WO2008125134A1 - Process for the preparation of perindopril-tert-butylamine adsorbates - Google Patents

Process for the preparation of perindopril-tert-butylamine adsorbates Download PDF

Info

Publication number
WO2008125134A1
WO2008125134A1 PCT/EP2007/003305 EP2007003305W WO2008125134A1 WO 2008125134 A1 WO2008125134 A1 WO 2008125134A1 EP 2007003305 W EP2007003305 W EP 2007003305W WO 2008125134 A1 WO2008125134 A1 WO 2008125134A1
Authority
WO
WIPO (PCT)
Prior art keywords
perindopril
tert
butylamine
adsorbates
process according
Prior art date
Application number
PCT/EP2007/003305
Other languages
French (fr)
Inventor
Klaus GLÄNZER
Original Assignee
Helm Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Helm Ag filed Critical Helm Ag
Priority to EP07724243A priority Critical patent/EP1998749A1/en
Priority to PCT/EP2007/003305 priority patent/WO2008125134A1/en
Publication of WO2008125134A1 publication Critical patent/WO2008125134A1/en

Links

Classifications

    • 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
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • 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
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing

Definitions

  • the present invention relates to a novel process for the preparation of Perindopril Adsorbates.
  • the adsorbates obtained according to the present invention contain the active ingredient Perindopril-tert-Butylamine is deposited in a purely amorphous or in a morphologically defined crystalline form.
  • the invention further relates to Perindopril Adsorbates that are obtained by said process, as well as pharmaceutical formulations prepared by employing said Perindopril Adsorbates.
  • Preferred drug formulations according to the invention are tablets, capsules, pellets and granules prepared with the usual pharmaceutically acceptable excipients known per se. Particularly preferred are fast disintegrating tablets, rapidly releasing the active ingredient, that are obtained by direct compression of said Perindopril Adsorbates using standard techniques.
  • Perindopril is a pharmaceutical drug used in the treatment of cardiovascular diseases, e. g. hypertension and heart failure.
  • the mode of action of the active metabolite "Perindoprilat", a diacid of Perindopril, is ACE ( Angiotensin Converting Enzyme)-inhibition, i. e. the inhibition of converting Angiotensin I into Angiotensin II (U. Fricke, W. Klaus, Neue Arzneistoff 1989/90, p. 107, Academicliche Verlags Stuttgart, 1990).
  • Perindopril was first disclosed in EP 0049658 and described as an oily, amorphous or hardly crystalline material.
  • Perindopril-tert-Butylamine is slightly hygroscopic and chemically highly sensitive. It is readily isomerized in protic solvents, may undergo hydrolysis, or be affected by oxidation. Depending on crystal growth conditions (solvent, temperature, seeding etc.), (see Ph.Eur. 5.3, p. 3589) the crystalline material is obtained in the form of different polymorphs or as mixtures of such polymorphs. These ambiguities lead to a risky situation regarding the properties associated with phase purity, phase transformations and drug stability, since all of these have an effect on the dissolution rate of the drug product, which is required to be reproducible and unchanged over its whole shelf life in order to guarantee reliable and constant pharmaceutical properties of the medicine for the patient.
  • WO 2005/068490 Al instead describes the preparation of "complexes" or “inclusion complexes” of Perindopril-tert-Butylamine, where the salt is included “inside the three- dimensional net of polymers” or in "the inner cavity of the cyclodextrin cyclic structure", respectively.
  • the complexes are prepared by first dissolving the complex-forming host polymers (polyvinylpyrrolidone, hydroxyalkylcellulose derivatives, or cyclodextrins and their alkylated and hydroxyalkylated derivatives) in water or a water/alcohol solvent.
  • the Perindopril-tert-Butylamine is added and the mixture is stirred for 1 to 3 hours at temperatures in the range of 20°C to 60°C until the Perindopril-tert-Butylamine is inserted into the host polymer to form the complex.
  • the solution is filtered to remove any undissolved material.
  • the filtrate is dried, preferably by lyophillization or spray drying methods.
  • the resulting "complexes" are amorphous.
  • the results of the analytical investigation did not indicate the presence of any free crystalline or amorphous Perindopril- tert-Butylamine, indicating that all the active ingredient is trapped in these "complexes".
  • hydroxypropylmethylcellulose a polymer which is often used for film- coating, a solid-solution or dispersion-like product with a glass transition temperature at 130-150 0 C is obtained.
  • the objective is reached by a process for the preparation of adsorbates containing Perindopril-tert-Butylamine, which can briefly be described by the following the steps: a) Perindopril-tert-Butylamine is completely dissolved in water or in a pharmaceutically acceptable organic solvent, or a mixture of these solvents. b) An adsorbent (or adsorbing material) which is insoluble in water or in the chosen solvent system, respectively, is mixed with or dispersed in the solution according to a). c) The solvent is then removed by suitable drying techniques, as for example vacuum drying, fluid bed drying, spray drying, or lyophilization.
  • suitable drying techniques as for example vacuum drying, fluid bed drying, spray drying, or lyophilization.
  • Adsorbate The combination product of adsorbed active ingredient on the adsorbent is called "Adsorbate”. (Rompp Chemie Lexikon, 9 th Ed. (1995), Georg Thieme Verlag Stuttgart/New York, and literature cited therein). Accordingly, in the present case, with the active ingredient being Perindopril-tert-Butylamine, its adsorbates are called “Perindopril Adsorbates”.
  • adsorbates characterized by a morphological pure phase of Perindopril- tert-Butylamine deposited on an adsorbent can be obtained by the method of preparation as described.
  • a purely amorphous Perindopril-tert-Butylamine can be deposited on an adsorbent by removal of the liquid phase using lyophilization as the drying technique at low or ambient temperature.
  • a phase-pure crystalline form like the form "beta" of Perindopril-tert-Butylamine can be deposited on an adsorbent by removal of the liquid phase using vacuum drying at elevated temperatures.
  • adsorbates containg mixed-phase crystalline deposits can also be prepared.
  • the invention further relates to pharmaceutical formulations containing these Perindopril Adsorbates.
  • the pharmaceutical formulations according to the invention contain further excipients. Both the pure adsorbates and the preparations with excipients can can be converted into the appropriate drug delivery form.
  • Microcrystalline Cellulose prepared according to Example 2
  • Microcrystalline Cellulose prepared according to Example 3
  • Microcrystalline Cellulose prepared according to Example 4.
  • Microcrystalline Cellulose prepared according to Example 5
  • Microcrystalline Cellulose prepared according to Example 6
  • Powder x-ray diffraction pattern of Perindopril-tert-Butylamine obtained by lyophilization of an aqueous solution of the drug (obtained according to Example 7) 5.
  • both water and organic solvents are suitable as solvents for the solutions containing Perindopril-tert-Butylamine.
  • Water is the most preferred solvent.
  • the organic solvents are more particularly selected from the group of lower alcohols, like methanol, ethanol, 1- or 2- propanol, acetone, ethyl acetate, acetonitrile, diethylether, or mixtures thereof, or mixtures of these solvents with water.
  • Common pharmaceutical excipients can be used as adsorbent, provided they are not soluble in the selected solvent or solvent mixture in which the Perindopril-tert-Butylamine is dissolved.
  • Particularly preferred adsorbents for Perindopril-tert-Butylamine dissolved in water or solvent mixtures with water are Microcrystalline Cellulose, native Cellulose, or pharmaceutical acceptable mineral products like Attapulgite, Bentonite, colloidal or dispersed Silica, Kaolin, and Magnesium Aluminium Silicate. All these adsorbents are common pharmaceutical excipients as described in: "Handbook of Pharmaceutical Excipients", 4 th Ed., 2003, American Pharmaceutical Association. In order to perform efficiently as adsorbents, the materials have to be applied in a finely dispersed form with high specific surface area.
  • the preferred adsorbents are again those mentioned above for the aqueous systems, but complemented by carbohydrates, including sugars (e. g., Lactose, Fructose, Saccharose, Glucose, Maltose), sugar alcohols (e. g., Lactitol, Mannitol, Sorbitol, Xylitol) and starches or starch derivatives (e. g., Maize Starch, Potato Starch, Pregelatinized Starches), as well as inorganic fillers (e. g. calcium phosphates, carbonates and sulfates). All these excipients are also described in the "Handbook of Pharmaceutical Excipients”.
  • sugars e. g., Lactose, Fructose, Saccharose, Glucose, Maltose
  • sugar alcohols e. g., Lactitol, Mannitol, Sorbitol, Xylitol
  • Perindopril Adsorbates Most common pharmaceutical excipients can be used to prepare suitable pharmaceutical formulations of Perindopril Adsorbates, tablets being particularly preferred. Tablets produced by direct compression of Perindopril Adsorbates, which are characterized by fast disintegration and rapid dissolution of Perindopril-tert-Butylamine, are particularly preferred in a free or coated form.
  • the removal of the respective solvent can be achieved by heating and/or by applying a vacuum.
  • Equipment for the drying process are drying ovens, fluid bed dryers, spray dryers, or freeze dryers. Detailed descriptions of the techniques and of the equipment used in drying processes are given in: P. H. Stahl, "Feuchtmaschine und Trocknen in der Pharmazeutica Technologie", Dr. Dietrich Steinkopff Verlag, Darmstadt 1980.
  • a freeze drying technique is particularly preferred.
  • tablets manufactured by the process according to the invention release the active ingredient without limitations in a way essentially similar to marketed tablet formulations. 6. Examples:
  • Perindopril-tert-Butyl-Adsorbate containing pure polymorph "beta” ( ⁇ ), as obtained according to Example 5
  • excipients according to the following formulation:
  • Suitable amounts of excipients in the formulation are familiar to those skilled in the art from their basic knowledge, and further information can be obtained from standard reference books for tablet formulation (e. g. Ritschel et al., "Die Tablette”, Editio Cantor, Aulendorf,
  • Dissolution rate 90% dissolved after 30 min.
  • the tablets thus obtained may be coated if required.
  • Perindopril-tert-Butylamine Adsorbate (containing purely amorphous active ingredient, obtained according to Example 7, are mixed with excipients according to the following formulation: Perindopril-tert-Butylamine/Microcrystalline Cellulose Adsorbate 12 mg
  • Tablets equivalent to 4 mg of the active ingredient obtained by direct compression have the following properties:
  • Dissolution rate 100% dissolved after 30 min.
  • the tablets thus obtained may be coated if required.

Abstract

The present invention relates to a novel process for the preparation of Perindopril Adsorbates. In particular, in the adsorbates obtained according to the present invention contain the active ingredient Perindopril-tert-Butylamine is deposited in a purely amorphous or in a morphologically defined crystalline form. The invention further relates to Perindopril Adsorbates that are obtained by said process, as well as pharmaceutical formulations prepared by employing said Perindopril Adsorbates. Preferred drug formulations according to the invention are tablets, capsules, pellets and granules prepared with the usual pharmaceutically acceptable excipients known per se. Particularly preferred are fast disintegrating tablets, rapidly releasing the active ingredient, that are obtained by direct compression of said Perindopril Adsorbates using standard techniques.

Description

Process for the Preparation of Perindopril-tert-Butylamine Adsorbates
1. Field of the Invention:
The present invention relates to a novel process for the preparation of Perindopril Adsorbates. In particular, in the adsorbates obtained according to the present invention contain the active ingredient Perindopril-tert-Butylamine is deposited in a purely amorphous or in a morphologically defined crystalline form. The invention further relates to Perindopril Adsorbates that are obtained by said process, as well as pharmaceutical formulations prepared by employing said Perindopril Adsorbates. Preferred drug formulations according to the invention are tablets, capsules, pellets and granules prepared with the usual pharmaceutically acceptable excipients known per se. Particularly preferred are fast disintegrating tablets, rapidly releasing the active ingredient, that are obtained by direct compression of said Perindopril Adsorbates using standard techniques.
2. Description of Related Art:
Perindopril is a pharmaceutical drug used in the treatment of cardiovascular diseases, e. g. hypertension and heart failure. The mode of action of the active metabolite "Perindoprilat", a diacid of Perindopril, is ACE (= Angiotensin Converting Enzyme)-inhibition, i. e. the inhibition of converting Angiotensin I into Angiotensin II (U. Fricke, W. Klaus, Neue Arzneimittel 1989/90, p. 107, Wissenschaftliche Verlagsgesellschaft Stuttgart, 1990). Perindopril was first disclosed in EP 0049658 and described as an oily, amorphous or hardly crystalline material. The low purity, the adverse physical properties and the limited stability of the compound, which all depend strongly on the process of preparation, preclude a direct application in pharmaceutical preparations. Improved properties have been reported for the tert-butylammonium salt of the carboxylic acid function of Perindopril, which has become known as "Perindopril erbumine", "Perindopril-tert-butylamine salt" or simply "Perindopril- tert-Butylamine". Details are described in a monograph of the European Pharmacopeia (Ph.Eur. 5.3, p. 3589).
However, Perindopril-tert-Butylamine is slightly hygroscopic and chemically highly sensitive. It is readily isomerized in protic solvents, may undergo hydrolysis, or be affected by oxidation. Depending on crystal growth conditions (solvent, temperature, seeding etc.), (see Ph.Eur. 5.3, p. 3589) the crystalline material is obtained in the form of different polymorphs or as mixtures of such polymorphs. These ambiguities lead to a risky situation regarding the properties associated with phase purity, phase transformations and drug stability, since all of these have an effect on the dissolution rate of the drug product, which is required to be reproducible and unchanged over its whole shelf life in order to guarantee reliable and constant pharmaceutical properties of the medicine for the patient.
Prominent polymorphs of Perindopril-tert-Butylamine that have been disclosed in the prior art are the crystalline forms called "alpha" (α) (EP 1296947 Bl), "beta" (β) (EP 1676839 A2) or "gamma" (γ) (EP 1296948 Bl). For the parent Perindopril compound processes to prepare a crystalline or an amorphous material (WO 2005/068452 Al) are also known. However, in the case of Perindopril-tert-Butylamine, which is used in the marketed drug product, pure amorphous material (although claimed in WO 2005/068490 Al), or a method of preparation thereof, has not been disclosed yet.
WO 2005/068490 Al instead describes the preparation of "complexes" or "inclusion complexes" of Perindopril-tert-Butylamine, where the salt is included "inside the three- dimensional net of polymers" or in "the inner cavity of the cyclodextrin cyclic structure", respectively. The complexes are prepared by first dissolving the complex-forming host polymers (polyvinylpyrrolidone, hydroxyalkylcellulose derivatives, or cyclodextrins and their alkylated and hydroxyalkylated derivatives) in water or a water/alcohol solvent. Then, the Perindopril-tert-Butylamine is added and the mixture is stirred for 1 to 3 hours at temperatures in the range of 20°C to 60°C until the Perindopril-tert-Butylamine is inserted into the host polymer to form the complex. Subsequently, the solution is filtered to remove any undissolved material. Then the filtrate is dried, preferably by lyophillization or spray drying methods. The resulting "complexes" are amorphous. The results of the analytical investigation did not indicate the presence of any free crystalline or amorphous Perindopril- tert-Butylamine, indicating that all the active ingredient is trapped in these "complexes". In the case of choosing hydroxypropylmethylcellulose, a polymer which is often used for film- coating, a solid-solution or dispersion-like product with a glass transition temperature at 130-1500C is obtained.
The pharmaceutical value of active ingredients incorporated in complexes and their dispersions is doubtful due to the fact that the complex structure alters the availability and therefore the absorption of the drug. This is a very important aspect in cases where rapid release of the active ingredient is required or where the latter is a pro-drug undergoing complicated biopharmaceutical transformations, which applies to Perindopril. After being absorbed in vivo, the Perindopril-tert-Butylamine is converted into its active metabolite, the "Perindoprilate", in the liver. The overall bioavailability of Perindopril administered as the "tert-Butylamine salt" is known to be only 60-65% after oral administration. Any strong binding or trapping like the inclusion of the active principle in a host polymer to form a complex or a dispersion will further reduce the bioavailability of the drug.
3. Summary of the Invention:
One object of the present invention is to develop a simple method of preparing a morphologically stable and yet fast and reproducibly dissolving Perindopril-tert-Butylamine material, in which the active component is not trapped in a complex. Another object is to develop a simple and economical method of producing Perindopril-tert-Butylamine powder systems which can be used directly for the production of pharmaceutical products, this method not being limited to a particular morphology of the active component. According to the invention, the objective is reached by a process for the preparation of adsorbates containing Perindopril-tert-Butylamine, which can briefly be described by the following the steps: a) Perindopril-tert-Butylamine is completely dissolved in water or in a pharmaceutically acceptable organic solvent, or a mixture of these solvents. b) An adsorbent (or adsorbing material) which is insoluble in water or in the chosen solvent system, respectively, is mixed with or dispersed in the solution according to a). c) The solvent is then removed by suitable drying techniques, as for example vacuum drying, fluid bed drying, spray drying, or lyophilization. The combination product of adsorbed active ingredient on the adsorbent is called "Adsorbate". (Rompp Chemie Lexikon, 9th Ed. (1995), Georg Thieme Verlag Stuttgart/New York, and literature cited therein). Accordingly, in the present case, with the active ingredient being Perindopril-tert-Butylamine, its adsorbates are called "Perindopril Adsorbates".
We have found that adsorbates characterized by a morphological pure phase of Perindopril- tert-Butylamine deposited on an adsorbent can be obtained by the method of preparation as described. Surprisingly, on the one hand a purely amorphous Perindopril-tert-Butylamine can be deposited on an adsorbent by removal of the liquid phase using lyophilization as the drying technique at low or ambient temperature. On the other hand, a phase-pure crystalline form, like the form "beta" of Perindopril-tert-Butylamine can be deposited on an adsorbent by removal of the liquid phase using vacuum drying at elevated temperatures. Finally, adsorbates containg mixed-phase crystalline deposits can also be prepared.
The invention further relates to pharmaceutical formulations containing these Perindopril Adsorbates. Where applicable, the pharmaceutical formulations according to the invention contain further excipients. Both the pure adsorbates and the preparations with excipients can can be converted into the appropriate drug delivery form.
4. Description of the Drawings:
Fig. 1:
Powder x-ray diffraction pattern of Perindopril-tert-Butylamine Adsorbate on lactose
(prepared according to Example 1 ) Fig. 2:
Powder x-ray diffraction pattern of Perindopril-tert-Butylamine Adsorbate on
Microcrystalline Cellulose (prepared according to Example 2)
Fig. 3:
Powder x-ray diffraction pattern of Perindopril-tert-Butylamine Adsorbate on
Microcrystalline Cellulose (prepared according to Example 3)
Fig. 4:
Powder x-ray diffraction pattern of Perindopril-tert-Butylamine Adsorbate on
Microcrystalline Cellulose (prepared according to Example 4)
Fig. 5:
Powder x-ray diffraction pattern of Perindopril-tert-Butylamine Adsorbate on
Microcrystalline Cellulose (prepared according to Example 5)
Fig. 6:
Powder x-ray diffraction pattern of Perindopril-tert-Butylamine Adsorbate on
Microcrystalline Cellulose (prepared according to Example 6)
Fig. 7:
Powder x-ray diffraction pattern of Perindopril-tert-Butylamine obtained by lyophilization of an aqueous solution of the drug (obtained according to Example 7) 5. Detailed description of the preferred embodiments
For the process according to the present invention of manufacturing Perindopril Adsorbates, both water and organic solvents are suitable as solvents for the solutions containing Perindopril-tert-Butylamine. Water is the most preferred solvent. The organic solvents are more particularly selected from the group of lower alcohols, like methanol, ethanol, 1- or 2- propanol, acetone, ethyl acetate, acetonitrile, diethylether, or mixtures thereof, or mixtures of these solvents with water.
Common pharmaceutical excipients can be used as adsorbent, provided they are not soluble in the selected solvent or solvent mixture in which the Perindopril-tert-Butylamine is dissolved. Particularly preferred adsorbents for Perindopril-tert-Butylamine dissolved in water or solvent mixtures with water are Microcrystalline Cellulose, native Cellulose, or pharmaceutical acceptable mineral products like Attapulgite, Bentonite, colloidal or dispersed Silica, Kaolin, and Magnesium Aluminium Silicate. All these adsorbents are common pharmaceutical excipients as described in: "Handbook of Pharmaceutical Excipients", 4th Ed., 2003, American Pharmaceutical Association. In order to perform efficiently as adsorbents, the materials have to be applied in a finely dispersed form with high specific surface area.
For solutions of Perindopril-tert-Butylamine in organic solvent systems, the preferred adsorbents are again those mentioned above for the aqueous systems, but complemented by carbohydrates, including sugars (e. g., Lactose, Fructose, Saccharose, Glucose, Maltose), sugar alcohols (e. g., Lactitol, Mannitol, Sorbitol, Xylitol) and starches or starch derivatives (e. g., Maize Starch, Potato Starch, Pregelatinized Starches), as well as inorganic fillers (e. g. calcium phosphates, carbonates and sulfates). All these excipients are also described in the "Handbook of Pharmaceutical Excipients".
Most common pharmaceutical excipients can be used to prepare suitable pharmaceutical formulations of Perindopril Adsorbates, tablets being particularly preferred. Tablets produced by direct compression of Perindopril Adsorbates, which are characterized by fast disintegration and rapid dissolution of Perindopril-tert-Butylamine, are particularly preferred in a free or coated form.
The removal of the respective solvent (= the drying process) can be achieved by heating and/or by applying a vacuum. Equipment for the drying process are drying ovens, fluid bed dryers, spray dryers, or freeze dryers. Detailed descriptions of the techniques and of the equipment used in drying processes are given in: P. H. Stahl, "Feuchtigkeit und Trocknen in der Pharmazeutischen Technologie", Dr. Dietrich Steinkopff Verlag, Darmstadt 1980. In order to produce Perindopril Adsorbates in which purely amorphous Perindopril-tert- Butylamine is deposited on the adsorbent, a freeze drying technique is particularly preferred.
It has been found surprisingly that tablets manufactured by the process according to the invention release the active ingredient without limitations in a way essentially similar to marketed tablet formulations. 6. Examples:
Methods of analysis used
1. Release of active ingredient (dissolution test) according to USP paddle method, 500 ml 0.1 M HCl, 37°C, 50 rpm, HPLC with UV detection (215 nm)
2. The powder x-ray diffraction patterns were recorded as follows: Instrument: STADI P transmission diffractometer
Cu Ka, radiation (λ = 1.54056 A), U = 4OkV,
I = 30 mA; secondary beam monochromator (flat, graphite) Detector: Scintillation counter
Aperture: 2 x 8 mm, 0.7 mm, 0.35 mm
Linear PSD: 2Θ = 2° to 35°, 5s / 0.04° in steps
Sample: Powder, reflection mode
Example 1
3.34 g of Perindopril-tert-Butylamine is dissolved in 20 ml of methanol. 6.66 g of lactose is added to the clear solution and homogeneously suspended. With continuous stirring, the solvent is removed (drying temperature 50°C, vacuum < 2 mbar). A free-flowing powder is obtained, the x-ray diffraction pattern of which is shown in Fig. 1. The Perindopril-tert- Butylamine adsorbed on lactose thus obtained shows the presence of a mixture containing different polymorphs. Example 2
3.34 g of Perindopril-tert-Butylamine is dissolved in a solvent mixture of 5 ml of methanol and 15 ml of acetone. 6.66 g of Microcrystalline Cellulose is added to the clear solution and homogeneously suspended. With continuous stirring, the solvent is removed (drying temperature 50°C, vacuum < 2 mbar). A free-flowing powder is obtained, the x-ray diffraction pattern of which is shown in Fig. 2. The Perindopril-tert-Butylamine adsorbed on Microcrystalline Cellulose thus obtained shows the presence of a mixture containing different polymorphs.
Example 3
3.34 g of Perindopril-tert-Butylamine is dissolved in 5 ml of methanol and 15 ml of ethyl acetate. 6.66 g of microcrystalline Cellulose is added to the clear solution and homogeneously suspended. With continuous stirring, the solvent is removed (drying temperature 50°C, vacuum < 2 mbar). A free-flowing powder is obtained, the x-ray diffraction pattern of which is shown in Fig. 3. The Perindopril-tert-Butylamine adsorbed on Microcrystalline Cellulose thus obtained shows the presence of a mixture containing different polymorphs.
Example 4
3.34 g of Perindopril-tert-Butylamine is dissolved in 20 ml of methanol. 6.66 g of Microcrystalline Cellulose is added to the clear solution and homogeneously suspended. With continuous stirring, the solvent is removed (drying temperature 5O0C, vacuum < 2 mbar). A free-flowing powder is obtained, the x-ray diffraction pattern of which is shown in Fig. 4. The Perindopril-tert-Butylamine adsorbed on Microcrystalline Cellulose thus obtained shows the crystalline structure of the polymorph called "beta" (β).
Example 5
3.34 g of Perindopril-tert-Butylamine is dissolved in 5 ml of water. The clear solution and 6.66 g of Microcrystalline Cellulose are homogenously mixed. The solvent is removed (drying temperature 50°C, vacuum < 2 mbar). A free-flowing powder is obtained, the x-ray diffraction pattern of which is shown in Fig. 5. The Perindopril-tert-Butylamine adsorbed on Microcrystalline Cellulose thus obtained shows the crystalline structure of the known polymorph called "beta" (β).
Example 6
3.34 g of Perindopril-tert-Butylamine is dissolved in 10 ml of water. The clear solution is mixed with 6.66 g of Microcrystalline Cellulose and lyophilized (freezing temperature -45°C; primary drying temperature -10 to 0°C; secondary drying temperature 35°C) to a residual moisture content below 0.5%. A free-flowing powder is obtained, the x-ray diffraction pattern of which is shown in Fig. 6. The Perindopril-tert-Butylamine adsorbed on Microcrystalline Cellulose thus obtained has a purely amorphous structure.
Example 7 (for comparison purposes')
3.34 g of Perindopril-tert-Butylamine is dissolved in 10 ml of water. The clear solution is lyophilized (freezing temperature -45°C; primary drying temperature -10 to 0°C; secondary drying temperature 35°C; vacuum < 1 mbar) to a residual moisture content below 0.5%. The powder x-ray diffraction pattern is shown in Fig. 7. The Perindopril-tert-Butylamine thus obtained shows crystalline structure. Example 8
Preparation of Perindopril tablets (I): Perindopril-tert-Butyl-Adsorbate (containing pure polymorph "beta" (β), as obtained according to Example 5) is mixed with excipients, according to the following formulation:
Perindopril-tert-Butylamine/Microcrystalline Cellulose Adsorbate 12 mg
Excipients (Microcrystalline Cellulose, Lactose Monohydrate,
Silica, Magnesium Stearate) 88 mg
Suitable amounts of excipients in the formulation are familiar to those skilled in the art from their basic knowledge, and further information can be obtained from standard reference books for tablet formulation (e. g. Ritschel et al., "Die Tablette", Editio Cantor, Aulendorf,
2nd Ed., 2002). Tablets equivalent to 4 mg of the active ingredient obtained by direct compression show the following properties:
Tablet weight: 100 mg
Assay: 4 mg Perindopril-tert-Butylamine
Disintegration time: 1 min.
Hardness: 50-60 N
Dissolution rate: 90% dissolved after 30 min.
The tablets thus obtained may be coated if required.
Example 9
Preparation of Perindopril tablets (2): Perindopril-tert-Butylamine Adsorbate (containing purely amorphous active ingredient, obtained according to Example 7, are mixed with excipients according to the following formulation: Perindopril-tert-Butylamine/Microcrystalline Cellulose Adsorbate 12 mg
Excipients (Microcrystalline Cellulose, Lactose Monohydrate,
Silica, Magnesium Stearate) 88 mg
Tablets equivalent to 4 mg of the active ingredient obtained by direct compression have the following properties:
Tablet weight: 100 mg
Assay: 4 mg Perindopril-tert-Butylamine
Disintegration time: 1 min.
Hardness: 50-60 N
Dissolution rate: 100% dissolved after 30 min.
The tablets thus obtained may be coated if required.

Claims

Claims
1. A process for the preparation of Perindopril Adsorbates containing Perindopril-tert- Butylamine, starting from a solution of Perindopril-tert-Butylamine and an adsorbent, which is mixed or dispersed, but remains insoluble in said solution, and subsequently removing the solvent by a suitable drying technique.
2. The process according to claim 1, where the concentration of the Perindopril-tert- Butylamine in the solution is in the range of 1% to 75%, by weight.
3. The process according to claim 1, where the solvent is water.
4. The process according to claim 1, where the solvent is a pharmaceutically acceptable organic solvent selected from the group of lower alcohols, acetone, ethyl acetate, acetonitrile, dialkylethers, mixtures thereof, or mixtures of these solvents with water.
5. The process according to claim 1, where the ratio of Perindopril-tert-Butylamine to adsorbent in the Perindopril Adsorbates is in the range of 2:1 to 1:100 by weight.
6. The process according to claim 1, where the ratio of Perindopril-tert-Butylamine to adsorbent in the Perindopril Adsorbates is in the range of 1 : 1 to 1 :5.
7. The process according to claim 1, where the adsorbents are Microcrystalline Cellulose, Native Cellulose, Attapulgite, Bentonite, Colloidal or Dispersed Silica, Kaolin, Magnesium Aluminium Silicates, Lactose, Fructose, Saccharose, Glucose, Maltose, Lactitol, Mannitol, Sorbitol, Xylitol, Calcium Phosphates, Calcium Carbonates, Calcium Sulfates, Maize Starch, Potato Starch and/or Pregelatinized Starches.
8. The process according to claim 1, where the solvent is removed by vacuum drying, fluid bed drying, spray drying, and/or lyophilization.
9. The process according to claim 1, containing Perindopril-tert-Butylamine on an adsorbent in a purely amorphous form, in a single-phase crystalline form or as a mixture of polymorphic crystalline forms, which may be anhydrous or hydrates.
10. Adsorbates containing Perindopril-tert-Butylamine wherein the adsorbates are prepared by the process according to claim 1.
11. A pharmaceutical formulation comprising powders that contain pharmaceutically acceptable excipients and adsorbates according to claim 10.
12. The pharmaceutical formulation according to claim 1 1 in the form of tablets or granules prepared with pharmaceutically acceptable excipients.
3. The pharmaceutical formulation according to claim 12, obtained by direct compression, to produce fast disintegrating tablets that rapidly release the active ingredient.
PCT/EP2007/003305 2007-04-13 2007-04-13 Process for the preparation of perindopril-tert-butylamine adsorbates WO2008125134A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP07724243A EP1998749A1 (en) 2007-04-13 2007-04-13 Process for the preparation of perindopril-tert-butylamine adsorbates
PCT/EP2007/003305 WO2008125134A1 (en) 2007-04-13 2007-04-13 Process for the preparation of perindopril-tert-butylamine adsorbates

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP2007/003305 WO2008125134A1 (en) 2007-04-13 2007-04-13 Process for the preparation of perindopril-tert-butylamine adsorbates

Publications (1)

Publication Number Publication Date
WO2008125134A1 true WO2008125134A1 (en) 2008-10-23

Family

ID=38668664

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2007/003305 WO2008125134A1 (en) 2007-04-13 2007-04-13 Process for the preparation of perindopril-tert-butylamine adsorbates

Country Status (2)

Country Link
EP (1) EP1998749A1 (en)
WO (1) WO2008125134A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109700774A (en) * 2019-03-05 2019-05-03 上药东英（江苏）药业有限公司 A kind of perindopril tert-butylamine piece and its powder vertical compression technique

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005019173A1 (en) * 2003-08-21 2005-03-03 Hetero Drugs Limited Process for pure perindopril tert-butylamine salt
WO2005055983A2 (en) * 2003-12-09 2005-06-23 Medcrystalforms, Llc Method of preparation of mixed phase co-crystals with active agents
WO2005068490A1 (en) * 2004-01-14 2005-07-28 Lek Pharmaceuticals D.D. Inclusion complexes of perindopril

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005019173A1 (en) * 2003-08-21 2005-03-03 Hetero Drugs Limited Process for pure perindopril tert-butylamine salt
WO2005055983A2 (en) * 2003-12-09 2005-06-23 Medcrystalforms, Llc Method of preparation of mixed phase co-crystals with active agents
WO2005068490A1 (en) * 2004-01-14 2005-07-28 Lek Pharmaceuticals D.D. Inclusion complexes of perindopril

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109700774A (en) * 2019-03-05 2019-05-03 上药东英（江苏）药业有限公司 A kind of perindopril tert-butylamine piece and its powder vertical compression technique

Also Published As

Publication number Publication date
EP1998749A1 (en) 2008-12-10

Similar Documents

Publication Publication Date Title
CN108938583B (en) Formulations comprising amorphous dapagliflozin
AU2015319831B2 (en) Crystalline forms of trisodium supramolecular complex comprising valsartan and AHU-377 and methods thereof
TWI673051B (en) Formulations of enzalutamide
RU2417084C2 (en) Compositions containing bazedoxifene acetate
EP2870163B1 (en) Pharmaceutical compositions comprising rifaximin and amino acids, preparation method and use thereof
WO2008027600A2 (en) Imatinib compositions
US11013736B2 (en) Oral solid preparation and use thereof
WO2016051393A2 (en) Crystalline form iv of trisodium supramolecular complex comprising valsartan and ahu-377 and methods thereof
ES2672472T3 (en) Pharmaceutical composition comprising amorphous ivabradine
RU2700164C2 (en) Solid preparations containing tofogliflozin, and method for production thereof
PT2165702E (en) Stable and readily dissolved compositions of candesartan cilexetil prepared with wet granulation
BR112013010704B1 (en) COMPOSITION INCLUDING S-[2-([[1-(2-ETHYL-BUTYL)-CYCLOHEXYL]-CARBONY]AMINO)PHENYL]2-METHYLPROPANOTIOATE AND SODIUM CROSCARMELOSE
CN104045615B (en) (1S) crystal form A and its preparation method and application of-1-[the chloro-3-of 4-(4-ethoxy benzyl) phenyl]-1,6-dideoxy-D-Glucose
KR20040079936A (en) Stable salts of o-acetylsalicylic acid containing basic amino acids ii
WO2008125134A1 (en) Process for the preparation of perindopril-tert-butylamine adsorbates
US20080255231A1 (en) Polymorphs of rivastigmine hydrogentartrate
US7785629B2 (en) Bicalutamide-adsorbates, process for preparing same, and pharmaceutical compositions thereof
KR102078691B1 (en) Solid dispersion comprising Fimasartan
US10471156B2 (en) Pharmaceutical composition comprising amorphous lenalidomide
US20110021631A1 (en) Method of preparing stabilized pharmaceutical compositions comprising active ingredients susceptible to conversion to alternate polymorph forms
CN104045614B (en) (1S) crystal C and its preparation method and application of-1-[the chloro-3-of 4-(4-ethoxy benzyl) phenyl]-1,6-dideoxy-D-Glucose
CN110790675A (en) Colchicine compound, and preparation method, preparation, application and pharmaceutical composition thereof
JP2001213890A (en) Trehalose particle
CN104045613B (en) (1S) the cocrystallization I and its preparation method and application of-1-[the chloro-3-of 4-(4-ethoxy benzyl) phenyl]-1,6-dideoxy-D-Glucose and L-PROLINE
EP3079702B1 (en) Pharmaceutical composition comprising amorphous ivabradine

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 2007724243

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: DE