Azepur99® is only sparingly soluble in water: 2,1 g/l (20ºC). At elevated temperature the solubility markedly improves with increasing temperature: at 50ºC 22 g/l Azepur99 will dissolve. Saturated solutions of azelaic acid react slightly acidic: azelaic acid is a diprotic acid with pKz values of 4,55 & 5,50. The solubility of saturated linear α,ω-dicarboxylic acid (table 1) decreases quite significantly with increasing chain length while the dissociation constants do not show much variance (with the exception of oxalic and malonic acid).
TABLE 1: SOLUBILITY IN WATER OF LINEAR α,ω-DICARBOXYLIC ACIDS
|Oxalic acid||C2H2O4||220 g/l (25ºC)|
|Malonic acid||C3H4O4||763 g/l (25ºC)|
|Succinic acid||C4H6O4||83 g/l (25ºC)|
|Glutaric acid||C5H8O4||639 g/l (20ºC)|
|Adipic acid||C6H10O4||14 g/l (20ºC)|
|Pimelic acid||C7H12O4||50 g/l (20ºC)|
|Suberic acid||C8H14O4||12 g/l (20ºC)|
|Azelaic acid||C9H16O4||2,1 g/l (20ºC)|
|Sebacic acid||C10H18O4||0,1 g/l (20ºC)|
The monosodium and disodium salt of azelaic acid are reasonably soluble in water, and very well soluble at elevated temperature. The sodium salts are best made in situ by neutralisation with sodium hydroxide. That enables processing of Azepur99® in the water phase of emulsion systems or in gel preparations, having said that the final emulsions or gels will react alkaline. Adjustment of the pH to acidic values comes with a price as in acidic conditions the acid will be regenerated and may be subjected to crystallisation. The crystallised product will not contribute to the bio-availability of Azepur99®.
Neutralisation with organic nitrogen bases is also possible, preferably with products that do not form stable N-nitrosamines. For pharmaceutical preparations tromethamine (TRIS, 2-amino-2-(hydroxymethyl)propane-1,3-diol) or AMP (2-amino-2-methylpropan-1-ol) are preferred. Upon neutralisation of azelaic acid with TRIS or AMP a pH buffer is formed.
There is only a limited number of solvents for Azepur99® available to prepare clear solutions at ambient temperature: polyethylene glycol and (poly)propylene glycol ethers. Ethoxydiglycol (Transcutol® P; Gattefosse) is probably the best solvent for Azepur99® available. Also butoxydiglycol is a good solvent for Azepur99. These solvents enable the production of clear gels of azelaic acid, at high concentration (see also Tag: Formulation Clear products).
Some esters are suitable to incorporate azelaic acid in emulsions. Esters of dicarboxylic acids or esters derived from isostearic acid. Reference is made to Tag: Formulation Emulsions.
Bio-availability of Azepur99® is the prime parameter to enable the product to perform to the best of its abilities. Crystallisation of azelaic acid is frequently encountered in commercially available gel & emulsion preparations of azelaic acid. In practice these preparations may contain up to 15-20% Azepur99, but only a small percentage is bio-available.
Crystallisation of azelaic acid is best researched using microscopy using polarised light. Crystals of azelaic acid in emulsions or gels are birefringent and are easily detected. To avoid crystallisation suitable solvent(s) shall be used that is able to keep azelaic acid mono-molecularly in solution. That is applicable for emulsions in both the water or oil phase, but also for aqueous/hydrophilic gel preparations. Eventually also a solubiliser can be applied, but the amount of azelaic acid that can be solubilised is rather limited indeed. An exception are phospholipids, more particularly phosphatidylcholine (see Tag: Formulation Organogels). These are the so-called organogels that exhibit an extreme potential for transdermal transport for pharmaceutical and cosmetic actives.
Solubility and bio-availability are prime parameters for working with Azepur99®. The use of Azepur99® in the water phase of emulsions was already described (see Tag: Solubility), and this enables the use of azelaic acid in waterborne gels based on carbomers, cellulose ethers or polysaccharides such as xanthan gum or sclerotium gum. However, these gels are alkaline and show only a limited degree of bio-availability.
The solubility of Azepur99® in ethoxydiglycol is 360 g/l. A clear solution will be obtained that will not show crystallisation. Ethoxydiglycol is miscible with water in any proportion, and also soluble in many polar lipids. An example of such an application is given in table 2
TABLE 2: CLEAR AZELAIC ACID SOLUTION
|Azelaic Acid||20,0 %|
|PEG-40 hydrogenated Castor Oil||4,5 %|
|Dimethyl Adipate||3,0 %|
The formulation according to table 2 enables transdermal transport, as ethoxydiglycol is swiftly absorbed through the skin. This results in transport of Azepur99® to the location where it is required, such as for the treatment of acne. The preparation according to table 2 is very low viscous, but can effectively be converted into a transparent transdermal gel using hydroxypropylcellulose (HPC). For serum preparations 1-2% HPC is required, depending on the desired viscosity. For gel preparations 2-4% is needed, dependent on the preferred viscosity. As an alternative for ethoxydiglycol butoxydiglycol may also be used although the solubility of azelaic acid is less, estimated at 15%.
For personal care & cosmetic products both ethoxydiglycol and butoxydiglycol are limited in use because of their extreme penetration power. In stay-on products the maximum allowed concentration ethoxydiglycol is 2,6% while a maximum of 9% butoxydiglycol is allowed. These concentration limitations are not applicable for medical devices and pharmaceutical products. Taking the risk of stating the obvious, anti-acne preparations, anti-rosacea preparations and product for the treatment of alopecia areata or hair growth products are not covered by EU Regulation 1223/2009.
Several other non-restricted glycol ethers may be used as solvent for azelaic acid, although the solubility of azelaic acid is markedly lower compared to ethoxydiglycol and butoxydiglycol. These products are commercially made available by DOW Chemical under the trademark Dowanol®. Some examples are.
- Triglycol Ethyl Ether. Common name: ethoxytriglycol. CAS: 112-50-5. No INCI name assigned. Excellent solvent for azelaic acid.
- PPG-2 Methyl Ether Acetate. Common name: dipropylene glycol monomethyl ether acetate. CAS: 88917-22-0 . Cosmetic limitations: none.
- Propylene Glycol Butyl Ether. Common name: 1-butoxy 2-propanol. CAS: 5131-66-8. Cosmetic limitations: none.
- Propylene Glycol Propyl Ether. Common name: 1-propoxypropan-2-ol. CAS: 1569-01-3 . Cosmetic limitations: none.
There is a massive set of other glycol ethers available, many of those are used in large quantities in chemical/technical applications and some of those are suitable for use in personal care & cosmetic products. Attention shall be given to the residual monomer concentration (ethylene oxide) and [substituted] p-dioxanes.
Solubility and bio-availability are prime parameters for working with Azepur99®. The use of Azepur99® in the water phase of emulsions was already described (see Tag: Solubility), and this enables the use of Azepur99® in waterborne gels based on carbomers, cellulose ethers or polysaccharides such as xanthan gum or sclerotium gum. However, these gels are alkaline and show only a limited degree of bio-availability.
For emulsion systems clarity of the azelaic acid solutions is not significant. Especially polar esters are advantageously applied, preferably in water-in-oil (W/O) emulsions. Good solvents for Azepur99® in the oil phase of emulsions are dimethyl, diisopropyl esters & diethylhexyl esters of succinic acid or adipic acid. Also some isostearic acid based esters, more particularly isopropyl isostearate and ethylhexyl isostearate, are good solvents for Azepur99® in the oil phase of the emulsion. For all emollients mentioned is applicable that hot processing must be used to properly formulate Azepur99®. The ratio of the before mentioned emollient(s) and azelaic acid used is best set at 2:1, assuring that crystallisation will not occur. Control on the presence of azelaic acid crystals is essential.
The choice of the emulsifier for W/O emulsions is rather limited indeed. This limitation arises from the fact, that the emulsifier is also required to suppress crystallisation of azelaic acid. Superior results are achieved with PEG-30 dipolyhydroxystearate (Cithrol® DPHS, formerly Arlacel® P135). This emulsifier also tolerates high electrolyte concentrations. In a similar fashion polyglyceryl-3 diisostearate (Cithrol® PG32IS; previously Prisorine® 3700) is an excellent co-emulsifier for PEG-30 dipolyhydroxystearate that enables to tune the sensorial and organoleptic properties of the final emulsion. The azelaic acid loading of W/O-emulsions may be rather high, up to 15% without crystallisation.
The azelaic acid loading for oil-in-water (O/W) emulsions is significantly lower compared to W/O-emulsions, while simultaneously avoiding crystallisation of azelaic acid. In O/W-emulsions non-ionic emulsifiers/emulsifier pairs must be used that form a liquid crystalline phase in the continuous phase of the emulsion, the water phase. There are numerous examples of emulsifiers that may be used. A small anthology, according to INCI, is given in table 3.
TABLE 3: LIQUID CRYSTALLINE EMULSIFIER PAIRS
|Cetearyl alcohol / Ceteareth-6 / Ceteareth-25|
|Steareth-2 / Steareth-21|
|Methyl Glucose Sesquistearate / PEG-20 Methyl Glucose Sesquistearate|
|Sorbitan Stearate / Polysorbate 60|
|Sucrose Stearate / Sucrose Distearate / Cetearyl alcohol|
|Ceteareth-12 / Ceteareth-20 / Glyceryl Stearate|
In these systems azelaic acid is “dissolved” in the liquid crystalline double layer as first described by Israelachvili, Ninham & Bingham (1976). Numerous examples of inclusion of physiologically active ingredients. Processing is best done by combining the emulsifier pair and azelaic acid at elevated temperature, followed by the addition of the water phase and the remaining ingredients of the oil phase. In many situations the use of a hydrocolloid is required as the mechanical strength of the liquid crystalline double layer is usually insufficient, and that may lead to emulsion instability. The addition of a hydrocolloid does not necessarily leads to an increased viscosity.
Solubility and bio-availability are prime parameters for working with Azepur99®. The use of Azepur99® in the water phase of emulsions was already described in (see Tag: Solubility), and this enables the use of Azepur99® in waterborne gels based on carbomers, cellulose ethers or polysaccharides such as xanthan gum or sclerotium gum. However, these gels are alkaline and show only a limited degree of bio-availability.
Organogels, for the first time introduced by Scartazzini, are formed from phospholipids, more particularly unsaturated phosphatidylcholine (PC). Phosphatidylcholine (Phospholipon® 85G; Lipoid), 5-10%, is dissolved in a suitable solvent that is also able to dissolve azelaic acid (5-10%): dimethyl, diisopropyl esters & diethylhexyl esters of succinic acid or adipic acid, and isostearic acid based esters, more particularly isopropyl isostearate and ethylhexyl isostearate. After complete dissolution of phosphatidylcholine, this may take considerable time, azelaic acid is added while gently heating. A clear, transparent and low viscous solution will be obtained. To this solution an aqueous solution of poloxamer 407 (Synperonic® PE/F127) is added. The viscosity of the product will increase whereby a viscous emulsion-gel will be formed (sometimes abbreviated to “emulgel”).
These organogels are frequently used as a vehicle for transdermal application of pharmaceutical actives: pain relieve agents such as morphine or diclofenac, nicotine (smoking cessation), transdermal patches for contraceptives, etc. They distinguish themselves from regular emulsions & gels by the extreme degree of bio-availability, and thus high degree of functionality whereby the side effects are virtually completely suppressed compared to oral or intravenous application.