Sanosuke
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found this was kinda interesting
RLA is a highly unstable compound that easily polymerizes into a sticky rubber or glue-like substance if it is not prepared, stored and processed correctly. Even under the best conditions, RLA is extremely unstable. Exposure to air, light, moisture and temperatures slightly above ambient drastically reduces shelf life and increases the formation of this unwanted degradation product that may adversely affect bioavailability.
After great effort, we rediscovered the S-S bond is homolytically cleaved by light, heat and acid (water is acidic enough) yielding thiyl radicals that polymerize into a chain of linear disulfides with the carboxyl groups free. The structure of this polymer was known and reported in 1956, in Disulfide Polymers of DL-alpha-lipoic acid by Richard Thomas and Lester Reed at the Clayton Foundation for Research, The Biochemical Institute and the Dept. of Chemisrty at the University of Texas. Only 44 years before us.
Time may be better spent in the library than the laboratory.
GeroNova did not invent the problem of RLA polymerization as a marketing ploy, although we have been frequently accused of this. In fact, we were shocked, and dismayed when we discovered (several years ago) that our very first batch of capsules (made from 99.5% enantiomerically pure RLA) contained 22% polymer! Subsequent research revealed that what was new to us is actually a well known characteristic of disulfides and was observed from the very first laboratory preparations of racemic ALA in the early 50's. (see JACS references below and Characterization and Stability of Cyclic Disulfides and Cyclic Dimeric Bis (Disulfides) Tetrahedron 45, 91 (1989).
It is also important to recognize the new USP 27 monolog of rac- ALA (p.2019, which incidently shows a molecular diagram of RLA, not rac- ALA) has a simple (and approximate) TLC test for polymer content in the raw material (but not the capsules or tablets) limiting it to NGT 2%. When we adapted the method to tablets and capsules of previously assayed ALA, the polymer content grew 5-10 fold over the raw material, showing that polymerization is also a potentially significant problem with dosage forms of racemic ALA, and why the allowable ranges of ALA content is 90-115% label claim.
According to Asta Medica, [6,348,490] RLA tablets were characterized by poor disintegration and dissolution profiles, such that RLA was only 9% dissolved in simulated gastric juice after 30 minutes, whereas racemic ALA was 100 % dissolved after 30 minutes. This means that unless the product has been stabilized and is not polymeric, use racemic ALA .
This also suggests the possibility that the insoluble polymer may accumulate in the GI tract over time, since it is essentially insoluble in water or gastric juice. In the lab it is insoluble in strong acids or any of the common organic solvents (even powerful solvents like DMF and DMSO). Strong base will depolymerize it in time and under forceful conditions but requires much more heat and alkalinity than what is found in the intestinal environment. This could be significant for diabetics, Alzheimer's sufferers, MS patients or the HIV infected who take high daily doses (up to 6 gm per day).
The revolutionary research (and subsequent media coverage) of Bruce Ames, Lester Packer and Tory Hagen has been largely responsible for the consumer demand for lipoic acid products in the US (which consumes most of the lipoic acid in the world).
Ame's group has shown the role of mitochondrial decay in age-related disease and how it can be reversed with ALC, lipoic acid, and the "spin trap", PBN. Dr Ames has recently filed a patent called:
“Stability of Lipoic Acid� (US Application 20040044046, March 4, 2004)
[0011] LA suffers from certain disadvantages, however. In particular, the natural form R-LA is unstable above 40° C., so it can degrade under some warehousing conditions. Also LA is hygroscopic. What is needed is stabilization of this natural form of LA with a natural salt.
The natural salt in the patent is a salt pair formed by reacting RLA with nicotinamide. This was an example of a fortuitous discovery that may ultimately be commercially successful. As an incidental note, the salt was actually made by a famous local organic chemist and friend of Ames who found it in a vial on a lab shelf 17 months after he synthesized it. He decided to re-test it utilizing IR spectrophotometry and realized that the spectral data was identical to the original, indicating that it was stable.
He then reported his finding to Ames .
According to Juvenon (the patent holder of Ames ’ ALC / ALA cocktail) RLA is not used in their formulas, even though the research was done with the R-form because,
“The R form can be purified from the S form. However, the major problem with this compound, when separated from the S form, is stability. The compound deteriorates relatively rapidly at room temperature. The R form is also significantly more expensive. Work is ongoing to solve the stability problem, and when we feel this is complete to our satisfaction, Juvenon will offer a product containing only the R form.
Here are a few more patents mentioning the polymer problem, innovative solutions, the problems of RLA tablet dissolution, poor bioavailability and the enhanced bioavailability of the salt forms.
Alpha-Lipoic Acid with Novel Modification. (US Patent 5,994,393 Nov 30, 1999 )
“The melting range of the pure enantiomers of thioctic acid (47-49° C) is lower compared to the racemic compound (58-61° C). In the production of solid galenic formulations, the use of pressure on the material is indispensable so that on the one hand a heating and on the other hand a melting of thioctic acid takes place. Concentrated solutions of thioctic acid or its melts polymerize immediately and can no longer be converted into a crystalline form by cooling.�
According to "Method of Producing Flowable R, S-Thioctic Acid, R,S-Thioctic Acid and its Use" (US Patent 5,705,192 Jan 6, 1998 )
…it is possible to make a thioctic acid form available which does not adhere to the pressing tool or exhibit a tendency to form fissures on the tablet, even when tablets with 600mg or more active substance content are prepared.�
According to “Dosage Forms containing thioctic acid or solid salts of thioctic acid with improved release and bioavailability� ( US Patent 6,348,490)
“In contrast with dosage forms prepared from free R-thioctic acid, the dosage forms prepared from salts of R-Thioctic acid have not only the advantage of better release and bioavailability of the active ingredient, but are moreover more easily produced.�
The best methods to prove the structure of the polymer conclusively is by x-ray diffraction, and by UV spectrophotometry which has a spectral profile distinct from the crystalline forms [JACS 78, 5079 (1956)].
The melting point is a simple test to quickly verify the reality of the RLA polymer problem and can be rapidly performed in any lab. The melting point is used in chemistry as a rough guide to purity, since a pure crystalline compound will generally melt over a range of a few degrees, and is depressed by impurities (or polymorphs). Liquefaction, and in many cases subsequent recrystallisation upon cooling follows the initial melting.
In the case of RLA, the material actually polymerizes simultaneously with melting and there are no subsequent observable changes upon heating up to 250°C, where the material begins burning. When cool it is a sticky insoluble linear chain composed of oligomeric disulfides. The only way to get a usable "melting point" is to have a device pre-set to 49°C, place a sample on a microscope cover slip and to drop it on the pre-heated surface. Even then you get sintering (polymerization) rather than a true melting point. This is why we do not use the melting point has the sole criteria of purity. The sintering temperature is a good way to quickly differentiate RLA or SLA from racemic ALA , which melts about ten degrees C higher.
While ALA is more stable in the solid form than in solution, the hygroscopic nature of ALA initiates polymerization. Even a partially polymerized product can pose significant problems in the manufacturing and stability of a dosage form. The polymer reduces dintegration, dissolution of tablets or capsules, GI absorption and lowers the bioavailability, since it is so poorly absorbed from the GI tract.
We placed RLA capsulesof known RLA and Polymer contents in simulated gastric juice in a dissolution tester, and tested concentrations of active RLA over time by HPLC. In five runs, the amount of detectable RLA was significantly less than the assay result of the same dosage forms, suggesting that the polymer is trapping active material.
The results of our experiment supported our intuitive hunches, i.e. even if the entire dosage form has not become polymeric, the stickiness of the material will limit the dissolution, absorption and bioavailability of RLA.
The fact that the product has not been completely polymerized, and that there is some material still available to enter the circulation can account for the positive (albeit limited) results obtained with the preparations.
RLA is a highly unstable compound that easily polymerizes into a sticky rubber or glue-like substance if it is not prepared, stored and processed correctly. Even under the best conditions, RLA is extremely unstable. Exposure to air, light, moisture and temperatures slightly above ambient drastically reduces shelf life and increases the formation of this unwanted degradation product that may adversely affect bioavailability.
After great effort, we rediscovered the S-S bond is homolytically cleaved by light, heat and acid (water is acidic enough) yielding thiyl radicals that polymerize into a chain of linear disulfides with the carboxyl groups free. The structure of this polymer was known and reported in 1956, in Disulfide Polymers of DL-alpha-lipoic acid by Richard Thomas and Lester Reed at the Clayton Foundation for Research, The Biochemical Institute and the Dept. of Chemisrty at the University of Texas. Only 44 years before us.
Time may be better spent in the library than the laboratory.
GeroNova did not invent the problem of RLA polymerization as a marketing ploy, although we have been frequently accused of this. In fact, we were shocked, and dismayed when we discovered (several years ago) that our very first batch of capsules (made from 99.5% enantiomerically pure RLA) contained 22% polymer! Subsequent research revealed that what was new to us is actually a well known characteristic of disulfides and was observed from the very first laboratory preparations of racemic ALA in the early 50's. (see JACS references below and Characterization and Stability of Cyclic Disulfides and Cyclic Dimeric Bis (Disulfides) Tetrahedron 45, 91 (1989).
It is also important to recognize the new USP 27 monolog of rac- ALA (p.2019, which incidently shows a molecular diagram of RLA, not rac- ALA) has a simple (and approximate) TLC test for polymer content in the raw material (but not the capsules or tablets) limiting it to NGT 2%. When we adapted the method to tablets and capsules of previously assayed ALA, the polymer content grew 5-10 fold over the raw material, showing that polymerization is also a potentially significant problem with dosage forms of racemic ALA, and why the allowable ranges of ALA content is 90-115% label claim.
According to Asta Medica, [6,348,490] RLA tablets were characterized by poor disintegration and dissolution profiles, such that RLA was only 9% dissolved in simulated gastric juice after 30 minutes, whereas racemic ALA was 100 % dissolved after 30 minutes. This means that unless the product has been stabilized and is not polymeric, use racemic ALA .
This also suggests the possibility that the insoluble polymer may accumulate in the GI tract over time, since it is essentially insoluble in water or gastric juice. In the lab it is insoluble in strong acids or any of the common organic solvents (even powerful solvents like DMF and DMSO). Strong base will depolymerize it in time and under forceful conditions but requires much more heat and alkalinity than what is found in the intestinal environment. This could be significant for diabetics, Alzheimer's sufferers, MS patients or the HIV infected who take high daily doses (up to 6 gm per day).
The revolutionary research (and subsequent media coverage) of Bruce Ames, Lester Packer and Tory Hagen has been largely responsible for the consumer demand for lipoic acid products in the US (which consumes most of the lipoic acid in the world).
Ame's group has shown the role of mitochondrial decay in age-related disease and how it can be reversed with ALC, lipoic acid, and the "spin trap", PBN. Dr Ames has recently filed a patent called:
“Stability of Lipoic Acid� (US Application 20040044046, March 4, 2004)
[0011] LA suffers from certain disadvantages, however. In particular, the natural form R-LA is unstable above 40° C., so it can degrade under some warehousing conditions. Also LA is hygroscopic. What is needed is stabilization of this natural form of LA with a natural salt.
The natural salt in the patent is a salt pair formed by reacting RLA with nicotinamide. This was an example of a fortuitous discovery that may ultimately be commercially successful. As an incidental note, the salt was actually made by a famous local organic chemist and friend of Ames who found it in a vial on a lab shelf 17 months after he synthesized it. He decided to re-test it utilizing IR spectrophotometry and realized that the spectral data was identical to the original, indicating that it was stable.
He then reported his finding to Ames .
According to Juvenon (the patent holder of Ames ’ ALC / ALA cocktail) RLA is not used in their formulas, even though the research was done with the R-form because,
“The R form can be purified from the S form. However, the major problem with this compound, when separated from the S form, is stability. The compound deteriorates relatively rapidly at room temperature. The R form is also significantly more expensive. Work is ongoing to solve the stability problem, and when we feel this is complete to our satisfaction, Juvenon will offer a product containing only the R form.
Here are a few more patents mentioning the polymer problem, innovative solutions, the problems of RLA tablet dissolution, poor bioavailability and the enhanced bioavailability of the salt forms.
Alpha-Lipoic Acid with Novel Modification. (US Patent 5,994,393 Nov 30, 1999 )
“The melting range of the pure enantiomers of thioctic acid (47-49° C) is lower compared to the racemic compound (58-61° C). In the production of solid galenic formulations, the use of pressure on the material is indispensable so that on the one hand a heating and on the other hand a melting of thioctic acid takes place. Concentrated solutions of thioctic acid or its melts polymerize immediately and can no longer be converted into a crystalline form by cooling.�
According to "Method of Producing Flowable R, S-Thioctic Acid, R,S-Thioctic Acid and its Use" (US Patent 5,705,192 Jan 6, 1998 )
…it is possible to make a thioctic acid form available which does not adhere to the pressing tool or exhibit a tendency to form fissures on the tablet, even when tablets with 600mg or more active substance content are prepared.�
According to “Dosage Forms containing thioctic acid or solid salts of thioctic acid with improved release and bioavailability� ( US Patent 6,348,490)
“In contrast with dosage forms prepared from free R-thioctic acid, the dosage forms prepared from salts of R-Thioctic acid have not only the advantage of better release and bioavailability of the active ingredient, but are moreover more easily produced.�
The best methods to prove the structure of the polymer conclusively is by x-ray diffraction, and by UV spectrophotometry which has a spectral profile distinct from the crystalline forms [JACS 78, 5079 (1956)].
The melting point is a simple test to quickly verify the reality of the RLA polymer problem and can be rapidly performed in any lab. The melting point is used in chemistry as a rough guide to purity, since a pure crystalline compound will generally melt over a range of a few degrees, and is depressed by impurities (or polymorphs). Liquefaction, and in many cases subsequent recrystallisation upon cooling follows the initial melting.
In the case of RLA, the material actually polymerizes simultaneously with melting and there are no subsequent observable changes upon heating up to 250°C, where the material begins burning. When cool it is a sticky insoluble linear chain composed of oligomeric disulfides. The only way to get a usable "melting point" is to have a device pre-set to 49°C, place a sample on a microscope cover slip and to drop it on the pre-heated surface. Even then you get sintering (polymerization) rather than a true melting point. This is why we do not use the melting point has the sole criteria of purity. The sintering temperature is a good way to quickly differentiate RLA or SLA from racemic ALA , which melts about ten degrees C higher.
While ALA is more stable in the solid form than in solution, the hygroscopic nature of ALA initiates polymerization. Even a partially polymerized product can pose significant problems in the manufacturing and stability of a dosage form. The polymer reduces dintegration, dissolution of tablets or capsules, GI absorption and lowers the bioavailability, since it is so poorly absorbed from the GI tract.
We placed RLA capsulesof known RLA and Polymer contents in simulated gastric juice in a dissolution tester, and tested concentrations of active RLA over time by HPLC. In five runs, the amount of detectable RLA was significantly less than the assay result of the same dosage forms, suggesting that the polymer is trapping active material.
The results of our experiment supported our intuitive hunches, i.e. even if the entire dosage form has not become polymeric, the stickiness of the material will limit the dissolution, absorption and bioavailability of RLA.
The fact that the product has not been completely polymerized, and that there is some material still available to enter the circulation can account for the positive (albeit limited) results obtained with the preparations.
