Azeco Cosmeceuticals

Frequently asked questions Azeco Cosmeceuticals

When quality and reliability c ome first

In this document we collected the frequently asked questions from our customers.

Version 1.00

July 2020

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Index of Change

Version number Description

Date

1.00

Original Ingredient Information File

02-2020

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Question: How to improve the solubility of azelaic acid? Answer

A METHOD TO IMPROVE THE SOLUBILITY OF AZELAIC ACID

Azelaic acid is poorly soluble in water, as described earlier by Brand-Garnys & Brand. The monosodium & disodium slats are slightly better soluble but as a result the pH of these solutions is alkaline, frequently a disadvantage. Mather & Stahl (WO 1996.039119) des- cribed several combinations of solvent, frequently glycols that enable to properly dissolve azelaic acid. Example 1. 40 parts ethoxydiglycol

3 parts diisopropyl adipate 1-10% azelaic acid Mix & stir until a clear solution has been obtained.

Example 2. 40 parts dipropylene glycol 1-10% azelaic acid

Mix & stir while heating to 60°C until a clear solution has been obtained. Dipropylene glycol and ethoxydiglycol are excellent solvent systems for azelaic acid. It is recommended to further dilute the solutions of example 1 and example 2 with other glycols, more particularly propanediol (1,3-dihydroxypropane), pentylene glycol (1,2- dihy- droxypentane), glycerol, ethoxylated glycerol (glycereth-12, 18,20 & 26) and similar polyols. The solutions enable to dissolve up to 25% azelaic acid, and may function as the basis of serum preparations for use in personal care & cosmetic preparations as well as medical device, as well as a starting product for e.g. emulsion & gel preparations.

Answer Customer:

As you know from earlier my previous emails, I am looking at incorporating Azpur99 into my professional use and retail products. This includes developing a professional use ‘prescriptives’ range where I have a base gel serum product and I add to it a range of actives depending on the skin type that I am treating to make a bespoke serum. I would use that serum in the facial treatment in the clinic and I would ‘dispense’ a bespoke mix of actives that the client could then take with them for home use in conjunction with the my standard serums. My query is whether it is possible to prepare a concentration of Azpur99 that could be added to the bespoke serums?

I read in your literature that there is 15% hydrogel available - is this available to purchase?

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Developing new products from scratch is a lengthy business, as you will know and it would be up to 12 months before I could have a product ready to take to market. I need useable products NOW and so developing a prescriptive range where the products are mixed immediately prior to use is an attractive option.

Reply to Customer Customer wishes to have a base formulation containing azelaic acid. To that base formulation active ingredients can be added on demand. In this way a personalised product can be made for a particular customer. Such a base formulation can be generated by dissolution of azelaic acid in propanediol (Zemea, ex.Dupont), chemically identified as 1,3-propanediol. The solution of azelaic acid in propanediol does not require preservation and may be thickened using 3-4% hydroxy- propylcellulose (HPC; Ashland). To the obtained gel other active ingredients can be added, provided the additive is miscible with the azelaic acid/propanediol gel. That is the case for hydrophilic extracts, but also oil-in-water emulsions. The solubility of azelaic acid in propanediol is relatively high. We frequently use solutions of 10-15%. We do not know what the maxi- mum solubility of azelaic acid in propanediol would be. That would need to be researched. Note that gelation of propanediol with HPC is a tedious process.

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Question: Pricing is fine….I make a lot of margin on these products. This is a mens hair care product but I’m looking to use fairly diversly. I’m pretty happy with the Azalaic acid. To be ho- nest its better than those bogus herbal additives that do nothing but boost INCI. I’ve been formulating with ozone grade but I’ll order a kg in the next couple of weeks. I see you guys micronize it. I have questions on the activity in the free acid or neutralized state. I’ve been pretty careful not to neutralize by post adding it to a PH of 5.5. But not sure if the is any difference in the free or salt state. Answer: Azelaic acid is a dicarboxylic acid and has therefore two dissociation constants. pKA1 = 4,55 & pKA2 = 5,50. As a consequence of being a weak dicarboxylic acid the ratio azelaic acid/monosodium azelate/disodium azelate is pH dependant. To give an example of the calculation for pH=5,0 ([H3O+]= 1x10-5).

Two equilibrium equations:

H2A + H2O ç è HA- + H3O+ HA- + H2O çè A2- + H3O+

With the two dissociation constants.

KA1=[H3O+]x[HA-]/[H2A] = 2,82x10-5 KA2=[H3O+]x[A2-]/[HA-] = 3,16x10-6

Furthermore the mass balance reads: [H2A] + [HA-] + [A2-] = C After substitution of [H3O+]= 1x10-5): we are left with three equations with three unknowns, and that gives only one solution. Calcu- lus gives: [H2A] = 0,213xC

[HA-] = 0,598xC [A2-] = 0,189xC

In other words: at pH=5,00 21,3% of the amount of azelaic acid present as the free dicarboxylic acid, 59,8% is present as the monoso- dium salt and 18,9% is present as the disodium salt. When another pH value would have been chosen another concentration profile is applicable. I do not have a picture for azelaic acid, but I have a picture for another dicarboxylic acid: fumaric acid.

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The picture shows that the concentration of the three species is pH dependant. At very low pH (e.g. pH=1,5 most fumaric acid is pre- sent as the free acid. At very high pH the disodium salt is dominant. At pH=3 we have almost equal quantities of the free acid and the monosodium salt, and at pH=5 we have almost equal amounts of the monosodium salt and disodium salt, and only a small quantity of the free acid. So, the pH determines how much of each species is present. That is valid for fumaric acid, but also for azelaic acid.. Does this affect the functionality of azelaic acid ? No ! In the tallow gland where azelaic acid must do the job all species act equally. However, at eleva- ted pH the solubility of azelaic acid increase.

I trust this clarifies the situation and is an answer to the question.

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Question: I found that you are supplying Azelaic acid and I’m doing my masters project for pigmentation and using Azelaic Acid. However, I cannot find what was the highest % of Azelaic Acid we can use in cosmetics in EU. I found, that one website suggests to use up to 10% for pigmentation and in USA max 14% are allowed in cosmetics. Answer: The mechanisms of skin pigmentation, hyperpigmentation and depigmentation are poorly understood. Several mechanisms have been proposed but none of those give a closed answer, for example inhibition of tyrosinase and related melanogenic enzymes. I have attached an interesting paper for you reviewing the various proposed mechanisms and the products enabling skin lightening. The paper comes with an impressive citation list. Ebanks paper describes several products related to hydroquinone. Hydroquinone is not allowed in personal care & cosmetic pro- ducts because of the toxicity profile of hydroquinone. Azelaic acid is also in the list, and probably it is the best skin lightening ingre- dient, with a superb toxicological profile. Azelaic acid has in vitro been demonstrated to be superior to all other skin lightening pro- ducts, but in vivo the results are frequently disappointing. The problem is that azelaic acid is at ambient temperature poorly soluble in the usual cosmetic “solvents”: water, lower alcohols, mineral hydrocarbons, silicone oil, cosmetic esters, vegetable oils, etc. There is a second problem: how to get the product where it is needed: in the living dermis. Both themes can be approached by using the so-called “super solvents”. A good example is dimethyl sulfoxide (DMSO): this is not allowed in personal care & cosmetic products, but may be used in medical devices (provided the cytotoxicity of the final product is OK) or in pharmaceutical products. Other good solvents for azelaic acid are alkylated polyethylene glycols and alkylated polypropylene glycols, as their ethers. Than you will be able to properly dissolve azelaic acid in concentrations up to 20%. To control the effective concentration of azelaic acid there where it needs to give its performance you will need transdermal trans- port. One of the techniques to do so is using organogels, that also are the basis for transdermal patches such as pain relief patches, smoking cessation patches, contraceptive patches, etc. These are based on phosphatidylcholine. You will find more information and leads in two papers that I have attached for you. In systems where (1) azelaic acid is properly dissolved and (2) wherein transdermal has been made possible you will be able to make effective skin lightening products, using a concentration azelaic acid of 5-8%. Note that in the EU azelaic acid is not restricted in con- centration for skin lightening products. There are no real temperature limitations I also cannot find what is the max temperature I can heat AA to. I thought maybe you would have any suggestions/information.

I trust this information satisfies your needs.

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Question : The Method of Azelaic Acid Assay in Cream (as finished Product)

Answer: DETERMINATION OF AZELAIC ACID IN CONSUMER PRODUCTS.

There is no formal standardised method of analysis available for the determination of the assay of azelaic acid in consumer products. However, to determine the assay of azelaic acid is common practice for the skilled analytical chemist. The methods described here are not unique but are merely an interpretation of the current standards in analytical chemistry.

It is important to distinguish between the vehicles used for azelaic acid. This may be gels or emulsions (oil-in- water or water-in-oil); usually gels are more easy to analyse than emulsion systems.

1.

Gels.

Gels may contain 1-25% azelaic acid. The commercially available gels are either configured around acrylic acid- based polymers (carbomers, acrylic acid copolymers), exo-polysaccharides (xanthan gum, sclerotium gum, carrageenans, algins, karaya gum), and/or commercially available cellulose ethers.

1.1.

Acrylic acid-based polymers.

Gels made of cross-linked acrylic acid-based homopolymers are usually identified as carbomers. Direct quantitative determination of azelaic acid in these gels is not possible; the first step must be to break the gel structure. The matrix has to be opened up and this is best done using a saturated NaCl solution. Carbomers are highly sensitive for electrolytes and the gel particles will “implode”. The viscosity of the original gel is completely eliminated. As it is frequently seen that azelaic acid is present in those gels as azelaic acid crystals it is very well possible that the precipitate also will contain azelaic acid crystals. To avoid that this quantity is not quantitatively determined ethoxydiglycol (Trancutol CG; Gattefossé) is added to the aliquot, double the weight of the sample, to dissolve crystalline azelaic acid. Subsequently the sample is centrifuged to eliminate the precipitated carbomer, using a standard centrifuge @10,000 rpm during eight minutes. The sample is decanted and the aliquot is than subjected to further analysis. It shall be obvious that the aliquot may also contain other products than azelaic acid only, and the composition may be rather complex indeed. Quantitative analysis is best done by HPLC, if possible combined with MS (although not strictly necessary). A C18 reversed phase column, 20 cm, is preferred; detection is best done using an UV detector @253,9 nm. To quantitatively determine the assay of azelaic acid the technique of standard addition is used. For that reason a calibration is made using several, preferably five, concentrations of azelaic acid dissolved in ethoxydiglycol to determine the response of the detection unit. Subsequently a well-known quantity azelaic acid is added to the aliquot. Using the calibration curve the quantity azelaic acid is than easily determined. The methodology is not only valid for carbomers, but is also applicable for all other acrylic & methacrylic acid polymers, usually copolymers with other mono- mers, provided that the polymers are electrolyte-sensitive.

This methodology described for acrylic acid-based polymers is not applicable for exo-polysaccharides and cellulosics as these gels are only limited sensitive for electrolytes..

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1.2.

Exo-polysaccharides & cellulose ethers.

The most frequently used exo-polysaccharides (EPS’s) are xanthan gum, carrageenans and alginates. These biopolymers are usually insoluble in lower alcohols such methanol, ethanol, propanol and isopropanol. Gels based on exo-polysaccharides are broken with a lower alcohol of choice; the alcohol shall not be denatured as the denaturant would complicate the product mixture. The amount alcohol needed must be determined on a case-to-case basis. To the mixture of the precipitated EPS an amount ethoxydiglycol double

the weight of the sample is added to the aliquot to dissolve crystalline azelaic acid. From this point onwards the analytical procedure as described in § 1.1 is followed.

This methodology is usually also applicable for cellulose ethers: methylcellulose (MC), hydroxyethylcellulose (HEC), hydroxypropyl methylcellulose (HPMC), but is not applicable for hydroxypropylcellulose (HPC). HPC is a polymer mostly used to gel anhydrous hy- drophilic solvents such as ethanol, low molecular weight polyethylene glycols (n=6,8) or diacetin/triacetin.

2.

Emulsions.

Emulsion systems are less easily handled than gel systems. It is not always easy to break the emulsion: the emulsifiers used for making the emulsions determine what chemicals must be used to break the emulsion.

2.1.

Emulsions based on non-ionic emulsifiers.

These emulsions are stabilised by the formation of a liquid crystalline system (Israelachvili et.al., 1975) and that is frequently translated in the HLB value of the emulsifier(s): the HLB value is usually 9-11 for stable emulsions. The HLB can be greatly increased to vales > 20 using an anionic emulsifier such as sodium lauryl sulfate or an aliphatic amines such as hexylamine. The addition of alcohol (30% w/w) is usually required to improve the kinetics of emulsion breaking (and to deactivate exo-polysaccharides and/or cellulosics), and a saturated NaCl is added to deactivate acrylic acid-based polymers. The relative amount of the emulsion destabilisers must be de- termined on a case-to case basis. Phase separation may be tedious and time consuming, and therefore the test sample is centrifuged using a standard centrifuge @10,000 rpm during eight minutes. The oil/water interface must be sharp. The two phases are separated and the oil phase is dried with anhydrous sodium sulphate.

Both the oil phase and the water phase may contain azelaic acid and must be analysed according to the methodology as described in § 1.1.

2.2.

Emulsions based on anionic/cationic emulsifiers.

2.2.1. Anionic emulsions are best broken by the addition of sodium chloride (salting out). The amount of sodium chloride may be substantial. Emulsion breaking can further be accelerated by the addition of ethanol. Phase separation may be tedious and time consuming, and therefore the test sample is centrifuged using a standard centrifuge @10,000 rpm during eight minutes. The oil/water interface must be sharp. The two phases are separated and the oil phase is dried with anhydrous sodium sulphate. Both the oil phase and the water phase may contain azelaic acid and must be analysed according to the methodology as described in § 1.1. 2.2.2. Cationic emulsions usually have an acidic pH. These emulsions are best broken by adjustment of the pH to alkaline values (pH>10). The processing should be done quickly as other ingredients may be subjected to hydrolysis. Also here the oil/water interfa- ce must be sharp. The two phases are separated and the oil phase is dried with anhydrous sodium sulphate. Both the oil phase and the water phase may contain azelaic acid and must be analysed according to the methodology as described in § 1.1

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2.3.

Emulsions based on polymeric emulsifiers.

Polymeric emulsifiers behave in a similar fashion as acrylic acid-based polymers (see § 1.1) and these emulsions are easily broken using a saturated NaCl solution. The test sample is centrifuged using a standard centrifuge @10,000 rpm during eight minutes. The oil/water interface must be sharp. The two phases are separated and the oil phase is dried with anhydrous sodium sulphate. Both the oil phase and the water phase may contain azelaic acid and must be analysed according to the methodology as described in § 1.1.

= = = = = =

There is no general procedure available for the quantitative determination of the assay of azelaic acid in consumer products; a general procedure is also not possible.. Good laboratory practice and creativity of the analytical chemist(s) are prerequisites for the performance of the quantification of azelaic acid in consumer products.

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Question: We have now received the Azepur sample and started testing. We are formulating a Azelaic Acid Peel with 10- 15 % AA. The final product should be a liquid or a gel. Could you provide formulating advices and possibly some frame formulas? Thank you in advance.

Answer: Customer wishes to develop a product containing 10-15% azelaic acid.

Azelaic acid is poorly soluble in water (2.1 g/l [20ºC]). The solubility increases with (partial neutralisation). Azelaic acid is a diprotic acid, with pKA1= 4,55 and pKA2=5,50. The solubility of disodium azelate is quite good: dissolved in water a translucent solution will be obtained. However, the pH of disodium azelate solutions is rather high (>7,0).

To dissolve a relatively high concentration azelaic acid requires a thorough choice of the solvent(s)/emollient(s). There are several possibilities to achieve proper dissolution.

1. Probably the best solvent for azelaic acid is ethoxydiglycol (diethylene glycol monoethyl ether). The solubility of azelaic acid in ethoxydiglycol is better than 250 g/l. However, according to EU Regulation 1223/2009 this solvent is subject to concentration limitations (page 291, item #297). In cosmetic & personal care stay-on products only 2,6%. For medical devices and/or pharmaceutical products a higher concentration ethoxydiglycol is not a constraint. Ethoxydiglycol is commercially available from Gattefossé as Trans- cutol® P. 2. The solubility of disodium azelate is relatively high (~180 g/l), but this results in a relatively high pH. For personal care pre- parations this is considered as less appropriate. Neutralisation with a weak organic base leads to a lower pH value that simultaneously acts as a pH buffer. To be mentioned are TRIS (2-amino-2- (hydroxymethyl)propaan-1,3-diol) or AMP (aminomethyl propanol), both are available as a pharmaceutical grade. An even more elegant method is by using amino acids, more particularly arginine (2-amino-5- guanidinopentanoic acid) that also aids in wound healing. 3. The use of aminosugars, glucosamine being an exponent thereof, is a very elegant method as well, using a natural product that also enables irritation quenching. A cheap and effective method. In emulsion systems particular emollients may beneficially be used as well, more particularly the used of dimethyl or diisopropyl esters of adipic or sebacic acid. These are also powerful solvents that enhance the solubility of azelaic acid. Particular attention shall also be given to triglycol ethyl ether, PPG-2 methyl ether acetate. propylene glycol butyl ether and propylene glycol propyl ether. These products are known with their tradename Dowanol®, commercially made available from DOW Chemical. Finally, the use of micro-emulsions base on polyglyceryl ethers is recommended, such as {polyglyceryl-4 laurate + isopropyl palmitate + demineralised water + pentylene glycol}, whereby polyglyceryl-4 oleate is a good alternative for polyglyce- ryl-4 laurate. This system enables even to dissolve hard-to-dissolve ceramides.

I trust this answer satisfies the needs of Naviter Cosmetics. Please let me know if further information is required.

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Question Can you recommend some formulation concepts?

Answer You asked me for more details on the formulation concepts that we apply/have applied on azelaic acid. As is valid for all actives used in personal care & cosmetic products, chemical-medical devices and pharmaceutical preparations applied on the skin: a product can only be effective when it will arrive at the place where it should exhibit its activity. In the case of azelaic acid a sincere complication is the solubility of azelaic acid: it is poorly soluble in the usual solvents, either hydrophilic or lipophilic. To be able to be subjected to transdermal transport azelaic acid must first be made soluble in the carrier: hydrophilic or lipophi- lic solvent preparations, emulsions or gels. Solubility of azelaic acid can be tuned using specific solvents such as ethoxydiglycol, ethoxytriglycol, esters isostearic acid, dimethyl esters of linear dicarboxylic acids (including azelaic acid) and some glycols. If solubility is achieved the solubilised/dissolved azelaic acid can be incorporated into a carrier that enables transdermal transport. There is no doubt whatsoever that ethoxydiglycol is superior to all other cosmetically suitable solvent, directly followed by ethoxytriglycol. It is also possible to solubilise azelaic acid by neutralisation with an organic base such as TRIS or neutralise with acetylglucosamine. In medical practice transdermal drug delivery has become very important since the 1990’s. Having said that the potential of trans- dermal transport is still largely untapped and has yet to fully achieve its position as an alternative to oral delivery or hypodermic injections. First-generation transdermal delivery systems, as we use it, face a gradual increase for the delivery of small hydrophilic or lipophilic, low-dose drugs. Second-generation delivery systems use chemical enhancers, ultrasound and iontophoresis to control de- livery rates in real time and provides added functionality. Third-generation delivery systems target their effects to skin’s barrier layer of stratum corneum using microneedles, microdermabrasion and ultrasound. Microneedles are currently progressing through clinical trials for delivery of macromolecules and vaccines, such as insulin, parathyroid hormone and influenza vaccine. It is pretty obvious to state that second- and third-generation impact pharmaceutical applications and not personal & cosmetic products and medical devices. To enable transport of chemicals for each and any cell in the dermis a vast vascular network (capillaries) is present that also plays a role in wound healing and immune response. Capillary permeability is the rate- determining factor for the material exchange across the tissue/capillary barrier. Molecular transport is steered by physical driving forces such as concentration and pressure gradients, in other words diffusion & osmosis; diffusion is resisted by osmosis. This is described by the famous Kedem-Katchalsky equations (1958). Three types of capillaries are recognised in the human body: continuous, fenestrated and discontinuous capillaries. Continuous ca- pillaries, especially the ones in skin and skeletal muscle, are the least permeable. Continuous capillaries are also found in the cardiac muscle, in the brain and lungs. Fenestrae (windows) may be present as small circular openings, membrane-bounded circular disconti- nuities in the body of an endothelial cell. Discontinuous capillaries allow the passage of erythrocytes in and out of the systemic circulation through large gaps. Useful, to resist all kinds of riffraff. It is not surprising that these are found in the liver and in the lymphatic organs. Also in the dermal tissue, disconti- nuous capillaries are the majority, next to continuous capillaries.

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Question Customer How to dissolve azelaic acid?

Answer

The limited solubility of azelaic acid in aqueous conditions requires some creativity. There are several methods to incorporate azelaic acid in a final formulation using a premix. The most straight forward approach is to dissolve azelaic acid in ethanol or isopropanol. For many preparations these alcohols are not the most preferred substances. In that case a suitable diol will do the job. We have tested propanediol (Zemea®; Dupont), as well as 1,3-butylene glycol and pentylene glycol. Pentylene offers the advantage that it also gives a massive microbiological protection. Pentylene glycol is available from petrochemical origin (Symrise, Minasolve), but also from vegetable origin, obtained by hydroge- nation of furfuraldehyde (from wood processing; Minacare Pentiol Green/Minasolve). Also glycerin and glycerin/water mixtures are suitable solvent systems; the maximum concentration water in this solvent mixture are not properly defined and not reported in the literature. A second, but far more expensive option is to dissolve azelaic acid is a mixture of phosphatidylcholine & isopropyl palmitate. In this case a premix is made of azelaic acid in an aqueous glycerin solution. This procedure is only recommended when dissolution in gly- cols of glycerin/water mixtures fails.

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Question: You kindly sent us a sample of Azepur 99 over a year ago and we have been testing it for re- ducing hair loss with some success. We would like to develop a product using it so can I please ask a few questions? What is the most effective level of use for treating androgenic alopecia? We have so far put the Azelic acid into propylene glycol and glycerine with some ethanol, but this can be too heavy. What is the best mixture to use as a carrier? Do you have a sample formulation available as a guide? We intend to carry out our development over the next few months, so can I please request two further samples to be sent to me – otherwise I am happy to buy a small quantity for development purposes. Answer This answer relates to azelaic acid for the treatment of androgenic alopecia. To give a certified answer to your question is impossi- ble: by all means, it all depends on the bio-availability of azelaic acid how effective the product will be. If you would be able to make 100% of the amount of azelaic acid bio-available you would need a concentration of 1,0-1,5% calculated on the basis of a gel-like preparation. 1. Add 2% ethoxydiglycol. This is a superb solvent for azelaic acid and improves the dryness of the product when applied to the scalp. Ethoxydiglycol enables transdermal transport in the follicle, with a high degree of efficacy. For personal care & cosmetic products a maximum of ethoxydiglycol of 2,6% applies. This is not applicable for medical devices, given the “mode of action” of the medical device has been properly defined and that the consumer product is not subject to cytotoxicity. Ethoxydiglycol is supplied by Gattefosse as Transcutol CG. 2. Cytotoxicity can be suppressed by using 5% betaine (trimethylglycine), supplied by Dupont under the tradename Genenca- re OSMS BA. 3. It would properly better to use Zemea (INCI: propanediol; chemical name 1,3-propylene glycol). This product reduces the skin irritation induced by 1,2-propylkene glycol. Zemea is commercially made available by Dupont. 4. A system as applicable to your wishes is best thickened by 2-3% hydroxypropylcellulose (HPC). This polymer does not give a resident feel on the scalp. To prepare a gel the polymer shall first be dissolved in the final HPC before adding other products to be dissolved to avoid dissolution competition. HPC is commercially made available by Ashland as Klucel. The current system based on propylene glycol, glycerin & ethanol is rather resident on the scalp indeed, but it is a well-chosen sol- vent for azelaic acid. The system can be greatly improved using the following system:

Let me know if any further questions remain.

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Question: I have a question concerning the solubility of the acid, I’ve tried various tests in the laborato- ry and I have not been able to solubilize it. I have tried a few solubility tests in the laboratory and I’ve made a solution of 0,79 % Azelaic acid and it has NOT completely solubilized. Do you mean 10-15 % acid in Propanediol? Can you please give me the contact details to a technician who can help me with this. Answer Such a base formulation can be generated by dissolution of azelaic acid in propanediol (Zemea, ex.Dupont), chemically identified as 1,3-propanediol. The solution of azelaic acid in propanediol does not require preservation and may be thickened using 3-4% hydroxy- propylcellulose (HPC; Ashland). To the obtained gel other active ingredients can be added, provided the additive is miscible with the azelaic acid/propanediol gel. That is the case for hydrophilic extracts, but also oil-in-water emulsions. The solubility of azelaic acid in propanediol is relatively high. We frequently use solutions of 10-15%. We do not know what the maximum solubility of azelaic acid in propanediol would be. That would need to be researched. Note that gelation of propanediol with HPC is a tedious process. Does this answer your question?

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Question: • Would Azelaic solubility in propanediol 1,3 be similar to that of propylene glycol? (mar- keting constraints, limited solvents) • We are planning to experiment with solubilizing in propanediol then suspending in scle- rotium gum adjusted to 3.8 pH (as part of a combination AHA formulation) • Would this adversely affect bio-availability and/or risk crystallization? The solubility of azelaic acid in 1,2-propylene glycol (INCI: Propylene Glycol) is comparable with 1,3-propylene glycol (INCI: Propanediol). I understand where your client s coming from as 1,2- propylene glycol is from petrochemical origin and 1,3-propylene glycol is obtained by fermentation of corn sugar and has an EcoCert/Cosmos approval. Having said that, the solubility of azelaic acid in both solvents is rather limited indeed. The solubility of azelaic acid in both solvents can be greatly increased as follows: a. Add ethoxydiglycol or ethoxytriglycol to the glycols to further increase the solubility. Ethoxydiglycol is limited in concentra- tion for personal care & cosmetics by the EU Legislator; ethoxy triglycol can be used freely without concentration limitations. For the USA the FDA has not put any constraints to both solvents. b. Azelaic acid can properly be dissolved in these glycols using chitosan in a (semi)-stoichiometric quantity. Reference is made to your booklet and the publication in SPC. 2. Azelaic acid is well tolerated by sclerotium gum (Alban Muller) and vice versa. While working in an anhydrous environment there is no concern for the pH of the system. Having said that, quantitative data on the acid/base behavior in non-aqueous solvents have not been published. When following the instructions as laid down in §1 the risk of crystallization will be minimized (but not zero !), to be confirmed by a shelf life study. Usually crystallization phenomena pop up already after a few days. Answer: 1.

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For technical and / or sales service contact

Azeco Cosmeceuticals BV | The Netherlands Ms. Annet Verhaegen service@azeco-cosmeceuticals.com

www.azeco-cosmeceuticals.com