DESC:
Field of the invention: The invention relates to a process for the reduction of N-nitroso dimethyl amine impurity in pharmaceutical formulations such as metformin, ranitidine, nizatidine. The invention further relates to a novel process for the reduction of N-nitroso dimethyl amine impurity using scavengers of silica and activated carbon.
Background of the invention: N-nitrosodimethyl amine known as NDMA is an N-nitrosamine, a type of compound that has the generic chemical structure R2N–N=O, a deprotonated amine bonded to a nitroso group. N-nitrosamines are generally formed when a secondary or tertiary amine reacts with a nitrosating agent. The compounds are found at low levels in many foods, such as roasted meats, cheese, and beer, because of cooking and fermentation processes. NDMA impurity has the following structure given below:

In the past few years, scientists have found the potential carcinogen N-nitrosodimethylamine (NDMA) in multiple pharmaceuticals such as metformin, ranitidine, nizatidine etc. While the amounts of the contaminant in the drugs are generally low, some levels have been above the US Food and Drug Administration’s acceptable daily limit, potentially exposing many people to a slightly increased risk of cancer. Many of the affected drugs have been recalled, and industry and other labs are scrambling to figure out where the contaminants came from.
Because these N-nitrosamine contaminants are possible carcinogens, regulatory agencies have been deeming the drugs unsafe for people to take and recalling them from shelves. Valsartan was recalled in July 2018, followed that October by irbesartan and in November by losartan. 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 pulled it from the shelves in the next few months. Nizatidine, another heartburn medication, was recalled by manufacturer Mylan in January 2020. And most recently, the FDA suggested that manufacturers of ranitidine recall all lots and types of these medications. NDMA has also been found in metformin, a diabetes drug taken by over 15.8 million people worldwide.
NDMA at high doses, is a "potent hepatotoxin that can cause fibrosis of the liver" in rats. The induction of liver tumors in rats after chronic exposure to low doses is well documented. Its toxic effects on humans are inferred from animal experiments. NDMA is classified as an extremely hazardous substance in the United States as defined in Section 302 of the U.S. Emergency Planning and Community Right-to-Know Act. The acceptable daily dose of NDMA is 96 ng/day hence the limit of NDMA for 500 mg ER tablet is 24 ng/tablet whereas 1000 mg ER tablet is 48 ng/tablet.
Still, because people taking drugs with N-nitrosamine impurities over long periods may have even a small increased risk of cancer, the FDA decided to recall some of these medications. The recalls have caused disruptions, especially for doctors and the tens of millions of people in the world who take the drugs to treat chronic illnesses. Hence, there remains a need for the removal of the NDMA impurity from these drugs.
Summary of the Invention: The present invention is related to a novel process for the reduction of NDMA impurity. The present invention is related to the process for the reduction of the NDMA impurity by exposure to scavengers.
Detailed description of the invention:
The invention provides a novel process for the reduction of NDMA impurity in the pharmaceutical formulations that contains active pharmaceutical ingredient like metformin, ranitidine, nizatidine. The pharmaceutical formulation may be in the form of tablets, capsules, syrups, lozenges. The pharmaceutical formulation includes tablets, coated tablets, layered tablets, granules, powders, microparticles, capsules which may be hard gelatin or soft gelatin, caplets, sachets, pellets, spheroids, mini-tablets, beads, microcapsules and pills.
The invention provides a novel process for the reduction of NDMA impurity in the pharmaceutical formulation, wherein the pharmaceutical formulation is exposed to one or more scavengers in closed containers. The pharmaceutical formulation is exposed to one or more scavengers for a period of a week to six months, preferably for ten days to three months. The pharmaceutical formulation is exposed to one or more scavengers for a period of a week to six months, preferably for ten days to three months.
According to present invention, the scavengers are selected from a group comprising of silica scavengers, oxygen absorbing scavengers, activated carbon scavengers. The scavengers are further selected from a group comprising of Stabilox H-60, Stabilox H-42, Molecular sieves, silica gels, activated carbon and mixtures thereof.
The invention provides a novel process for the reduction of NDMA impurity in the drugs like metformin, ranitidine, nizatidine. The drugs are in the form of tablets. The tablets of the drugs can be immediate release (IR) or extended release (ER) of various strengths. These drugs can be combined with any other drug as per requirement and made into a tablet. The preferred drug is Metformin IR/ER tablets with strengths 500/1000 mg.
In an embodiment of the present invention the NDMA impurity in Metformin is reduced by exposing metformin to scavengers. In another embodiment of the present invention, the metformin IR/ER tablets of various batches were filled in closed HDPE container with scavenger and kept for one month at 60°C. The analysis results showed that the NDMA impurity showed reduction after exposure to scavengers.
The analysis results are tabulated below in Table 1, which clearly showing impact of scavenger (Stabilox H-60) on formation of NDMA in Metformin 1000 mg ER tablets kept at 60°C for one month. The results are showing that NDMA content is lowered in tablets stored with scavenger in HDPE bottle. These are also showing that NDMA content is also lowered in batches where processed API a processed excipients were used.

Batch Number Experimental conditions Scavenger details NDMA ng/tablet
Batch 1 (PLACEBO) 1M/60°C WITH SCAVENGER 0
Batch 1 (PLACEBO) 1M/60°C WITHOUT SCAVENGER 0
Batch 2 1M/60°C WITH SCAVENGER 12.8
Batch 2 1M/60°C WITHOUT SCAVENGER 62.5
Batch 3 1M/60°C WITH SCAVENGER 15.6
Batch 3 1M/60°C WITHOUT SCAVENGER 66.7
Batch 4 1M/60°C WITH SCAVENGER 9.9
Batch 4 1M/60°C WITHOUT SCAVENGER 31.2
Batch 5 1M/60°C WITH SCAVENGER 0
Batch 5 1M/60°C WITHOUT SCAVENGER 15.6

Table 1
In yet another embodiment of the present invention, Metformin HCl 1000 mg ER tablets of Batch 2 and Batch 3, kept in bottle without scavenger were exposed to vacuum at 40°C for 36 Hrs. The analysis results are tabulated in Table 2, which is showing decrease in NDMA content of tablets due to volatile nature of NDMA.

The analysis results are tabulated in Table 2, which is showing decrease in NDMA content of tablets in the absence of scavengers.

Batch Number Scavenger details NDMA ng/tablet
Batch 2 WITHOUT SCAVENGER 48
Batch 3 WITHOUT SCAVENGER 20.02
Table 2

In a further embodiment of the present invention, different types of scavengers were exposed to NDMA for different time intervals (0.5, 1.0 and 2.0 hours) and analyzed at respective time intervals. The results are tabulated in Table 3, which shows that all scavengers are showing increasing trend of NDMA absorption with time. Out of all these scavengers, two scavengers, namely activated carbon and silica gel, absorb maximum amount of NDMA after two hours of NDMA exposure.

Scavenger Type 0.5 hrs (NDMA in ppb) 1.0 hrs
(NDMA in ppb) 2.0 Hrs (NDMA in ppb)
Stabilox H-60 75 351 510
Stabilox H-42 36 118 316
Molecular Seive 52286 118126 193295
Silica Gel + Activated Carbon 25553 51256 142587
Activated Carbon 30053 48917 238861
Silica Gel 38240 84453 225347

Table 3

The aforementioned process for the reduction of the NDMA impurities has the following advantages:
i) simple and quick process,
ii) can be used on a higher scale,
iii) economical process and
iv) avoids multiple techniques for impurity reduction and
The principles, preferred embodiments, and modes of operation of the present invention have been described in the foregoing examples. The following examples are provided to illustrate the process of the present invention and are not intended to be construed as limitations of the present invention.

Examples :
Example 1: Metformin HCl 1000 mg ER tablets of Batch 2 were filled in closed HDPE container with and without scavenger (Stabilox H-60) and were kept for one month at 60°C.

Example 2: Metformin HCl 1000 mg ER tablets of Batch 3 were filled in closed HDPE container with and without scavenger (Stabilox H-60) were kept for one month at 60°C.

Example 3: Metformin HCl 1000 mg ER tablets of Batch 4 were filled in closed HDPE container with & without scavenger (Stabilox H-60) were kept for one month at 60°C.

Example 4: Metformin HCl 1000 mg ER tablets of Batch 5 were filled in closed HDPE container with & without scavenger (Stabilox H-60) were kept for one month at 60°C.

The results of Example 1, 2, 3 and 4 are tabulated in Table 1 below.
Batch Number Experimental conditions Scavenger details NDMA ng/tablet
Batch 1 (PLACEBO) 1M/60°C WITH SCAVENGER 0
Batch 1 (PLACEBO) 1M/60°C WITHOUT SCAVENGER 0
Batch 2 1M/60°C WITH SCAVENGER 12.8
Batch 2 1M/60°C WITHOUT SCAVENGER 62.5
Batch 3 1M/60°C WITH SCAVENGER 15.6
Batch 3 1M/60°C WITHOUT SCAVENGER 66.7
Batch 4 1M/60°C WITH SCAVENGER 9.9
Batch 4 1M/60°C WITHOUT SCAVENGER 31.2
Batch 5 1M/60°C WITH SCAVENGER 0
Batch 5 1M/60°C WITHOUT SCAVENGER 15.6
Table 1
Example 5: After completion of one month at 60°C tablets of Batch 2 and Batch 3, kept in bottle without scavenger were exposed to vacuum at 40°C for 36 hours. The analysis results are tabulated in Table 2 below.

Batch Number Scavenger details NDMA ng/tablet
Batch 2 WITHOUT SCAVENGER 48
Batch 3 WITHOUT SCAVENGER 20.02

Table 2

Example 6: Scavengers such as Stabilox H-60, Stabilox H-42, molecular sieve, silica gel + activated carbon, activated carbon and silica gel were exposed to NDMA for different time intervals (0.5, 1.0 and 2.0 hours) and analyzed at respective time intervals. The results are tabulated in Table 3 below.

Scavenger Type 0.5Hrs (in ppb) 1.0 Hrs (in ppb) 2.0 Hrs (in ppb)
Stabilox H-60 75 351 510
Stabilox H-42 36 118 316
Molecular Seive 52286 118126 193295
Silica Gel + Activated Carbon 25553 51256 142587
Activated Carbon 30053 48917 238861
Silica Gel 38240 84453 225347

Table 3

,CLAIMS:1) A process for the reduction of N-nitroso dimethyl amine (NDMA) impurity in pharmaceutical formulation.

2) A process of claim 1, wherein the NDMA impurity is reduced by exposing the pharmaceutical formulation to scavengers.

3) A process of claim 2, wherein the scavengers are selected from group consisting of silica scavengers, oxygen absorbing scavengers, activated carbon scavengers.

4) A process of claim 3, wherein the scavengers are selected from group consisting of Stabilox H-60, Stabilox H 42, molecular sieves, silica gels, activated carbon and mixtures thereof.

5) A process of claim 1, wherein the pharmaceutical formulation contains active pharmaceutical ingredient as metformin, ranitidine or nizatidine.

6) A process of claim 1, wherein the NDMA impurity is reduced by keeping the pharmaceutical formulation in closed container with one or more scavengers.

7) A process according to claim 10, wherein the pharmaceutical formulation is kept in container with one or more scavengers for a period of 10 days to 3 months.

8) A process according to claim 11, wherein the pharmaceutical formulation is kept in HDPE container with one or more scavengers at 40 to 100°C.