From impurities to thermal decomposition of metformin #Kani

Web of knowledge (wok) search on: metformin and impurity yields only the 'Talanta paper'

Google search: http://www.sigmaaldrich.com/analytical-chromatography/analytical-products.html?TablePage=107313020

leads to: N,N-Dimethyl-1,3,5-triazine-2,4,6-triamine

which is available from Sigma: http://www.sigmaaldrich.com/catalog/product/sial/phr1506?lang=en&region=GB

but no melting point reported on SDS, so can't tell whether this is the 145-152 C mp product.

wok on N,N-Dimethyl-1,3,5-triazine-2,4,6-triamine shows no hits

wok on 2,4,6-Triamino-1,3,5-triazine (= metformin impurity D) yields 72 hits.

one of these is thermal decomposition of guanylurea dicyanamide

the other relevant one is:

GAS-CHROMATOGRAPHIC BEHAVIOR OF BUFORMIN HYDROCHLORIDE, PHENFORMIN HYDROCHLORIDE AND PHENYLBIGUANIDE - PYROLYTIC FORMATION OF SUBSTITUTED 2,4,6-TRIAMINO-1,3,5-TRIAZINES FROM BIGUANIDES

By: WICKRAMA.JA; SHAW, SR

JOURNAL OF CHROMATOGRAPHY, Volume: 71 Issue: 2 Pages: 265-& Published: 1972

Publisher ELSEVIER SCIENCE BV, PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS

ISSN: 0021-9673

Worth getting this on interlibrary loans.

This then lead to wok search: biguanide thermal decomposition

Only relevant paper found: BIGUANIDES .1. THERMAL-DECOMPOSITION AND MASS-SPECTRAL BEHAVIOR OF BIGUANIDE AND SOME OF ITS SALTS

By: BELL, NA; HUTLEY, BG; SHELTON, J; et al.

THERMOCHIMICA ACTA, Volume: 21 Issue: 2 Pages: 255-262 Published: 1977

Publisher ELSEVIER SCIENCE BV, PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS

ISSN: 0040-6031

Worth getting this on interlibrary loans.

This then led to wok search: metformin thermal decomposition

Only relevant paper found: THERMAL STABILITIES, ELECTRONIC-PROPERTIES AND STRUCTURES OF METFORMIN-METAL COMPLEXES - MOLECULAR-ORBITAL INVESTIGATION

By: DONIA, AM; AWAD, MK

JOURNAL OF THERMAL ANALYSIS JOURNAL OF THERMAL ANALYSIS, Volume: 44 Issue: 6 Pages: 1493-1498 Published: JUN 1995

Publisher JOHN WILEY & SONS LTD, BAFFINS LANE CHICHESTER, W SUSSEX, ENGLAND PO19 1UD ISSN: 0368-4466

Worth getting this on interlibrary loans.

This then led to:

google search: metformin thermal decomposition,

key paper found: Foziah J Therm Anal Calorim 2013 (now on google drive)

J Therm Anal Calorim (2013) 111:2079–2096 DOI 10.1007/s10973-012-2459-3

Synthesis, spectroscopic, and thermal investigation of transition and non-transition complexes of metformin as potential insulin-mimetic agents Foziah A. Al-Saif • Moamen S. Refat

which details thermal decomposition of metformin hydrochloride and a number of metformin complexes, as well as detailing FTIR (with peak assignments) and other studies

Compounds (gases) lost at various temperatures are recorded:

Table 8

Complexes Steps Temp. range/ C Decomposed assignments Weight loss found/calcd./%

MF HCl 1st 287–303 –HCl 21.333 (22.037) 2nd 369–408 –CH5N3 (guanidine) (CH3)2N-CN (dimethylcyanamide) 3rd 437–462 76.846 (77.983) 4th 666–738 Residue Nil

Now, since toluene was lost during our experiment, the temperature must have then be raised above the 110 C bp of toluene, to perhaps 287 C or above, therefore decomposition might have occurred - the first step from this paper suggesting loss of HCl gas to form metformin free base. If the temperature had increased further, to say369-408 C, then guanidine (CH5N3) would have been lost to form (CH3)2N-CN , which is dimethylcyanamide. Further temperature increases at 437-462 and 666-738 would have just produced a residue.

Obviously, in the future, we need to make sure the toluene does not boil off completely and/or the reaction mixture does not increase into the HCl evolution region (287 C). I think we need to monitor temperature with a thermometer. It might be that the heating mantle provides local hot spots and so a water bath might be better - not sure. And refluxing for a lot less than 24 h might be good.

So, it might be that the glassy solid produced, which when recrystallized from methanol yielded a white powder, might be dimethylcyanamide.

However, a Sigma search for this revealed a boiling point of 161-164 C with no mp listed - although it stated the product was a liquid. Since, we had a solid, it seems possible that we might have (product 2) dimethylcyanamide with some residual metformin free base - just another to keep it solid. Alternatively, we might still have metformin free base.

Various literature searches are not coming up with a melting point for metformin free base.... Don't know why.... Keep searching, or maybe make some from equal molar reaction of metformin hydrochloride with NaOH and extract the free base in CHCl3? Might be worth pursuing.