DISPOSAL OF MEDICINAL PRODUCTS. CHEMICAL DESTRUCTION OF CARVEDILOL AND LOSARTAN
- Authors: Sazonenka K.1
-
Affiliations:
- Belarusian state medical university
- Issue: Vol 10 (2021): Материалы XVII Международной Бурденковской научной конференции 22-24 апреля 2021 года
- Pages: 456-459
- Section: Фармация
- URL: https://new.vestnik-surgery.com/index.php/2415-7805/article/view/6499
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Abstract
Relevance. Currently, the disposal and neutralization of pharmaceutical waste is most often carried out by thermal methods, but the use of such methods has a number of disadvantages, the most significant of which is the release of dioxins-substances that can have a negative impact on the human body, including the development of cancer.
Goal. Development and proof of the effectiveness of methods of chemical disposal of medicines on the example of carvedilol and losartan with the help of available reagents, followed by verification of the effectiveness of the destruction of medicinal substances. Evaluation of the toxicity of the products of the neutralization of drugs in silico.
Materials and methods. The structure of the obtained products was determined using the method of Raman spectroscopy.
For the decomposition of medicines, chemical reagents are necessary:
– hydrobromic acid 5% and hydrobromic acid 5%%;
– Fenton reagent (FeSO4 solution 5% + H2O2 solution 33%).
Assessment of the toxicity of starting substances and products of degradation reactions – Toxicity Estimation Software Tool.
Results. During the toxicity analysis, it was revealed that the semi-annual concentration of carvedilol hydrolysis products increased by 15-166055 times. The hydroxylation of losartan reduces the toxicity of the reaction products by 1.8-2.4 times.
Conclusion. The use of the method of chemical neutralization of the active substance can become a new way of safe disposal of medicines. The main difficulty lies in the rational choice of reagents for the destruction of medicinal substances, so that the chemical reaction proceeds under conditions close to normal, without the use of high-tech and expensive equipment.
The proposed methods of destruction of medicines are significantly safer than high-temperature incineration, the rejection of complex equipment and the reduction of energy costs will optimize and simplify the process of disposal of pharmaceutical waste and expired medicines.
Full Text
Relevance.
The problem of environmental pollution has been worrying the minds of mankind since the beginning of the XX century. Along with the scientific and technological revolutions, the problems of pollution of the atmosphere, hydrosphere and pedosphere not only with oil products, but also with medicines, including pharmaceutical waste, have become much more obvious. According to WHO, about 85% of this medical waste is non-hazardous, but the remaining 15% may be radioactive, carry an infection, or pose other toxic hazards [1].
Currently, the disposal and neutralization of pharmaceutical waste and expired medicines is carried out by high-temperature combustion of the components of medicines. This method has many disadvantages, which can lead to the release of heavy metals, arsenic, and toxic organic compounds into the environment [2].
Due to the fact that the collection of expired medicines from the population is practically not organized, dangerous substances can get into the soil together with household waste. Such substances include cardiac glycosides, cytostatics, and antibiotics. In addition to soil pollution, when drugs enter the sewers, wastewater is polluted, and then these substances will enter the world's oceans.
Diseases of the cardiovascular system, according to WHO, is the first cause of death worldwide. A huge number of different names of medicines are produced, aimed at normalizing blood pressure, heart rate, treatment of heart failure and CHD [3].
Goal.
Development and proof of the effectiveness of methods of chemical disposal of medicines on the example of carvedilol and losartan with the help of available reagents, followed by verification of the effectiveness of the destruction of medicinal substances. Evaluation of the toxicity of the products of the neutralization of drugs in silico.
Materials and methods.
The structure of the obtained products was determined using the method of Raman spectroscopy.
For the decomposition of medicines, chemical reagents are necessary:
– hydrobromic acid 5% and hydrobromic acid 5%%;
– Fenton reagent (FeSO4 solution 5% + H2O2 solution 33%).
The giant Raman scattering spectra were recorded using a Confotec NR500 3D scanning confocal Raman microscope (SOL instrument, Republic of Belarus). Then, by comparing the two GCR spectra, the completeness of the destruction of drugs and the qualitative composition of the mixture will be determined.
The two-dimensional drug structures and chemical formulas of the reaction products were constructed using the NCBI PubChem database and the ChemDraw Ultra – CambridgeSoft chemical editor.
The toxicity assessment of the starting substances and degradation reaction products was performed using the Toxicity Estimation Software Tool, this program was developed by the US Environmental Protection Agency[4].
The research base. Department of Pharmaceutical Chemistry of the Belarusian State Medical University, Department of Micro-and Nanoelectronics of the Belarusian State University of Informatics and Radioelectronics.
Methodology. For the inactivation of both drugs under consideration, Fenton's reagent was chosen, since it is a strong hydroxylating agent, hydrobromic or hydroiodic acids, which are effective for the hydrolysis of esters, esters, lactams and other products obtained as a result of intra - or intermolecular condensation.
0.1 grams of powdered carvedilol tablets were dissolved in 50 ml of distilled water, mixed after 15 minutes, then the resulting solution was filtered through filter paper. The first 10 ml of filtrate was drained, two 10 ml samples were taken: a mixture of 1: 1 (vol.) hydrobromic and hydrobromic acids with a volume of 20 ml was added to the first, and 10 ml of a freshly prepared five percent solution of iron sulfate II and 1 ml of 33% hydrogen peroxide was added to the second. They were kept for 30 minutes at a temperature of +20 ° C.
0.1 grams of powdered losartan tablets were dissolved in 50 ml of distilled water, mixed after 15 minutes, and then the resulting solution was filtered through filter paper. The first 10 ml of the filtrate was drained, 10 ml of the solution was taken, and 10 ml of a freshly prepared five percent solution of iron sulfate II and 1 ml of 33% hydrogen peroxide were added. They were kept for 30 minutes at a temperature of +20 ° C.
Results.
During the toxicity analysis, it was revealed that the semi-lethal concentration of carvedilol hydrolysis products increased by 15-166055 times, that is, the reaction products are significantly less dangerous. Thus, it can be said that acid hydrolysis for carvedilol is the preferred option for neutralization.
The hydroxylation of losartan reduces the toxicity of the reaction products by 1.8-2.4 times, which is also a positive result [4].
Discussion.
The carvedilol molecule contains ester groups. As products of acid hydrolysis, the following are formed: pyrocatechin; 3 - ((2-hydroxyel)amino)propane-1,2-diol and 9H-carbazole-4-ol. Product of the hydroxylation reaction, using Fenton's reagent– 4-(2-((3-((9H-carbazole-4-yl) oxy) - 2-hydroxypropyl)amino)ethoxy)-3-methoxyphenol [5].
For the utilization of losartan, an example of interaction with a Fenton reagent can be given, as a result of which a hydroxylated derivative is formed: 1-(1-((2'-(2H-terazole-5-yl)-[1,1' - biphenyl] - 4-yl)methyl) - 4-chloro-5-(hydroxymethyl)-1H-imidazole-2-yl)butane-1-ol [5].
Comparing the spectrum before and after destruction, we draw conclusions about the success or failure of the degradation reaction, and also decipher the qualitative composition of the mixture after degradation.
The GCR spectrum for carvedilol before destruction has a peak characteristic of esters at 570 cm-1. Fluctuations in the N—H bond in the pyrrole core of carbazole give a peak at 1100 cm-1. The peak at 1270 cm-1 corresponds to the deformation vibrations of alkyl-aryl esters. The peak at 1640 cm-1 is characteristic of the deformation oscillations of the N—H bond in secondary amines [6].
After the action of acids on carvedilol, a change is immediately noticeable in the form of the absence of a massive peak in the region of 570 cm-1, but two new peaks appeared at 400 cm-1 and 575 cm-1 – such values are characteristic for halogen-derived hydrocarbons, this is interference from the reagents used: hydrogen iodide or hydrogen bromine, which formed a salt with a secondary amine. Due to the fact that the hydrolysis of esters occurred – alcohols were formed, the valence fluctuations of C-O in primary aliphatic alcohols are in the zone of 1050 cm-1-a very intense peak appears at 1058 cm-1. There is no peak at 1270 cm-1 – which means that the alkyl-aryl ether has collapsed. It is worth noting that the peak at 1640 cm-1 did not change, which indicates that the secondary amino group remained in the same localization [6].
Based on the results of the analysis of the GCR spectra, it can be concluded that the destruction of carvedilol with acids is an effective method of degradation of this compound.
The initial losartan spectrum has a peak in the region of 390 cm-1, which characterizes the deformation oscillations of C-Cl in the imidazole ring. Peaks at 530 cm-1 and 620 cm-1 indicate the presence of a biphenyl group. The peak in the region of 1520 cm-1 refers to the valence vibrations of the N—H bond in the imidazole ring. The peak at 1600 cm-1 is characteristic of valence oscillations between carbon atoms in the phenyl group.
After the destruction of the Fenton reagent, characteristic changes appear on the spectrum: it has a pronounced peak at 885 cm-1, this peak corresponds to 1 -, 2 -, 3-tri-substituted benzene.
The peaks in the area of 1520 cm-1 and 1600 cm-1 remained in their places with the same intensity. The absence of peaks at 530 cm-1 and 620 cm-1 indicates that the biphenyl group has collapsed [6].
Resume. Acid hydrolysis and hydroxylation with Fenton reagent are effective ways to neutralize substances. As a result of the destruction of carvedilol and losartan, substances are formed that are significantly less toxic than the original active pharmaceutical ingredients. Giant Raman spectroscopy is a convenient analytical method for studying a mixture of drug degradation products.
Conclusion.
The topic of recycling of medicines and pharmaceutical waste is being actively raised at the moment; it is necessary to regulate at the legislative level the collection of medicines with an expired expiration date from the population.
Methods of chemical inactivation allow to achieve a reduction in the toxicity of products, in relation to the starting substances. Chemical degradation is an effective method of reducing the toxicity of drugs, proved by comparing the spectra of giant Raman scattering of light. For each active pharmaceutical ingredient, you can select the necessary combination of reagents for their effective neutralization and subsequent disposal.
The use of the method of chemical neutralization of the active substance can become a new way of safe disposal of medicines. As a result of the study, we achieved a reduction in the toxicity of the reaction products in comparison with the initial medicinal substances by 1.8 – 166055 times. This method will reduce the release of hazardous substances into the atmosphere, water bodies and soil. Chemical destruction of medicines is significantly safer than high-temperature incineration, eliminating complex equipment and reducing energy costs will optimize and simplify the process of disposing of pharmaceutical waste and medicines in the future.
About the authors
Kiryl Sazonenka
Belarusian state medical university
Author for correspondence.
Email: sazonenko7@gmail.com
ORCID iD: 0000-0002-8893-2026
Belarus, г. Минск, Республика Беларусь
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