Utility of native emission quenching of erythrosine B for the determination of diltiazem in different dosage forms.

This study introduces a practical and cost-effective method for tracking diltiazem (DLZ) analytically. It utilizes a fluorimetric approach that relies on the modulation of fluorescence intensity of a dye called erythrosine B. Through a one-pot experiment performed in an acidic environment, a complex is rapidly formed between DLZ and erythrosine B. By observing the decrease in erythrosine B emission, a linear calibration plot is established, enabling the detection and quantification of DLZ concentrations ranging from 40 to 850 ng/ml. The estimated limits of detection and quantitation were 10.5 and 32.1 ng/ml, respectively. The variables affecting the DLZ-dye complex system were carefully adjusted. The validity of the approach was confirmed through a thorough evaluation based on the criteria set by ICH guidelines. The accuracy and precision of the methodology were evaluated, and the standard deviation and relative standard deviation were below 2. The strategy was successfully employed to analyze DLZ in tablets and capsules, and no significant variation between the proposed and reported methods as the values of the estimated t-test and F-test at five determinations were below 2.306 and 6.338, respectively. Notably, the method adheres to the principle of green chemistry by utilizing distilled water as the dispersing medium.

Optimization of Diltiazem hydrochloride osmotic formulation using QBD approach

Abstract Diltiazem hydrochloride (DLH) is a calcium channel blocker useful for the treatment of angina pectoris, arrhythmia, and hypertension. DLH having a short half-life needs frequent administration for successful treatment but this poses a problem of poor patient compliance. These requirements are served by elementary osmotic pump tablets (EOP) based controlled-release (CR) systems. Quality by design (QbD) approach assists in screening various factors with subsequent assessment of critical parameters that can have a major impact on the scalability of EOP. Tablets were formulated using wet granulation method followed by osmotic coating. Factorial design based QbD strategy aided in defining the risk assessment of influential variables such as hydrophilic polymers and osmotic coat component on the in-vitro release kinetics of the designed EOP tablets. These formulated EOP systems followed zero-order kinetics, a characteristic feature of EOPs. EOP tablets were formulated applying a systematic QbD statistical approach. The formulated DLH EOP systems with improved concentration-independent behavior helped to address the challenges of IR formulation. Application of QbD strategy in ascertaining the scalability of DLH EOP formulation would help pharmaceutical industries in the translation of EOP based drug delivery systems from R&D to market.

Green fabrication of 3D hierarchical blossom-like hybrid of peeled montmorillonite-ZnO for in-vitro electrochemical sensing of diltiazem hydrochloride drug.

Herein, a 3D hierarchical blossom-like of Montmorillonite-ZnO (MMt/ZnO) micro-hybrids modified sensors have been successfully fabricated as an extraordinarily electrochemical sensor for detecting of the Diltiazem hydrochloride (DZM.HCl). The 3D hierarchical blossom-like of ZnO and series of MMt/ZnO hybrids have been synthesized using different contents of MMt [FMZ1-5] via a hydrogel polymer template method using alginate ions. The effect of incorporation of different contents of MMt on the morphology, surface area of hybrids were investigated using Fourier transform infrared (FTIR), X-ray diffraction (XRD), Field emission scanning electron microscopy (FE-SEM), Energy-dispersive X-ray spectroscopy (EDS), Brunauer-Emmett-Teller (BET) surface area method, and High-resolution transmission electron microscopy (HR-TEM). The obtained hybrid [FMZ3] with 2.0% of MMt presented the most perfect blossom-like morphology and the highest surface area (190.06 m2/g) with the lowest resistivity. The hierarchical structure of [FMZ3] reveals nanospheres of ZnO with an average diameter of 5.49 nm, which are assembled into nanorods followed by assembling to form a blossom-like shape with the inclusion of MMt peeled layers inside the rod with d-spacing ranges from 1.1-7.4 nm. Meanwhile, the implemented modified sensor 1.0% [FMZ3] CPS retained excellent conductivity and electrocatalytic activity as appraised from the cyclic voltammetry (CV) measurements. Consequently, the electrochemical behavior and the oxidation mechanism of DZM.HCl drug has been investigated at the surface of the constructed sensor. Under the optimum operational conditions, the proposed sensor was successfully achieved detection limits 0.177, and 0.21 nmol·L-1 of DZM.HCl in a commercial and human biological fluid (Serum samples), respectively. The constructed sensor accomplished an appropriate accuracy and free of obstruction from other ordinarily drug excipients.

A QCM-based assay of drug content in Eudragit RS 100-based delivery systems.

A specific version of the quartz crystal microbalance method has been proposed for quantitative evaluation of drug content in polymeric drug carrier systems. In this study, ammonio methacrylate copolymer (type B) microparticles and their standard solutions have been prepared and loaded with set amounts of the medications diltiazem (base) and lidocaine. The analytes have been segregatim deposited on the surface of the resonator and the drug content in them has been derived from the downshift of the resonance frequency produced by irreversible interaction of the drug molecules with irradiating hydrochloric gas. The obtained results have been statistically processed on a number of samples and have been found to exhibit excellent coherence to set theoretical values. As an alternative, the conventional pharmacopoeial UV-Vis spectral method has also been separately applied to studied samples, revealing worsened performance in the case of lidocaine due to polymer matrix interference. Thus the universality of the QCM method has been proved to add to its versatility and precision. The method appears to be readily applicable to the routine pharmaceutical quantity control of bulk and multiparticulate drug forms.

Analysis of cocaine adulterants in human brain in cases of drug-related death.

For different reasons, street cocaine is often diluted with pharmacologically active substances, the so-called adulterants such as levamisole or hydroxyzine. A controversial debate exists currently on the uptake of adulterants from cocaine preparations and drug-related death. Previous research convincingly argues that serious adverse side effects that affect the central nervous and cardiovascular systems can be a consequence of adulterated cocaine. AIMS: Having identified the presence of adulterants in lung tissue and blood, the concentrations of these substances in brain, an important target location, was of interest. This provides an opportunity to assess their role in cases of drug-related deaths. MATERIALS AND METHODS: We developed and validated a method for the analysis of cocaine, two cocaine metabolites and six adulterants, which can typically be found in cocaine preparations, and one adulterant metabolite in brain tissue by gas chromatography-mass spectrometry (GC-MS)1. Ten brain samples which were tested positive for cocaine were analyzed. The homogenized brain tissue was embedded into drying paper for protein precipitation. During a subsequent solid-phase extraction (SPE), the eluate and one of the wash fractions were collected. After derivatization with N-Methyl-N-(trimethylsilyl)trifluoroacetamide (MSTFA) in pyridine and isooctane, the extracts were analyzed by GC-MS. RESULTS AND DISCUSSION: The method was fully validated for cocaine (COC), benzoylecgonine (BZE), ecgonine methyl ester (EME), diltiazem (DIL), hydroxyzine (HYD), and levamisole (LEV) and partly validated for cetirizine (CET), lidocaine (LID), phenacetin (PHE), and procaine (PRO) in brain material. By analyzing post-mortem brain tissue of ten cocaine users, LEV, LID, and HYD as well as PHE were identified in contrast to DIL, PRO, and the HYD metabolite CET. HYD and LEV were found in moderate to high concentrations in some cases. Therefore, it cannot be excluded that they have caused adverse side effects. CONCLUSION: Because adulterants can potentially affect the central nervous and cardiac systems, it is likely that they enhance COC toxicity.

[The chemico-toxicological determination of dilthiasem].

The objective of the present study was to determine the optimal conditions for isolation of dilthiasem, its purification by the combination of the extraction and column chromatography techniques, and the development of the universal method for the detection of this compound in the biological material. Other research methods included thin layer chromatography (TLC), gas chromatography mass-spectrometry (GH-MS), extraction, low-pressure column chromatography, and spectrophotometry. The effectiveness of dilthiasem isolation from the biological material with the use of 12 organic substances, water, and aqueous solutions was compared. The use of acetone as the universal solvent for dilthiasem isolation from the tissues and biological fluids of the cadaveric organs was substantiated. It was shown that dilthiasem can be purified from endogenous substances contained in the biological materials by means of combined liquid-liquid extraction and chromatography on the 30 mcm Silasorb C-18 column. The new modifications of thin layer chromatography and gas chromatography mass-spectrometry (GH-MS) are proposed for the identification and quantitative determination of dilthiasem isolated from cadaveric blood and hepatic tissue.

Drug-related death: adulterants from cocaine preparations in lung tissue and blood.

The abuse of drugs such as street cocaine is known to cause a variety of toxic effects, some of which involve the lungs and often induce lethal complications. While the toxicity of cocaine itself is reviewed well, the influence of toxic effects of its adulterants on the human body is not thoroughly studied. Therefore, we examined heart blood, femoral vein blood and lung tissue from 11 cases for typically used adulterants in cocaine preparations and check whether if the concentrations in the lung tissue are higher than in the blood. The adulterants were isolated using solid-phase (SPE) and liquid-liquid extraction (LLE) and quantified via high-pressure-liquid-chromatography-time-of-flight-mass spectrometry (LC/TOF-MS). Five adulterants, i.e., phenacetin, lidocaine, diltiazem, levamisole and hydroxyzine, were detected. We found out that the concentration of these substances was often higher in the lung than in the analogous analysed body fluids. It should therefore be considered whether - for the determination in the cause of death - the lung should be examined in addition to heart blood, urine or brain tissue.

Removal of endocrine disrupting compounds in a lab-scale anaerobic/aerobic sequencing batch reactor unit.

The fate and removal of six selected endocrine disrupting compounds in a lab-scale anaerobic/aerobic (A/O) sequencing batch reactor (SBR), operating at 5 days, solids retention time (SRT) were investigated. A carbamazepine (CBZ), acetaminophen (ATP), diltiazem (DTZ), butyl benzyl phthalate (BBP), estrone and progesterone mix was spiked as model endocrine disrupting compounds (EDC) into domestic wastewater obtained from a nearby sewage treatment plant. The influent, effluent and sludge samples from the SBR unit were analysed by using an LC/MS/MS instrument equipped with electrospray ionization. More than 80% removal was observed for all the EDCs tested. It was found that biodegradation is the most important mechanism for BBP, ATP and progesterone. Biodegradation constants were calculated according to the simplified Monod model for these compounds. The DTZ seemed to have lower rate of biodegradation. The CBZ appeared totally resistant to biodegradation. However, it presented a high rate of sorption onto the sludge and was thereby treated. This contradicts with the literature studies.

Pharmacokinetics of diltiazem hydrochloride delay-onset sustained-release pellet capsules in healthy volunteers

The pharmacokinetics (PK) of ordinary tablets and sustained release capsules of diltiazem hydrochloride in human clinical trials had been studied. The PK of diltiazem hydrochloride delay-onset sustained-release pellet capsules, a new dosage form, has not been reported, although it is very important to clinical use. In this paper, we investigated the PK of diltiazem hydrochloride delay-onset sustained-release pellet capsules and the food influence in Chinese healthy volunteers. The PK parameters indicated that the diltiazem hydrochloride delay-onset sustained-release pellet capsules appeared marked characteristics of delayed and controlled release. An opened-label, randomized and parallel clinical trial was conducted in 36 Chinese healthy volunteers with single oral dose (90 mg, 180 mg or 270 mg) and a multiple oral dose (90 mg d-1×6 d) administration. The effect of food on the PK of one single oral dose (360 mg) was investigated in 24 healthy Chinese volunteers. Plasma diltiazem concentration was determined by reversed-phase high-performance liquid chromatography (RP-HPLC) and the main pharmacokinetic parameters were analyzed by PKSolver (Ver 2.0). All clinical studies were conducted in the Clinical Pharmacological Center (No. JDX1999064) of Xiangya Hospital Affiliated Central South University, China. The PK parameters suggested that the new formulation had marked characteristics of delayed and controlled release of diltiazem, and food intake did not alter significantly diltiazem pharmacokinetic parameters.

Embora a farmacocinética (PK) do cloridrato de diltiazem nas formas de comprimidos de liberação imediata e cápsulas de liberação modificada em ensaios clínicos já tenha sido relatada, a pesquisa da PK do cloridrato de diltiazem na forma de cápsulas com peletes de liberação retardada e sustentada ainda é muito importante. Neste trabalho, propusemos avaliar a farmacocinética do cloridrato de diltiazem administrado através desta nova forma farmacêutica em voluntários chineses sadios, assim como a influência da ingestão de alimentos neste perfil farmacocinético. Foi realizado um ensaio clínico aberto, randomizado e paralelo em 36 voluntários, que receberam dose oral única de 90 mg, 180 mg ou 270 mg e dose múltiplas (90 mg/d × 6 d) pela mesma via de administração. Para avaliar o efeito da ingestão de alimentos sobre a PK do diltiazem foi realizada a administração de dose única (360 mg) em 24 voluntários chineses sadios. A concentração plasmática do diltiazem foi determinada por Cromatografia Liquida de Alta Eficiência em fase reversa (CLAE-FR) e os principais parâmetros farmacocinéticos foram analisados através do emprego do software PKSolver (Ver 2.0). O ensaio de farmacocinética clínica foi conduzido na clínica Pharmacological Center (No.JDX1999064) do Hospital de Xiangya, Central South University, China. Os parâmetros PK obtidos indicaram que a nova formulação de cápsulas de liberação retardada e sustentada de cloridrato de diltiazem possue marcantes características de liberação retardada e controlada do fármaco.

Determination of selected natural hormones and endocrine disrupting compounds in domestic wastewater treatment plants by liquid chromatography electrospray ionization tandem mass spectrometry after solid phase extraction.

A new analytical method for the simultaneous determination of two natural hormones (progesterone and estrone) and two selected endocrine disrupter compounds (EDCs) (diltiazem and carbamazepine (Cbz)) was developed by liquid chromatography electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) after pre-concentration with solid phase extraction (SPE). Influent and effluent samples taken from five different wastewater treatment plants throughout Turkey namely Hurma/Antalya, Lara/Antalya, Kemer-1 and Kemer-2 and METU/Ankara were analyzed for their EDCs contents under the optimum conditions. All of the parameters in the pre-concentration step were optimized and the best recoveries for all compounds of interest were achieved at pH 7 (about 100%). Progesterone was not detected in any of the treatment plants while diltiazem was found in all samples with the exception of Lara effluent.

Biodegradable microparticulate drug delivery system of diltiazem HCl

The efficacy of a drug in a specific application requires the maintenance of appropriate drug blood level concentration during a prolonged period of time. Controlled release delivery is available for many routes of administration and offers many advantages (as microparticles and nanoparticles) over immediate release delivery. These advantages include reduced dosing frequency, better therapeutic control, fewer side effects, and, consequently, these dosage forms are well accepted by patients. Advances in polymer material science, particle engineering design, manufacture, and nanotechnology have led the way to the introduction of several marketed controlled release products and several more are in pre-clinical and clinical development. The objective of this work is to prepare and evaluate diltiazem HCl loaded albumin microparticles using a factorial design. Albumin (natural polymer) microparticles were prepared by emulsion heat-stabilization method. Selected formulations were characterized for their entrapment efficiency, particle size, surface morphology, and release behavior. Analysis of variance for entrapment efficiency indicates that entrapment efficiency is best fitted to a response surface linear model. Surface morphology was studied by scanning electron microscopy. Scanning electron microscopy of the microparticles revealed a spherical, nonporous and uniform appearance, with a smooth surface. The geometric mean diameter of the microparticles was found to be 2-9 µm, which more than 75% were below 3.5 µm and drug incorporation efficiency of 59.74 to 72.48% (w/w). In vitro release profile for formulations containing diltiazem HCl loaded BSA microparticles with heat stabilization technique shows slow controlled the release of the drug up to 24 hours. The release pattern was biphasic, characterized by an initial burst effect followed by a slow release. All selected microparticles exhibited a prolonged release for almost 24 hours. On comparing regression-coefficient (r²) values for Hixson Crowel, Higuchi and Peppas kinetic models, different batches of microparticles showed Fickian, non-Fickian, and diffusion kinetics. The release mechanism was regulated by D:P ratio. From the statistical analysis it was observed that as the drug:polymer (D:P) ratio increased, there was a significant increase in the encapsulation efficiency. Based on the particle size, entrapment efficiency and physical appearance, DTM-3 formulations were selected for in vivo release study and stability study. The in vivo result of drug loaded microparticles showed preferential drug targeting to liver followed by lungs, kidneys and spleen. Stability studies showed that maximum drug content and closest in vitro release to initial data were found in the formulation stored at 4 ºC. In present study, diltiazem HCl loaded BSA microparticles were prepared and targeted to various organs to satisfactory level and were found to be stable at 4 ºC.

A eficácia terapêutica de um fármaco depende da manutenção de seu nível plasmático adequado em determinado intervalo de tempo. Nesse sentido, a liberação modificada de fármacos está disponível em muitas vias de administração e oferece muitas vantagens (como micropartículas e nanopartículas) quando comparada às formulações de liberação imediata. Essas vantagens incluem reduzida frequência da dosagem, melhor controle terapêutico e menos efeitos colaterais. Assim sendo, esses produtos apresentam maior aceitação pelos pacientes. Os avanços na ciência dos materiais, na engenharia das partículas, em manufatura e em nanotecnologia permitiram a introdução no mercado de vários produtos de liberação modificada e vários outros se encontram em desenvolvimento pré-clínico e clínico. O objetivo do presente trabalho foi preparar e avaliar o fármaco cloridrato de diltiazem associado a micropartículas de albumina utilizando planejamento fatorial. As micropartículas de albumina, um polímero natural, foram preparadas por método de emulsão empregando estabilização por calor. As formulações selecionadas foram caracterizadas no que se refere à sua eficiência de encapsulamento, tamanho médio de partículas, morfologia de superfície e perfil de liberação do fármaco. A análise de variância relativa à eficiência de encapsulamento indicou superfície de resposta linear. Com referência à morfologia superficial, essa foi avaliada empregando microscopia eletrônica de varredura. Essa análise revelou micropartículas esféricas, não porosas e de aparência uniforme, com superfície lisa. O diâmetro médio das micropartículas foi entre 2 e 9 µm, sendo que mais de 75% das micropartículas se apresentaram abaixo de 3,5 µm. Além disso, a eficiência de encapsulamento foi entre 59,74 e 72,48%. Quanto ao ensaio para avaliação do perfil de liberação in vitro do fármaco associado às micropartículas, as formulações apresentaram liberação lenta até 24 horas. O comportamento foi caracterizado por liberação inicial (efeito burst) seguida por liberação lenta. Todas as fórmulas selecionadas apresentaram liberação prolongada por aproximadamente 24 horas. Na comparação entre os valores de coeficientes de regressão (R²), os modelos propostos por Hixson Crowel, Higuchi e Peppas, para diferentes formulações de micropartículas, demonstraram cinética de liberação de acordo com modelo Fickiano e não-Fickiano. O mecanismo de liberação do fármaco foi regulado pela razão entre o fármaco e o polímero. A análise estatística revelou significativo aumento da eficiência de encapsulamento quando essa razão aumentou. As avaliações relativas à análise dimensional das micropartículas, à eficiência de encapsulamento do fármaco e à morfologia permitiram a seleção da formulação DTM-3 para os ensaios de liberação in vivo e para o estudo da estabilidade. O ensaio de liberação in vivo do fármaco associado às micropartículas demonstrou sítio-alvo preferencial no fígado, seguido pelos pulmões rins e baço. No presente estudo, as micropartículas de albumina contendo cloridrato de diltiazem foram adequadamente preparadas e orientadas satisfatoriamente para vários órgãos. Além disso, a formulação selecionada apresentou estabilidade físico-química a 4 ºC.

Liquid-liquid microextraction without phase separation in a multicommuted flow system for diltiazem determination in pharmaceuticals.

Liquid-liquid microextraction without phase segmentation was implemented in a multicommuted flow system for determination of the anti-hypertensive diltiazem. The procedure was based on ion pair formation between the drug and the dye bromothymol blue at pH 3.5. The detection was performed without phase separation in a glass tube coupled to a fiber-optics spectrophotometer. The total volume of chloroform was reduced to 50 µL in comparison with 10 mL consumed in batch. A linear response was observed between 9 and 120 µmol L(-1), with a detection limit of 0.9 µmol L(-1) (99.7% confidence level). The coefficient of variation (n=10), sampling rate and extraction efficiency were estimated as 0.6%, 78 determinations per hour and 61%, respectively. About 30 µg of bromothymol blue was consumed and the waste volume was 380 µL per determination. The results for pharmaceutical samples agreed with those obtained by the reference procedure at the 95% confidence level.

Formulation and in vitro evaluation of taste-masked oro-dispersible dosage form of diltiazem hydrochloride

Diltiazem hydrochloride is a calcium channel blocker generally indicated for the treatment of angina and hypertension, and it is extensively metabolized due to the hepatic metabolism. Formulation of diltiazem hydrochloride into an oro-dispersible dosage form can provide fast relief with higher bioavailability. The bitter taste of the drug should be masked to formulate it in a palatable form. In the present work, an attempt was made to mask the taste by complexation technique, with a formulation into an oro-dispersible dosage form, using superdisintegrants Doshion P544, crospovidone (CP) and sodium starch glycolate (SSG). The complexes of diltiazem hydrochloride with β-CD (1:1 molar ratio) were prepared by kneading, co-evaporation, co-grounding, freeze-drying and melting methods. Phase solubility showed stability constant 819.13M-1. Prepared inclusion complexes were evaluated for taste masking and characterized by I.R, XRD, DSC. Using the drug β-CD complex, oro-dispersible tablets were prepared and evaluated for hardness, friability, weight variation, thickness, disintegrating time (DT), dissolution rate and taste. Formulations with 4 percent Doshion, 8 percent CP and 4 percent SSG showed DT of 0.54, 0.35 and 1.23 minutes, respectively.

O cloridrato de diltiazem é bloqueador do canal de cálcio geralmente indicado para o tratamento de angina e de hipertensão e é extensamente biotransformado devido ao metabolismo hepático. A formulação do cloridrato de diltiazem em orodispersão pode prover rápida liberação com maior biodisponibilidade. O sabor amargo do fármaco deve ser mascarado para ser formulado em forma palatável. No presente trabalho tentou-se mascarar o sabor pela técnica de complexação, com uma orodispersão, usando superdesintegrantes, como Doshio P544, crospivodina (CP) e glicolato de amido sódico (SSG). Os complexos de cloridrato de diltiazem com β-CD (razão molar 1:1) foram preparados por mistura, coevaporação, comoagem, liofilização e métodos de fusão. A solubilidade de fase mostrou estabilidade constante de 819,13 M-1. Os complexos de inclusão preparados foram avaliados com relação ao mascaramento do sabor e caracterizados por IV, Difração de Raios X e DSC. Empregando-se o fármaco complexado com β-CD, prepararam-se comprimidos dispersíveis e avaliaram-se os mesmos quanto à dureza, friabilidade, variação de peso, espessura, tempo de desintegração (DT), taxa de dissolução e sabor. Formulações com 4 por cento de Doshion, 8 por cento de CP e 4 por cento de SSG mostraram DT de 0,54, 0,35 e 1,23 minutos, respectivamente.

The relationship between the drug concentration profiles in plasma and the drug doses in the colon.

After the dosing of an extended-release (ER) formulation, compounds may exist in solutions at various concentrations in the colon because the drugs are released at various speeds from the ER dosage form. The aim of this study was to investigate the relationship between the drug concentration profiles in plasma and the drug doses in the colon. Several drug solutions of different concentrations were directly administered into the ascending colon of dogs using a lubricated endoscope, and the effects of the drug dose on colonic absorption were estimated. As a result, dose-dependency of colonic absorption varied from compound to compound. Although the relative bioavailability of colonic administration of diclofenac, metformin and cevimeline compared to oral administration was similar regardless of the drug doses in the colon, colonic absorption of diltiazem varied according to the doses. From the results of the co-administration of verapamil and fexofenadine, it was clear that diltiazem underwent extensive hepatic and gastrointestinal first-pass metabolism, resulting in a low area under the curves (AUC) at a low drug dose. During the design of oral ER delivery systems, a colonic absorption study of candidate compounds should be carried out at several solutions of different drug concentrations and assessed carefully.

Composition, purity and perceived quality of street cocaine in France.

BACKGROUND: There is little knowledge about the composition and cocaine content of street cocaine, nor about what users know about it. METHOD: 373 cocaine users were face to face interviewed between May and December 2006 about the last sample of cocaine they had consumed and residual amounts of the substances actually used were analysed using gas phase chromatography coupled to mass spectrometry (GC-MS). Users rated the perceived quality of their product ("good", "average", "poor"), its "estimated percentage of cocaine" and any cutting agents it contained. Price, quantity, place of purchase (street, dealer's premise, appointment), mode of administration (sniffing, injection, smoking) and the supposed nature of the sample (natural, synthetic, no distinction ever made) were also reported. Perceived quality was modelled using multivariate multinomial regression. RESULTS: The median cocaine content was 22%. Altogether, 343 samples contained cocaine, among which 75% contained at least one adulterant. The most frequently occurring were phenacetin (54% of the samples), caffeine (17%), paracetamol (14%), diltiazem and lidocaïne (11%). Users showed relatively poor discrimination concerning cocaine purity, and only 12% reported at least one of the detected adulterants. The major determinants of their perception of cocaine quality were: place of purchase, natural origin, price per gram, actual cocaine content and mode of administration. CONCLUSION: The composition of street cocaine is largely unknown to users. Users' perceptions of cocaine quality are based partly on false beliefs and certain administration modes. This may contribute to favouring very risky practices. The effects of adulterants on users' health should be investigated.

Dissipation and leaching potential of selected pharmaceutically active compounds in soils amended with biosolids.

Biosolids land application is an important pathway introducing pharmaceuticals into the environment. In this work, laboratory column and dissipation experiments were performed using soils of varying properties in order to study the fate and transport of pharmaceutical residues introduced by the land application of biosolids. For experimentation, five pharmaceutical compounds (carbamazepine, diphenhydramine, fluoxetine, diltiazem, and clindamycin) and two metabolites (carbamazepine-10,11-epoxide and norfluoxetine) commonly found in biosolids were selected. Leaching experiments indicate that the selected pharmaceuticals have low mobility in tested soils. However, small portions of the applied pharmaceuticals were recovered in the leachates, likely attributed to sorption to dissolved organic matter. Dissipation experiments show that carbamazepine, diphenhydramine, and fluoxetine were persistent in soils, whereas the dissipation of diltiazem and clindamycin was affected by redox conditions and soil properties.

Effect of increasing concentration of ammonium acetate as an additive in supercritical fluid chromatography using CO2-methanol mobile phase.

The effects of increasing concentrations of ammonium acetate additive in supercritical fluid chromatography were studied on silica, 2-ethyl-pyridine and endcapped 2-ethyl-pyridine stationary phases. The study involved the addition of increasing concentrations of the ammonium acetate either in the mobile phase modifier (methanol) or in the sample solvent. The effects of ammonium acetate on retention and peak shape of the analytes were evaluated. Compounds that exhibited satisfactory chromatographic behaviour in the absence of the additive were virtually unaffected by its presence in the mobile phase or sample solvent. Nevertheless, compounds that exhibited late elution and strongly tailing peak shapes when pure methanol was used showed dramatically improved chromatographic behaviour in the presence of the additive. Shorter retention was observed not only when the modifier was introduced in the mobile phase but also when it was in the sample solvent.

Formulation and evaluation of oral sustained release of Diltiazem Hydrochloride using rosin as matrix forming material

Rosin, a natural resin, was used as a hydrophobic matrix material for the controlled release, using diltiazem HCl as model drug. Matrix tablets were prepared by direct compression method using rosin as matrix forming material in different proportions and with different diluent combinations. The tablets prepared were flat faced, retained their shape throughout. The method of preparation of matrix system and its concentration were found to have pronounced effect on the release of diltiazem HCl. The release was found to follow both the first order kinetics and fickian diffusion. The drug delivery was analyzed using the paddle method according to USP XXIII. All the studies were done in phosphate buffer pH 7.4. The matrix tablets were evaluated for its thickness, hardness, friability, weight variation, drug content and invitro release studies. The results suggest that the rosin is useful in developing sustained release matrix tablets, prolong release of water soluble drug for up to 24h. Rosin thus promises considerable utility in the development of oral sustained release drug delivery systems(AU)

Microbial degradation of pharmaceuticals in estuarine and coastal seawater.

Microbial degradation rates were measured for 19 pharmaceuticals in estuarine and coastal surface water samples. Antipyrine, carbamazepine, cotinine, sulfamethoxazole, and trimethoprim were the most refractory (half-lives, t(1/2)=35 to >100 days), making them excellent candidates for wastewater tracers. Nicotine, acetaminophen, and fluoxetine were labile across all treatments (t(1/2)=0.68-11 days). Caffeine, diltiazem, and nifedipine were also and relatively labile in all but one of the treatments (t(1/2)=3.5-13 days). Microbial degradation of caffeine was further confirmed by production (14)CO(2). The fastest decay of non-refractory compounds was always observed in more sewage-affected Jamaica Bay waters. Degradation rates for the majority of these pharmaceuticals are much slower than reported rates for small biomolecules, such as glucose and amino acids. Batch sorption experiments indicate that removal of these soluble pharmaceuticals from the water column to sediments is a relatively insignificant removal process in these receiving waters.

Raman spectroscopy as a process analytical technology (PAT) tool for the in-line monitoring and understanding of a powder blending process.

The aim of this study is to propose a strategy to implement a PAT system in the blending step of pharmaceutical production processes. It was examined whether Raman spectroscopy can be used as PAT tool for the in-line and real-time endpoint monitoring and understanding of a powder blending process. A screening design was used to identify and understand the significant effects of two process variables (blending speed and loading of the blender) and of a formulation variable (concentration of active pharmaceutical ingredient (API): diltiazem hydrochloride) upon the required blending time (response variable). Interactions between the variables were investigated as well. A Soft Independent Modelling of Class Analogy (SIMCA) model was developed to determine the homogeneity of the blends in-line and real-time using Raman spectroscopy in combination with a fiber optical immersion probe. One blending experiment was monitored using Raman and NIR spectroscopy simultaneously. This was done to verify whether two independent monitoring tools can confirm each other's endpoint conclusions. The analysis of the experimental design results showed that the measured endpoints were excessively rounded due to the large measurement intervals relative to the first blending times. This resulted in effects and critical effects which cannot be interpreted properly. To be able to study the effects properly, the ratio between the blending times and the measurement intervals should be sufficiently high. In this study, it anyway was demonstrated that Raman spectroscopy is a suitable PAT tool for the endpoint control of a powder blending process. Raman spectroscopy not only allowed in-line and real-time monitoring of the blend homogeneity, but also helped to understand the process better in combination with experimental design. Furthermore, the correctness of the Raman endpoint conclusions was demonstrated for one process by using a second independent endpoint monitoring tool (NIR spectroscopy). Hence, the use of two independent techniques for the control of one response variable not only means a mutual confirmation of both methods, but also provides a higher certainty in the determined endpoint.