Chlorhexidine solubility

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 di-cation. The cationic nature of the compound results in activity being reduced by anionic compounds including soap and many anions 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. Reduction in activity will also occur in the presence of blood, pus and other organic matter. 

Gluconic acid Gluconobacter suboxydans Aspergillus niger Calcium gluconate is a source of Ca for oral administration gluconates are used to render bases more soluble, e.g. chlorhexidine gluconate... 

Chlorhexidtne is a symmetrical cationic molecule that is most stable as a salt the highly water-soluble digluconate is the most commonly used preparation. Because of its cationic properties, it binds strongly to hydroxyapatite (the mineral component of tooth enamel), the organic pellicle on the tooth surface, salivary proteins, and bacteria. Much of the chlorhexidine binding in the mouth occurs on the mucous membranes, such as the alveolar and gingival mucosa, from which sites it is slowly released in active form. 

Controlled solubility and ionic diffusion of the antimicrobial agent, such as, chlorhexidine, to the microorganisms (see Figs. 2.23 and 2.24), and... 

Chlorhexidine diacetate is partially soluble in water, and the solubility increases with temperature, which provides a particulate form for application, and... 

In a microorganism prone environment, it is preferable to protect a dressing with a preservative such as chlorhexidine to prevent the contamination of the dressing. It is necessary to consider the solubility of an agent in the liquid phase of the dressing during the selection of an antimicrobial agent. The formulated polyvinyl acetate and polybutyral materials were dissolved in ethanol that is also a solvent for chlorhexidine diacetate. The information (Block, 2001) in Table 2.12 provides solubilities of chlorhexidine compounds in different solvents. 

From inspection of Table 2.12, it is apparent that only chlorhexidine diacetate is sufficiently soluble in ethanol, so the liquid applied barrier dressing consisting of polymers dissolved in ethanol must be preserved by chlorhexidine diacetate, because water is not an option. The concentration of this agent is another consideration, but the range of options is clear from the above table. 

Chlorhexidine is a strong base (Lewis acid-base theory) because it reacts with acids to form salts of the RX2 type, and it is practically insoluble in water (<0.008% wt/vol at 20°C). The water solubility of the different salts varies widely as demonstrated in Table 2.13. Chlorhexidine is moderately surface-active (a net+chare over its surface) and forms micelles (molecular aggregates form colloidal particles) in solution the critical micellar concentration of the acetate is 0.01% wt/vol at 25°C (Heard and Ashworth 1969). Aqueous solutions of chlorhexidine are most stable within the pH range of 5-8, and above pH 8.0 chlorhexidine is precipitated because conditions for a base (>pH 7) reaction are present. 

Chlorhexidine salts of low aqueous solubility are formed and may precipitate from chlorhexidine solutions of concentration greater than 0.05% w/v, when in the presence of inorganic acids, certain organic acids, and salts (e.g. benzoates, bicarbonates, borates, carbonates, chlorides, citrates, iodides, nitrates, phosphates, and sulfates). At chlorhexidine concentrations below 0.01% w/v precipitation is less likely to occur. 

Table 5.14 Aq ueous solubilities of tetracycline, erythromycin and chlorhexidine salts...

Cetrimonium bromide (cetrimide, Bromat, Cetab, Cetavlon, Cetylamine, C.T.A.B., Lissolamine V, Micol, Quamonium, CAS no. 57-09-0). It is easily soluble in water, in concentrations of 1-40%. Concentrations greater than 1% in quaternary ammonium compounds are very irritant under occlusion (Polano 1984). Savlon is a mixture of cetrimide 15% w/v and chlorhexidine 1.5% w/v aqua. Patch-test concentrations are 0.01 and 0.1% aqua. Allergic reactions are uncommon. 

Chlorhexidine is mainly used as an active ingredient in disinfectants, deodorants and antiseptics and as a preservative in cosmetics and pharmaceuticals. The EC positive list of preservatives permitted for use in cosmetics mentions Chlorhexidine and its salts with a maximum authorized concentration of 0-3%. Formulating and using the active ingredient one has to remember its cationic nature which causes reduction of activity in the presence of organic matter, e.g. blood, serum, soaps and other anionic compounds. Another cause of activity loss is based on the very low water-solubility of certain Chlorhexidine salts borate, citrate, carbonate, bicarbonate, chloride or phosphate salts precipitate in systems containing such anions. 

Solubilities of many active substances are listed in Merck Index [6] and in Martindale [11]. When a pharmaceutical preparation contains various salts there may be (multiple) combinations of ions that are incompatible and may result in the formation of a precipitate. For example, after addition of a chloride salt to a chlorhexidine digluconate solution, the insoluble salt chlorhexidine chloride is formed resulting in precipitation. Exact data on this are hard to find. In general, the risks of precipitation are high for combinations of large positive and negative ions. Examples are carmellose anion and lauryl sulfate, which is a component of Lanette wax. 

An important point can be the difference in application of certain salts. An example is chlorhexidine digluconate, that is available as 20 % solution (Hibitane ). Chlorhexidine chloride is not water-soluble and is available as dry powder (under the same brand name Hibitane ). If in the doctor s request the brand name is used, it will be seen from the context what salt is intended and, in the case of the gluconate, whether the strength indication relates to the digluconate as such or to the 20 % solution. To complicate the matter even more, a third variant is available. 

Chlorhexidine is used as a preservative in the form of the very water-soluble chlorhexidine digluconate. The active... 

PU/nanoclay nanocomposite nanofibrous webs prepared by electrospinning were reported. Chlorhexidine acetate was loaded in the prepared clay and was then incorporated into PU nanofibers. The nanofibers were evaluated for moisture vapor transmission, porosity, contact angle, and antibacterial activity, important for topical drug delivery application [94]. Verreck et al. described the preparation of nanofibers by electrospinning of itraconazole and ketanserin in a non-biodegradable matrix. It improved the transdermal delivery of these poorly soluble drugs. It was shown that these two drugs exist in the amorphous state in the PU nanoflbers [95]. 

Fig. 38.8 Chlorhexidine inclusion complex and co-crystals with anionic water-soluble calix[4] arenes (a) inclusion complex with para-sulphonatocalix[4]arene (b) co-crystal with calix[4] arene dimethoxycarboxylic acid co-crystal with calix[4]arene dihydroxyphosphonic acid [13]...

Chlorhexidine possesses marked bactericidal action against a wide range of micro-organisms. The base has a low aqueous solubility (0.008 % w/v) a wide range of salts have been prepared and their solubilities measured (Table 6.8). The dihydrochloride has a solubility of 0.06%, the diacetate 1.8% and as the gluconate has a solubility > 70 % there would appear to be little need for the preparation of solubilized formulations. However, surfactants may be present in chlorhexidine formulations because of the low solubility of chlorhexidine sulphate and related salts with inorganic ions present in water, extemporaneously prepared solutions diluted from concentrates may precipitate. Non-ionic and... 

Differences in micellar uptake would affect the bactericidal effect of the chlorhexidine formulation the choice of salt and surfactant must, therefore, involve a careful analysis of intrinsic solubilities and activities of the salts and their percentage solubilization in surfactant micelles. 

Figure 6.13 Solubility of chlorhexidine diacetate ( ) and dihydrochloride (O) as a function of concentration of the decaoxyethylene oleic ether, Brij 96. Each point is the average of two or three independent determinations. From Wesoluch et al. [66] with permission.

Evidence of decreased solubility of both chlorhexidine diacetate and chlor-hexidine dihydrochloride in Brij surfactant mixtures has been adduced [203] though this is only clear in the case of the dihydrochloride at concentrations higher than 5% when uptake is some 30% higher in Brij 96 than in Brij 92-96 mixtures if HLB =11. 

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