RU2470633C1 - Method for ecological, explosion and fire proof technological production of injection forms of antidote amylnitrite - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical technology and represents a method for producing injection forms of the preparation 'amylnitrite' in the form of ampoules characterised by the fact that: cooled ampoules are supplied; a container of the diametre of max. 30 mm cooled by dry ice and containing amylnitrite in the amount of max.100 g is mounted; transport system hoses of the internal diametre of 2.5-3 mm are connected through a sampling needle; amylnitrite is filled out with a flexible-hose pump; the ampoules are sealed with the use of the distant introduction of filling-out and sealing; provided: the procedure performed in workplaces of range of purity 'B' and higher in the presence of local extraction ventilation available to provide min. 10 air chambers per hour, equipped with BAU-a grade absorbent chemical filter; the amylnitrite vapour concentration is maintained in the workplace and in vent air at a level not exceeding the maximum allowable of amylnitrite in 1 mg/m.

EFFECT: invention provides ecological value, explosion and fire proof production of the ampoule forms of the antidote 'amylnitrite'.

Description

The invention relates to medicine, namely to a method of environmentally friendly, explosion-proof, fireproof technological production of injection forms of the amylnitrite antidote, used as an antidote for poisoning with hydrocyanic acid and its salts, as well as hydrogen sulfide.

Currently, Amyl nitrite is not produced as an antidote in injectable form. In the 80s of the last century, it was produced by the Lviv Pharmaceutical Plant, however, due to the high volatility of amyl nitrite (AN), production was difficult in terms of ensuring environmentally friendly fire, explosion-proof production, which led to its closure.

Amylnitrite (Amyliinitris) in 0.5 ml glass ampoules is approved for medical use by order of the Ministry of Health and Social Development of the Russian Federation; No. LS-002436 dated December 29, 2006, GIKiMP (Russia). It is included in the list of antidotes and other drugs used in acute poisoning, as a means of specific pharmacotherapy (order of the Ministry of Health of the Russian Federation of January 8, 2002 No. 9, Appendix No. 7).

It is a clear, yellowish, slightly mobile liquid with high volatility (evaporates at low temperature) and a characteristic fruity smell (pear essence). Highly flammable. Very slightly soluble in water, miscible in all proportions with ethanol, ether and chloroform. The density of the AN is 0.869-0.879 g / cm ³ , the boiling point is 97-98 ° C. The density of the vapor is 4.1 g / l. The amyl nitrite substance contains 97-98% of the basic substance. Possible impurities are diphenylamine, phenylamine, benzylamine. Their number does not exceed 2%. As a stabilizer, it may contain potassium or sodium carbonate. AN is not stable in contact with moist air and water. When AN is decomposed, nitric oxide, monoxide and carbon dioxide are released.

The vasodilating effect upon inhalation of AN begins to appear 30-60 seconds after inhalation, reaches a maximum after 1-2 minutes, lasts 3-5 minutes (sometimes up to 10 minutes).

After inhalation, amyl nitrite is completely adsorbed in the pulmonary alveoli. It is rapidly metabolized by hydrolytic denitration in the blood and partially in the liver with the formation of sodium nitrite, which is excreted in the urine, and isoamyl alcohol, secreted by the lungs. Approximately 33% of an unchanged form is excreted by the kidneys. AN is also absorbed upon contact with the skin and inside, while causing a mild irritating reaction of the mucous membranes, skin and eyes.

The filling and sealing operation is performed on a semi-automatic "Rota".

Given the increased volatility of AN at room temperature, the vial with the original amyl nitrite, as well as the ampoules, are cooled with dry ice before bottling. In order to avoid heating the ampoules, they are fed to the Rota machine with pre-chilled dry ice in a small amount. Sealed ampoules control the tightness and quality of the seal. A label is glued onto the finished conditioning ampoule, placed in a cylindrical bandage. The ampoule, together with the instructions for use, is placed in a polystyrene case. The pencil case is sealed.

Isoamyl nitrite is a weak blasting explosive with a negative oxygen balance. The estimated heat of the explosion according to the method [10] is 2019 kJ / kg, the volume of gaseous products of the explosion is 574 l / kg, TNT equivalent

those. AN is 3.6 times weaker than TNT. Using data on the critical burning diameter of similar mixtures based on nitroglycerin of the same heat of explosion [10], we can assume that the critical diameter of AN burning at a temperature of –50 ° C is 30 mm, 20 ° C is 20 mm, and at + 65 ° C it is 5 mm .

It was determined that to ensure fire and explosion safety during bottling of AN it is necessary to carry out work with small quantities of AN, for example 100 ml. The diameter of the vessel where AN is located should not exceed 30 mm. At the same time, lowering the temperature upon receipt of the drug is a favorable factor contributing to increased safety.

When working with AN, its flammability, the ability to form hazardous concentrations with air, leading to the burning of mixtures or even explosion when ignited, are dangerous.

AN vapors form dangerous combustible mixtures with air. The combustion process of AN in air can be described by the thermochemical equation for maximum heat

(CH ₃ ) ₂ (CH ₂ ) ₂ CHONO + 6.75O ₂ + 25.39N ₂ = 5CO ₂ + 5.5H ₂ O + 25.89N ₂ + Q _{burned up.}

или 26095 кДж/кг амилнитрита

or 26095 kJ / kg of amyl nitrite

The stoichiometric ratio of the components of the combustible mixture corresponds to 3% volume content of AN in air.

The lower flammability limit can be estimated using data and an analogy depending: the lower flammability limit in a mixture with air is the combustible gas content in a stoichiometric mixture [10]. Then the lower flammability limit of AN can be taken equal to 1.7% by volume. According to this characteristic, the flammability of AN is close to that of diethyl ether.

To obtain a combustible mixture, liquid AN must evaporate (case of product spilling onto the table surface) and mix with air.

Taking the volatility of AN equal to the volatility of ethyl ether, which is 0.0129 g / cm ² min. at 18 ° С, and the spill spot of 100 g of AN (115 cm ³ ) ~ 700 cm ^2, we can estimate the time of complete evaporation of AN.

To ensure a safe concentration of AN in air, the dilution air flow rate is determined from the ratio

;

;

или 7,6 м³/час

or 7.6 m ³ / hour

In practice, ventilation is usually used more powerful with 5-20-fold dilution.

So, with an exhaust ventilation capacity of 120 m ³ / h (fifteen-fold dilution).

In 11 minutes the air exchange will be

The concentration of AN in the air will be

those. far from the lower flammability limit (1.75%).

Thus, the use of good exhaust ventilation is a guarantee of fire and explosion safety of the process of filling AN into ampoules.

The most difficult in terms of environmental hazard should be considered the case of a spill on the surface of the table "Company" bottle containing 100 g AN.

During evaporation, a gas-air mixture is formed containing 0.087% by volume AN, exceeding the MPC equal to 1 mg / m ³ .

In order to prevent the release of the concentrated mixture into the atmosphere, it is necessary to install an absorption filter in the ventilation system, for example, filled with activated carbon.

The adsorption capacity of activated carbon BAU-a brand is 60% in iodine.

If we take the same adsorption activity with respect to AN, then the absorption of spilled 100 g of AN requires 167 g or 694 cm ^{3 of} activated carbon (bulk density of BAU-a is 240 g / l).

Thus, the volume of the activated carbon filter should be at least 0.7 liters. In the event of a spill and evaporation of 100 g of AN, the filter with BAU must be replaced.

In a normally proceeding bottling process, the evaporation of AN occurs from two simultaneously filled ampoules ("Rota") with a filling hole diameter of 4 mm and needles. In 12 minutes (the time for filling AN weighing 400 g on the Rota machine into ampoules at a capacity of 1000 amp / h), the operation will evaporate only

For a shift - 4 hours: (12 min + 5 min) = 14 bottling,

where 5 min is the preparation time between operations.

A total of 14 · 0.039 g = 0.55 g will evaporate.

раб. дней.A carbon filter of 1 liter is enough for

slave. days.

With this operating mode, the filter must be changed every six months.

Thus, to ensure safe bottling of AN, it is necessary:

- work is carried out at low temperatures, which reduces volatility and increases the critical diameter of combustion;

- work is carried out with small amounts of amyl nitrite, for example, 100 g in a vessel diameter of up to 30 mm;

- during operation, it is necessary to use ventilation that provides at least 10-fold hourly air exchange from the installation of an absorbing filter (BAU) with a volume of at least 1 liter.

Technological methods for ensuring environmentally, fire, explosion-proof production of AN

To ensure fire and explosion safety, the work was carried out with small amounts of AN.

At present, AN is produced by Merck in plastic containers of 100 or 200 g.

It is for low weight (100 g) that this installation for filling AN into ampoules and their sealing is designed.

The propagation of a possible flame from the place of filling and sealing of ampoules to the container with AN is excluded when using transporting AN hoses of small internal diameter (3 mm), which is lower than the critical diameter of the AN burning, under these conditions, 30 mm.

The ignition of AN itself is unlikely, because ampoules and substance to a temperature below 42 ° C are cooled with dry ice (the freezing temperature of carbon dioxide is 56 ° C), i.e. the combustion of such a product is very difficult in the conditions of the adopted technology, and the transition of combustion to explosion is also excluded by the small volume of the processed AN.

Environmental safety is ensured by the use of additional local forced ventilation from the place of filling the drug into ampoules, by installing a BAU-a carbon filter in the air discharge line, connecting the AN pairs.

Work is carried out on the Rota filling and sealing machine. Instead of laminar, exhaust ventilation is used. "Rota" is installed in a clean room of class "B", the working area is limited to a folding "cap" made of transparent polycarbonate with a distance from the walls of the "Rota" to the walls of the "cap" about 80 cm, the volume of the cap is 14 m ³ . The "Rota" removed protruding nodes:

- the feed chute is shortened to the size of the table feeding the ampoules to the rotor of the filling and filling machine. ~ 400 ampoules for feeding to the screw enter there;

- the receiving chute is shortened to 20 ÷ 30 cm from the plug of the ejection of ampoules from the rotor.

Ampoule, emergency stop switches are duplicated for remote inclusion. At the bottom of the “cap” intake holes are made, and exhaust ventilation provides a 15-fold hour exchange. A gateway (double door) is provided for entry (exit) under the hood.

In order to reduce the length of the transporting AN hoses from the container with the substance to the filling needles, dosing is carried out by a peristaltic pump, the inclusion of which is consistent with the lowering of the filling needles into the ampoules, and the shutdown is with the beginning of the lifting of the needles from the ampoules.

The work of Rota is preliminarily adjusted to ethanol - providing a dose in a 0.5 ml ampoule and high-quality sealing.

The technological process consists of the following operations:

- the apparatchik brings to the “Rota” cold ampoules (stored on dry ice), a container with AN cooled in a Dewar vessel with dry ice (Tp. - 56.6 ° C);

- sets the AN in the Dewar vessel on the table of the "Company";

- connects through the intake needle the hoses from the filling needles to the substance AN. (Hoses with a small bore diameter of ~ 2.5 ÷ 3 mm, with this supply, it is possible to squeeze air out of the hoses without the formation of bubbles);

- comes out from under the "cap" and turns on the remote supply of ampoules.

At a speed of 1000 amp. Per hour, the installation works for 12 minutes.

Installation stops remotely. The apparatchik enters under the cap, within ~ 5 min changes the cassette with cold ampoules, the container with the AN, takes the finished product.

Again comes out from under the “cap”.

Finished products are monitored for the content of AN. With satisfactory bottling quality, the Rota launch is repeated again until the entire planned amount of AN is developed.

The characteristics of the prototypes of the ampoule form "Amylnitrite" obtained by the claimed technology are shown in the table in comparison with the data of FSP 42-0212-6872-05.

INFORMATION SOURCES

1. GOST R50766-95. The rooms are clean. Classification. Certification Methods. Primary requirements.

2. The State Pharmacopoeia of the USSR XI Edition 1987-90.

3. OST 42-510-98. Rules for the organization of production and quality control of medicines (GMP).

4. PB 09-170-97. General Explosion Safety Rules for Explosive Fire Chemical, Petrochemical, and Oil Refining Industries, Moscow, PIO OBT, 1999.

5. Harmful substances in industry, parts I, II, III. Handbook Ed. N.V. Lazareva, Chemistry, Moscow, 1977.

6. Fire and explosion hazard of substances and materials and their extinguishing agents, part 1, 11. Handbook, ed. A.N. Baratova. Moscow, 1990.

7. GOST 12.1.005-88. General hygiene requirements for the air of the working area. Addition to GOST No. 1-12.

8. RD 00001910-5-92. Classification of substances into groups according to the degree of danger for the selection of personal protective equipment in the production of medicines and perfumes and cosmetics, approved. Ministry of Health of the Russian Federation, 1992.

9. Labor protection and environmental safety in the chemical industry. A.S. Bobkov, A.A. Blinov, I.A. Rozdin, E.I. Khabarova, Chemistry, Moscow, 1997.

10. K.K. Andreev and A.F. Belyaev, Theory of explosives., M. Oborongiz, 1960.

Claims (1)

A method for the production of injection forms in the form of ampoules, characterized in that it serves chilled ampoules; establish a container cooled with dry ice with a diameter of less than 30 mm, containing amyl nitrite in an amount not exceeding 100 g; connect the hoses of the conveying system through an intake needle, the inner diameter of which is 2.5-3 mm; amyl nitrite is bottled using a peristaltic pump and ampoules are sealed using remote filling and sealing processes; provided that operations are carried out in industrial premises with a cleanliness class of at least “B” in the presence of additional local exhaust ventilation that provides at least 10-hour air exchange, equipped with an BAU-a absorption charcoal filter; the concentration of amyl nitrite vapor in the workplace and in the air discharged into the atmosphere is maintained at a level not exceeding the maximum permissible concentration of amyl nitrite in 1 mg / m ³ .