Injection dosage form Injection dosage form with stabilizerswith stabilizers

Author: as. Yu.Yu. Plaskonis

Injection dosage forms - a specific group of drugs that require special conditions of preparation, the strictest adherence to aseptic, technological discipline, full responsibility for the preparation, quality control and design to dispensing drugs.

Injection solutions are prepared in aseptic unit

Aseptic conditions - defined conditions, and complex institutional arrangements required to enable to save the drugs from getting into these microorganisms.

Technology process of preparation of Technology process of preparation of solutions for injection consists of the following solutions for injection consists of the following

stages:stages: Preparation of aseptic unit and the organization of work Preparation of aseptic unit and the organization of work

in aseptic conditions. in aseptic conditions. Preparation of vessels and auxiliary materials. Preparation of vessels and auxiliary materials. Preparation of solvents and drugs. Preparation of solvents and drugs. dissolved drugs. dissolved drugs. stabilization or isotones solutions stabilization or isotones solutions Quality control solutions. Quality control solutions. Filtering solutions to filling bottles, checking the Filtering solutions to filling bottles, checking the

absence of mechanical inclusions. absence of mechanical inclusions. closing, leak check, preparation for sterilization closing, leak check, preparation for sterilization

(marking). (marking). Sterilization. Sterilization. Quality control and design of drugs to leave. Quality control and design of drugs to leave.

Preparatory work Preparatory work

Solutions preparing by volumetric- mass in which medicines taken by weight, and solvent added to obtain the desired volume of solution.

DissolutionDissolution

Stability is achieved by adding stabilizers or use of special methods of preparation.

Stabilization solutions when necessaryStabilization solutions when necessary

AnalysisAnalysis

Filtering solutionsFiltering solutions

Corking bottlesCorking bottles

Sterilization- solutions exposed within 1,5-2 hours after manufacture. The only exception is glucose, which sterilized immediately after production.

Stability of drug injection is achieved compliance with the aseptic conditions of their preparation, choice of optimal conditions (temperature, time) sterilization, antimicrobial use valid tools to achieve the effect of sterilization at lower temperatures and also the use of stabilizers - substances that enhance the chemical stability injecting drugs in the solutions.

Stabilizers can be divided into three Stabilizers can be divided into three groups:groups:

substances that provide chemical substances that provide chemical stabilization - antioxidants that prevent stabilization - antioxidants that prevent oxidation. oxidation.

substances that prevent the hydrolysis substances that prevent the hydrolysis of salts and esters saponification. of salts and esters saponification.

Antiseptics providing microbiological Antiseptics providing microbiological stabilization. stabilization.

№ Name of matter which needs to be stabilized Stabilizator

1 Solutions of salts, formed by weak bases and strong acids (atropine sulfate, Scopolamine hydrobromide, cocaine hydrochloride, pilocarpine hydrochloride, Novocain, Strychnine nitrate, Dibazol et al)

Acid hydrochloride (HCl) -10 ml a 0,1 M solution on 1 lNovocain of 0,25% - 3 ml a 0,1 M on 1 lNovocain of 0,5%- 4 ml a 0,1 M on 1 lNovocain of 1% - 9 ml a 0,1 M on 1 lNovocain of 2% - 12 ml a 0,1 M on 1 l

2 Solutions of salts, formed by strong bases and weak acids (sodium nitrite, caffeine- benzoate of sodium, sodium thiosulphate, euphillin)

Sodium hydroxide (NaOH) 0.1 M10%, 20% caffeine- benzoate of sodium- 4 ml 0.1 M on 1 l30% caffeine- benzoate of sodium- 20 ml 0.1 M on 1 l

3 Solutions of easily oxidable matters (acid ascorbic, vicasol, sodium salicylate, streptocide, adrenalin hydrotartrat)

Streptocide 5%, 10% - sodium sulfit 2 g on 1 l of solutionSodium salicylate 10% -sodium metabisulfite- a 1 g on 1 l of solutionAcid ascorbic 5% - sodium metabisulfite- 2 g on 1 l of solution

4 Solution of glucose A stabilizator of Weibel (is composition: sodium chloride- 5,2 g, acids chloride - 4,4 ml water for the injections to 1 l. Stabilizator is added by 5% from the volume of solution, which needs to be stabilized.

The main changes in drugs are chemical processes: • oxidation • hydrolysis • isomerization

Oxidizing substancesOxidizing substances

Oxidation are medicinal substances of different chemical structure: - derivatives of aromatic amines, fenotiazin, many salts of alkaloids, salts of bases, vitamins and other substances containing phenolic , alcohol, carbonyl groups, amino groups mobilize with hydrogen atoms.

Oxidation process can be slow in ways:Oxidation process can be slow in ways:

a) introduce a substance that rapidly a) introduce a substance that rapidly reacts with alkireacts with alkill radicals, resulting in radicals, resulting in peroxide will become only part of the peroxide will become only part of the radicals; radicals;

b) enter the compound, which quickly b) enter the compound, which quickly reacts with peroxide radicals. This will reacts with peroxide radicals. This will reduce the rate of formation of peroxides reduce the rate of formation of peroxides and radicals regeneration; and radicals regeneration;

c) enter Substances that Deplete hydro c) enter Substances that Deplete hydro peroxide peroxide RООН.RООН.

Pharmacy used antioxidants that Pharmacy used antioxidants that slow oxidation and prevent the formation slow oxidation and prevent the formation of active radicals. The most effective of of active radicals. The most effective of them are phenols, naftolthem are phenols, naftolumum, , aminofenolum, aromatic amines.aminofenolum, aromatic amines.

Effective antioxidants are substances that deplete hydro peroxide (sodium sulfit, sodium meta-bisulfit, tiosechovyna, ronhalit, unitiol) But there are other antioxidants, such as paraaminofenol, ascorbic acid. ..

It is known that redox processes strengthened influenced by several factors such as the presence of heavy metal ions, pH value, oxygen, temperature, etc.

Stabilization easily oxidation substances Stabilization easily oxidation substances are holding a set of measures:are holding a set of measures:

Introduction of antioxidants (for binding oxygen). Introduction of antioxidants (for binding oxygen). Introduction of chelating agent (for binding heavy Introduction of chelating agent (for binding heavy

metal ions). metal ions). Creating boundaries pH optimum solution with Creating boundaries pH optimum solution with

acids (hydrochloric, citric, ascorbic). acids (hydrochloric, citric, ascorbic). Removal of oxygen in solvent and in the air Removal of oxygen in solvent and in the air

above the solution (boiling, filling bottles to the top, above the solution (boiling, filling bottles to the top, saturating the solution with carbonic acid, filling saturating the solution with carbonic acid, filling bottles in current inert gas). bottles in current inert gas).

Rp.: Solutionis Acidi ascorbinici 5% 50 ml Sterilisa! Da. Signa

TECHNOLOGY TECHNOLOGY stabilize ascorbic acid solutions introduction antioxidant stabilize ascorbic acid solutions introduction antioxidant

sodium metabisulfitis 1 g per liter or solution or sodium sodium metabisulfitis 1 g per liter or solution or sodium sulphite anhydrous 2 g per 1 liter. In addition, solutions of sulphite anhydrous 2 g per 1 liter. In addition, solutions of ascorbic acid ascorbic acid strongly acidicstrongly acidic. In order to neutralize the . In order to neutralize the environment of the sodium carbonate solution is introduced environment of the sodium carbonate solution is introduced 23.85 g per 1 liter. Solution of sodium that is formed, 23.85 g per 1 liter. Solution of sodium that is formed, askorbinat is pH 6-7. askorbinat is pH 6-7.

In aseptic conditions in sterile volumetric flask dissolve In aseptic conditions in sterile volumetric flask dissolve 2.5 g of ascorbic acid, 1.19 sodium hydrogen carbonate and 2.5 g of ascorbic acid, 1.19 sodium hydrogen carbonate and

0.1 g anhydrous sodium sulphite in part 0.1 g anhydrous sodium sulphite in part freshly freshly prepared prepared water for injection. After the allocation of gas bubbles make water for injection. After the allocation of gas bubbles make up the solution to 50 ml, mixed, filtered in sterile bottles and up the solution to 50 ml, mixed, filtered in sterile bottles and sterilized at 120 ° C 8 min. Issuing labels "for injection", sterilized at 120 ° C 8 min. Issuing labels "for injection", "aseptically”."aseptically”.

WPC (front side) Date №

рецепта Natrii sulfitis anhydrici 0,1 Acidi ascorbinici 2,5 Natrii hydrocarbonatis 1,19 Aquae pro injectionibus ad

50 ml Vобщ = 50 ml Sterilis Prepared:

Signature Checked:

Signature

Hydrolysis - a reaction of ion exchange between drugs and water. Hydrolysis are different classes of compounds: alkaloids, glycoside, vitamins, esters, proteins, carbohydrates and especially salt. Hydrolysis are only salt in which one or both components are weak.

Hydrolysis of salts formed by weak base Hydrolysis of salts formed by weak base and strong acid, and their stabilization.and strong acid, and their stabilization.

This group includes salts of alkaloids containing synthetic nitrogen bases (solutions of salts of novocaine, dybazol, strychnine nitrate, etc.).. This group of salts stabilize adding 0.1 M solution of hydrochloric acid, since excess hydroxyl ions (OH +3) reduces the degree of dissociation of water and suppresses hydrolysis, causing a shift of equilibrium to the left.

Recommended stabilize hydrochloric acid solutions Apomorphini g / h, atropini sulfate, dybazoli, novocaine, spazmolityni, strychnine nitrate, cocaine g / s, dykayini. Stabilization of solution for injection, representing the salt of weak bases and strong acids by 0.1 M hydrochloric acid solutions. Examples are the solution of novocaine.

Rp.: Solutionis Novocaini 0,5% 100 ml Sterilisa! Da. Signa

For stabilization the 0.5% solution of novocaine 0.1 M hydrochloric acid

solution to pH 3,8-4,5 taking 4 ml per 1 liter of solution. Sterilizing at 120С 8 min.

Issuing blue label "for injection", which indicate: solution of novocaine 0.5% 100 ml for

infiltration anesthesia, aseptically.

WPC (front side)

Date № recipe

Aquae pro injectionibus 100 ml Novocaini 0,5Solutionis Аcidi hydrocarbonici 0,1 M gtts. VIII

Vобщ = 100 млSterilis

Prepared: Signature

Checked: Signature

Hydrolysis of salts formed a strong base Hydrolysis of salts formed a strong base and weak acidand weak acid

These are solutions of caffeine-sodium These are solutions of caffeine-sodium benzoate, sodium thiosulfate, sodium nitrite.benzoate, sodium thiosulfate, sodium nitrite.

In this case, hydrolytic processes enhanced in an acidic environment. To suppress hydrolysis is necessary: a weak alkaline medium by add-ing 0.1 M sodium hydroxide and adding sodium hydrogen carbonate. For stabilization of 1 liter of 10 and 20% solutions of caffeine-sodium benzoate SPh Ukraine X edition recommends adding 4 ml of 0.1 M sodium hydroxide and 30% sodium thiosulfate as a stabilizer is added sodium hydrogen carbonate (20 m per 1 liter).

Stabilization of glucoseStabilization of glucose

For stabilization glucose added stabilizer Veybelya, prepare for the words:

Natrii chloridi 5.2 ml Natrii chloridi 5.2 ml Hydrochloric acid divorced 4.4 ml Hydrochloric acid divorced 4.4 ml Water for injection to 1 literWater for injection to 1 liter

When preparing glucose, regardless of its When preparing glucose, regardless of its concentration, stabilizer added 5% by concentration, stabilizer added 5% by

volume solution.volume solution.