AU689928B2 - Glutaraldehyde neutralizer - Google Patents

Description

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AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

ORIGINAL

Kr N~ 'i1

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o Name of Applicant: W;ITEEn p~iT Hf.CAL PTY LTD A.C.N. 000 906 678 Xr^~ASLu ^L o e• Actual Inventors: Address for Service: Reginald Keith WHITELEY and Gunars OZOLS SHELSTON WATERS 60 Margaret Street SYDNEY NSW 2000 "GLUTARALDEHYDE NEUTRALIZER" Invention Title: Details of Associated Provisional Application No: PM7730 dated August 1994 The following statement is a full description of this invention, including the best method of performing it known to us:- -L131 IIL TECHNICAL FIELD The invention concerns a composition and a method for effective, quick and practical neutralisation of glutaraldehyde contained in sterilising, disinfectant or chemical treatment solutions.

BACKGROUND ART It is common for hospitals, clinics and similar establishments to use chemical sterilants containing glutaraldehyde as the active ingredient. The sterilants contain about 1% to 2% glutaraldehyde which is usually in one of several forms: as simple glutaraldehyde buffered to pH 8 10; as buffered acidal glutaraldehyde at pH 6-7 with or without added surfactants and as buffered (pH 6-7) mildly acid glutaraldehyde in chemical equilibrium with a polyol, The products are used in baths of various sizes to :clean and disinfect dirty medical instruments after use in operations and various medical invasive and non-invasive procedures. The baths after use are disposed of to the sewer when the; useful life has been reached.

Previously formaldehyde (formalin) was widely used as a chemical sterilant.

However, it is now recognised as an alleged carcinogen and has serious limitations as a biocide and has been replaced by glutaraldehyde in such products. Formaldehyde has a sharp, pungent, unpleasant odour. Glutaraldehyde has a milder formalin type odour S'which is still unpleasant and irritant to users of chemical sterilants.

S 20 Glutaraldehyde is a dialdehyde and has a chain of 5 carbon atoms. Because of the longer carbon chain its carbonyl groups react more slowly than that of formaldehyde. The latter also undergoes chemical reactions which do not occur with glutaraldehyde to any appreciable extent (rapid cyclisation and formation of polymers e.g. urea formaldehyde resins).

Formaldehyde is not regarded as acceptable for disposal to the sewer due to risk of its killing of the microorganisms that decompose sewage. Some authorities extend the same objection to glutaraldehyde and require that it be deactivated or neutralized before being disposed of to a sewerage system. To achieve this, it must be converted to a different chemical entity by a neutralizer.

Aldehydes are regarded as reactive chemicals. However, most examples given in text books on organic chemistry relate to the first two members of the aliphatic series, namely formaldehyde and acetaldehyde, the chemistry of which is extensively established. Published chemistry of glutaraldehyde normally assumes that the same chemistry is applicable. In practical applications this is not always so due to different processes of hydration of the carbonyl groups and rates of reaction under practical use conditions of temperature and time.

II I Practical applications must also give due consideration to possibly noxious properties of the neutralizer and the end product of its reaction with glutaraldehyde, in particular to toxics or other untoward effect on microorganisms present in normal sewerage.

The neutralizer has to attack the polyol blocked carbonyl groups under practical conditions in a hospital setting. This means that the glutaraldehyde level in a used bath must be reduced to a negligible level (for example, less than in a reasonable time (for example, 60 minutes). The neutralizer must be based on commercially available raw materials at affordable cost. The neutralizer must be acceptable to users with regard to odour, colour, consistency and ease of use. The most important characteristic is the rate at which a chemical reaction can occur which removes the carbonyl group from the solution.

The removal of the carbonyl group deactivates glutaraldehyde.

Most reactions of organic compounds are neither instantaneous nor go to completion under room temperature conditions. Glutaraldehyde has a 5-carbon chain 15 which means that reactions of glutaraldehyde are much slower than for example those of formaldehyde. In addition, the carbonyl groups are blocked with hydrogen bonded polyol molecules which would slow down any chemical attack on the carbonyl groups. The low starting concentration of glutaraldehyde normally encountered in hospital sterilants, which must be reduced further, slows down any reactions that the carbonyl group would undergo.

Thus the practical deactivation/neutralization of glutaraldehyde under hospital conditions is fraught with complications and despite the reactivity of carbonyl groups generally the practical formulation of an effective neutralizer suffers from severe limitations.

25 Products designed to deactivate formaldehyde have been used as glutaraldehyde neutralizers. These, however, contain urea and an acid as catalyst. With formaldehyde they form a polymer rapidly. With glutaraldehyde, on the other hand, they react only to a limited extent, lowering glutaraldehyde content by 20 25% over a 24 hour period.

To date no rapid acting, completely effective practical product has been available as a glutaraldehyde neutralizer. Trade publications from manufacturers of glutaraldehyde give the following generalised suggestions for deactivating/neutralizing glutaraldehyde: reaction with ammonium hydroxide or salt, such as ammonium sulfate.

reaction with amines.

reaction with dibasic ammonium phosphate.

There are serious practical problems using each of these reactant neutralisers.

Ammonium hydroxide has an unacceptably high odour level. Most primary amines are either commercially unavailable hazardous or expensive. Ammonium phosphate is not Ill sufficiently soluble in water for practical slug dosaging as a neutralizer. All have the crucial objection that the rate of reaction under hospital conditions is too slow and therefore not within a practical time frame required in a routine hospital procedure.

For example ammonium phosphate is stated to leave 0.12% of glutaraldehyde after 24 hours at a pH of up to 10. The rate with ammonium sulfate is even slower. Both reactions are pH dependent, requiring careful pH adjustment to optimise reaction rates which is not practical in a hospital medical location where glutaraldehyde is used.

It is known that glutaraldehyde polymerises at a measurable rate above pH obtained by adding a strong alkali. Apart from the inadequate rate of reaction, handling strong alkalis under hospital conditions is most undesirable. It is known that bisulfites react readily with aldehydes to form addition compounds. Glutaraldehyde does undergo this reaction and its contents can be reduced from 1% to less than 0.1% in 15 minutes by this type of reaction. However, the following disadvantages prohibit its practical use: The most effective is sodium metabisulfite (the anhydride of sodium bisulfite) which is a powder with a pungent and toxic sulphur dioxide (SO 2 odour. On exposure to air it is oxidised and gradually loses its reactivity. Solutions in water are even more unstable.

Ammonium bisulfite reacts readily but the reactant gives off a pungent toxic sulphur dioxide (SO 2 gas.

Sulphites and bisulphite are not wanted in sewerage systems due to corrosivity.

None of the chemicals generally known and recommended as reactive with glutaraldehyde are satisfactory on their own as practical, acceptable, effective and efficient neutralizers/deactivators. There are indeed no known commercial products which would comply with all the desiderata for such a product at this point of time, 25 namely: reduction of glutaraldehyde level from 2.0 to 0.1% or less in 90 minutes or less and to less than 0.3% or under in 15 minutes.

based on commonly available commercial chemicals at acceptable cost.

a colour change of bath, indicating that it has been treated with a neutralizer.

acceptable odour of the neutralizer itself.

immediate reduction of glutaraldehyde odour of the bath after addition of the neutralizer.

preferably a liquid form of product.

SUMMARY OF THE INVENTION The present invention is a product which effectively neutralizes and deactivates "uncomplexed" and "complexed" glutaraldehyde (as used in a sterilant bath) within a desirable time frame and has desirable properties as described above.

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A composition for neutralising glutaraldehyde in glutaraldehyde-containing solutions, comprising: an ammonium salt of an aliphatic carboxylic acid, and a primary amine with a hydroxyl equivalent sufficient to create a buffer between ammonium and amine ions when in aqueous solution.

The combination of an ammonium salt of a low molecular weight aliphatic carboxylic acid and a low molecular weight amine according to the invention have been found to act synergistically, ie. is more effective as a combination than either alone at equivalent concentration.

According to a second aspect the invention consists in a method of neutralising glutaraldehyde in a glutaraldehyde-containing solution, comprising the step of adding a neutralising composition according to the first aspect to a solution containing glutaraldehyde, in quantity sufficient to achieve neutralisation of glutaraldehyde.

DESCRIPTION OF THE PREFERRED EMBODIMENTS 15 The invention will now be more particularly described by way of example only with reference to specific embodiments.

Although currently recommended, ammonium salts such as monoarmnonium sulfate and phosphate, are not satisfactory as practical glutaraldehyde neutralizers for hospital sterilants. The rate of neutralization of glutaraldehyde increases with an increase 20 in strength of the carboxylic acid and as molecular size decreases. In other words, the more loosely the ammonium ion is held by the anion and the more mobility it has in the solution the faster it will attack the glutaraldehyde. The maximum rate is reached by S. annmmonium formate and acetate in concentrated solutions. Ammonium acetate was found to be more efficient than citrate.

The effectiveness and rate of neutralization is related to the NH 4 ions being readily available to the carbonyl groups of glutaraldehyde. The small molecular size helps them to penetrate the "blocked" (or complexed) carbonyl groups more quickly, however amines by themselves such as mono, di and tri ethanolamines react with glutaraldehyde too slowly to be of practical significance.

When an alkanolamine is added to a solution of the ammonium salt of a lower aliphatic carboxylic acid at a low concentration (1 the combined solution is significantly more effective as a practical neutralizer for glutaraldehyde based sterilant solutions than the two individual solutions separately at equivalent concentrations. Such a product, hereinafter referred to as the "neutralizer", will reduce glutaraldehyde levels in instrument sterilants from 2% or 1% to approximately 0.1% or less in 60 minutes, or to I -aI less than 0.5% in 15 minutes, at 20 0 C. The exact rate of neutralising is dependent on the temperature and concentrations of the sterilant solution.

The efficiency of the neutralizer i, partly dependent on the alkanolamine displacing some ammonium ions from the salt, it being a slightly stronger base than ammonium hydroxide. The ammonium ions are readily and immediately available to react with the carbonyl groups on glutaraldehyde. Thus, the neutralizer in a preferred form could be described as a stabilised, buffered and synergistic solution of ammonium ions, formed between a hydroxy amine, an ammonium salt and the anions of a lower organic aliphatic carboxylic acid in water. Some of the ammonium ions may also combine with hydroxyl ions of water to form a weak solution of ammonium hydroxide.

One particular advantage of the invention is the ability to pre-set the concentration of the hydroxy amine to achieve a fast but practical rate of neutralization of glutaraldehyde, without the solution having an unacceptable level of ammonia odour due to the above reaction.

15 The neutralizer thus constructed has all other desired properties for a practical and acceptable commercial product. It is not noxious and is acceptable for use in hospitals and similar establishments. The product has very slight ammoniacal odour at quite acceptable level. The neutralizer, when added to a glutaraldehyde preparation, turns green then brown within 5 minutes, thus warning the user that a deactivator has been added to the sterilant bath. The end product of an ammonia-induced reaction with glutaraldehyde has been found by one manufacturer of glutaraldehyde to be an inert harmless polymer.

EXAMPLES

Example 1. Evaluation Methods Apart from the visual and olfactory examination of such properties as colour, consistency, smell and stability, the rate of reaction was measured by determining residual glutaraldehyde in a glutaraldehyde sterilant preparation after various reaction time intervals, usually 15 minutes, 1 hour and 24 hours.

The two commercial glutaraldehyde preparations used for evaluation contained 1.2 and 2.3% glutaraldehyde respectively. The carbonyl groups were "complexed" by hydrogen bonding with a glycol and an aliphatic nonionic surfactant as described in Australian Patent No 589,267. A desired dose of an experimental neutralizer was added to 100 mL lots of the preparation at 21 0 C 0.5 0 C. This was left for the desired time interval, then analysed for residual glutaraldehyde content.

Determination of glutaraldehyde content: There are a number of analytical methods available for glutaraldehyde. The inclusion of complexing agents and other ingredients in a sterilant solution can make a.

a.

some methods doubtful. The method used was one which is in current used for checking commercial batches of sterilant products, i.e. where the input of glutaraldehyde to a formulation was known and found to be accurate over a period of years.

The method consists in taking a 25 mL sample of the neutralized sterilant solution, adjusting its pH to 4.0 with 0.1 N HC1, adding 50 mL of standardised hydroxylamine hydrochloride solution, waiting for 5 minutes, then back-titrating with 0.1 N sodium hydroxide solution to pH 4.0 0.01.

Table 1 below demonstrates the comparable reaction rates of common neutraliser compositions with formulations according to the present invention, designated A, B, C, D and E.

TABLE 1. Residual glutaraldehyde in 500mL of 2% complexed glutaraldehyde solution after varying reaction neutralisation times.

COMPOSITION TESTED RESIDUAL GLUTARALDEHYDE composition 15 min. 60 min. 24 hrs Sodium bisulphite 5 0.08 0 N/A Ammonium bisulphite 5 0.08 0.06 0.04 Mono Ammonium phosphate 4 0.32 0.22 0.1 Monoethanolamine 3 0.58 0.42 0.21 Mono Ammonium formate 6 0 33 0.11 Nil Mono Ammonium acetate 7 0.35 0.12 Nil Mono Ammonium citrate 7 0.62 0.40 0.2 (Ammonium acetate A 7 0.25 0.02 Nil (Monoethanolamine 1% (Ammonium acetate B 7 0.10 Nil Nil (Monoethanolamine 3% (Ammonium acetate C 7 0.08 Nil Nil (Monoethanolamine (Ammonium citrate D 7 0.54 0.37 0.2 (Monoethanolamine Final content of neutralising composition, expressed as a percentage after its addition to 100 mL of 2% complexed glutaraldehyde solution.

of total volume Example 2. Formulations The preferred composition of the present invention consists of the following ingredients: 1. 30 50 parts by weight of water, preferably deionised or distilled.

2. 50 70% by weight of an ammonium salt of a lower straight chain aliphatic carboxylic acid.

3. 1 5% of mono, di or tri, ethanolamine or isopropanolamine.

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1 to C 3 chain aliphatic carboxylic acid salts can be used but acetic or formic acid salts are preferred. The ammonium salt may be incorporated into the invention as purchased or may be prepared in situ in the water component or separately by .'eacting ammonium hydroxide or gaseous ammonia or an appropriate ammonium salt (e.g.

ammonium carbonate) with the appropriate organic acid.

The concentration of the ammonium salt in the composition of the invention can be varied within wide limits but below 50%w/w the maximum rate of neutralization at a fixed practical dose is not achieved. Above 70%, whilst the rate of neutralization at a fixed dose is increased, the odour level of the product increases at the low temperature stability of the solution decreases and more heat must be applied to incorporate the ammonium salt into water. This is undesirable as heating can cause the ammonium salt to evolve ammonia gas with high unpleasant odour level in the product and in production.

Less or more of the hydroxylamine can be used. However less than 1% will reduce the required effect whilst more than 5% will increase odour level unacceptably.

•Monoethanolamine is preferred although any water soluble primary amine can be used.

The selected amine must be a stronger base than ammonia to displace it in ionised form •from the ammonium salt but not strong enough to upset the buffered environment of the •system which should contain the following entities in equilibrium:-

S.NH

4 ion .iNH3

CH

3 COO' ion

R-NH

2 OH ion t from water H ion J

CH

3

COONH

4 The three ingredients are weighed and stirred at room temperature until a clear solution is obtained. The dissolution is endothermic and some warming is needed to bring the solution to room temperature. The pH of the concentrated ammonium acetate solution before adding the amine should be 7.0 8.5 whilst after the addition of the amine the pH should be in the range of 9.0 10.0 0.05.

I I I dl I I l I 9 The dose of the neutralizer used to neutralize/deactivate glutaraldehyde in a sterilant determines the exact rate at which it will take place. The dose in practice will be determined by cost, packaging, convenience of use and size of available vessels. The practical dosage available is recognised as being 500mL (0.5L) of neutralizer for 10L of used sterilant containing approximately 1% glutaraldehyde. At this dose a neutralizer containing 67 parts by weight of ammonium acetate or formate and 3 parts by weight of monoethanolamine will reduce glutaraldehyde in a sterilant preparation from 2.0% to 0.26% in 15 minutes and to 0.04% in 1 hour. The rate of neutralization will vary with the quantity of the ammonium salt/amine system added to the bath (the dose) and the temperature and the pH of the neutralizer. The invention enables one to maximise the rate of neutralization so that a practically acceptable neutralization can be carried out under hospital conditions.

It will be understood that although the product is desirably supplied in solution ready for use, it may also be supplied as a concentrate or as a combination suitable for 15 dissolution in water.

Although the present invention has been described in terms of preferred embodiments it will be appreciated by those skilled in the art that variations and modifications are possible whilst not departing from the basic principles and the spirit of the present invention. It is intended that the appended claims should cover all such equivalent variations which come within the scope of the invention claimed.

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Claims (16)

1. A composition for neutralising glutaraldehyde in glutaraldehyde-containing solutions, comprising: an ammonium salt of an aliphatic carboxylic acid, and a primary amine with a hydroxyl equivalent sufficient to create a buffer between ammonium and amine ions when in aqueous solution.

2. A composition according to claim 1, which is a solution.

3. A composition according to claim 1 or claim 2, wherein the aliphatic carboxylic acid is selected from the group consisting of formic acid, acetic acid and propionic acid, or a hydroxy acid selected from the group consisting of glycolic acid, tartaric and citric acid, or mixtures thereof.

4. A composition according to any one of claims 1 to 3, wherein the primary amine is an amine or a hydroxylamine selected from the group consisting of monoethanolamine, diethanolamine, triethanolamine and isopropanolamine, or mixtures thereof. 15

5. A composition according to any one of claims 1 to 4, having a pH at ambient temperature of 6.5 to 10.0.

6. A composition according to claim 5, having a pH at ambient temperature of 6.5 to

7. A composition according to any one of claims 1 to 6, containing from 30% to 20 by weight of the ammonium salt and from 0.5% to 7.5% by weight of a primary amine and having a pH of from 6.5 to 10.0 at ambient temperature.

8. A composition according to any one of the preceding claims, comprising: 50% to 70% by weight ammonium salt of an aliphatic carboxylic acid, 1% to 5% by weight of an amine, 25 and the balance water, said composition being adjusted to a pH of 9.0 to 10.0.

9. A method of neutralising glutaraldehyde in a glutaraldehyde-containing solution, comprising the step of adding a composition according to any one of claims 1 to 8, to a solution containing glutaraldehyde, in quantity sufficient to achieve neutralisation of glutaraldehyde.

10. A method according to claim 9, wherein the glutaraldehyde-containing solution contains from 1% to 3.5% glutaraldehyde.

11. A method according to claim 9 or claim 10, wherein the composition is added to the glutaraldehyde-containing solution as an aqueous solution in a final concentration of by volume.

12. A method according to any one of claims 9 to 11, wherein the quantity of said composition added is sufficient to reduce the content of glutaraldehyde by 90% in minutes. 1~113%1 -1 i i I *I I 11

13. A method according to any one of claims 9 to 12, wherein the quantity of said composition added is sufficient to reduce the content of glutaraldehyde by 98% in minutes.

14 A method according to any one of claims 10 to 13, wherein the neutralisation of the glutaraldehyde-containing solution is carried out at room temperature.

A synergistic composition for neutralising glutaraldehyde in glutaraldehyde- containing solutions, substantially as hereinbefore described with reference to any one of the Examples.

16. A method of neutralising glutaraldehyde in a glutaraldehyde-containing solution, substantially as hereinbefore described with reference to any one of the Examples. DATED this TWENTY-EIGHTH day of AUGUST 1995 1 5 WHITELEY CHEMICALS AUSTRALIA PTY LTD Attorney: IAN T. ERNST Fellow Institute of Patent Attorneys of Australia of SHELSTON WATERS 4 ABSTRACT The invention concerns a composition for neutralising glutaraldehyde in glutaraldehyde-containing solutions which are commonly used for sterilising, disinfecting or chemical treatment applications. The glutaraldehyde neutralizer comprises an ammonium salt of an aliphatic carboxylic acid, and a primary amine with a hydroxyl equivalent, sufficient to create a buffer between ammonium and amine ions when in aqueous solution. The invention also concerns an effective, quick and practical method of neutralising glutaraldehyde in a glutaraldehyde-containing solution, which method makes use of the glutaraldehyde neutralizer described above. oe, -Fir