Preservative Activity

Manufacturing controls necessary to maintain the antimi-crobiological effectiveness of preservatives should be evaluated. For example, for those products that separate on standing, there should be data available that show the continued effectiveness of the preservative throughout the product s shelf life. 

For concepts relating to sterility assurance and bioburden controls on the manufacture of sterile topicals, see the Guideline on Sterile Drug Products Produced by Aseptic Processing. 

Of particular concern are the effects that formulation and process changes may have on the therapeutic activity and uniformity of the product. For example, changes in vehicle can affect absorption, and processing changes can alter the solubility and microbiological quality of the product. 

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These systems are allowed in many food appHcations, but there also exists a range of nonfood preservatives active over a broad pH range. However, these may not be compatible with all enzymes because of their inhibitory or denaturing effects. A usefiil reference on this subject is available (31). 

The intended application of an antimicrobial agent, whether for preservation, antisepsis or disinfection, will influence its selection and also affect its performance. For example, in medicinal preparations the ingredients in the formulation may antagonize preservative activity. The risk to the patient will depend on whether the antimicrobial is in close contact with a break in the skin or mucous membranes or is introduced into a sterile area of the body. 

These parabens, the methyl, ethyl, propyl and butyl esters, are less readily ionized having pK values in the range 8-8.5 and exhibit good preservative activity even at pH... 

In the weakly acidic preservatives, activity resides primarily in the unionized molecules and they only have significant efficacy at pHs where ionization is low. Thus, benzoic and sorbic acids (pKa = 4.2 and 4.75, respectively) have limited preservative usefulness above pH 5, while the 4(p)-hydroxybenzoate esters with their non-ionizable ester group and poorly ionizable hydroxyl substituent (pKa ca. 8.5) have moderate protective effect even at neutral pH levels. The activity of quaternary ammonium preservatives and chlorhexidine probably resides with their cations and are effective in products of neutral pH. Formulation pH can also directly influence the sensitivity of microorganisms to preservatives (see Chapter 11). 

The major competing reaction in acyl azide coupling is hydrolysis. The higher the pH, the faster the reactivity, both with regard to amine conjugation and hydrolysis. Crosslinkers or modification reagents containing this compound must be kept dry to preserve activity. Reactions are complete in 2-4 hours at room temperature. 

The real challenge could be in the high-throughput, highly parallel, micropreparation of this structurally diverse class of biomolecules in their native states. Low abundance proteins will most likely require enrichment prior to detection (Figure 1.13). Frotein complexes will need to be isolated, some along with associated membrane components, in order to preserve activity. It will also be important to be able to reassemble these multiprotein complexes in their native and active states. 

Benzoic acid was found to be more sensitive to acidity changes than was anticipated from the Henderson-Hasselbach equation relating dissociated and non-dissociated fractions at pH 3 and pH 4 [51]. However, the sensitivity of preservative activity to dilution at both pH values remained similar. 

The EM studies show that the novel glide shear mechanism in the solid state heterogeneous catalytic process preserves active acid sites, accommodates non-stoichiometry without collapsing the catalyst bulk structure and allows oxide catalysts to continue to operate in selective oxidation reactions (Gai 1997, Gai et al 1995). This understanding of which defects make catalysts function may lead to the development of novel catalysts. Thus electron microscopy of VPO catalysts has provided new insights into the reaction mechanism of the butane oxidation catalysis, catalyst aging and regeneration. 

Resistance to acyclovir can develop in HSV or VZV through alteration in either the viral thymidine kinase or the DNA polymerase, and clinically resistant infections have been reported in immunocompromised hosts. Most clinical isolates are resistant on the basis of deficient thymidine kinase activity and thus are cross-resistant to valacyclovir, famciclovir, and ganciclovir. Agents such as foscarnet, cidofovir, and trifluridine do not require activation by viral thymidine kinase and thus have preserved activity against... 

Numerous materials-handling activities are required to move the biomass in the field to the factory. These activities include harvesting, storage, transportation, and, possibly, preservation activities. 

Preservatives such as sodium benzoate, sorbic acid, and methyl and propyl parabens have been used in liquid and semisolid dosage forms. There have been reports that the parabens have been inactivated when used in the presence of various surfactants. This loss of activity was thought to be due to the formation of complexes between the preservative and the surfactant. The interaction between polysorbate (Tween) 80 and the parabens has been demonstrated by a dialysis technique (Ravin and Radebaugh, 1990). It has also been shown that molecular complexes form when the parabens are mixed with polyethylene glycol (PEG) and methylcellulose. The degree of binding was less than that observed with Tween 80. Sorbic acid also interacts with Tweens but does not interact with PEGs. The quaternary ammonium compounds are also bound by Tween 80, which reduces their preservative activity. 

In multiuse parenteral products that require the use of a preservative system, studies have shown that preservative effectiveness can beiiienced by the cosolvents. Darwish and Bla ld [135] determined that the presence of a cosolvent produced an increase in the preservative activity of methyl and propyl paraben because ofthe increase in solubility afforded by the presence of cosolvents. Furtherstudies revealed that cosolvents alsaiience preservativeiafacy by causing cell membrane damage in and of themselves [136],... 

H. Kumatsu, K. Higazi, H. Okamoto, K. Miyakwa, M. Hashida, and H. Sezaki, Preservative activity and in vivo percutaneous penetration of butylparaben entrapped in liposomes, Chem. Pharm. Bull. 34 3415-3422 (1986). 

In the near future, the Preservation Office will be issuing a newsletter entitled, The National Preservation Report. The Preservation Office does this in response to a long-felt need and will attempt to provide news of preservation activities to the librarian, archivist, conservator, and scientist. 

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