[0001] Priority is claimed of Slovenian patent application no. P-2020 00132 filed on July 31, 2020 and European patent application no. 20209 718.4 filed on November 25, 2020.

[0002] The invention relates to a pharmaceutical composition or dosage form of metformin or a physi ologically acceptable salt thereof, possibly in combination with one or more other active pharmaceutical ingredients. The pharmaceutical composition or dosage form has a content of N-nitroso dimethylamine (NDMA) below 48 ppb. The invention further relates to analytical methods for determining the content of NDMA and dimethylamine (DMA). These methods are suitable for monitoring the correlation be tween DMA that is entrained as an impurity along with metformin used as staring material and the NDMA content of the final pharmaceutical composition or dosage form containing metformin.

[0003] Metformin is an antidiabetic agent that has become one of the most widely used drugs in the treatment of type 2 diabetes mellitus (T2DM) since its approval in the United Kingdom in 1958 and in the United States in 1995, with doses ranging from 500 to 2,000 mg/day. It is the first-line therapy for patients with T2DM according to the American Diabetes Association/European Association for Study of Diabetes guidelines. Metformin works by decreasing intestinal glucose absorption, improving periph eral glucose uptake, lowering fasting plasma insulin levels and increasing insulin sensitivity, which re sult in a reduction of blood glucose concentrations without causing overt hypoglycemia.

[0004] Metformin is marketed in immediate-release formulations and extended-release formulations and is available in several products in combination with other active pharmaceutical ingredients, espe cially antidiabetic agents.

[0005] N-nitroso dimethylamine (NDMA) is an N-nitrosamine (RR'N-N=0). N-nitrosamines are gen erally formed when certain amines react with suitable nitrosating agents. The main sources tend to be tobacco, cured meats such as bacon, fermented foods such as beer and cheese, shampoo and cleansers, and detergents and pesticides. In bacon, for example, NDMA formation occurs when during cooking nitrite preservatives react with amines and with amino acids that are contained in the meat.

[0006] NDMA is classified as a group 2A carcinogen, or “probably carcinogenic to humans,” according to the International Agency for Research on Cancer. This means that there is no direct evidence that NDMA causes cancer in humans, but it is likely that NMDA is cancerogenic because it has caused cancer in animals. On the basis of animal studies, both FDA and Health Canada have set an acceptable intake limit for NDMA of 0.096 pg per day.

[0007] The amount of NDMA that has been found in pharmaceuticals has varied widely. Analytical results vary with laboratory performing the analysis, manufacturer of active pharmaceutical ingredient, and batch of medication that is subjected to analysis.

[0008] In the past few years, private, pharmaceutical, and regulatory agency labs around the world have been finding NDMA and other N-nitrosamine contaminants in various active pharmaceutical ingredients and formulations thereof. In 2018, the first discovery was made in a formulation of valsartan as manu factured by Novartis. Valsartan is an angiotensin II receptor blocker (ARB) used to treat high blood pressure. Since this discovery, NDMA and similar compounds have been found in at least six formula tions that are taken by tens of millions of people each year.

[0009] Because these N-nitrosamine contaminants are potential carcinogens, regulatory agencies have deemed these formulations unsuitable for commercialization over the counter (OTC). Valsartan was recalled in July 2018, followed by irbesartan in October and by losartan in November. Irbesartan and losartan are another two ARBs and their formulations were found to also contain NDMA and the related compound N-nitroso diethylamine (NDEA).

[0010] In September 2019, the FDA alerted the public to the presence of NDMA in certain lots of ranitidine, available over the counter as Zantac, and manufacturers recalled it in the following months. Nizatidine, another heartburn medication, was recalled by manufacturer Mylan in January 2020. Most recently, FDA suggested that manufacturers of ranitidine recall all lots and types of these medications.

[0011] NDMA has also been found in metformin, an antidiabetic agent that is taken by over 15.8 million people worldwide. On May 28, 2020 FDA recommended that five companies supplying the drug should recall their products.

[0012] Meanwhile, pharmaceutical companies, under the direction of regulatory agencies, are scram bling to figure out how NDMA ended up in such a wide range of formulations and medicinal products and to figure out how to prevent contamination in the future. Experts in the pharmaceutical field point to multiple sources, including side reactions from drug syntheses, the breakdown of unstable drug com pounds, and contamination from recycled solvents used in manufacturing. For further details, reference is made to https ://cen. acs. org/ pharmaceuticals /phar maceutical-chemicals/NDMA-contaminant-found- multiple-drugs/98/H5 https://www.fda.gov/drugs/drug-safety-and-availability/ laboratory-tests-met- formin and https ://www.lachmanconsultants. com/2020/02/the-unwelcome-guest-spares-metformin/. [0013] A. Zmylowski et al., Molecules 2020, 25, 5304, pp. 1-15 relates to NMDA contamination of pharmaceutical products comprising metformin.

[0014] WO 2012/031124 A2 relates to solid, semisolid, or liquid formulations comprising water soluble antioxidants that prevent or reduce formic acid and/or formyl species generation in the dos-age form during the manufacturing process and/or during shelf-life storage. The formulations of the present in vention prevent or reduce formation of N-formyl impurities (and gelatin crosslinking) during the man ufacturing process and/or during shelf-life storage.

[0015] US 8,414,921 B2 relates to pharmaceutical compositions comprising fixed-dose combinations of a dipeptidyl peptidase-4 inhibitor and metformin, methods of preparing such pharmaceutical compo sitions, and methods of treating Type 2 diabetes with such pharmaceutical compositions.

[0016] US2011/0021634 Al discloses a process for reducing dimethylamine content in metformin hy drochloride. The process comprises: (a) providing metformin hydrochloride having dimethylamine con tent more than 15 ppm; (b) pulverizing the metformin hydrochloride; (c) slurrying the metformin hy drochloride in one or more C1-C4 alcohol solvents; and (d) isolating the metformin hydrochloride. Ex amples 1 and 2 of US2011/0021634 Al disclose the preparation of metformin hydrochloride. The prep aration process includes various purification steps of metformin hydrochloride, which inter alia require the use of water and methanol and purging with nitrogen gas. The process further includes grinding the metformin hydrochloride in the presence of methanol, which could lead to residues of methanol in the final metformin hydrochloride. Such residues would be undesirable, particularly in a substance for phar maceutical application, due to the toxicity of methanol. The entire process results in metformin hydro chloride with a DMA content of less than 5 ppm, but is comparatively laborious. US2011/0021634 A 1 does not relate to reducing the NDMA content of pharmaceutical compositions or dosage forms com prising metformin or a physiologically acceptable salt thereof.

[0017] Thus, there is a demand for methods for determining NMDA at very low concentrations. Fur ther, there is a demand for pharmaceutical compositions that have proven to be prone to considerable contents of NMDA, but that contain NMDA at very low concentrations, if any.

[0018] It is an object of the invention to provide pharmaceutical compositions and pharmaceutical dos age forms that have improved safety, preferably because they do not contain excessive quantities of NMDA, and that can be prepared in an economic manner on industrial scale.

[0019] This object has been achieved by the subject-matter of the patent claims. [0020] It has been surprisingly found in forced-degradation experiments that metformin is most labile in alkaline and oxidative environments. During the degradation of metformin, among others, ammonia and DMA are formed, which can react by one of the possible reaction pathways to form N,N-dime- thylhydrazine. The latter can then be oxidized to NDMA. DMA can react to NDMA in alkaline envi ronment even in the simultaneous presence of nitrite ions and formaldehyde.

[0021] Further, it has been surprisingly found that regardless of the mechanism, DMA and an alkaline environment are therefore crucial for the formation of NDMA in metformin. No correlation has been found between the presence of peroxide species or nitrite ions and the NDMA content in the final prod uct.

[0022] Yet further, experimental data currently available surprisingly show that the incorporation of metformin containing less DMA as impurity results in formation of less NDMA in the final product upon storage.

[0023] Furthermore, it has been surprisingly found that the content of DMA that is already contained in the metformin starting material does not increase during the production of the final product; on the contrary, its content is even slightly decreased. Without wishing to be bound to any scientific theory, there is indication that the content of DMA can be decreased because of its gaseous nature in unproto- nated form under ambient conditions, whereas the hydrochloride salt of DMA is a solid.

[0024] Moreover, it has been surprisingly found that by heating and/or drying under reduced pressure, by grinding under simultaneous heating, and the like, DMA can be evaporated from metformin starting material and from compositions containing metformin, respectively. It has been found that grinding of metformin is possible under dry conditions, i.e. without solvent, resulting in a reduced content of DMA.

[0025] It has been surprisingly found that no laborious procedure is necessary to reduce the DMA con tent of metformin. Comparatively simple process steps such as heating and/or drying under reduced pressure, or grinding under simultaneous heating and/or reduced pressure are sufficient to reduce the DMA content of metformin, in particular below 200 ppm. In particular, it has been surprisingly found that in order to keep the NMDA content in pharmaceutical formulations below the acceptable threshold as set by regulatory authorities, it is not necessary to achieve a residual DMA content of metformin amounting to 5 ppm or below. On the contrary, it has been surprisingly found that when the residual DMA content of metformin is reduced by the comparatively simple process steps according to the in vention, the NMDA content in pharmaceutical formulations that are made from such metformin is below the acceptable threshold as set by regulatory authorities. [0026] The total number of process steps required is comparatively low and no solvents, particularly no toxic solvents, are required in such process steps. The overall procedure for reducing the DMA con tent of metformin is comparatively economic and industrially applicable.

[0027] Further, it has been surprisingly found that due to the above described instability of metformin in an alkaline environment, the formation of NDMA from metformin or DMA, respectively, can be reduced by lowering the pH value. This can be achieved in the final product e.g. by adding comparatively small amounts of organic acids such as e.g. succinic acid or ascorbic acid, or by adding comparatively small amounts in inorganic acids such as sulfamic acid (sulfaminic acid, sulfamidic acid).

[0028] Yet further, during the monitoring of NDMA in finished products containing metformin hydro chloride in combination with additional active pharmaceutical ingredients (e.g., sitagliptin, vildagliptin, linagliptin), it has been found that by the incorporation of metformin starting material with a DMA content below 200 ppm as determined by analytical method according to the invention as described herein, the final product may contain NDMA in contents of less than the permitted limit of 48 ppb.

[0029] The finished product comprising metformin or physiologically acceptable salt thereof according to the present invention, prepared by technology comprising drying and/or milling of metformin before and/or during the manufacture of the finished product and/or the addition of organic acid to the pharma ceutical composition, ensures an NDMA content below the safe limit of 48 ppb or 48 ng NDMA / 1 g metformin hydrochloride during the shelf life, as determined by the GC-MS method according to the invention as describe herein.

[0030] A first aspect of the invention relates to a pharmaceutical dosage form comprising metformin or a physiologically acceptable salt thereof and having a content of N-nitroso dimethylamine of not more than 48 ppb, relative to the total weight of metformin in the pharmaceutical dosage form.

[0031] Preferably, the invention relates to a pharmaceutical composition and pharmaceutical dosage forms of metformin hydrochloride or combinations of metformin hydrochloride with any other pharma ceutically active ingredient that provides an NDMA (N-nitroso dimethylamine) content below the per missible limit of 48 ppb.

[0032] For the purpose of the specification, a pharmaceutical dosage form is any administration unit that is suitable to administer a therapeutically effective amount of metformin or a physiologically ac ceptable salt thereof to a subject in need thereof. Preferably, the pharmaceutical dosage form is solid, preferably a capsule, tablet, sachet, or the like. [0033] Unless expressly stated otherwise, all percentages are weight percent and refer to the total weight of the pharmaceutical dosage forms. Content of DMA in metformin or pharmaceutically accepta ble salt thereof is reported with respect to the total weight of metformin active ingredient. Content of NDMA and DMA in pharmaceutical dosage forms, on the other hand, are reported with respect to the total weight of metformin in the pharmaceutical dosage forms.

[0034] Unless expressly stated otherwise, values provided in ppm and ppb are based upon weight, i.e. ppmw and ppbw, respectively. Unless expressly stated otherwise, any reference to standard test methods or pharmacopoeia refers to the version that is valid at the patent application fding date.

[0035] The pharmaceutical dosage form is typically devoted for administering a therapeutically effec tive amount of metformin (ATC A10BA02) or a physiologically acceptable salt thereof to a subject in need thereof. The dose of metformin or a physiologically acceptable salt thereof that is contained in the pharmaceutical dosage form preferably amounts to 100 mg, 200 mg, 250 mg, 500 mg, 750 mg, or 1000 mg, in each case expressed as equivalent dose relative to metformin hydrochloride.

[0036] Metformin can generally be prepared by any known process such as the processes described in US20110021634, W02016059507, IN201621016063, IN2010MUM1409 and the examples provided below.

[0037] Preferably, preparation of the pharmaceutical composition or pharmaceutical dosage form ac cording to the invention involves

(A) incorporating metformin starting material comprising less than 200 ppm of DMA, and/or

(B) drying of optionally ground metformin or a physiologically acceptable salt thereof in a fluid bed dryer before the start of the granulation phase, and/or

(C) adding a physiologically acceptable acid to the granulating liquid, to the extragranular excipients and/or to the coating composition for applying a fdm coating to the pharmaceutical dosage form.

[0038] In preferred embodiments, the pharmaceutical dosage form contains not more than 45 ppb N- nitroso dimethylamine; preferably not more than 40 ppb, more preferably not more than 35 ppb, still more preferably not more than 30 ppb, yet more preferably not more than 25 ppb, even more preferably not more than 20 ppb, most preferably not more than 15 ppb, and in particular not more than 10 ppb N- nitroso dimethylamine, in each case relative to the total weight of metformin incorporated in the phar maceutical dosage form. Preferably, the content of N-nitroso dimethylamine is determined according to the method of the invention as described herein, preferably as described in the experimental section. [0039] According to Eur. Ph., DMA (EP impurity F) is limited to 0.05 wt.-% (= 500 ppm) in metformin or a physiologically acceptable salt thereof and is controlled by a limit HPLC test.

[0040] Preferably, the pharmaceutical dosage form according to the invention has a content of dime- thylamine of not more than 200 ppm, relative to the total weight of metformin in the pharmaceutical dosage form.

[0041] Preferably, the pharmaceutical composition or pharmaceutical dosage form according to the in vention

- comprises at least metformin or a physiologically acceptable salt thereof with a DMA content (di- methylamine; EP impurity F) lower than 200 ppm, and/or

- comprises a physiologically acceptable acid, and/or

- is manufactured by a suitable technology that ensures a DMA content in the composition below 200 ppm and/or

- is manufactured by incorporation of metformin starting material comprising less than 200 ppm of DMA.

[0042] Preferably, the pharmaceutical composition or pharmaceutical dosage form according to the in vention

- comprises at least metformin or a physiologically acceptable salt thereof with a DMA content (di- methylamine; EP impurity F) lower than 100 ppm, and/or

- comprises a physiologically acceptable acid, and/or

- is manufactured by a suitable technology that ensures a DMA content in the composition below 100 ppm and/or

- is manufactured by incorporation of metformin starting material comprising less than 100 ppm of DMA.

[0043] In preferred embodiments, the pharmaceutical dosage form according to the invention contains not more than 180 ppm dimethylamine; preferably not more than 160 ppm, more preferably not more than 140 ppm, still more preferably not more than 120 ppm, yet more preferably not more than 100 ppm, even more preferably not more than 80 ppm, most preferably not more than 60 ppm, and in particular not more than 40 ppm dimethylamine, in each case relative to the total weight of metformin incorporated in the pharmaceutical dosage form. Preferably, the content of dimethylamine is determined according to the method of the invention as described herein, preferably as described in the experimental section. [0044] In preferred embodiments, the pharmaceutical dosage form according to the invention contains a physiologically acceptable acid. Preferably, the acid in pure form under ambient conditions is a solid, preferably a crystalline material.

[0045] Preferably, the acid is an organic acid or an inorganic acid.

[0046] The acid is not particularly limited and may contain other functional groups such as hydroxyl groups, amino groups, and the like.

[0047] Preferably, the acid has an acidic functional group selected from the group consisting of carbox ylic acid functional groups, vinylogous carboxylic acid functional groups, and sulfonic acid functional groups.

[0048] Preferably, the acid has a pKA value within the range of from 0.5 to 6.0. When the acid is multiprotonic, preferably at least one of the PK _A values of the acidic functional groups is within this range, preferably the PK _A value of the most acidic functional group (typically also referred to as PK _AI ).

[0049] In preferred embodiments, the acid has a pKA value within the range of 1.0±0.5, or 1 5± 1.0, or 1.5±0.5 or 2.0±1.5, or 2.0±1.0, or 2.0±0.5 or 2.5±2.0, or 2.5±1.5, or 2.5±1.0, or 2.5±0.5 or 3.0±2.5, or 3.0±2.0, or 3.0±1.5, or 3.0±1.0, or 3.0±0.5 or 3.5±2.5, or 3.5±2.0, or 3.5±1.5, or 3.5±1.0, or 3.5±0.5 or 4.0±2.0, or 4.0±1.5, or 4.0±1.0, or 4.0±0.5 or 4.5±1.5, or 4.5±1.0, or 4.5±0.5 or 5.0±1.0, or 5.0±0.5 or 5.5±0.5.

[0050] Preferably, the acid is a monoprotonic acid or a multiprotonic acid.

[0051] Preferably, the acid is selected from the group consisting of formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caprylic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, mandelic acid, ascorbic acid, methylsulfonic acid, benzene sulfonic acid, toluene sulfonic acid, and sulfamic acid; pref erably ascorbic acid, succinic acid, oxalic acid, maleic acid or sulfamic acid; more preferably succinic acid, ascorbic acid, or sulfamic acid.

[0052] In preferred embodiments, the content of the acid is within the range of from 0.01 to 30 wt.-%, relative to the total weight of the pharmaceutical dosage form; preferably 0.01 to 20 wt.-%, relative to the total weight of the pharmaceutical dosage form; more preferably 0.01 to 10 wt.-%, relative to the total weight of the pharmaceutical dosage form. [0053] In preferred embodiments, the content of the acid is within the range of 0.10±0.05 wt.-%, or 0.15±0.10 wt.-%, or 0.15±0.05 wt.-%, or 0.20±0.15 wt.-%, or 0.20±0.10 wt.-%, or 0.20±0.05 wt.-%, or

0.25±0.20 wt.-%, or 0.25±0.15 wt.-%, or 0.25±0.10 wt.-%, or 0.25±0.05 wt.-%, or 0.30±0.25 wt.-%, or

0.30±0.20 wt.-%, or 0.30±0.15 wt.-%, or 0.30±0.10 wt.-%, or 0.30±0.05 wt.-%, or 0.35±0.30 wt.-%, or

0.35±0.25 wt.-%, or 0.35±0.20 wt.-%, or 0.35±0.15 wt.-%, or 0.35±0.10 wt.-%, or 0.35±0.05 wt.-%, or

0.40±0.35 wt.-%, or 0.40±0.30 wt.-%, or 0.40±0.25 wt.-%, or 0.40±0.20 wt.-%, or 0.40±0.15 wt.-%, or

0.40±0.10 wt.-%, or 0.40±0.05 wt.-%, or 0.45±0.40 wt.-%, or 0.45±0.35 wt.-%, or 0.45±0.30 wt.-%, or

0.45±0.25 wt.-%, or 0.45±0.20 wt.-%, or 0.45±0.15 wt.-%, or 0.45±0.10 wt.-%, or 0.45±0.05 wt.-%, or

0.50±0.45 wt.-%, or 0.50±0.40 wt.-%, or 0.50±0.35 wt.-%, or 0.50±0.30 wt.-%, or 0.50±0.25 wt.-%, or

0.50±0.20 wt.-%, or 0.50±0.15 wt.-%, or 0.50±0.10 wt.-%, or 0.50±0.05 wt.-%, in each case relative to the total weight of the pharmaceutical dosage form.

[0054] Preferably, the pharmaceutical dosage form is prepared by granulation and comprises an intra- granular phase as well as an extragranular phase. In a preferred embodiment, the acid, more preferably essentially the total amount of the acid, is contained in the intragranular phase, preferably together with the metformin or the physiologically acceptable salt thereof, preferably in a homogenous intimate mix ture. In another preferred embodiment, the acid, more preferably essentially the total amount of the acid, is contained in the extragranular phase, whereas the metformin or the physiologically acceptable salt thereof is contained in the intragranular phase. In still another preferred embodiment, the pharmaceutical dosage form comprises a fdm coating and the acid, more preferably essentially the total amount of the acid, is contained in the fdm coating, whereas the metformin or the physiologically acceptable salt thereof is contained in the core that is encapsulated by the fdm coating, preferably in the intragranular phase of said core.

[0055] In a preferred embodiments metformin starting material for incorporation into a pharmaceutical dosage form comprising metformin or a physiologically acceptable salt thereof, wherein the content of metformin or the physiologically acceptable salt thereof is at least 99.0 wt.-%, relative to the total weight of the metformin starting material; and wherein the metformin starting material has a content of dime- thylamine of not more than 180 ppm dimethylamine; preferably not more than 160 ppm, more preferably not more than 140 ppm, still more preferably not more than 120 ppm, yet more preferably not more than 100 ppm, even more preferably not more than 80 ppm, most preferably not more than 60 ppm, and in particular not more than 40 ppm dimethylamine, in each case relative to the total weight of the metformin starting material.

[0056] In preferred embodiments the metformin starting material for incorporation into a pharmaceuti cal dosage form comprising metformin or physiologically acceptable salt thereof is present as a powder having a median diameter D(50), determined by laser diffraction analysis, of not more than 200 mih; preferably not more than 100 pm;.

[0057] Preferably, metformin or the physiologically acceptable salt thereof as contained in the pharma ceutical dosage form or in metformin starting material is a solid, crystalline or amorphous material. It may comprise any polymorph, solvate, cocrystal, and the like of metformin or the physiologically ac ceptable salt thereof.

[0058] Preferably, the physiologically acceptable salt of metformin is the hydrochloride.

[0059] Preferably, the content of metformin or the physiologically acceptable salt thereof is within the range of from 60 to 90 wt.-%, relative to the total weight of the pharmaceutical dosage form and the weight of metformin or the physiologically acceptable salt thereof.

[0060] In preferred embodiments, the content of metformin or the physiologically acceptable salt thereof is within the range of 65±5 wt.-%, or 70±10 wt.-%, or 70±5 wt.-%, or 75±15 wt.-%, or 75±10 wt.-%, or 75±5 wt.-%, or 80±15 wt.-%, or 80±10 wt.-%, or 80±5 wt.-%, or 85±10 wt.-%, or 85±5 wt.- %, in each case relative to the total weight of the pharmaceutical dosage form and the weight of metfor min or the physiologically acceptable salt thereof.

[0061] In preferred embodiments, the pharmaceutical dosage form according to the invention contains one or more binders/diluents.

[0062] Preferably, the one or more binders/diluents independently of one another are selected from the group consisting of sucrose, lactose, starch, cellulose, cellulose ethers (preferably selected from hydrox- yethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose), sugar alcohols (prefera bly selected from xylitol, sorbitol, and mannitol), gelatin, polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymers and polyethylene glycol.

[0063] Preferably, the total content of the one or more binders/diluents is within the range of 1.0 to 30 wt.-%, relative to the total weight of the pharmaceutical dosage form.

[0064] In preferred embodiments, the pharmaceutical dosage form according to the invention contains one or more lubricants.

[0065] Preferably, the one or more lubricants independently of one another are selected from the group consisting of sodium stearyl fumarate, magnesium stearate, calcium stearate, and talk. [0066] Preferably, the total content of the one or more lubricants is within the range of 0.1 to 5.0 wt- %, relative to the total weight of the pharmaceutical dosage form.

[0067] In preferred embodiments, the pharmaceutical dosage form according to the invention contains an additional active pharmaceutical ingredient other than metformin or the physiologically acceptable salt thereof.

[0068] Preferably, the additional active pharmaceutical ingredient is an antidiabetic agent.

[0069] Preferably, the additional active pharmaceutical ingredient is selected from the group consisting of thiazolidinediones, such as pioglitazone or rosiglitazone; sulfonylureas, such as gliclazide, glimepiride or gluburide; meglitinides, such as repaglinide or nataglinide; dipeptidyl peptidase-4 (DPP- 4) inhibitors, such as sitagliptin, vildagliptin, linagliptin or saxagliptin; SGLT-2 inhibitors, such as dapagliflozin, canagliflozin, empagliflozin, and the physiologically acceptable salts of any of the fore going.

[0070] Preferably, the additional active pharmaceutical ingredient is selected from the group consisting sitagliptin, vildagliptin, linagliptin, dapagliflozin, canagliflozin and empagliflozin, and the physiologi cally acceptable salts of any of the foregoing.

[0071] Preferably, the content of the additional active pharmaceutical ingredient is within the range of from 0.5 to 15 wt.-%, relative to the total weight of the pharmaceutical dosage form.

[0072] Preferably, the pharmaceutical dosage form according to the invention is a tablet.

[0073] Preferably, the pharmaceutical dosage form according to the invention is film coated. Suitable materials for film coating are known to the skilled person. Preferably, the material for film coating is selected from water soluble polymers such as polyvinylalcohol, hydroxypropylmethylcellulose, and the like. Preferably, the material for film coating is not an enteric coating material.

[0074] In a preferred embodiment, the pharmaceutical dosage form according to the invention has been prepared by direct compression.

[0075] Preferably, the pharmaceutical dosage form according to the invention has been prepared by granulation. [0076] In a preferred embodiment, the pharmaceutical dosage form according to the invention has been prepared by dry granulation.

[0077] In another preferred embodiment, the pharmaceutical dosage form according to the invention has been prepared by wet granulation.

[0078] Another aspect of the invention relates to a process for the preparation of a pharmaceutical dosage form according to the invention as described above, the process comprising the steps of:

(i) providing metformin or a physiologically acceptable salt thereof;

(ii) optionally, grinding the metformin or physiologically acceptable salt thereof thereby obtaining ground metformin or physiologically acceptable salt thereof;

(iii) optionally, subjecting the metformin or physiologically acceptable salt thereof, or the ground met formin or physiologically acceptable salt thereof, to elevated temperature and/or reduced pressure thereby obtaining dried metformin or physiologically acceptable salt thereof;

(iv) mixing the metformin or physiologically acceptable salt thereof, or the ground metformin or phys iologically acceptable salt thereof, or the dried metformin or physiologically acceptable salt thereof, with one or more excipients, and optionally with one or more additional active pharma ceutical ingredients, thereby obtaining a first mixture;

(v) optionally, granulating the first mixture thereby obtaining a granulate;

(vi) optionally, drying the granulate thereby obtaining a dried granulate;

(vii) optionally, mixing the granulate or the dried granulate with one or more excipients, and optionally with one or more additional active pharmaceutical ingredients, thereby obtaining a second mix ture;

(viii) compressing the first mixture, the granulate, the dried granulate, or the second mixture thereby obtaining a compressed core;

(ix) optionally, film coating the compressed core by applying a liquid coating composition which op tionally comprises one or more additional active pharmaceutical ingredients

[0079] The manufacture of a pharmaceutical dosage form according to the invention preferably com prises drying and/or grinding metformin or a physiologically acceptable salt thereof, wet granulation, tableting and tablet coating (film coating).

[0080] Steps (ii), (iii), (v), (vi), (vii) and (ix) of the process according to the invention are optional. [0081] In preferred embodiments, the process according to the invention comprises steps (i), (iv), and (viii); or (i), (ii), (iv), and (viii); or (i), (iii), (iv), and (viii); or (i), (iv), (v) and (viii); or (i), (iv), (vii) and (viii); or (i), (iv), (viii) and (ix); or (i), (ii), (iii), (iv), and (viii); or (i), (ii), (iv), (v) and (viii); or (i), (ii), (iv), (vii) and (viii); or (i), (ii), (iv), (viii), and (ix); or (i), (ii), (iii), (iv), and (viii); or (i), (iii), (iv), (v), and (viii); or (i), (iii), (iv), (vii) and (viii); or (i), (iii), (iv), (viii), and (ix); or (i), (ii), (iv), (v) and (viii); or (i), (iii), (iv), (v) and (viii); or (i), (iv), (v), (vii) and (viii); or (i), (iv), (v), (viii) and (ix); or (i), (ii), (iv), (viii) and (ix); or (i), (iii), (iv), (viii) and (ix); or (i), (iv), (v), (viii) and (ix); or (i), (iv), (vii), (viii) and (ix); or (i), (ii), (iii), (iv), (v), (vi), (vii), (viii), and (ix).

[0082] Steps (i) to (ix) of the process according to the invention may be performed simultaneously or consecutively, continuously or batchwise. Preferably, steps (i) to (ix) are performed in numerical order, whereas it is contemplated that consecutive steps may by performed simultaneously or partially simul taneously.

[0083] Step (i) of the process according to the invention involves providing metformin or a physiolog ically acceptable salt thereof. Step (i) contemplates chemical synthesis of metformin or a physiologically acceptable salt thereof from suitable starting materials. Alternatively, a commercially available metfor min or a physiologically acceptable salt thereof may be provided in step (i). Preferably metformin com prising less than 200 ppm of DMA is provided.

[0084] Optional step (ii) of the process according to the invention involves grinding the metformin or physiologically acceptable salt thereof thereby obtaining ground metformin or physiologically accepta ble salt thereof. Preferably, step (ii) is performed under standard conditions known to the skilled person by means of technical equipment that is known to the skilled person as well and that is commercially available.

[0085] In preferred embodiments, the ground metformin or physiologically acceptable salt thereof ob tained in step (ii) has a median diameter D(50), determined by laser diffraction analysis, of not more than 200 pm; preferably not more than 100 pm.

[0086] Optional step (iii) of the process according to the invention involves subjecting the metformin or physiologically acceptable salt thereof, or the ground metformin or physiologically acceptable salt thereof, to elevated temperature and/or reduced pressure thereby obtaining dried metformin or physio logically acceptable salt thereof. Preferably, step (iii) is performed under standard conditions known to the skilled person by means of technical equipment that is known to the skilled person as well and that is commercially available. [0087] Preferably, step (iii) is performed for at least 10 minutes; preferably for at least 20 minutes.

[0088] Preferably, step (iii) is performed in a fluid bed dryer or drying chamber.

[0089] Preferably, step (iii) is performed at an elevated temperature of at least 40°C, preferably of at least 50°C, more preferably of at least 70°C.

[0090] Step (iv) of the process according to the invention involves mixing the metformin or physiolog ically acceptable salt thereof, or the ground metformin or physiologically acceptable salt thereof, or the dried metformin or physiologically acceptable salt thereof, with one or more excipients, and optionally with one or more additional active pharmaceutical ingredients, thereby obtaining a first mixture. Pref erably, step (iv) is performed under standard conditions known to the skilled person by means of tech nical equipment that is known to the skilled person as well and that is commercially available.

[0091] Preferably, the one or more excipients that are employed in step (iv) are selected from binders, fillers, diluents, disintegrants and the like, preferably binders/diluents as defined above. When the first mixture obtained in step (iv) is subsequently granulated, the one or more excipients form the intragran- ular phase of the pharmaceutical dosage form together with the metformin or physiologically acceptable salt thereof and optionally together with the additional active pharmaceutical ingredient.

[0092] Optional step (v) of the process according to the invention involves granulating the first mixture thereby obtaining a granulate. Preferably, step (v) is performed under standard conditions known to the skilled person by means of technical equipment that is known to the skilled person as well and that is commercially available.

[0093] Preferably, step (v) is performed as wet granulation by granulating the first mixture with a gran ulation fluid, optionally containing one or more excipients, and optionally containing one or more addi tional active pharmaceutical ingredients. Suitable granulation fluids involve water, acetone and alcohols, preferably ethanol, or any mixture thereof.

[0094] Optional step (vi) of the process according to the invention involves drying the granulate thereby obtaining a dried granulate. Preferably, step (vi) is performed under standard conditions known to the skilled person by means of technical equipment that is known to the skilled person as well and that is commercially available.

[0095] Optional step (vii) of the process according to the invention involves (vii) mixing the granulate or the dried granulate with one or more excipients, and optionally with one or more additional active pharmaceutical ingredients, thereby obtaining a second mixture. Preferably, step (vii) is performed un der standard conditions known to the skilled person by means of technical equipment that is known to the skilled person as well and that is commercially available. The one or more excipients, and optionally the one or more additional active pharmaceutical ingredients, form the extragranular phase of the phar maceutical dosage form.

[0096] Preferably, the one or more excipients that are employed in step (vii) are selected from binders, fdlers, diluents, disintegrants and the like, preferably lubricants as defined above. The excipients em ployed can have more functions simultaneously, e.g. microcrystalline cellulose can act as a diluent, binder or disintegrant.

[0097] Step (viii) of the process according to the invention involves compressing the first mixture, the granulate, the dried granulate, or the second mixture thereby obtaining a compressed core. Preferably, step (viii) is performed under standard conditions known to the skilled person by means of technical equipment that is known to the skilled person as well and that is commercially available.

[0098] Optional step (ix) of the process according to the invention involves film coating the compressed core by applying a liquid coating composition. Preferably, step (ix) is performed under standard condi tions known to the skilled person by means of technical equipment that is known to the skilled person as well and that is commercially available.

[0099] The liquid coating composition employed in step (ix) preferably comprises a coating material selected from water soluble polymers such as polyvinylalcohol, hydroxypropylmethylcellulose, and the like. Preferably, the coating material is not an enteric coating material. Optionally the liquid coating compositions comprises at least one other active ingredient.

[0100] In preferred embodiments of the process according to the invention, an acid as defined above is

(a) among the one or more excipients employed in step (iv);

(b) among the one or more excipients employed in step (vii);

(c) contained in the liquid coating composition applied in step (ix); and/or

(d) among the one or more excipients that are contained in the granulation fluid.

[0101] Another aspect of the invention relates to a pharmaceutical dosage form obtainable by the pro cess according to the invention as described above.

[0102] Another aspect of the invention relates to a pharmaceutical dosage form according to the inven tion as described above for use in the treatment of diabetes. Another aspect of the invention relates to the use of metformin or a physiologically acceptable salt thereof for the manufacture of a pharmaceutical dosage form according to the invention as described above for treatment of diabetes. Another aspect of the invention relates to a method for treating diabetes comprising administering a pharmaceutical dosage form according to the invention as described to a subject in need thereof. Preferably, the diabetes is type 2 diabetes mellitus (T2DM).

[0103] Preferably, the pharmaceutical dosage form according to the invention is for oral administration; preferably once daily, twice daily or thrice daily.

[0104] Another aspect of the invention relates to a process for the preparation of a metformin starting material according to the invention as described above, the process comprising the steps of:

(i) providing metformin or a physiologically acceptable salt thereof;

(ii) grinding the metformin or physiologically acceptable salt thereof thereby obtaining ground met formin or physiologically acceptable salt thereof; and

(iii) subjecting the metformin or physiologically acceptable salt thereof, or the ground metformin or physiologically acceptable salt thereof, to elevated temperature and/or reduced pressure thereby obtaining dried metformin or physiologically acceptable salt thereof.

[0105] Preferably, step (iii) is performed for at least 10 minutes; preferably for at least 20 minutes.

[0106] Preferably step (iii) is performed in a fluid bed dryer or drying chamber.

[0107] Preferably, step (iii) is performed at an elevated temperature of at least 40°C, preferably of at least 50°C.

[0108] Another aspect of the invention relates to a metformin starting material that is obtainable by the process according to the invention as described above.

[0109] A GC-MS method for determining the content of NDMA as well as a LC-MS methods for de termining the content of DMA were developed. Another aspect of the invention relates to these methods. To monitor the correlation between the DMA content of starting metformin or physiologically accepta ble salt thereof and the NDMA content of the final product containing metformin or physiologically acceptable salt thereof, the following methods were developed (DL = detection limit, QL = quantifica tion limit):

(1) GC-MS method for may be used for the determination of NDMA content in - metformin or physiologically acceptable salt thereof (DL 10 ppb, QL 30 ppb, linear range of 30 ppb

- 100 ppb);

- the pharmaceutical dosage form comprising metformin or physiologically acceptable salt thereof (DL 10 ppb, QL 30 ppb, linear range of 30 ppb - 72 ppb);

- the pharmaceutical dosage form comprising vildagliptin or physiologically acceptable salt thereof and metformin or physiologically acceptable salt thereof (DL 10 ppb, QL 30 ppb, linear range of 30 ppb - 72 ppb);

- the pharmaceutical dosage form comprising sitagliptin or physiologically acceptable salt thereof and metformin or physiologically acceptable salt thereof (DL 10 ppb, QL 30 ppb, linear range of 30 ppb

- 72 ppb);

- the pharmaceutical dosage form comprising linagliptin or physiologically acceptable salt thereof and metformin or physiologically acceptable salt thereof (DL 10 ppb, QL 30 ppb, linear range of 30 ppb

- 72 ppb);

(2) LC-MS method for the determination of NDMA content in

- metformin or physiologically acceptable salt thereof (DL 10 ppb, QL 30 ppb, linear range 30 ppb to 300 ppb);

- the pharmaceutical dosage form comprising sitagliptin or physiologically acceptable salt thereof and metformin or physiologically acceptable salt thereof (DL 10 ppb, QL 30 ppb, linear range 30 ppb to 300 ppb);

- the pharmaceutical dosage form comprising vildagliptin or physiologically acceptable salt thereof and metformin or physiologically acceptable salt thereof (DL 10 ppb, QL 30 ppb, linear range 30 ppb to 300 ppb) in each case for the purpose of verifying the results obtained by the GC-MS method.

(3) LC-MS method for determination of DMA content in

- the pharmaceutical dosage form comprising metformin or physiologically acceptable salt thereof (DL 0.6 ppm, QL 2.1 ppm, linear range 5 ppm to 100 ppm);

- the pharmaceutical dosage form comprising sitagliptin or physiologically acceptable salt thereof / metformin or physiologically acceptable salt thereof (DL 0.6 ppm, QL 2.1 ppm, linear range 5 ppm to 100 ppm);

- the pharmaceutical dosage form comprising vildagliptin or physiologically acceptable salt thereof / metformin or physiologically acceptable salt thereof (DL 0.6 ppm, QL 2.1 ppm, linear range 5 ppm to 100 ppm).

[0110] A GC-MS method for determining the content of NDMA as well as a LC-MS methods for de termining the content of DMA according to the present invention can be used for analysis of any phar maceutical dosage form comprising metformin and in any metformin or pharmaceutically acceptable salt thereof. The GC-MS method according to the invention provides for detection limit of 10 ppb and quantification limit of 30 ppb of NDMA relative to the total weight of metformin in the pharmaceutical dosage form. The LC-MS method according to the invention provides for detection limit of 0.6 ppm and quantification limit of 2.1 ppm of DMA relative to the weight of metformin.

[0111] The details of these methods are further described in the experimental section.

[0112] Preferred embodiments of the invention are summarized as clauses 1 to 47 hereinafter:

1. A pharmaceutical dosage form comprising metformin or a physiologically acceptable salt thereof and having a content of N-nitroso dimethylamine of not more than 48 ppb, relative to the total weight of metformin in the pharmaceutical dosage form.

2. The pharmaceutical dosage form according to clause 1, which contains not more than 45 ppb N- nitroso dimethylamine; preferably not more than 40 ppb, more preferably not more than 35 ppb, still more preferably not more than 30 ppb, yet more preferably not more than 25 ppb, even more preferably not more than 20 ppb, most preferably not more than 15 ppb, and in particular not more than 10 ppb N-nitroso dimethylamine, in each case relative to the total weight of metformin in the pharmaceutical dosage form.

3. The pharmaceutical dosage form according to clause 1, which has a content of dimethylamine of not more than 200 ppm, relative to the total weight of metformin in the pharmaceutical dosage form.

4. The pharmaceutical dosage form according to clause 3, which contains not more than 180 ppm dimethylamine; preferably not more than 160 ppm, more preferably not more than 140 ppm, still more preferably not more than 120 ppm, yet more preferably not more than 100 ppm, even more preferably not more than 80 ppm, most preferably not more than 60 ppm, and in particular not more than 40 ppm dimethylamine, in each case relative to the total weight of metformin in the pharmaceutical dosage form.

5. The pharmaceutical dosage form according to any of the preceding clauses, which contains a physiologically acceptable acid.

6. The pharmaceutical dosage form according to clause 5, wherein the acid is an organic acid or an inorganic acid.

7. The pharmaceutical dosage form according to any of clauses 5 or 6, wherein the acid has an acidic functional group selected from the group consisting of carboxylic acid functional groups, vinylo- gous carboxylic acid functional groups, and sulfonic acid functional groups.

8. The pharmaceutical dosage form according to any of clauses 5 to 7, wherein the acid has a pKA value within the range of from 0.5 to 6.0.

9. The pharmaceutical dosage form according to clause 8, wherein the acid has a pKA value within the range of 1.0±0.5, or 1.5±1.0, or 1.5±0.5 or 2.0±1.5, or 2.0±1.0, or 2.0±0.5 or 2.5±2.0, or 2.5±1.5, or 2.5±1.0, or 2.5±0.5 or 3.0±2.5, or 3.0±2.0, or 3.0±1.5, or 3.0±1.0, or 3.0±0.5 or 3.5±2.5, or 3.5±2.0, or 3.5±1.5, or 3.5±1.0, or 3.5±0.5 or 4.0±2.0, or 4.0±1.5, or 4.0±1.0, or 4.0±0.5 or 4.5±1.5, or 4.5±1.0, or 4.5±0.5 or 5.0±1.0, or 5.0±0.5 or 5.5±0.5. The pharmaceutical dosage form according to any of clauses 5 to 9, wherein the acid is a mono protonic acid or a multiprotonic acid. The pharmaceutical dosage form according to any of clauses 5 to 10, wherein the acid is selected from the group consisting of formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caprylic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, maleic acid, fu- maric acid, malic acid, tartaric acid, citric acid, benzoic acid, mandelic acid, ascorbic acid, me- thylsulfonic acid, benzene sulfonic acid, toluene sulfonic acid, and sulfamic acid; preferably pref erably ascorbic acid, succinic acid, oxalic acid, maleic acid or sulfamic acid; more preferably succinic acid, ascorbic acid, or sulfamic acid. The pharmaceutical dosage form according to any of clauses 5 to 11, wherein the content of the acid is within the range of from 0.01 to 30 wt.-%, relative to the total weight of the pharmaceutical dosage form; preferably 0.01 to 20 wt.-%, relative to the total weight of the pharmaceutical dosage form; more preferably 0.01 to 10 wt.-%, relative to the total weight of the pharmaceutical dosage form. The pharmaceutical dosage form according to clause 12, wherein the content of the acid is within the range of 0.10±0.05 wt.-%, or 0.15±0.10 wt.-%, or 0.15±0.05 wt.-%, or 0.20±0.15 wt.-%, or 0.20±0.10 wt.-%, or 0.20±0.05 wt.-%, or 0.25±0.20 wt.-%, or 0.25±0.15 wt.-%, or 0.25±0.10 wt- %, or 0.25±0.05 wt.-%, or 0.30±0.25 wt.-%, or 0.30±0.20 wt.-%, or 0.30±0.15 wt.-%, or 0.30±0.10 wt.-%, or 0.30±0.05 wt.-%, or 0.35±0.30 wt.-%, or 0.35±0.25 wt.-%, or 0.35±0.20 wt- %, or 0.35±0.15 wt.-%, or 0.35±0.10 wt.-%, or 0.35±0.05 wt.-%, or 0.40±0.35 wt.-%, or 0.40±0.30 wt.-%, or 0.40±0.25 wt.-%, or 0.40±0.20 wt.-%, or 0.40±0.15 wt.-%, or 0.40±0.10 wt- %, or 0.40±0.05 wt.-%, or 0.45±0.40 wt.-%, or 0.45±0.35 wt.-%, or 0.45±0.30 wt.-%, or 0.45±0.25 wt.-%, or 0.45±0.20 wt.-%, or 0.45±0.15 wt.-%, or 0.45±0.10 wt.-%, or 0.45±0.05 wt- %, or 0.50±0.45 wt.-%, or 0.50±0.40 wt.-%, or 0.50±0.35 wt.-%, or 0.50±0.30 wt.-%, or 0.50±0.25 wt.-%, or 0.50±0.20 wt.-%, or 0.50±0.15 wt.-%, or 0.50±0.10 wt.-%, or 0.50±0.05 wt- %, in each case relative to the total weight of the pharmaceutical dosage form. The pharmaceutical dosage form according to any of the preceding clauses, wherein the physio logically acceptable salt of metformin is the hydrochloride. The pharmaceutical dosage form according to any of the preceding clauses, wherein the content of metformin or the physiologically acceptable salt thereof is within the range of from 60 to 90 wt.-%, relative to the total weight of the pharmaceutical dosage form and the weight of metformin or the physiologically acceptable salt thereof. The pharmaceutical dosage form according to clause 15, wherein the content of metformin or the physiologically acceptable salt thereof is within the range of 65±5 wt.-%, or 70±10 wt.-%, or 70±5 wt.-%, or 75±15 wt.-%, or 75±10 wt.-%, or 75±5 wt.-%, or 80±15 wt.-%, or 80±10 wt.-%, or 80±5 wt.-%, or 85±10 wt.-%, or 85±5 wt.-%, in each case relative to the total weight of the pharmaceutical dosage form and the weight of metformin or the physiologically acceptable salt thereof. The pharmaceutical dosage form according to any of the preceding clauses, which contains one or more binders/diluents. The pharmaceutical dosage form according to clause 17, wherein the one or more binders/diluents independently of one another are selected from the group consisting of sucrose, lactose, starch, cellulose, cellulose ethers (preferably selected from hydroxyethylcellulose, hydroxy-propylcellu- lose, and hydroxypropylmethylcellulose), sugar alcohols (preferably selected from xylitol, sorbi tol, and mannitol), gelatin, polyvinylpyrrolidone, and polyethylene glycol. The pharmaceutical dosage form according to clause 17 or 18, wherein the total content of the one or more binders/diluents is within the range of 1.0 to 30 wt.-%, relative to the total weight of the pharmaceutical dosage form. The pharmaceutical dosage form according to any of the preceding clauses, which contains one or more lubricants. The pharmaceutical dosage form according to clause 20, wherein the one or more lubricants in dependently of one another are selected from the group consisting of sodium stearyl fumarate, magnesium stearate, calcium stearate, and talk. The pharmaceutical dosage form according to clause 20 or 21, wherein the total content of the one or more lubricants is within the range of 0.1 to 5.0 wt.-%, relative to the total weight of the pharmaceutical dosage form. The pharmaceutical dosage form according to any of the preceding clauses, which contains an additional active pharmaceutical ingredient other than metformin or the physiologically accepta ble salt thereof. The pharmaceutical dosage form according to clause 23, wherein the additional active pharma ceutical ingredient is an antidiabetic agent. The pharmaceutical dosage form according to clause 23 or 24, wherein the additional active phar maceutical ingredient is selected from the group consisting of sitagliptin, vildagliptin, linagliptin, dapagliflozin, canagliflozin, empagliflozin and the physiologically acceptable salts of any of the foregoing. The pharmaceutical dosage form according to any of clauses 23 to 25, wherein the content of the additional active pharmaceutical ingredient is within the range of from 0.5 to 15 wt.-%, relative to the total weight of the pharmaceutical dosage form. The pharmaceutical dosage form according to any of the preceding clauses, which is for oral administration. The pharmaceutical dosage form according to any of the preceding clauses, which is a tablet. The pharmaceutical dosage form according to any of the preceding clauses, which is film coated. The pharmaceutical dosage form according to any of the preceding clauses, which has been pre pared by direct compression. The pharmaceutical dosage form according to any of the preceding clauses, which has been pre pared by granulation. The pharmaceutical dosage form according to clause 31, which has been prepared by dry granu lation. The pharmaceutical dosage form according to clause 31, which has been prepared by wet granu lation. A process for the preparation of a pharmaceutical dosage form according to any of the preceding clauses, comprising the steps of:

(i) providing metformin or a physiologically acceptable salt thereof;

(ii) optionally, grinding the metformin or physiologically acceptable salt thereof thereby ob taining ground metformin or physiologically acceptable salt thereof;

(iii) optionally, subjecting the metformin or physiologically acceptable salt thereof, or the ground metformin or physiologically acceptable salt thereof, to elevated temperature and/or reduced pressure thereby obtaining dried metformin or physiologically acceptable salt thereof;

(iv) mixing the metformin or physiologically acceptable salt thereof, or the ground metformin or physiologically acceptable salt thereof, or the dried metformin or physiologically ac ceptable salt thereof, with one or more excipients, and optionally with one or more addi tional active pharmaceutical ingredients, thereby obtaining a first mixture;

(v) optionally, granulating the first mixture thereby obtaining a granulate;

(vi) optionally, drying the granulate thereby obtaining a dried granulate;

(vii) optionally, mixing the granulate or the dried granulate with one or more excipients, and optionally with one or more additional active pharmaceutical ingredients, thereby obtaining a second mixture;

(viii) compressing the first mixture, the granulate, the dried granulate, or the second mixture thereby obtaining a compressed core; and

(ix) optionally, film coating the compressed core by applying a liquid coating composition. The process according to clause 34, wherein step (v) is performed as wet granulation by granu lating the first mixture with a granulation fluid, optionally containing one or more excipients, and optionally containing one or more additional active pharmaceutical ingredients. The process according to clause 34 or 35, wherein an acid as defined in any of clauses 5 to 13 is (a) among the one or more excipients employed in step (iv);

(b) among the one or more excipients employed in step (vii);

(c) contained in the liquid coating composition applied in step (ix); and/or

(d) among the one or more excipients that are contained in the granulation fluid. The process according to any of clauses 34 to 36, wherein the ground metformin or physiologi cally acceptable salt thereof obtained in step (ii) has a median diameter Dw50, determined by sieve analysis in accordance with Ph. Eur., of not more than 200 pm; preferably not more than 100 pm; more preferably not more than 40 pm. The process according to any of clauses 34 to 37, wherein step (iii) is performed for 0.1 to 2 hours; preferably 0.5 to 1 hour. The process according to any of clauses 34 to 38, wherein step (iii) is performed in a fluid bed dryer or drying chamber. The process according to any of clauses 34 to 39, wherein step (iii) is performed at an elevated temperature of at least 40°C, preferably of at least 50°C, more preferably of at least 70°C. A pharmaceutical dosage form obtainable by the process according to any of clauses 34 to 40. A metformin starting material for incorporation into a pharmaceutical dosage form comprising metformin or a physiologically acceptable salt thereof, wherein the content of metformin or the physiologically acceptable salt thereof is at least 99.0 wt.-%, relative to the total weight of the metformin starting material wherein the material has a content of dimethylamine of not more than 180 ppm dimethylamine; preferably not more than 160 ppm, more preferably not more than 140 ppm, still more preferably not more than 120 ppm, yet more preferably not more than 100 ppm, even more preferably not more than 80 ppm, most preferably not more than 60 ppm, and in particular not more than 40 ppm dimethylamine, in each case relative to the weight of metformin. A metformin starting material for incorporation into a pharmaceutical dosage form according to clause 42, wherein the metformin or a physiologically acceptable salt thereof is present as a pow der having a median diameter D(50), determined laser diffraction analysis, of not more than 200 pm; preferably not more than 100 pm. A process for the preparation of a metformin starting material for incorporation into a pharma ceutical dosage form according to clause 42 or 43, comprising the steps of:

(i) providing metformin or a physiologically acceptable salt thereof;

(ii) grinding the metformin or physiologically acceptable salt thereof thereby obtaining ground metformin or physiologically acceptable salt thereof; and

(iii) subjecting the metformin or physiologically acceptable salt thereof, or the ground metformin or physiologically acceptable salt thereof, to elevated temperature and/or reduced pressure thereby obtaining dried metformin or physiologically acceptable salt thereof. 45. The process according to clause 44, wherein step (ii) is performed under dry conditions.

46. The process according to clause 44 or 45, wherein step (iii) is performed for at least 10 minutes; preferably for at least 20 minutes.

47. The process according to any of clauses 44 to 46, wherein step (iii) is performed in a fluid bed dryer or drying chamber.

48. The process according to any of clauses 44 to 47, wherein step (iii) is performed at an elevated temperature of at least 40°C, preferably of at least 50°C.

[0113] The following examples further illustrate the invention but are not to be construe as limiting its scope:

The method for determining the particle size distribution - laser diffraction analysis

[0114] The term median diameter refers to the volume median diameter of the particle size distribution. The term average particle size refers to the volume average or volume mean diameter of the particle size distribution. The median particle size and average particle size can be determined by laser light scatter ing using e.g. Malvern Mastersizer equipped with »wet« dispersion unit. Particle sizes are determined by measuring the angular distribution of laser light scattered by a homogeneous suspension of particles. The particles to be subjected to the particle size measurement are first suspended in appropriate non polar dispersant such as acetone and then subjected to a size determination in a Malvern Mastersizer instrument. Usually, 100-800 mg of substance is dispersed in 5-10 mL of dispersant. Values D(10), D(50) and D(90) indicate that 10%, 50% and 90% of the particles, respectively, are smaller than the specified values. For further details of the determination method according to the invention, reference is made to Ph. Eur. 10.4, 2.9.31 " Particle size analysis by laser light diffraction" .

General GC-MS method for determining the content of NDMA:

[0115] The content of NDMA in tablets was analyzed using the following GC-MS method:

[0116] The sample was suspended in a water based solvent to ensure total metformin solubility. Typi cally, an amount of sample, corresponding to about 400 mg of metformin was suspended in 8.0 mL of 1M NaOH. After mixing and centrifugation, clear supernatant was extracted with 0.5 mL organic sol vent. The organic solvent for the determination of NDMA in metformin, sitagliptin/metformin and linagliptin/metformin pharmaceutical dosage forms is chloroform. The organic solvent for the determi nation of NDMA in vildagliptin/metformin tablets is dichloromethane.

[0117] Chromatographic conditions :

[0118] The above method has shown appropriate sensitivity for the detection and quantification of NDMA in various metformin film coated tablets. In comparison with other similar GC-MS methods (e.g. LGL method, CVUA Karlsruhe method, Singapore HSA method) this method is simple, straight forward and fully validated. A single quadrupole MS detector as an available and widespread detection mode is employed. Quantification can be performed by means of a calibration curve that was previously measured with samples of known content of NDMA.

General LC-MS method for determining the content of DMA:

[0119] The content of DMA in API and tablets (sitagliptin/metformin or vildagliptin/metformin) was analyzed using the following LC-MS method:

[0120] Preparation of a sample: Accurately measure 50 mg of metformin and dilute with a solvent (acetonitrile : water =1 : 1) to volume and mix well.

[0121] Preparation of mobile Phase A: Add 1 mL of formic acid in to 1000 mL of milli-q-water. Filter through 0.45 pm membrane filter and degas it.

[0122] Preparation of mobile Phase B: Add 1 mL of formic acid in to 1000 mL of methanol. Filter through 0.45 pm membrane fdter and degas it.

[0123] Chromatographic conditions:

[0124] Quantification can be performed by means of a calibration curve that was previously measured with samples of known content of DMA.

[0125] Above method is more sensitive and does not require derivatization of DMA as HPLC method in the monography of metformin hydrochloride (Ph. Eur. 10.3). The method is specific and allows quan titation in the range from 5 to 100 ppm.

General process of drying of metformin:

[0126] Metformin hydrochloride is sieved on sieve size 0.6 - 2.0 mm or is ground by the process de scribed below. Metformin hydrochloride or a mixture of metformin hydrochloride and mannitol is dried in a fluid bed dryer or drying chamber for at least 10 minutes, preferably for at least 20 minutes at a temperature of at least 40 °C, preferably at least 50°C.

General process of grinding of metformin:

[0127] Metformin hydrochloride, optionally after drying as described above, is ground when passing through a mechanical mill at the prescribed speed [rpm] using the prescribed type of mesh [mm] . Grind ing is performed in stages in a stream of nitrogen. If the product does not meet the particle size require ment after the first stage of grinding, the grinding is repeated at settings within the prescribed limits.

[0128] Particle size of metformin used in the examples according to the present invention:

[0129] According to the present invention, the milled metformin has an average and median particle size D(50) in the range of 100 pm to 200 pm. Further, the milled metformin preferably has a particle size distribution of D(10) in the range of 10 to 70 pm, D(50) in the range of 80 pm to 200 pm, and D(90) in the range 150 pm to 400 pm; preferably D(10) from 20 pm to 60 pm, D(50) from 100 pm to 180 pm, and D(90) from 150 pm to 350 pm.

[0130] According to the present invention, the finely milled metformin preferably has an average and median particle size D(50) of less than 100 pm, preferably less than 80 pm. Further, the finely milled metformin preferably has a particle size distribution of D(10) less than 30 pm, D(50) less than 100 pm, and D(90) less than 150 pm; preferably D(10) is less than 20 pm, D(50) less than 80 pm, and D(90) less than 120 pm.

A) - Manufacturing process of Examples 1, 9, 10 and 11:

[0131] Dosage forms were prepared having the following composition:

[0132] The pharmaceutical dosage forms were prepared as follows:

[0133] a) Metformin granulation: Hydroxypropylcellulose is added to ethanol, anhydrous and mixed for minimum 10 minutes until a clear granulation liquid is obtained. The granulation liquid for metfor min granulation and joint granulation is the same, i.e. comprising hydroxypropylcellulose and ethanol, anhydrous, and can be prepared in a single step for both granulations. Metformin hydrochloride is de- lumped and sieved on sieve size 0.6 - 2.0 mm. The blend of metformin hydrochloride and mannitol is granulated with the granulation liquid, comprising hydroxypropylcellulose and ethanol, anhydrous. Af ter completing granulation, the metformin granulate is dried until the specified loss on drying is achieved. The temperature of the granulate must reach at least 35°C.

[0134] b) Joint granulation: Vildagliptin and mannitol are sieved on sieve size 0.6 - 2.0 mm and added into the fluid bed granulator with the metformin granulate, prepared in step 01. Sieving of raw materials can be omitted if no visible agglomerates are present in the weighted amount thereof. The blend of vildagliptin and mannitol is granulated with the remaining granulation liquid, comprising hydroxypro- pylcellulose and ethanol, anhydrous. After completing granulation, the joint granulate is dried until the specified loss on drying is achieved. The temperature of the granulate must reach at least 35°C. [0135] c) Sieving: After completing the granulation, the joint granulate is dried until the specified loss on drying is achieved and sieved on sieve size 0.6 - 2.0 mm.

[0136] d) Blending (compression mixture preparation): Sodium stearyl fumarate and Magnesium stea rate are sieved on sieve size 0.6 - 2.0 mm and added to the joint granulate. Sieving of raw materials can be omitted if no visible agglomerates are present in the weighted amount thereof. The lubricants and joint granulate are mixed for 30 - 70 revolutions.

[0137] c) Tableting: Compression mixture is tableted to obtain tablet cores using an automatic rotary tablet machine at tableting rotor speeds 10 - 150 rpm.

[0138] f) Film-coating: Coating mixture and colorant ferric oxide yellow (E 172) are homogeneously dispersed in water, purified and mixed in a vessel for not less than 15 minutes to obtain homogeneous film coating dispersion. Tablet cores are coated at continuous spraying of film coating suspension. Film coating is performed at the following process parameters:

- inlet air temperature (setting): 40-80°C

- outlet air temperature/temperature of cores during coating: 30-55°C,

- minimal spraying rate: 20 g/min.

[0139] Temperature of outlet air represents the temperature of the product and could differ from it up to approx. 5°C. After spraying, film coated tablets are kept rotating to dry and cooled until reaching the temperature of film coated tablets below 30°C.

B) - Manufacturing process of Examples 2. 3 and 4 (organic acid in granulation liquid):

[0140] Dosage forms were prepared having the following composition: [0141] The pharmaceutical dosage forms were prepared as follows:

[0142] a) Metformin granulation: Hydroxypropylcellulose and organic acid are added to ethanol, an hydrous and mixed for minimum 10 minutes until a clear granulation liquid is obtained. The granulation liquid for metformin granulation and joint granulation is the same, i.e. comprising hydroxypropylcellu lose and ethanol, anhydrous, and can be prepared in a single step for both granulations. Metformin hy drochloride is delumped and sieved on sieve size 0.6 - 2.0 mm. The blend of metformin hydrochloride and mannitol is granulated with the granulation liquid, comprising hydroxypropylcellulose and ethanol, anhydrous. After completing granulation, the metformin granulate is dried until the specified loss on drying is achieved. The temperature of the granulate must reach at least 35°C.

[0143] b) Joint granulation: Vildagliptin and mannitol are sieved on sieve size 0.6 - 2.0 mm and added into the fluid bed granulator with the metformin granulate, prepared in step 01. Sieving of raw materials can be omitted if no visible agglomerates are present in the weighted amount thereof. The blend of vildagliptin and mannitol is granulated with the remaining granulation liquid, comprising hydroxypro pylcellulose and ethanol, anhydrous. After completing granulation, the joint granulate is dried until the specified loss on drying is achieved. The temperature of the granulate must reach at least 35°C.

[0144] c) Sieving: After completing the granulation, the joint granulate is dried until the specified loss on drying is achieved and sieved on sieve size 0.6 - 2.0 mm.

[0145] d) Blending (compression mixture preparation): Sodium stearyl fumarate and Magnesium stea rate are sieved on sieve size 0.6 - 2.0 mm and added to the joint granulate. Sieving of raw materials can be omitted if no visible agglomerates are present in the weighted amount thereof. The lubricants and joint granulate are mixed for 30 - 70 revolutions.

[0146] c) Tableting: Compression mixture is tableted to obtain tablet cores using an automatic rotary tablet machine at tableting rotor speeds 10 - 150 rpm.

[0147] f) Film-coating: Coating mixture and colorant ferric oxide yellow (E 172) are homogeneously dispersed in water, purified and mixed in a vessel for not less than 15 minutes to obtain homogeneous film coating dispersion. Tablet cores are coated at continuous spraying of film coating suspension. Film coating is performed at the following process parameters:

- inlet air temperature (setting): 40-80°C

- outlet air temperature/temperature of cores during coating: 30-55°C,

- minimal spraying rate: 20 g/min. [0148] Temperature of outlet air represents the temperature of the product and could differ from it up to approx. 5°C. After spraying, fdm coated tablets are kept rotating to dry and cooled until reaching the temperature of fdm coated tablets below 30°C.

B) Manufacturing process of Examples 5. 6. 7. 18. 19. 20 and 21 (organic acid added cxtragranularlv):

[0149] Dosage forms were prepared having the following composition:

[0150] The pharmaceutical dosage forms were prepared as follows: [0151] a) Metformin granulation: Hydroxypropylcellulose is added to ethanol, anhydrous and mixed for minimum 10 minutes until a clear granulation liquid is obtained. The granulation liquid for metfor min granulation and joint granulation is the same, i.e. comprising hydroxypropylcellulose and ethanol, anhydrous, and can be prepared in a single step for both granulations. Metformin hydrochloride is de- lumped and sieved on sieve size 0.6 - 2.0 mm. The blend of metformin hydrochloride and mannitol is granulated with the granulation liquid, comprising hydroxypropylcellulose and ethanol, anhydrous. Af ter completing granulation, the metformin granulate is dried until the specified loss on drying is achieved. The temperature of the granulate must reach at least 35°C.

[0152] b) Joint granulation: Vildagliptin and mannitol are sieved on sieve size 0.6 - 2.0 mm and added into the fluid bed granulator with the metformin granulate, prepared in step 01. Sieving of raw materials can be omitted if no visible agglomerates are present in the weighted amount thereof. The blend of vildagliptin and mannitol is granulated with the remaining granulation liquid, comprising hydroxypro pylcellulose and ethanol, anhydrous. After completing granulation, the joint granulate is dried until the specified loss on drying is achieved. The temperature of the granulate must reach at least 35°C.

[0153] c) Sieving: After completing the granulation, the joint granulate is dried until the specified loss on drying is achieved and sieved on sieve size 0.6 - 2.0 mm.

[0154] d) Blending (compression mixture preparation): Sodium stearyl fumarate and Magnesium stea rate are sieved on sieve size 0.6 - 2.0 mm and added to the joint granulate. Organic acid is sieved on sieve size 0.6 - 2.0 mm and added to the joint granulate. Sieving of raw materials can be omitted if no visible agglomerates are present in the weighted amount thereof. The lubricants, organic acid and joint granulate are mixed for 30 - 70 revolutions.

[0155] c) Tableting: Compression mixture is tableted to obtain tablet cores using an automatic rotary tablet machine at tableting rotor speeds 10 - 150 rpm.

[0156] f) Film-coating: Coating mixture and colorant ferric oxide yellow (E 172) are homogeneously dispersed in water, purified and mixed in a vessel for not less than 15 minutes to obtain homogeneous film coating dispersion. Tablet cores are coated at continuous spraying of film coating suspension. Film coating is performed at the following process parameters:

- inlet air temperature (setting): 40-80°C

- outlet air temperature/temperature of cores during coating: 30-55°C,

- minimal spraying rate: 20 g/min. [0157] Temperature of outlet air represents the temperature of the product and could differ from it up to approx. 5°C. After spraying, film coated tablets are kept rotating to dry and cooled until reaching the temperature of film coated tablets below 30°C.

C) Manufacturing process of Examples 12. 13. 14. 15. 16. and 17 (organic acid added in coating disper sion):

[0158] Dosage forms were prepared having the following composition:

[0159] The pharmaceutical dosage forms were prepared as follows:

[0160] a) Metformin granulation: Hydroxypropylcellulose and are added to ethanol, anhydrous and mixed for minimum 10 minutes until a clear granulation liquid is obtained. The granulation liquid for metformin granulation and joint granulation is the same, i.e. comprising hydroxypropylcellulose and ethanol, anhydrous, and can be prepared in a single step for both granulations. Metformin hydrochloride is delumped and sieved on sieve size 0.6 - 2.0 mm. The blend of metformin hydrochloride and mannitol is granulated with the granulation liquid, comprising hydroxypropylcellulose and ethanol, anhydrous. After completing granulation, the metformin granulate is dried until the specified loss on drying is achieved. The temperature of the granulate must reach at least 35°C.

[0161] b) Joint granulation: Vildagliptin and mannitol are sieved on sieve size 0.6 - 2.0 mm and added into the fluid bed granulator with the metformin granulate, prepared in step 01. Sieving of raw materials can be omitted if no visible agglomerates are present in the weighted amount thereof. The blend of vildagliptin and mannitol is granulated with the remaining granulation liquid, comprising hydroxypro- pylcellulose and ethanol, anhydrous. After completing granulation, the joint granulate is dried until the specified loss on drying is achieved. The temperature of the granulate must reach at least 35°C.

[0162] c) Sieving: After completing the granulation, the joint granulate is dried until the specified loss on drying is achieved and sieved on sieve size 0.6 - 2.0 mm.

[0163] d) Blending (compression mixture preparation): Sodium stearyl fiimarate and Magnesium stea rate are sieved on sieve size 0.6 - 2.0 mm and added to the joint granulate. Sieving of raw materials can be omitted if no visible agglomerates are present in the weighted amount thereof. The lubricants and joint granulate are mixed for 30 - 70 revolutions.

[0164] c) Tableting: Compression mixture is tableted to obtain tablet cores using an automatic rotary tablet machine at tableting rotor speeds 10 - 150 rpm.

[0165] f) Film-coating: Coating mixture, organic acid and colorant ferric oxide yellow (E 172) are ho mogeneously dispersed in water, purified and mixed in a vessel for not less than 15 minutes to obtain homogeneous film coating dispersion. Tablet cores are coated at continuous spraying of film coating suspension. Film coating is performed at the following process parameters:

- inlet air temperature (setting): 40-80°C

- outlet air temperature/temperature of cores during coating: 30-55°C,

- minimal spraying rate: 20 g/min.

[0166] Temperature of outlet air represents the temperature of the product and could differ from it up to approx. 5°C. After spraying, film coated tablets are kept rotating to dry and cooled until reaching the temperature of film coated tablets below 30°C.

D) Manufacturing process of Example 8 (drying of metformin in fluid bed dryer):

[0167] Dosage forms were prepared having the following composition:

[0168] The pharmaceutical dosage forms were prepared as follows:

[0169] a) Metformin drying: Metformin hydrochloride is de lumped and sieved on sieve size 0.6 - 2.0 mm. The blend of metformin hydrochloride and mannitol is dried in fluid bed dryer at product temper ature of 70°C for one hour.

[0170] b) Metformin granulation: Hydroxypropylcellulose is added to ethanol, anhydrous and mixed for minimum 10 minutes until a clear granulation liquid is obtained. The granulation liquid for metfor min granulation and joint granulation is the same, i.e. comprising hydroxypropylcellulose and ethanol, anhydrous, and can be prepared in a single step for both granulations. Dry blend of metformin hydro chloride and mannitol is granulated with the granulation liquid, comprising hydroxypropylcellulose and ethanol, anhydrous. After completing granulation, the metformin granulate is dried until the specified loss on drying is achieved. The temperature of the granulate must reach at least 35°C.

[0171] c) Joint granulation: Vildagliptin and mannitol are sieved on sieve size 0.6 - 2.0 mm and added into the fluid bed granulator with the metformin granulate, prepared in step 01. Sieving of raw materials can be omitted if no visible agglomerates are present in the weighted amount thereof. The blend of vildagliptin and mannitol is granulated with the remaining granulation liquid, comprising hydroxypro pylcellulose and ethanol, anhydrous. After completing granulation, the joint granulate is dried until the specified loss on drying is achieved. The temperature of the granulate must reach at least 35°C.

[0172] d) Sieving: After completing the granulation, the joint granulate is dried until the specified loss on drying is achieved and sieved on sieve size 0.6 - 2.0 mm.

[0173] c) Blending (compression mixture preparation): Sodium stearyl fumarate and Magnesium stea rate are sieved on sieve size 0.6 - 2.0 mm and added to the joint granulate. Sieving of raw materials can be omitted if no visible agglomerates are present in the weighted amount thereof. The lubricants and joint granulate are mixed for 30 - 70 revolutions.

[0174] f) Tableting: Compression mixture is tableted to obtain tablet cores using an automatic rotary tablet machine at tableting rotor speeds 10 - 150 rpm. [0175] g) Film-coating: Coating mixture and colorant ferric oxide yellow (E 172) are homogeneously dispersed in water, purified and mixed in a vessel for not less than 15 minutes to obtain homogeneous film coating dispersion. Tablet cores are coated at continuous spraying of film coating suspension. Film coating is performed at the following process parameters:

- inlet air temperature (setting): 40-80°C

- outlet air temperature/temperature of cores during coating: 30-55°C,

- minimal spraying rate: 20 g/min.

[0176] Temperature of outlet air represents the temperature of the product and could differ from it up to approx. 5°C. After spraying, film coated tablets are kept rotating to dry and cooled until reaching the temperature of film coated tablets below 30°C.

[0177] h) Packaging procedure: Packaging process is being carried out under the same conditions as manufacturing process.

E) Content of DMA and NDMA before and after storage:

[0178] For each of the pharmaceutical dosage forms according to Examples 1 to 21 described above, DMA content of the metformin hydrochloride that was employed as staring material was determined by the LC-MS method according to the invention as described above. When metformin hydrochloride was specifically treated e.g. by milling and/or drying, DMA content after treatment was also determined.

[0179] NDMA content was determined by the GC-MS method according to the invention as described above. NMDA content of the manufactured pharmaceutical dosage forms was measured before storage under stressed conditions and after 14 days of storage, in some cases additionally after 1 month of stor age, in each case under stressed storage conditions (50°C/75% rh).

[0180] The results are compiled in the table here below.

[0181] NDMA content depending on the amount of DMA in the starting material and addition of weak acids in the formulation: milled metformin dried in a fluid bed dryer for lh at T = 70°C

DL: detection limit

[0182] As demonstrated by the data in the above table, the pharmaceutical dosage forms according to the invention have a significantly reduced content of NDMA. This can be achieved by (i) reducing the DMA content in the starting material of the active pharmaceutical ingredient, i.e. metformin or physio logically acceptable salt thereof, preferably by drying and/or milling; and (ii) adding an acid that appears to stabilize metformin or physiologically acceptable salt thereof thereby suppressing DMA release. The results show that the pharmaceutical dosage forms which comprise milled metformin and a pharmaceu tically acceptable acid are more stable on storage at stress conditions and exhibit lower increase of the content of NDMA. This is further improved by incorporation of the active ingredient comprising lower contents of DMA.

F) Influence of pretreatment of metformin on its DMA content:

[0183] Metformin hydrochloride was treated under various conditions (with and without milling, dry ing at 50°C and 70°C) and the influence on DMA content over time was investigated. DMA content was determined by the LC-MS method according to the invention as described above.

[0184] The results are compiled in the table here below.

[0185] Decrease in DMA content during the drying process at different temperatures in fluid bed dryer

(50°C, 70°C):

[0186] The time denoted as t=0 min means the time when the temperature of the sample subjected to heating reached the desired temperature of drying, e.g. 50°C or 70°C.

[0187] The data in the above table shows the decrease in the DMA content (presumably of the volatile part of DMA) in metformin, depending on the drying time. The decrease in content is more pronounced (relative to the initial content) in metformin with a smaller average particle size (milled), indicating trapping of the volatile part of DMA in the crystal lattice of metformin.