Antimicrobial Preservatives Part Two: Choosing a Preservative

Sunday, January 1, 2012

Introduction

The second article in this series deals with the many constraints that face the pharmaceutical scientist tasked with developing preservation systems for multi-use oral, topical and parenteral medicinal products. The key role that pH plays in antimicrobial efficacy, as well as general stability considerations (both chemical and physical), will be covered.

Evaluating Performance

Latest APR Issue

Compendial tests [1-3] for antimicrobial efficacy set high performance standards. It is also a regulatory requirement to assess the antimicrobial efficacy of the drug product (in its final container) at the end of the product’s proposed shelf-life. Activity needs to be broad spectrum, encompassing bacteria (Gram-positive and Gram-negative), yeasts, fungi and molds; but not viruses. An effective preservative must reduce a microbial population significantly and prevent subsequent re-growth and these effects must be both microcidal and microstatic in nature.

Combining preservatives that act synergistically may help meet performance standards. Benzalkonium chloride (BKC) is ineffective against some strains of Pseudomonas aeruginosa, Mycobacterium and Trichophyton [4], but combinations with EDTA, benzyl alcohol, 2-phenylethanol or 3-phenylpropanol enhances anti-Pseudomonad activity [5]. Synergy is also observed in combination with cetrimide, 3-cresol, chlorhexidine and organo mercurials [6,7].

The amino benzoic acid esters (parabens) are more active against Gram-positive, than Gram-negative bacteria, and more active against yeasts and molds than bacteria. Activity increases with increased alkyl chain length (butyl > propyl > ethyl > methyl) but aqueous solubility commensurately decreases, and consequently the parabens are also often used in combination, e.g. methyl and propyl paraben. Parabens also show some synergy with EDTA [8], 2-phenylethanol [9] and imidurea [10].

The complexity of multi-phase dermal products, formulated as creams, lotions or ointments mean that adequate microcidal efficacy may not be attainable. The best that can be achieved is a microstatic effect. In practical terms such performance may be perfectly acceptable. If the bioburden is low most preservative systems can adequately kill or attenuate growth of most organisms. Current GMP (good manufacturing practice) standards, encompassing operating and sampling procedures, controls on input materials, use of clean room and automated technologies in manufacturing and packaging, when viewed holistically ensure that high standards of microbial cleanliness can be routinely achieved in fi nished products. Additionally, the state of the art in packaging technology is now such that contamination, prior to use is unlikely. Hence the risk of contamination is probably greatest during patient use of multi-dose liquid products. Microstasis may be an acceptable performance standard for non-parenteral products at this stage, if the in-use period is short (< 1-month).

Influence of Product pH

Table 1    -    Effect of pH on Preservative Efficacy

pH can affect the rate of growth of microbes, the interaction of the preservative with cell wall components and the MIC (minimum inhibitory concentration) of many preservatives [11,12]. In general, microbial growth is optimal between pH 6-8. Outside this range growth rate signifi cantly declines. In contrast, the product pH may refl ect the intrinsic pH of the active pharmaceutical ingredient (API), or the product may require pH modifi cation to enhance product solubility, stability, palatability or optimal microbial effectiveness (MICmax). Specifi c excipients may also infl uence product pH. Hence, pH adjustment to regions less favorable to microbial viability i.e. away from pH 6-8, may not be feasible or must take account of competing effects on overall product quality versus the activity of the preservative system. Table 1 lists pH ranges for optimum activity for common preservatives.

Such pH effects refl ect the chemical composition of the active moiety in the preservative molecule. For instance, if activity is associated with the non-ionized moiety (acids, alcohols and phenols) the effect is usually optimal at acidic pH but ultimately refl ects the pKa of the individual agent. However and almost inevitably, there are exceptions. For example, phenol is most active in acidic solutions, despite its high pKa (10.0). Substituted alcohols are also less reliant on pH. Bronopol (2-bromo-2-nitro-1, 3-propanediol) is not markedly infl uenced by pH in the range 5.0-8.0, perhaps refl ecting that its main activity is via release of formaldehyde, whose microcidal activity is not signifi cantly infl uenced by pH [22].

Phenolic preservatives tend to be active over a wider pH range than alcohols or acids. Chlorocresol [19] is most effective at acidic solutions but can retain activity at pH regions up to its pKa (9.2). Similarly, m-cresol [25] is also effective at pHs below its pKa (9.6). Solution pH does not have a marked effect on the anti-microbial efficacy of 4-chloroxylenol [31].

Esterifi cation of acids can extend the pH span of activity. The parabens are active over the range pH 4-8. Efficacy decreases at higher pH due to the formation of phenolate ion (pKa ca. 8.4). Efficacy increases with the longer alkyl chain, but conversely aqueous solubility decreases as hydrophobicity increases [13].

In contrast to acid preservatives, the quaternary ammonium compounds (QACs) such as benzalkonium chloride (BKC) and benzethonium chloride have anti-microbial efficacy over a wide pH range (pH 4-10), activity being associated with the ionized (cationic) moiety and being optimal at high pHs [4,11,14]. Efficacy is also linked with alkyl chain length (C18 > C16 > C14 > C12). Cetrimide [17] has a slightly narrower effective pH range (7-9), probably caused by the presence of a methyl rather than a benzyl moiety (less effective at stabilizing the charge). High pH causes the microbial cell wall to be negatively charged, thereby favoring the binding of cationic species.

There are no reported pH constraints on the permeation enhancing capability of EDTA, probably a consequence of its multiple pKa’s. However, its limited intrinsic anti-microbial efficacy means that it is rarely used on its own, but in combination with other preservatives [32,33].

pH-related effects can sometimes be more complex than those summarized in Table 1. The antifungal activity of benzoic acid is less susceptible to pH than are its antibacterial effects [15]. The substituted benzoic acid derivative thiomersal, which has a pKa of 3.1 is bacteriostatic and fungistatic at neutral and even mildly alkaline pHs. However, the microcidal activity of organic mercury also needs to be taken into account [30]. A similar effect is evident with propionic acid [23] and sorbic acids [24], which have appreciable antifungal but little or no antibacterial activity at pH 6.0.

Biguanide anti-microbials are active over the pH range 3-9. However, chlorhexidine is effective over a narrower pH range (5-7), and above pH 8.0 the base may precipitate from aqueous solutions [18]. Imidurea is effective over this whole pH range (3-9), although optimum efficacy is seen at acidic pH [21].

Organo mercurial preservatives, for example, phenylmercurate salts, have broad spectrum bactericidal and fungicidal activities, being more potent with increasing pH. Efficacy against Pseudomonad’s have also been demonstrated at pH 6 or below [27,28,29]. These preservatives have been utilized in several eye drop product having acidic pH values. Activity is enhanced at acidic pH in the presence of sodium metabisulphite, which can enhance activity at low pH, but has the opposite effect at alkaline pH [34,35]. In topical products phenylmercurate salts have been reported as being active at pH 5-8 [36].

Factors that Compromise Preservative Efficacy

Preservatives are no different from any other group of organic compounds. They possess reactive functional groups and may have pH-solubility profiles that need to be considered on a case-by-case basis when formulating the drug product. Preservative efficacy can be compromised by interactions with active ingredients, excipients, container / closures or by other physicochemical behaviors. Deterioration can occur during manufacture or throughout the product shelf life or use. Effects can be ascribed to:

  • interactions with other components within the product (drug, excipients, pack or delivery device)
  • chemical instability
  • physical losses or changes

Possibilities for degradation are manifold, but the risk can be mitigated at the outset by a thorough knowledge of all the product components and by appropriate pre-formulation studies to determine interaction propensity. It is important that such awareness be available at the product design stage, i.e. a QbD (Quality by Design) approach. Pharmaceutical products generally have much longer shelf life requirements than food or beverage products and quality must obviously be retained over such periods. The relatively insensitive nature of preservative efficacy tests [1-3] may mean that modest but inexorable deterioration of effectiveness during storage may take time to be considered significant. A consequent reformulation and evaluation program having deleterious effects on development timelines.

Chemical Stability of Preservatives

In addition to antimicrobial effectiveness testing (AET), it is a regulatory requirement to monitor the chemical stability of the drug product (in its final container) throughout the product’s proposed shelf-life. It should not surprise that most acidic preservatives e.g. benzoic, sorbic and propionic acids are incompatible with strong bases [15,23,24]. Strong oxidizing agents degrade sorbic acid [24], 2-phenylethanol [37], hexetidine [38], EDTA [32], thimerosal [30], propyl gallate [39] and butylated hydroxyanisole [40]. This latter material (BHT) is particularly unstable in the presence of peroxides and permanganates and interaction may even result in spontaneous combustion [40]. The deliberate inclusion of such potent materials in a dosage form might be unusual (although benzoyl peroxide is formulated as lotions to treat acne), but excipients such as povidone, crospovidone, polyethylene glycol and polysorbates may contain residual peroxides [41]. Residues may be low but a high excipient-to-preservative ratio may be sufficient to fuel interactions.

The antimicrobial efficacy of several preservatives is compromised by surface-active agents:

  • benzalkonium chloride [4], benzethonium chloride [14] and cetrimide [17], all being cationic in nature are incompatible with anionic surfactants.
  • benzyl alcohol [16], 2-phenoxyethanol [42], 4-chloroxylenol [20] and m-cresol [25] should not be formulated with non-ionic surfactants. Chlorobutanol [43] and 2-phenylethanol [37] are adversely affected by the presence of non-ionic surfactants, e.g. polysorbate 80.

Such interactions may not involve conventional chemical transformation, but concern more subtle phenomena e.g. hydrogen bonding and complex formation. Thus the overall level of preservative in the product may not change, but unless the preservative is available in the “free” form its efficacy may be compromised. Determination of preservative efficacy is therefore mandated [1-3].

Some preservatives interact with other preservatives, for example: EDTA [32] interacts with thimerosal, propyl gallate and phenylmercuric salts; chlorhexidine [18] can interact with benzoic acid and cetrimide [17] is incompatible with phenyl mercuric nitrate.

Most of the available preservatives seem ostensibly to be stable structures. This may explain why reports on intrinsic chemical instability (i.e. that do not involve interaction with other product components) of preservatives are less widespread than those interactions discussed above. Paraben [13,44,45] preservatives are susceptible to base-catalyzed ester hydrolysis, degrading by classic pseudo-first order kinetics, with shorter chain analogues being least stable [13]. Stability in solution is not markedly affected by pH up to about pH 6.5, but degradation rates increase significantly at pH 7.5 and above [46]. As parabens are reputedly active over the pH range 4-8 it would seem that caution is advised if product pH is likely to be higher than neutral. In the light of the predictable degradation kinetics of these agents scientifically relevant accelerated (high temperature) stability studies at the formulation development stage may well predict long term stability (or instability) in the final product. The formulation scientist may need to include excess parabens to compensate for chemical instability of the preservative system, including losses during manufacture, and this is allowable from a regulatory perspective. The guiding principle however is to minimize levels in the formulation commensurate with adequate preservative efficacy at the end of shelf-life [47].

Despite its many advantages as a preservative and its undoubted stability in the solid state, sorbic acid is unstable in semi-solid and liquid preparations. The principal degradation pathway is auto-oxidation resulting in acetaldehyde and β-carboxyacreloin end-products; as well as numerous other volatile aldehydes, e.g. malonaldehyde, acrolein, crotonaldehyde and related furans (2-methylfuran, 2-acetyl-5-methylfuran, 2,5-dimethylfuran) [48]. Sorbic acid may be stabilized by phenolic anti-oxidants, for example 0.02% w/w propyl gallate [39].

Macromolecules can be adversely affected by preservatives. Benzyl alcohol causes aggregation of rhIFN (recombinant human interferon), while several commercial biopharmaceutical products specify that diluent for constitution must not contain preservative(s) because of potential adverse effects on the protein [49].

Preservatives for insulin preparations must be chosen carefully. Insulin zinc suspensions cannot contain phenol as it destroys the crystallinity of the insulin and mixtures of parabens are used instead. In contrast neutral protamine insulin requires the use of phenol or meta-phenol to form and preserve the crystal form that provides the long-acting effect [50].

Physical Stability of Preservatives

Preservative content in products can be depleted during manufacture, storage or use.

The parabens [13,45,46], benzoic acid [15], benzyl alcohol [16], 2-phenoxyethanol [42], m-cresol [25], chlorocresol [19] and chlorbutanol [44] are all volatile to greater or lesser extents. This renders them susceptible to losses by sublimation or evaporation during manufacture or throughout product life. m-Cresol [25] and phenol [26] are not suitable as preservatives for preparations that need to be lyophilized due to their volatility. In addition, if any of the container / closure components are permeable to gases, e.g. plastic bottles or elastomeric closures, then this can result in the depletion of volatile preservatives.

Polyvalent ions may cause precipitation of preservative from solution e.g.:

  • sorbic acid [24] and chlorhexidine [18] can be “salted out” by Ca2+ ions.
  • chlorobutanol [44] and chlorhexidine [18] interact with Mg2+ ions.
  • bronopol [22] and phenylmercuric nitrate [29] can be precipitated by Al3+ ions.
  • Fe3+ ions can salt out butylated hydroxyanisole [40] and butylated hydroxytoluene [51].
  • EDTA [32] is precipitated by most polyvalent cations.

The overall level of the preservative in the product may remain unchanged but solution concentration is diminished, as a consequence of precipitation, leading to reduction of microbiological efficacy. Analytical techniques to monitor preservative content need to refl ect such considerations, viz assessing the free versus bound concentrations within the product.

Table 2    -    Examples of Preservatives Susceptible to Adsorption

Adsorption onto excipients, especially those with large surface areas or on to container / closure systems can also remove preservative(s) from solution. Table 2 lists some documented examples.

Antacid formulations illustrate that physical and chemical interactions can combine to make preservation difficult. pH of such products is usually neutral to slightly alkaline, where intrinsic preservative activity can be low. Additionally, the presence of polyvalent cations (e.g. Al 3+, Ca 2+, Mg 2+) associated with the actives can lead to precipitation. Adsorption of the preservative on to the insoluble antacid substrate is also possible. All contribute to the overall loss of preservative efficacy. Antacid suspensions are notoriously difficult to preserve to the standards defi ned in pharmacopoeias because of such behaviors. This is refl ected in the lowered acceptance criteria for Antacids (category 4 products) in USP <51> [1], i.e. ‘No increase (in bacteria, yeasts and molds) from the initial calculated count at 14 and 28 days’.

Multiphase products such as creams and lotions, as well as some parenteral and nasal / opthalmic products, can have aqueous and oily phases maintained in equilibrium by surface active agents. Viscosity enhancers may also be included as suspending agents. Such agents can interact with the preservatives as articulated above. The chlorinated preservatives, e.g. chlorobutanol [43], chloroxylenol [20] and chlorhexidine [18] can partition to or migrate on to polymeric suspending agents by competitive displacement of water of solvation. Similarly, the antimicrobial efficacy of 2-phenoxyethanol [42] is reduced in the presence of the cellulosic suspending agents, methylcellulose, sodium carboxymethyl cellulose and hydroxypropyl methylcellulose [61].

Preservatives will also distribute between oil and aqueous phases and at the interface containing the surface active agent, depending on distribution coefficient. Aqueous concentration, where the antimicrobial effect is required, is thereby reduced. Such behaviors reduce the efficacy of the parabens preservatives, particularly the longer chain analogues such as butyl paraben [46]. Chlorhexidine activity can also be reduced because of micelle formation [18]. Some preservatives can form ion-pairs with the corresponding API, e.g. timolol and sorbic acid. Whilst this has been proposed as a mechanism for enhancing the ocular bioavailability of timolol, the impact on the efficacy of the preservative system has not been reported [68].

The possibilities for reduced anti-microbial efficacy in multi-phase systems, has engendered efforts to devise in silico predictive approaches to determine the impact of formulation parameters on preservative activity. The infl uence of partition coefficients, binding constants (surfactants and polymers), and oil-in-water ratios have all been investigated but with limited success [12]. The pragmatic approach, involving optimizing the preservation system and inclusion levels by conventional assessment techniques therefore remains the desired approach for the present.

Conclusions

Preservatives, either singly or in synergistic combinations remain necessary to prevent microbial contamination of multi-use liquid or semi-solid medicinal products, particularly from opportunistic pathogens. Non-inclusion can result in serious patient health consequences. There are a limited number of regulatory approved preservatives that can be included in these multi-use medicinal oral or topical products and the number is constrained even further in parenteral products. The optimal conditions for preservative efficacy (pH, physical and chemical stability) are rarely the same as for the product itself and as such compromises are often necessary to ensure an optimal product shelf-life.

To Learn More

Click here to read part three of this series: Challenges Facing Preservative Systems

Acknowledgements

Dr. Paul Newby and Dr. Don Singer, GSK for their review and comments on this manuscript.

References

  1. United States Pharmacopeia General Chapter <51> Antimicrobial Effectiveness Testing, USP 34-NF29, US Pharmacopeia, Rockville, Maryland, USA, 2010.
  2. European Pharmacopoeia 5.1.3, Efficacy of Antimicrobial Preservation, EP 6.4, European Directorate for Quality of Medicines, Strasbourg, France, 2010.
  3. Japanese Pharmacopeia, General Information: 19. Preservative Effectiveness Test, 15th Edition, Society of Japanese Pharmacopeia, Tokyo, Japan.
  4. A.H. Kibbe: Benzalkonium Chloride Monograph in: R.C. Rowe, P.J. Sheskey, P. J. Weller (Eds.), Handbook of Pharmaceutical Excipients, Fifth Edition, Pharmaceutical Press, 2006, pp. 61-63.
  5. R.M.E. Richards, R.J. McBride, Enhancement of Benzalkonium Chloride and Chlorhexidine Acetate Activity against Pseudomonas aeruginosa by Aromatic Alcohols, J. Pharm. Sci., 62: 2035-2037 (1973).
  6. P.J. Hugbo, Additivity and Synergism In Vitro as Displayed by Mixtures of Some Commonly Employed Antibacterial Preservatives, Can. J. Pharm. Sci., 11: 17-20 (1976).
  7. T.J. McCarthy, J.A., Myburgh, N. Butler, Further Studies on the Influence of Formulation on Preservative Activity, Cosmet. Toilet., 92: 33-36 (1977).
  8. T.E. Haag, D.F. Loncrini, Esters of para-Hydroxybenzoic Acid, in: J.J. Kabara (Ed.), Cosmetic and Drug Preservation, Marcel-Dekker, New York,1984, pp. 63-77.
  9. R.M.E. Richards, R.J. McBride, Phenylethanol Enhancement of Preservatives Used in Ophthalmic Preparations, J. Pharm. Pharmac., 23: 141S-146S (1971).
  10. W.E. Rosen, P.A. Berke, T. Matzin, A.F. Peterson, Preservation of Cosmetic Lotions with Imidizolidinyl Urea plus Parabens, J. Soc. Cosmet. Chem., 28: 83-87 (1977).
  11. R.A. Fassihi, Preservation of Medicines against Microbial Contamination, in: S.A.Block (Ed.) Disinfection Sterilization and Preservation, 4th Edition, Lea and Febiger, 1991, pp. 871-886.
  12. W.B. Hugo, A.D. Russell (Eds.), Pharmaceutical Microbiology, 6th Edition, Blackwell Science, 1998, pp. 201-262 and 365-373.
  13. R.Johnson, R.Steer, Methylparaben Monograph in: R.C. Rowe, P.J. Sheskey, P. J. Weller (Eds.), Handbook of Pharmaceutical Excipients, Fifth Edition, Pharmaceutical Press, 2006, pp. 466-470.
  14. A.H. Kibbe: Benzethonium Chloride Monograph in: R.C. Rowe, P.J. Sheskey, P. J. Weller (Eds.), Handbook of Pharmaceutical Excipients, Fifth Edition, Pharmaceutical Press, 2006, pp. 64-65.
  15. P.J.Weller, Benzoic Acid Monograph in: R.C. Rowe, P.J. Sheskey, P. J. Weller (Eds.), Handbook of Pharmaceutical Excipients, Fifth Edition, Pharmaceutical Press, 2006, pp. 66-68.
  16. E.Cahill, Benzyl Alcohol Monograph in: R.C. Rowe, P.J. Sheskey, P. J. Weller (Eds.), Handbook of Pharmaceutical Excipients, Fifth Edition, Pharmaceutical Press, 2006, pp. 69-71.
  17. S.C.Owen, Cetrimide Monograph in: R.C. Rowe, P.J. Sheskey, P. J. Weller (Eds.), Handbook of Pharmaceutical Excipients, Fifth Edition, Pharmaceutical Press, 2006, pp. 152-154.
  18. S.C. Owen, Chlorhexidine Monograph in: R.C. Rowe, P.J. Sheskey, P. J. Weller (Eds.), Handbook of Pharmaceutical Excipients, Fifth Edition, Pharmaceutical Press, 2006, pp. 163-167.
  19. S.Nema, Chlorocresol Monograph in: R.C. Rowe, P.J. Sheskey, P. J. Weller (Eds.), Handbook of Pharmaceutical Excipients, Fifth Edition, Pharmaceutical Press, 2006, pp. 171-173.
  20. L.M.E.McIndoe, Chloroxylenol Monograph in: R.C. Rowe, P.J. Sheskey, P. J. Weller (Eds.), Handbook of Pharmaceutical Excipients, Fifth Edition, Pharmaceutical Press, 2006, pp. 180-181.
  21. R.T.Guest, Imidurea Monograph in: R.C. Rowe, P.J. Sheskey, P. J. Weller (Eds.), Handbook of Pharmaceutical Excipients, Fifth Edition, Pharmaceutical Press, 2006, pp. 359-361.
  22. S.P.Denyer, N.A.Hodges, Bronopol Monograph in: R.C. Rowe, P.J. Sheskey, P. J. Weller (Eds.), Handbook of Pharmaceutical Excipients, Fifth Edition, Pharmaceutical Press, 2006, pp. 76-78.
  23. G.E.Amidon, Propionic Acid Monograph in: R.C. Rowe, P.J. Sheskey, P. J. Weller (Eds.), Handbook of Pharmaceutical Excipients, Fifth Edition, Pharmaceutical Press, 2006, pp. 617-618.
  24. W.Cook, Sorbic Acid Monograph in: R.C. Rowe, P.J. Sheskey, P. J. Weller (Eds.), Handbook of Pharmaceutical Excipients, Fifth Edition, Pharmaceutical Press, 2006, pp. 710-712.
  25. L.Y.Galichet, m-Cresol Monograph in: R.C. Rowe, P.J. Sheskey, P. J. Weller (Eds.), Handbook of Pharmaceutical Excipients, Fifth Edition, Pharmaceutical Press, 2006, pp. 208-210.
  26. R.T.Guest, Phenol Monograph in: R.C. Rowe, P.J. Sheskey, P. J. Weller (Eds.), Handbook of Pharmaceutical Excipients, Fifth Edition, Pharmaceutical Press, 2006, pp. 514-516.
  27. S.E.Hepburn, Phenylmercuric acetate Monograph in: R.C. Rowe, P.J. Sheskey, P. J. Weller (Eds.), Handbook of Pharmaceutical Excipients, Fifth Edition, Pharmaceutical Press, 2006, pp. 521-523.
  28. S.E.Hepburn, Phenylmercuric borate Monograph in: R.C. Rowe, P.J. Sheskey, P. J. Weller (Eds.), Handbook of Pharmaceutical Excipients, Fifth Edition, Pharmaceutical Press, 2006, pp. 524-525.
  29. S.E.Hepburn, Phenylmercuric nitrate Monograph in: R.C. Rowe, P.J. Sheskey, P. J. Weller (Eds.), Handbook of Pharmaceutical Excipients, Fifth Edition, Pharmaceutical Press, 2006, pp. 526-529.
  30. P.J.Weller, Thimerosal Monograph in: R.C. Rowe, P.J. Sheskey, P. J. Weller (Eds.), Handbook of Pharmaceutical Excipients, Fifth Edition, Pharmaceutical Press, 2006, pp. 777-779.
  31. J.Judis, Studies on the Mechanism of Action of Phenolic Disinfectants, J. Pharm. Sci., 51: 261-265 (1962).
  32. S.C. Owen, Edetic Acid Monograph, in: R.C. Rowe, P.J. Sheskey, P. J. Weller (Eds.), Handbook of Pharmaceutical Excipients, Fifth Edition, Pharmaceutical Press, 2006, pp. 260-263.
  33. G.Whalley, Preservative Properties of EDTA, Manuf. Chem., 62: 22-23 (1991).
  34. J.Buckles, M.W.Brown, G.S Porter, The Inactivation of Phenylmercuric Nitrate by Sodium Metabisulphite, J. Pharm. Pharmac., 23: 237S-238S (1971).
  35. R.M.E. Richards, A.F. Fell, J.M.E. Buchart, Interaction between Sodium Metabisulphite and PMN, J. Pharm. Pharmac, 24: 999-1000 (1972).
  36. M.S. Parker, The Preservation of Pharmaceuticals and Cosmetic Products, in Principles and Practices of Disinfection, Preservation and Sterilization, Editors: A.D.Russell, W.B. Hugo, W.B. G.A.J. Ayliffe, Oxford, Blackwell Scientific, (1982) pp. 287-305.
  37. S.C.Owen, 2-Phenylethanol Monograph in: R.C. Rowe, P.J. Sheskey, P. J. Weller (Eds.), Handbook of Pharmaceutical Excipients, Fifth Edition, Pharmaceutical Press, 2006, pp. 519-520.
  38. D.S.Jones, C.P.McCoy, Hexetidine Monograph in: R.C. Rowe, P.J. Sheskey, P. J. Weller (Eds.), Handbook of Pharmaceutical Excipients, Fifth Edition, Pharmaceutical Press, 2006, pp. 323-324.
  39. P.J.Weller, Propyl Gallate Monograph in: R.C. Rowe, P.J. Sheskey, P. J. Weller (Eds.), Handbook of Pharmaceutical Excipients, Fifth Edition, Pharmaceutical Press, 2006, pp. 619-621.
  40. R.T.Guest, Butylated Hydroxy Anisole Monograph in: R.C. Rowe, P.J. Sheskey, P. J. Weller (Eds.), Handbook of Pharmaceutical Excipients, Fifth Edition, Pharmaceutical Press, 2006, pp. 79-80.
  41. P.J. Crowley, L.G. Martini, Drug-Excipient Interactions, Pharm. Technology Europe, 13(3): 26-34 (2001).
  42. S.C.Owen, 2-Phenoxyethanol Monograph in: R.C. Rowe, P.J. Sheskey, P. J. Weller (Eds.), Handbook of Pharmaceutical Excipients, Fifth Edition, Pharmaceutical Press, 2006, pp. 517-518.
  43. R.A.Nash, Chlorobutanol Monograph in: R.C. Rowe, P.J. Sheskey, P. J. Weller (Eds.), Handbook of Pharmaceutical Excipients, Fifth Edition, Pharmaceutical Press, 2006, pp. 168-170.
  44. R.Johnson, R.Steer, Propylparaben Monograph in: R.C. Rowe, P.J. Sheskey, P. J. Weller (Eds.), Handbook of Pharmaceutical Excipients, Fifth Edition, Pharmaceutical Press, 2006, pp. 629-632.
  45. R.Johnson, R.Steer, Butylparaben Monograph in: R.C. Rowe, P.J. Sheskey, P. J. Weller (Eds.), Handbook of Pharmaceutical Excipients, Fifth Edition, Pharmaceutical Press, 2006, pp. 83-85.
  46. S.M. Blaug, D.E. Grant, Kinetics of Degradation of the Parabens; J.Soc Cosmetic Chemistry 25: 495-506 (1974).
  47. Draft Note for Guidance on Excipients, Antioxidants and Antimicrobial Preservatives in the Dossier for Application for Marketing Authorisation of a Medicinal Product, Committee for Proprietary Medicinal Products (CPMP), The European Agency for the Evaluation of Medicinal Products Evaluation of Medicines for Human Use, CPMP/QWP/419/03, London 20th February 2003.
  48. S.Yarramaraju, V.Akurathi, K.Wolfs, A. Van Schepdael, J.Hoogmartens, E.Adams, Investigation of Sorbic Acid Volatile Degradation Products in Pharmaceutical Formulations using Static Headspace Gas Chromotography, J. Pharm. Biomed. Anal., 44: 456-463 (2007).
  49. M.J. Akers, Excipient-Drug Interactions in Parenteral Formulations, J.Pharm.Sciences 91; 2283-2300 (2002).
  50. J.Brange, Galenics of Insulin, Springer-Verlag (1987) Berlin.
  51. R.T.Guest, Butylated Hydroxy Toluene Monograph in: R.C. Rowe, P.J. Sheskey, P. J. Weller (Eds.), Handbook of Pharmaceutical Excipients, Fifth Edition, Pharmaceutical Press, 2006, pp. 81-82.
  52. R.M.E.Richards, Effect on Hypromellose on the Antibacterial Activity of Benzalkonium Chloride, J.Pharm. Pharmacol., 28:264 (1976).
  53. T.Bin, A.K. Kulshreshtha, R.Al-Shakshir, S.L. Hem, Adsorption of Benzalkonium Chloride by Filter Membranes: Mechanisms and Effect of of Formulation and Processing Parameters, Pharm. Dev. Technol., 4: 151-165 (1999).
  54. C.D.Clarke, N.A. Armstrong, Influence of pH on the Adsorption of Benzoic Acid by Kaolin, Pharm. J., 209: 44-45 (1972).
  55. M.S.Roberts, A.E. Polack, G. Martin, H.D. Blackburn, The Storage of Selected Substances in Aqueous Solution in Polyethylene Containers, Int. J. Pharm., 2: 295-306 (1979).
  56. N.E. Richardson, D.J.G. Davies, B.J. Meakin, D.A. Norton, The Interaction of Preservatives with Polyhydroxymethylmethacrylate (polyHEMA), J. Pharm. Pharmacol., 30: 469-475 (1978).
  57. R.T. Yousef, M.A. El-Nakeeb, S. Salama, Effect of Some Pharmaceutical Materials on the Bactericidal Activities of Preservatives, Can. J. Pharm. Sci., 8: 54-56 (1973).
  58. D.P.Elder, A. Park, P. Patel, N. Marzolini, Development of a Palatable Liquid Formulation of a Bitter Tasting Drug Using Ion-Exchange Resins for Taste Masking, Editor J.A. Greig, in Ion Exchange at the Millenium Imperial College Press, pp. 306-313, (2002).
  59. K.Kakemi, H. Sezaki, E. Arakawa, Interactions of Parabens and other Pharmaceutical Adjuvants with Plastic Containers, Chem. Pharm. Bull., 19: 2523-2529 (1971).
  60. M.G. Lee, Phenoxyethanol Absorption by Polyvinyl Chloride, J. Clin. Hosp. Phar., 9: 353-355 (1984).
  61. T.R.R. Kurup, L.S.C. Wan, L.W. Chan, Interaction of Preservatives with Macromolecules, Part II: Cellulose Derivatives, Pharm. Acta. Helv., 70: 187-193 (1995).
  62. K. Eriksson, Loss of Organomercurial Preservatives from Medicaments in Different Types of Containers, Acta. Pharm. Suec., 4: 261-264 (1967).
  63. J.A. Aspinall, T.D. Duffy, M.B. Saunders, C.G. Taylor, The Effect of Low Density Polyethylene Containers on Some Hospital - Manufactured Eye drop Formulations I: Sorption of Phenylmercuric Acetate, J.Clin. Hosp. Pharm., 5: 21-29 (1980).
  64. J.A. Aspinall, T.D. Duffy, C.G. Taylor, The Effect of Low Density Polyethylene Containers on Some Hospital - Manufactured Eye drop Formulations II: Inhibition of Sorption of Phenylmercuric Acetate, J.Clin. Hosp. Pharm., 8: 223-240 (1983).
  65. T.J. McCarthy, Interactions between Aqueous Preservative Solutions and their Plastic Containers, Pharm. Weekbl.,107: 1-7 (1972).
  66. S. Wiener, The interference of Rubber with the Bacteriostatic Action of Thiomersalate, J. Pharm. Pharmacol., 7: 118-125 (1955).
  67. J. Birner, J.R. Garnet, Thimerosal as a Preservative in Biological Preparations. III: Factors Affecting the Concentration of Thimerosal in Aqueous Solutions and in Vaccines Stored in Rubber-Capped Bottles, J. Pharm. Sci., 53: 1424-1426 (1964).
  68. M.Higashiyama, K.Indana, A.Ohtori, K.Kakehi, NMR Analysis of Ion Pair Formation between Timolol and Sorbic Acid in Ophthalmic Preparations, J.Pharm. Biomed. Anal., 43: 1335-1342 (2007).

Author Biographies

David P. Elder has 34-years experience in the pharmaceutical industry. He is a director in the pre-clinical SCINOVO group at GSK. He has a PhD from Edinburgh University, UK. He is a member of the British Pharmacopoeia Commission and an FRSC. He has written and lectured widely on the theme of product development and the challenges of preservation.

Patrick Crowley is a pharmacist by training (FRPhSGB). He worked in the Pharmaceutical Industry for over 40 years and was a VP of product development at GSK. He currently operates as a consultant and teaches Pharmaceutical Sciences at a number of Institutions. Has authored / presented on over 40 topics related to pharmaceutical sciences.

  • <<
  • >>

Join the Discussion