Stability Of Drugs:Factors Affecting Rates Of Hydrolysis And Oxidation
From Pharmpedia
Students,
we studied at length what is hydrolysis and oxidation. Though other mechanisms of degradation such as race misation and photolysis happen the two most important offenders are hydrolysis and oxidation. Let us now see what are all the factors that enhance these reactions. You must have understood by now that these very same reactions are used in synthetic chemistry and the chemist tries to enhance their speed so that his job of synthesis is over soon. The very same reactions are responsible for degradation and the pharmaceutical technologist tries to suppress them in order to prolong the shelf life of his product.
Imagine an aquarium having a few fish in it leisurely moving from one place to the other. For a while imagine our molecules (imagine the three dimensional models) are like fish in an aquarium, let us suppose the drug is an oral solution. The molecules are initially moving in a haphazard manner and sometimes some molecules are energized and they hit another energized molecule with the proper orientation and then the reaction happens. If the acquarium is full of sand loosely placed, the fish cannot move much and the reaction is less possible ! (This is like a solid drug). So all the factors that help the molecules move faster, or energized better enhance decomposition. All factors that reduce the speed of the molecules or interfere with their surface such that proper orientation is prevented reduce the decomposition. The key has to fit into the lock, but if the key’s surface is interfered with the lock cannot be opened!
Contents |
pH
The acidity or the alkalinity of a solution has a profound influence on the decomposition of drug compound.
Aspirin probably is the most widely studied drug for decomposition by hydrolysis. Edwards studied the degradation of aspirin in various buffer solutions and treated the overall reaction as pseudo first order. The classical study was given in the Theory and Practice of Industrial Pharmacy by Lachman.
Look at the following table and the accompanying graph.
|
pH |
K(days-1) |
pH |
K(days-1) |
|
0.53 1.33 1.80 2.48 2.99 4.04 5.03 |
0.578 0.0835 0.045 0.0267 0.0343 0.088 0.130 |
6.0 6.98 8.00 9.48 10.5 11.29 12.77 |
0.120 0.10 0.13 0.321 1.97 13.7 530 |
Overall velocity constant for aspirin hydrolysis at 17oc as a function of pH (from Edwards, L.J. Trans. Farad. Soc. 46:723,
1950).
This graph, based on the data contained in the Table tells us that an aspirin buffered solution is maximum stable at a pH of 2.4, its decomposition is independent of pH between pH 5 and 7 and above a pH of 10 the decomposition rate rapidly increases.
pH can also influence the rate of oxidation. This can be partially explained by the fact that the redox potential for many reactions depends on pH. Look at the following example
Using the Nernst equation
When Eo is the standard potential
E is the actual potential
1 is the number of electrons. Participating in change from oxidation form to reduction form.
0.06 calculated approximate constant.
This equation helps us to understand that an increase in the concentration of hydrogen ion causes an increase in the value of E.
So the reduced form of the system is less readily oxidized when the pH is low. Since the drugs that are undergoing oxidative
decomposition are usually in the reduced stage, minimum decomposition or maximum stability is usually found in the pH range of 3
to 4. So we understand that pH is of extreme importance both in the case of hydrolysis and oxidation.
Type of solvent: You have already seen that moisture or water is a big villain and plays a big role in decomposition. The reasons are many. It plays the role of a solvent vector, its thermal conductivity is high, it is polar in nature, its dielectric constant is high and it can take part in a reaction as a reactant. If we take off water from a product and replace it with another solvent having lower dielectric constant the decomposition rate will come down. Ethanol and glycols are examples for such solvents.
Complexation
Complex formation reduces the rate of hydrolysis and oxidation. Complex formation affects decomposition in two ways, (1) steric and (2) polar. For example, if a large caffeine molecule is attached to a benzocaine molecule by complexation, it will reduce the movement rate as well as ease of movement. So complexation reduces the ease of encounter of the ester with various catalytic species such as H+ and OH- through steric hindrance and thus reduces the rate of hydrolysis. Another effect is there for the complexing agent. Its electronic influence may alter the affinity of the ester carbonyl ion for the catalytic species – this alteration may increase or decrease the rate of hydrolysis. Lachman et. al have shown that caffeine complexes with local anesthetics, such as benzocaine, procaine and tetracaime to cause a reduction in their rate of hydrolytic degradation.
Chelating agents also complex with trace metals that enhance oxidative degradation and apply brakes to that process. Scientists studied the oxidative decomposition with and without 0.1% disodium salt of ethylenediamine tetracetic acid at different buffer concentrations. They found that the solutions not containing any chelating agent decomposed more rapidly as the buffer concentration increased. The buffered solutions containing chelating agent showed that the rate of degradation was independent of the concentration of the buffer.
Surfactants
Nonionic, cationic and anionic surfactants when added to solutions containing drugs form micelle and the drug particles become trapped in the micelle. The hydrolytic groups such as OH cannot penetrate this micelle cover and reach the drug particles, hence hydrolysis rate is decreased.
Riegelman studied the effect of surfactants on the rate of hyhdrolysis of esters and this study is discussed by Lachman in the Theory and Practice of Industrial Pharmacy. His data obtained is shown in the following table.
Influence of surfactant on benzocaime degradation at 30oc using 0.04n NaOH
|
Half life t1/2 in minutes |
Nonionic(%) | Cationic (%) | Anoinic (%) |
|
64 188 324 57 425 650 420 1150 |
0 1.333 3.3 |
0
0.067 1.34 2.46 |
0
1 5 |
A 5% sodium lauryl sulfate solution (anionic) caused an 18 fold increase in the half life of benzocaine. When 2.46% cetyl
trimethyl ammonium bromide is solution (cationic) was used a 10 – fold increase in the half life of benzocaine resulted. This
reduction in protective effect of the micelle was explained like this. The negatively charged hydroxyl ion is attracted by the
cationic group, but it apparently can not penetrate beyond this polar head into the deeper confines of the micelle wherein the
benzocaime appears to be held. So the cationic surfactants protection is less than that of the anionic’s but still some
protection is there. When a non-ionic surfactant at 3.3% concentration is used only about a 4 to 5 fold increase in half life was
obtained for benzocaime. Because of the relatively high degree of hydration at the surface of the nonionic surfactant micelle, it
seems that considerable hydrolytic attack could take place within the micelle, as well as in the aqueous phase.
Presence of heavy metals
Heavy metals, especially those possessing two or more valency states, with a suitable oxidation – reduction potential between them such as copper, iron, cobalt and nickel generally catalyze oxidative degradations. These metals increase the rate of formation of free radicals and enhance oxidative decomposition.
Light and humidity
Light, especially ultraviolet light enhances photolysis and humidity enhances decomposition of many drugs, especially the decomposition of drugs sensitive to hydrolytic decomposition.
Stabilization of drugs against hydrolysis, oxidation and photolysis
Stabilization against decomposition basically involves working against all the factors that cause decomposition. WHO has issued guidelines for storage of drug products.
Temperature
All the drug products are stored at suitable temperatures to avoid thermal acceleration of decomposition. In general drug products (for which room temperature storage is suggested should be stored at around 25oc and should never exceed 30oc or fall below 15oc as per USP XVII. The relative humidity should be in the range of 40 – 60 % RH. Three varieties of temperatures are suggested for storage of drug products. Room temperature, cool storage and cold storage.
Light
Light sensitive materials are stored in amber coloured bottles.
Humidity
Packing materials are so chosen (usually glass and plastic) to prevent exposure of drug products to high humid condition.
Oxygen
Proper packing keeping the oxygen content of the solution less and leaving very little head space in the bottle above the drug products are methods to fight against oxidation by exposure to free oxygen.
Oxidation
Anti oxidants are added to pharmaceutical formulations as oxygen scavengers – that is they have a higher capacity to undergo oxidation than the drug moiety. Table taken from the Theory and Practice of Industrial Pharmacy by Lachman gives lists of antioxidants usually used.
| Antioxidants commonly used for | |
|
Aqueous systems |
Oil systems |
|
Sodium Sulfite Sodium metabisulfite Sodium bisulfite Sodium thiosulfate Sodium formaldehyde sulfoxylate Acetone sodium metabisulfite Ascorbic acid Isoascorbic acid Thioglycerol Thiosorbitol Thiourea Thioglycolic acid Cysteire hydrochloride |
Ascorbyl palmitate Hydroquinone Propyl gallate Nordi hydroguaiaretic acid Butylaled hydroxy tolene Butylated hydroxy anisole 2 - tocophenol Phenyl – 2 – napthylamine Lecithin |
Theoretically speaking, we have to choose for every drug product an antioxidant which can undergo oxidation faster than the drug
itself, i.e. based on the difference in redox potential. But practically what pre-formulation scientists do is, after selecting
the antioxidant, the drug is placed together with the antioxidant and they are subjected to standard oxidative conditions. The
products are periodically assayed both for the drug content and the antioxidant content. Based on this type of practical studies
a suitable antioxidant is fixed for the formulation. The effectiveness of antioxidants can be enhanced through the use of
synergists such as chelating agents.
Chelating Agents
Chelating agents form complexes with heavy metal ions and prevent them from catalyzing oxidative decomposition. Some good examples of chelating agents are ethylenediamine tetracetic acid derivatives and salts, dihydroxyethyl glycine, citric acid and tartaric acid.
PH: For different drug products the pH of optimum stability is determined and maintained by the addition of buffering solutions.
Solvents
By the addition of a suitable solvent hydrolysis rate may be decreased. Modification of chemical structure of the drug moiety and the use of salts and esters of the drug which have lesser solubility are also methods used to reduce hydrolytic decomposition. But these methods have the very big limitation that they alter the physiological activity of the drug molecule or bio-availability of the drug molecule.
Thus drug products are designed in a way that minimizes decomposition. Then they are stored under appropriate conditions of temperature, humidity, and light so that the identity, strength, quality and purity of the drug products are not affected
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