DESC:STABLE PHARMACEUTICAL COMPOSITIONS OF LINAGLIPTIN
Field of the Invention
The present invention relates to stable pharmaceutical compositions comprising Linagliptin and process for
preparation thereof, wherein the composition is free of microcrystalline cellulose, mannitol and
pregelatinsed starch. It further relates to a stable pharmaceutical composition comprising Linagliptin
prepared by a wet granulation process, wherein Linagliptin is present extra granularly.
Background of the Invention
Linagliptin is a DPP-IV inhibitor, commercially available under the trade name Tradjenta® in the form of
film- coated tablets in 5 mg strength for the treatment of type 2 diabetes mellitus. Chemically it is 1HPurine-
2, 6-dione, 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butyn-1-yl)-3,7-dihydro-3-methyl-1-[(4-methyl-2
quinazolinyl)methyl]. U.S. Patent No. 7,407,955 discloses Linagliptin specifically.
DPP-IV is an enzyme that degrades the incretin hormones such as GLP- 1(glucagon- like peptide 1) and
GIP (glucose dependent insulin tropic polypeptide), being a DPP-IV inhibitor blocks DPP-IV enzyme, and
thus inhibits the degradation of GLP-1 and GIP, which in turn increases insulin secretion and decreases
blood glucose levels.
European Patent Application No. 3144000 discloses a pharmaceutical composition comprising Linagliptin
as a first active pharmaceutical ingredient and one or more excipients. It mentions that that DPP-IV
inhibitors with a primary or secondary amino group show incompatibilities, degradation problems, or
extraction problems with a number of customary excipients such as microcrystalline cellulose, sodium
starch glycolate, croscarmellose sodium, tartaric acid, citric acid, glucose, fructose, saccharose, lactose,
maltodextrines.
PCT Publication No. 2014/080384 discloses pharmaceutical composition comprising Linagliptin and one
or more pharmaceutically acceptable excipients, wherein the said composition is free of mannitol. The
pharmaceutically acceptable excipients are selected from the group comprising diluents, binders,
disintegrants, lubricants, or mixtures thereof. Particularly, the diluent is microcrystalline cellulose.
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U.S. Publication No. 2018/0250304 discloses pharmaceutical composition comprising Linagliptin as a sole
active agent in an amount less than 5.0% w/w of the total weight of the composition, mannitol in an amount
between 80.0 w/w to 90.0% w/w of the total weight of the composition, at least one binder and at least one
disintegrant and optionally other pharmaceutically acceptable excipients present in the composition, with
the proviso that the composition is free of pregelatinsed starch. This application discloses use of 80-90%
mannitol for obtaining Linagliptin formulation with appropriate release profile.
PCT Publication No. 2020/009675 discloses pharmaceutical formulation comprising Linagliptin or a
pharmaceutically acceptable salt thereof, wherein the composition is free of microcrystalline cellulose,
croscarmellose sodium and stearates
U.S. Publication No. 2014/0357646 describes crystalline Forms A, B, C, D, and E of Linagliptin, and
processes for the preparation of the polymorphic forms.
Stability of a drug is of paramount importance and is required so that the drug product meets its acceptance
criteria throughout the lifetime and also to gain regulatory approval.
In order to avoid unacceptable degradation of Linagliptin, prior art teaches use of specific diluents. It was
however still desirable to provide an alternate stable Linagliptin composition wherein the degradation level
of amine is negligible and the pharmaceutical tablet composition fulfils the regulatory stability criteria for
pharmaceutical tablets.
We have surprisingly found that Linagliptin compositions which are free of microcrystalline cellulose,
mannitol and pregelatinsed starch are stable. Additionally, it was observed that formulation process that is
used to formulate the composition plays a major role in the stability of the composition. Wet granulation
is advantageous over dry granulation as it reduces sticking of blend and affects the stability of the
composition. It was observed that Linagliptin composition prepared by wet granulation were effectively
more stable when compared with composition prepared by direct compression. Further, composition
wherein Linagliptin is present extra granularly is more stable, compared to composition wherein Linagliptin
is present intragranularly.
The present invention uses crystalline form F of Linagliptin to develop tablet dosage form. It is known in
art that polymorphic conversion may occur during formulation process. As a consequence of the higher
mobility and ability to interact with moisture, heat or air, crystalline drug substances are also likely to
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undergo solid-state reactions leading to degradation and subsequent loss of activity and purity. However, it
was surprisingly found that the crystalline form F remains unchanged during formulation and even after at
40oC and 75% humidity for 3 months.
Thus, the present invention provides stable Linagliptin compositions and process of preparation thereof.
The compositions have acceptable stability in terms of related substances and crystallinity, even after
storage at accelerated conditions.
Summary of the Invention
A first aspect of the present invention provides a stable Linagliptin composition comprising Linagliptin or
a pharmaceutically acceptable salt thereof, wherein the composition is free of microcrystalline cellulose,
mannitol and pregelatinsed starch, and the said composition has less than 0.3% w/w of total impurity when
stored at 40oC/75% RH and 25oC/60% RH for a period of six months.
According to one embodiment of the present invention, Linagliptin is present in an amount of 0.5% to 20%,
preferably in an amount of 0.5% to 10%, more preferably 0.5% to 7% based on the total weight of the
composition.
According to another embodiment of the present invention, Linagliptin is present as crystalline form. The
crystalline Linagliptin is polymorphic form F.
According to another embodiment of the present invention, the composition further comprises one or more
pharmaceutically acceptable excipients selected from diluents, disintegrants, lubricants, or mixtures
thereof.
According to another embodiment of the present invention, the composition is a tablet.
According to another embodiment of the present invention, the composition is prepared by wet granulation.
According to another embodiment of the present invention, Linagliptin is present extra granularly.
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According to another embodiment, there is provided a wet granulation process for the preparation of a
stable Linagliptin composition comprising Linagliptin or a pharmaceutically acceptable salt thereof,
wherein Linaglitpin is added extragranularly in the composition.
According to another embodiment, there is provided a wet granulation process for the preparation of a
stable Linagliptin composition comprising Linagliptin or a pharmaceutically acceptable salt thereof,
wherein the composition is free of microcrystalline cellulose, mannitol and pregelatinsed starch, and the
said composition has less than 0.3% w/w of total impurity when stored at 40oC/75% RH and 25oC/60% RH
for a period of six months.
According to another embodiment of the present invention, the composition is prepared by a wet
granulation process comprising the steps of:
(i) preparing a granulation fluid by dispersing a binder in a solvent;
(ii) premixing one or more diluent, and one or more disintegrant to obtain a premix;
(iii) granulating the premix obtained in step (ii) with the granulation fluid
obtained in step (i) to form a wet mass;
(iv) drying the wet mass obtained in step (iii) and then milling to obtain granules;
(v) blending Linagliptin with the granules obtained in step (iv).
(vi) lubricating the blended granules obtained in step (v) and finally compressing into tablets; and
(vii) optionally coating the tablet obtained in step (vi) wherein said composition is free of microcrystalline
cellulose, mannitol and pregelatinsed starch, and the said composition less than 0.3% w/w of total impurity
when stored at 40oC/75% RH and 25oC/60% RH for a period of six months.
Alternatively, according to another embodiment, there is provided a dry granulation process for the
preparation of a stable Linagliptin composition comprising Linagliptin or a pharmaceutically acceptable
salt thereof, wherein the composition is free of microcrystalline cellulose, mannitol and pregelatinsed
starch, and the said composition has less than 0.3% w/w of total impurity when stored at 40oC/75% RH and
25oC/60% RH for a period of six months.
Detailed description of drawings:
Figure 1 shows the X-Ray powder diffraction (XRD) pattern of Linagliptin API, placebo blend and
Linagliptin tablets.
Figure 2 is X-Ray powder diffraction (XRD) pattern of Linagliptin tablets after storage at 40o C and 75%
humidity for 3 months.
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Fig No 03: Dissolution graph for Tradjenta® Tablets 5 mg, Example 3, Example 4 and Example 5
Detailed description of the invention
The term "Linagliptin", as used herein, refers to Linagliptin and one or more pharmaceutically acceptable
salts thereof, including hydrates and solvates thereof, and crystalline or amorphous forms thereof. The
present invention comprises Linagliptin in an amount of from about 0.5% to about 20% by weight of the
composition. Preferably, the Linagliptin is present in an amount of from about 0.5% to about 7% by weight
of the composition. The present invention comprises Linagliptin Form F. Linagliptin is approved at
strengths of 5 mg per day. As such, a therapeutically effective amount includes, but is not limited to, about
1 mg to about 10 mg per day.
The term "stable" as used herein refers to less than 0.3% w/w of total impurity when stored at 40oC/75%
RH and 25oC/60% RH for a period of six months.
The term “Form F” refers to polymorphic form of Linagliptin, having characteristic peak at 6.8 2?.
The term "about", as used herein, refers to any value, which lies within the range defined by a variation of
up to ±10% of the value.
The term "pharmaceutically acceptable excipients", as used herein, includes any physiologically inert
additives that are routinely used in pharmaceutical dosage forms. Pharmaceutically acceptable excipients
may include, but are not limited to, diluents, binders, disintegrants, and lubricants/glidants.
Suitable diluents or fillers are selected from the group comprising of magnesium carbonate, calcium silicate,
calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, lactose
monohydrate, lactose anhydrous, sucrose, sorbitol, xylitol, erythritol, kaolin, calcium silicate, maltodextrin,
maize starch, corn starch, or mixtures thereof. The present invention comprises one or more diluents in an
amount of from about 40% to about 90% by weight of the composition. Among the diluents, magnesium
carbonate and calcium silicate are the preferred diluents. According to one embodiment of the invention,
the composition has a diluent that is not microcrystalline cellulose, mannitol and pregelatinsed starch such
that the composition is free of microcrystalline cellulose, mannitol and pregelatinsed starch.
Suitable binders are selected from the group comprising povidone, copovidone, hydroxypropyl methyl
cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, ethyl cellulose, xanthan gum,
gum acacia, gum arabic, tragacanth, sorbitol, dextrose, sucrose, gelatin, pullulan, sodium alginate,
propylene glycol, polyvinyl alcohol, corn syrup, methacrylates, carboxyvinyl polymers like carbomers, or
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mixtures thereof. The present invention comprises one or more binders in an amount of from about 3% to
about 20% by weight of the composition.
Suitable disintegrants are selected from the group comprising sodium starch glycolate, crospovidone,
hydroxypropyl cellulose (L-HPC), croscarmellose sodium, carboxymethyl cellulose sodium,
carboxymethyl cellulose calcium, gums, alginic acid or alginates, starch, cornstarch, modified starch,
carboxymethyl starch, polyacrylates, or mixtures thereof. The present invention comprises one or more
disintegrants in an amount of from about 2% to about 18% by weight of the composition.
Suitable lubricants/glidants/antiadherents are selected from the group comprising magnesium stearate,
calcium stearate, hydrogenated vegetable oil, glyceryl behenate, glyceryl monostearate, stearic acid, sodium
stearyl fumarate, sodium starch fumarate, zinc stearate, aluminium silicate, talc, colloidal silicon dioxide,
sucrose esters of fatty acid, waxes, silica gel, or mixtures thereof. The present invention comprises one or
more lubricants in an amount from about 0.1% to about 4% by weight of the composition.
The pharmaceutical compositions of the present invention are prepared by wet granulation process. During
the wet granulation process, moist granules can be wet milled, if needed, prior to final drying.
The pharmaceutical composition prepared above may further be coated with a film-forming polymer and
one or more pharmaceutically acceptable excipients, using techniques well known in the art, e.g., spray
coating in a conventional coating pan or a fluidized bed processor, or dip coating. Alternatively, the coating
step can also be performed using a hot melt technique.
The film coating may contain one or more film-forming polymers and optionally one or more
pharmaceutically acceptable excipients. Suitable film-forming polymers are selected from
hydroxypropylmethyl cellulose, ethyl cellulose, methylcellulose, hydroxyethyl cellulose, hydroxypropyl
cellulose, sodium carboxymethyl cellulose, cellulose acetate, hydroxypropylmethyl cellulose phthalate,
cellulose acetate trimellitate, methacrylic acid copolymers, e.g., Eudragit®, polyvinylpyrrolidone, polyvinyl
alcohol, polyethylene glycol, or mixtures thereof. A preferred film-forming polymer is
hydroxypropylmethyl cellulose. Other suitable film-forming polymers which are known in the art may also
be used.
Examples of solvents used for preparing the granulation fluid or coating solution are selected from the
group comprising methyl alcohol, ethyl alcohol, isopropyl alcohol, n-butyl alcohol, acetone, acetonitrile,
chloroform, methylene chloride, water, or mixtures thereof.
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The pharmaceutical composition of the present invention is intended for oral use, and can be in the form of
tablets, capsules, mini tablets, granules, or pellets, wherein the composition can be further film coated.
The invention is further illustrated by the following examples, which are provided for illustrative purposes
only and should not be construed as limiting the scope of the invention in any way.
EXAMPLES
Example 1
Ingredients mg/tab
Intragranular
Heavy magnesium carbonate 137.00
Calcium silicate (Zeopharm®250) 10.00
Crospovidone (Kollidon CL) 10.00
Copovidone (Kollidon VA 64) 20.00
Extragranular
Linagliptin (Form F) 5.00
Magnesium stearate
(Ligamed MF-2-V)
3.00
Film coating
Opadry Pink 5.00
Purified Water Qs
Total film coated tablet weight 190.00
Process Dry granulation
Procedure
1. Magnesium carbonate, calcium silicate, crospovidone and copovidone are sifted and mixed to obtain a
blend.
2. The blend obtained in step 1 is compacted using roller compactor to obtain granules.
3. The granules of step 2 are mixed with Linagliptin and magnesium stearate and final blend is compressed
to obtain tablets.
4. Tablets obtained in step 3 are then coated with Opadry pink coating to obtain coated tablets.
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Dry granulation process was not found to be appropriate process for preparing Linagliptin tablets due to
sticking problem, poor flow property and rough tablet surface during compression.
Example 2 – Composition of Linagliptin with intra-granular Linagliptin
Ingredients
Example 2
mg/tablet
Intragranular
Linagliptin (Form F) 5.00
Magnesium carbonate extra light 94.00
Calcium silicate (Zeopharm®250) 20.00
Sodium starch glycolate (Primojel®) 25.00
Copovidone (Kollidon VA 64) 8.00
Purified Water q.s.
Extragranualr
Sodium starch glycolate (Primojel®) 25.00
Magnesium stearate (Ligamed MF-2-V) 3.00
Film coating
Opadry Pink 03F540386 * 5.00
Purified Water q.s.
Total film coated tablet weight 185.00
* Opadry Pink 03F540386 contains Hypromellose, Titanium Dioxide, Polyethylene Glycol, and Talc, Red
iron oxide, Yellow iron oxide, FD&C Red #40 /Allura Red AC Aluminum Lake.
Procedure:
1. Linagliptin, Magnesium carbonate, calcium silicate, sodium starch glycolate were sifted to obtain
a mixture.
2. A solution of copovidone was prepared in purified water.
3. The mixture of step 1 was mixed in rapid mixer granulator followed by granulation with
copovidone solution of step 2 to obtain granules.
4. The granules obtained in step 3 were dried in fluid bed drier, and then sifted to obtain magnesium
carbonate granules.
5. Magnesium carbonate granules obtained in step 4, sodium starch glycolate and magnesium stearate
were all mixed to obtain a blend.
6. The blend obtained in step 5 was then compressed to tablets followed by coating with opadry to
obtain Linagliptin tablets.
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Table 1: Stability data for Example 2
Initial 3M-40°C/75% RH * 6M- 40°C/75% RH *
Assay (%) 99.9 98.8 98.8
RRT 1.240 Un imp-1 0.088 0.284 0.327
RRT 1.750 Un imp-2 0.079 0.105 0.148
RRT 3.330 Un imp-3 0.222 0.285 0.175
Impurity - A ND ND ND
Impurity - B ND ND 0.057
Impurity - C ND ND ND
Impurity - D ND ND 0.068
Highest unknown 0.222 0.285 0.327
Total impurities 0.850 1.476 1.379
* Pack Type: 60 CC heavy weight HDPE bottle with 30's count and cotton coil 0.5 gm per bottle
The above data shows that composition of Example 2 showed increasing trend of related substances from
initial to 3 months 40°C /75RH and 6 months 40°C /75% RH. Hence, Linagliptin API adding in intragranular
stage is not suitable. Linagliptin API to be added in extra-granular stage or dry granulation process
is essential for stability of Linagliptin composition.
Example 3-5
Ingredients
Example 3 Example 4 Example 5
mg/tablet mg/tablet mg/tablet
Intragranular
Magnesium carbonate extra light 147.00 117.00 129.00
Calcium silicate (Zeopharm®250) 5.00 8.00 8.00
Sodium starch glycolate (Primojel®) 5.00 20.00 10.00
Copovidone (Kollidon VA 64) 15.00 20.00 20.00
Purified Water q.s. q.s. q.s.
Extragranular
Linagliptin (Form F) 5.00 5.00 5.00
Sodium starch glycolate (Primojel®) - 7.00 5.00
Magnesium stearate (Ligamed MF-2-V) 3.00 3.00 3.00
Film coating
Opadry Pink 03F540386 * 5.00 5.00 5.00
Purified Water q.s. q.s. q.s.
Total film coated tablet weight 185.00 185.00 185.00
* Opadry Pink 03F540386 contains, Hypromellose, Titanium Dioxide, Polyethylene Glycol, Talc, Red iron
oxide, Yellow iron oxide, FD&C Red #40/Allura Red AC Aluminum Lake.
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Procedure:
1. Magnesium carbonate, calcium silicate, sodium starch glycolate were sifted to obtain a mixture.
2. A solution of Copovidone was prepared in purified water.
3. The mixture of step 1 was mixed in rapid mixer granulator followed by granulation with
Copovidone solution of step 2 to obtain granules.
4. The granules obtained in step 3 were dried in fluid bed drier, and then sifted to obtain magnesium
carbonate granules.
5. Magnesium carbonate granules obtained in step 4, were mixed with Linagliptin and sodium starch
glycolate & later mixed with magnesium stearate to obtain a blend.
6. The blend obtained in step 5 was then compressed to tablets followed by coating with Opadry to
obtain Linagliptin tablets.
Dissolution studies:
The dissolution tests were carried out using tablets prepared in Example 3, Example 4, Example 5 and
reference-listed drug Tradjenta® Tablets 5mg. The dissolution studies (Table 2) were carried out in USP
type II apparatus, paddle rotating at 50 rpm, at a temperature of 37o
C ± 0.5o
C, in 500ml of 0.1N HCl for
45 min.
Table 2: Percentage of drug released in 500 ml of 0.1 N Hydrochloric acid
Time
(min)
Tradjenta® Tablets 5 mg Example 3 Example 4 Example 5
5 48 55 60 40
10 90 82 89 85
15 96 82 91 96
20 97 82 91 97
30 96 82 91 98
45 97 82 91 98
F2 - 47 60 71
The above results show that dissolution profile of Example 5 matches closely with the reference listed
product (Tradjenta? tablets)
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Dissolution Graph:
Dissolution graph for Tradjenta® Tablets 5 mg, Example 3, Example 4 and Example 5 as shown in figure
3.
Further, it was observed that the Linagliptin tablets of the present invention have good stability. The assay
value and the amount of impurities (at initial time point and after 6 months storage at accelerated conditions
and 12 months storage at long term condition) for Example 5 are given below in Table 3.
Table 3: Stability data for Example 5
Initial 6M (40°C/75% RH)* 6M (25°C/60% RH)* 12M (25°C/60% RH)*
Assay (%) 100 97.2 96.8 101.8
(RRT 1.24) Un
imp-1
0.042 0.039 0.013
0.034
(RRT 1.75) Un
imp-2
0.030 0.036 0.033
0.006
(RRT 3.33) Un
imp-3
0.026 ND ND
0.017
Impurity - A 0.010 0.013 0.008 0.01
Impurity - B 0.004 0.023 0.021 0.022
Impurity - C 0.025 0.005 0.003 0.004
Impurity - D ND 0.035 ND 0.032
Highest
Unknown
0.042 0.039 0.033 0.034
Total
impurities
0.184 0.203 0.119 0.178
The above results show that composition of the present invention is stable even after storage for 6 months
at 40°C and 75% RH and 12 months at 25°C and 60% RH.
Dissolution Studies
The dissolution tests were carried out using tablets prepared in Example 5 (both at initial time point and
after storage). The dissolution studies (Table 4) were carried out in USP type II apparatus, paddle rotating
at 50 rpm, at a temperature of 37o
C ± 0.5o
C, in 500 ml of 0.1N HCl for 45 minutes.
Table 4: Dissolution Data for Example 5
Time (min) Initial 6M (40°C/75% RH)* 6M (25°C/60% RH)* 12M (25°C/60% RH)*
5 40 40 44 31
10 85 91 86 89
15 96 99 98 99
20 97 100 98 99
30 98 99 93 99
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45 98 99 98 100
infinity 98 99 99 100
* Pack Type: 60 CC heavy weight HDPE bottle with 30's count and 3 no’s of 1 gm silica gel pillow pack
and cotton coil 1.2 gm per bottle
The above data shows that composition of Example 5 showed favorable dissolution profile even after
storage for 6 months at 40°C and 75% RH and 12M 25°C and 60% RH.
Table 5 Comparative stability data at various intervals (40°C/75% RH) with reference to the total
related substances.
Example 2
(Linagliptin Intragranular)
Example 5
(Linagliptin Extragranular)
Initial 6M Initial 6M
Total RS
(% w/w)
0.850 1.379 0.184 0.203
The above table clearly shows that Linagliptin tablets comprising extragranular Linagliptin are more stable
as compared to tablets having intragranular Linagliptin.
After the three months stability, tablets were subjected to an XRD analysis in order to see if the crystalline
form used remained the same. The XRD analysis proved that the crystalline form F was maintained. ,CLAIMS:1. A stable Linagliptin composition comprising Linagliptin or a pharmaceutically acceptable salt
thereof, wherein the composition is free of microcrystalline cellulose, mannitol and pregelatinsed
starch, and the said composition has less than 0.3% w/w of total impurity when stored at 40oC/75%
RH and 25oC/60% RH for a period of six months.
2. The stable Linagliptin composition according to claim 1 wherein the composition is a tablet.
3. The stable Linagliptin composition according to claim 1 wherein the composition is prepared by a
granulation process.
4. The stable Linagliptin composition according to claim 3 wherein the composition is prepared by
wet granulation process.
5. The stable Linagliptin composition according to claim 4 wherein the composition is prepared by
dry granulation process.
6. According to another embodiment of the present invention, Linagliptin is present extra granularly.
7. A process for the preparation of stable Linagliptin composition comprising Linagliptin or a
pharmaceutically acceptable salt thereof, wherein the composition the composition is prepared by
a wet granulation process and the linagliptin is added extragranularly.
8. The process for the preparation of stable Linagliptin composition according to claim 7 comprising
the steps of:
(i) preparing a granulation fluid by dispersing a binder in a solvent;
(ii) premixing one or more diluent, and one or more disintegrant to obtain a premix;
(iii) granulating the premix obtained in step (ii) with the granulation fluid
obtained in step (i) to form a wet mass;
(iv) drying the wet mass obtained in step (iii) and then milling to obtain granules;
(v) blending Linagliptin with the granules obtained in step (iv).
(vi) lubricating the blended granules obtained in step (v) and finally compressing into tablets; and
(vii) optionally coating the tablet obtained in step (vi).
9. The process for the preparation of stable Linagliptin composition according to claim 7 wherein the
composition is free of microcrystalline cellulose, mannitol and pregelatinsed starch.
10. The process for the preparation of stable Linagliptin composition according to claim 7 wherein the
said composition less than 0.3% w/w of total impurity when stored at 40oC/75% RH and 25oC/60%
RH for a period of six months