Principles and kinetics of drug stability (PHR 416)

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Nahla S Barakat, PhD

Professor of Pharmaceutics

Pure drugs, solids, liquids, or gases are usually more stable than their formulations.

When they are formulated into medicines decomposition happens faster because of the presence of excipients, and moisture and because of processing .

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Factors affecting drug stabilityEach ingredient, whether therapeutically active or

pharmaceutically necessary can affect the stability of drug and dosage forms.

The primary environmental factors that can reduce stability include exposure to adverse temperature , light, humidity, oxygen, carbon dioxide.

The major dosage form factors that influence drug stability include particle size (emulsion, suspension), pH, solvent composition (% of free water and polarity), solution ionic strength, compatibility of anion and cation, primary container, specific chemical additive.

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The chemical decomposition of the drug

In this lecture we examine various ways in which drugs in both liquid and solid formulations can lose their activity, so that we can be aware of those chemical groups which, when present in drug molecules, can cause stability problems.

We will later see how to prevent or minimize the chemical breakdown for each type of decomposition process.

It should be noted that with some drug molecules more than one type of decomposition may be occurring at the same time; this, of course, complicates the analysis of the system.

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Drugs susceptible to hydrolytic degradation

How can we tell whether a drug is likely to besusceptible to this type of degradation?

If the drug is a derivative of carboxylic acid or contains

functional groups based on this moiety,for example an ester, amide, lactone,

lactam,imide or carbamate,

Examples of chemical groups susceptible to hydrolysis

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Drugs that contain ester linkages include acetylsalicylic acid (aspirin), physostigmine, methyldopate, tetracaine and procaine. Ester hydrolysis is usually a bimolecular reaction involving acyl–oxygen cleavage. For example, the hydrolysis of procaine is shown in Scheme 1

The hydrolysis of amides involves the cleavage of the amide linkage as but at slower rate than esters, for example, in the breakdown of the local anaesthetic procaine, cinchocaine (Scheme 2)

This type of link is also found in drugs such as chloramphenicol, ergometrine and benzylpenicillin sodium.

As examples of lactam ring hydrolysis we can consider the decomposition of nitrazepam and chlordiazepoxide, penicillin, cephalosporine.

The major chemical accelerator or catalysit of hydrolysis of lactam are adverse pH and specific chemicals (e.g. dextrose and copper in case of ampicillin hydrolysis)

Lactones, or cyclic esters pilocarpine, dalvastatin and warfarin undergoes hydrolysis due to ring opening.

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Hydrolysis of the amide linkage of cinchocaine

Hydrolysis of the ester group of procaine.

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Barbiturates, hydantoins, and imides contain functional groups related to amides but tend to be more reactive.

Barbituric acids such as barbital, phenobarbital and amobarbital, undergo ring-opening hydrolysis.

Decomposition products formed from these drug substances are susceptible to further decomposition reactions such as decarboxylation.

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Controlling drug hydrolysis in solution Optimisation of formulation Hydrolysis is frequently catalysed by hydrogen ions (specific

acid-catalysis) or hydroxyl ions (specific base-catalysis) and also by other acidic.

Several methods are available to stabilize a solution of a drug which is susceptible to acid–base catalysed hydrolysis. The usual method is to determine the pH of maximum stability from kinetic experiments at a range of pH values and to formulate the product at this pH .

Alteration of the dielectric constant by the addition of no-naqueous solvents such as alcohol, glycerin or propylene glycol may in many cases reduce hydrolysis.

In many cases solubilization of a drug by surfactants protects against hydrolysis

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it is possible to suppress degradation by making the drug less soluble. The stability of penicillin in procaine–penicillin suspensions was significantly increased by reducing its solubility by using additives such as citrates, dextrose, sorbitol and gluconate.

Adding a compound that forms a complex with the drug can increase

stability. Ex. The addition of caffeine to aqueous solutions of

benzocaine, procaine and tetracaine was shown to decrease the base-catalysed hydrolysis of these local anaesthetics in this way.

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2- Oxidation Oxidative degradation can occur by autoxidation, in which

reaction is uncatalysed and proceeds quite slowly under the influence of molecular oxygen, or may involve chain processes.

Steroids and sterols represent an important class of drugs that are subject to oxidative degradation through the possession of carbon–carbon double bonds polyunsaturated fatty acids, commonly used in drug formulations, are particularly susceptible to oxidation

Polyene antibiotics, such as amphotericin B which contains seven conjugated double bonds (heptaene moiety), are subject to attack by peroxyl radicals, leading to aggregation and loss of activity.

The ether group in drugs such as econazole nitrate (III) and miconazole nitrate (IV) is susceptible to oxidation

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Stabilisation against oxidationVarious precautions should be taken during manufacture

and storage to minimize oxidation. The oxygen in pharmaceutical containers should be replaced with nitrogen or carbon dioxide; contact of the drug with heavy-metal ions such as iron, cobalt or nickel, which catalyse oxidation, should be avoided; and storage should be at reduced temperatures.

AntioxidantsIt is very difficult to remove all of the oxygen from a

container and even traces of oxygen are sufficient to initiate the oxidation chain. by adding low concentrations of compounds that act as inhibitors.

Such compounds are called antioxidantsReducing agents such as sodium metabisulfite may also

be added to formulations to prevent oxidation. These compounds are more readily oxidized than the drug

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3- IsomerisationIsomerisation is the process of conversion of a

drug into its optical or geometric isomers. Since the various isomers of a drug are frequently of different activity, such a conversion may be regarded as a form of degradation, often resulting in a serious loss of therapeutic activity. For example, the appreciable loss of activity of solutions of adrenaline at low pH

has been attributed to racemisation – the conversion of the therapeutically active form, in this case the levorotary form, into its lessactive isomer.

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In acidic conditions the tetracyclines undergo epimerisation at carbon atom 4 to form an equilibrium mixture of tetracycline and the epimer, 4-epi-tetracycline .

The 4-epi-tetracycline is toxic and its content in medicines is restricted to not more than 3%.

Vitamin A (all-trans-retinol) is enzymatically oxidized to the aldehyde and then isomerised to yield 11-cis-retinal , which has a decreased activity compared with the all-trans molecule

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4- Photochemical decompositionMany pharmaceutical compounds, including

the phenothiazine tranquillizers, hydrocortisone, prednisolone, riboflavin, ascorbic acid and folic acid, degrade when exposed to light.

As a result there will be a loss of potency of the drug, often accompanied by changes in the appearance of the product, such as discoloration or formation of a precipitate.

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sunlight is able to penetrate the skin to a sufficient depth to cause photodegradation of drugs circulating in the surface capillaries or in the eyes of patients receiving the drug.

The rate of the photodegradation is dependent on the rate at which light is absorbed by the system and also the efficiency of the photochemical process

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Stabilization against photochemical decomposition Pharmaceutical products can be adequately protected

from photo-induced decomposition by the use of coloured glass containers and storage in the dark.

Amber glass excludes light of wavelength ˂470 nm and so affords considerable protection of compounds sensitive to ultraviolet light.

Coating tablets with a polymer film containing ultraviolet absorbers has been suggested as an additional method for protection from light.

In this respect, a film coating of vinyl acetate containing oxybenzone as an ultraviolet absorber has been shown to be effective in minimizing the discoloration and photolytic degradation of sulfasomidine tablets.

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5. PolymerisationPolymerisation is the process by which two or

more identical drug molecules combine together to form a complex molecule. It has been demonstrated that a polymerisation process occurs during the storage of concentrated aqueous solutions of aminopenicillins, such as ampicillin sodium.

The process can continue to form higher polymers. Such polymeric substances have been shown to be highly antigenic in animals

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The hydrate of formaldehyde, HOCH2OH, may under certain conditions polymerise in aqueous solution to form paraformaldehyde, HOCH2(OCH2)nOCH2OH, which appears as a white deposit in the solution.

The polymerisation may be prevented by adding to the solution 10–15% of methanol.

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6- DehydrationThe preferred route of dergradation of Prostaglandin E2 and

tetracycline is the elimination of water molecule from their structures. Acid catalyzed dehydration of tetracycline form epianhydrotetracycline, a product that lack antibiotic activity and causes toxicity.

The driving force for this type of covalent dehydration is the formation of a double bond .

In physical dehydration such as those occurring in theophyline hydrate and ampicillin trihydrate, water removal does not create new bond but often change s the crystalline structure of the drug.

Dehydration reactions involving water of crystallization may potentially affect the absorption rate of the dosage form.

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7- IncompatibilitiesChemical interactions between two or more

drug components in the same dosage form, or between active ingredient and a pharmaceutical excipient, occur frequently.

Ex., inactivation of cationic aminoglycoside antibiotic and anionic penicillins in IV admixture . The formation of inactive complex between these two classes of antibiotics occurs not only in vitro but also in vivo in patients with severe renal failure.

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Incompatibilities have also been observed in solid dosage forms. A typical tablet contain binders, disintegrant, lubricant and fillers.

Screening model may predict interaction of drug substances with excipients.

Many pharm. Incompatibility are the result of reactions involving the amine functional group Table 1

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Reaction of bisulphite and antioxidant epinephrine, a catecholamine, undergoes

displacement of its hydroxyl group by bisulfite.

Dexamethasone 21-phosphate, an α/β-unsaturated ketone, is known to undergo addition by bisulfite.

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Table 1. some potential drug incompatibility

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Other chemical degradation reactionsSuch as hydration, decarboxylation, or pyrolysis

are also potential routes for drug degradation. E.g. Cyanocobalamin may absorb about 12% of water

when exposed to air, and p-aminisalicylic acid decomposes with evolution of carbon dioxide to form m-aminophenol when subject to

temperature above 40 C.

Decarboxylation-some dissolved carboxylic acids, such as p-aminosalicylic acid, lose carbon dioxide from the carboxyl group when heated. The resulting product has reduced pharmacological potency.

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Physical degradation route

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Polymorphic transformation: Exposure to changes in temperature, pressure, relative

humidity and comminution during drying, granulation, milling and compression may lead to polymorphic transformation

Steroids, sulfonamides and barbiturates can form polymorphs

Polymorph may exhibit significant differences in physicochemical parameters such as solubility, melting point, dissolution rate.

Ex. Conversion of more soluble crystal form (form II) of cortisone acetate to a less soluble crystal form (form V) when the drug is formulated as an aqueous suspension.

The phase change leads to caking of the cortisone acetate suspension

conversion from solvated to nonsolvated form or hydrate to anhydrous can lead to change in solid-state properties.

For example: a moisture-mediated phase transformation of carbamazepine to the dihydrate has been reported to be responsible for whisker growth on the surface of tablets. The effect can be retarded by inclusion of Polyoxamer in the tablet formulation.

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Another physical property that affect the appearance, bioavailability and chemical stability is degree of crystalinity.

Amorphous materials tend to be more hygroscopic than their crystalline form.

Also amorphous form of drugs are less stable than their crystalline form.

Example: the crystalline cyclophosphamide is much more stable than the amorphous form.

The amorphous form of biosynthetic human insulin is more stable

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VaporizationFlavours, are mainly ketones, aldehyde, and

ester and cosolvents may be lost from the formulation

Example: nitroglycerine, significant drug loss to the environment can occur during patient storage and use.

(FDA)The addition of macromolecules such as PEG,

PVP and MCC allows for preparation of stabilized nitroglycerin SL tablet

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AgingChanges in the disintegration and dissolution

characteristics of the dosage forms are caused by alteration in the physicochemical properties of the inert ingredients or the active drug in the dosage form,

Changes in the processes as a function of the age of the dosage form may result in corresponding changes in the bioavailability of the drug product

Melting time of aminophylline supp increase from 20 min- 1 hr after 24 weeks storage at 22 C.

Aging of solid dosage form can cause a decrease in their in vitro rate of dissolution

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AdsorptionUp to drug loss can occur after nitroglycerine

is stored in PVC infusion bags for 7 days at room temperature. This loss can be attributed to adsorption

More than 40% of a dose of quinidine gluconate when the drug was administered with a conventional PVC intravenous administration set.

Drug loss was reduced by using a winged iv cather and short tubing

Diazepam, isosorbide dinitrate, insulin has shown substantial adsorption to PVC

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