Chemical disinfectants antiseptics and preservatives

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Preservation of medicines using antimicrobial agents:

Preservation of medicines using antimicrobial agents By Dr Shahla Mirzaeei Kermanshah University of medical Sciences 1 1 1 1 1 Shahla Mirzaeei University of Kermanshah

Slide 2:

Preservative: in a formulation to minimize the risk of spoilage and preferably to kill low levels of contaminants introducedduring storage or repeated use of a multidose container. should never be added to mask poor manufacturing processes . 2 Shahla Mirzaeei University of Kermanshah

ideal preservative:

ideal preservative broad spectrum of activity rapid rate of kill selectivity in reacting with the contaminants not the formulation ingredients nonirritant non-toxic to the patient Stable effective throughout the life of the product 3 Shahla Mirzaeei University of Kermanshah

Effect of con.,temp.,inoculum:

Effect of con.,temp.,inoculum Effect of preservative concentration halving the concentration of phenol (h=6) gives a 64-fold (26) reduction in killing activity temperature reduction from 30°C to 20°C result in reduced rate of kill for E.coli fivefold in phenol (Q10 = 5) 45-fold in ethanol (Q10 = 45) size of inoculum Preservative ‘capacity’ is a term used to describe the cumulative level of contamination that a preserved formulation can tolerate before becoming so depleted as to become ineffective 4 Shahla Mirzaeei University of Kermanshah

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Preservative ‘capacity’ is a term used to describe the cumulative level of contamination that a preserved formulation can tolerate before becoming so depleted as to become ineffective 5 Shahla Mirzaeei University of Kermanshah

Factors affecting the ‘availability’ of preservatives:

Factors affecting the ‘availability’ of preservatives Effect of product pH weakly acidic preservatives,activity in unionized molecules(benzoic and sorbic acids) pH directly influence sensitivity of microorganisms to preservatives 6 Shahla Mirzaeei University of Kermanshah

Efficiency in multiphase systems :

Efficiency in multiphase systems unstable equilibrium in bulk aqueous phase ( i ) the oil phase by partition, (ii) the surfactant micelles by solubilization , (iii) polymeric suspending agents and other solutes (v)by competitive displacement of water of solvation , (iv) particulate and container surfaces by adsorption (v) any microorganisms present 7 Shahla Mirzaeei University of Kermanshah

Effect of container or packaging :

Effect of container or packaging Phenolics in rubber chloroform lost by the routine opening and closing of containers QAPs by plastic and glass containers 8 Shahla Mirzaeei University of Kermanshah

Quality assurance (QA):

Quality assurance (QA) all the procedures necessary to provide a high probability that a medicine will conform consistently to a specified description of quality R&D formulation design & development GPMP good pharmaceutical manufacturing practice QC quality control post-marketing surveillance 9 Shahla Mirzaeei University of Kermanshah

Introduction:

Introduction Disinfectants, antiseptics and preservatives are chemicals that have the ability to destroy or inhibit the growth of microorganisms and that are used for this purpose. Disinfectants. Disinfection is the process of removing microorganisms, including potentially pathogenic ones, from the surfaces of inanimate object 10 Shahla Mirzaeei University of Kermanshah

Antiseptics:

Antiseptics Destruction or inhibition of M.O. on living tissues having the effect of limiting or preventing the harmful results of infection Antiseptics are often lower concentrations of the agents used for disinfection 11 Shahla Mirzaeei University of Kermanshah

Preservatives:

Preservatives in pharmaceutical preparations to prevent microbial spoilage of the product and to minimize the risk of the consumer acquiring an infection when the preparation is administered. 12 Shahla Mirzaeei University of Kermanshah

Factors affecting choice of antimicrobial agent:

Factors affecting choice of antimicrobial agent • properties of the chemical agent • microbiological challenge • intended application • environmental factors • toxicity of the agent. 13 Shahla Mirzaeei University of Kermanshah

properties of the chemical agent:

properties of the chemical agent chemical reaction and the rate and extent influenced by: concentration of chemical temperature pH formulation 14 Shahla Mirzaeei University of Kermanshah

• intended application :

• intended application in medicinal preparations the ingredients in the formulation may antagonize preservative activity break in the skin or mucous membranes disinfection of instruments, the chemicals used must not adversely affect the instruments 15 Shahla Mirzaeei University of Kermanshah

environmental factors:

environmental factors by adsorption or chemical inactivation, thus reducing the concentration of active agent in solution or by acting as a barrier to the penetration of the disinfectant 16 Shahla Mirzaeei University of Kermanshah

toxicity of the agent:

toxicity of the agent that specify the precautions required in handling toxic or potentially toxic agents 17 Shahla Mirzaeei University of Kermanshah

microbiological challenge:

microbiological challenge types of microorganism present the levels of microbial contamination ( bioburden ) categorize chemicals according to their antimicrobial capabilities and what level of antimicrobial action is required in a particular situation 18 Shahla Mirzaeei University of Kermanshah

Types of compound:

Types of compound 1.Acids and esters 2.cohols 3 Aldehydes 4 Biguanides 5 Halogens 6 Heavy metals 7 Hydrogen peroxide and peroxygen compounds 8 Phenols 9 Surface-active agents 10 Other antimicrobials 19 Shahla Mirzaeei University of Kermanshah

1.Acids and esters :

1.Acids and esters (HA, H+ , A- in solution) HA, is the active antimicrobial agent Benzoic acid pH < 4.0. Con. 0.05–0.1% e for oral preparations Salicylic acid, in the treatment of superficial fungal infections Dis : metabolism of the acid resistance by some organisms 20 Shahla Mirzaeei University of Kermanshah

1.Acids and esters :

1.Acids and esters Sorbic acid In products such as gums, mucilages and syrups are usefully Sulphur dioxide, sulphites , metabisulphites 21 Shahla Mirzaeei University of Kermanshah

1.Acids and esters :

1.Acids and esters Esters of p- hydroxybenzoic acid ( parabens ) pH 7–8(broader pH range) active against a wide range of fungi but are less so against bacteria In emulsions, creams and lotions methyl ester (0.25%) for aqueous phasethe propyl or butyl esters(0.02%) for oil phase 22 Shahla Mirzaeei University of Kermanshah

Alcohols :

Alcohols aliphatic alcohols used for disinfection and antisepsis poor penetration of organic matter and their use is therefore restricted to clean conditions 90%, (most viruses HIV) Ethanol:presence of water is essential for activity(con:60% - 95% ,70% best solution 23 Shahla Mirzaeei University of Kermanshah

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Isopropanol : has slightly greater bactericidal activity than ethanol but is also about twice as toxic . It is less active against viruses, particularly nonenveloped viruses , and should be considered a limited-spectrum virucide . Used at concentrations of 60–70%, 24 Shahla Mirzaeei University of Kermanshah

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aralkyl alcohols as preservatives: Benzyl alcohol 2% Chlorbutol 0.5% : It has been used as a preservative in injections and eye-drops. It is unstable, decomposition occurring at acid pH during autoclaving, while alkaline solutions are unstable at room temperature Phenylethanol 0.25–0.5% Phenoxyethanol 1% Bronopol 0.01–0.1% 25 Shahla Mirzaeei University of Kermanshah

Aldehydes:

Aldehydes Chemosterilant Glutaraldehyde ( biocidal activity) an acidic 2% or greater aqueous solution Ortho- phthalaldehyde requires no activation, pH range 3–9 26 Shahla Mirzaeei University of Kermanshah

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Formaldehyde liquid or gaseous state Humidity 70%. Formalin, diluted 1:10 to give 4% formaldehyde for surface, poor penetration and a tendency to polymerize Formaldehyde-releasing agents to reduce the irritancy Noxythiolin Polynoxylin Taurolidine 27 Shahla Mirzaeei University of Kermanshah

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28 Shahla Mirzaeei University of Kermanshah

Biguanides:

Biguanides Chlorhexidine and alexidine A related compound is the bisbiguanide alexidine , which has use as an oral antiseptic and anti-plaque agent . 29 Shahla Mirzaeei University of Kermanshah

Slide 30:

Chlorhexidine base is not readily soluble in water,therefore the freely soluble salts, acetate, gluconate and hydrochloride are used in formulation. Chlorhexidine exhibits the greatest antibacterial activity at pH 7–8 where it exists exclusively as a dication . 30 Shahla Mirzaeei University of Kermanshah

Slide 31:

The cationic nature of the compound results in activity being reduced by anionic compounds including soap due to the formation of insoluble salts. Anions to be wary of include bicarbonate, borate,carbonate , chloride, citrate and phosphate with due attention being paid to the presence of hard water . Deionized or distilled water should preferably be used for dilution purposes 31 Shahla Mirzaeei University of Kermanshah

Slide 32:

Reduction in activity will also occur in the presence of blood, pus and other organic matter. Chlorhexidine has widespread use , in particular as an antiseptic 32 Shahla Mirzaeei University of Kermanshah

Slide 33:

pseudomonad contamination of aqueous chlorhexidine solutions have prompted the inclusion of small amounts of ethanol or isopropanol chlorhexidine is well tolerated and nontoxic when applied to skin or mucous membranes and is an important preoperative antiseptic. 33 Shahla Mirzaeei University of Kermanshah

Polyhexamethylene biguanides:

Polyhexamethylene biguanides Within the structure, n varies with a mean value of 5.5. The compound has a broad spectrum of activity against Gram-positive and Gram-negative bacteria and has low toxicity. PHMB is employed as an antimicrobial agent in various ophthalmic products. 34 Shahla Mirzaeei University of Kermanshah

Halogens:

Halogens Chlorine and iodine have been used More recent formulations of these elements have improved activity , stability and ease of use. 35 Shahla Mirzaeei University of Kermanshah

Chlorine:

Chlorine most important as liquid chlorine The terms liquid and gaseous chlorine refer to elemental chlorine as a mixture of OCl -, Cl2, HOCl and other active chlorine compounds in aqueous solution. The potency of chlorine disinfectants is usually expressed in terms of parts per million (ppm) or percentage of available chlorine ( avCl ). 36 Shahla Mirzaeei University of Kermanshah

Hypochlorites:

Hypochlorites inexpensive and compatible with most anionic and cationic surface-active agents . Hypochlorites are available as powders or liquids, most frequently as the sodium or potassium salts of hypochlorous acid ( HOCl ). 37 Shahla Mirzaeei University of Kermanshah

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disadvantage they are corrosive, suffer inactivation by organic matter and can become unstable. 38 Shahla Mirzaeei University of Kermanshah

Slide 39:

Undissociated hypochlorous acid is a strong oxidizing agent and its potent antimicrobial activity is dependent on pH as shown: HOCl H+ + OCl - At low pH the existence of HOCl is favoured over OCl - (hypochlorite ion). The relative microbiocidal effectiveness of these forms is of the order of 100:1.   39 Shahla Mirzaeei University of Kermanshah

Slide 40:

By lowering the pH of hypochlorite solutions the antimicrobial activity increases to an optimum at about pH 5; however , this is concurrent with a decrease in stability of the solutions. This problem may be alleviated by addition of NaOH in order to maintain a high pH during storage for stability . 40 Shahla Mirzaeei University of Kermanshah

Slide 41:

The absence of buffer allows the pH to be lowered sufficiently for activity on dilution to use-strength. It is preferable to prepare use-dilutions of hypochlorite on a daily basis. 41 Shahla Mirzaeei University of Kermanshah

Organic chlorine compounds :

Organic chlorine compounds A number of organic chlorine, or chloramine, compounds are now available for disinfection and antisepsis. N - chloro (= N -Cl) derivatives eg:sulphonamides giving compounds such as chloramine–T and dichloramine –T and halazone for the disinfection of contaminated drinking water. 42 Shahla Mirzaeei University of Kermanshah

Slide 43:

These are available in granule or tablet form and, in contrast to hypochlorite, are very stable on storage, if protected from moisture. Important to note that where inadequate ventilation exists , care must be taken not to apply the compound to acidic fluids or large spills of urine in view of the toxic effects of chlorine production . Exposure Standard (OES) short-term exposure limit at 1 ppm 43 Shahla Mirzaeei University of Kermanshah

Chloroform :

Chloroform Chloroform (CHCl3 ) volatilization from products resulting in the possibility of microbial growth. 44 Shahla Mirzaeei University of Kermanshah

Iodine:

Iodine Gram-negative and Gram-positive organisms , bacterial spores (on extended exposure), mycobacteria , fungi and viruses are all susceptible. The active agent is the elemental iodine molecule, I2 . Aqueous Iodine Solution, BP containing 5% iodine in 10% potassium iodide solution 45 Shahla Mirzaeei University of Kermanshah

Slide 46:

The antimicrobial activity of iodine is less dependent than chlorine on temperature and pH, although alkaline pH should be avoided . Iodine is also less susceptible to inactivation by organic matter . Disadvantages in the use of iodine in skin antisepsis are staining of skin and fabrics coupled with possible sensitizing of skin and mucous membranes . 46 Shahla Mirzaeei University of Kermanshah

Iodophors:

Iodophors 47 Shahla Mirzaeei University of Kermanshah

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