FIELD OF THE INVENTION

The present invention relates to the salt of Doxylamine. More specifically, the present
invention is related to a novel Doxylamine foliate salt, and a pharmaceutical composition
comprising the same. The present invention also relates to a process for the synthesis of
Doxylamine foliate salt, and a method for purification of the same.
BACKGROUND OF THE INVENTION
Doxylamine i.e., (RS)-N,N-dimethyl-2-[1-phenyl-1-(pyridin-2-yl) ethoxy] ethan-1-amine is a
first-generation histamine receptor Hl antagonist. Doxylamine is used to manage and treat
nausea and vomiting of pregnancy (NVP), allergic rhinitis, insomnia, multiple anaphylaxis
dermatosis, spring fever, asthmatic bronchitis etc.
Doxylamine is in liquid state at room temperature. Therefore, it is converted into its succinic
acid salt which is a white/creamy solid to facilitate its use in solid pharmaceutical
compositions. Doxylamine succinate is the active ingredient in many over-the-counter sleepaids
brands. It is studied extensively both in monotherapy as well as combination therapy.
Combination therapy involving fixed dose formulations of Doxylamine and other active
ingredients like Vitamin B, antitussives, decongestants, analgesics etc. have been studied.
Under brand names e.g., Diclcgis"~. Diclectin''', combination or Doxylamine and Vitamin B6
is prescribed for alleviating symptoms of morning sickness during pregnancy.
Solid state of Doxylamine succinate is advantageous but it has some highly undesirable
properties which are disadvantageous in terms of manufacturing cost, shelf life, and customer
satisfaction.
Doxylamine succinate is a highly hygroscopic solid. Therefore, formulations containing it
require specialized manufacturing processes and conditions. During powder milling it is
difficult to control size of drug particles as absorbed water will make the material tough and
resistant to powder milling. During tablet compounding, unwanted moisture retard
appropriate reactions, forms unwanted end products which results in minimum quality and
reduced shelf life. During powder flow, the capacity of the powder materials to flow evenly is
reduced due to enhanced moisture content. This is due to the enhancement of thickness of the
adsorbed liquid layer. This in tum improves the stability or firmness of liquid bridges formed
between particles. Increased surface tension is due to the increased surface moisture, this

concludes in attraction between particles. For Effervescent Tablets, uncontrolled moisture in
manufacturing areas affects surface finish and result in softened tablets. While in cough drop,
material adhere to the stamping machine when humidity is high. Since aluminium is moisture
sensitive in nature. It can result in penetration of moisture inside the packing during storage.
At the time of Dry Powder filling I Vial filling, due to uncontrolled moisture powders get
adhere to the conveyor, and influence process of filling. During strip packaging, increased
moisture content in the atmospheric air present in the packaging area will eventually pave the
way for the tablets and capsules to absorb moisture from the environment thus decrease the
shelf life. This may also reduce efficiency of the final materials.
Another limitation associated with use of Doxylamine Succinate is its extremely unpleasant
bitter taste. A formulation into simple tablet may induce vomiting. This negative sensory
attribute of Doxylamine Succinate is highly undesirable when mode of administration is oral.
Studies suggest that undesirable taste of pharmaceutical compositions leads to
discontinuation of medication course by a patient. Efforts have been made to mask the bitter
taste of Doxylamine Succinate formulations using taste masking agents like sweetening
agents, flavouring agents, lipid encapsulants, complexing agents, mucosa numbing agents etc.
EP25000 16A 1 discloses a doxylamine resinate complex which is substantially free from
bitter taste. US20210386732Al provides a semi-solid pharmaceutical composition containing
antihistamine complex which has reduced bitterness. Although, these strategies are not
satisfactory, and an unpleasant after-taste may remain in the mouth.
Still another limitation associated with use of Doxylamine Succinate is its incompatibility
with various commonly used pharmaceutical ingredients/excipients e.g., aspartame,
acetaminophen, dextromethorphan hydrobromide, codeine phosphate, pseudoephedrine
hydrochloride, magnesium stearate, stearic acid, P. V .P. and lactose.
Keeping in mind the disadvantages associated with use of Doxylamine succinate in oral dry
pharmaceutical compositions, there is need for Doxylamine which is solid at room
temperature and have better palatability, moisture resistant, and compatibility.
Combination therapy involving fixed dose formulation comprising Doxylamine succinate,
Pyridoxine (Vitamin B6) and folic acid (Vitamin B9) is known under the brand name
Evanorm" which is prescribed to alleviate symptoms of morning sickness. Evanorm:" is a

20mg/20mg/5mg fixed dose tablet containing Doxylamine succinate, pyridoxine
hydrochloride and folic acid. Preparation of fixed dose tablets like Evanorm'"1 requires
specialized manufacturing practices which increases cost of manufacturing. Further, a minor
mismatch in fixed dosage may have dire consequences due to side effects associated.
Therefore, it will be highly advantageous if the individual effects of doxylamine and folic
acid can be combined synergistically.
Keeping in v1ew the abovementioned disadvantages associated with monotherapy and
combination therapy involving doxylamine, it will be highly desirable to prepare doxylamine
foliate salt which is solid at room temperature and has highly desirable qualities in terms of
taste, moisture control and compatibility.
SUMMARY OF THE INVENTION
Accordingly, the present invention discloses a doxylamine foliate salt of Formula I.
•
Formula I
The present invention also discloses a process for synthesis of a doxylamine foliate salt of
Formula I, comprising,
dissolving N,N-dimethyl-2-[ 1-phenyl-1-(pyridin-2-yl) ethoxy] ethan-1-amine
(Doxylamine) in a solvent, adding folic acid, and refluxing the reaction mass for a
time period in a range of 600 to 720 minutes,
cooling down the reaction mass to the room temperature and stirring the reaction mass
for a time period in a range of 60 to 120 minutes.
filtering the reaction mass to obtain crude doxylamine foliate salt as a residue,
washing the residue with a solvent to obtain a washed residue, and
drying the washed residue to obtain a crude Doxylamine foliate salt of Formula I.

The present invention further discloses a process for purification of a crude doxylamine
foliate salt of Formula I, comprising,
dissolving the crude Doxylamine foliate salt of Formula I in a solvent and heating the
solution to a temperature range of 50 to 55°C,
stirring the solution for 1 hour while maintaining the temperature range of 50 to 55°C,
cooling down the solution to a temperature range of 25 to 30°C,
stirring the solution for 1 hour while maintaining the temperature range of 25 to 30°C,
filtering the solution to obtain a residue and washing the residue with a solvent to
obtain a washed residue, and
drying the washed residue to obtain a pure Doxylamine foliate salt of Formula I.
The solvent used in the process is a ketone solvent selected from methyl ethyl ketone, methyl
isobutyl ketone, and acetone.
The present invention further discloses a pharmaceutical composition compnsmg a
Doxylamine foliate salt of Formula I and at least one pharmaceutically acceptable excipient.
The present invention further discloses a pharmaceutical composition comprising a
Doxylamine foliate salt of Formula I and at least one pharmaceutically active ingredient.
OBJECTIVES OF THE PRESENT INVENTION
It is the primary objective of the present invention to provide a Doxylamine foliate salt of
Formula I.
Formula I
It is another objective of the present invention to synthesize a Doxylamine foliate salt of
Formula I.
It is another objective of the present invention to purify a Doxylamine foliate salt of Formula I.

It is further objective of the present invention to provide a pharmaceutical composition
comprising a Doxylamine foliate salt of Formula I and at least one pharmaceutically
acceptable excipient.
It is further objective of the present invention to provide a pharmaceutical composition
comprising a Doxylamine foliate salt of Formula I and at least one pharmaceutically active
ingredient.
BRIE.F DESCRIPTION OF THE DRAWINGS
To further clarify advantages and aspects of the disclosure, a more particular description of
the present disclosed process and Doxylamine foliate salt will be rendered by reference to
specific embodiments thereof, which is illustrated in the appended drawing(s) and explained
hereinafter in the description section. It is appreciated that the drawing(s) as provided herein
depicts only typical embodiments of the process and are therefore not to be considered
limiting of its scope.
Figure 1: synthesis route of Doxylamine Foliate of formula I.
Figure 2: X-ray diffraction (XRD) pattern of Doxylamine Foliate of formula I, prepared
according to Example 1.
Figure 3: IR spectra of Doxylamine Foliate of formula I, prepared according to Example 1.
Figure 4: HNMR of Doxylamine Foliate of formula I, prepared according to Example 1.
DESCRIPTION OF THE PRESENT INVENTION
It is evident from that Doxylamine is generally used in salt form i.e., succinate salt. Further,
since it is always recommended to take folic acid during pregnancy, the formulation of
Doxylamine succinate is also available with folic acid. However, there are not enough
evidence, whether succinic acid is safe during pregnancy.
According to the main embodiment, the present disclosure provides a process for synthesis of
a doxylamine foliate salt of Formula I.

Formula I
The process includes dissolving N,N-dimethyl-2-[1-phenyl-1-(pyridin-2-yl) ethoxy] ethan-1-
amine (Doxylamine) in a solvent, adding folic acid, and refluxing the reaction mass for a time
period in a range of 600 to 720 minutes. Then cooling down Lhe reaction mass to the room
temperature and stirring the reaction mass for a time period in a range of 60 to 120 minutes.
Filtering the reaction mass to obtain crude doxylamine foliate salt as a residue, washing the
residue with a solvent to obtain a washed residue, and drying the washed residue to obtain a
crude Doxylamine foliate salt of Formula I.
According to the main embodiment, the present disclosure provides a process for purification
of a crude doxylamine foliate salt of Formula I. The purification process includes dissolving
the crude Doxylamine foliate salt of Formula I in a solvent and heating the solution to a
temperature range of 50 to 55°C. Stirring the solution for 1 hour while maintaining the
temperature range of 50 to 55°C. Cooling down the solution to a temperature range of 25 to
30°C, and stirring the solution for 1 hour while maintaining the temperature range of 25 to
30°C. Filtering the solution to obtain a residue and washing the residue with a solvent to
obtain a washed residue, and drying the washed residue to obtain a pure Doxylamine foliate
salt of Formula I.
The solvent used in the process as provided herein is a ketone solvent selected from methyl
ethyl ketone, methyl isobutyl ketone, and acetone.
Doxylamine foliate salt of Formula I according to the invention has a characteristic IR
spectrum as shown in Figure-3.
In an embodiment Doxylamine foliate salt of Formula I obtained by using present invention
having purity more than 99.85%.
A powder X-ray powder diffraction pattern as depicted in Figure 2 characterizes the
crystalline form of Doxylamine foliate salt of Formula I of the invention.

Another aspect of the invention provides a crystalline form of Doxylamine foliate salt of
Formula I, wherein the X-ray powder diffraction (XRPD) pattern having peaks at 2 theta
values 10.68±0.2, 13.09±0.2, 18.15±0.2, 19.21±0.2 and 31.05±0.2.
Another aspect of the invention crystalline form of Doxylamine foliate salt of Formula I
having PXRD characteristic peaks, d-spacing and relative intensity shown in below Table I.
No. Position Height [ cts] Rel.Int. FWHM Area d-spacing
[
0 28] [%] Total lA 0
]
[
0 28] [cts *0 28]
1 5.43 329.48 42.21 0.1314 56.95 16.25
2 10.68 780.52 100.00 0.1501 135.38 8.12
,.,
.) 11.58 154.91 19.85 0.1067 15.70 7.63
4 13.09 600.11 76.89 0.1553 123.15 6.75
5 16.38 356.21 45.64 0.1713 33.85 5.40
6 17.05 294.72 37.76 0.1599 62.94 5.19
7 18.15 446.12 57.16 1.0059 487.73 4.88
8 19.21 534.91 68.53 0.7038 275.39 4.61
9 21.31 272.89 34.96 2.5331 645.28 4.16
. -
10 26.71 279.37 35.79 0.3722 182.62 3.33
11 27.84 339.79 43.53 0.4539 185.82 3.20
12 29.44 90.17 11.55 0.3208 39.76 ,., 0'"' .) . .)
13 31.05 407.55 52.22 4.8328 214.09 2.87
EXAMPLES:

1: Synthesis of Doxylamine foliate salt of Formula I
Example 1.1
Charge Methyl Ethyl Ketone 173.0 ml inN, N-dimethyl-2-[1-phenyl-1-(pyridin-2-yl) ethoxy]
ethan-1-amine 17.3 gm and Charge 14.1 gm Folic acid. Reaction mass were heated to get
reflux temp. Stir the reaction mass for 600 min to 720 min. after maintaining completion cool
the reaction mass to room temp. Stir the reaction mass at room temp. Filter the reaction mass
and wash the wet cake using Methyl Ethyl Ketone after drying gives Doxylamine Foliate
22.4 gm (89%).
1H-NMR (DMSO): 1H NMR: 8 1.9 (3H, s), 1.92 (2H q), 2.33 (6H, s), 2.47 (2H t), 2.86 (2H t
), 3.82 (2H t), 4.34 (lH t), 4.43 (2H s), 6.96 (2H ddd), 7.36 (6H,tt), 7.72-8.63 ((7H, 7.78 ddd,
), 7.78 (ddd, ), 7.90 (dddd, ), 7.90 (dddd, ), 7.96 (s)).
Melting point: 164 to 181.6 oc
Molecular formula: C36H41N907
Molecular weight: 711.76
Example 1.2
Charge Methyl Isobutyl Ketone 170.0 ml in N, N-dimethyl-2-[1-phenyl-1-(pyridin-2-yl)
ethoxy] ethan-1-amine 17.3gm and Charge 14.1 gm Folic acid. Reaction mass were heated to
get reflux temp. Stir the reaction mass for 600 min to 720 min. after maintaining completion
cool the reaction mass to room temp. Stir the reaction mass at room temp. Filter the reaction
mass wash the wet cake using Methyl Isobutyl Ketone after drying gives Doxylamine Foliate
22.0 gm (89%).
Example 1.3
Charge Acetone 170.0 ml inN, N-dimethyl-2-[1-phenyl-1-(pyridin-2-yl) ethoxy] ethan-1-
amine 17.3 gm and Charge 14.1 gm Folic acid. Reaction mass were heated to get reflux temp.
Stir the reaction mass for 600 min to 720 min. after maintaining completion cool the reaction
mass to room temp. Stir the reaction mass at room temp. Filter the reaction mass wash the
wet cake using Acetone after drying gives Doxylamine Foliate 20.0 gm (81 %).
2: Purification of Doxylamine foliate salt of Formula I
Example 2.1

Charge Acetone 100 ml and Doxylamine foliate crude 10 gm. Heat the reaction mass to 50 -
55°C and stir at 50 - 55°C for 1 hr. Cool the reaction mass to ·25 - 30°C, stir the reaction
mass at 25 - 30°C for 1 hr. Filter the reaction mass and wash the cake using 25 ml Acetone
after drying gives pure Doxylamine Foliate 8 gm, purity: 99.8%
Example 2.2
Charge Methyl Isobutyl Ketone 100 ml and Doxylamine foliate crude 10 gm. Heat the
reaction mass to 65 - 75°C and stir at 65 - 75°C for 1 hr. Cool the reaction mass to ·25 -
30°C, stir the reaction mass at 25 - 30°C for 1 hr. Filter the reaction mass and wash the cake
using 25 ml Methyl Isobutyl Ketone after drying gives pure Doxylamine Foliate 7.5 gm,
purity: 99.5%
Example 2.3
Charge Methyl Ethyl Ketone 100 ml and Doxylamine foliate crude 10 gm. Heat the reaction
mass to 60- 70°C and stir at 60- 70°C for 1 hr. Cool the reaction mass to ·25 - 30°C, stir the
reaction mass at 25 - 30°C for 1 hr. Filter the reaction mass and wash the cake using 25 ml
Methyl Ethyl Ketone after drying gives pure Doxylamine Foliate 7.8 gm, purity: 99.7%.
3. Preparation of enteric coated tablet comprising Doxylamine foliate salt of Formula I
and Pyridoxine HCI
Example 3.1
Dibasic calcium phosphate and/or lactose, microcrystalline cellulose (MCC), pyridoxine HCl,
pre-gelatinised starch or povidone, doxylamine foliate, and croscarmcllosc sodium or sodium
starch glycollate are sifted through #40 mesh and collected in a polythene bag. The sifted
content is then mixed well in a rapid mixer granulator (RMG) and doxylamine is added to the
mixture. The mixture is then mixed again for 5 minutes, and purified water is added to
facilitate granulation. The granules obtained are then dried at a temperature between 40°C
and 60°C at a target Loss on Drying (LOD) of not more than (NMT) 3 % and sifted through a
#30 mesh. The dried granules are then lubricated with croscarmellose sodium/sodium starch
glycollate and colloidal silicon dioxide followed by further lubrication with magnesium
stearate/sodium stearyl fumarate. The lubricated blend is then compressed using suitable
punches and seal coated using dispersion of HPMC/polyvinyl alcohol, talc and

PEG6000/triethyl citrate to gain weight between 2.5-3.5 % w/w. The seal coated tablet is then
further coated using enteric coating polymeric system to obtain enteric coated tablets with
weight up to 7- 12 % w/w. The enteric coated tablets are then subjected to Disintegration
Time and Drug limit release as per monograph for enteric coated tablet requirement. The
chemical composition of an enteric coated tablet containing Doxylamine Foliate and
Pyridoxine equivalent to 10 mg of Doxylamine, 2.5 mg of folic acid, and 10 mg of
Pyridoxine HCL is provided in Table-] below:
Tablc-1: Chemical composition of each enteric coated tablet
Ingredients
Stage I: Dry-mix mg/ Tablets % Comp.
Doxylamine foliate eqto folic acid
4.031
2.5 mg
Doxylamine foliate eqto Doxylamine 1.531 mg
Dibasic Calcium Phosphate Anhydrous/Lactose - 10-25%
Microcrystalline cellulose - 45-68%
Croscarmellose sodium I Sodium starch
- 2-6% glycollate
Partially Pregelatinized maize starch/Povidone - 4-6%
Pyridoxine HCL 10.000 6.67
Granulation
Doxylamine free base 8.469 5.65
Purified Water q.s. q.s.
Stage II: Lubrication
Croscarmellose sodium/Sodium starch glycollate - 2-6.67%
Colloidal silicon dioxide - 0.53-1.67%
Magnesium Stearate/Sodium stearyl
fumarate/Talc - 1.33-3.33%
Total weight 150.000 100.00
Coating
Seal Coating -
HPMC/Polyvinyl Alcohol - 2-20%
Talc - 0.5-5%
PEG 6000/Triethyl citrate - 0.5-5%
Purified Water
Enteric Coating -
Enteric coating system 15.500 7-10%
Purified Water -
Enteric Coating Total Weight 170.000 -

The present invention is carried out using scale up scale down dose weight proportionate for
lower and higher strength and above composition is given for lower strength.
Advantages:
The present process provides Doxylamine foliate compound and thus the synthesis of
Doxylamine foliate does not involve the use of succinic acid and hence avoid the
consumption of succinic acid. Accordingly, the present process provides many advantages,
the present process avoids the use of succinic acid and hence avoid unnecessary
consumption/exposure of succinic acid during pregnancy.
Instead of using succinic acid, the present process discloses preparation of folic acid salt of
Doxylamine. Therefore, present process involves use of folic acid salt which also has
therapeutic properties and recommended in pregnancy.
The present process avoids preparation of combination drug of Doxylamine salt and folic
acid, as folic acid is provided in the API itself. The present process overcome all drawbacks
such as hygroscopicity, bitter taste etc. as it does not involve the use of succinic acid.
We claim,
1. A compound Doxylamine foliate of formula I.
Formula I
2. A Crystalline form of the Doxylamine foliate of formula I.
3. The crystalline form of Doxylamine foliate of formula I as claimed 111 claim 2,
wherein crystalline form having XRPD pattern as shown in figure 1.
4. The crystalline form of Doxylamine foliate of formula I as claimed in claim 2,
wherein the X-ray powder diffraction (XRPD) pattern having peaks at 2 theta values
at 10.68±0.2, 13.09±0.2, 18.15±0.2, 19.21±0.2 and 31.05±0.2.
5. The Doxylamine foliate of formula I having purity ranges from 99.5% to 99 .8%.
6. The process for preparation of the compound of formula I
~-~c
Formula I
comprising the steps of;
a) reacting N,N-dimethyl-2-[1-phenyl-1-(pyridin-2-yl) ethoxy] ethan-1-amine
(Doxylamine) with folic acid in solvent at reflux temperature;
b) cooling the reaction mass of step (a) to the 35-40°C to obtained Doxylamine
foliate of Formula I;
c) optionally purifying the Doxylamine foliate salt of Formula I to obtained pure
compound of formula I.
7. The process as claimed in claim no. 6 wherein solvent is ketone solvent selected from
methyl ethyl ketone, methyl isobutyl ketone, and acetone.
8. The process as claimed in claim no. 6 wherein N,N-dimethyl-2-[1-phenyl-1-(pyridin-
2-yl) ethoxy] ethan-1-amine (Doxylamine) reacted with folic acid for a time period of
600 to 720 minutes.
9. Pharmaceutical composition compnsmg Doxylamine foliate of formula I and
pharmaceutically acceptable excipient.
10. The composition as claimed in claim no. 5, wherein pharmaceutically acceptable
excipient selected from Dibasic Calcium Phosphate Anhydrous/Lactose,
Microcrystalline cellulose, Croscarmellose sodium, Sodium starch, glycollate,
Partially Pregelatinized maize starch, Pyridoxine HCL, Croscarmellose sodium,
Sodium starch glycollate , Colloidal silicon dioxide, Magnesium Stearate, Sodium
stearyl fumarate, HPMC, Polyvinyl Alcohol, PEG 6000, Triethyl citrate and Talc.