Polymerization, G.I. Absorption & Bioavailability

Polymerization and Instability in Dosage Forms

Racemic Lipoic Acid is a relatively unstable molecule due its propensity to form polymeric chains. There are significant stability problems, especially with the pure enantiomers which have a lower melting point and polymerize more readily than the racemic mixture. It is not surprising that some people doubt our claims concerning this problem on a product that has only been commercially available as a nutritional supplement for a few years.

Most supplement companies have no experience with the actual doing of the chemistry on the products they manufacture. Consumers and supplement manufacturers are bombarded with so much hype that suspicion is a natural result. It can be difficult to discriminate between scientific fact and "marketing hype". Since most people do not have the time to dig out old chemistry journals, we decided to publish what we have discovered from both the library and the laboratory.

Hands-on Experience

R-Lipoic Acid derived products are our specialty and we have gained significant experience working with this compound in the laboratory and in production during the last four years. At times, we have literally been "up to our elbows" in R-Lipoic Acid polymer, and process 100's of kilograms of R-Lipoic Acid at a time. We have gained considerable hands on experience in dealing with this "sticky rubber" which is unavoidable and all too real.

GeroNova did not invent the problem of R-Lipoic Acid 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 R-Lipoic Acid, 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.

Novel, Patented Methods of Stabilization

While vitamin resellers are still largely unaware of the stability problems of R-Lipoic Acid, primary manufacturing companies know all too well about its reality. Asta Medica (now Viatris), BASF, Degussa, Labochim and Antibioticos, have developed novel methods of dealing with this annoying property of an otherwise valuable supplement.

Asta Medica [US Patent 5,455,264] modified the usual isolation and crystallization of ALA or R-Lipoic Acid to yield a product with a novel crystalline structure, characterized by a novel x-ray diffraction pattern and dissolution profile. It was also easy to isolate the product from polymeric starting materials.

The next Asta Medica invention [US Patent 5,994,393] utilized a special resolution technique to alter the R/S ratio. The resulting products have varying melting points depending on the how much of the S isomer is present. The more SLA present, the higher the melting point, so that a R/S mixture of 65.8 % RLA: 34.2% SLA has a melting point of 54-58 degrees C and is less prone to polymerize. Labochim (Italy) has a dosage form commercially available containing a 70:30 mixture of RLA: SLA and that is more stable and less prone to polymerization than the usually encountered RLA.

BASF jumped in on the act [US 6,441,024] and developed a process (similar to Asta Medica's) utilizing a mixed solvent system and precise temperature control which modified the crystalline structure and physical properties of RLA.

Polymerization Problems in Commercial R-Lipoic Acid Products

GeroNova did not set out to gain a market advantage over our competitors by publicizing this problem. We actually set out to discover what they were doing that we were not in order to prevent polymerization. This sticky elastomer was the cause of many sleepless nights, and two years of subsequent R&D to develop a stable/heat resistant dosage form. It was only after testing competitors products (by third party HPLC analysis) that we discovered that not only were most companies not doing anything to prevent polymerization, but were obviously also not doing any quality control on their finished products, since they were not delivering anything close to their label claims.

Commercial R-Lipoic Acid products tested had polymer contents ranging from 13-64%

We brought the issue of R-Lipoic Acid instability and our test results to the attention of vitamin companies as well as to the public in an attempt to raise the quality of products reaching the consumer. While many companies choose to deny any problem exists, we reported it from the beginning and have subsequently discovered novel ways to overcome the limiting physical properties.

Our K-RALA™ and Na RALA, while effective, is not novel. The processing of a carboxylic acid into its salt is a standard process in industrial chemistry and pharmaceutical technology. While conceptually simple, the practical achievement is a formidable task presenting many challenges when done on a large commercial scale. Even the salts can retain significant quantities of polymer, resulting in a sticky, hygroscopic tablets and capsules with poor dissolution profiles.

Since we believe the old philosophy of business (bashing your competitors) is outdated, GeroNova endorses any of our "competitors" involved with this fascinating molecule, and support them in their attempts to bring it to the public, as long as they are delivering what they claim. Since we believe that every living, breathing human being needs R-Lipoic Acid, there is room for quite a few good R-Lipoic Acid companies, and we believe R-Lipoic Acid will outgrow CoQ10 and Vitamin E within 10 years.

On the other hand, it makes no sense to report all the health benefits of R-Lipoic Acid if you cannot deliver it into the body in a usable form. GeroNova will not endorse companies selling products containing largely polymerized R-Lipoic Acid, with poor dissolution properties and low bioavailability, even at discount prices. If you are using a cheap R-Lipoic Acid product, with no mention of the polymer content, or if the companies that produce finished tablets and capsules deny the reality of R-Lipoic Acid instability, you may be better off to use or take high quality racemic ALA.

According to Asta Medica, [6,348,490] R-Lipoic Acid tablets were characterized by poor disintegration and dissolution profiles, such that R-Lipoic Acid 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).

Here are a few more patents mentioning the polymer problem, innovative solutions, the problems of R-Lipoic Acid 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."

According to the article "Disulfide Polymers of DL-alpha-Lipoic Acid" by Thomas and Reed (JACS 78, 6148 (1956)

"The ease with which ALA polymerizes has been noted. The several Lipoic Acids described in this paper polymerized to various extents during their distillation and recrystallisation. The liquid esters of Lipoic Acid polymerized with extreme ease".

The previous note referred to by Reed was reported by his group at the University of Texas in JACS 77, 416 (1955) and about the same time by a team from Merck Sharp & Dohme [JACS 78, 5079 (1956)]. The polymer problem was recognized from the very first laboratory preparations of Lipoic Acid because the oxidation of DHLA produced not only the disulfide (ALA ) but also an insoluble chain of oligomeric disulfides.

This polymer is the same polymer found in commercial dosage forms of RLA

It is important to realize that Reed was working with the racemic ALA, i.e. DL-Lipoic Acid and not R-Lipoic Acid, which was not yet available in any sizeable quantities. (In 1957 he isolated R-Lipoic Acid by classical resolution in 60% yield).

The optical isomers were first made by Merck in 1955 [JACS 77, 416 (1955)] and later by DuPont [JACS 79, 6483 (1957)].

Heat and Polymer Formation

Extreme heat is NOT a necessary requisite for polymer formation, as indicated in the above patents and the citation by Reed. Reed heated the product to 65°C because he knew heat would accelerate the polymerization, but in the case of R-Lipoic Acid this occurs instantly at 46°C.

A key point that needs recognition is that even the so called "stable" ALA used extensively in the nutritional supplement industry is still prone to polymerization, and is also hygroscopic, although more heat stable than RLA. Anyone that has worked with this material knows how sticky it gets during its conversion into solid dosage forms. The pure enantiomers are even more unstable since they melt at a lower temperature, lose crystallinity and form a non-recrystallizable glass. Technically, a "glass" is an amorphous substance, i.e. without crystallinity. The isolation of crystalline R-Lipoic is a formidable problem during commercial production, and one of the key factors influencing the cost of the product. Even processed under high vacuum and below room temperature, it is very common to get a pot of "rubber" rather than "golden crystals".

Melting Point Test, Polymeric Structure

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 heat of friction during encapsulation and the compression of tableting are sufficient to initiate this process. Polymerization is also catalyzed by light and acid, and de-polymerized by strong base and more heat. The rate of polymerization is slower in acid than by light or heat.

"In the solid state ALA appears to be stable. In the cases noted above the instability of the compound was apparent only when it was in a dissolved or fluid state. It appears therefore that once the crystal lattice of ALA is broken the molecules tend to polymerize under certain conditions. These conditions must provide for the opening the 1,2 dithiolane ring of Lipoic Acid. The necessary energy for opening or at least loosening the disulfide bond comes from the absorption of light in the visible or on the edge of the visible spectrum. Once these bonds are activated, the molecules in a non rigid state tend to polymerize." [JACS 78, 5079 (1956)]

Dissolution

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 R-Lipoic Acid capsulesof known R-Lipoic Acid and Polymer contents in simulated gastric juice in a dissolution tester, and tested concentrations of active R-Lipoic Acid over time by HPLC. In five runs, the amount of detectable R-Lipoic Acid 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.

Baffling Molecular Behaviour

It should also be realized that the peculiar behavior of R-Lipoic Acid which drives pharmaceutical technologists crazy is related to the ring strain of the dithiolane ring, imparting unique reactivity to the disulfide/dithiol bonds, the same phenomena that imparts R-Lipoic Acid with unique and beneficial biological properties!