In accordance with the instructions of the GFC, water for injection, peach and almond oils are used as solvents for the preparation of injection solutions. Water for injection must meet the requirements of Article 74 GFH. Peach and almond oils must be sterile, and their acid number must not exceed 2.5.
Injection solutions must be clear. The check is carried out when viewed in the light of a reflector lamp and the vessel with the solution must be shaken. Testing solutions for injections for the absence of mechanical contamination is carried out in accordance with special instructions approved by the USSR Ministry of Health.
Injection solutions are prepared in a mass-volumetric manner: the drug is taken by weight (weight), the solvent is taken to the required volume.
The quantitative determination of medicinal substances in solutions is carried out according to the instructions in the relevant articles. Permissible deviation of the content of the medicinal substances in solution should not exceed± 5% from what is stated on the label, unless otherwise indicated in the relevant article.
The original medicinal products must meet the requirements of the GFC. Calcium chloride, caffeine-sodium benzoate, hexamethylenetetramine, sodium citrate, as well as magnesium sulfate, glucose, calcium gluconate and some others should be used as a grade "for injection" with an increased degree of purity.
To avoid contamination with dust, and with it the microflora, the preparations used for the preparation of injection solutions and aseptic medicines "are stored in a separate cabinet in small jars closed with ground glass stoppers, protected from dust by glass caps. When filling these vessels with new portions of the jar preparations , stopper, cap must be thoroughly washed and sterilized each time.
Due to the very responsible method of application and the great danger of mistakes that can be made during work, the preparation of injection solutions requires strict regulation and strict adherence to technology.
Simultaneous preparation of several injectable drugs containing different ingredients or the same ingredients, but in different concentrations, as well as the simultaneous preparation of injectable and any other medicine is not allowed.
At the workplace during the manufacture of injectable drugs, there should be no barbells with drugs that are not related to the drug being prepared.
In pharmacy conditions, the cleanliness of the utensils for the preparation of injectable drugs is of particular importance. For washing dishes, mustard powder diluted in water in the form of a suspension of 1:20 is used, as well as a freshly prepared solution of hydrogen peroxide 0.5-1% with the addition of 0.5-1% detergents ("News", "Progress", "Sulfanol" and other synthetic detergents) or a mixture of 0.8-1% solution of the Sulfanol detergent and trisodium phosphate in a 1: 9 ratio.
The dishes are first soaked in a washing solution heated to 50-60 ° C for 20-30 minutes, and heavily soiled - up to 2 hours or more, after which they are thoroughly washed and rinsed first several (4-5) times with tap water, and then 2-3 times with distilled water. After that, the dishes are sterilized in accordance with the instructions of the GFC (article "Sterilization").
Poisonous substances necessary for the preparation of injectable drugs are weighed by the recipe controller in the presence of an assistant and are immediately used by the latter to prepare the medicine. Receiving a poisonous substance, the assistant is obliged to make sure that the name of the pants-voice corresponds to the purpose in the recipe, as well as the correctness of the set of weights and weighing.
For all, without exception, injectable drugs prepared by an assistant, the latter must immediately draw up a control passport (coupon) with an exact indication of the names of the drug ingredients taken, their quantities and a personal signature.
Before sterilization, all injectable drugs must undergo chemical control for authenticity, and if there is an analytical chemist in the pharmacy, quantitative analysis. Solutions of novocaine, atropine sulfate, calcium chloride, glucose and isotonic sodium chloride solution are subject to qualitative (identification) and quantitative analysis under any circumstances.
In all cases, injectable drugs should be prepared under conditions of the most limited microflora contamination of the drug (aseptic conditions). Compliance with this condition is mandatory for all injectable drugs, including those undergoing final sterilization.
The correct organization of work on the preparation of injectable drugs presupposes providing the assistants in advance with a sufficient set of sterilized dishes, auxiliary materials, solvents, ointment bases, etc.
No. 131. Rp .: Sol. Calcii chloridi 10% 50.0 Sterilisetur! DS. Intravenous injection
To prepare an injection solution, sterilized utensils are required: a tempering bottle with a stopper, a volumetric flask, a funnel with a filter, a watch glass or a piece of sterile parchment as a roof for the funnel. To prepare a solution of calcium chloride for injection, a sterilized graduated pipette with a pear is also required for measuring a concentrated solution of calcium chloride (50%). Before preparing the solution, wash the filter repeatedly with sterile water; with filtered water, rinse and rinse the tempering bottle and stopper.
Measure (or weigh) the required amount of the drug, wash it into a volumetric flask, add a small amount of sterile water, then bring the volume of the solution to the mark. The prepared solution is filtered into a tempering bottle. During filtration, the vessel with the solution and the funnel are closed with a watch glass or sterile parchment. Examine the solution for the absence of mechanical impurities.
After capping the bottle with the injection solution, tightly tie the cork with wet parchment, write the composition and concentration of the solution on the strapping, put a personal signature and sterilize the solution at 120 ° C for 20 minutes.
No. 132. Rp .: Sol. Glucosi 25% 200.0 Sterilisetur! DS.
To stabilize the specified solution, a previously prepared solution of the Weibel stabilizer is used (see p. 300), which is added to the injection solution in an amount of 5%, regardless of the glucose concentration. The stabilized glucose solution is sterilized by running steam for 60 minutes.
When making injection solutions of glucose, it should be borne in mind that the latter contains 1 molecule of crystallization water, therefore, correspondingly more glucose should be taken using the following GPC equation:
where a- the amount of the drug prescribed in the prescription; b- the moisture content of glucose available in the pharmacy; NS- the required amount of glucose available in the pharmacy.
If the moisture analysis shows a moisture content in the glucose powder equal to 9.6%, then the drug should be taken:
and for 200 ml of solution - 55 g.
No. 133. Rp .: Sol. Cofieini-natrii benzoatis 10% 50.0 Sterilisetur! DS. 1 ml under the skin 2 times a day
Recipe No. 133 gives an example of a solution of a substance that is a salt of a strong base and a weak acid. According to the instructions of the State Pharmaceutical Chemistry (article No. 174), guided by the prescription for an ampouled solution of sodium caffeine-benzoate, 0.1 N is used as a stabilizer. sodium hydroxide solution at the rate of 4 ml per 1 liter of solution. In this case, add 0.2 ml of sodium hydroxide solution (pH 6.8-8.0). The solution is sterilized with flowing steam for 30 minutes.
No. 134. Rp .: 01. Camphorati 20% 100.0 Sterilisetur! DS. 2 ml under the skin
Recipe # 134 is an example of an injection solution that uses oil as a solvent. Camphor is dissolved in most of the warm (40-45 ° C) sterilized peach (apricot or almond) oil. The resulting solution is filtered through a dry filter into a dry volumetric flask and brought up to the mark with oil, rinsing the filter with it. Next, the contents are transferred into a sterile bottle with a ground stopper.
Sterilization of a solution of camphor in oil is carried out with fluid steam for 1 hour.
Physiological solutions. Physiological solutions are those that, in terms of the composition of solutes, are capable of supporting the vital activity of cells, surviving organs and tissues, without causing significant shifts in physiological equilibrium in biological systems. Physicochemical properties of physiological solutions and adjacent blood-substituting fluids are very close to human blood plasma. Physiological solutions must be isotonic, contain chlorides of potassium, sodium, calcium and magnesium in proportions and quantities characteristic of blood serum. Their ability to maintain a constant concentration of hydrogen ions at a level close to blood pH (~ 7.4) is very important, which is achieved by introducing buffers into their composition.
Most saline solutions and blood-substituting fluids usually contain glucose, as well as some high-molecular compounds to provide better nutrition of cells and create the necessary redox potential.
The most common saline solutions are Petrov's liquid, Tyrode's solution, Ringer-Locke's solution and a number of others. Sometimes a 0.85% sodium chloride solution is conventionally called physiological, which is used in the form of injections under the skin, into a vein, in enemas for blood loss, intoxication, shock, etc., as well as for dissolving a number of medicines during injection.
Course work
Solutions for injection
I. Introduction
II. Targets and goals
III. Injection solutions as a dosage form
IV. Process stages
1. Preparatory work
2. Making a solution
Filtration and packing
Sterilizing the solution
Quality control of finished products
Vacation registration
V. Practical part
Vi. experimental part
Used Books
I introduction
One of the most important dosage forms is solutions for injections - solutionses pro injectionibus.
Solution - a liquid dosage form obtained by dissolving one or more medicinal substances, intended for injection use.
The unusual breadth of use of injection solutions is due to the relatively greater efficacy and speed of the onset of the effect with parenteral administration of medicinal substances. This is due to the fact that with this method of administration, medicinal substances enter the internal environment of the body, bypassing natural barriers. Thus, firstly, the onset of the pharmacological effect is accelerated; secondly, the dosage accuracy increases, since those natural losses of the medicinal substance are eliminated, which are inevitable when it is absorbed by the mucous membrane of the digestive system; thirdly, the substance, reacting with the tissues of the body with its entire mass (especially with intravenous administration), causes a more pronounced effect than with the enteral route of administration. Another advantage of these solutions is that injections can be given to a patient who is unable to take medications due to loss of consciousness, the presence of a craniofacial injury, etc. In addition, ampouled injection solutions are portable, easy to store and transport. All this makes them one of the most acceptable dosage forms in the practice of medical institutions of the most diverse profile. The mass production of ampoules-syringes further expands the possibilities of using injection solutions for emergency care.
At the same time, the injection method of drug administration also has disadvantages, which should be taken into account by doctors and pharmacists. Due to the fact that drugs are administered bypassing the protective barriers of the body, there is a risk of infection, therefore, one of the most important requirements for injectable drugs is sterility. Direct injection into tissue can cause changes in osmotic pressure, pH and other physiological disturbances. In this case, there is a sharp pain, burning sensation, and sometimes febrile symptoms. When the drug is injected directly into the blood, there is a danger of blockage of small blood vessels with solid particles or air bubbles, the size of which exceeds the diameter of the vessels, which is very dangerous. In this regard, strict requirements are imposed on injectable drugs, which exclude the possibility of changes in the composition of the blood and blockage of blood vessels (embolism).
II. Goals and objectives of the course
To study the theoretical foundations of the technology for the preparation of dosage forms for injections.
Get acquainted with the latest research and achievements in this area (in the preparation of auxiliary material, stabilization, isotonization and sterilization of injection solutions, as well as their quality control).
Under the conditions of a production pharmacy, carry out the following work:
) Study and compare with regulatory documents:
conditions for the manufacture of injectable dosage forms;
conditions for obtaining water for injection;
equipment and equipment of the aseptic unit, its care;
) Evaluate the quality of the infusion solution by microbiological indicators, using the example of isotonic sodium chloride solution.
III. Injection solutions, as a dosage form
There are two forms of introducing fluids into the body - injection (injectio - injection) and infusion (infusio - infusion). The difference between them lies in the fact that the former are relatively small volumes of liquid injected with a syringe, and the latter are large volumes injected by drip or jet.
Infusion solutions are able to maintain body functions without causing a shift in physiological equilibrium or bringing this equilibrium back to normal. They, as a rule, contain macronutrients characteristic of blood plasma, but they can also be saturated with microelements that perform an important physiological function.
Blood in the human body is 7.8% in relation to the total mass, plasma - 4.4%, blood corpuscles - 3.4%. The diameter of the erythrocyte is on average 7.55 ± 0.0009 microns.
The widespread use of injectable dosage forms in medical practice has become possible as a result of the search for effective methods of sterilization, the invention of special vessels (ampoules) for storing sterile dosage forms.
The idea of introducing medicinal substances with a violation of the skin belongs to the doctor A. Furcroix (1785). The Russian physician P. Lazarev (1851) was the first to use subcutaneous injection with a silver tip extended into a needle. In 1852, the French physician Sh.G. Pravats proposed a syringe of modern design.
Injection classification
Intradermal injections, or intracutaneous (injections intracutantat). Very small volumes of liquid (0.2 - 0.5 ml) are injected into the skin between its outer (epidermis) and inner (dermis) layers.
Subcutaneous injections (injections subcutaneae). Solutions (aqueous or oily), suspensions, emulsions, usually in small volumes (1-2 ml), can be introduced into the subcutaneous tissue. Sometimes up to 500 ml of liquid can be injected subcutaneously within 30 minutes by the drip method.
When injected subcutaneously, the injection is carried out into the outer surface of the shoulders and subscapularis. Absorption occurs through the lymphatic vessels, from where the medicinal substances enter the bloodstream. The absorption rate depends on the nature of the solvent. Aqueous solutions are absorbed quickly, oil solutions, suspensions and emulsions are absorbed slowly, providing a prolonged action.
Intramuscular injections (injectiones intramusculares). Small volumes (sometimes up to 50 ml) of liquid, usually 1-5 ml, are injected into the thickness of the muscles, mainly in the buttocks, in the upper outer square, the least rich in blood vessels and nerves. The absorption of medicinal substances occurs through the lymphatic vessels.
As in the case of subcutaneous injections, solutions (aqueous, oily) suspensions and emulsions can be administered intramuscularly. The absorption rate also depends on the nature of the dispersed system and the nature of the solvent (dispersion medium), but, as a rule, the absorption of medicinal substances is faster than in the case of subcutaneous injections.
Intravascular injection. Only aqueous, completely transparent solutions that mix well with blood can be injected inside the vessels.
Intravenous injections (injections intravenosae) are most widely used in medical practice. Aqueous solutions in volumes from 1 to 500 ml or more are injected directly into the venous bed, more often into the ulnar vein. The action of medicinal substances is developing rapidly. Infusion of large volumes of solution is carried out slowly 120-180 ml for 1 hour, often drip (in this case, the solution is injected into a vein not through a needle, but through a cannula at a rate of 40-60 drops per minute). The method allows you to inject up to 3000 ml of liquid.
When administered intravenously, the drug enters immediately and completely into the systemic circulation, while showing the maximum possible therapeutic effect. In this way, the absolute bioavailability of the medicinal substance is achieved. At the same time, the intravenous solution can serve as a standard form in determining the relative bioavailability of medicinal substances prescribed in other dosage forms.
Intra-arterial injections (injections intraartheriales) is the injection of solutions, usually into the femoral or brachial artery. In this case, the action of medicinal substances manifests itself especially quickly (after 1-2 s).
The buffering properties of blood, which regulate pH, make it possible to inject fluids with a pH from 3 to 10 into the blood. Oil solutions cause embolism (capillary clogging), and liquid paraffin as a solvent is unsuitable even for intramuscular and subcutaneous administration, since it forms painfully resistant oleomas (oily tumors ). It is also impossible to inject suspensions into the blood; emulsions can be injected, but only with a particle diameter not exceeding the diameter of erythrocytes (no more than 1 micron). These are emulsions for parenteral nutrition and emulsions that function as oxygen carriers.
Injections into the central spinal canal (injectiones intraarachnoidales, s. Injections cerebrospinales, s. Injections endolumbales0. Small volumes of fluid (1-2 ml) are injected into the subarachnoid space between the soft and arachnoid membranes in the region III-V of the lumbar vertebrae. Usually this method is used to inject anesthetic solutions and solutions of antibiotics, while absorption is slow.For spinal injections, use only true solutions with a pH of at least 5 and not more than 8.
Spinal injections should only be performed by an experienced surgeon, as earlier the filament of the spinal cord can lead to paralysis of the lower extremities.
Less commonly, other types of injections are used: suboccipital (intracranial - injectones suboccipitales), peri-root (injections paravertebrales), intraosseous, intraarticular, intrapleural, etc. For intracranial injections, only true aqueous solutions (1 - 2 ml) of a neutral reaction are used. The action of the medicinal substance develops instantly.
In recent decades, the method of drug administration using needleless injectors has been widely used. Medicinal substances are injected with a very thin stream (with a diameter of tenths and hundredths of a millimeter) under high pressure (up to 300 kgf / cm). The method is relatively painless, does not damage the skin, provides a rapid onset of the pharmacological effect, requires more rare sterilization of the injector, and can provide a large number of injections per unit of time (up to 1000 injections per hour).
IV. Process stages
In the technological process for the production of injection solutions, 6 main stages are distinguished:
Preparatory activities.
1. Creation of aseptic manufacturing conditions (preparation of aseptic unit, personnel, equipment, auxiliary material, container closures).
2. Preparation of medicinal and auxiliary substances.
Dissolution and chemical control.
1. Dosing (measuring) the solvent.
2. Adding medicinal substances.
3. Adding a stabilizer.
4. Chemical control.
Filtration and packing.
1. Filtration
2. Dosing of the solution.
3. Capping with rubber stoppers.
4. Primary control of the absence of mechanical inclusions.
5. Capping (rolling) with metal caps.
6. Labeling of vials (preparation for stage 4)
Sterilization.
Quality control of manufactured medicinal products.
1. Secondary control of the absence of mechanical inclusions.
2. Physical and chemical analysis.
3. Braking.
Marking (registration for vacation).
Particular attention should be paid to the fact that in accordance with the order of the Ministry of Health of the Russian Federation No. 214 of July 16, 1997. the manufacture of sterile solutions is prohibited in the absence of data on the chemical compatibility, medicinal substances included in them, technology and sterilization mode, as well as in the absence of analysis methods for complete chemical control.
Preparatory work
Preparatory work includes preparation of premises, equipment, air disinfection, preparation of dishes, container closures, auxiliary materials, solvent, medicinal substances, and personnel. These activities are regulated by the order of the Ministry of Health of the Russian Federation No. 309 dated October 21, 1997. The list of preventive measures is also given in clause 3 of the Instruction for quality control of medicines manufactured in pharmacies, approved by the Ministry of Health of the Russian Federation dated June 16, 1997. by order No. 214.
1.1 Requirements and preparation for operation of the premises and equipment of the aseptic unit
Preparation of injection solutions is carried out in an aseptic unit. The premises of the aseptic unit should be located in an isolated compartment and exclude the intersection of "clean" and "dirty" air flows. The aseptic unit should have a separate entrance or be separated from other production areas by locks.
Before entering the aseptic unit, there should be rubber mats or porous mats soaked in disinfectants (0.75% chloramine B solution with 0.5% detergent or 3% hydrogen peroxide solution with 0.5% detergent).
The sluice should provide a bench for changing shoes with cells for specials. shoes, a wardrobe for a dressing gown and biks with sets of sterile clothes, a sink (a faucet with an elbow or a foot drive), an air dryer and a mirror, a hygienic kit for treating hands, instructions on how to dress and handle hands, rules of conduct in the aseptic unit.
In the assistant-aseptic, water and sewerage connections are not allowed.
To protect the walls from damage during the transportation of materials or products (carts, etc.), it is necessary to provide special corners or other devices.
To exclude the flow of air from the corridor and production premises into the aseptic unit, it is necessary to provide supply and exhaust ventilation in the latter. In this case, the movement of air flows should be directed from the aseptic unit to the adjacent premises, with the predominance of the inflow over the exhaust.
It is recommended, using special equipment, to create horizontal or vertical laminar flows of clean air throughout the room or in separate local areas to protect the most critical areas or operations (clean chambers), or tables with laminar air flow. They should have work surfaces and a hood made of smooth, durable material.
The laminar flow rate is within 0.3-0.6 m with regular monitoring of sterility at least 1 time per month.
The aseptic unit room must be kept impeccably clean. Wet cleaning assistant - aseptic is carried out at least once a shift at the end of the shift using disinfectants. Dry cleaning of the premises is not allowed under any circumstances. A general cleaning is carried out once a week, if possible with the release of equipment.
It is necessary to strictly observe the sequence of stages when cleaning the aseptic unit. You should start with aseptic. First, the walls and doors are washed from ceiling to floor. Movements should be smooth, always from top to bottom. The stationary equipment is then washed and disinfected and, last but not least, the floors.
All equipment and furniture brought into the aseptic unit are pre-treated with a disinfectant solution.
The preparation of solutions of disinfectants should be carried out by specially trained personnel in accordance with applicable instructions.
For disinfection of hard surfaces, walls and floors, the following disinfectants are allowed. Waste from production and garbage should be collected in special containers with a drive lid. Garbage should be removed at least once a shift. Hand wash basins and trash containers are washed and disinfected daily. 2 Air disinfection For disinfection of air and various surfaces in an aseptic room, bactericidal emitters (stationary or mobile) with open or shielded lamps are installed. The number and power of germicidal lamps should be selected at the rate of at least 2-2.5 W, the power of an unshielded emitter per 1 m³ of the room volume. With shielded bactericidal lamps - 1 W per 1 m³. Wall-mounted bactericidal irradiators OBN-150 are installed at the rate of 1 irradiator per 30 m³ of the room; ceiling-mounted OBP-300 - one per 60 m³; OBP-450 mobile with open lamps is used for quick disinfection of air in rooms with a volume of up to 100 m³. The optimal effect is observed at a distance of 5 m from the irradiated object. Open bactericidal lamps are used in the absence of people during breaks between work, at night or at a specially designated time before starting work for 1-2 hours. Switches for open lamps should be located in front of the entrance to the production area and equipped with a signal inscription "Germicidal lamps are on" or "Do not enter, germicidal irradiator is on". Staying in rooms where unshielded lamps are operating is prohibited. The entrance to the room is allowed only after the unshielded germicidal lamp has been turned off, and a long stay in the specified room - only 15 minutes after the shutdown. When using shielded lamps, air disinfection can be carried out in the presence of people. In these cases, the lamps are placed in special fittings at a height of at least 2 m from the floor. The fittings should direct the beam of the lamp beams upward at an angle ranging from 5 to 80º above a horizontal surface. Shielded germicidal lamps can operate up to 8 hours a day. If, after 1.5-2 hours of continuous operation of the lamps, in the absence of sufficient ventilation, you smell ozone in the air, it is recommended to turn off the lamps for 30-60 minutes. When using a tripod irradiation unit for special irradiation of any surfaces, it must be as close as possible to carry out irradiation for at least 15 minutes. 3 Personnel training The personnel is one of the main sources of pollution of the ambient air and drug solutions with microorganisms and foreign particles. Therefore, he is subject to increased demands for responsibility, accuracy and discipline. The personnel working in the aseptic unit must know the basics of hygiene and microbiology, sanitary requirements and rules for working in aseptic conditions. Periodically (annually) personnel must undergo retraining, and newcomers to work must be familiar with the relevant documents governing the production of sterile solutions. To work in aseptic conditions (at the site of preparation, filling, capping), a set of clothing must be sterile and consist of a gown, a hat, rubber gloves, shoe covers and a bandage (for example, a 4-layer gauze "petal" type). It is optimal to use a trouser suit with a helmet or overalls. In this case, clothes should be gathered at the wrists and high on the neck. The personnel are not allowed to have clothing in which they are on the street, as well as bulky, fleecy clothing under sterile sanitary clothing. A set of clothes is sterilized in bixes in steam sterilizers at 120 ° C for 45 minutes or at 132 ° C for 20 minutes and stored in closed bixes for no more than 3 days. The footwear of the personnel of the aseptic unit is disinfected from the outside before and after the end of work (wiping twice with a disinfectant solution) and stored in closed cabinets or boxes in the airlock. At the entrance to the gateway, they put on shoes, wash their hands, put on a dressing gown, a hat, a bandage that is changed every 4 hours, shoe covers, and disinfect hands. Sterile rubber gloves (talc-free) should be worn on the treated hands of the personnel employed in the filling and sealing area of the solution, especially not subject to thermal sterilization, with the sleeves tucked into gloves. When processing hands, it is necessary to minimize the number of microorganisms on the skin of the hands and slow down the flow of new ones from the depths of the skin. For mechanical removal of dirt and microflora, hands are washed with warm running water with soap and a brush for 1 - 2 minutes, paying attention to the periungual spaces. To remove soap, hands are rinsed with water and wiped dry, after wearing sterile clothing, hands are washed off with water and treated with disinfectants. It is optimal to use such varieties of soap as gift, bath, baby, household soaps, which have a high foaming ability. Varieties with the addition of special components (sulsen, tar, boron-thymol, carbolic soaps) are not effective enough to reduce microbial contamination of the skin of personnel's hands. The brushes are pre-washed, dried and sterilized in a steam sterilizer at a temperature of 120 ° C for 20 minutes, or boiled in water or 2% sodium bicarbonate solution in an enamel bowl for 15 minutes. They are stored in sterile bixes or dishes, taking out as needed with a sterile forceps, which should be stored in a glass with a 0.5% solution of chloramine B. For hand disinfection, the following agents are used: chlorhexidine bigluconate (gibitana) solution 0.5%, iodopyrone solution 1%, chloramine solution 0.5%. They must be alternated every 5-6 days to prevent the emergence of resistant forms of microorganisms. When disinfecting hands with iodopyrone or chlorhexidine solution, the drug is applied to the palms in an amount of 5 - 8 ml and rubbed into the skin of the hands; when processing hands with a solution of chloramine, they are immersed in the solution and washed for 2 minutes, then they are allowed to dry. After finishing work, hands are washed with warm water and treated with emollients, for example, a mixture of equal parts of glycerin, 10% ammonia solution and water. When working under aseptic conditions: it is forbidden to enter the aseptic room in non-sterile clothing and leave the aseptic unit in sterile clothing; smoking and eating; pick up and reuse objects that have fallen to the floor during work; personnel movements should be slow, smooth and rational. It is advisable to provide distinctive signs in special clothing of personnel, for example, hats of a color other than white, so that it is easy to recognize violations of the order of movement of someone from the personnel in the aseptic area, between rooms or outside the aseptic unit. talking and moving around in the aseptic unit should be limited so as not to increase the number of excreted microorganisms and particles. If necessary, oral communication with an employee; outside the aseptic unit, use a telephone or other intercom. the nose should be cleaned in the airlock using a sterile handkerchief or napkin; hands should then be washed and disinfected. it is recommended to wear a short haircut while the hair should be. be tucked away under a tight-fitting hat or kerchief, do hygienic manicure without nail polish, do not powder yourself before and during work, paint your lips only with oily lipstick, do not wear jewelry (earrings, rings, brooches, etc.). In order to avoid the spread of microorganisms, all cases of the disease (skin, colds, cuts, abscesses, etc.) must be notified to the administration. 4 Preparation of dishes and container closures 1. Preparation of dishes includes the following operations: aging, viewing and rejection, disinfection (if necessary), soaking and washing (or washing and disinfecting treatment), rinsing, sterilization, quality control of processing. For the packaging of sterile solutions, bottles and vials made of neutral glass of the HC-1 and HC-2 brands are used. For solutions with a shelf life of no more than 2 days, it is allowed to use AB-1 type alkaline glass bottles after their preliminary processing (Appendix No. 2). If glassware arrives at the pharmacy without specifying the brand of glass, its alkalinity is determined (Appendix No. 3) and, if necessary, the glassware is subjected to appropriate processing and control. New and used dishes (in non-infectious departments of medical institutions) are washed outside and inside with tap water to remove mechanical impurities and residues of medicinal substances, soaked in a solution of detergents for 25 - 30 minutes. Heavily soiled dishes are soaked for a longer time (up to 2-3 hours) (Appendix No. 4). Dishes used in the infectious diseases ward are disinfected before washing (Appendix No. 5). After disinfection, the dishes should be rinsed in running water. Repeated use of the same disinfectant solution is not allowed. After soaking in a detergent or detergent-disinfectant, the dishes are washed in the same solution using a brush or a washing machine. For the completeness of rinsing of detergents containing surfactants, the dishes are rinsed 5 times with running tap water and 3 times with purified water, filling the bottles and bottles completely. With machine rinsing, depending on the type of washing machine, the holding time in rinsing mode is 5 - 10 minutes. After treatment with detergent solutions of mustard or sodium bicarbonate with soap, five times treatment with water is sufficient (2 times with tap water and 3 times with purified water). Optimally, the last rinsing of the dishes is carried out with purified water or water for injection (for injection solutions), filtered through a microfilter with a pore size of no more than 5 microns. The quality control of the washed dishes is carried out visually by the absence of stains and smudges, by the uniformity of water flowing from the walls of the bottles after rinsing them. In washes from the inner surface of the dishes, there should be no mechanical inclusions visible to the naked eye. If necessary, the completeness of the rinse off of synthetic detergents and detergents and disinfectants is determined by the pH value by the potentiometric method, the pH of the water after the last rinsing of the dishes must correspond to the pH of the original water. After rinsing, it is advisable to cover each bottle or bottle with aluminum foil to prevent contamination of the dishes during the sterilization of the movement. Clean dishes are sterilized with hot air at 180 ° C for 60 minutes. or saturated steam under pressure at 120 ° C for 45 minutes. After reducing the temperature in the sterilizer to 60. At 70 o C, the dishes are taken out, closed with sterile stoppers and immediately used for filling solutions. It is allowed to store utensils for 24 hours in conditions excluding contamination. As an exception, large-capacity cylinders are allowed to be disinfected after washing by steaming with live steam for 30 minutes. After sterilization (or disinfection, containers) are closed with sterile stoppers, foil or tied with sterile parchment and stored under conditions that prevent contamination for no more than 24 hours. 5 Processing of closures, auxiliary material 1. The preparation process makes it possible to obtain sterile plugs that do not contain visible mechanical impurities and consists of the following operations: viewing and rejection, washing, sterilization, drying (if necessary). For sealing vials and bottles with aqueous, aqueous-alcoholic and oil solutions, corks from a rubber compound of the IR-21 brands (light beige), IR-119, IR-119A (gray), 52-369, 52-369 / 1, 52-369 / 2 (black), it is allowed to use rubber stoppers of 25P grade (red) for aqueous solutions of extemporal production. New rubber plugs are washed by hand or in a washing machine in a hot (50-60 ° C) 0.5% solution of "Lotos" or "Astra" detergents for 3 minutes (the weight ratio of plugs and detergent solution is 1: 5) ; washed 5 times with hot tap water, each time replacing it with fresh, and 1 time with purified water; boiled in 1% sodium bicarbonate solution for 30 minutes, washed once with tap water and 2 times with purified water. Then they are placed in glass or enameled containers, filled with purified water, closed and kept in a steam sterilizer at -120 ° C for 60 minutes. The water is then drained and the plugs are washed again with purified water. After processing, the plugs are sterilized in bixes in a steam sterilizer at 120 ° C for 45 minutes. Sterile stoppers are stored in closed containers for no more than 3 days. After opening the bix, the plugs must be used within 24 hours. When preparing for future use, rubber plugs after processing (clause 2.3.), Without subjecting to sterilization, are dried in an air sterilizer at a temperature not exceeding 50 ° C for 2 hours and stored for no more than 1 year in closed containers or cans in a cool place. Before use, rubber stoppers are sterilized in a steam sterilizer at 120 ° C for 45 minutes. Used rubber plugs are washed with purified water, boiled in purified water 2 times for 20 minutes, each time replacing the water with fresh one, and sterilized as described above. Used rubber stoppers in the infectious diseases ward are disinfected and not reused. Washes from treated corks should not contain mechanical impurities visible to the naked eye. After viewing and rejection, aluminum caps are kept for 15 minutes in a 1 - 2% solution of detergents heated to 70 - 80 o C. The ratio of the weight of the caps to the volume of the cleaning solution is 1: 5. Then the solution is drained and the caps are washed with running tap water, then with purified water ... Clean caps are placed in bixes and dried in an air sterilizer at a temperature of 50-60 ° C. They are stored in closed containers (bixes, cans, boxes) under conditions excluding their contamination. The auxiliary material (cotton wool, gauze, parchment paper, filters, etc.) is placed in bixes or jars and sterilized in a steam sterilizer at 120 ° C for 45 minutes. Store in closed boxes or jars for 3 days, after opening the material is used within 24 hours. Various glass, porcelain and metal objects (flasks, cylinders, funnels, etc.) are sterilized in an air sterilizer at 180 ° C for 60 minutes or in a steam sterilizer at 120 ° C for 45 minutes using sterilization boxes, bixes, two-layer coarse calico or parchment packaging. Removable parts of technological equipment that are in direct contact with the drug solution (rubber and glass tubes, filter holders, membrane microfilters, gaskets, etc.) are processed, sterilized and stored in the modes described in the documentation for the use of the corresponding equipment. 6 Preparation and selection of solvent Medicinal substances and solvents used for the preparation of injection solutions must comply with the requirements of the State Pharmacopoeia, FS or VFS. Special requirements apply to solvents for the preparation of injection solutions. Sterilization only leads to the death of microorganisms; killed microbes, their waste products and decay products remain in the water and have pyrogenic properties, causing severe chills and other undesirable phenomena. The most sharply pyrogenic reactions are manifested with vascular, spinal and intracranial injections. Therefore, the preparation of injection solutions should be carried out in water that does not contain pyrogenic substances. A method for the detection and norms of the content of pyrogen-forming microorganisms before sterilization for injection and infusion solutions of pharmaceutical manufacture, for which there is a normative and technical documentation, has been introduced. To prevent the oxidation of medicinal substances, it is necessary that the water used contains a minimum amount of dissolved oxygen. Therefore, it is necessary to use freshly boiled water for injection. Water for injection must meet the requirements for purified water and be pyrogen-free. It can be stored for no more than 24 hours under aseptic conditions. In pharmacies, control and tests for the pyrogenicity of water for injection are carried out at least 2 times a quarter. Purified water and water for injection must undergo a qualitative analysis (samples are taken from each cylinder, and when water is supplied through the pipeline at each workplace) for the absence of Cl²¯, SO ²¯ Ca² + salts. Water intended for the preparation of sterile solutions, in addition to the tests indicated above, is checked for the absence of reducing substances, ammonium salts and carbon dioxide in accordance with the requirements of the current State Pharmacopoeia. On a quarterly basis, water for injection and purified water are sent to the analytical laboratory for complete chemical analysis. The results of the control of purified water and water for injection must be recorded in a journal, the form of which is given in Appendix 3 to the instruction of the order of the Ministry of Health of the Russian Federation No. 214. Requirements for the receipt, transportation and storage of water for injection are given in clause 7 of the instruction of order No. 309. Obtaining water for injection should be carried out in the room of the aseptic distillation unit, where it is strictly forbidden to perform any work not related to distillation of water using water distillers AE-25, DE-25, AA-1, A-10, AEVS-4, etc. Water distillers of these brands are equipped with separators that prevent the passage of water droplets, which may contain microorganisms, into the condensation chamber. Water for injection is used freshly prepared and stored at a temperature of 5-10 ° C or 80-95 ° C in closed containers made of materials that do not change the properties of water, protecting it from mechanical impurities and microbiological contaminants, no more than 24 hours. The resulting water for injection is collected in sterilized industrial containers treated with steam (as an exception, glass cylinders). Collections should have a clear inscription "Water for injection", a tag is attached indicating the date of receipt, the analysis number and the signature of the person who checked it. If several collections are used at the same time, they are numbered. Containers for collecting and storing water for injection must indicate on the labels that the contents are not sterilized. In addition to the instruction of Order No. 309, several FSs have now been developed to regulate the quality of water for injection: FS42-2620-97 "Water for injection" FS42-213-96 "Water for injection in ampoules" FS42-2980-99 "Water for injection in vials." Peach, almond, olive and other fatty oils are also used as a solvent in the preparation of injection solutions. These are low-viscosity, highly mobile liquids that can pass through the narrow channel of the needle. GFCI requires that oils for injection be obtained by cold pressing from fresh seeds, well dehydrated, containing no protein. In addition, the acidity of the oil is of particular importance. Oils for injection must have an acid number of at least 2.5, otherwise they can cause soreness at the injection site. Alcohols (ethyl, benzyl, propylene glycol, polyethylene oxide 400, glycerin), some ethers (benzyl benzoate, etiooleate) can also be used as a solvent for injection solutions. It is unacceptable to use vaseline oil as a solvent for injections, which is not absorbed by the body, but when injected under the skin forms non-absorbable oily tumors. 7 Preparation of medicinal and auxiliary substances Medicinal substances used in the manufacture of injection solutions must meet the requirements of the State Pharmacopoeia, FS, VFS, GOST, reagent grade qualifications. (chemically pure) and analytical grade (clean for analysis). Some substances undergo additional purification and are produced with increased purity, qualification "Suitable for injection". Impurities in the latter can either have a toxic effect on the patient's body, or reduce the stability of the injection solution. Glucose and gelatin (a favorable environment for the development of microorganisms) may contain pyrogenic substances. Therefore, a test dose for pyrogens is determined for them in accordance with article GFKh1 "Pyrogenicity test". Glucose should not give a pyrogenic effect when a 5% solution is introduced at the rate of 10 mg / kg rabbit weight, gelatin when a 10% solution is introduced. Benzylpenicellin potassium salt is also tested for pyrogenicity and toxicity. For some drugs, additional studies are carried out for purity: calcium chloride is checked for dissolution in ethanol and the iron content, hexamethylenetetramine - for the absence of amines, ammonium salts and chloroform; caffeine sodium benzoate - for the absence of organic impurities (the solution should not grow cloudy or precipitate within 30 minutes when heated); magnesium sulfate for injection should not contain manganese and other substances, which is noted in the regulatory documentation. Some substances affect the stability of injection solutions. For example, sodium bicarbonate of chemically pure grade. and analytical grade, meets the requirements of GOST 4201-66, as well as "Suitable for injection", must withstand additional requirements for the transparency and colorlessness of a 5% solution, calcium and magnesium ions must be no more than 0.05%, otherwise During thermal sterilization of the solution, opalescence of the carbonates of these cations will be released. Eufilin for injection should contain an increased amount of ethylenediamine (18-22%), used as a stabilizer of this substance in an amount of 14-18% in solutions for oral administration, and withstand additional dissolution tests. Sodium chloride (chemically pure), produced in accordance with GOST 4233-77, must meet the requirements of GF, potassium chloride (reagent grade) must meet the requirements of GOST 4234-65 and GF. Reagent grade sodium acetate must meet the requirements of GOST 199-68, sodium benzoate must not contain more than 0.0075% iron. Thiamine bromide injection solution must withstand additional tests for clarity and colorlessness. Medicinal substances used for the preparation of injection solutions are stored in a separate cabinet in sterile barbells, closed with ground stoppers and the inscription "For sterile dosage forms". Heat-resistant substances are subjected to thermal sterilization before filling the rod. The barbells are washed and sterilized before filling. Each rod must be affixed with a tag indicating: batch number, manufacturer's enterprise, analysis number of the control and analytical laboratory, expiration date, date of filling and the signature of the person who filled in the rod. Filling in and control over the expiration dates is carried out in accordance with the order of the Ministry of Health of the Russian Federation No. 214 of July 16, 1997. 2. Making a solution Sterile solutions are made by mass-volumetric method. In a measuring tank-mixer or other container, medicinal substances are dissolved in part of the water, auxiliary substances (stabilizers, isotonizing, etc.) are added, if necessary, the solution is mixed and brought to a certain volume with a solvent. In the absence of volumetric glassware, the volume of water is calculated using the density values of a solution of a given concentration or the volume increase factor. The sequence of measuring or mixing solutions is determined by the specifics of the recipe. The volume of injection solutions in vials in accordance with the GF should always be greater than the nominal. Nominal volume, ml Filling volume, ml Number of vessels for filling control, pcs Non-viscous solutions Viscous solutions 2% more than nominal 3% more than nominal In the absence of volumetric glassware of large volumes, tables should be used to determine the amount of the solvent (see table No. 1). Isotonic equivalents of medicinal substances for sodium chloride are given in the appendix are given in table. # 2. Tab. # 1. Coefficients of increasing the volume of an aqueous solution when dissolving medicinal substances *
Name of medicinal substances Volume increase factors, ml / g Amidopyrine Ammonium chloride Analgin Antipyrine Barbamil Barbital sodium Benzylpenicillin sodium salt Hexamethylenetetramine - // - (humidity 10%) Diphenhydramine Gelatose Isoniazid Iodine (in potassium iodide solution) Potassium bromide Potassium permanganate - // - chloride Calcium gluconate - // - lactate - // - chloride Urea Ascorbic acid - // - boric Glutamic acid - // lemon Collargol Caffeine-sodium benzoate Magnesium sulfate Methylcellulase Sodium acetate - // - acetate (anhydrous) - // - benzoate - // - bromide - // - hydrocarbonate - // - hydrocitrate - // - nitrate Sodium nitrite - // - nucleinate - // - para-aminosalicylate - // - salicylate - // - sulfate (crystalline) - // - tetraborate - // - thiosulfate Sodium chloride - // - citrate Novocaine Novocainamide Norsulfazole sodium Osarsol (in sodium bicarbonate solution) Papaverine hydrochloride Pachikarpina hydroiodide Pilocarpine hydrochloride Pyridoxine hydrochloride Polyvinylpyrrolidone Protargol Resorcinol Sucrose Lead Acetate Silver nitrate Spasmolitin Polyvinyl alcohol Streptomycin sulfate Soluble streptocide Sulfacyl sodium Thiamine bromide Trimecaine Crystalline phenol Quinine hydrochloride Chloramine B Chloral hydrate Choline chloride Zinc sulfate (crystalline) Extract-concentrate of adonis dry standardized 1: 1 Extract-concentrate of marshmallow root dry standardized 1: 1 Etazole sodium Ethylmorphine hydrochloride Eophylline Ephedrine hydrochloride * - The coefficient of increase in volume (ml / g) shows the increase in the volume of the solution in ml when 1 g of the drug is dissolved at 20 ° C. Calculation example: Prepare a solution of magnesium sulfate 20% - 1000 ml. The coefficient of increase in the volume of magnesium sulfate is 0.5. When 200 g of magnesium sulfate is dissolved, the volume of the solution increases by 100 ml (0.5 x 200). The required volume of water is determined by the difference: 1000 - (0.5 x 200) = 900 ml. Tab. # 2. Isotonic equivalents of medicinal substances for sodium chloride
The simultaneous production of several sterile solutions containing medicinal substances with different names or of the same name, but in different concentrations, is strictly prohibited. After the solution is prepared, a sample is taken for complete chemical control, and when satisfactory analysis results are obtained, the solution is filtered. 2 Isotonization of injection solutions Solutions in which the osmotic pressure is equal to the osmotic pressure of the blood are called isotonic. Blood plasma, lymph, lacrimal and spinal fluid have constant osmotic pressure maintained by special osmoreceptors. The introduction into the bloodstream of large quantities of injection solutions with a different osmotic pressure can lead to a shift in the osmotic pressure and cause serious consequences. This is explained by the following circumstances. Cell membranes, as you know, have the property of semi-permeability, that is, letting water through, do not let through many substances dissolved in it. If there is a liquid outside the cell with a different osmotic pressure than inside the cell, then the liquid moves into the cell (exoosmosis) or out of the cell (endoosmosis) until the concentration is equalized. If a solution with a high osmotic pressure (hypertonic solution) is introduced into the blood, as a result, in the surrounding plasma, the liquid from the erythrocytes is directed to the plasma, while the erythrocytes, losing part of the water, shrink (plasmolysis). On the contrary, if you introduce a solution with a low osmotic pressure (hypotonic solution), then the liquid will go inside the cell, the erythrocytes will swell, the membrane may burst, and the cell will die (hemolysis will occur). To avoid these osmotic shifts, solutions with an osmotic pressure equal to the osmotic pressure of blood, cerebrospinal and lacrimal fluid should be injected into the bloodstream, i.e. 7.4 atm and correspond to the osmotic pressure of 0.9% sodium chloride solution. Isotonic concentrations of medicinal substances in solutions can be calculated in different ways: Calculation according to Van't Hoff's law. According to Van't Hoff's law, dissolved substances behave similarly to gases and therefore gas laws are applicable to them with sufficient approximation. Considering that 1 gram-molecule of any non-dissociable substance occupies in an aqueous solution at a temperature of 0 ° C and a pressure of 760 mm. rt. Art. - 22.4 liters, i.e. exactly the same as 1 gram-molecule of gas. This means that if you dissolve 1 gram-molecule of a substance in 22.4 liters of solvent, then the solution will create a pressure of 1 atm. To use this solution, it is necessary to raise the pressure to the osmotic pressure of blood plasma. To do this, we will reduce the volume of the solvent for 1 gram-molecule of the substance, until the moment when the solution creates a pressure of 7.4 atm. The osmotic pressure of the solution will be equal to the osmotic pressure of blood plasma if 7.4 gram-molecules of a substance are dissolved in 22.4 liters of water, or if 1 gram-molecule of a substance is dissolved in X1 liters of water. Since the law is valid at a temperature of 273〫K (0〫C), it is necessary to introduce a correction for the temperature of the human body. Since the osmotic pressure of the air is proportional to the temperature, we will increase the volume of the solvent in order to maintain the osmotic pressure equal to the osmotic pressure of blood plasma. At a temperature of 273K, 1 gram-molecule occupies a volume of 3.03 liters, and at a temperature of 310K (human body temperature) - X2 liters. Hence, To prepare 3.44 liters of solution, 1 gram-molecule of the substance is required, and for the preparation of 1 liter of solution - X3 gram-molecule. According to Van't Hoff's law, in order to prepare an isotonic solution, it is necessary to dissolve 0.29 gram-molecules of the substance in water and bring the volume of the solution to 1 liter. Let's derive the formula for calculation mlv = 0.29M, where M is the molecular weight of the substance, 29 - non-electrolyte isotonization factor. The isotonation factor is easier to derive from the Cliperon equation: where p is the osmotic pressure of blood plasma (atm), is the volume of the solution, is the number of gram-molecules of particles, is the gas constant, expressed in atmospheric liters (0.082), is the absolute temperature. Hence, The above calculations are correct if we are dealing with non-electrolytes, i.e. not decomposing when dissolved into ions (glucose, urotropin, sucrose, etc.). If it is necessary to dissolve electrolytes, it must be borne in mind that they dissociate in aqueous solutions and their osmotic pressure is the higher, the higher the degree of dissociation. Suppose it has been established that a substance in solution dissociates by 100%: NaCl Na + + Cl. Then the number of elementary particles doubles, therefore, if a sodium chloride solution contains 0.29 gram-molecules of a substance in 1 liter, then its osmotic pressure is 2 times higher. Therefore, an isotonic factor of 0.29 for electrolytes is not applicable. It should be reduced depending on the degree of dissociation. To do this, it is necessary to introduce a coefficient into the Cliperon equation, which shows how many times the number of particles increases due to dissociation. This factor is called the isotonic factor and is denoted by i. Thus, the Cliperon equation will take the form: The coefficient i depends on the degree and nature of electrolytic dissociation and can be expressed by the equation: i = 1 + α (n + 1), where α is the degree of electrolytic dissociation, is the number of elementary particles formed from 1 molecule during dissociation. For different groups of electrolytes i can be calculated as follows: A) for binary electrolytes with singly charged ions of the K + A type: α = 0.86, n = 2; = 1 + 0.86 * (2-1) = 1.86 For example, sodium chloride, potassium chloride, ephedrine hydrochloride, etc. B) For binary electrolytes with doubly charged ions of type K + ²A²: i = 1 + 0.5 * (2-1) = 1.5 For example, magnesium sulfate, atropine sulfate, etc. B) For trinar electrolytes such as K² + A2 and K2 + A²: α = 1; n = 3; = 1 + 1 * (3-1) = 3 For example, calcium chloride, sodium hydrogen phosphate, etc. For isotoning a solution with another substance, which is very common when the substances are prescribed in small quantities and their concentration is not enough to isotonize the solution. This makes the calculations more complicated. For example: Rp .: Cocaini hydrochloridi 0.1chloride q.s. ut f. sol. isotonici 10 ml.S. For injection, 1 ml. Let's calculate its isotonic concentration: According to the calculation, the prescribed concentration of cocaine is significantly lower than that required for isotonizing the solution. Let us determine the volume that isotonizes 0.1 g of cocaine. 57 g isotonized with 100 ml of solution, and 1 g - X ml of solution. From this it follows that sodium chloride is necessary for isotonation 10-1.5 = 8.5 ml. Let's calculate the required mass of sodium chloride: for isotoning 100 ml of the solution, you need to take 0.91 g of sodium chloride, and for isotoning 8.5 ml - X g. In practical work, calculations can be simplified by applying general formulas: If isotonicity is achieved by one substance, the formula is used to calculate it: m is the amount of the substance added to isotonize the solution, is the volume of the isotonized solution (ml), is the molecular weight of the substance, The number of milliliters. If the isotonicity of a solution of a medicinal substance is achieved with the help of another (additional) substance, then the formula is used: Molecular weight of the additional substance; Isotonic coefficient for the additional substance; The amount of additional substance (g); I - mass (g), molecular weight and isotonic coefficient for the main substance. For more complex recipes (with three or more components), it is initially calculated what volume of solution isotonized by substances whose masses are known. Then the mass of the isotonizing component is determined. Cryoscopic method. According to this method, solutions isotonic with respect to blood serum should have a depression (lowering) of the freezing point equal to the depression of blood serum. Its depression is equal to 0.52 ° C. When calculating, it is necessary to take into account that the depression constants in the reference book are given for a 1% solution. The calculations will look like this: % solution of a substance has a depression Δt º, and X% solution of the substance - 0.52º. Hence, Sometimes a graphical method for calculating the isotonic concentration is used, which allows, using the developed diagrams (nonograms), quickly, but with some approximation, to determine the amount of substance required to isotonize a solution of a medicinal substance. The disadvantage of these methods can be considered that either the calculations of the isotonic concentration are carried out for one component, or the calculations of the mass of the second substance are too cumbersome. And since the range of one-component solutions is not so large, and more and more often two- and more-component recipes are used, it is much easier to carry out calculations using the isotonic equivalent. Currently, no other calculation methods are used. The isotonic equivalent for sodium chloride is the amount of sodium chloride that, under the same conditions, creates an osmotic pressure equal to the osmotic pressure of 1 g of a substance. Knowing the sodium chloride equivalent, you can isotonize any solutions, as well as determine their isotonic concentrations. The table of isotonic equivalents for sodium chloride is given in the SP I edition, issue 2. Calculation example: Rp .: Dicaini 3,0chloridi q.s. ut f. sol. isotonici 1000 ml.S. To prepare an isotonic solution only from sodium chloride, you need to take 9 g to prepare 1 liter of solution (the isotonic concentration of sodium chloride is 0.9%). According to the table GFXI, we determine that the isotonic equivalent of sodium chloride for dicaine is 0.18 g. This means that g dicaine is equivalent to 0.18 g of sodium chloride, and dicaine - 0.54 g of sodium chloride. Therefore, according to the prescription of sodium chloride, it is necessary to take: 9.0 - 0.54 = 8.46 g. 3 Stabilization of injection solutions The stability of injection solutions is understood as the invariability of the composition of the concentration of medicinal substances in solution during the established storage periods. It primarily depends on the quality of the initial solvents and medicinal substances, which must fully meet the requirements of the State Pharmacopoeia or GOST. In some cases, special purification of medicinal substances intended for injection is envisaged. Hexamethylenetetramine, glucose, calcium gluconate, caffeine sodium benzoate, sodium benzoate, sodium bicarbonate, sodium citrate, aminophylline, magnesium sulfate, etc. should have an increased degree of purity. The higher the purity of the preparations, the more stable the solutions obtained from them. The consistency of medicinal substances is also achieved by observing the optimal sterilization conditions (temperature, duration), the use of acceptable preservatives, which allow achieving the required sterilization effect at a lower temperature, and the use of stabilizers corresponding to the nature of medicinal substances. The choice of the stabilizer depends on the physicochemical properties of the medicinal substances. They are conventionally divided into three groups: ) salts formed with weak bases and strong acids are stabilized with hydrochloric acid; ) salts formed by strong bases and weak acids are stabilized by alkalis; ) easily oxidizing substances are stabilized by antioxidants (antioxidants). Stabilization of solutions of salts of weak bases and strong acids This group includes a large number of salts of alkaloids and synthetic nitrogenous bases, which are widely used in the form of injection solutions. Such salts in aqueous solution may exhibit a slightly acidic reaction due to hydrolysis. In this case, a weakly dissociated base and a strongly dissociated acid are formed with the formation of free hydronium ions. D The addition of free acid to such solutions creates an excess of hydronium ions, which suppresses hydrolysis (causes a shift in the equilibrium to the left). A decrease in the concentration of hydronium ions is facilitated by the alkali released by the glass, in connection with which the equilibrium shifts to the right and the solutions are enriched in a slightly dissociated base. Heating the solution increases the intensity of salt hydrolysis, shifting the reaction to the right, therefore, during heat sterilization and subsequent storage, the pH of the injection solutions rises. Alkaloid bases, which are poorly soluble in water, can precipitate during this process. When sterilizing injection solutions in alkaline glass, the release of even relatively strong free bases, for example, novocaine, is observed, which is evident from the oiling of the walls of the vessel. It should be noted that some alkaloids and synthetic drugs with complex ester and lactone groups (atropine sulfate, scopolamine hydrobromide, homatropine hydrochloride, physostigmine salicylate, novocaine), when heated in weakly alkaline or even neutral media, can partially hydrolyze to form products with altered pharmacological action. Preparations containing phenolic hydroxyls (morphine hydrochloride, apomorphine hydrochloride, salsolin hydrochloride, epinephrine hydrotartrate, etc.) oxidize when heated in weakly alkaline solutions to form more toxic colored products. Pachikarpina hydroiodide is tarred even in a weakly alkaline solution. All this necessitates the stabilization of solutions of salts of weak bases and strong acids by adding 0.1 N. hydrochloric acid. The amount of acid required to stabilize solutions varies depending on the properties of the preparation, but, as a rule, does not depend on the concentration of the solution to be stabilized, since the main purpose of the added acid is to create the optimal pH range of the solution. Typically, 1 liter of injection solution is stabilized with 10 ml of 0.1 N hydrochloric acid. hydrochloric acid solution. This is how solutions of strychnine nitrate (pH 3.0 - 3.7), 1% solution of morphine hydrochloride (pH 3.0 - 3.5) are stabilized. Lobeline hydrochloride solutions are stabilized by adding 15 ml of 0.1 N hydrochloric acid. acid solution per 1 liter, and solutions of scopolamine hydrobromide (pH 2.8 - 3.0) - 20 ml 0.1 N. acid per 1 liter. Stabilization of solutions of salts of strong bases and weak acids These drugs include sodium nitrite, sodium thiosulfate, caffeine-sodium benzoate. Their aqueous solutions are alkaline due to hydrolysis. Alkali is added to suppress hydrolysis. According to the instructions of GF XI, sodium nitrite solutions are stabilized by adding 2 ml of 0.1 N hydrochloric acid. caustic soda solution per 1 liter of solution. A solution of sodium thiosulfate, having a medium close to neutral, decomposes with a slight decrease in pH with the release of sulfur, therefore it is stabilized by adding 20 g of sodium bicarbonate per 1 liter of solution (pH 7.8 - 8.4). To stabilize caffeine-sodium benzoate, add 4 ml 0.1 N. caustic soda solution per 1 liter of solution. Stabilization of solutions of easily oxidizable substances Various antioxidants are used to stabilize solutions of easily oxidizing substances. These include reducing agents and negative catalysts. Reducing agents, having a high redox potential, are more easily oxidized than the preparations stabilized by them. This group includes, for example, sodium sulfite, bisulfite and metabisulfite, rongalite (sodium formaldehyde sulfoxylate), ascorbic acid, unithiol, etc. Thiourea, paraminophenol, methiaminoacetic anhydride (sarcosic anhydride), etc. are also used abroad. Negative catalysts form complex compounds with heavy metal ions, which catalyze unwanted oxidation processes. This group includes complexones: EDTA - ethylenediaminetetraacetic acid, Trilon B - disodium salt of ethylenediaminetetraacetic acid, etc. The addition of antioxidants is necessary for the preparation of solutions of ascorbic acid for injection, which is easily oxidized to form inactive 2,3-diketogulonic acid. In acidic solutions (at pH 1.0 - 4.0), ascorbic acid decomposes with the formation of furfural aldehyde, which causes a yellow color of the decomposed solutions. Ascorbic acid solutions are prepared in the presence of sodium bicarbonate. Anhydrous sodium sulfite 0.2% or sodium metabisulfite 0.1% is added as an antioxidant. The solutions are prepared in water saturated with carbon dioxide and sterilized at 100 g. With flowing steam for 15 minutes (GF X, Art. 7). Readily oxidizing drugs include phenothiazine derivatives aminazine, diprazine. Aqueous solutions of these substances are easily oxidized even with short-term exposure to light with the formation of products colored in a dark red color (oxides, carbonyl derivatives and other oxidation products are formed. and metabisulfite, 2 g of ascorbic acid and 6 g of sodium chloride (under aseptic conditions, without heat sterilization). Many derivatives of aromatic amines are easily oxidized: PASK, novocainamide, soluble streptocid, etc. Solutions of these drugs, being oxidized, form more toxic colored products due to the formation of quinones, quinoneimines and their condensation products. To obtain stable liquids, solutions of soluble streptocide are stabilized with sodium sulfite (2 g per 1 L), solutions of novocainamide with sodium metabisulfite (5 g per 1 L), 3% solutions of sodium para-aminosalicylate with Rongalite (5 g per 1 L). Solutions of adrenaline g / chl and hydrotartrate are easily oxidized due to the content of phenolic hydroxyls with the formation of adrenochrome. GF X (Art. 616 and Art. 26) gives prescriptions in which the stabilizers and the sterilization regime are indicated when preparing solutions of these drugs. Glucose solutions are relatively unstable during long-term storage. The main factor determining the stability of glucose in solution is the pH of the medium. At pH 1.0 - 3.0, the aldehyde oxymethylfurfural is formed in glucose solutions, causing the solution to turn yellow. At pH 3.0-5.0, the decomposition reaction is slowed down, and at pH above 5.0, the decomposition of oxymethylfurfural is again enhanced. An increase in pH causes chain-breaking decomposition of the lucose. Among the decomposition products, traces of acetic, lactic, formic, and gluconic acids were found. Traces of heavy metals (Cu, Fe) accelerate the decomposition process. The optimum pH value of the glucose solution is 3.0 - 4.0. To obtain stable glucose solutions, it is recommended to pre-treat them with activated carbon (0.4%) to remove iron and colored products. Then the solutions are stabilized, filtered and sterilized at C with flowing steam for 60 minutes or at 119-121 C for 8 minutes with a volume of up to 100 ml. GF X prescribes to stabilize glucose solutions (regardless of their concentration) with sodium chloride 0.26 g per 1 L and 0.1 N. a solution of hydrochloric acid to pH 3.0 - 4.0. In a pharmacy, for the convenience of work, the stabilizer is made according to the following recipe: sodium chloride - 5.2 g, diluted hydrochloric acid - 4.4 ml, water for injection - up to 1 liter. This stabilizer is taken at 5%. The mechanism of the stabilizing action, according to some authors, is that sodium chloride forms complex compounds at the site of the aldehyde group of glucose. This complex is fragile, and sodium chloride, moving from one molecule to another, protects aldehyde groups, thereby suppressing redox reactions. Hydrochloric acid neutralizes the alkali produced by the glass and creates an optimal pH value for the solution. There is another theory explaining the complexity of the ongoing processes. As you know, in the solid state, glucose is in a cyclic form. In solution, partial ring opening occurs with the formation of aldehyde groups, and a mobile equilibrium is established between the acyclic and cyclic forms. The addition of sodium chloride creates conditions in the solution that shift the equilibrium towards the formation of a cyclic form that is more resistant to oxidation. There are also indications of the interaction of sodium chloride with some forms of glucose with the formation of stable double complex salts. Stabilizers Solution concentration,% Stabilizer and its weight, g / l, or volume, ml / l solution pH Apomorphine hydrochloride Analgin 0.5 g Cysteine 0.2 g Hydrochloric acid solution 0.1 M - 10 ml Atropine sulfate 0,05; 0,1; 1; 2,5; 5 Hydrochloric acid solutions 0.1M - 10 ml Vicasola Sodium metabisulfite (1.0 g) or sodium bisulfite (2.0 g) hydrochloric acid solution 0.1 M - 1.84 ml Anhydrous glucose 5; 10; 20; 25; 40 Hydrochloric acid solutions 0.1 M - up to pH 3.0 - 4.1 Sodium chloride 0.26 g Sodium bicarbonate 6.0 g there is no data Ascorbic acid Sodium metabisulfite 2.0 g Dibazola Hydrochloric acid solution 0.1 M - 10 ml Sodium thiosulfate 0.5 g Ascorbic acid Nariya bicarbonate 23.85 g; 47.70 g Sodium sulfite anhydrous 2.0 g Caffeine sodium benzoate Sodium hydroxide solution 0.1 M - 4 ml Sodium bicarbonate Trilon B: 0.1g 0.2g Sodium nitrite Sodium hydroxide solution 0.1 M - 2 ml Sodium paroaminosalicylate Sodium sulfite 5.0 g Sodium salicylate Sodium metabisulfite 1.0 g Sodium thiosulfate Sodium bicarbonate 20.0 g Novocainamide Sodium metabisulfite 5.0 g Novocaine 0,25; 0,5; 1 2; 5; 10 A solution of hydrochloric acid 0.1 M: 3 ml; 4 ml; 9 ml Sodium thiosulfate 0.5 g Hydrochloric acid solution 0.1 M: 4 ml; 6 ml; 8 ml 3,8 - 4,5 4,0 - 5,0 Ringer acetate Sodium chloride 0.526 g Sodium acetate 0.410 g Calcium chloride 0.028 g Magnesium chloride 0.014 g Potassium chloride 0.037 g Hydrochloric acid solution 8% - 0.2 ml Soluside soluble Disodium salt of ethylenediaminetetraacetic acid 0.1 g Scopolamine hydrobromide Sovkain Hydrochloric acid solution 0.1 M - 6 ml Spasmolitin Hydrochloric acid solution 0.1 M - 20 ml Sulfacyl sodium Sodium metabisulfite 3.0 g Sodium hydroxide solution 1M - 18 ml Soluble streptocide Sodium sulfite 2.0 g or sodium thiosulfate 1.0 g Strychnine nitrate Hydrochloric acid solution 0.1 M - 10 ml Tamine bromide Thiamine chloride Unitiol 2.0 g Etazole sodium Anhydrous sodium sulfite 3.5 g Sodium hydrocitrate 1.0 g; 2.0 g 4 Complete chemical analysis After the preparation of the solution for injection and before its sterilization, it must undergo complete chemical control, including the qualitative and quantitative analysis of its constituent components, determination of pH, isotonic and stabilizing substances. In addition, additional polling control is possible after the preparation of the solution. The results of the control are recorded in a journal, the form of which is given in Appendix 2 to the Instruction for quality control, approved by order of the Ministry of Health of the Russian Federation No. 214 of July 16, 1997. Filtration and packaging of solutions This stage of the preparation of injection solutions is carried out only with satisfactory results of a complete chemical analysis. 1 Filtration and filling into vials, capping Filtration is carried out to free injection solutions from mechanical impurities. For a reliable selection of the filter system, it is desirable to analyze the following information on the purification technology: the nature of the medium being filtered (name, ingredients, density, viscosity, concentration); the nature of the contamination (particle size); filtrate requirements (visual transparency); used equipment and filter elements with an indication of the type, brand, material, main operational characteristics according to the passport. The first portions of the filtrate are re-filtered. Filtration of the solution is combined with its simultaneous filling into prepared glass vials. During filtering and filling, personnel should not bend over empty or full bottles. Optimal filling and sealing in a laminar air flow using appropriate equipment. For filtering solutions for injections, filter funnels with a glass filter (pore size 3-10 microns) are used. In this case, installations of two designs are used: Tripod type apparatus Carousel-type apparatus. In addition, installations for filtering and bottling UFZH-1 and UFZH-2 liquids are used; they can be used to filter several solutions at the same time. With a focus on filtering large quantities of injection solutions, filters are used that work under vacuum on the principle of "fungus" using an inverted Büncher funnel. At the bottom of the funnel, the filter material is sequentially stacked one on top of the other, which achieves a more thorough filtration. As a filtering material, combined filters are used in combination with various filtering materials (filter paper, gauze, cotton wool, coarse calico cotton fabric, belting, natural silk fabrics). It should be noted that nowadays, the method of microfiltration through membrane filters is increasingly used. Microfiltration is a process of membrane separation of colloidal solutions and microsuspensions under pressure. In this case, particles with a size of 0.2-10 microns (inorganic particles, large molecules) are subjected to separation. Ordinary filter material allows these particles to pass through, which is very dangerous because they are capillary-tight and prone to conglomeration. The use of microfiltration allows you to get rid of mechanical impurities during visual inspection and to reduce the total microbial count. This is due to the fact that the membranes retain not only particles that are larger than pore sizes, but also particles of smaller sizes. The following effects play an important role in this process: 1) capillary effect; 2) the phenomenon of adsorption; 3) electrostatic forces; 4) Van der Waals forces. Filters of foreign brands are most often used - MELIPOR, SARTERIDE, SINPOR and others. Filters of the domestic brand VLADIPOR are also often used, which are fine-porous acetate cellulose films of white color, of various thicknesses. Filtration of solutions using membrane microfilters involves the use of membrane installations, which are a complex device consisting of membrane holders and other auxiliary equipment. After filling the solutions with simultaneous filtration, the vials are sealed with rubber stoppers (for brands, see "Preparation of dishes and tare-closures") and subjected to primary visual control for the absence of mechanical impurities in accordance with Appendix 8 to the Instruction for quality control of medicinal products manufactured in pharmacies, approved by order No. 214 of the Ministry of Health of the Russian Federation of July 16, 1997. 2 Primary control for the absence of mechanical impurities Mechanical inclusions are understood as constantly moving insoluble substances, except for gas bubbles that are accidentally present in solutions. Primary control is carried out after filtration and filling of the solution. Each bottle or vial of solution is subject to review. If mechanical impurities are found, the solution is re-filtered and re-examined, sealed, labeled and sterilized. For solutions subjected to membrane microfiltration, selective primary control for the absence of mechanical impurities is allowed. To view the solutions, there must be a specially equipped workplace, protected from direct sunlight. The control is carried out using the "Device for monitoring the solution for the absence of mechanical inclusions" (UK-2), it is allowed to use a black and white screen, illuminated in such a way as to exclude light from entering the eyes of the inspector directly from its source. The solution is controlled by viewing with the naked eye on a black and white background, illuminated by a 60 W matt electric lamp or a 20 W fluorescent lamp; for colored solutions, respectively, 100 W and 30 W. The distance from the eyes to the viewed object should be 25-30 cm, and the angle of the optical viewing axis to the direction of light should be about 90º. The line of sight should be directed downward with the head upright. A pharmacist-technologist must have a visual acuity equal to one. Corrects with glasses if necessary. The surface of the tested bottles or vials must be clean and dry on the outside. Depending on the volume of the bottle or vial, from one bottle to 5 pieces are viewed simultaneously. Bottles or vials are taken in one or both hands by the necks, brought into the control zone, turned upside down with smooth movements and viewed against black and white backgrounds. Then, with smooth movements, without shaking, they are turned over to their original position "bottom-down" and also viewed against black and white backgrounds. The control time is accordingly: one bottle with a capacity of 100-500 ml - 20 sec; two bottles with a capacity of 50-100 ml - 10 sec; from two to five bottles with a capacity of 5-50 ml - 8-10 sec. The specified control time does not include the time for auxiliary operations. 3 Capping and labeling Vials with solutions for injection, sealed with rubber stoppers, after satisfactory control for the absence of mechanical impurities, are rolled in with metal caps. For this purpose, K-7 type aluminum caps with a notch (hole) with a diameter of 12-14 mm are used. After running in the bottle, the quality of the closure is checked: the metal cap should not rotate when manually checked and the solution should not spill out when the bottle is overturned. Then the bottles and vials are marked by signature, stamping on the cap or using metal tags indicating the name of the solution and its concentration. Sterilization Sterilization is the complete destruction of living microorganisms and their spores in a particular object. Sterilization is of great importance in the manufacture of all dosage forms, and especially injectable ones. In this case, the dishes, auxiliary material, solvent and ready-made solution should be sterilized. Thus, the work on the manufacture of solutions for injection must begin with sterilization and end with sterilization. SP XI defines sterilization as the process of killing in an object or removing from it all types of microorganisms at all stages of development. The complexity of the sterilization process lies, on the one hand, in the high viability and a wide variety of microorganisms, on the other hand, in the thermolability of many medicinal substances and dosage forms, or in the impossibility for a number of reasons to use other sterilization methods. Hence, the requirements for sterilization methods come: to preserve the properties of dosage forms and to free them from microorganisms. Sterilization methods should be convenient for use in pharmacies, especially in pharmacies of health care facilities, in the formulation of which injectable solutions are up to 60-80%. In the technology of dosage forms, different methods of sterilization are used: thermal methods, sterilization by filtration, radiation sterilization, chemical sterilization. Thermal sterilization. Thermal methods of sterilization include sterilization with steam under pressure and air sterilization; sterilization with flowing steam is excluded from the State Pharmacopoeia Institute. Air sterilization This method of sterilization is carried out with hot air in an air sterilizer at a temperature of 180-200 ° C. In this case, all forms of microorganisms die due to the pyrogenetic decomposition of protein substances. The effectiveness of air sterilization is temperature and time dependent. The uniformity of heating objects depends on the degree of thermal conductivity and the correct location inside the sterilization chamber to ensure free circulation of hot air. The objects to be sterilized must be filled in appropriate containers or sealed and freely placed in the sterilizer. Due to the fact that the air has a low thermal conductivity, the heating of the sterilized objects occurs rather slowly, therefore, the loading should be carried out into unheated sterilizers, or when the temperature inside them does not exceed 60 ° C. The time recommended for sterilization should be counted from the moment of heating in the sterilizer to a temperature of 180-200 ° C. The air sterilization method is used to sterilize heat-resistant drugs, oils, fats, lanolin, petroleum jelly, wax, as well as glass, metal, silicone rubber, porcelain, filter sterilization systems, small glass and metal objects. This method is not used for sterilizing solutions. Steam sterilization With this method of sterilization, a combined effect on microorganisms of high temperature and humidity occurs. A reliable method of sterilization is sterilization with saturated steam at overpressure, namely: a pressure of 0.11 MPa (1.1 kgf / cm²) and a temperature of 120 ° C or a pressure of 0.2 MPa (2.2 kgf / cm²) and a temperature of 132 ° C ... Saturated steam is steam that is in equilibrium with the liquid from which it is formed. A sign of saturated steam is the strict dependence of its temperature on pressure. Steam sterilization under pressure is carried out in steam sterilizers. Steam sterilization at 120 ° C is recommended for solutions of thermostable medicinal substances. The sterilization holding time depends on the physicochemical properties of the substances and the volume of the solution. Sterilization of injectable medicinal substances is carried out in hermetically sealed, pre-sterilized vials. This method also sterilizes fats and oils in hermetically sealed vessels at a temperature of 120 ° C for 2 hours; glassware, porcelain, metal, dressing and auxiliary material (cotton wool, gauze, bandages, gowns, filter paper, rubber stoppers, parchment) - holding time 45 min at 120 ° C or 20 min at 132 ° C. In exceptional cases, sterilized at temperatures below 120 ° C. The sterilization regime must be justified and indicated in private articles of GF XI or other regulatory and technical documentation. The effectiveness of thermal sterilization methods is monitored using instrumentation with thermometers, as well as chemical and biological methods. Certain substances are used as chemical tests that change their color or physiological state under certain sterilization parameters. For example, benzoic acid (melting point 122-124.5 ° C), sucrose (180 ° C) and other substances. Bacteriological control is carried out by sterilizing an object inseminated with test microbes; samples of garden soil can be used. This sterilization method is most often used in pharmacies for sterilizing injectable solutions, while the following requirements must be taken into account: Sterilization should be carried out no later than 3 hours from the moment of preparation of the solution; Sterilization is carried out only once, re-sterilization is not allowed; Filled boxes or packages must be labeled with the name of the contents and the date of sterilization; Control of thermal sterilization during sterilization of injection solutions is mandatory; Sterilization has the right to be carried out only by a person who has undergone special training and knowledge testing and has a document certifying this. Sterilization by filtration Microbial cells and spores can be considered as insoluble formations with a very small (1-2 µm) diameter. Like other inclusions, they can be separated from the liquid mechanically - by filtration through finely porous filters. This method of sterilization is also included in GFXI for sterilization of solutions of thermolabile substances. Radiation sterilization Radiant energy has a detrimental effect on the cells of living organisms, including various microorganisms. The principle of the sterilizing effect of radiation is based on the ability to induce in living cells, at certain doses of absorbed energy, such changes that inevitably lead to their death due to the violation of metabolic processes. The sensitivity of microorganisms to ionizing radiation depends on many factors: the presence of moisture, temperature, etc. Radiation sterilization is effective for large scale industries. Chemical sterilization This method is based on the high specific sensitivity of microorganisms to various chemicals, which is determined by the physicochemical structure of their shell and protoplasm. The mechanism of the antimicrobial action of substances is still insufficiently understood. It is believed that some substances cause coagulation of the protoplasm of the cell, others act as oxidants, a number of substances affect the osmotic properties of the cell, and many chemical factors cause the death of a microbial cell due to the destruction of oxidative and other enzymes. Chemical sterilization is used to sterilize dishes, auxiliary products, glassware, porcelain, metal, and is also used to disinfect walls and equipment. Control of the sterility of injectable drugs manufactured in pharmacies, by order of the Ministry of Health of the Russian Federation No. 309 dated October 21, 1997. carried out by sanitary and epidemiological supervision. The latter is obliged at least twice a quarter to monitor solutions for injection, eye drops and water for injection for sterility; on a quarterly basis, conduct random sampling of water for injection and injection solutions prepared in pharmacies for pyrogenic substances in accordance with the requirements of the State Fund of the XII. Quality control of finished products Quality control of solutions for injections should cover all stages of their preparation from the moment the medicinal substances arrive at the pharmacy and until they are dispensed in the form of a dosage form. In accordance with the Instruction on quality control of medicines manufactured in pharmacies, approved by order No. 214 of July 16, 1997, in order to prevent substandard medicines from entering the pharmacy, acceptance control is carried out, which consists in checking the existing medicines for compliance with the requirements for indicators: Description "," Packaging "," Marking "; in checking the correctness of the execution of various documents and the availability of certificates of the corresponding manufacturer and other documentation confirming the quality of the medicinal product. At the same time, the label of the package with medicinal substances intended for the manufacture of solutions for injections and infusions must indicate "Suitable for injection." In the manufacturing process, there must be written, organoleptic control and control during dispensing - mandatory; interrogation, physical - selectively and complete chemical in accordance with the requirements of section 8 of order No. 214. During written control, in addition to the general rules for issuing passports, it should be remembered that the concentration and volume (mass) of the isotonizing and stabilizing substances added to solutions for injections and infusions must be indicated not only in passports, but also on prescriptions. Survey control is carried out selectively after the manufacture of no more than five dosage forms. Organoleptic control consists in checking the dosage form according to the indications: description (appearance, color, smell); uniformity; absence of visible mechanical impurities (in liquid dosage forms). Physical control consists in checking the mass or volume of a dosage form, the amount and mass of individual components included in this dosage form. At the same time, each batch of a drug solution that requires sterilization is checked after filling and before sterilization. During the check, the quality of the packaging is also controlled (the aluminum cap should not be turned by hand and the solution should not be poured out when the bottle is overturned). Before sterilization, all solutions for injections and infusions are subject to complete chemical control, including determination of the pH value, isotonic and stabilizing substances. All stages of the manufacture of solutions for injections and infusions should be reflected in the register of the results of control of individual stages of the manufacture of solutions for injections and infusions. 1 Secondary control for the absence of mechanical impurities After sterilization, the clogged solutions are subjected to a secondary control for the absence of mechanical impurities. "Primary control for the absence of mechanical inclusions." At the same time, a check is also carried out at the same time for the completeness of the filling of the bottle and the quality of the closure. 2 Complete chemical control For complete chemical control after sterilization, one bottle is taken from each batch of the drug. Products obtained in one container are considered a series. Complete chemical control includes, in addition to the qualitative and quantitative determination of active substances, also the determination of the pH value. Stabilizing and isotonizing substances are checked in cases stipulated by the current regulatory documentation (Methodological instructions). 3 Braking Sterile solutions are considered rejected if they do not meet the requirements of regulatory documents in terms of appearance, pH value; authenticity and quantitative content of incoming substances; the presence of visible mechanical impurities; unacceptable deviations from the nominal volume of the solution; violations of the fixing closure; violations of the current requirements for the registration of medicines intended for dispensing. Registration Medicinal substances for injection, like other dosage forms, are issued with a label. In this case, the labels should have a blue signal strip on a white background and clear inscriptions: "For injection", "Sterile", "Keep out of the reach of children", printed by typographic method. The dimensions of the labels must not exceed 120 ›‹ 50 mm. In addition, labels must include the following: location of the manufacturer's office; the name of the manufacturer's institution; Hospital number; branch name; method of administration (intravenously, intravenously (drip), intramuscularly); date of preparation ____; shelf life____; analysis No. ___; prepared ________; checked ___________; opted ___________. V. Practical part The practical part of the work was carried out on the basis of data obtained during the period of my practical training. Preparation of dosage forms for injections is carried out in the prescription-production department. Characteristics of the conditions for the manufacture of injection solutions. The production of injection solutions is carried out in an isolated room of the aseptic unit. The assistant room of the aseptic unit is separated from other production facilities by a gateway, but at the same time it is connected by windows with the office of the pharmacist-analyst and the autoclave room. In the airlock there are wardrobes for staff clothes and for storing bix with sets of sterile clothes, a mirror, a sink, an electric dryer, as well as instructions on the rules for handling hands, the sequence of dressing and the rules of behavior in the aseptic unit. The aseptic assistant room is finished with materials that can withstand frequent disinfection treatments. The floor is covered with unglazed ceramic tiles, the floor and walls are finished with a plastic coating, which meets the requirements of Order No. 309 of October 21, 1997. Plastic windows, protected by air filters, allow sufficient natural light to enter the room. The artificial light is created by fluorescent fluorescent lamps. The room has supply and exhaust ventilation with a predominance of supply over exhaust. Before working in the aseptic unit, the air is disinfected using wall-mounted bactericidal unshielded lamps installed on a time relay (from 6.00 to 8.00). The work of the personnel is carried out in a set of sterile clothing, which consists of shoe covers, a trouser suit, a disposable mask and a cap. Hand treatment is performed with an alcohol solution of chlorhexidine bigluconate 0.5%. At the end of the shift, the premises must be cleaned using disinfectants. A 0.75% solution of chloramine B with a 0.5% detergent solution is used as disinfectants. Cleaning is carried out according to the rules regulated by order No. 309 of October 21, 1997: first, the walls are washed in smooth movements from top to bottom from window to door, and then furniture and equipment are washed and disinfected. Once a week, a general cleaning of the premises is carried out; for this, the premises are freed from equipment. Equipment for aseptic unit To facilitate the work of specialists in the aseptic unit, small-scale mechanization means are used. The filling and filtration of solutions is carried out by a vacuum surgical suction device US-NS-11, equipped with two (air and mechanical) submerged bacterial filters made of stainless steel. For weighing bulk solids, scales TU-64-1-3849-84 up to 1 kg are used; for the same purpose, hand scales up to 100 g, up to 20 g, up to 5 g and up to 1 g are used. With the help of the device for controlling injection solutions UK-2, the primary control of solutions for the absence of mechanical impurities is carried out. Running-in bottles with a capacity of 250 and 500 ml is carried out by means of semiautomatic seaming machines ZPU-00 OPS (labor productivity 1000 fl / h) and PZR (1440 fl / h). Pennicilines are rolled in with the help of a device for wringing out the caps POK-1. Sterilization of solutions is carried out in three GK-100-3M autoclaves. Obtaining water for injection and checking its quality Water for injection is obtained by means of DE-25 and AE-25 equipped with separators preventing the passage of water droplets into the condensation chamber. Distillation of water is carried out in a separate room. Before starting work, the water distiller is steamed for 15 minutes with the water supply valves to the water distiller and refrigerator closed. The first portions of the resulting water are drained within 15-20 minutes. Water for injection is collected in clean, sterilized cylinders clearly labeled "Water for Injection" and the cylinder number; there is a label on the cylinders where the date of sterilization is indicated. In addition, there is a label indicating that the contents of the cylinders have not been sterilized, the date, the chemical analysis number and the signature of the analyst. Before water enters the aseptic unit, a sample is taken from each cylinder for analysis. A pharmacist-analyst tests water for injection for the absence of chlorides, sulfates, calcium salts, as well as for the absence of reducing substances, ammonium salts and carbon dioxide in accordance with the requirements of the current State Pharmacopoeia. The results of the control of purified water and water for injection are recorded in a journal, the form of which is given in Appendix 3 to the instructions of the order of the Ministry of Health of the Russian Federation No. 214. Most often, the following prescriptions are prepared in a pharmacy: Rp .: Sol. Novocaini 0.25% - 200 ml 10 fl. S. Intramuscularly. The preparation is carried out by the mass-volumetric method: the calculated amount of novocaine and the stabilizer is dissolved in a measuring container in ⅔ volumes of water, and then brought to the required volume with water. 0.1 N. is used as a stabilizer. a solution of hydrochloric acid in a ratio per 1 liter of novocaine solution: 0.25% - 3 ml, The addition of this amount of hydrochloric acid reduces the pH of the medium to 3.8-4.5, which corresponds to the recipe specified in the appendix of the order of the Ministry of Health of the Russian Federation No. 214 of July 16, 1997. In this case, we calculate the volume of the solution: 200 * 10 = 2000 ml. We calculate the mass of novocaine: We calculate the volume of the stabilizer: 3 ml in 1 liter, X ml in 2 liters. Based on the calculations, we are preparing a solution. We collect ⅔ of the volume of water for injection into a 2 liter container, dissolve 5 g of novocaine in it, mix. Then add 6 ml of 0.1 N hydrochloric acid solution, the preparation of which see "Stabilization of solutions". We bring the solution with water for injection to the required volume and mix again, give the solution for chemical analysis. Rp .: Sol. Natrii chloridi 0.9% - 200 ml 10 vials. S. Intravenously. In order to destroy pyrogenic substances, sodium chloride powder is calcined in an air sterilizer at a temperature of 180 C for 2 hours with a layer thickness of no more than 2 cm before preparing the solution, after which the dishes are closed and used within 24 hours. Calcination data is recorded in the log. Based on the calculations, we are preparing a solution. We collect ⅔ volume of water for injection into a 2 liter container, dissolve 18 g of sodium chloride in it, mix. We bring the solution with water for injection to the required volume and mix, we give the solution for chemical analysis. Stabilization is not required in this case, since the substance is a salt formed by a strong acid and a strong base. After obtaining satisfactory results of the analysis, the solution is packed with simultaneous filtration using a US-NS-11 vacuum surgical aspirator, we subject the solutions to primary control for the absence of mechanical impurities, seal with rubber stoppers and roll in caps. We send one bottle for bacterial analysis with an indication on the label that the contents have not been sterilized, the batch number and the start time of the solution. Then the solution is sterilized in a steam sterilizer under pressure at a temperature of 120 C for 12 minutes. After secondary control for the absence of mechanical impurities and repeated chemical analysis, we make out the bottles for dispensing. The composition and technology of the solution corresponds to the prescription specified in the appendix of the order of the Ministry of Health of the Russian Federation No. 214 of July 16, 1997. Rp .: Sol. Kalii chloridi 3% - 200 ml 10 fl. S. Intravenous (drip). Preparation of solutions is carried out by mass-volumetric method. Based on the calculations, we prepare the solution. We collect ⅔ volume of water for injection into a 2 liter container, dissolve 60 g of potassium chloride in it, mix. We bring the solution with water for injection to the required volume and mix again, give the solution for chemical analysis. After obtaining satisfactory results of the analysis, the solution is packed with simultaneous filtration using a US-NS-11 vacuum surgical aspirator, we subject the solutions to primary control for the absence of mechanical impurities, seal with rubber stoppers and roll in caps. Then the solution is sterilized in a steam sterilizer under pressure at a temperature of 120 C for 12 minutes. After secondary control for the absence of mechanical impurities and repeated chemical analysis, we make out the bottles for dispensing. Rp .: Sol. Natrii hydrocarbonatis 4% - 180 ml 20 vials. S. Intravenously For the preparation of solutions, sodium bicarbonate is used that meets the requirements of GOST 4201-79 of reagent grade qualification. and ch.d. During the preparation of the solution, sodium bicarbonate undergoes hydrolysis with the formation of sodium carbonate and carbon dioxide, which in turn leads to an increase in the pH of the solution. In this regard, it is advisable to observe the conditions that prevent the loss of carbon dioxide: dissolve the drug at a temperature not exceeding 20 C, in a closed vessel, while avoiding strong agitation. Preparation of solutions is carried out by mass-volumetric method. After obtaining satisfactory results of the analysis, the solution is packed with simultaneous filtration using a US-NS-11 vacuum surgical aspirator. We subject the solutions to primary control for the absence of mechanical impurities, while shaking the bottle is strictly prohibited. Then we seal the solutions with rubber stoppers and roll them in with caps. We send one bottle for bacterial analysis with an indication on the label that the contents have not been sterilized, the batch number and the start time of the solution. Then the solution is sterilized in a GK-100-3M sterilizer with steam under pressure at a temperature of 120 C for 12 minutes. To avoid rupture of bottles due to the release of carbon dioxide, the sterilizer should be unloaded no earlier than 20-30 minutes after the pressure inside the sterilization chamber drops to zero. After secondary control for the absence of mechanical impurities and repeated chemical analysis, we make out the bottles for dispensing. The composition and technology of the solution meets the requirements for the solution by order of the Ministry of Health of the Russian Federation No. 214 of July 16, 1997. Rp .: Sol. Calcii chloridi 1% - 200 ml 100 fl. S. Intravenously Preparation of solutions is carried out by mass-volumetric method. Based on the calculations, we prepare the solution. We collect ⅔ volume of water for injection into a 2 liter container, dissolve 200 g of calcium chloride in it, mix. We bring the solution with water for injection to the required volume and mix again, give the solution for chemical analysis. Stabilization is not required in this case, since the substance is a salt formed by a strong acid and a strong base. After obtaining satisfactory results of the analysis, the solution is packed with simultaneous filtration using a US-NS-11 vacuum surgical aspirator, we subject the solutions to primary control for the absence of mechanical impurities, seal with rubber stoppers and roll in caps. Then the solution is sterilized in a GK-100-3M sterilizer with steam under pressure at a temperature of 120 C for 12 minutes. After secondary control for the absence of mechanical impurities and repeated chemical analysis, we make out the bottles for dispensing. The composition and technology of the solution corresponds to the prescription specified in the appendix of the order of the Ministry of Health of the Russian Federation No. 214 of July 16, 1997. Extemporal Formulation Analysis The industry produces the following analogues of injection solutions manufactured in pharmacies: Drug solution Industrial analog Novocaine solution 0.25% - 200 ml Sodium bicarbonate solution 4% - 180 Sodium bicarbonate solution 2% - 100 Only 500 mg tablets # 10 Sodium chloride solution 0.9% - 200 ml Potassium chloride solution 3% - 200 ml Potassium chloride solution 4% - 10 ml in amp. No. 10 Novocaine solution 1% - 200 ml Novocaine solution 1% - 10 ml in amp. No. 10 Calcium chloride solution 1% - 200 ml Calcium chloride solution 1% - 10 ml in amp. No. 10 Sodium chloride solution 10% - 200 Sodium chloride solution 10% - 200 ml Glucose solution 5% - 200 ml Glucose solution 5% - 200 ml The table shows that not all injectable dosage forms manufactured in a pharmacy have industrial analogs. Solutions of novocaine, calcium chloride are produced in ampoules, which is not always convenient when using them in healthcare facilities. Potassium chloride solutions of the required concentration are not produced, and there is no official dosage form of sodium bicarbonate solution at all. Consequently, no healthcare facility can do without injectable dosage forms manufactured in pharmacies. The shelf life of most injectable solutions varies from 20 to 30 days, which allows them to be prepared as an intra-pharmaceutical preparation in vials for running-in, which is done in a pharmacy with a focus on the demand for injection solutions in the departments of healthcare facilities. Vi. experimental part Objects: Sodium chloride solution for infusion 0.9% 200 ml Materials: Petri dish, test tubes, flask, pipette. Purpose: To master the method of determining the sterility of an injection solution. Objective: To compare microbiological indicators and assess the quality of two solutions, given that one of them was made without observing the manufacturing technology (there is no sterilization stage). Preparation of the solution. Rp .: Sol. Natrii chloridi 0.9% - 200 ml 2 fl. D.S. Intravenously. In order to destroy pyrogenic substances, sodium chloride powder is calcined in an air sterilizer at a temperature of 180 C for 2 hours with a layer thickness of not more than 2 cm before preparing the solution, after which we close the dishes and use them only for 24 hours. Record the calcination data in the log. We prepare solutions using the mass-volumetric method. Based on the calculations, we are preparing a solution. In a 500 ml container, measure ⅔ the volume of water for injection, dissolve 3.6 g of sodium chloride in it, mix. We bring the solution with water for injection to the required volume and mix, we give the solution for chemical analysis. Stabilization is not required in this case, since the substance is a salt formed by a strong acid and a strong base. We filter with US-NS-11, subject the solutions to primary control for the absence of mechanical impurities, seal with rubber stoppers and roll in caps. We send one bottle (A) for bacterial analysis with an indication on the label that the contents have not been sterilized, the batch number and the time of the beginning of the preparation of the solution. Another bottle (B) is sterilized in a sterilizer with steam under pressure at a temperature of 120 C for 12 minutes. 2. Determination of sterility of isotonic sodium chloride solution We send the vials with the test solution to the thermostat before sowing, and incubate for 3 days at 37C to identify spore forms of microorganisms, which during this time become vegetative. Further, from each bottle to identify aerobes, we sow 2 ml in 5 bottles with 50 ml of mesopatamia broth with glucose. To identify anaerobes, we sow 0.5 ml in 4 tubes with Kitta-Tarozzi medium. To identify molds and yeasts, we sow 0.5 ml in 4 test tubes with Sabouraud's liquid medium. The inoculated media are kept in a thermostat: at 37C - 3 vials of MPB with glucose, 4 tubes with Kitt-Tarozzi medium; at 24C - 2 vials of BCH with glucose, 4 tubes with Sabouraud's medium. The samples are kept for 8 days with daily inspection. 3. Results of microbiological research Upon visual inspection of media inoculated with solution A (isotonic sodium chloride solution, not sterilized), we observe: Vials with mesopatamia broth with glucose. The solution is cloudy, at the bottom of the vials is a white flocculent precipitate. Test tubes with Kitta-Tarozzi medium. The solution is cloudy, opaque, with a precipitate. Tubes with Sabouraud's medium. The solution is clear, without sediment and turbidity. Upon visual inspection of the media inoculated with solution B (sterile isotonic sodium chloride solution), we see that there is no turbidity and the presence of sediment. Conclusion In the first and second cases, we observed changes that indicate the growth of the microbial culture. In the third case (Sabouraud's medium), the solution remained unchanged, which indicates the absence of molds and yeasts. All drugs produced for injection must be sterile. Sterility of medicines is achieved by observing the sanitary conditions of manufacture and the sterilization regime established by the State Pharmacopoeia of the Russian Federation or the corresponding Specifications. Injection solutions are one of the most important pharmaceutical dosage forms available. The preparation of these solutions requires special care and careful quality control. The pharmacy manufactures injectable dosage forms, most of which are not produced by the industry, which is extremely necessary for many departments of health care facilities. Injection solutions are prepared in conditions that meet all the requirements of the order of the Ministry of Health of the Russian Federation No. 309 dated October 21, 1997. The production of solutions for injections is carried out in the most convenient and comfortable conditions of the aseptic unit, according to the work schedule. The pharmacist-analyst carefully monitors the process of preparation of injection solutions, according to the order of the Ministry of Health of the Russian Federation No. 214 of July 16, 1997. Used Books medicinal solution for injection 1. Technology of dosage forms. study. for stud. higher. study. institutions; ed. I.I. Krasnyuk, G.V. Mikhailova. - M.: Publishing Center "Academy", 2006.-592s. Order of the Ministry of Health of the Russian Federation No. 309 of 10.21.1997 "On approval of instructions on the sanitary regime of pharmacies" Order of the Ministry of Health of the Russian Federation No. 214 dated 07.16.1997 "On quality control of drugs in pharmacies." V.M. Gretsky, V.S. Khomenok, Guide to Practical Exercises in Drug Technology - Med., Moscow, 1984 State Pharmacopoeia edition X, XI edition 6. Technology of dosage forms. study. for stud. higher. study. institutions; ed. I.I. Krasnyuk, G.V. Mikhailova. - M.: Publishing Center "Academy", 2006.-592s. 7. Teaching aid for practical training in pharmacy technology of medicines (part 3, 4) - Smolensk: SGMA, 2006. Losenkova S.O. Fundamentals of pharmaceutical biotechnology: Textbook / T.P. Prischep, V.S. Chuchalin.-Rostov n / a .: Phoenix; Publishing house NTL, 2006. - 256 p. Microbiology, V.S. Dukov Publishing House 2007 274 p. The most widely used solvents for injection solutions are water for injection.- Aqua pro injectionibus - and vegetable oils. Ordinary distilled water is not suitable for preparing injection solutions, as it may contain pyrogenic substances. Sterilization of water only leads to the death of microorganisms, killed microbes, waste products and decay of microorganisms remain in the water and have pyrogenic properties, cause a sharp chill, and in large quantities - even death. WITH the remainder of pyrogenic substances is still not well understood. It is believed that they belong to complex compounds such as complex proteins, polysaccharides, lipopolysaccharides; some pyrogenic substances include up to 75% of phosphorus-containing polysaccharides and up to 25% of fat-like substances. The pyrogenic effect is believed to be due to the presence of phosphate groups. The most sharply pyrogenic reactions are manifested with intravascular, spinal and intracranial injections. In this regard, the manufacture of solutions for injection should be carried out on water that does not contain pyrogenic substances. Pyrogenic substances are not volatile and are not steam distilled. Their ingress into the distillate is explained by the entrainment of the smallest droplets of water with a stream of steam into the refrigerator. Therefore, the main task in obtaining pyrogen-free water is to purify water vapor from the droplet aqueous phase. For this, the AA-1 apparatus (apparatus for producing pyrogen-free water) is currently widely used. In this apparatus, chemical reagents are added to tap water (potassium permanganate - to oxidize organic substances, potassium alum - to trap ammonia and convert it into non-volatile ammonium sulfate and disodium phosphate - to convert hydrochloric acid into non-volatile sodium chloride). The resulting mixture is distilled. The steam, passing through the traps, is cleaned of the droplet phase, enters the condensation chamber, cooled from the outside with cold water, and, condensing, turns into pyrogen-free water. Water for injection must meet all the requirements for distilled water and be pyrogen-free. It is usable for no more than 24 hours if stored under aseptic conditions. The sanitary-epidemiological stations are obliged to carry out a selective bacteriological control of water for injection on a quarterly basis and the absence of pyrogenic substances. "A guide for pharmacists of pharmacies", D.N. Sinev Page 16 of 19 10. Calculate isotonic concentrations. Water for injection (GFH, p. 108), peach and almond oils are used as solvents. Water for injection must meet all the requirements for distilled water and, in addition, be free of pyrogenic substances. CONDITIONS FOR PREPARATION OF MEDICINES FOR INJECTION The preparation of injectable dosage forms should be carried out under conditions that maximally limit the possibility of microorganisms entering the drug (aseptic conditions). PREPARATION OF DISHES AND AUXILIARY MATERIALS FOR THE MANUFACTURE OF INJECTION MEDICINES A bottle with a ground glass stopper is thoroughly washed with a brush, mustard powder or synthetic non-alkaline powder until the glass surface is well degreased. The water used to rinse the bottle should drain off its walls in an even layer, without leaving drops. PREPARATION OF SOLUTIONS FOR INJECTION Solutions for injection should be prepared at a concentration by weight. This requirement becomes especially important in the manufacture of solutions, the concentration of which is more than 5%, when there is a significant difference between the volumetric weight and weight concentration. The density of a 20% sodium salicylate solution is 1.083. The coefficient of increase in the volume of sodium salicylate is 0.59. Therefore, 20 g of sodium salicylate, when dissolved in water, increases the volume of the solution by 11.8 ml (20X0.59). PREPARATION OF SOLUTIONS FOR INJECTION FROM SALTS OF WEAK BASES AND STRONG ACIDS Solutions of salts of alkaloids and synthetic nitrogenous bases - morphine hydrochloride, strychnine nitrate, novocaine, etc. - are stabilized by adding 0.1 N. a solution of hydrochloric acid, which neutralizes the alkali released by the glass, suppresses the reactions of hydrolysis, oxidation of phenolic groups and the reaction of saponification of ester bonds. In a sterile volumetric flask, place 0.05 g of strychnine nitrate, dissolve in water for injection, add 0.5 ml of sterile 0.1 N. a solution of hydrochloric acid (measured with a microburette or dosed in drops) and add the solvent to 50 ml. The solution is filtered and sterilized at 100 ° for 30 minutes. PREPARATION OF SOLUTIONS FOR INJECTION FROM SALTS OF STRONG BASES AND WEAK ACIDS The salts of strong bases and weak acids include sodium nitrite, which decomposes in an acidic environment with the release of nitrogen oxides. To obtain stable solutions of sodium nitrite for injection, it is necessary to add sodium hydroxide solution. Take: Sodium nitrite solution 1% -100.0 Sterilize! PREPARATION OF SOLUTIONS FOR INJECTION FROM PRE-OXIDIZING SUBSTANCES To stabilize easily oxidized substances (ascorbic acid, chlorpromazine, diprazine, ergotal, novocainamide, vicasol, etc.), antioxidants, which are strong reducing agents, are added to their solutions. PREPARATION OF GLUCOSE SOLUTIONS When sterilized (especially in alkaline glass), glucose is easily oxidized and polymerized. PREPARATION OF INJECTION SOLUTIONS WITH THERMAL SUBSTANCES Solutions of thermolabile substances are prepared without heat sterilization. This group includes solutions of akrikhin, barbamil, barbital sodium, hexamethylenetetramine lactate ethacridine, salicylate physostigmia, apomorphine hydrochloride. PREPARATION OF PHYSIOLOGICAL (PLASMA SUBSTITUTING AND ANTI-SHOCK) SOLUTIONS Physiological solutions are called solutions that can support the vital activity of the cells of the body without causing serious changes in the physiological balance. Examples of saline solutions are Ringer's, Ringer-Locke's solutions, saline infusions of various compositions, Petrov's liquid, etc. CALCULATIONS OF ISOTONIC CONCENTRATIONS To determine isotonic concentrations, three main calculation methods are usually used: 1) calculation based on Van't Hoff's law; 2) calculation based on Raoult's law; 3) calculation using isotonic equivalents for sodium chloride. For the manufacture of injection solutions, purified water of high purity is used, obtained by distillation or by reverse osmosis (water for injection). Water for injection (Aqua pro injectionibus) must meet the requirements for purified water, but, in addition, must be pyrogen-free and free of antimicrobial substances and other additives. Pyrogenic substances are not distilled with water vapor, but can get into condensate with water droplets if the distillation apparatus is not equipped with devices for separating water droplets from steam. The collection of water for injection, like purified water, is carried out in sterilized (steam-treated) collections of industrial production or glass cylinders, which must be appropriately marked (tags indicating the date of receipt of water). It is allowed to have a daily supply of water for injection, provided it is sterilized immediately after receipt, stored in tightly closed vessels under aseptic conditions. In order to avoid contamination with microorganisms, the resulting pyrogenic water is used for the manufacture of injectable dosage forms immediately after distillation or within 24 hours, keeping at temperatures from 5 to 10 ° C or from 80 to 95 ° C in closed containers, excluding water contamination by foreign particles and microorganisms. For injectable dosage forms manufactured under aseptic conditions and not subject to subsequent sterilization, water for injection is pre-sterilized with saturated steam. The production and storage of pyrogen-free water for injection dosage forms are under the systematic control of the sanitary-epidemiological and control-analytical services. For the manufacture of injectable and aseptic dosage forms, it is allowed to use non-aqueous solvents (fatty oils) and mixed solvents (mixtures of vegetable oils with ethyl oleate, benzyl benzoate, water-glycerol, ethanol-water-glycerol). As part of complex solvents, propylene glycol, PEO-400, benzyl alcohol, etc. are used. Non-aqueous solvents have different dissolving properties, antihydrolysis, bactericidal properties, are able to lengthen and enhance the effect of medicinal substances. Mixed solvents tend to have a higher dissolving power than either solvent alone. Co-solvents have found application in the manufacture of injection solutions of substances that are hardly soluble in individual solvents (hormones, vitamins, antibiotics, etc.). For the manufacture of injection solutions, peach, apricot and almond oils (Olea pinguia) are used - esters of glycerin and higher fatty acids (mainly oleic). Having a low viscosity, they pass relatively easily through the narrow channel of the syringe needle. Oils for injection are obtained by cold pressing from well-dehydrated seeds. They should not contain protein, soap (<0,001 %). Обычно масло жирное содержит липазу, которая в присутствии ничтожно малого количества воды вызывают гидролиз сложноэфирной связи триглицерида с образованием свободных жирных кислот. Кислые масла раздражают нервные окончания и вызывают болезненные ощущения, поэтому кислотное число жирных масел не должно быть более 2,5 (< 1,25 % жирных кислот, в пересчете на кислоту олеиновую). The negative properties of oil solutions are high viscosity, painful injections, difficult resorption of oil, the possibility of oleoma formation. To reduce the negative properties, in some cases, co-solvents (ethyl oleate, benzyl alcohol, benzyl benzoate, etc.) are added to the oil solutions. Oils are used for the manufacture of solutions of camphor, retinol acetate, synestrol, deoxycorticosterone acetate and others, mainly for intramuscular injections and quite rarely for subcutaneous injections. Ethanol(Spiritus aethylicus) is used as a co-solvent in the preparation of solutions of cardiac glycosides and as an antiseptic, it is used in the composition of anti-shock fluids. Ethanol used in solutions for injection must have a high degree of purity (free from aldehydes and fusel oils). It is used in a concentration of up to 30%. Ethyl alcohol is sometimes used as an intermediate solvent for substances that are insoluble in either water or oil. For this, the substance is dissolved in a minimum volume of alcohol, mixed with olive oil, and then the ethanol is distilled off under vacuum and an almost molecular solution of the substance in oil is obtained. This technological method is used in the manufacture of oil solutions of some anticancer substances. Bvnzilovy alcohol(Spiritus benzylicus) is a colorless, easily mobile, neutral liquid with an aromatic odor. Let's dissolve in water at a concentration of about 4%, in 50% ethanol - in a 1: 1 ratio. Mixes with organic solvents in all proportions. It is used as a co-solvent in oil solutions at a concentration of 1 to 10%. Possesses bacteriostatic and short-term anesthetic action. Glycerol(Glycerinum) at a concentration of up to 30% is used in injection solutions. In high concentrations, it has an irritating effect due to a violation of osmotic processes in cells. Glycerin improves the water solubility of cardiac glycosides, etc. As a dehydrating agent (for edema of the brain, lungs), glycerin is administered intravenously in the form of 10 - 30% solutions in isotonic sodium chloride solution. Ethyl oleate(Ethylii oleas). It is an ester of unsaturated fatty acids with ethanol. It is a light yellow liquid, insoluble in water. Ethyl oleate is mixed with ethanol and fatty oils in all proportions. Fat-soluble vitamins and hormones dissolve well in ethyl oleate. They are used as part of oil solutions to increase solubility and lower the viscosity of solutions. Benzyl benzoate(Benzylii benzoas) - benzoic acid benzyl ester - a colorless, oily liquid, mixed with ethanol and fatty oils, increases the solubility of steroid hormones in oils, prevents the crystallization of substances from oils during storage. CONTROL QUESTIONS 1. Give the definition of "container". What materials are used to make containers? 2. What types of closures are used in pharmacy practice? 3. How are pharmaceutical containers and closures processed? 4. How is the control of the cleanliness of dishes carried out in pharmacy practice? 5. What is the sterilization regime for pharmaceutical containers and closures?
Based on the calculations, we prepare the solution. We collect ⅔ volume of water for injection into a 5 liter container, dissolve 144 g of sodium bicarbonate in it, mix gently. We bring the solution to the required volume with water for injection and send the solution for chemical analysis.
To facilitate the work of specialists in equipping a pharmacy, there are various means of small-scale mechanization. The pharmacy complies with the standard for all the requirements of regulatory documents and follows all the recommendations of the Ministry of Health.
Medicines for injection include aqueous and oily solutions, suspensions, emulsions, as well as sterile powders and tablets, which are dissolved in sterile water for injection immediately before administration (see the article of the State Pharmaceutical Institute "Dosage forms for injection", page 309).
The following basic requirements are imposed on injectable solutions: 1) sterility; 2) pyrogen-free;
Testing of water and solutions for injection for the absence of pyrogenic substances is carried out according to the method specified in the article of the State Pharmacopoeia ("Determination of pyrogenicity", p. 953).
Pyrogen-free water is obtained under aseptic conditions in distillation apparatuses with special devices for releasing water vapor from water droplets (see "Temporary instructions for obtaining pyrogen-free distilled water for injection in pharmacies", Appendix No. 3 to the order of the USSR Ministry of Health No. 573 of 30 November 1962).
Asepsis is a specific mode of operation, a set of measures that minimize the possibility of drug contamination by microflora.
The creation of aseptic conditions is achieved by the preparation of drugs for injection in a specially equipped room, from sterile materials, in sterile containers (for the provisions on the aseptic room-box, see the Handbook of Basic Guiding Materials on Pharmacy, 1964).
Get acquainted with the device, equipment and organization of work in the aseptic room.
Disassemble and sketch in the diary the diagrams of the device for obtaining pyrogen-free water, installation for vacuum filtration, autoclave and table box.
Study the instructions for use, safety precautions and autoclave care.
For the conditions of preparation, quality control and storage of drugs for injections, see the order of the USSR Ministry of Health No. 768 dated October 29, 1968 (Appendix 11).
The flasks together with the stoppers are placed in a special metal box and sterilized in an autoclave or hot air, according to the instructions of the State Pharmacopoeia (article “Sterilization”, p. 991).
The sterile vials are kept in a closed box until they are used. They also sterilize volumetric dishes, beakers, coasters and funnels.
Folded filters, folded from thick high-quality filtered paper with a spatula and, if possible, without touching the hands, are individually wrapped in parchment capsules. The packaged filters are sterilized in an autoclave at the same time with a funnel and a cotton swab. The sterile filter wrappers are opened immediately before use.
WITH A CONCENTRATION OF PREPARATIONS OVER 5%
Take: Sodium salicylate solution 20% -100.0 Give. Designate. For injection.
The solution can be prepared as follows. 1. In a measuring container - sodium salicylate (20 g) is placed in a sterile volumetric flask, dissolved in a portion of water for injection, and then the solvent is added to 100 ml.
100 ml of solution weighs: 100X1.083 = 108.3 g.
Water for injection must be taken: 108.3-20.0 = = 88.3 ml. In a sterile stand, 20 g of sodium salicylate is placed and dissolved in 88.3 ml of water for injection.
Water must be taken: 100-11.8 = 88.2 ml.
The resulting sodium salicylate solution is filtered into a sterile bottle through a sterile glass filter No. 3 or 4. Wash water should never enter the bottle for dispensing. If necessary, the filtration is repeated several times through the same filter until a solution is obtained free of any mechanical impurities.
The bottle is closed with a ground stopper, tied with moistened parchment and sterilized with flowing steam at 100 ° for 30 minutes.
Take: Strychnine nitrate solution 0.1% - 50.0 Sterilize!
Give. Designate. For injection
Check the correct dosage of strychnine nitrate (list A).
When manufacturing, it should be taken into account that according to the State Pharmacopoeia of Chemistry (p. 653), the strychnine nitrate solution is stabilized with 0.1 hydrochloric acid solution at the rate of 10 ml per 1 liter.
Solutions of salts of stronger or more readily soluble bases - codeine phosphate, pachicarpine hydroiodide, ephedrine hydrochloride, etc. - do not need acidification.
In an alkaline medium, solutions of sodium thiosulfate, caffeine-sodium benzoate, and theophylline are also more stable.
Give. Designate. For injection
A sodium nitrite solution is prepared with the addition of 2 ml of 0.1 N. solution of caustic soda per 1 liter of solution (GF1H, p. 473).
Place 1 g of sodium nitrite in a sterile volumetric flask, dissolve in water for injection, add 0.2 ml of sterile 0.1 N. sodium hydroxide solution and add solvent to 100 ml. The solution is filtered and sterilized at 100 ° for 30 minutes.
Take a solution of ascorbic acid -100.0 Sterilize
Give. Indicate Injection
But GPC (p. 44) a solution of ascorbic acid is prepared in ascorbic acid (50 g per J l) and sodium bicarbonate (23.85 g per 1 l). The need to add sodium bicarbonate to the ascorbic acid solution is explained by the fact that it has a sharply acidic reaction of the medium. To stabilize the resulting sodium ascorbinate add anhydrous sodium sulfite in the amount of 2 g or sodium metabisulfite in the amount of 1 g per 1 liter of solution.
In a sterile volumetric flask, 5 g of ascorbic acid, 2.3 g of sodium bicarbonate and 0.2 g of anhydrous sodium sulfite (or 0.1 g of sodium metabisulfite) are placed, dissolved in water for injection and the volume is adjusted to 100 ml. The solution is poured into a sterile support, saturated with carbon dioxide (for at least 5 minutes) and filtered into a tempering bottle. Sterilize the solution at 100 ° for 15 minutes.
Take: Glucose solution 40% -100.0 Sterilize!
Give. Designate. 20 ml for intravenous administration
GPC solutions of glucose (p. 335) are stabilized by adding 0.26 g of sodium chloride per 1 liter of solution and 0.1 N. solution of hydrochloric acid to pH 3.0-4.0. The indicated pH value of the solution (3.0-4.0) corresponds to the addition of 5 ml of 0.1 N. hydrochloric acid solution per 1 liter of glucose solution (see GF1H, p. 462).
For the convenience of work, a sterile solution of the stabilizer is prepared in advance according to the prescription:
Sodium chloride 5.2 g
Diluted hydrochloric acid 4.4 ml Water for injection up to 1 liter
The specified stabilizer is added in an amount of 5% to the glucose solution, regardless of its concentration.
When preparing a glucose solution, it is necessary to take into account that its concentration is expressed in weight-volume percentages of anhydrous glucose. A standard glucose preparation contains one molecule of water of crystallization, therefore, when making a glucose solution, the drug is taken in a larger amount than indicated in the prescription, taking into account the percentage of water.
The solution is filtered and sterilized at 100 ° for 60 minutes. Glucose solutions are tested for pyrogenicity.
Take: Barbital sodium solution 5% -50.0 Sterilize!
Give. Designate. For injection
2.5 g of barbital sodium are weighed aseptically, placed in a sterile volumetric flask, dissolved in sterile chilled water for injection, and the volume is adjusted to 50 ml. The solution is filtered into a tempering flask under a glass cover. Dispense the solution with the label: "Prepared aseptically."
Solutions for injection from thermolabile substances can be prepared according to the instructions of the State Pharmacopoeia of Chemistry (p. 992). 0.5% phenol or 0.3% tricresol is added to the solutions, after which the flask is immersed in water, heated to 80 ° and kept at this temperature for at least 30 minutes.
Take: Ringer's solution - Locke 1000.0 Sterilize!
Give. Designate. For intravenous administration
Ringer-Locke's solution is prepared according to the following recipe:
Sodium chloride 8.0 Sodium bicarbonate 0.2 Potassium chloride 0.2 Calcium chloride 0.2 Glucose 1.0
Water for injection up to 1000.0
The peculiarity in the manufacture of the Ringer-Locke solution is that a sterile solution of sodium bicarbonate and a sterile solution of the remaining ingredients are prepared separately. The solutions are decanted before administration to the patient. Separate preparation of solutions eliminates the possibility of calcium carbonate precipitation.
Chlorides of sodium, potassium, calcium and glucose are dissolved in water for injection, the solution is filtered and sterilized at 100 ° for 30 minutes. In another part of the water, sodium bicarbonate is dissolved, the solution is filtered, if possible, saturated with carbon dioxide, tightly sealed and sterilized at 100 ° for 30 minutes. The sodium bicarbonate solution is opened after complete cooling.
When making a small volume of Ringer-Locke's solution (100 ml), you can use sterile concentrated salt solutions, dispensing them with drops: sodium bicarbonate solution 5%, potassium chloride solution 10%. calcium chloride solution 10%.
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