FIELD OF THE INVENTION
The present invention relates to crystalline Ranitidine hydrochloride Form 2 with a residual isopropanol solvent below 100 ppm.
The present invention particularly relates to crystalline Ranitidine hydrochloride Form -2 with a residual isopropanol solvent below 100 ppm and contains NDMA impurity less than 0.05 ppm as measured by LC-MS/MS method.
The present invention further relates to an industrial process for the preparation of crystalline Ranitidine hydrochloride Form 2 with a residual isopropanol solvent below 100 ppm and contains NDMA impurity less than 0.05 ppm as measured by LC-MS/MS method.
BACKGROUND OF THE INVENTION
Ranitidine hydrochloride is a competitive, reversible inhibitor of the action of histamine at the histamine H2-receptors, including receptors on the gastric cells. Ranitidine hydrochloride chemically described as N[2-[[[5-[(dimethylamino)methyl]-2-furanyl]methylJthio]ethyl]-N'-methyl-2-nitro-l.l-ethenediamine; HC1. It has the following structure:
Crystalline Ranitidine hydrochloride Form 2 and its process is first described in US 4,521,431 A, wherein the process comprises dissolving Ranitidine base in isopropanol solvent followed by the addition of concentrated hydrochloric acid. The solution was heated and seeded with Form 2 of Ranitidine hydrochloride. The Form 2 of Ranitidine hydrochloride product was dried in a vacuum oven at 50°.
The above process does not disclose the isopropanol content present in the Form 2 of Ranitidine hydrochloride. The inventors of the present invention repeated the same process in
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hydrochloride contains residual isopropanol solvent in the ra;?.ge of 1500-2600 ppm,'wherein

the solvent content of Isopropanol was find out to be a one of the cause for the presence and rise of the NDMA levels in the pharma.
NDMA is a nitrosamine known potential impurity which became a focus for the FDA and EMA. This impurity is classified as a probable human carcinogen and is believed to have been introduced into the finished products as a result of the manufacturing process. Due to the presence of NDMA there were lot of recalls happened for Ranitidine HO in US and EP. The FDA has been working closely with industry to ensure products entering the market do not contain these impurities in the future, whilst establishing suitable analytical methods to determine levels of these impurities and establish interim limits for nitrosamine impurities.
The inventors of the present invention surprisingly found that the presence of isopropanol solvent content in the Form 2 of Ranitidine hydrochloride causes the rise in the content of NDMA impurity, which may be due to the conversion of isopropanol to isopropyl nitrite which further converted to NDMA impurity.
OBJECT OF THE INVENTION
The main object of the invention is to provide crystalline Ranitidine hydrochloride Form 2 which contains a residual isopropanol solvent below 100 ppm and contains NDMA impurity less than 0.05 ppm as measured by LC-MS/MS method.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides crystalline Ranitidine hydrochloride Form 2 which contains a residual isopropanol solvent below 100 ppm and contains NDMA impurity less than 0.05 ppm as measured by LC-MS/MS method, wherein the Form 2 is characterized by an X-ray powder diffraction pattern comprising 28 values in degrees of 8.2, 20.0, 23.3 and 31.7.
In a preferred aspect, the present invention provides industrial process for the
preparation of crystalline Ranitidine hydrochloride Form 2, which contains a residual
isopropanol solvent below 100 ppm and contains NDMA impurity less than 0.05 ppm as
measured by LC-MS/MS method, wherein the process comprises:
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b) Filter the mass of step of a) to get particle free of Ranitidine base,

c) Isopropanol HC1 was added to the filtrate of step b), ■ d) Reaction mass was maintained at 30-50°C,
e) Dried the material to obtain crystalline Ranitidine hydrochloride Form 2 which contains a
residual isopropanol solvent below 100 ppm and contains NDMA impurity less than 0.05
ppm as measured by LC-MS/MS method.
In another preferred aspect, the present invention provides industrial process for the preparation of crystalline Ranitidine hydrochloride Form 2, which contains a residual isopropanol solvent below 100 ppm and contains NDMA impurity less than 0.05 ppm as measured by LC-MS/MS method, wherein the process comprises:
a) Dissolving Ranitidine hydrochloride which contains isopropanol solvent in the range of 1500-2600 ppm in methanol,
b) Reaction mass was heated to 40-50°C,
c) Reaction mass was cooled to 25-35°,
d) Dried the material to obtain crystalline Ranitidine hydrochloride Form 2 which contains a residual isopropanol solvent below 100 ppm and contains NDMA impurity less than 0.05 ppm as measured by LC-MS/MS method.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG: 1 is the X-ray powder diffraction pattern of crystalline Ranitidine hydrochloride Form 2 which contains a residual isopropanol solvent below 100 ppm and contains NDMA impurity less than 0.05 ppm as measured by LC-MS/MS method.
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, crystalline Ranitidine hydrochloride Form 2 which contains a residual isopropanol solvent below 100 ppm and contains NDMA impurity less than 0.05 ppm as measured by LC-MS/MS method. In a preferred embodiment the solvent content is preferably below 50 ppm. In another preferred embodiment the solvent content is preferably below 10 ppm.
The present invention provides crystalline Ranitidine hydrochloride Form 2 which is
substantially free of NDMA. In particular, crystalline Ranitidine hydrochloride Form 2
=:k~iToT#rfrre^bM ., . —

NDMA is a potent carcinogen in experimental animals by several routes of exposure, including through ingestion of drinking-water. N-Nitrosodimethylamine, or NDMA, can occur from several industrial processes. The following are the general thinking of how NDMA can be formed in the industrial process of any API.
In a preferred embodiment, the present invention provides industrial process for the preparation of crystalline Ranitidine hydrochloride Form 2, which contains a residual isopropanol solvent below 100 ppm and contains NDMA impurity less than 0.05 ppm as measured by LC-MS/MS method, wherein the process comprises:
a) Dissolving Ranitidine base in methanol,
b) Filter the mass of step of a) to get particle free of Ranitidine base,
c) Isopropanol HC1 was added to the filtrate of step b),
d) Reaction mass was maintained at 30-50°C,
e) Dried the material to obtain crystalline Ranitidine hydrochloride Form 2 which contains a residual isopropanol solvent below 100 ppm and contains NDMA impurity less than 0.05 ppm as measured by LC-MS/MS method.
In another preferred embodiment, the present invention provides industrial process for
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isopropanol solvent below 100 ppm and contains NDMA impurity less than 0.05 ppm as

measured by LC-MS/MS method, wherein the process comprises:
a) Dissolving Ranitidine hydrochloride which contains isopropanol solvent content in the range of 1500-2600 ppm in methanol
b) Reaction mass was heated to 40-50°C,
c) Reaction mass was cooled to 25-35° C,
d) Dried the material to obtain crystalline Ranitidine hydrochloride Form 2 which contains a residual isopropanol solvent below 100 ppm and contains NDMA impurity less than 0.05 ppm as measured by LC-MS/MS method.
Due to the carcinogenicity of NDMA and its presence in the final API, it became a big challenge for the industry to prepare Ranitidine HC1 with a permitted control of NDMA. The inventors of the present invention have tried numerous ways to reduce the content of NDMA by optimizing the process and using different crystalline techniques for the enhancement of purity of Ranitidine hydrochloride and surprisingly it has found that the raise in the content of isopropanol solvent also causes a raise in the content of NDMA in the final API.
The inventors of the present invention have verified that the product obtained using the process described in US 4,521,431 A contains residua) isopropanol solvent approximately in the range of 1500-2600 ppm. The drying step, even though prolonged, does not allow one to reduce the isopropanol content to below several hundred parts per million. The product also found to be containing NDMA more than the permitted level i.e 2.5 ppm (as per ICH)
After the research in the lab, the inventors of the present invention found (hat the reduction in the content of isopropanol leads, to the reduction in the NDMA content of the final API. As a part of investigation studies all the possible areas were investigated with systematic approach such as manufacturing process contamination/ Equipment/ Solvents/ Stores contamination etc..
At a point of time it has been identified that the crystalline Ranitidine HCl Form 2 prepared according to the prior art US '431 k lime being degrading on Jong striding and generating the NDMA content as reported in the below table (using LCMS/MS), whereas crystalline Ranitidine HCl Form 2 prepared according to the present invention is Mpblc on

long standing and NDMA content is comparatively very less against the crystalline Ranitidine HC1 Form 2 prepared as per the prior art process.

From the above two strategy analysis report we have suspected that isopropyl alcohol is the precursor for formation of NDMA, wherein we suspect that the isopropyl alcohol when exposed to a free Nitrite ion which may available through any of the contamination (Process water/Aerial) then there will be a chances of formation of Isopropyl nitrite which is active precursor for NDMA with tertiary amine/ secondary amine present in Ranitidine Hydrochloride. After the above results it has been successfully found that NDMA can be avoided in Ranitidine by changing the solvent from isopropanol to methanol or reducing the volumes of isopropanol in the preparation of Ranitidine hydrochloride.
To evident the presence or formation of isopropyl nitrite it has been explored carry over study for isopropyl nitrite for few Ranitidine Hydrochloride batches and it has proven that the formation of Isopropyl nitrite generation.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. The invention is illustrated below with reference to inventive and comparative examples and should not be construed to limit the scope of the invention.
Examples:
Example-1: Preparation of Ranitidine Hydrochloride Form 2 prepared according to the
present invention:
In a 500.0 mL RB flask 100.0 gm of Ranitidine base was dissolved in 122.0 mL of Methanol under gentle stirring for 10-15 minutes for complete dissolution of Ranitidine base, the reaction mass was filter through micron filter to get particle free material and further wash the bed with 22.0 mL of Methanol. Take the filtrate mother liquor into a 500.0 mL another clean & dry RB flask, reaction mass pH was adjusted to 4.5-5.5 with 1PA.HC1 (66.6

mL) at 25-35°C. The resulting reaction mass was maintained for 90 minutes at 35-40°C to complete formation of salt material. The reaction mass temperature was cooled to 5-10°C under gentle stirring further maintained for 1.0 hour at 5-10°C. The resulting precipitate was filtered and washed the cake with 38.0mL of excess IPA, allowed for spin dry for 25-35 minutes. The filtered solid was dried under vacuum not less than 600 mm/Hg at 50-55°C for 6.0 hours and the obtained material was sieved through 10 meshes. Yield: 92.0 gm.
Examplc-2: Procedure for conversion of crystalline Ranitidine Hydrochloride Form 2 containing isopropanol in the range of 1500-2600 ppm to Ranitidine Hydrochloride Form 2 of the present invention
In a 500.0 mL RB flask 100.0 gm of Ranitidine Hydrochloride is taken in 80.0 mL of Methanol and 8.0 mL of Process water under gentle stirring for 10-15 minutes at 25-35°C. Raise the reaction mass temperature to 40-50°C and stir the reaction mass for 30 minutes for complete dissolution of Ranitidine Hydrochloride. After complete dissolution of material reaction mass was allowed to cool down to 25-35°C and filter through micron filter to-get particle free and keep aside. Take 300.0 mL of IPA into 500.0 mL RB flask and cool to 8-10°C and slowly add the above particle mass which is kept aside during 15-20 minutes at 8-10°C and stir the reaction mass for 30 minutes to get complete formation of material. After complete formation of material observed, stir the reaction mass for 1.0 hour at below 17-23°C. Further cool the reaction mass temperature to 8-10°C and stir for 30 minutes at 8-10°C and filter the material and wash the cake with 50.0mL of IPA and spin dry the material for 15-20 minutes. The filtered solid was dry under vacuum not less than 600 mm/Hg at 50-55°C by consistent weight obtained. Yield: 95.0 gm.

We Claim:
1. Crystalline Ranitidine hydrochloride Form 2 which contains a residual isopropanol solvent below 100 ppm and contains NDMA impurity less than 0.05 ppm as measured by LC-MS/MS method, wherein the Form 2 is characterized by an X-ray powder diffraction pattern comprising 28 values in degrees of 8.2, 20.0,23.3 and.31.7.
2. Crystalline Ranitidine hydrochloride Form 2 as claimed in claim 1, wherein Form 2 contains NDMA impurity less than 0.05 ppm as measured by LC-MS/MS method.
3. Industrial process for the preparation of crystalline Ranitidine hydrochloride Form 2, which contains a residual isopropanol solvent below 100 ppm and contains NDMA impurity less than 0.05 ppm as measured by LC-MS/MS method, wherein the process comprises:

a) Dissolving Ranitidine base in methanol,
b) Filter the mass of step of a) to get particle free of Ranitidine base,
c) Isopropanol HC1 was added to the filtrate of step b),
d) Reaction mass was heated to 30-50°C,
e) Dried the material to obtain crystalline Ranitidine hydrochloride Form 2 which contains a residual isopropanol solvent below 100 ppm and contains NDMA impurity less than 0.05 ppm as measured by LC-MS/MS method.
4. Industrial process for the preparation of crystalline Ranitidine hydrochloride Form 2,
which contains a residual isopropanol solvent below 100 ppm and contains NDMA
impurity less than 0.05 ppm as measured by LC-MS/MS method, wherein the process
comprises:
a) Dissolving Ranitidine hydrochloride which contains isopropanol solvent in the range of 1500-2600 ppm in methanol,
b) Reaction mass was heated to 40-50°C,
c) Reaction mass was cooled to 25-35°,
d) Dried the material to obtain crystalline Ranitidine hydrochloride Form 2 which contains a residual isopropanol solvent below 100 ppm and contains NDMA impurity less than 0.05
ppm as measured by LC-MS/MS method.
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