BRONOPOL PHYSICAL AND CHEMICAL PROPERTIES

APPEARANCE

Bronopol is supplied as crystals or crystalline powder, which may vary from white to pale yellow in colour depending on the grade of material being offered.

BULK DENSITY

The bulk density is approximately 1.1g/ml.

VAPOUR PRESSURE

The vapour pressure of Bronopol at 20°C is 1.26 x 10-5mm Hg equivalent to 1.68 x 10-3 Pa.  At higher temperatures the vapour pressures are 0.066 Pa at 42°C, 0.143 at 48°C and 0.357 Pa at 54°C.

STABILITY IN SOLID FORM

As supplied, Bronopol is stable for a minimum of 3 years when kept under good storage conditions.  The stability of Bronopol as a crystalline solid has been assessed for up to 12 months under varying conditions of temperature, relative humidity and exposure to natural light.  The results show that the substance is stable and that there was no evidence of photo-decomposition during the study period.

MELTING POINT

As a pure material, Bronopol has a melting point of about 130°C.  However due to its polymorphic character, Bronopol undergoes a lattice rearrangement at 100 to 105°C and this can often be wrongly interpreted as the melting point.  Care must be taken to ensure that the correct test conditions are used during melting point determinations.

At temperatures above 140°C Bronopol will decompose exothermically releasing Hydrogen bromide and oxides of Nitrogen.

SOLUBILITY

Bronopol is readily soluble in water although the dissolution process is endothermic.  Solutions containing up to 28% w/v are possible at ambient temperature.  This feature allows for the preparation of "stock solutions" for ease of handling and mixing or for use with automated manufacturing systems.  Concentrated aqueous solutions may show a tendency to crystallise at low temperatures and care should be taken to avoid this.  BASF MicroCheck Limited can advise on frost-protected formulations.

Bronopol is poorly soluble in non-polar solvents but shows a high affinity for polar organic solvents.  Details are provided in Table 1.

Table 1: Solubility of Bronopol at 22-25°C in Some Common Solvents.

SOLVENTS	%w/v
Water Methanol Ethanol Isopropanol Ethylene Glycol Propylene Glycol Dipropylene Glycol Propylene Glycol Methyl Ether * (Dowanol PM) Dipropylene Glycol Methyl Ether ** (Dowanol DPM) Propylene Carbonate Methyl Carbitol Diethyl Sebacate N-methylpyrrolidone Isopropyl Myristate Arachis Oil Castor Oil Cottonseed Oil Olive Oil Liquid Paraffin	28 89 56 41 61 52 48 61 54 42 54 10 102      <0.5      <0.5      <0.5      <0.5      <0.5      <0.5

With the solubility profile displayed by Bronopol it is unlikely that formulators will encounter any problems incorporating the compound at use levels into aqueous based formulation systems.  In non-aqueous systems (e.g. ointments, suppositories) it is possible to achieve effective levels of Bronopol by careful choice of excipients or by using a suitable carrier solvent.

PARTITION COEFFICIENT

Study of the solubility data clearly shows that Bronopol has a high affinity for polar rather than non-polar environments.  In two phase systems, Bronopol partitions preferentially into the polar (usually aqueous) phase.  Evidence for this is provided in Table 2, which lists the partition coefficients for Bronopol in a number of water/organic solvent combinations.

Table 2: Partition Coefficient of Bronopol in some Common Solvent Mixes at 22-24°C.

Solvent Combinations	Partition Co-efficient
Hexanol/Water Cyclohexanol/Water Iso-octane/Water Liquid Paraffin/Water Arachis Oil/Water Chloroform/Water Dichloromethane/Water	0.74 1.63 <0.01 0.043 0.11 0.068 0.045

This feature is a particular advantage in complex two phase systems, e.g. emulsions, lotion creams, the Bronopol will remain in the aqueous phase or partition into it to exert maximum effect against any spoilage organism.  In similar situations, other preservatives can have their effectiveness reduced by partitioning into the oil phase.

Further evidence of Bronopol's affinity for the aqueous phase of two phase systems was provided by a study using ¹⁴C radiolabelled Bronopol.  In this instance the common fuels, diesel oil and kerosene were examined to determine the partition coefficient.  In one experiment the Bronopol was dissolved in the aqueous phase while in the other methoxyethanol was used as a carrier to dissolve the Bronopol in the oil phase.

The results are reported in Table 3 and these indicate that >99.5% of Bronopol was retained in the aqueous phase from the first experiment.  In the second experiment >99.3% was shown to partition from the oil phase into the aqueous phase.

Table 3: Fuel Oil/Aqueous Partition Coefficients for Bronopol at 22-24°C.

System	Bronopol in aqueous phase	Bronopol in oil phase
Diesel oil/water Kerosene/water	0.003 0.0018	0.006 0.002

STABILITY IN AQUEOUS SOLUTION

In aqueous solutions, Bronopol is most stable when the pH of the system is on the acid side of neutral.  In the absence of buffers, solutions of Bronopol tend to self stabilise.  The optimum pH for stability is around pH 4 and data from studies on dilute solutions of Bronopol (0.03%) suggests that the half-life at 22-25°C and pH 4 is in excess of 5 years (see Table 4).  As the pH increases Bronopol solutions become less stable.  Temperature also has a significant effect on stability in alkaline systems.

Table 4: Half-Lives of Bronopol when Prepared as a 300ppm Buffered Aqueous Solution

Temperature	pH 4	pH 6	pH 8
5ºC 25ºC 40ºC 60ºC	> 5 Years > 5 Years    2 Years     2 Weeks	> 5 Years > 5 Years      4 Months < 2 Days	6 Months   4 Months 8 Days       < 1 Day

 

These half lives are derived from high pressure liquid chromatographic (HPLC) assays on the dilute solutions.  If a microbiological assay procedure is used then the half lives generated are longer than those derived chemically.  This suggests that some of the decomposition products may be contributing to the microbiological activity.<![endif]>

PHOTOSTABILITY IN SOLUTION

Raab (1980) exposed aqueous solutions of Bronopol (0.1 and 1%) to a high pressure UV source.  The irradiations were performed at a distance of 20cm with steady stirring and cooling for periods up to 30 mins.  Every 5 mins samples were taken and photoabsorption determined over a wavelength range of 200-700nm.  The absorption curves of Bronopol solution before and after irradiation were identical suggesting that Bronopol is stable in aqueous solution to UV exposure over short time periods.

When exposed to light over longer periods of time, especially under alkaline conditions, solutions of Bronopol may become yellow or brown.  There is, however, no evidence of close correlation between colour change and loss of antibacterial activity.

For environmental fate purposes, very dilute solutions of radiolabelled Bronopol (5ppm) have been subjected to a standard photodegradation test protocol involving continuous exposure to artificial sunlight from a xenon light source.  Under these test conditions, Bronopol at very low concentrations had a half-life of around 24 hours.

BRONOPOL DEGRADATION

When conditions are such that Bronopol decomposes in aqueous solution, very low levels of formaldehyde are produced.  IT HAS BEEN CLEARLY ESTABLISHED, HOWEVER, THAT THE BIOLOGICAL ACTIVITY OF BRONOPOL IS NOT DUE TO LIBERATED FORMALDEHYDE.

Amongst other decomposition products detected after Bronopol breakdown are, bromide ion, nitrite ion, Bromonitroethanol and 2-Hydroxymethyl-2-nitropropane-1,3-diol.

The information contained in this document is believed to be accurate but is given without warranty.