Fiber Laser-Generated Silver-109 Nanoparticles for Laser Desorption/Ionization Mass Spectrometry of Illicit Drugs.

Cannabinoids and opioids are the most prominently used drugs in the world, with fentanyl being the main cause of drug overdose-related deaths. Monitoring drug use in groups as well as in individuals is an important forensic concern. Analytical methods, such as mass spectrometry (MS), have been found most useful for the identification of drug abuse on a small and large scale. Pulsed fiber laser 2D galvoscanner laser-generated nanomaterial (PFL 2D GS LGN) was obtained from monoisotopic silver-109. Nanomaterial was used for laser desorption/ionization mass spectrometry of selected illicit drug standards with standard high-resolution reflectron-based time-of-flight MALDI apparatus. Δ9-THC, 11-OH-THC, 11-COOH-THC, fentanyl, codeine, 6-monoacetylmorphine (6-MAM), heroin, tramadol, and methadone were chosen as test compounds. Illicit drugs were tested in a concentration range from 100 µg/mL to 10 pg/mL, equating to 50 µg to 50 fg per measurement spot. For all analyzed compounds, identification and quantification by silver-109-assisted laser desorption/ionization (LDI) MS was possible, with uncommon [M + 109Ag3]+ and [M - H]+ ions present for certain structures. The results of the quantitative analysis of drugs using silver-109 PFL 2D GS LGN for LDI MS are presented. Laser-generated NPs are proven to be useful for the analysis of selected drugs, with exceptionally good results for fentanyl monitoring in a broad range of concentrations.

Synthesis of 3-O-Carboxyalkyl Morphine Derivatives and Characterization of Their Acid-Base Properties.

The C-3 phenolic hydroxy group containing morphine derivatives (morphine, oxymorphone, naloxone, naltrexone) are excellent candidates for the synthesis of 3-O-functionalized molecules. Achieving free carboxylic group containing derivatives gives the opportunity for further modification and conjugation that could be used for immunization and immunoassays. For this purpose ethyl bromo- and chloroacetate can be used as O-alkylating agents. Hydrolyzing the products affords the appropriate free carboxylic group containing 3-O-carboxyalkyl derivatives. As these molecules contain an acidic and a basic functional group the protonation macro- and microconstants were determined too, using pH-potentiometry and NMR-pH titration, beside fully characterizing their structure using IR, CD, NMR and HR-MS measurements.

A pharmacokinetic study of morphine-6-O-sulfate in rat plasma and brain.

Morphine-6-O-sulfate (M6S), a polar, zwitterionic sulfate ester of morphine, is a powerful and safe analgesic in several rat models of pain. A sensitive liquid chromatography-tandem mass spectrometry bioanalytical method was developed and validated for the simultaneous determination of M6S and morphine (MOR) in rat plasma and brain after M6S administration. Morphine-d6 was used as internal standard. Multiple reaction monitoring was used for detection and quantitation of M6S, MOR, and morphine-d6 in the turbo ion spray positive mode. The chromatographic separation was carried out on an Alltech Altima C18 column. The analytical method was validated for linearity, precision, accuracy, specificity, and stability over a concentration range of 3-8000 ng/ml in rat plasma and 10-10,000 ng/ml in brain samples for both M6S and MOR. The validated method was applied to determine the PK profile of M6S in plasma after i.v., i.p., and oral dosing in male Sprague-Dawley rats. Rats were administered M6S by i.p. administration (5.6 and 10.0 mg/kg) or orally (10 and 30 mg/kg) and bioavailability compared to an i.v. injection (1 mg/kg) of M6S. The in vivo results indicate that M6S is not a prodrug of morphine, since M6S is not biotransformed into MOR in plasma after either i.p. or oral administration, and MOR was not detected in brain. The bioavailability of M6S was >93% and about 5% after i.p. and oral dosing, respectively. The low oral bioavailability of M6S may be due to poor permeation of the intestinal epithelial membrane. After i.p.-administration, M6S appears to reach brain tissues in low, but significant, concentrations.

The mechanism of the selective binding ability between opiate metabolites and acyclic cucurbit[4]uril: an MD/DFT study.

Subtle changes in molecular structure often lead to significant differences in host-guest interactions, which result in different host-guest recognition capabilities and dynamics behaviours in complex formation. Herein, we reveal the influence of the guest substituents on host-guest molecular recognition by molecular dynamics (MD) simulation and density functional theory (DFT) approaches. The results suggest that the binding energy barrier of acyclic cucurbit[4]uril (ACB[4]) with opiate metabolites gradually decreases. The methyl group in morphine (MOR) and morphine-3-glucuronide (M3G) strengthens the hydrophobicity of the guest, while depressing the energy loss of the desolvation of polar groups (e.g. hydroxyl) inside the ACB[4] cavity. However, in M3G, the 3-glucuronide group located outside the ACB[4] host cavity effectively alleviates the unfavourable desolvation effect of the hydroxyl and increases the binding constant by two orders of magnitude (compared with normorphine (NMOR)). Our findings stressed the essentiality of the binding mode and intermolecular noncovalent interactions in the host-guest selective binding ability.

Development and validation of a UPLC-MS/MS method with a broad linear dynamic range for the quantification of morphine, morphine-3-glucuronide and morphine-6-glucuronide in mouse plasma and tissue homogenates.

The aim of this study was to develop and to validate a UPLC-MS/MS method for the quantification of morphine, morphine-3-glucuronide, and morphine-6-glucuronide in mouse plasma and tissue homogenates to support preclinical pharmacokinetic studies. The sample preparation consisted of protein precipitation with cold (2-8 °C) methanol:acetonitrile (1:1, v/v), evaporation of the supernatant to dryness, and reconstitution of the dry-extracts in 4 mM ammonium formate pH 3.5. Separation was achieved on a Waters UPLC HSS T3 column (150 × 2.1 mm, 1.8 µm) maintained at 50 °C and using gradient elution with a total runtime of 6.7 min. Mobile phase A consisted of 4 mM ammonium formate pH 3.5 and mobile phase B of 0.1% formic acid in methanol:acetonitrile (1:1, v/v). Detection was carried out by tandem mass spectrometry with electrospray ionization in the positive ion mode. The method was validated within a linear range of 1-2,000 ng/mL, 10-20,000 ng/mL, and 0.5-200 ng/mL for morphine, morphine-3-glucuronide, and morphine-6-glucuronide, respectively. In human plasma, the intra- and inter-run precision of all analytes, including the lower limit of quantification levels, were ≤ 15.8%, and the accuracies were between 88.1 and 111.9%. It has been shown that calibration standards prepared in control human plasma can be used for the quantification of the analytes in mouse plasma and tissue homogenates. The applicability of the method was successfully demonstrated in a preclinical pharmacokinetic study in mice.

Use of a Noninvasive Brain-Penetrating Peptide-Drug Conjugate Strategy to Improve the Delivery of Opioid Pain Relief Medications to the Brain.

The analgesic potency of morphine-6-glucuronide (M6G) has been shown to be 50-fold higher than morphine after intracerebral injection. However, the brain penetration of M6G is significantly lower than morphine, thus limiting its usefulness in pain management. Here, we created new entities by the conjugation of the angiopep-2 peptide (An2) that crosses the blood-brain barrier (BBB) by low-density lipoprotein receptor-related protein 1 receptor-mediated transcytosis with either morphine or M6G. We demonstrated improvement of BBB permeability of these new entities compared with that of unconjugated M6G and morphine. Intravenous or subcutaneous administration of the An2-M6G conjugate exerted greater and more sustained analgesic activity than equivalent doses of either morphine or M6G. Likewise, subcutaneous An2-morphine induced a delayed but prolonged antinociceptive effect. The effects of these conjugates on the gastrointestinal tract motility were also evaluated. An2-morphine significantly reduced the intestinal transit time, whereas An2-M6G exhibited a reduced constipation profile, as compared with an equimolar dose of morphine. In summary, we have developed new brain-penetrant opioid conjugates exhibiting improved analgesia to side effect ratios. These results thus support the use of An2-carrier peptides as an innovative BBB-targeting technology to deliver effective drugs, such as M6G, for pain management. SIGNIFICANCE STATEMENT: The metabolite morphine-6-glucuronide (M6G) does not efficiently cross the blood-brain barrier. The low-density lipoprotein receptor-related protein 1 peptide ligand angiopep-2 may serve as an effective drug delivery system to the brain. Here, we demonstrated that the coupling of M6G to angiopep-2 peptide (An2) improves its brain penetration and significantly increases its analgesic potency. The An2-M6G conjugate has a favorable side effect profile that includes reduction of developing constipation. An2-M6G exhibits a unique pharmacodynamic profile with a better therapeutic window than morphine.

Optimization of morphine extraction method for the assay of its urinary 3-glucuronideconjuguate by gas chromatography-mass spectrometry.

In the field of doping, a great interest is carried for the analysis of morphine, a powerful narcotic analgesic opiate which use is prohibited during competitions. In order to confirm the abnormal analytical result in our anti-doping laboratory, a sensitive and selective gas chromatography-mass spectrometry (GC-MS) method was performed for the quantification of urinary morphine. As sample preparation is a key step for the determination of drugs in biological samples, the aim of this work consists of the optimization of the urinary human sample pretreatment conditions before quantification by GC/MS. Enzymatic hydrolysis associated with liquid-liquid extraction constitute the major pre-treatment steps. Our study has first focused on the optimization of the extraction solvents then to enzymatic hydrolysis which morphine is released from its glucuronide conjugated form. Onboard premiums, a study involving the effect of "amount of enzyme", "incubation temperature" and "duration of hydrolysis" was conducted. This univariate study has enabled us to evaluate the influence of each of these operating variables on the area ratio of morphine to the internal standard (Amorphine/AIS) response and to set the experimental fields for each one of them. Based on these results, an experimental design was established using the Box-Behnken model to determine, by multivariate analysis, the optimal operating conditions maximizing the "Amophine/AIS" response. After validation, the analysis of response surface makes it possible to set the optimum operating conditions, which the ratio "Amorphine/AIS" is maximized. The retained conditions for enzymatic hydrolysis are 160µl of Escherichia coli glucuronidase enzyme during 6hours of incubation at a temperature of 36°C. The solvent mixture Methyl-t-Butyl Ether/isopropanol (4:1, v/v) was selected since it has improved morphine extraction from the urinary matrix allowing a gain of 50% when compared to that used in our routine laboratory. Our developed extraction method can be successfully applied for our forensic anti-doping analysis of morphin in human sample urine.

Validation of a HPLC/MS method for simultaneous quantification of clonidine, morphine and its metabolites in human plasma.

A high-performance liquid chromatography-tandem mass spectrometry method was developed and validated for the simultaneous quantification of morphine, morphine's major metabolites morphine-3-glucuronide and morphine-6-glucuronide, and clonidine, to support the pharmacokinetic analysis of an ongoing double-blinded randomized clinical trial that compares the use of morphine and clonidine in infants diagnosed with neonatal abstinence syndrome. Plasma samples were processed by solid-phase extraction and separated on an Inertsil ODS-3 (4 µm) column using an 0.1% formic acid in water-0.1% formic acid in methanol gradient. Detection of the analytes was conducted in the positive multiple reaction monitoring mode. The range of quantitation was 1-1000 ng/mL for morphine, morphine-3-glucuronide and morphine-6-glucuronide, and 0.25-100 ng/mL for clonidine. Intra-day and inter-day accuracy and precision were ≤15% for all analytes across the quantitation range. Extraction recovery rates were ≥94% for morphine, ≥90% for M3G, ≥87% for M6G and ≥ 79% for clonidine. Matrix effect ranged from 85-94% for clonidine to 101-106% for M3G. The method fulfilled all predetermined acceptance criteria and required only 100 µL of starting plasma volume. Furthermore, it was successfully applied to 30 clinical trial plasma samples.

Kinetic characterization of cholinesterases and a therapeutically valuable cocaine hydrolase for their catalytic activities against heroin and its metabolite 6-monoacetylmorphine.

As the most popularly abused one of opioids, heroin is actually a prodrug. In the body, heroin is hydrolyzed/activated to 6-monoacetylmorphine (6-MAM) first and then to morphine to produce its toxic and physiological effects. It has been known that heroin hydrolysis to 6-MAM and morphine is accelerated by cholinesterases, including acetylcholinesterase (AChE) and/or butyrylcholinesterase (BChE). However, there has been controversy over the specific catalytic activities and functional significance of the cholinesterases, which requires for the more careful kinetic characterization under the same experimental conditions. Here we report the kinetic characterization of AChE, BChE, and a therapeutically promising cocaine hydrolase (CocH1) for heroin and 6-MAM hydrolyses under the same experimental conditions. It has been demonstrated that AChE and BChE have similar kcat values (2100 and 1840 min-1, respectively) against heroin, but with a large difference in KM (2170 and 120 µM, respectively). Both AChE and BChE can catalyze 6-MAM hydrolysis to morphine, with relatively lower catalytic efficiency compared to the heroin hydrolysis. CocH1 can also catalyze hydrolysis of heroin (kcat = 2150 min-1 and KM = 245 µM) and 6-MAM (kcat = 0.223 min-1 and KM = 292 µM), with relatively larger KM values and lower catalytic efficiency compared to BChE. Notably, the KM values of CocH1 against both heroin and 6-MAM are all much larger than previously reported maximum serum heroin and 6-MAM concentrations observed in heroin users, implying that the heroin use along with cocaine will not drastically affect the catalytic activity of CocH1 against cocaine in the CocH1-based enzyme therapy for cocaine abuse.

Hydrolysis of food-derived opioids by dipeptidyl peptidase IV from Lactococcus lactis spp. lactis.

Food-derived opioid peptides that are released from proteins by digestion, fermentation, or food production processes lead to several health problems. The opioids are generally resistant to hydrolyze by proteases, except the dipeptidyl peptidase IV (DPPIV, EC 3.4.14.5) enzyme, because of proline amino acid. ß-casomorphin (BCM) from milk casein, gluteomorphin (GM) from wheat gluten, and soymorphin (SM) from the soybean ß-conglycinin ß-subunit are natural substrates of DPPIV because of their amino acid sequences and proline location. In the present study, DPPIV from Lactococcus lactis spp. lactis was purified and characterized by mass spectrometry. Purified DPPIV was added to standard BCM, GM, and SM, and hydrolysis percentages of morphins were measured by HPLC analysis. The results indicated that DPPIV enzyme hydrolyzed food-derived opioids (from 0.1 mM to 2 mM), BCM (33.42% for 2 mM), SM (83.81% for 2 mM), and GM (45.73% for 2 mM) in vitro. Hydrolysis percentages of SM were considerably higher than the same concentrations with BCM and GM. For dietary supplements to be promising for reducing the adverse effects of food derived opioids, this must be supported by in vivo studies of DPPIV use in the human body.

Simultaneous determination of morphine-6-d-glucuronide, morphine-3-d-glucuronide and morphine in human plasma and urine by ultra-performance liquid chromatography-tandem mass spectrometry: Application to M6G injection pharmacokinetic study.

A robust ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the determination of morphine-6-d-glucuronide (M6G), morphine-3-d-glucuronide (M3G) and morphine (MOR) in human plasma and urine has been developed and validated. The analytes of interest were extracted from plasma by protein precipitation. The urine sample was prepared by dilution. Both plasma and urine samples were chromatographed on an Acquity UPLC HSS T3 column using gradient elution. Detection was performed on a Xevo TQ-S tandem mass spectrometer in multiple reaction monitoring mode using positive electrospray ionization. Matrix interferences were not observed at the retention time of the analytes and internal standard, naloxone-D5. The lower limits of quantitation of plasma and urine were 2/0.5/0.5 and 20/4/2 ng/mL for M6G/M3G/MOR, respectively. Calibration curves were linear over the concentration ranges of 2-2000/0.5-500/0.5-500 and 20-20,000/4-4000/2-2000 ng/mL for M6G/M3G/MOR in plasma and urine samples, respectively. The precision was <7.14% and the accuracy was within 85-115%. Furthermore, stability of the analytes at various conditions, dilution integrity, extraction recovery and matrix effect were assessed. Finally, this quantitative method was successfully applied to the pharmacokinetic study of M6G injection in Chinese noncancer pain patients.

A one-pot multicomponent approach to a new series of morphine derivatives and their biological evaluation.

A novel and facile domino reaction has been developed to synthesize a variety of new derivatives from hydromorphone, amines and paraformaldehyde in good yields in a catalyst-free fashion with high atom efficiency. The products show a mixed MOR/DOR biological characteristic which makes them valuable for further study as opioid analgesics.

Physicochemical and Pharmacological Characterization of Permanently Charged Opioids.

BACKGROUND: The main aim of synthesizing permanently charged opioids is to ensure that they do not enter the central nervous system. Such drugs can provide analgesic activity with reduced sedation and other side effects on the central nervous system. METHODS: We undertook a search of bibliographic databases for peer-reviewed research literature and also summarized our published results in this field. RESULTS: The present review focuses on the characterization of permanently charged opioids by various physicochemical methods, and in vitro as well as in vivo tests. The basicity and lipophilicity of opioid alkaloids are discussed at the microscopic, speciesspecific level. Glucuronide conjugates of opioids are also reviewed. Whereas the primary metabolite morphine-3-glucuronide does not bind to opioid receptors with high affinity, morphine-6-glucuronide is a potent analgesic, at least, partly due to its unexpectedly high lipophilicity. We discuss the quaternary ammonium opioid derivatives of a permanent positive charge, detailing their antinociceptive activity and effects on gastrointestinal motility in various in vivo animal tests and in vitro studies. Compounds with antagonistic activity are also reviewed. The last part of our study concentrates on sulfate conjugates of morphine derivatives that display unique pharmacological properties because they carry a negative charge at any pH value in the human body. CONCLUSION: In conclusion, the findings of this review confirm the importance of permanently charged opioids in the investigated fields of pharmacology.

Modeling in-sewer transformations at catchment scale - implications on drug consumption estimates in wastewater-based epidemiology.

To which extent illicit drugs are transformed during in-sewer transport, depends on a number of factors: i) substance-specific transformation rates, ii) environmental conditions, iii) point of discharge (location of drug user) and iv) sewer network properties, primarily hydraulic residence time (HRT) and the ratio of biofilm contact area to wastewater volume (A/Veq). Assessing associated uncertainties typically requires numerous simulations. Therefore, we propose a new two-step modeling framework: 1) Quantify hydrodynamic conditions. This computationally demanding step was performed once in SWMM to derive HRT and A/Veq for each potential point of discharge (node) in three catchments of different size. 2) Estimate biomarker loss. In this step, Monte Carlo simulations were performed for defined scenarios. Depending on assumptions about drug user distribution and prevalence, a number of nodes was sampled. For each node an empirical first-order transformation model was applied with flow-path-corresponding HRT and A/Veq from step 1. Biotic and abiotic transformation rates were sampled from distributions combining variability of different biofilms. In our modeling study, median losses were >30% for amphetamine, 6-monoacetylmorphine and 6-acetylcodeine in all three catchments with high uncertainty (5%-100% loss), which would imply a systematic underestimation of consumption when neglecting in-sewer processes. Median losses for 21 other investigated biomarkers were <10% with different uncertainty ranges - "no substantial transformation" was confirmed for nine substances in a real sewer segment with a 2-h residence time. Transferability of these results must be tested for other catchments. To further reduce uncertainty, mainly additional knowledge on transformation rates, particularly in biofilm, and their distribution across a sewer network is needed to update model input objectively. Our approach allows efficient testing and, furthermore, can be expanded for many other human biomarkers. Accounting for biomarker stability during in-sewer transport will avoid biased estimates and further improve wastewater-based epidemiology.

Stability studies of potent opioid analgesic, morphine-6-O-sulfate in various buffers and biological matrices by HPLC-DAD analysis.

The 6-O-sulfate ester of morphine (M6S) has previously been shown to be an analgesic with greater potency and fewer side effects than morphine. However, being a sulfate ester derivative of morphine, the question exists as to whether this compound is stable in biological fluids and tissues with regard to pH- and esterase-mediated degradation. To date, no studies have focused on the stability profile of M6S across the physiologically relevant pH range of 1.2-7.4. In addition, the stability of M6S is not known in rat plasma and rat brain homogenate, or in simulated rat gastric and intestinal fluids. This study determines the stability profile of M6S (utilized as the sodium salt) and demonstrates that M6S is highly stable and resilient to either enzymatic- or pH-dependent hydrolysis in vitro.

Development of Poly(lactide-co-glicolide) Nanoparticles Incorporating Morphine Hydrochloride to Prolong its Circulation in Blood.

BACKGROUND: Formulations incorporating nanoparticles (NPs) are widely used to prolong drug release. In this regard, poly(lactide-co-glicolide) (PLGA) is often used in their preparation due to its high degree of biocompatibility and biodegradability. In the present study, morphine HCl is incorporated in PLGA-NPs and different preparation alternatives are evaluated for their effects on the properties, stability and capacity of encapsulation. METHODS: NPs were prepared by a double emulsion solvent diffusion-ammonium loading (DESD-AL) or double emulsion solvent diffusion-traditional (DESD-T) technique. NP morphology, size, zeta potential and encapsulation efficiency were investigated. In vitro studies were performed in phosphate buffer pH 7.4 at 37 ºC and deionized water at 4ºC. Adult male Swiss mice were used to study the pharmacokinetic behavior in vivo. RESULTS: Our results show that DESD-AL provides a higher level of morphine entrapment and that increasing the sonication time reduces the size but does not appreciably reduce the entrapment percentage. It was also observed that NP stability was greater when Pluronic F68 was used rather than PVA, and that in vitro assays provided better results with low concentrations of both stabilizers. Lyophilized NPs, after rehydration showed properties that were only slightly different from those of the untreated ones, with no sign of precipitation or aggregation. Finally, the obtained NPs enhanced morphine bioavailability. CONCLUSIONS: In conclusion, a useful method for encapsulating morphine in order to obtain an extended delivery period is described and its effects are compared with those of the free drug.

A structural insight into the negative effects of opioids in analgesia by modulating the TLR4 signaling: An in silico approach.

Opioids are considered the gold standard therapy for pain. However, TLR-dependent negative effects in analgesia have highlighted the complexities in the pharmacodynamics of opioids. While successive studies have reported that morphine and Morphine-3-glucuronide (M3G) activate the TLR4 pathway, the structural details of this mechanism are lacking. Here, we have utilized various computational tools to reveal the structural dynamics of the opioid-bound TLR4/MD2 complex, and have proposed a potential TLR4 activation mechanism. Our results support previous findings, and include the novel insight that the stable binding of morphine and naloxone, but not M3G, in the MD2 cavity, is TLR4 dependent. Morphine interacts with MD2 near its Phe126 loop to induce the active conformation (MD2C); however, this binding is likely reversible, and the complex gains stability upon interaction with TLR4. M3G also induces the MD2C state, with both the Phe126 loop and the H1 loop being involved in MD2-M3G complex stability. Remarkably, naloxone, which requires TLR4 interaction for complex stability, switches the conformation of the gating loop to the inactive state (MD2°). Cumulatively, our findings suggest that ligand binding and receptor clustering occur successively in opioid-induced TLR4 signaling, and that MD2 plasticity and pocket hydrophobicity are crucial for the recognition and accommodation of ligands.

Site- and species-specific hydrolysis rates of heroin.

The hydroxide-catalyzed non-enzymatic, simultaneous and consecutive hydrolyses of diacetylmorphine (DAM, heroin) are quantified in terms of 10 site- and species-specific rate constants in connection with also 10 site- and species-specific acid-base equilibrium constants, comprising all the 12 coexisting species in solution. This characterization involves the major and minor decomposition pathways via 6-acetylmorphine and 3-acetylmorphine, respectively, and morphine, the final product. Hydrolysis has been found to be 18-120 times faster at site 3 than at site 6, depending on the status of the amino group and the rest of the molecule. Nitrogen protonation accelerates the hydrolysis 5-6 times at site 3 and slightly less at site 6. Hydrolysis rate constants are interpreted in terms of intramolecular inductive effects and the concomitant local electron densities. Hydrolysis fraction, a new physico-chemical parameter is introduced and determined to quantify the contribution of the individual microspecies to the overall hydrolysis. Hydrolysis fractions are depicted as a function of pH.

Photostability of 6-MAM and morphine exposed to controlled UV irradiation in water and methanol solution: HRMS for the characterization of transformation products and comparison with the dry state.

The UVA and UVB light-induced behaviour of 6-monoacetylmorphine (6-MAM) and morphine, the main metabolites of heroin, was studied in methanol, aqueous solution and in the dry state. UVA and UVB irradiations were performed for different times (radiant energies of 20-300J/cm(2)). UV spectra of irradiated samples were compared with samples kept in the dark. To estimate the extent of photolysis, positive ion electrospray ionization experiments were performed on the irradiated samples by LC-HRMS. Tentative identification of photoproducts was performed on the basis of their elemental formula as calculated by HRMS results. Morphine and 6-MAM demonstrated to be quite stable under UVA light but very sensitive to UVB irradiation. In methanol solutions they undergo a similar pattern, both reaching 90% photodegradation after 100J/cm(2) of UVB, with a slightly faster kinetic for morphine at lower doses. In water, the yields of photodegradation are nearly one third lower than in methanol. In the solid state, the yield of photodegradation is lower than in solution. The structures of some UVB-induced degradation products are proposed. Photoaddition of the solvent and photooxidation seem the main pathways of phototransformation of these molecules. Moreover, both compounds revealed to generate singlet oxygen under UVB exposure.

Photocatalytic mineralization of codeine by UV-A/TiO2--Kinetics, intermediates, and pathways.

This study investigated the photocatalytic degradation of codeine by UV-irradiated TiO2. The degradation kinetics was determined under varied conditions including the TiO2 loading, codeine concentration, and pH. Codeine and several reaction intermediates including morphine were identified and tracked during degradation using HPLC/MS-MS technique, along with TOC and IC measurements. Specifically, removal of 100 µg/L of spike codeine was complete in 3 min by contact with a 0.1 g/L suspension of TiO2 under UV irradiation at pH 7. The degradation kinetics of codeine was first-order with respect to both the catalyst TiO2 and the reactant codeine, with enhanced reaction rates with increasing pH up to pH 9. Mineralization of codeine was possible upon prolonged contact; near complete mineralization of 10 mg/L of codeine was achieved in 90 min with 0.1 g/L TiO2 under irradiation at pH 5, during which the organic nitrogen was converted to NH3-N (74%) and NO3-N (22%). Based on the identified intermediates, two degradation pathways were proposed of which one involved ipso-substitution followed by cleavage of the aromatic ring and another involved repeated hydroxylation of the codeine molecule followed by its fragmentation.