of chlorpyrifos, and folpet (sum of folpet and phtalimide, expressed as folpet) were also observed.The study provides analytical protocols, analytical specifications and a drafted monograph for consideration for African pharmacopoeias, and reveals potential challenges in the quality of C. mucronatum.

Antimalarial Properties of Sida cordifolia L. Leaf Extract in Mice: Survivability Depends Less on Parasitaemia Suppression.

Sida cordifolia has been used to treat malaria in Ghana albeit without scientific evidence of antimalarial activity and safety. This work aimed to assess the antimalarial properties and acute toxicity of the aqueous leaf extract of S. cordifolia in murine models. Aqueous extract of the plant was analysed for both suppressive and curative antimalarial properties in chloroquine-sensitive ANKA strains of rodent Plasmodium berghei-infected mice. Acute toxicity evaluation was performed in rats according to the OECD 425 guidelines. The extract displayed antiplasmodial activity in vivo with ED50 of 117.49 ± 15.22 mg/kg and 144.84 ± 18.17 mg/kg in suppressive and curative studies, respectively. The highest % parasitaemia suppression exerted was 76.90 ± 0.64% and 61.50 ± 0.97%, respectively, in the suppressive and curative studies. Survival of infected mice treated with the extract was significantly prolonged. This was dependent on the dose of the extract but imperfectly related to the % parasitaemia suppression. Related antimalarial parameters including percentage hematocrit, changes in body weight, and temperature of experimental mice indicated alleviation of malarial symptoms of treated animals. The extract did not show toxicity in rats. Sida cordifolia L. has antimalarial properties, and was safe. It suppressed parasitaemia in both suppressive and curative studies, was not toxic to animals and prolonged the life of infected animals under treatment. This, therefore, justifies the traditional use of S. cordifolia for the treatment of malaria in Ghana.

Quality assessment of African herbal medicine: A systematic review and the way forward.

BACKGROUND: In Africa, herbalism supplements allopathic medicine's efforts to ensure Universal Health Coverage attainment. This review was conducted to identify and to summarise current literature on methodological approaches used for quality control of herbal medicines in Africa, to evaluate the gaps associated with existing strategies within context of best practices, and make recommendations for future improvements. METHODS: A systematic search was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Articles were screened and assessed for eligibility. RESULTS: 118 articles were included into the study. There was a high preference for impurity profiling tests (77%) indicating the prioritization for tests that guarantee safety despite the limited analytical resources available. Other classes of tests reported included identification tests (29%), physicochemical tests (18%), and content assays (12%). Although standard methods exist in preparing samples for impurity tests, different techniques were observed in different studies, and this could lead to differences in analytical outcomes. Content assays focused on single marker assessments, which may be inadequate to comprehensively assess the quality of products. CONCLUSION: This review provides knowledge of existing strengths and challenges for herbal medicine quality assessments in Africa. For future it is recommended to implement more studies on contaminants (e.g. mycotoxins) and pharmaceutical adulterants. The use of chemometrics to develop analytical methods should be promoted. Also, stakeholders in the medicine quality industry in Africa need to effectively collaborate to establish a well co-ordinated and harmonized system to provide a sustainable framework for the GACP and GMP guided production and quality assurance of herbal medicines.

The Unethical Use of Paracetamol As a Food Tenderizer in Four Selected African Countries: A Major Public Health Concern?

Paracetamol poisoning is the commonest cause of acute liver injury. Therefore, the unethical use of paracetamol as a food tenderizer poses a threat to human health. Although this is a common practice in Ghana, Uganda, Nigeria, and Kenya, there are few or no scientific records on the use of paracetamol as a food tenderizer and its deleterious effects, thus making it difficult to regulate this practice. This review aims to fully collate and present a systematic overview of the literature on the use of paracetamol as a food tenderizer in these countries, the potentially harmful effects posed by the practice, and measures in place to curb the situation. Additionally, this review aims to reveal the scientific gaps and areas requiring more research, thus providing a reference for further research to regulate this unscrupulous practice. From our extensive review of the literature, the high cost of fuel used in cooking and longer cooking times are the main reasons for the inappropriate use of paracetamol as a food tenderizer. Also, this review concludes that little has been done to create public awareness of this unethical practice. Furthermore, few ways to monitor, control and regulate this practice have been proposed.

Reservoir of Antibiotic Residues and Resistant Coagulase Negative Staphylococci in a Healthy Population in the Greater Accra Region, Ghana.

Antimicrobial resistance threatens infectious disease management outcomes, especially in developing countries. In this study, the occurrence of resistant coagulase-negative staphylococci (rCoNS) and antibiotic residues in urine samples of 401 healthy individuals from Korle-Gonno (KG) and Dodowa (DDW) in Ghana was investigated. MALDI-ToF/MS with gram-staining techniques detected and identified the CoNS. SPE-LC-MS/MS detected and quantified nine commonly used antibiotics in the samples. The results showed 63 CoNS isolates detected in 47 (12%) samples, with S. haemolyticus (78%) and S. epidermidis (8%) being predominant. Most of the isolates (95%) were resistant to at least one antibiotic, with the highest resistance observed against sulphamethoxazole (87%). Resistance profiles in samples from DDW and KG were largely comparable, but with some differences. For instance, DDW isolates were more resistant to gentamicin (p = 0.0244), trimethoprim (p = 0.0045), and cefoxitin (p = 0.0078), whereas KG isolates were more resistant to erythromycin (p = 0.0356). Although the volunteers had not knowingly consumed antibiotics two weeks before sampling, antibiotic residues, ranging between 1.44-17000 ng mL-1 were identified in 22% of urine samples. Samples with antibiotic residues were likely to also contain rCoNS (89%). The most frequent antibiotics detected were tetracycline (63%) and ciprofloxacin (54%). Healthy individuals could thus be reservoirs of antibiotic residues and rCoNS at the community level.

2.2.2-Cryptand complexes of neptunium(III) and plutonium(III).

New coordination environments are reported for Np(III) and Pu(III) based on pilot studies of U(III) in 2.2.2-cryptand (crypt). The U(III)-in-crypt complex, [U(crypt)I2][I], obtained from the reaction between UI3 and crypt, is treated with Me3SiOTf (OTf = O3SCF3) in benzene to form the [U(crypt)(OTf)2][OTf] complex. Similarly, the isomorphous Np(III) and Pu(III) complexes were obtained similarly starting from [AnI3(THF)4]. All three complexes (1-An; An = U, Np, Pu) contain an encapsulated actinide in a THF-soluble complex. Absorption spectroscopy and DFT calculations are consistent with 5f3 U(III), 5f4 Np(III), and 5f5 Pu(III) electron configurations.

Anthelmintic Agents from African Medicinal Plants: Review and Prospects.

Soil-transmitted helminthiasis affects more than 1.5 billion people globally and largely remains a sanitary problem in Africa. These infections place a huge economic burden on poor countries and affect livestock production, causing substantial economic losses and poor animal health. The emergence of anthelmintic resistance, especially in livestock, and the potential for its widespread in humans create a need for the development of alternative therapies. Medicinal plants play a significant role in the management of parasitic diseases in humans and livestock, especially in Africa. This report reviews anthelmintic studies that have been conducted on medicinal plants growing in Africa and published within the past two decades. A search was made in various electronic databases, and only full articles in English were included in the review. Reports show that aqueous and hydroalcoholic extracts and polar fractions obtained from these crude extracts form the predominant (80%) form of the extracts studied. Medicinal plants, extracts, and compounds with different chemical groups have been studied for their anthelmintic potential. Polyphenols and terpenoids are the most reported groups. More than 64% of the studies employed in vitro assays against parasitic and nonparasitic nematode models. Egg hatch inhibition, larval migration inhibition, and paralysis are the common parameters assessed in vitro. About 72% of in vivo models involved small ruminants, 15% rodents, and 5% chicken. Egg and worm burden are the main factors assessed in vivo. There were no reports on interventions in humans cited within the period under consideration. Also, few reports have investigated the potential of combining plant extracts with common anthelmintic drugs. This review reveals the huge potential of African medicinal plants as sources of anthelmintic agents and the dire need for in-depth clinical studies of extracts, fractions, and compounds from African plants as anthelmintic agents in livestock, companion animals, and humans.

Fruits of Vitex doniana sweet: toxicity profile, anti-inflammatory and antioxidant activities, and quantification of one of its bioactive constituents oleanolic acid.

BACKGROUND: Vitex doniana Sweet fruit, an under-utilised crop specie of Ghana, has not been validated for its ethnomedical use in managing inflammatory conditions. Therefore, the study sought to investigate its anti-inflammatory and antioxidant activities as well as isolate and quantify one of its active constituents. MATERIALS AND METHODS: In-vivo anti-inflammatory activity of the methanol fruit extract was evaluated using the carrageenan-induced oedema model in chicks. The in-vitro antioxidant property was also investigated using the 2, 2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay. The acute and subacute toxicity studies of the fruit extract were evaluated in rodent models. RESULTS: No signs of autonomic and central nervous system stimulation/depression were recorded. The LD50 by oral route, was estimated to be beyond 3000 mg/kg. Subacute studies revealed an increase in red blood cell and lymphocyte counts. Liver enzymes, serum proteins and bilirubin levels did not significantly increase. The crude extracts at doses of 10, 30 and 100 mg/kg inhibited paw oedema considerably. The ethyl acetate fraction showed the highest antioxidant activity (IC50 = 99.35 ± 0.77 µg/mL). Oleanolic acid, isolated from the ethyl acetate extract, showed significant anti-inflammatory and antioxidant activities. A sensitive high-performance liquid chromatography method for the detection and estimation of oleanolic acid, as a biomarker compound for V. doniana fruit, was developed and validated for quality assurance purposes. CONCLUSION: The extract of V. doniana fruits possesses considerable anti-inflammatory and antioxidant properties and was non-toxic under laboratory conditions.

Antimalarial Property and Acute Toxicity of the Leaves of Theobroma cacao L.

The leaf of Theobroma cacao L. is used in traditional medicine in Ghana for the treatment of malaria, yet, with no scientific evidence of its antimalarial property in animals. It was, therefore, studied to validate the antimalarial property in Plasmodium berghei-infected mice. Infected mice were treated with an aqueous extract of T. cacao leaf at different doses of 100, 200, and 400 mg/kg daily for four days. Parasitaemia was determined before treatment and 24 hours following the last dose of extract. The % reduction in parasitaemia and ED50 and ED90 of the extract were determined. Body weight, rectal temperature, and daily mortality of mice were also recorded. The extract had ED50 and ED90 of 242.20 ± 29.38 and 351.00 ± 29.52 mg/kg/day, respectively. Percentage parasitaemia suppression was significant for all doses. The extract at the maximum dose of 400 mg/kg body weight had the highest % parasitaemia suppression of 79.19%; mean survival time of 24.00 ± 2.19 days and median survival of 23 days; body weight increase of 3.82 ± 0.59; and the lowest body temperature reduction of 0.79 ± 0.11°C. T. cacao leaf extract showed an antimalarial property in P. berghei-infected mice. This reinforces the justification for the use of the plant material in treating malaria in Ghana.

Monitoring and risk assessment of pesticide residues in selected herbal medicinal products in Ghana.

The high patronage of herbal medicinal products in Ghana for the treatment of diverse disease conditions raises concerns about patient safety, given that much of the raw materials for production are obtained from the wild or farmlands potentially exposed to varied agrochemical residues. Therefore, the work sought to investigate the contamination of herbal medicinal products with pesticide residues and assess the potential risk posed to patients. As a result, validated gas chromatography with mass spectrometry as a detector was used to determine forty-two pesticides in thirty herbal medicinal products. The performance parameters of the method such as linearity, accuracy, and precision were found as acceptable. Pesticide residues such as chlorpyrifos and/or bifenthrin were found in 4/30 herbal medicinal products. Specifically, 3/30 herbal medicinal products contained only one pesticide, while 1/30 was contaminated with both pesticide residues. The levels of pesticide residue contamination ranged between 2.5 and 5.0 µg/kg. The acute hazard quotient and chronic hazard quotient for the two pesticide residues were evaluated and ranged between 0.21 and 0.92% and between 8.21 × 10-4 and 5.88 × 10-3%. The detected pesticide residue levels are below the maximum residue limit values, which may not cause acute and chronic health risks due to intake of the selected herbal medicinal product. Nevertheless, patient safety and potential public health risk can be reduced by regular monitoring, and regulation of pesticide residue levels in herbal medicinal products.

Exposure of consumers to substandard antibiotics from selected authorised and unauthorised medicine sales outlets in Ghana.

OBJECTIVE: To assess the quality of antibiotics sampled from authorised sales outlets (ATs) (i.e. hospitals/health centres, pharmacies and licensed chemical shops) and unauthorised sales outlets (UATs) (mainly street vendors) in Ghana and to explore the health-seeking behaviour of medicine consumers. METHODS: The contents of 14 active pharmaceutical ingredients (APIs) in 348 sampled products were determined using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Data on health-seeking practices were collected through entry and exit interviews and field observations from ATs and UATs. RESULTS: It was observed that 66.38% of all sampled antibiotic products were substandard; they either contained less (<90%) or more API (>110%) than the label claim. Medicines from UATs recorded substantially less API contents than those from ATs (F(2,419)  = 43.01, P < 0.0001). For example, 90.54% of street vendor samples contained < 90% of the APIs. 75.93% of consumers often sought self-treatment with drugs without a prescription from UATs, as they perceived UATs as easily accessible, trustworthy and knowledgeable, and their medicines as inexpensive. These consumers rather thought of the formal healthcare providers as alternative sources. CONCLUSIONS: Consumers who purchase from UATs are at high risk of receiving substandard medicines. The quality of medicines in the national healthcare system, in the supply chain and in the distribution system needs to be monitored regularly to reduce the incidence of substandard medicines and their impact on antimicrobial resistance. The fight against substandard medicines needs to incorporate a full understanding of socioeconomic factors that drive consumer decisions regarding their health and choice of healthcare providers.

OBJECTIF: Evaluer la qualité des antibiotiques prélevés auprès des vendeurs autorisés (VA) (c'est-à-dire les hôpitaux/centres de santé, les pharmacies et les magasins de produits chimiques agréés) et des vendeurs non autorisés (VNA) (principalement les vendeurs de rue) au Ghana et étudier le comportement des utilisateurs de médicaments en quête de santé. MÉTHODES: Le contenu de 14 principes actifs (PA) pharmaceutiques dans 348 produits échantillonnés a été déterminé à l'aide d'une méthode validée de chromatographie liquide et de spectrométrie de masse en tandem (LC-MS/MS). Les données sur les pratiques de recherche de santé ont été collectées par le biais d'entretiens d'entrée et de sortie, et d'observations sur le terrain des VA et des VNA. RÉSULTATS: Il a été observé que 66,38% de tous les produits antibiotiques échantillonnés étaient inférieurs aux normes; ils contenaient soit moins (<90%), soit plus de PA (>110%) que ce qui était indiqué sur la notice. Les médicaments provenant des VNA ont enregistré une quantité de PA sensiblement inférieure à celle des VA (F(2,419)  = 43.01, P < 0,0001). Par exemple, 90,54% des échantillons de vendeurs de rue contenaient <90% de PA. 75,93% des utilisateurs ont souvent cherché à se soigner eux-mêmes avec des médicaments sans ordonnance des VNA, car ils ont perçu les VNA comme étant facilement accessibles, fiables et bien informés, et leurs médicaments comme étant peu coûteux. Ces utilisateurs considéraient également les prestataires de soins de santé officiels comme des sources alternatives. CONCLUSIONS: Les utilisateurs qui s'approvisionnent auprès des VNA courent un risque élevé de recevoir des médicaments de qualité inférieure. La qualité des médicaments dans le système national de santé, dans la chaîne d'approvisionnement et dans le système de distribution doit être contrôlée régulièrement pour réduire l'incidence des médicaments de qualité inférieure et leur impact sur la résistance aux antimicrobiens. La lutte contre les médicaments de qualité inférieure doit intégrer une compréhension complète des facteurs socioéconomiques qui déterminent les décisions des utilisateurs concernant leur santé et le choix des prestataires de soins de santé.

Synthesis of LnII -in-Cryptand Complexes by Chemical Reduction of LnIII -in-Cryptand Precursors: Isolation of a NdII -in-Cryptand Complex.

Lanthanide triflates have been used to incorporate NdIII and SmIII ions into the 2.2.2-cryptand ligand (crypt) to explore their reductive chemistry. The Ln(OTf)3 complexes (Ln=Nd, Sm; OTf=SO3 CF3 ) react with crypt in THF to form the THF-soluble complexes [LnIII (crypt)(OTf)2 ][OTf] with two triflates bound to the metal encapsulated in the crypt. Reduction of these LnIII -in-crypt complexes using KC8 in THF forms the neutral LnII -in-crypt triflate complexes [LnII (crypt)(OTf)2 ]. DFT calculations on [NdII (crypt)]2+ ], the first NdII cryptand complex, assign a 4f4 electron configuration to this ion.

MALDI-HRMS imaging and HPLC-HRESI-MSn characterisation of kaurane diterpenes in the fruits of Xylopia aethiopica (Dunal) A. Rich (Annonaceae).

INTRODUCTION: Kaurane diterpenes, notably xylopic acid, have demonstrated important biological activities including analgesia, anti-oxidant, antimicrobial and cytotoxicity. The fruits of Xylopia aethiopica have been reported to be a rich source of kaurane diterpenes. OBJECTIVE: An analytical approach for detailed imaging and characterisation of selected kaurane diterpenes was developed using matrix-assisted laser desorption/ionisation high-resolution mass spectrometry (MALDI-HRMS) imaging techniques and high-performance liquid chromatography-high resolution electrospray ionisation-tandem mass spectrometry (HPLC-HRESI-MSn ) studies, respectively. METHODS: The images of the compounds were constructed based on selected ions from their HRESI-MS spectra. The matrix employed comprised a solution of α-cyano-4-hydroxycinnamic acid (HCCA) in acetonitrile-water with trifluoroacetic acid (TFA). HPLC-HRESI-MSn measurements were conducted on an LTQ-Orbitrap spectrometer equipped with a heated electrospray ionisation (HESI)-II source. RESULTS: The analytical strategy adopted showed the spatial distribution of the compounds in the fruits of X. aethiopica based on the dominant ions at m/z 301.2163 [M + H - HOCOCH3 ]+ and m/z 399.1932 [M + K]+ for xylopic acid, m/z 317.2111 [M + H]+ and m/z 355.1670 [M + K]+ for 15-oxo-ent-kaur-16-en-19-oic acid and m/z 303.2319 [M + H]+ for ent-kaur-16-en-19-oic acid. The fragmentation patterns of the compounds were proposed based on the HRESI-MSn measurements. CONCLUSIONS: The study revealed the spatial variability, differential behaviours and specificity of the selected kaurane diterpenes in the fruit, seed and pericarp. The compounds under study were predominantly restricted to the pericarp of the fruit with trace amounts in the seed.

In search of tris(trimethylsilylcyclopentadienyl) thorium.

Reduction of Cp'3ThCl, Cp'3ThBr, and Cp'3ThI (Cp' = C5H4SiMe3) with potassium graphite generates dark blue solutions with reactivity and spectroscopic properties consistent with the formation of Cp'3Th. The EPR and UV-visible spectra of the solutions are similar to those of crystallographically-characterized tris(cyclopentadienyl) Th(iii) complexes: [C5H3(SiMe3)2]3Th, (C5Me4H)3Th, (C5tBu2H3)3Th, and (C5Me5)3Th. Density functional theory (DFT) analysis indicates that the UV-visible spectrum is consistent with Cp'3Th and not [Cp'3ThBr]1-. Although single crystals of Cp'3Th have not been isolated, the blue solution reacts with Me3SiCl, I2, and HC[triple bond, length as m-dash]CPh to afford products expected from Cp'3Th, namely, Cp'3ThCl, Cp'3ThI, and Cp'3Th(C[triple bond, length as m-dash]CPh), respectively. Reactions with MeI give mixtures of Cp'3ThI and Cp'3ThMe. Evidence for further reduction of the blue solutions to a Cp'-ligated Th(ii) complex has not been observed. The crystal structures of Cp'3ThMe and (Cp'3Th)2(µ-O) were also determined as part of these studies.

Density functional theory studies on the generation of trimethylenemethanes from the ring opening of dialkoxymethylenecyclopropanes and methylenecyclopropanethioacetals and follow-up reactions.

This work reports a detailed DFT study on the generation of trimethylenemethanes (TMMs) from the ring opening of dialkoxymethylenecyclopropane (DMCP), methylenecyclopropanethioacetal (MCPT), and substituted derivatives of DMCP and MCPT, as well as follow-up reactions of the TMMs. The singlet DMCP and MCPT were found to be 51.32 and 53.77 kcal mol-1 more stable than the triplet DMCP and MCPT respectively, corresponding to triplet:singlet population ratios of 1:1038 and 1:1040, respectively, at 25 °C using Boltzmann distribution, implying that the proportion of the triplet species is negligible at 25 °C. The ring-opening reactions occur through singlet transition states with barriers of 40.68 and 42.27 kcal mol-1 for DMCP and MCPT, respectively, and yield TMMs that are very unstable compared to the precursors, with the triplet TMM being far more stable than the singlet. Whereas the singlet TMMs readily undergo cycloaddition reactions with olefins to form five-membered carbocyclic rings, the triplet species do not. The selectivity of the reactions of the DMCP TMMs is very sensitive to temperature; at 25°C, cycloaddition with olefins and ring-closure to form ketenes have very comparable barriers while temperatures above 150 °C favor the exclusive formation of a ketene followed by dimerization. In MCPT, ring closure to form ketenes is the favored reaction at all temperatures studied. Pathways for the generation of trimethylenemethanes from their precursors and follow-up reactions.

Novel HPLC Analysis of Hydrocortisone in Conventional and Controlled-Release Pharmaceutical Preparations.

An isocratic sensitive and precise reverse phase high-performance liquid chromatography (RP-HPLC) method was developed and validated for the determination and quantification of hydrocortisone in controlled-release and conventional (tablets and injections) pharmaceutical preparations. Chromatographic separation was achieved on an ODS (C18), 5 µm, 4.6 × 150 mm, with an isocratic elution using a freshly prepared mobile phase of composition methanol : water : acetic acid (60 : 30 : 10, v/v/v) at a flow rate of 1.0 ml/min. The detection of the drug was successfully achieved at a wavelength of 254 nm. The retention time obtained for the drug was 2.26 min. The proposed method produced linear detectable responses in the concentration range of 0.02 to 0.4 mg/ml of hydrocortisone. High recoveries of 98-101% were attained at concentration levels of 80%, 100%, and 120%. The intraday and interday precision (RSD) were 0.19-0.55% and 0.33-0.71%, respectively. A comparison of hydrocortisone analyses data from the developed method and the official USP method showed no significant difference (p > 0.05) at a 95% confidence interval. The method was successfully applied to the determination and quantification of hydrocortisone in six controlled-release and fifteen conventional release pharmaceutical preparations.

In Vitro Evaluation of Cocoa Pod Husk Pectin as a Carrier for Chronodelivery of Hydrocortisone Intended for Adrenal Insufficiency.

This study evaluated the in vitro potential of cocoa pod husk (CPH) pectin as a carrier for chronodelivery of hydrocortisone intended for adrenal insufficiency. FTIR studies found no drug-CPH pectin interactions, and chemometric analysis showed that pure hydrocortisone bears closer similarity to hydrocortisone in hot water soluble pectin (HWSP) than hydrocortisone in citric acid soluble pectin (CASP). CPH pectin-based hydrocortisone matrix tablets (~300 mg) were prepared by direct compression and wet granulation techniques, and the tablet cores were film-coated with a 15% HPMC formulation for timed release, followed by a 12.5% Eudragit® S100 formulation for acid resistance. In vitro drug release studies of the uncoated and coated matrix tablets in simulated gastrointestinal conditions showed that wet granulation tablets exhibit greater retardation of drug release in aqueous medium than directly compressed tablets. CASP showed greater suppression of drug release in aqueous medium than HWSP. Wet granulation HWSP-based matrix tablets coated to a final coat weight gain of ~25% w/w were optimized for chronodelivery of hydrocortisone in the colon. The optimized tablets exhibited a lag phase of ~6 h followed by accelerated drug release in the colonic region and have potential to control night time cortisol levels in patients with adrenal insufficiency.