FORM 2
THE PATENTS ACT, 1970 (39 OF 1970)
&
Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10; rule 13)
1, Title of the invention - Identification and residual detection of Ivabradine hydrochloride
α- crystalline form in δ- crystalline form and 8d- crystalline form of Ivabradine hydrochloride drug substance and drug product by Solid State NMR:
2. Applicant(s)
(a) NAME: ALEMBIC PHARMACEUTICALS LIMITED
(b) NATIONALITY: An Indian Company,
(c) ADDRESS: Alembic Campus, Alembic Road,
Vadodara-390, 003, Gujarat, India

3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which is to be performed:

FIELD OF INVENTION:
The present invention relates to the technique in which the residual level of α-crystalline form in δ- crystalline form and δd- crystalline form of Ivabradine hydrochloride drug substance or drug product of formula (I) identified by Solid State NMR.

BACKGROUND OF INVENTION:
Ivabradine, and addition of salts thereof with a pharmaceutically acceptable acid , and more especially it hydrochloride , have very valuable pharmacological and therapeutic properties, especially bradycaric properties, making those compounds useful in the treatment or prevention of various clinical situations of myocardial ischaemia such as anginapectoris, myocardial infarct and associated rhythm disturbance, and also in various pathologies involving rhythm disturbances, especially supraventricular rhythm disturbances, and in heart failure.
The preparation and therapeutic use of Ivabradine and addition salts thereof with a pharmaceutically acceptable acid, and more especially its hydrochloride, have been described in the European patent specification EP0534859.
In view of the pharmaceutical value of this compound, it has been of prime importance to obtain it with excellent purity. It has also been important to be able to synthesise it by

means of a process that can readily be converted tot the industrial scale, especially in a form that allows rapid filtration and drying. Finally, that form had to be perfectly reproducible, easily formulated and sufficiently stable to allow its storage for long periods without particular requirements for temperature, light or oxygen level.
The patent specification EP0534859 describes a synthesis process for Ivabradine and its hydrochloride. However, that document does not specify the conditions for obtaining Ivabradine in a form that exhibits those characteristics in a reproducible manner.
The Applicant has now found that a particular salt of Ivabradine, the hydrochloride, can be obtained in a well defined crystalline form that exhibits valuable characteristics in a reproducible manner.
Polymorphism is the property of molecules and molecular complexes to assume more than one crystalline or amorphous form in the solid state. The different structures are referred to as polymorphs, polymorphic modification or polymorphic forms. Substances are known which only appear in a single crystal form; in addition, however, there are also substances which can form tow, three or even more polymorphic crystal modifications. In general, polymorphism is caused by the ability of the molecule of a substance to change its conformation or to form different inter molecular and intramolecular interactions, particularly hydrogen bonds, which is reflected in different atom arrangements in the crystal lattices of different polymorphs. Accordingly, polymorphs are distance solids sharing the same molecular formula, having distance advantageous physical properties compared to other forms in the polymorphic family.
The morphology and polymorphology of organo-chemical active substances is of great importance to the chemical and pharmaceutical development thereof. One crystalline form may provide significant advantages over other crystalline forms. Furthermore, a particular process suitable for one crystalline form may also provide drug manufactures several advantages such as economically or environmentally suitable solvents or process, or higher purity or yield of the desired product.

The relevant polymorphism of an organo-chemical substances is always unpredictable in respect of the number of crystal modification, the stability thereof and their behavior in a living organism.
The different polymorphs of a substance possess different energies of the crystal lattice and, thus, they show different physical properties of the solid state such as form, density, melting point, colour, stability, dissolution rate, milling facility, granulation, compacting etc. These differences in morphology and polymorphism may have drastic effects on the flowability of the milled solid (flowability affects the ease with which the material is handled during processing in to a pharmaceutical product), development, transport stability and storage stability of individual administration forms, on their application, on the solubility in polar or non-polar, protic or aprotic solvents, on solubility in aqueous solution, on solubility in the gastric juices, on solubility in blood serum, and finally on bio-availability. The rate of dissolution of an active ingredient in a patient's stomach fluid can have therapeutic consequences since it imposes a upper limit on the rate at which an orally-administrated active ingredient can reach the patient's blood stream. The rate of dissolution is also a consideration in formulating syrups, elixirs and other liquid medicaments. Other important properties of polymorphic forms relate to the ease of processing the form into pharmaceutical dosages, as the tendency of a powdered or granulated form to flow and the surface properties that determine whether crystals of the form will adhere to each other when compacted into a tablet. The polymorphic form may give rise to thermal behavior different from that of the amorphous material or another polymorphic form. Thermal behavior is measured in the laboratory by such techniques as capillary melting point, Differential Scanning Calorimetry (DSC) and can be used to distinguish some polymorphic forms from others. A particular polymorphic form may also give rise to distinct physical properties that may be detectable by X-Ray Powder Diffraction (XRPD).
The same applies in respect of the physical and chemical properties of Ivabradine hydrochloride.

According to EP1589005B1, α -crystalline form claimed, and was characterized by the XRPD.
According to US7358240B2, δ-crystalline form claimed, and was characterized by the XRPD.
According to US 7384932B2, δd-crystalline form claimed, and was characterized by XRPD.
SUMMARY OF INVENTION:
EP1589005B1 patent claims α -crystalline form of Ivabradine hydrochloride drug substance and δ-crystalline form of Ivabradine hydrochloride drug substance which are characterized by the following powder X-ray diffraction measured using a PANalytical X'Pert Pro diffractometer together with an X'celerator detector and expressed in terms of ray position (Bragg's angle 2 theta, expressed in degrees), ray height ( expressed in counts), ray area ( expressed in counts x degrees), ray width at half-height("FWHM", expressed in degrees) an interplanar distance d ( expressed in A0).
It is also an object of the present invention is to provide detection of α -crystalline form of Ivabradine hydrochloride drug substance in δ-crystalline form and 5d-crystalline form of Ivabradine hydrochloride drug substance by XRPD.
It is also an object of the present invention is to provide detection of α -crystalline form of Ivabradine hydrochloride drug substance to the extent of about 1.0 % in δ-crystalline form and 5d-crystalline form of Ivabradine hydrochloride drug substance by XRPD.
The present invention provides the residual detection of the α-crystalline form of Ivabradine drug substance in δ-crystalline form and δd-crystalline of Ivabradine hydrochloride drug product using solid- state C NMR.

BRIEF DESCRIPTION OF DRAWINGS:
Fig 1: Provides a solid-state 13 C NMR spectrum in the range of 0 to 190 ppm of α-crystalline form of Ivabradine hydrochloride.
Fig 2: Provides a solid-state 13C NMR spectrum in the range of 0 to 190 ppm of δ -crystalline form of Ivabradine hydrochloride.
Fig 3: Provides a solid-state 13C NMR spectrum in the range of 0 to 190 ppm of δ -crystalline form of Ivabradine hydrochloride drug product.
DESCRIPTION OF INVENTION:
The present invention provides the characterization of a-crystalline form and δ-crystalline form of Ivabradine hydrochloride drug substance and drug product using solid-state-13C NMR.
All terms are used herein in this application, unless otherwise stated, shall be understood in their ordinary meaning as known in the art. Other more specific definitions for certain terms as used in the present application are as set forth below and are intended to apply uniformly through-out the specification and claims unless an otherwise expressly set out definition provides a border definition.
XRPD analysis, Raman spectroscopic analysis and solid-state 13CNMR were used to characterize the polymorphic form of Ivabradine hydrochloride.
XRPD analysis for residual detection of a-crystalline form of Ivabradine hydrochloride drug substance in δ-crystalline form of Ivabradine hydrochloride drug substance and δd-crystalline form of Ivabradine hydrochloride drug substance to the extent preferably from 1.0 % to 5.0 % and more preferably from 1.0 % to 3.0 % by quantitative mode.

XRPD analysis for residual detection of α-crystalline form of Ivabradine hydrochloride in δ-crystalline form of Ivabradine hydrochloride drug product and δd-crystalline form of Ivabradine hydrochloride drug product become futile due to the low dosage marketed tablet of Ivabradine hydrochloride as 5.0mg and 7.5 mg.
Raman spectroscopic analysis for residual detection of α-crystalline form of Ivabradine hydrochloride in δ-crystalline form of Ivabradine hydrochloride drug product and δd-crystalline form of Ivabradine hydrochloride drug product become futile due to the low dosage marketed tablet of Ivabradine hydrochloride as 5.0mg and 7.5 mg.
XPRD analysis was performed on a PANalytical X'Pert Pro diffractometer together with an X'celerator detector at room temperature, using CuK α tube (45kV, 40mA, λ=1.5406) as the X-ray source. Data collection was made in 2θ continuous scan mode, at scan step time[s]of 12.0650 in the range of 2.5° to 40° in 2θ.
The solid -state 13C NMR were measured on a Bruker Avance III 400 MHz FT NMR spectrometer, equipped with 4 mm MAS probe. Data points were acquired with a recycling time of 5s, using contact time of 400 microseconds and a spinning rate of 5KHz.
The α-crystalline form of Ivabradine hydrochloride drug substance is perfectly further characterized by having solid-state CNMR with chemical shifts (δ) at about: 22.749, 28.437, 33.967, 35.310, 36.336, 37.331, 38.308, 39.593, 40.225, 41.197, 49.399, 51.602, 52.644, 52.995, 54.337, 54.890, 55.621, 56.045, 58.066, 104.396, 107.290, 108.168, 111.271, 111.863, 112.299, 121.579, 126.190, 133.832, 136.293, 137.331, 145.236, 146.769, 147.798, 148.652, 149.011, and 168.939 ppm, as substantially depicted in Figure 1.

The δ -crystalline form of Ivabradine hydrochloride drug substance is perfectly further characterized by having solid-state 13CNMR with chemical shifts (δ) at about: 19.475, 31.024,34.406,36.472,40.011,41.142, 44.871, 49.130, 52.732, 53.501, 54.586, 55.733, 56.945, 104.444, 105.736, 108.722, 112.086, 112.860, 122.500, 126.689, 127.087, 132.401, 134.317, 135.613, 145.462, 146.715, and 171.562 ppm, as substantially depicted in Figure 2.
The δ-crystalline form of Ivabradine hydrochloride drug product is perfectly further characterized by having solid-state l3CNMR with chemical shifts (δ) at about:, 17.087, 21.694, 29.427, 31.227, 35.615, 38.323, 39.667, 41.691, 47.370, 24.419, 56.462, 59.859, 67.359, 69.443, 70.552, 72.542, 80.203, 85.163, 90.716, 95.348, 99.829, 101.044, 103.061, 105.040, 108.117, 112.646,113.499 122.193, 128.635, 134.017, 144.069,146.262,147.504, 148.375, 170.997, and 174.640 ppm, as substantially depicted in Figure 3.
The α-crystalline form of Ivabradine hydrochloride characterized by solid- state 13CNMR pattern substantially as depicted in figure 1 having the below structural formula.

The α-crystalline form of Ivabradine hydrochloride drug substance characterized by solid- state 13CNMR pattern substantially in accordance with figure 1.
The α-crystalline form of Ivabradine hydrochloride according to claim any claims of 1 to 2, characterized by a solid- state 13CNMR with chemical shift about: 22.749, 28.437, 33.967, 35.310, 36.336, 37.331, 38.308, 39.593, 40.225, 41.197, 49.399, 51.602, 52.644,

52.995, 54.337, 54.890, 55.621, 56.045, 58.066, 104.396, 107.290, 108.168, 111.271, 111.863, 112.299, 121.579, 126.190, 133.832, 136.293, 137.331, 145.236, 146.769, 147.798, 148.652, 149.011, and 168.939 (ppm).
The α-crystalline form of Ivabradine hydrochloride drug substance according to any of claims 1 to 3, for use as a medicament.
Use of α-crystalline form of Ivabradine hydrochloride for the preparation of medicament for the treatment of prevention of various clinical situations of myocardial ischaemia such as anginapectoris, myocardial infarct and associated rhythm disturbance, and also in various pathologies involving rhythm disturbances, especially supraventricular rhythm disturbances, and in heart failure.
The δ-crystalline form of Ivabradine hydrochloride drug substance characterized by solid- state 13CNMR pattern substantially as depicted in figure 2 having the below structural formula.

The δ -crystalline form of Ivabradine hydrochloride drug substance characterized by solid- state 13CNMR pattern substantially in accordance with figure 2,
The δ -crystalline form of Ivabradine hydrochloride drug substance according to claim any claims of 1 to 2, characterized by a solid- state 13CNMR with chemical shift about: 19.475, 31.024,34.406,36.472,40.011,41.142, 44.871, 49.130, 52.732, 53.501, 54.586, 55.733, 56.945, 104.444, 105.736, 108.722, 112.086, 112.860, 122.500, 126.689, 127.087,132.401, 134.317, 135.613, 145.462, 146.715, and 171.562 (ppm).

The δ-crystalline form of Ivabradine hydrochloride according to any of claims 1 to 3, for use as a medicament.
The α-crystalline form of Ivabradine hydrochloride drug substance in δ-crystalline form of Ivabradine hydrochloride drug substance preferably should be absent.
The α-crystalline form of Ivabradine hydrochloride drug substance in δ-crystalline form of Ivabradine hydrochloride drug substance should be absent preferably by XRPD and solid-state 13C NMR.
The α-crystalline form of Ivabradine hydrochloride drug substance in δ-crystalline form of Ivabradine hydrochloride drug substance should be absent more preferably by XRPD.
The residual level of a-crystalline form of Ivabradine hydrochloride drug substance in 8-crystalline form of Ivabradine hydrochloride drug substance to the extent of preferably from 1.0 % to 5.0 % by XRPD on quantitative mode.
The residual level of a-crystalline form of Ivabradine hydrochloride drug substance in 8-crystalline form of Ivabradine hydrochloride drug substance to the extent of more preferably from 1.0 % to 3.0 % by XRPD on quantitative mode.
The α-crystalline form of Ivabradine hydrochloride drug substance in δd-crystalline form of Ivabradine hydrochloride drug substance preferably should be absent.
The α-crystalline form of Ivabradine hydrochloride drug substance in δd-crystalline form of Ivabradine hydrochloride drug substance should be absent preferably by XRPD and solid-state 13CNMR.
The a-crystalline form of Ivabradine hydrochloride drug substance in 5d-crystalline form of Ivabradine hydrochloride drug substance should be absent more preferably by XRPD.

The residual level of α-crystal line form of Ivabradine hydrochloride drug substance in δd-crystalline form of Ivabradine hydrochloride drug substance to the extent of preferably from 1.0 % to 5.0 % by XRPD on quantitative mode.
The residual level of α-crystalline form of Ivabradine hydrochloride drug substance in δd-crystalline form of Ivabradine hydrochloride drug substance to the extent of more preferably from 1.0 % to 3.0 % by XRPD on quantitative mode.
The α-crystalline form of Ivabradine hydrochloride drug substance in δ-crystalline form of Ivabradine hydrochloride drug substance should be absent more preferably by solid-state 13 CNMR.
The characteristic chemical shift (δ) of α-crystalline form of Ivabradine hydrochloride drug substance at 126.190, 111.271, 58.066, 52.995, 51.602, 39.593, 38.308, 37.331, 33.967, 28.437, and 22.749 ppm in δ-crystalline form of Ivabradine hydrochloride drug substance more preferably should be absent.
The α-crystalline form of Ivabradine hydrochloride drug substance in δd-crystalline form of Ivabradine hydrochloride drug substance should be absent more preferably by solid-state 13CNMR.
The characteristic chemical shift (δ) of α-crystalline form of Ivabradine hydrochloride drug substance at 126.190, 111.271, 58.066, 52.995, 51.602, 39.593, 38.308, 37.331, 33.967. 28.437, and 22.749 ppm in 5-crystalline form of Ivabradine hydrochloride drug substance more preferably should be absent.
The a-crystalline form of Ivabradine hydrochloride drug substance in δ-crystaIIine form of Ivabradine hydrochloride drug product preferably should be absent.

The α-crystalline form of Ivabradine hydrochloride drug substance in δ-crystalline form of Ivabradine hydrochloride drug product preferably should be absent more preferably by solid-state 13CNMR.
The characteristic chemical shift (δ) of α-crystalline form of Ivabradine hydrochloride drug substance at 126.190, 111.271, 58.066, 52.995, 51.602, 39.593, 38.308, 37.331, 33.967. 28.437, and 22.749 ppm in δ-crystalline form of Ivabradine hydrochloride drug product of low dosage as 5.0 mg. more preferably should be absent.
The characteristic chemical shift (δ) of α-crystalline form of Ivabradine hydrochloride drug substance at 126.190, 111.271, 58.066, 52.995, 51.602, 39.593, 38.308, 37.331, 33.967, 28.437, and 22.749 ppm in 5-crystalline form of Ivabradine hydrochloride drug product of low dosage as 7.5 mg, more preferably should be absent.
The α-crystalline form of Ivabradine hydrochloride drug substance in δd-crystalline form of Ivabradine hydrochloride drug product preferably should be absent.
The α-crystalline form of Ivabradine hydrochloride drug substance in δd-crystalline form of Ivabradine hydrochloride drug product preferably should be absent more preferably by solid-state 13CNMR.
The characteristic chemical shift (δ) of α-crystalline form of Ivabradine hydrochloride drug substance at 126.190, 111.271, 58.066, 52.995, 51.602, 39.593, 38.308, 37.331, 33.967, 28.437, and 22.749 ppm in 8d-crystalline form of Ivabradine hydrochloride drug product of low dosage as 5.0 mg, more preferably should be absent.
The characteristic chemical shift (δ) of α-crystalline form of Ivabradine hydrochloride drug substance at 126.190, 111.271, 58.066, 52.995, 51.602, 39.593, 38.308, 37.331, 33.967, 28.437, and 22.749 ppm in Sd-crystalline form of Ivabradine hydrochloride drug product of low dosage as 7.5 mg, more preferably should be absent.

Use of δ-crystalline form of Ivabradine hydrochloride for the preparation of medicament for the treatment of prevention of various clinical situations of myocardial ischaemia such as anginapectoris, myocardial infarct and associated rhythm disturbance, and also in various pathologies involving rhythm disturbances, especially supraventricular rhythm disturbances, and in heart failure.

We Claim,
1. The α-crystalline form of Ivabradine hydrochloride characterized by solid- state l3CNMR with chemical shift about: 22.749,28.437, 33.967, 35.310, 36.336, 37.331, 38.308, 39.593,40.225, 41.197,49.399, 51.602, 52.644, 52.995, 54.337, 54.890, 55.621, 56.045, 58.066,104.396, 107.290,108.168,111.271, 111.863, 112.299, 121.579, 126.190, 133.832, 136.293,137.331, 145.236,146.769, 147.798, 148.652, 149.011, and 168.939 (ppm) and pattern substantially as depicted in figure 1 having the below structural formula.

2. The δ-crystalline form of Ivabradine hydrochloride drug substance characterized by solid- state 13CNMR with chemical shift about: 19.475, 31.024, 34.406, 36.472,40.011,41.142, 44.871,49.130, 52.732, 53.501, 54.586, 55.733, 56.945, 104.444, 105.736, 108.722,112.086, 112.860, 122.500, 126.689, 127.087, 132.401, 134.317, 135.613, 145.462, 146.715, and 171.562 (ppm); and pattern substantially as depicted in figure 2 having the below structural formula.

3. The a-crystalline form of Ivabradine hydrochloride drug substance inδ-crystalline form of Ivabradine hydrochloride drug substance preferably should be absent.
4. The a-crystalline form of Ivabradine hydrochloride drug substance in δd-crystalline form of Ivabradine hydrochloride drug substance preferably should be absent.

5. According to claim 3 and 4 the characteristic chemical shift (δ) of α-crystalline form of Ivabradine hydrochloride drug substance at 126.190, 111.271, 58.066, 52.995, 51.602, 39.593,38.308, 37.331, 33.967, 28.437, and 22.749 ppm in δ-crystalline and δd-crystalline form of Ivabradine hydrochloride drug substance more preferably should be absent.
6. The characteristic chemical shift (δ) of α-crystalline form of Ivabradine hydrochloride drug substance at 126.190, 111.271, 58.066, 52.995, 51.602, 39.593, 38.308, 37.331, 33.967, 28.437, and 22.749 ppm in δ-crystalline and δd-crystalline form of Ivabradine hydrochloride drug product of low dosage as 5.0 mg, more preferably should be absent.
7. The characteristic chemical shift (δ) of a-crystalline form of Ivabradine hydrochloride drug substance at 126.190, 111.271, 58.066, 52.995, 51.602, 39.593, 38.308, 37.331, 33.967, 28.437, and 22.749 ppm in δ-crystalline and δd-crystalline form of Ivabradine hydrochloride drug product of low dosage as 7.5 mg, more preferably should be absent.