Alharith Hassan. Q 10 Method of Shelf-life estimation. Methods of Chemical stabilisation 11/20/2015

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1 Q 10 Method of Shelf-life estimation Q 10 approach is an old concept that could be useful for estimating the shelf-life at room temperature of products recommended for cold storage. Calculations are based on the following equation: Q 10 is the factor by which a rate constant increases for a 10 rise in temperature; for an optimistic estimate Q 10 = 2, for a pessimistic estimate Q 10 = 4. t s (T1) and t s(t2) are the shelf-lives at temperature T 1 and T 2. The Q 10 approach is not suitable for the more precise predictions of shelf-life required in the development of a new product. 1 2 Methods of Chemical stabilisation Enhancement of the chemical stability of a medicinal product demands a sound knowledge of the nature of the degradation reactions that are likely to occur during manufacture and storage and of the factors that may influence the rate of degradation. The principal methods used to enhance chemical stability include the following: 3 Antoxidants:- They are added in small amounts to pharmaceutical preparations that are susceptible to oxidation to inhibit autoxidation reactions. They are classified in accordance with their mode of actions into three groups:- 1- True antoxidants:- block chain reactions by reacting with free radicals.(e.g. Vit E derivatives) 2- Reducing agents:- are substances that have a lower redox potential than the drug or adjuvant that they are intended to protect against oxidation. ( Ascorbic acid and its salts) 3- Antoxidant synergists:- are used in conjunction with true antoxidants to enhance their effects. They are supposed to act by chelating with ions of heavy metals or may provide hydrogen for the regeneration of inactivated radicals of the antoxidant. (Edetic acid and its salts) 4 1

2 An ideal antoxidant for a pharmaceutical product would possess the following properties:- 1- effective in low concentration over a wide range of temperature and ph. 2- readily soluble at concentration used. 3- stable (chemically and physically) over a wide range of temperature and ph values. 4- compatible with plastics, rubber, and other materials used in containers and closures. 5- Free from objectionable odour, taste or colour. 6- compatible with other components of the preparation. 7- Free from toxic, carcinogenic, irritant or sensitising effects at the concentration used. 5 Control of peroxides:- To minimise autoxidation especially of oils and fats care should be taken to use ingredients with concentrations of peroxides that are as low as possible. Control of heavy metals:- Where the drug or other ingredients are prone to degrade by oxidation the content of heavy metal ions should be kept as low as possible. 6 Control of oxygen content:- To minimise oxidation, it may be sufficient to recommend storage of the substance or product in well-filled, airtight or well-closed containers. Other measures are done during manufacturing to minimise oxygen content. Control of ph:- Knowledge of the effects of ph on degradation rate enables the formulator to adjust or buffer the ph near that corresponding to maximum stability. However, formulation of a solution near the ph of maximum stability is not always possible because solubility, absorption by the tissues, efficacy, and irritant effects must also be considered. Therefore, an intermediate ph should be selected as a compromise to achieve adequate stability, efficacy and comfort to the patient

3 Change of solvent:- The use of organic solvent in place of part or all of the water in an aqueous vehicle can enhance the stability of solutions of certain drugs.(e.g. phenobarbitone) Control of drug concentration:- Drug concentration in a medicine is usually determined by therapeutic considerations but it is sometimes possible to enhance stability by modifying the concentration. Conversion to sparingly soluble salts:- It is sometimes possible to convert a relatively unstable, soluble drug to a sparingly soluble drug that can be formulated as a stable suspension (e.g. procaine benzylpenicillin). Control of surfactant concentration:- In pharmaceutical products such as emulsions it may be necessary to control surfactant concentrations to enhance the chemical stability of the active constituents Formation of a complex:- Protection from degradation can sometimes be achieved by the formation of a complex, e.g. the hydrolysis of procaine can be retarded by the addition of caffeine to form a water-soluble complex. Another example, cyclodextrines have been used, in recent years, to enhance the stability of drugs by forming inclusion complexes. Control of water:- Drugs that are highly unstable in solutions or suspensions (e.g. many antibiotics) are often formulated as powder or granules for extemporaneous reconstitution with water. Protection against moisture in solid dosage forms can be achieved by many formulation processes and packaging measures. Control of carbon dioxide content:- Where instability of a product involves uptake of carbon dioxide, precautions should be taken to remove the gas as far as possible

4 Control of temperature:- Precise control of temperature and time in different pharmaceutical processes, such as sterilisation and drying, is crucial especially for thermolabile substances. Storage temperature recommended by the manufacturer should be followed by pharmacists and patients, for example some medicines are required to be stored at a low temperature to prolong the shelf-life such as insulin. Protection from light:- Medicinal products that are sensitive to light are usually protected from light by suitable packaging. Protection from light can also be achieved by skillful formulation, e.g. by coating tablets with an opaque material or using opaque shells for capsules. Control of ionising radiation Control of Mechanical processes Physical Stability Many medicinal products are complex physicochemical systems that may be subject to a diverse variety of physical changes during the period from preparation to administration. These such reactions may result in diminished bioavailability and efficacy or may adversely affect other properties such as dispersibility, acceptability to patient and convenience for use. Examples of physical reactions that are commonly encountered in medicines; factors that affect stability; and the methods of avoiding or minimising physical reactions:- 15 Volatility of constituents:- Drugs, solvents and excipients with high vapour pressure can be lost from medicinal products during manufacture and storage. Such drugs and products should be kept in well-closed or airtight containers to avoid loss of active constituent. In recent years, cyclodextrins have been used to reduce the volatility of drugs by the formation of inclusion complexes. Loss of solvents by evaporation may lead to hazardous concentration of the preparations or may lead to crystallisation of the drugs or excipients. Similarly, creams may lose water and form a skin on the surface ; emulsion may crack. 16 4

5 Changes in the water content of solids:- In many substances water is bound rather than unbound. Bound water interacts physically with the solid and its equilibrium vapour pressure is less than that of unbound; bound water may be entrapped in pores or may be molecularly bound to form a crystalline hydrate. Many materials are hygroscopic (e.g. glycerol), that is they gain (lose) water in accordance with the relative humidity; some(e.g. KOH) are deliquescent. In contrast, some salts (e.g. sodium sulphate) are efflorescent. Storage of hard gelatin capsules at a high relative humidity may results in the capsules becoming sticky and distorted due to a loss in mechanical strength. In very dry conditions water is desorbed from the capsule shell, which shrink and become brittle. Soft capsules are especially sensitive to conditions of relative humidity greater than 60% since irreversible softening may occur. In tablets, the uptake or loss of water can result in undesirable changes in properties such as hardness, disintegration time, dissolution rate, bioavailability, and efficacy Sorption:- Sorption of drugs or excipients such as antimicrobial preservatives may occur from solution on to solid drug particles, containers, or closures. Changes in crystal properties:- Changes in crystal form, habit, and size of a solid can affect not only the physical properties of a medicine but also its bioavailability. These changes can be minimised by addition of surfactants or polymers in low concentration, by use of a narrow size range of particles, by increasing viscosity of the vehicle and by avoiding large fluctuations in the temperature of storage. 19 Crystallisation from solution:- Crystal of a drug may be deposited from solutions because of a fall in temperature or a change in ph. Supersaturated solutions are especially likely to deposit crystals. 20 5

6 Physical changes in emulsions:- The physical instability of emulsions occurs in four main forms: 1- Flocculation where the dispersed globules aggregate to form clumps but where the interfacial film is not broken. 2- Cracking where the globules coalesce because of rupture of the interfacial film. 3- Creaming where the globules move towards the surface of the product. 4- Sedimentation where the movement of globules is downwards. These changes are often accompanied by changes in viscosity of the emulsion. These adverse changes in emulsions can be avoided by careful formulation. 21 Physical changes in suspensions:- The physical state of particles of a solid drug in suspension in a liquid depends largely on the magnitude of the opposing forces of attraction (Van der Waals forces) and repulsion (electrical double layer). If the forces of repulsion are greater than those of attraction, the suspension is deflocculated. In contrast, if attractive forces predominate, the suspension is said to be flocculated. In the formulation of suspensions, the degree of flocculation should be controlled to avoid the extremes of caking and too rapid sedimentation by the addition of low concentrations of electrolytes, surfactants, polymers, or a combination of these agents. 22 Physical changes in semi-solids:- Ointments, creams and pastes may soften, harden or become granular or gritty during storage. Syneresis (separation of liquid) may occur in both aqueous and non aqueous gels because of elastic contraction of the polymeric molecules of the gelling agent. Suppositories and pessaries may soften or harden. Physical changes in tablets:- Tablets may crumble or break especially during packaging or transport to produce powder or pieces at the bottom of the container. Changes in hardness, disintegration rate, or dissolution rate may occur. In coated tablets, the clumping may occur and the coat may crack under tropical conditions or by abrasion during transport