FORM 2
THE PATENT ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003 COMPLETE SPECIFICATION
(See section 10 and rule 13)
Title of the invention "NOVEL CRYSTALLINE FORM OF TIEMONIUM METHYLSULPHATE"
Centaur Pharmaceutical Private Limited, an Indian Company, having its Registered Office at Centaur House, Near Grand Hyatt, Shanti Nagar, Vakola, Santacruz (East), Mumbai- Maharashtra, 400055, India
1. The following specification describes the invention.

FIELD OF THE INVENTION:
The present invention relates to crystalline forms of Tiemonium methylsulphate and the process for the preparation of crystalline forms of Tiemonium methylsulphate.
BACKGROUND OF THE INVENTION:
Tiemonium methylsulphate is chemically N-Methyl-N- [3-Hydroxy-3-phenyl-3- (α-thienyl) propyl] morpholine methyl sulfate and is described in Patent no. GB1047919.
Tiemonium methylsulphate is represented by compound of structural formula I.

Patent no. GB1047919 described the crystallization process of Tiemonium methylsulphate in 95% ethanol and the obtained Tiemonium methylsulphate takes the form of white crystals, has a melting point of 135.5-137°C and decomposes at about 150°C.
Tiemonium methylsulphate is an antispasmodic drug. It reduces muscle spasms of the intestine, biliary system, uterus & urinary bladder. It is indicated for the pain in gastrointestinal & biliary disease in the urology and gynecology such as gastroenteritis, diarrhea, dysentery, biliary colic, enterocolitis, cholecystytis, colonopathyes, mild cystitis, & spasmodic dysmenorrhoea. Tiemonium strengthens calcium bonding with phospholipids and proteins thus stabilizing the cell membrane of the Gl tract.

The oral tablet (40mg and 50mg); injectable (5mg/2ml) and suppository (20mg) dosage forms of Tiemonium methylsulphate are approved in Europe.
The polymorphism of Tiemonium methylsulphate is not disclosed in the prior art and only crystalline form of Tiemonium methylsulphate is disclosed in Patent no. GB1047919, we herein refer this form as alpha crystalline form. Alpha crystalline form of Tiemonium methylsulphate does not have good flow properties, which led to challenges in the granulation process for preparing tablet and suppository dosage forms.
Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule may give rise to a variety of crystalline forms having distinct crystal structures and physical properties like melting point, x-ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum. One crystalline form may give rise to thermal behavior different from that of another crystalline form. Thermal behavior can be measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis ("TGA"), and differential scanning calorimetry ("DSC") as well as by content of solvent in the crystalline form, which have been used to distinguish polymorphic forms.
The difference in the physical properties of different crystalline forms results from the orientation and intermolecular interactions of adjacent molecules or complexes in the bulk solid. Accordingly, polymorphs are distinct solids sharing the same molecular formula yet having distinct advantageous physical properties compared to other crystalline forms of the same compound or complex.
One of the most important physical properties of pharmaceutical compounds is their solubility in aqueous solutions, particularly their solubility in the gastric juices of a patient. For example, where absorption through the gastrointestinal tract is slow, it is often desirable for a drug that is unstable to conditions in the patient's stomach or intestine to dissolve slowly so that it does not accumulate in a deleterious environment. Different crystalline forms or polymorphs of the same pharmaceutical compounds can and reportedly do have different aqueous solubility.

The discovery of new polymorphic forms and solvates of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.
Accordingly there is a need in the art to develop new crystalline form of Tiemonium methylsulphate.
SUMMARY OF THE INVENTION:
A first aspect of the present invention is to provide a crystalline form of Tiemonium methylsulphate herein after referred as Form A.
A second aspect of the present invention is to provide a crystalline form of Tiemonium methylsulphate herein after referred as Form B.
A third aspect of the present invention is to provide a process of preparing crystalline form A of Tiemonium methylsulphate comprising the steps of:
a. providing a solution of Tiemonium in a ketone solvent;
b. adding dimethyl sulphate and
c. isolating crystalline form A of Tiemonium methylsulphate.
A fourth aspect of the present invention is to provide a process of preparing crystalline form B of Tiemonium methylsulphate comprising the steps of:
a. providing a solution of Tiemonium methylsulphate in an alcoholic solvent and
b. isolating crystalline form B of Tiemonium methylsulphate.

Another aspect of the present invention is to provide pharmaceutical composition containing crystalline form A of Tiemonium methylsulphate and a pharmaceutically acceptable carrier.
Another aspect of the present invention is to provide pharmaceutical composition containing crystalline form B of Tiemonium methylsulphate and a pharmaceutical^ acceptable carrier.
Another aspect of the present invention is to use crystalline form A of Tiemonium methylsulphate in preparing oral tablet (40mg and 50mg); injectable (5mg/2ml) and suppository (20mg) dosage forms.
Another aspect of the present invention is to use crystalline form B of Tiemonium methylsulphate in preparing oral tablet (40mg and 50mg); injectable (5mg/2ml) and suppository (20mg) dosage forms.
DETAIL DESCRIPTION OF THE INVENTION:
A crystalline form A of Tiemonium methyl sulphate can be characterized by Powder X-ray diffraction pattern as depicted in Figure 1.
A crystalline form A of Tiemonium methyl sulphate can be characterized by powder X-ray diffraction pattern having following peaks:

Position [°2Theta] d(A)
4.5 19.44
9.1 9.76
13.7 6.46
14.4 6.15

17.2 5.14
18.1 4.89
21.9 4.07
A crystalline form A of Tiemonium methyl sulphate can be characterized by Powder X-ray diffraction pattern having peaks selected from the group comprising of 4.5, 9.1,13.7,14.4, 17.2, 18.1 and 21.9 ±0.2 degrees 29.
A crystalline form A of Tiemonium methyl sulphate can be characterized by DSC thermogram as depicted in Figure 2.
A crystalline form A of Tiemonium methylsulphate can be characterized by its differential scanning calorimetry thermogram having endothermic peak at 146.18°C ± 2°C.
A solution of Tiemonium in a ketone solvent can be prepared by adding Tiemonium in ketone solvent at a temperature in the range of 0°C to 25°C. Alternatively, such a solution may be obtained directly from a reaction in which Tiemonium methyl sulphate is formed.
Dimethyl sulphate can be added at a temperature in the range of 0°C to 25°C, the resulting solution of Tiemonium methylsulphate in ketone solvent can be stirred for duration of 2 hours to 15 hours at a temperature in the range of 15°C to 30°C the resulting solids were filtered, washed with chilled acetone (0°C to 5°C) and dried at a temperature in the range of 40°C to 60°C under reduced pressure.
The ketone solvents can be selected from the group comprising of acetone, methyl ethyl ketone, methyl isobutyl ketone, dibutyl ketone, diethyl ketone, dipropyl ketone, diisopropyl ketone, methyl butyl ketone, methyl propyl ketone, methyl isopropyl ketone, ethyl isopropyl ketone or mixture(s) thereof.
A crystalline form B of Tiemonium methyl sulphate can be characterized by Powder X-ray diffraction pattern as depicted in Figure 3.

A crystalline form B of Tiemonium methyl sulphate can be characterized by powder X-ray diffraction pattern having following peaks:

Position [°2Theta] d(A)
8.4 10.54
10.2 8.68
10.3 8.55
12.5 7.07
13.3 6.65
15.5 5.74
18.6 4.76
20.5 4.34
22.4 3.97
24.2 3.67
A crystalline form B of Tiemonium methyl sulphate can be characterized by its Powder X-ray diffraction pattern having peaks selected from the group comprising of 8.4,10.2, 10.3, 12.5, 13.3, 15.5, 18.6, 20.5, 22.4 and 24.2 ± 0.2 degrees 20.
A crystalline form B of Tiemonium methyl sulphate can be characterized by DSC thermogram as depicted in Figure 4.
A crystalline form B of Tiemonium methylsulphate can be characterized by its differential scanning calorimetry thermogram having endothermic peak at 157.35°C ± 2°C.
A solution of Tiemonium methylsulphate in an alcoholic solvent can be prepared by adding Tiemonium methylsulphate in an alcoholic solvent at a temperature in the range

of 0°C to 25°C. Alternatively, such a solution may be obtained directly from a reaction in which Tiemonium methyl sulphate is formed.
A solution of Tiemonium methylsulphate in an alcoholic solvent can be refluxed for duration of 30 minutes to 15 hours at a temperature in the range of 50°C to 65°C and excess organic solvent may be distilled out from the reaction mixture.
The resulting reaction mixture can be further diluted with an alcohol solvent.
A crystalline form B of Tiemonium methylsulphate can be isolated by the steps of cooling and filtering of reaction mixture.
The crystalline form B of Tiemonium methylsulphate can be washed with alcohol solvent at a temperature in the range of 0°C to 5°C.
The crystalline form B of Tiemonium methylsulphate can be dried under reduced pressure at a temperature in the range of 40°C to 60°C.
The crystalline form B of Tiemonium methylsulphate can be prepared by seeding the solution of Tiemonium methylsulphate in an alcoholic solvent with crystalline form B of Tiemonium methylsulphate at a temperature in the range of 35°C to 65°C.
The alcoholic solvents can be selected from the group comprising of methanol, ethanol, propanol, isopropanol, butanol, isobutanol, t-butanol, pentanol or mixture(s) thereof.
BRIEF DESCRIPTION OF THE DRAWINGS:
Figure 1 depicts powder X-ray diffraction pattern of crystalline form A of Tiemonium
methylsulphate.
Figure 2 depicts DSC thermogram of crystalline form A of Tiemonium methylsulphate.

Figure 3 depicts powder X-ray diffraction pattern of crystalline form B of Tiemonium
methylsulphate.
Figure 4 depicts DSC thermogram of crystalline form B of Tiemonium methylsulphate.
XRD diffraction measurement was performed on X-Ray powder diffractometer PANalytical
X'Pert PRO, diffractometer equipped with X'Celerator detector. The analysis conditions were
as follows:
Scan range [°2-theta]: 2-39.98;
Scan mode: Continuous;
Step size [°2-theta]: 0.0170°;
Measurement Temperature [°C]: 25
Anode Material: Cu
K-Alpha[A]: 1.54060
Prior to analysis, the samples were gently ground by means of mortar and pestle in order to obtain a fine powder. The sample might be mixed with n-dodecane in order to avoid the environment contamination by airborne particles coming from the powder. The ground sample or its suspension with n-dodecane was adjusted into a cavity of the sample holder and the surface of the sample was smoothed by means of a cover glass.
Differential scanning calorimetry was carried out by means of a Mettler-Toledo DSC-822e calorimeter using aluminum crucibles, and a heating rate of 10°C/min, from 30° up to 300 °C. The measurements were carried out in a dry nitrogen atmosphere using a 50 ml/min flow rate. The calorimeter was calibrated with indium of 99.99% purity.
The differential scanning calorimetry thermogram for crystalline form A of Tiemonium methylsulphate showed a sharp endothermic peak with an onset at 142.11°C and a maximum at 146.18°C.

The differential scanning calorimetry thermogram for crystalline form B of Tiemonium methylsulphate showed a sharp endothermic peak with an onset at 155.65°C and a maximum at 157.35°C. EXAMPLES:
In the following examples, the preferred embodiments of the present invention are described only by way of illustrating the process of the invention. However, these are not intended to limit the scope of the present invention in any way.
Example: 1:
A solution of N-[3-hydroxy-3-phenyl-3-(a-thienyl) propyl] morpholine (20 gm) in acetone (80 ml) was cooled to 10°C. Dimethyl sulphate (7.1 gm) was added at 10-12°C and resulting reaction mixture was stirred for 12 hours at a temperature in the range of 25-30°C. The resulting solids were filtered, washed with acetone (10 ml) and dried at 55°C under reduced pressure. Yield= 21 gm
Purity: 99.70% (By HPLC)
XRD: As depicted in Figure 1
DSC: As depicted in Figure 2
Example: 2:
A solution of Tiemonium methylsulphate (10 gm) in methanol (10 ml) was heated to 60°C and methanol (5 ml) was distilled out from reaction mixture. The isopropanol (25 ml) was added in the reaction mixture at 60°C and resulting reaction mixture was again stirred for 30 minutes and then cooled to 25°C in 30 minutes. The resulting solids were filtered, washed with isopropanol (5 ml) and dried at 60°C under reduced pressure. Yield= 9.2 gm
Purity: 99.85% (By HPLC)

XRD: As depicted in Figure 3 DSC: As depicted in Figure 4
Example: 3:
A solution of Tiemonium methylsulphate (10 gm) in isopropanol (50 ml) was heated at 60°C for 30 minutes. Seed of Tiemonium methylsulphate form B was added at 60°C The resulting solids were filtered, washed with chilled isopropanol (10 ml) and dried at 55°C under reduced pressure. Yield= 9.2 gm
Purity: 99.82% (By HPLC)
XRD: As depicted in Figure 3
DSC: As depicted in Figure 4

WE CLAIM:
1. A crystalline form A of Tiemonium methylsulphate characterized by its powder X-ray diffraction pattern as depicted in figure no.1.
2. A crystalline form A of Tiemonium methylsulphate characterized by its powder X-ray diffraction pattern having peaks at 4.5, 9.1, 13.7, 14.4, 17.2, 18.1 and 21.9 ± 0.2 degrees 20.
3. A crystalline form A of Tiemonium methylsulphate characterized by differential scanning calorimetry thermogram showed a sharp endothermic peak with an onset at 142.11°C and a maximum at 146.18°C.
4. A crystalline form B of Tiemonium methylsulphate characterized by its powder X-ray diffraction pattern as depicted in figure no. 3.
5. A crystalline form B of Tiemonium methylsulphate characterized by its Powder X-ray diffraction pattern having peaks at 8.4, 10.2, 10.3, 12.5, 13.3, 15.5, 18.6,20.5, 22.4 and 24.2 ± 0.2 degrees 29.
6. A crystalline form B of Tiemonium methylsulphate characterized by differential scanning calorimetry thermogram showed a sharp endothermic peak with an onset at 155.65°C and a maximum at 157.35°C.
7. A process of preparing crystalline form A of Tiemonium methylsulphate comprising the steps of:
a. providing a solution of Tiemonium in a ketone solvent;
b. adding dimethyl sulphate and
c. isolating crystalline form A of Tiemonium methylsulphate.
8. The process according to claim no. 7, wherein ketone solvents can be selected from the group comprising of acetone, methyl ethyl ketone, methyl isobutyl ketone, dibutyl ketone, diethyl ketone, dipropyl ketone, diisopropyl ketone, methyl butyl ketone, methyl propyl ketone, methyl isopropyl ketone, ethyl isopropyl ketone or mixture(s) thereof.
9. A process of preparing crystalline form B of Tiemonium methylsulphate comprising the steps of:

a. providing a solution of Tiemonium methylsulphate in an alcoholic solvent
and
b. isolating crystalline form B of Tiemonium methylsulphate.
10.The process according to claim no. 9, wherein alcoholic solvents can be selected from the group comprising of methanol, ethanol, propanol, isopropanol, butanol, isobutanol, t-butanol, pentanol or mixture(s) thereof.