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Effect ofvarious environment/processing on stability of the formulation and techniques forstabilization of products against the same

Seminar submitted to:-Mr.Afrasim Moin Khan,Dept. of Pharmaceutics,JSSCP, Mysore. submitted by:- T.Manoj Kumar,Final year B.Pharm.

.All medical agents are to be investigated for their decomposition before being marketed.Most drugs contain one or more functional groups and therefore may undergo different chemical reactions.

Ingredients present in dosage forms and environmental factors affect the physical and chemical stability of of drugs, such as MoistureHeatLightRadiation etc.,

PHYSICAL DEGRADATION OF PHARMACEUTICAL PRODUCTS-preventive measures

Loss of volatile constituents :-Medicinal agents such as iodine, camphor, menthol, ethyl alcohol, anesthetic ether, chloroform have a tendency to evaporate from the product during storage.Similarly, nitroglycerine tablets may loose its potency owing to volatilisation of the medicament.The preventive measures include keeping the product in well-closed containers, and storing it in cool place.

Loss of water :-Loss of vehicle (water) from the product leads to decrease in weight, rises in concentration of drug and increase potency.Efflorescent substances, such as borax, caffeine and quinidine sulphate, have a natural tendency to loose water.Products such as emulsions and semisolids exhibit cracking. Loss of water depends on temperature and humidity.Preventive measures include preserving the product in a well-closed container and storing it in a cool place.

Absorption of water :-

Absorption of moisture from the atmosphere increase the weight of the product, dilutes the dose, and decreases the potency.Deliquescent substances, such as calcium chloride and potassium chloride have a natural tendency to absorb water. Gelatin capsules will absorb moisture and become soft and sticky. Preventive measures include storage of such products in well-closed containers.

Crystal growth :- Fluctuations in the ambient temperature (day & night or seasonal) cause crystal growth.Solutions- when temperature is lowered, the solution becomes supersaturated. Hence, precipitation & crystal growth of the drug is observed. For example, 10% W/V calcium gluconate in injection is a supersaturated solution. But in order to reduce the risk of crystallization, the I.P. suggests the use of calcium saccharate (More soluble calcium salt) as a stabilizer. A part of calcium gluconate (not more than 5%) is replaced by calcium saccharate.

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Suspensions particles slowly become bigger in size and finally may form a hard cake. These crystals, if present in the injection, may block the hypodermic needle. These particles produce gritty texture when applied as an ophthalmic preparation.

Preventive measures include :-Select suitable storage conditions to reduce fluctuations in ambient temperature.Increase the viscosity of the product so that diffusion of solute molecules onto the crystal surface will be hindered.Include surface active agents in formulations. These agents get adsorbed on the surface of the crystal and inhibit the further deposition of solute molecules.

Polymorphism :-

Polymorphs exhibit significant differences in important physicochemical properties such as solubility, dissolution rate and melting pont.In general, more soluble metastable drug is employed in the manufacture. For example, cortisone acetate, form II is more soluble (metastable) and formulated as an aqueous suspension. During storage, it may be converted into form IV (more stable form). Such changes lead to caking of the cortisone acetate suspension.

Normally suspending agents such as methyl cellulose are added to prevent the conversion owing to enhanced viscosity and limited diffusion of molecules.

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Colour changes :-

Colour changes indicate some kind of chemical or photochemical decomposition of the active ingredients, dyes or other ingredients.Colour-fading of dyes is a fairly common type of instability.Indigo carmine dye tends to fade in the presence of reducing substances (lactose and dextrose). Tartrazine tends to fade rapidly in the presence of additives (surface active agents) or light.

Colour development :- aspirin tablets become pink and ascorbic acid tablets turn yellowish brown. Adrenaline on exposure to air becomes red.

Preventive measures :-protect the product from light and air.Avoid using reducing substances (dextrose etc.,) as additives.Include UV-absorbing substances such as 2,4-dihydrobenzophenone in the formulation.

CHEMICAL DECOMPOSITION OF DRUGS-PREVENTIVE MEASURES

Hydrolysis :-

the general principles that govern hydrolysis reactions are,Drugs with ester and amide groups react with one molecule of water and undergo hydrolysis. Ester groups break faster than amide groups.Drugs are either weak acids or bases, so they may be available as ionic forms or neutral molecules. Hydrolysis reaction between ionic species proceeds faster than with neutral molecules.Hydrolysis reactions are catalysed by H+ and (OH)- ions. Hydroxyl ions catalyse hydrolysis by about 100 to 1000 times more actively than hydrogen ions.

These principles help in rationalising the design of formulations from stability point of view.

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Examples of drugs decompose by hydrolytic pathway are :-EstersAmidesAspirinChloramphenicolProcaineAmpicillinAtropineCephalosporinsBarbituric acids

Drugs that contain ester groups undergo hydrolysis to give acids and alcohols.Ex :- procaine undergoes hydrolysis & give P-amino benzoic acid and diethyl amino ethanol.

For the sterilization of procaine solution, it was suggested that autoclaving at 1200C for shorter period of time is preferred to prolonged heating at 1000C.

Amides undergo hydrolysis, though at a slower rate than esters.

Ex :- chloramphenicol decomposition is influenced by acids, bases, phosphate ions, acidic and citrate buffers.

Protection against hydrolysis :-Hydrolysis reactions are known to occur in presence of moisture, catalytic species H+ and (OH-). pretective measures should aim at eleminating the influence of these factors on the drug.

Buffers :-drugs may be stabilized by the use of buffers.The PH of the solution should be adjusted so that the drug will have maximum stability and therapeutic activity.In general, optimal PH will be between 3.5 and 5, since in that range the H+ and (OH-) catalysed hydrolysis are about equal.

Example :-Pilocarpine is highly active in alkaline PH and highly irritating to the eye and also decomposes rapidly.Therefore, to prevent hydrolysis, acidic PH has to be selected.Select a buffer with low buffer capacity so that when administered in the eye, the PH gradually rises and releases the free base for drug action.For this reason, boric acid buffer of a pH 5.0 with low buffer capacity is selected.

Complexation :-hydrolysis of benzocaine in aqueous solution can be inhibited by the addition of caffeine which forms a complex.As a result of complexation, the attack of catalytic species on benzocaine may be reduced.The ion-dipole interactions between (OH-) or H+ ions and drug molecules will be reduced.now the rate of hydrolysis depends on the amount of free uncomplexed benzocaine present in solution.As the amount of caffeine increases, more and more amount of benzocaine will be complexed. This leads to decreased hydrolysis. Thus, the self life of the product can be prolonged.

Other drugs which may be stabilized by complexation are procaine, tetracaine etc.

Suppression of solubility :-when the solubility of a drug decreases, the concentration of drug in solution phase will be decreased. Hence, the rate of hydrolysis is reduced. As most of the drug is in the insoluble state, only a small faction will be in solution form. Now, the rate depends on the saturation solubility of the drug and follows zero order reaction.Additives :- citrates, dextrose, sorbitol and gluconates, when combined with drugs, the solubility of drugs will be suppressed, probably because of decreased hydration of drug molecules.Salts :- the degradation of penicillin can be prevented by using poorly soluble salt of procaine penicillin in the dosage form. This preparation results in a suspension and follows zero order. Ex :- benzathine penicillin G.Derivatives :- poorly water soluble derivatives such as esters (higher fatty acids) of drugs can be used to reduce the tendency of hydrolysis. Ex :- erythromycin propionate, erythromycin stearate, chloramphenicol palmitate etc.

Removal of water :-as the presence of water is responsible for hydrolysis, it is better to avoid its contact with the drug in the preparation.

This is achieved by

Storing the drug in dry form. When desired, reconstitute the product. Ex :- streptomycin dry powder for injection.

Using water-immiscible vehicle for the dispersion of drug.Ex :- aspirin in silicone fluid.

Oxidation :-

Oxiditation involves the removal of electron from a molecule .The reaction between the compounds and molecular oxygen is called autooxidation.

In fats and oils, autooxidation of unsaturated fatty acids proceeds in the presence of atmospheric oxygen, light and traces of heavy metals or organic peroxides.

Ex :- The rate of oxidation of ascorbic acid is increased by a factor of 105, when copper ions are present in the concentration of 0.002 M. similarly hydroperoxides contained in polyethylene glycol suppository bases have been implicated in the oxidation of codeine to codeine-N-oxide.

The general principles that govern an oxidation reaction are :-

The presence of atmospheric oxygen (also air) promotes the rate of oxidation.Since oxidation frequently involves free radicals, chain reactions occur. Light provides the necessary energy to initiate the oxidation process.The presence of trace metals also accelerate the rate of oxidation.Organic peroxides promote the chain initiation and propagate the oxidation reaction.Drugs are either weak acids or bases. Therefore, these may be available as ionic forms or neutral molecules. Oxidation reaction between ionic species proceeds faster than with neutral molecules (to a large extent it is solubility related phenomenon).Oxidation reactions are catalysed by H+ and OH- ions. Hydroxyl ions catalyse oxidation faster than hydrogen ions. Alkaline solutions are known to react with atmospheric oxygen and forms oxides.

Drugs which decompose by oxidation pathways are :-Arachil oilVitamin AEthyl oleateRiboflavinClove oilVitamin B12Cinnamon oilAscorbic acidPromethazineMorphineEpinephrineprednisolone

The autooxidation kinetics of ascorbic acid has been extensively studied.

The overall reaction may be represented as :-

Influence of trace metals :-the scheme of oxidation of ascorbic acid by cupric ion is as follows :

Ascorbate ion in solution slow oxidation, Cu2+ semiquinone

rapid oxidation, O2 dehydro ascorbic acid

When solutions are free from traces of copper, ascorbic acid is not oxidized by molecular oxygen to a measurable extent, except in alkaline solutions. However, even traces of copper lead to the rapid oxidation of ascorbic acid. When CO and KCN are added to the above reaction mixture, they form complexes with metal ions, and therefore, oxidation of ascorbic acid is inhibited. These reactions demonstrate the influence of cupric ion on the oxidation of ascorbic acid.

Influence of air on oxidation :-The rate of decomposition decreases when higher concentration of ascorbic acid is used.It is presumed that a part of the ascorbic acid reacts with oxygen and thus depletes free oxygen. When air is bubbled through the reaction mixture, the rate of oxidation is enhanced. When dissolved oxygen is maintained at saturation level, the reaction rate remains constant.

Therefore, oxygen is responsible for the autooxidation reactions.

Influence of ionic species of drugs :-Ascorbic acid can exists as a singly charged or doubly charged ion.

In the absence of copper ions, oxygen is found to react with divalent ions at about 105 times faster compared to its reaction with monovalent ascorbate ion.

When copper ions are added, oxidation of singly charged ascorbate ion alone is found to be catalysed.

Influence of acidic and basic ion species :-The acid and base catalysed oxidation on ascorbic acid proceeds as follows. Dehydroascorbic acid (degradation product) further degrades to give ketogulonic acid, which inturn gives threonic acid and oxalic acid.

Ascorbic acid H, (OH) dehydro ascorbic acid ketogulonic acid Threonic acid + oxalic acid

In general, autooxidation proceeds more readily in alkaline medium than in acidic solution. Alkaline solutions are known to react with atmospheric oxygen and form oxides.

Protection against oxidation :-

Oxidation reactions are known to occur in presence of oxygen, trace metals, H+ and (OH-) ions.

Protective measures should aim at eliminating the influence of these factors on the drug.

Antioxidants :-Tocopherols are the naturally occurring antioxidants.Other ex :- butylated hydroxyl anisole (BHA) , butylated hydroxyl toluene (BHT), propyl gallate etc, These are widely used in foods, cosmetics and drugs. These agents are act by breaking the free radical chain reactions at the step of chain propagation. Most of these compounds are oil-soluble antioxidants.Water soluble antioxidants act by preferentially undergoing oxidation instead of the drug itself. Ex :- ascorbic acid. Compounds having SH groups consume molecular oxygen present in solution. Ex :- cysteine, acetylcysteine, thioglycolic acid etc.

Chelating agents :-Addition of a chelating agent to a product will be useful when traces of heavy metals catalyse the oxidation. Substances such as EDTA (ethylenediamine tetraacetic acid) citric acid and tartaric acid form complexes with heavy metals. Thus, metal ions are not available to catalyse the oxidation. ex:- addition of EDTA to the buffer system prevents the degradation of drugs such as prednisolone and ascorbic acid.

Another variation is that boric acid forms a one to one chelate directly with the drug, epinephrine. The chelated epinephrine is far less susceptible to sulfite attack than free epinephrine. Thus oxidation of epinephrine is inhibited.

Vehicles :-usually water is used as a solvent for most products.

The replacement of water by other solvents when used in combination with water, they have catalyzing effect on oxidation.

Production of hydroperoxides through these solvents is implicated in the degradation.

Several physicochemical properties of solvents such as internal pressure, solubility parameter, dielectric constant and ionic strength are correlated for the rates of a reaction.

.Micellar solubilisation :-

surfactants such as polysorbate 80 enhance the rate of oxidation of ascorbic acid at low concentration, but protect above its critical micelle concentration (CMC), presumably by entrapping the drugs in the spherical micelles. Sometimes, spherical micelles offer a site for surface adsorption of catalytic ions and enhance rate of reaction.Buffers :-

buffer system imparts stability when oxidation is catalysed by H+ or (OH-) ions.

Choose a buffer with appropriate PH to maintain maximum stability of the product.

Environmental control measures :-

One or more of the preventive measures are employed to stabilize the product from oxidation. Prevent the exposure to light :- light is responsible for oxidation. The preparation is protected from the light by employing amber coloured bottles or using appropriate packagingbmaterial (cardboard). Ex :- morphine sulphate injection USP is protected from light by using amber coloured ampoules.

Oxygen free environment :- oxygen enhances oxidative degradation. Therefore, air is replaced with inert gases such as nitrogen or carbon di oxide. Similarly, use of oxygen free solvents in manufacture is advisable.

Low temperature :- since high temperature enhances the rate of reaction, the product is stored in a cool place.

Miscellaneous reactions preventive measures

Isomerism :- some drugs often have some structural formula, but possess different stereochemical form into another leads to inactive or less active drugs.

Optical isomerisation :- in solutions, the optically active form of a drug gets converted into its enantiomorph. This process continues until the two forms are equal in concentration. The optical activity at equilibrium will be zero, i.e., optically in active. In general, recemisation reactions undergo degradation in accordance with first order kinetics.

Ex :- (-)Adrenaline (+/-) Adrenaline greater biological activity (+ and is 50:50) less potent

Preventive measures :- the product is protected from light and heat. Optimum PH has to be maintained for maximum activity.

.Epimerization :- In this case, the compound has more than one asymmetric carbon atoms. While one asymmetric atom remains static, the other carbon rotates to give an epimer. At equilibrium, both epimers are present, but need not to be in equal proportion. In other words, the solution may still exhibit optical activity.

Ex :- ergometrine ergometrinine in solution less active

Geometric isomerisation :- in this case, the compounds exists as trans and cis isomers, based on their relative spatial configuration of groups around a double bond(s). These changes may bring about a corresponding changes in its biological activity.

Ex :-vitamin A palmitate 6-momo-cis derivative + 2,6-di-cis derivative more acitve less active

.Polymerization :- These types of reactions are not often the initial cause of drug decomposition. Primary decomposition products may react further and polymerise. Ex :- dextrose injection autoclaving 5-hydroxymethyl furfural

polymerise straw coloured solutionAbsorption of carbon dioxide :- solutions absorb carbon dioxide from the atmosphere. Ex :- sodium hexobarbitone iv injection salt hydrolysis solution basic PH

absorb CO2 acidic PH hexobarbitone precipitate

Preventive measures :- the product is stored in well-filled and well-closed containers. Manufacturers supply the product as a dry sterile powder. The instruction should be to dissolve the drug before use in carbon dioxide free sterile water for injection.

.Decarboxylation :- These type of reactions are normally observed when a parentral solution contains sodium carbonate. During autoclaving, the carboxylic acid groups will be kocked off. Ex :- sodium p-aminosalicylic acid (PAS, Anti-TB drug), procaine hydrochloride (local anesthetic)

Procain (clear solution) hydrolysis p-amino benzoic acid

-CO2 aniline liquid light drak coloured liquid

Preventive measures :- carbon dioxide gas is passed into the solution for one minute. The container is sealed so as to be air-tigght prior to autoclaving.

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