WO2013093753A1 - Ivabradine hydrochloride premix - Google Patents
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- WO2013093753A1 WO2013093753A1 PCT/IB2012/057367 IB2012057367W WO2013093753A1 WO 2013093753 A1 WO2013093753 A1 WO 2013093753A1 IB 2012057367 W IB2012057367 W IB 2012057367W WO 2013093753 A1 WO2013093753 A1 WO 2013093753A1
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- Prior art keywords
- ivabradine hydrochloride
- premix
- ivabradine
- solvent
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
- A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
Definitions
- the present invention relates to Ivabradine hydrochloride premix comprising Ivabradine and process for preparing said premix.
- the present invention also relates to pharmaceutical compositions comprising said Ivabradine hydrochloride premix.
- Ivabradine hydrochloride of formula I has very valuable pharmacological and therapeutic properties, and is useful in many cardiovascular diseases such as angina pectoris, myocardial infarct and associated rhythm disturbances and is chemically known as (S)-7,8-dimethoxy-3- ⁇ 3- ⁇ N-[(4,5-dimethoxybenzocyclobut- l-yl)methyl]-N-(methyl)amino)propyl)-l,3,4,5-tetrahydro-2H-3-benzazepin-2-one hydrochloride.
- Ivabradine with a pharmaceutically acceptable acid have very valuable pharmacological and therapeutic properties, especially bradycardic properties, making those compounds useful in the treatment or prevention of various clinical situations of myocardial ischemia such as angina pectoris, myocardial infarct and associated rhythm disturbances, and also in various pathologies involving rhythm disturbances, especially supraventricular rhythm disturbances, and in heart failure.
- Ivabradine hydrochloride is first disclosed in U.S. Patent No. 5,296,482.
- the compound stability is one of the most important criteria by most of the regulatory agencies. Therefore one need to demonstrate that even after the formulation the stability of the compound or its respective form is intact over a period of shelf life.
- the compound transformations can occur also in the different solid state, because of changes in humidity or temperature or oxidative degradation conditions.
- the solvent-based process uses organic solvents to dissolve and intimately disperse the drug and carrier molecules. Identification of a common solvent for both drug and carrier can be problematic, and complete solvent removal from the product can be a lengthy process. In addition, large volumes of solvents are generally required which can give rise to toxicological problems.
- the drug and carrier are typically dissolved in a solvent such as methylene chloride, acetone, ethanol and mixtures thereof and the solvent is later removed by precipitation techniques, evaporation or the like, while the drug/carrier solid premix is collected as a powdered mass.
- the hybrid fusion- solvent method can be employed.
- the drag is first dissolved in a small quantity of organic solvent and added to the molten carrier.
- the solvent is then evaporated to generate a product that is subsequently milled to produce a powder.
- the pharmacokinetics, dissolution rates and processes for formulation of much different solid pharmaceutical dispersion is discussed at length in an article by Ford J., in Pharm. Acta. Helv. 61, 3; 69-88 (1986).
- Premix or co-precipitation techniques employ the use of an organic solvent or solvents to dissolve drag and carrier molecules. Separation of the drug and carrier from the solvent on precipitation can rely on the solubility properties of either the drug or carrier.
- Simonelli et al Journal of Pharmaceutical Sciences, Vol. 58, No. 5, May 1969, describes a co-precipitation process wherein sulfathiazole is dissolved in sodium hydroxide, followed by addition of polyvinylpyrrolidone; hydrochloric acid is then added to effect co-precipitation. This process is based on co-precipitation employing the solubility of the drag at different pH values.
- Typical premixes represent a compromise of the above properties, as for example, an increase in stability and dissolution properties of the premix.
- premixes there are a variety of premixes, there is a continual search in this field of art for premixes that exhibit an improved mix of properties.
- the instant invention provides a premix in which Ivabradine hydrochloride exists in stable crystalline form and process of manufacture of the premix and pharmaceutical compositions comprising said Ivabradine hydrochloride.
- the Ivabradine hydrochloride polymorphous forms ⁇ , 5d can easily convert into one other forms depending on the possibility to acquire or to lose water. These transformations can occur also in the different solid state, because of changes in humidity and temperature conditions.
- Ivabradine hydrochloride in premix form is an approach by the present inventors towards attaining a significantly more stable crystalline product having better dissolution properties that can be easily formulated to give pharmaceutical compositions.
- Ivabradine hydrochloride polymorphous forms ⁇ , 5d it was observed that this class of compounds is not stable during stability tastings.
- the Ivabradine hydrochloride has a tendency to change its polymorph and it appears that some different polymorph by-products are produced with time.
- the stability under nitrogen is known for Ivabradine hydrochloride from the European Pharmacopoeia and the US Pharmacopoeia. It was observed that these conditions are not sufficient for Ivabradine hydrochloride.
- Ivabradine hydrochloride polymorphous forms 5d in premix is an approach by the present inventors towards attaining a significantly more stable polymorph product having better dissolution properties that can be easily formulated to give pharmaceutical compositions.
- Another object of the invention is to provide pharmaceutical compositions comprising the aforementioned Ivabradine hydrochloride premix.
- Ivabradine hydrochloride premix having enhanced stability and dissolution properties and process for preparation thereof.
- a process of preparing a premix comprising Ivabradine hydrochloride, and a pharmaceutically acceptable carrier or excipient comprises: (i) providing an intimate mixture comprising the solvent system, Ivabradine hydrochloride and pharmaceutically acceptable carrier or excipient, and optionally, water;
- the invention provides for pharmaceutical compositions comprising said Ivabradine hydrochloride premix.
- the present invention provides a premix of Ivabradine hydrochloride having enhanced stability, dissolution properties that can be easily formulated into pharmaceutical compositions.
- Ivabradine hydrochloride premix having enhanced stability and dissolution properties according to the invention, wherein Ivabradine hydrochloride is stabilized by combining with suitable polymers/agents.
- Ivabradine hydrochloride is present in stable crystalline form in the premix of Ivabradine hydrochloride.
- the ratio of Ivabradine hydrochloride to pharmaceutical acceptable carrier or excipients is in a range of 1: 1 to 50: 1.
- the premix of the present invention is prepared by combining Ivabradine hydrochloride with suitable premixing agents in pharmaceutically acceptable proportions to yield desired characteristics of good stability and formulation properties.
- Suitable premixing agents are pharmaceutically acceptable carrier or excipients include polymers/agents used in the process for manufacturing of the premix may be selected from group of cellulose derivatives but not limited to croscarmellose Sodium, micro crystalline cellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), hydroxymethylethylcellulose (HEMC), ethylcellulose (EC), methylcellulose (MC), cellulose esters, cellulose glycolate, hydroxypropyl methyl cellulose phthalate, polyme thy lacry late (HPMCP), Hypromellose, vinylpyrrolidone monomers but not limited to Polyvinylpyrrolidone and polyol but not limited to Mannitol.
- the said polymers/agents are used to facilitate the presence of a crystalline Ivabradine hydrochloride.
- the solvent system used in the process for manufacturing of the premix may be selected from a group of organic, aqueous, hydroalcoholic solvents either alone or in combinations thereof.
- the said solvents are selected from toluene, acetone, Isopropyl alcohol, ethanol, methanol, methylene chloride, dimethylacetamide, dimethylsulphoxide, dimethylformamide, tetrahydrofuran and combinations thereof, and optionally, water.
- toluene/water, tetrahydrofuran/water, or acetone/methanol mixtures are employed in a process according to the present invention.
- the present invention provides process for preparing the said Ivabradine hydrochloride premix by co-precipitation technique which alleviates the above described disadvantages associated with known techniques, and have also found that co-precipitation offers an advantageous preparation route for premix of Ivabradine hydrochloride.
- intimate mixture can denote a solution, suspension, emulsion, colloid, dispersion or the like. Generally, the term “intimate mixture” as used herein denotes a solution.
- the carrier or excipient can be subjected to heating sufficient to facilitate dissolving. Remove any water present from the mixture azeotropically. Cool the reaction mixture co-precipitating the Ivabradine hydrochloride and the carrier or excipient. It is generally advantageous to first premix the Ivabradine hydrochloride together with the solvent or solvents and optional water, prior to addition carrier or excipient thereto. Subsequently, the carrier or excipient can be added to the initial intimate mixture contain Ivabradine hydrochloride. Optionally, the Ivabradine hydrochloride carrier or excipient and solvent system mixture can be subjected to heating sufficient to facilitate dissolving of the former in the latter.
- the resultant premix can be separated from the remaining components, suitably by filtering or the like, and the co-precipitate washed to remove residual solvent, and dried.
- the co-precipitate can then be formulated in a suitable pharmaceutical form employing known formulatory techniques, substantially as hereinafter described.
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Abstract
Ivabradine hydrochloride premix and process for preparing the premix are provided. The premix contains ivabradine hydrochloride and premixing agents selected from cellulose derivatives. Also provided is pharmaceutical composition comprising the premix.
Description
TITLE: - IVABRADINE HYDROCHLORIDE PREMIX
FIELD OF THE INVENTION
The present invention relates to Ivabradine hydrochloride premix comprising Ivabradine and process for preparing said premix. The present invention also relates to pharmaceutical compositions comprising said Ivabradine hydrochloride premix.
BACKGROUND OF THE INVENTION
Ivabradine hydrochloride of formula I, has very valuable pharmacological and therapeutic properties, and is useful in many cardiovascular diseases such as angina pectoris, myocardial infarct and associated rhythm disturbances and is chemically known as (S)-7,8-dimethoxy-3-{3-{N-[(4,5-dimethoxybenzocyclobut- l-yl)methyl]-N-(methyl)amino)propyl)-l,3,4,5-tetrahydro-2H-3-benzazepin-2-one hydrochloride.
Formula - 1
Ivabradine with a pharmaceutically acceptable acid have very valuable pharmacological and therapeutic properties, especially bradycardic properties, making those compounds useful in the treatment or prevention of various clinical situations of myocardial ischemia such as angina pectoris, myocardial infarct and
associated rhythm disturbances, and also in various pathologies involving rhythm disturbances, especially supraventricular rhythm disturbances, and in heart failure. Ivabradine hydrochloride is first disclosed in U.S. Patent No. 5,296,482. The compound stability is one of the most important criteria by most of the regulatory agencies. Therefore one need to demonstrate that even after the formulation the stability of the compound or its respective form is intact over a period of shelf life. The compound transformations can occur also in the different solid state, because of changes in humidity or temperature or oxidative degradation conditions.
The prior art discloses the importance of the production conditions of the medicinal products reported to undergo unwanted and undesirable transformations, if the process conditions are not opportunistically controlled. Consequently, a stable Ivabradine hydrochloride would be a significant contribution to the art.
The solvent-based process uses organic solvents to dissolve and intimately disperse the drug and carrier molecules. Identification of a common solvent for both drug and carrier can be problematic, and complete solvent removal from the product can be a lengthy process. In addition, large volumes of solvents are generally required which can give rise to toxicological problems. The drug and carrier are typically dissolved in a solvent such as methylene chloride, acetone, ethanol and mixtures thereof and the solvent is later removed by precipitation techniques, evaporation or the like, while the drug/carrier solid premix is collected as a powdered mass.
In the case where there is difficulty with thermal instability and immiscibility between the drug and the carrier, the hybrid fusion- solvent method can be
employed. The drag is first dissolved in a small quantity of organic solvent and added to the molten carrier. The solvent is then evaporated to generate a product that is subsequently milled to produce a powder. The pharmacokinetics, dissolution rates and processes for formulation of much different solid pharmaceutical dispersion is discussed at length in an article by Ford J., in Pharm. Acta. Helv. 61, 3; 69-88 (1986).
Premix or co-precipitation techniques employ the use of an organic solvent or solvents to dissolve drag and carrier molecules. Separation of the drug and carrier from the solvent on precipitation can rely on the solubility properties of either the drug or carrier. For example, Simonelli et al, Journal of Pharmaceutical Sciences, Vol. 58, No. 5, May 1969, describes a co-precipitation process wherein sulfathiazole is dissolved in sodium hydroxide, followed by addition of polyvinylpyrrolidone; hydrochloric acid is then added to effect co-precipitation. This process is based on co-precipitation employing the solubility of the drag at different pH values. Such reliance on the solubility of the drug may be problematic in that it is not generally applicable to ivabradine, as many such drugs do not exhibit a pH dependent solubility. Florence et al, Communications, J. Pharm. Pharmac, 1976, 28 601, describes co-precipitation of trifluoperazine embonate and the polymers poly DL-aspartic acid and polymethylmethacrylate. The co- precipitates were prepared by dissolving the drug and polymer in dimethylformamide and adding the solution to a rapidly stirred volume of water. Both polymers and drug are insoluble in water. Premixes are characterized by a variety of associated properties such as stability, flow, and solubility. Typical premixes represent a compromise of the above properties, as for example, an increase in stability and dissolution properties of the premix. Although there are a variety of premixes, there is a continual search in this field of art for premixes that exhibit an improved mix of properties. Thus, the
instant invention provides a premix in which Ivabradine hydrochloride exists in stable crystalline form and process of manufacture of the premix and pharmaceutical compositions comprising said Ivabradine hydrochloride. Moreover it is known from US7358240B2, US7384932B2 that the Ivabradine hydrochloride polymorphous forms δ, 5d can easily convert into one other forms depending on the possibility to acquire or to lose water. These transformations can occur also in the different solid state, because of changes in humidity and temperature conditions.
The prior art discloses the importance of the production conditions of the medicinal products reported to undergo unwanted and undesirable transformations, if the process conditions are not opportunistically controlled. Consequently, a stable crystalline Ivabradine hydrochloride would be a significant contribution to the art.
Though δ, and 5d crystalline form of Ivabradine hydrochloride and its process of manufacture have been described in Patent US7358240B2 and US7384932B2, Ivabradine hydrochloride in premix form, is an approach by the present inventors towards attaining a significantly more stable crystalline product having better dissolution properties that can be easily formulated to give pharmaceutical compositions.
During our research on Ivabradine hydrochloride polymorphous forms δ, 5d it was observed that this class of compounds is not stable during stability tastings. The Ivabradine hydrochloride has a tendency to change its polymorph and it appears that some different polymorph by-products are produced with time. The stability under nitrogen is known for Ivabradine hydrochloride from the European
Pharmacopoeia and the US Pharmacopoeia. It was observed that these conditions are not sufficient for Ivabradine hydrochloride.
It was surprisingly found during the research that that the premix of Ivabradine hydrochloride polymorphous forms 5d was more sable during the stability tastings than any other poly morph of the Ivabradine hydrochloride.
Therefore Ivabradine hydrochloride polymorphous forms 5d in premix is an approach by the present inventors towards attaining a significantly more stable polymorph product having better dissolution properties that can be easily formulated to give pharmaceutical compositions.
OBJECT OF THE INVENTION: Therefore, it is an object of the invention to provide a premix of Ivabradine hydrochloride and process for preparation of the said premix.
Another object of the invention is to provide pharmaceutical compositions comprising the aforementioned Ivabradine hydrochloride premix.
SUMMARY OF THE INVENTION:
In one of the aspect, of the present invention provides Ivabradine hydrochloride premix having enhanced stability and dissolution properties and process for preparation thereof.
In another aspect, of the present invention a process of preparing a premix comprising Ivabradine hydrochloride, and a pharmaceutically acceptable carrier or excipient, which process comprises:
(i) providing an intimate mixture comprising the solvent system, Ivabradine hydrochloride and pharmaceutically acceptable carrier or excipient, and optionally, water;
(ii) removing any solvent present from the mixture;
(iii) dissolving in another solvent;
(iv) precipitating the premix of Ivabradine hydrochloride.
In another aspect, the invention provides for pharmaceutical compositions comprising said Ivabradine hydrochloride premix.
Other features and advantages will be apparent from the specification which describes an embodiment of this invention.
DETAILED DESCRIPTION OF THE INVENTION:
The invention will now be described in details in connection with certain preferred and optional embodiments so that various aspects thereof may be more fully understood and appreciated. In an embodiment, the present invention provides a premix of Ivabradine hydrochloride having enhanced stability, dissolution properties that can be easily formulated into pharmaceutical compositions. Ivabradine hydrochloride premix having enhanced stability and dissolution properties, according to the invention, wherein Ivabradine hydrochloride is stabilized by combining with suitable polymers/agents. Further, Ivabradine hydrochloride is present in stable crystalline form in the premix of Ivabradine hydrochloride.
According to present invention, the ratio of Ivabradine hydrochloride to pharmaceutical acceptable carrier or excipients is in a range of 1: 1 to 50: 1.
The premix of the present invention is prepared by combining Ivabradine hydrochloride with suitable premixing agents in pharmaceutically acceptable proportions to yield desired characteristics of good stability and formulation properties.
Suitable premixing agents are pharmaceutically acceptable carrier or excipients include polymers/agents used in the process for manufacturing of the premix may be selected from group of cellulose derivatives but not limited to croscarmellose Sodium, micro crystalline cellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), hydroxymethylethylcellulose (HEMC), ethylcellulose (EC), methylcellulose (MC), cellulose esters, cellulose glycolate, hydroxypropyl methyl cellulose phthalate, polyme thy lacry late (HPMCP), Hypromellose, vinylpyrrolidone monomers but not limited to Polyvinylpyrrolidone and polyol but not limited to Mannitol. The said polymers/agents are used to facilitate the presence of a crystalline Ivabradine hydrochloride.
The solvent system used in the process for manufacturing of the premix may be selected from a group of organic, aqueous, hydroalcoholic solvents either alone or in combinations thereof. The said solvents are selected from toluene, acetone, Isopropyl alcohol, ethanol, methanol, methylene chloride, dimethylacetamide, dimethylsulphoxide, dimethylformamide, tetrahydrofuran and combinations thereof, and optionally, water. Generally toluene/water, tetrahydrofuran/water, or acetone/methanol mixtures are employed in a process according to the present invention.
In another embodiment, the present invention provides process for preparing the said Ivabradine hydrochloride premix by co-precipitation technique which
alleviates the above described disadvantages associated with known techniques, and have also found that co-precipitation offers an advantageous preparation route for premix of Ivabradine hydrochloride. There is therefore provided in a first aspect of the present invention a process of preparing a solid premix comprising Ivabradine hydrochloride thereof, and premixing agents, which process comprises:
(i) providing an intimate mixture comprising the solvent system, Ivabradine hydrochloride and premixing agents, and optionally, water;
(ii) removing any solvent present from the mixture;
(iii) dissolving in another solvent;
(iv) precipitating the premix of Ivabradine hydrochloride.
As used herein, the term "intimate mixture" can denote a solution, suspension, emulsion, colloid, dispersion or the like. Generally, the term "intimate mixture" as used herein denotes a solution.
It is generally advantageous to first premix the carrier or excipient together with the solvent or solvents and optional water, and Ivabradine hydrochloride. Optionally, the carrier or excipient, Ivabradine hydrochloride and solvent can be subjected to heating sufficient to facilitate dissolving. Remove any water present from the mixture azeotropically. Cool the reaction mixture co-precipitating the Ivabradine hydrochloride and the carrier or excipient. It is generally advantageous to first premix the Ivabradine hydrochloride together with the solvent or solvents and optional water, prior to addition carrier or excipient thereto. Subsequently, the carrier or excipient can be added to the initial intimate mixture contain Ivabradine hydrochloride. Optionally, the Ivabradine
hydrochloride carrier or excipient and solvent system mixture can be subjected to heating sufficient to facilitate dissolving of the former in the latter.
The resultant premix can be separated from the remaining components, suitably by filtering or the like, and the co-precipitate washed to remove residual solvent, and dried. The co-precipitate can then be formulated in a suitable pharmaceutical form employing known formulatory techniques, substantially as hereinafter described.
There is further provided by the present invention a process of preparing a pharmaceutical composition comprising a solid premix substantially as hereinbefore described, which process comprises mixing a solid premix substantially as hereinbefore described together with a pharmaceutically acceptable carrier. Conveniently the following combinations of carrier or excipient and co- precipitation medium can be employed in a process according to the present invention:
Example: 1.
Preparation of Ivabradine hydrochloride premix with Polyvinylpyrrolidone (PVP)
Charge methanol (750ml), Ivabradine hydrochloride (100g) and Polyvinylpyrrolidone (37.5 gm) at 25-30°C to the flask under stirring, after completion of reaction distilled out methanol under vacuum up to 55 °C from the reaction mixture. Cool the reaction mixture to 25-30°C. Seed the reaction mixture with Ivabradine hydrochloride. Add acetone (1875 ml) to reaction
mass in lhr at 25-35°C. Stir the reaction mixture for 1-3 hours at 25-30°C and distilled out the solvent. Filter the product and dry and unload the product.
Claims
1. Ivabradine hydrochloride premix comprising Ivabradine hydrochloride, and premixing agents which process comprises:
(i) providing an intimate mixture comprising the solvent system, Ivabradine hydrochloride and premixing agents and optionally, water;
(ii) removing any solvent present from the mixture;
(iii) dissolving in another solvent;
(iv) precipitating the premix of Ivabradine hydrochloride.
2. Ivabradine hydrochloride premix comprises of Ivabradine hydrochloride in combination with suitable premixing agents as claimed in claim 1, wherein the premixing agents is selected from group of cellulose derivatives but not limited to croscarmellose Sodium, Micro crystalline cellulose (MCC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), hydroxymethylethylcellulose (HEMC), ethylcellulose (EC), methylcellulose (MC), cellulose esters, cellulose glycolate, hydroxypropyl methyl cellulose phthalate, polymethylacrylate (HPMCP), Hypromellose, vinylpyrrolidone, Polyvinylpyrrolidone or Mannitol.
3. The premix of Linezolid according to claim 1, wherein ratio of Ivabradine hydrochloride to premixing agents is in a range of 1 : 1 to 30: 1.
4. A process of manufacturing a Ivabradine hydrochloride premix according to claims 1, wherein Ivabradine hydrochloride is dissolved in a solvent system selected from a group of organic solvents, aqueous solvents, alcoholic solvents either alone or in combination.
The premix of Ivabradine hydrochloride according to claim 4, wherein solvents selected are water, toluene, acetone, Isopropyl alcohol, ethanol, methanol, methylene chloride, dimethylacetamide, dimethylsulphoxide, dimethylformamide, tetrahydrofuran and combinations thereof, and optionally, water.
6. A pharmaceutical compositions comprising Ivabradine hydrochloride premix according to claim 1, along with pharmaceutically acceptable excipients.
7. A pharmaceutical compositions according to claims 6, wherein pharmaceutically acceptable excipients are selected from the group of diluents, chelating agents, disintegrant, glidant, lubricants and optionally anti adherents and coating material.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN3649MU2011 | 2011-12-24 | ||
| IN3649/MUM/2011 | 2011-12-24 |
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| WO2013093753A1 true WO2013093753A1 (en) | 2013-06-27 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015001569A1 (en) * | 2013-07-02 | 2015-01-08 | Genepharm India Private Limited | A solid pharmaceutical composition of ivabradine for oral administration |
| WO2015145234A1 (en) * | 2014-03-27 | 2015-10-01 | Laboratorio Chimico Internazionale S.P.A. | Ivabradine adsorbates |
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| CN101636416A (en) * | 2007-01-17 | 2010-01-27 | 连津格股份公司 | Forming solutions |
| WO2010128525A2 (en) * | 2009-05-04 | 2010-11-11 | Dinesh Shantilal Patel | A formulation of ivabradine for treating the cardiovascular disease |
| WO2011104723A2 (en) * | 2010-02-23 | 2011-09-01 | Ind-Swift Laboratories Limited | Acid addition salts of ivabradine and preparation thereof |
| CN101897682A (en) * | 2010-07-13 | 2010-12-01 | 石药集团欧意药业有限公司 | Ivabradine preparation or ivabradine medicinal salt solid preparation and preparation method thereof |
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| WO2015001569A1 (en) * | 2013-07-02 | 2015-01-08 | Genepharm India Private Limited | A solid pharmaceutical composition of ivabradine for oral administration |
| WO2015145234A1 (en) * | 2014-03-27 | 2015-10-01 | Laboratorio Chimico Internazionale S.P.A. | Ivabradine adsorbates |
| US20170100408A1 (en) * | 2014-03-27 | 2017-04-13 | Laboratorio Chimico Internazionale S.P.A. | Ivabradine adsorbates |
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