WO2008050185A2 - Nouveaux polymorphes de la périndopril erbumine - Google Patents

Nouveaux polymorphes de la périndopril erbumine Download PDF

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Publication number
WO2008050185A2
WO2008050185A2 PCT/IB2007/000364 IB2007000364W WO2008050185A2 WO 2008050185 A2 WO2008050185 A2 WO 2008050185A2 IB 2007000364 W IB2007000364 W IB 2007000364W WO 2008050185 A2 WO2008050185 A2 WO 2008050185A2
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WIPO (PCT)
Prior art keywords
perindopril erbumine
polymorph form
form theta
theta
perindopril
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/IB2007/000364
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English (en)
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WO2008050185A3 (fr
Inventor
David Churchley
Ameet Amberkhane
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Glenmark Pharmaceuticals Ltd
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Glenmark Pharmaceuticals Ltd
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Publication date
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Publication of WO2008050185A2 publication Critical patent/WO2008050185A2/fr
Anticipated expiration legal-status Critical
Publication of WO2008050185A3 publication Critical patent/WO2008050185A3/fr
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention generally relates to a novel polymorphic form of perindopril erbumine, process for its preparation and pharmaceutical compositions containing same.
  • Perindopril erbumine also known as (2S,3 ⁇ S,7 ⁇ S)-l-[(S)-N-[(S)-l- carboxy-butyl]alanyl]hexahydro-2-indolinecarboxylic acid, 1 -ethyl ester, with tert- butylamine (1:1), is represented by the structure of Formula I:
  • the tert-butylamine salt of perindopril also known as perindopril erbumine, is the form commercially sold under the trade name Aceon ® .
  • Perindopril is the free acid form of perindopril erbumine and is an ethyl ester of a non-sulfhydryl angiotensin-converting enzyme (ACE) inhibitor.
  • ACE non-sulfhydryl angiotensin-converting enzyme
  • Perindopril is a pro-drug and is metabolized in vivo by hydrolysis of the ester group to form perindoprilat, the biologically active metabolite.
  • Perindopril is ordinarily used to treat hypertension.
  • Perindopril erbumine is also known as an ACE inhibitor used in the treatment of hypertension.
  • ACE is a peptidyl dipeptidase that catalyzes conversion of the inactive decapeptide, angiotensin I 9 to the vasoconstrictor, angiotensin II.
  • Angiotensin II is a potent peripheral vasoconstrictor, which stimulates aldosterone secretion by the adrenal cortex, and provides negative feedback on renin secretion. Inhibition of ACE results in decreased plasma angiotensin II, leading to decreased vasoconstriction, increased plasma renin activity and decreased aldosterone secretion.
  • Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different x-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predicable solubility profiles.
  • polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry. Additionally, polymorphic forms of the same drug substance or active pharmaceutical ingredient, can be administered by itself or formulated as a drug product (also known as the final or finished dosage form), and are well known in the pharmaceutical art to affect, for example, the solubility, stability, flowability, tractability and compressibility of drug substances and the safety and efficacy of drug products. There is an ongoing need for new or purer polymorphic forms of existing drug molecules for improved drug formulations. [0006] Various polymorphic forms of perindopril erbumine are known. See, e.g.,
  • perindopril erbumine in polymorph Form Theta ( ⁇ ) is provided.
  • perindopril erbumine in polymorph Form Theta ( ⁇ ) and having a powder XRD pattern comprising characteristic peaks (expressed in degrees 20 ⁇ 0.2° ⁇ ) at approximately one or more of the positions: about 9.45, about 18.20 and/or about 20.46 is provided.
  • perindopril erbumine in polymorph Form Theta ( ⁇ ) characterized by having at least one physical measurement selected from the group consisting of: a powder XRD pattern substantially in accordance with Figure 1, a Raman spectrum containing peaks at about
  • a pharmaceutical composition comprising a therapeutically effective amount of perindopril erbumine in polymorph Form Theta ( ⁇ ).
  • a method of treatment comprising administering to a subject a pharmaceutical composition comprising a therapeutically effective amount of perindopril erbumine in polymorph Form Theta ( ⁇ ).
  • novel polymorphic form of perindopril erbumine of the present invention is generally easy to reproduce and believed to be easier to handle due to increased stability than various known polymorphic forms of perindopril erbumine.
  • terapéuticaally effective amount means the amount of a compound that, when administered to a mammal for treating a state, disorder or condition, is sufficient to effect such treatment.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the mammal to be treated.
  • treating means: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a mammal that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof, or (3) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.
  • the benefit to a subject to be treated is either statistically significant or at least perceptible to the patient or to the physician.
  • delivering means providing a therapeutically effective amount of an active ingredient to a particular location within a host means causing a therapeutically effective blood concentration of the active ingredient at the particular location. This can be accomplished, e.g., by topical, local or by systemic administration of the active ingredient to the host.
  • subject or "a patient” or “a host” as used herein refers to , mammalian animals, preferably human.
  • chemical stability means that the polymorph can be stored in an isolated form with an insignificant degree of chemical degradation or decomposition.
  • solid state stability means the polymorph can be stored in an isolated solid form with an insignificant degree of solid state transformation
  • Examples of "normal storage conditions” include temperatures of between minus 5 and plus 50 0 C and preferably between 0 and 40 0 C.
  • buffering agent as used herein is intended to mean a compound used to resist a change in pH upon dilution or addition of acid of alkali.
  • Such compounds include, by way of example and without limitation, potassium metaphosphate, potassium phosphate, monobasic sodium acetate and sodium citrate anhydrous and dehydrate and other such material known to those of ordinary skill in the art.
  • sweetening agent as used herein is intended to mean a compound used to impart sweetness to a preparation.
  • Such compounds include, by way of example and without limitation, aspartame, dextrose, glycerin, mannitol, saccharin sodium, sorbitol, sucrose, fructose and other such materials known to those of ordinary skill in the art.
  • binder as used herein is intended to mean substances used to cause adhesion of powder particles in tablet granulations.
  • Such compounds include, by way of example and without limitation, acacia alginic acid, tragacanth, carboxymethylcellulose sodium, poly (vinylpyrrolidone), compressible sugar (e.g., NuTab), ethylcellulose, gelatin, liquid glucose, methylcellulose, povidone and pregelatinized starch, combinations thereof and other material known to those of ordinary skill in the art.
  • binders include starch, poly(ethylene glycol), guar gum, polysaccharide, bentonites, sugars, invert sugars, poloxamers (PLURONICTM F68, PLURONICTM F127), collagen, albumin, celluloses in nonaqueous solvents, combinations thereof and the like.
  • Other binders include, for example, poly(propylene glycol), polyoxyethylene- polypropylene copolymer, polyethylene ester, polyethylene sorbitan ester, poly(ethylene oxide), microcrystalline cellulose, poly(vinylpyrrolidone), combinations thereof and other such materials known to those of ordinary skill in the art.
  • filler or “filler” as used herein is intended to mean inert substances used as fillers to create the desired bulk, flow properties, and compression characteristics in the preparation of tablets and capsules.
  • Such compounds include, by way of example and without limitation, dibasic calcium phosphate, kaolin, sucrose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sorbitol, starch, combinations thereof and other such materials known to those of ordinary skill in the art.
  • glidant as used herein is intended to mean agents used in tablet and capsule formulations to improve flow-properties during tablet compression and to produce an anti-caking effect.
  • Such compounds include, by way of example and without limitation, colloidal silica, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc, combinations thereof and other such materials known to those of ordinary skill in the art.
  • lubricant as used herein is intended to mean substances used in tablet formulations to reduce friction during tablet compression. Such compounds include, by way of example and without limitation, calcium stearate, magnesium stearate, mineral oil, stearic acid, zinc stearate, combinations thereof and other such materials known to those of ordinary skill in the art.
  • disintegrant as used herein is intended to mean a compound used in solid dosage forms to promote the disruption of the solid mass into smaller particles which are more readily dispersed or dissolved.
  • exemplary disintegrants include, by way of example and without limitation, starches such as corn starch, potato starch, pre- gelatinized and modified starched thereof, sweeteners, clays, such as bentonite, microcrystalline cellulose (e.g. AvicelTM), carsium (e.g. AmberliteTM), alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pectin, tragacanth, combinations thereof and other such materials known to those of ordinary skill in the art.
  • starches such as corn starch, potato starch, pre- gelatinized and modified starched thereof, sweeteners, clays, such as bentonite, microcrystalline cellulose (e.g. AvicelTM), carsium (e.g. AmberliteTM), alginates, sodium starch glycolate, gums such
  • wetting agent as used herein is intended to mean a compound used to aid in attaining intimate contact between solid particles and liquids.
  • exemplary wetting agents include, by way of example and without limitation, gelatin, casein, lecithin (phosphatides), gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, (e.g., TWEENTMs), polyethylene glycols, polyoxyethylene stearates colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxye
  • Figure 1 is a characteristic powder X-ray diffraction (XRD) pattern of perindopril erbumine in polymorph Form Theta ( ⁇ ).
  • Figure 2 is a 13 C solid state NMR spectrum of perindopril erbumine in polymorph Form Theta ( ⁇ ).
  • Figure 3 is a characteristic powder XRD pattern of perindopril erbumine in polymorph Form Theta ( ⁇ ) after storage for five months.
  • Figure 4 is a characteristic powder XRD pattern of perindopril erbumine in polymorph Form Theta ( ⁇ ) of the present invention.
  • One embodiment of the present invention is directed to a novel polymorph form of perindopril erbumine, designated polymorph Form Theta ( ⁇ ).
  • the present invention provides perindopril erbumine in polymorph Form Theta ( ⁇ ) of characterized as having a characteristic peak (expressed in degrees 2 ⁇ ⁇ 0.2° ⁇ ) at about 20.46.
  • the present invention provides perindopril erbumine in polymorph Form Theta ( ⁇ ) characterized as having characteristic peaks (expressed in degrees 20 ⁇ 0.2° ⁇ ) at approximately one or more of the positions: about 9.45 and about 20.46.
  • the present invention provides perindopril erbumine in polymorph Form Theta ( ⁇ ) characterized as having characteristic peaks (expressed in degrees 2 ⁇ ⁇ 0.2° ⁇ ) at approximately one or more of the positions: about 9.45, about 18.20 and about 20.46. [0039] In yet another embodiment, the perindopril erbumine in polymorph Form
  • Theta ( ⁇ ) can be characterized by having at least one, and preferably all, of the following properties: (a) an XRD substantially in accordance with Figures 1 or 4; and/or (b) a Raman spectrum containing peaks at about 541.1 cm “1 , about 551.2 cm “1 , about 858.7 cm “1 , about 881.1 cm '1 and about 898.2 cm “1 ; and/or (c) a 13 C solid state NMR spectrum substantially in accordance with Figure 2.
  • Perindopril erbumine in polymorph Form Theta ( ⁇ ) can be obtained by at least (a) heating a solution comprising perindopril erbumine in 1,4-dioxane at a temperature greater than or equal to about 50 0 C, and preferably greater than or equal to about 75°C; and (b) cooling and isolating perindopril erbumine in polymorph Form Theta ( ⁇ ).
  • the solution of perindopril erbumine in 1,4-dioxane can be heated at a temperature ranging from about 5O 0 C to about 150 0 C and preferably about 50 0 C to about 100 0 C.
  • the heated solution will be cooled to a temperature and for a time period sufficient to crystallize the polymorph of the present invention.
  • the solution of perindopril erbumine in 1,4-dioxane is prepared by heating at a temperature greater than about 50 0 C and cooling the solution gradually until crystallization is complete.
  • the solution may be seeded with theta ( ⁇ ) crystalline form of perindopril erbumine.
  • Perindopril erbumine in polymorph Form Theta ( ⁇ ) obtained from the processes of the present invention will be in relatively high purity, e.g., a purity greater than or equal to about 95% and preferably greater than or equal to about 99%, as measured by HPLC.
  • compositions containing a therapeutically effective amount of perindopril erbumine in polymorph Form Theta ( ⁇ ) of the present invention may be administered to a mammalian patient in any dosage form, e.g., liquid, powder, elixir, injectable solution, etc.
  • dosage forms may be adapted for administration to the patient by oral, buccal, parenteral, ophthalmic, rectal, transdermal routes and the like.
  • Oral dosage forms include, but are not limited to, tablets, pills, capsules, troches, sachets, suspensions, powders, lozenges, elixirs and the like.
  • the perindopril erbumine in polymorph Form Theta ( ⁇ ) disclosed herein also may be administered as suppositories, ointments and suspensions, and parenteral suspensions, which are administered by other routes. However, all modes of administrations are contemplated, e.g., orally, rectally, parenterally, intranasally and topically.
  • the most preferred route of administration of the novel perindopril erbumine in polymorph Form Theta ( ⁇ ) disclosed herein is oral.
  • the dosage forms may contain the novel perindopril erbumine in polymorph Form Theta ( ⁇ ) disclosed herein as is or, alternatively, may contain perindopril erbumine in polymorph Form Theta ( ⁇ ) disclosed herein as part of a composition.
  • compositions containing a therapeutically effective amount of perindopril erbumine in polymorph Form can be combined with, for example, one or more pharmaceutically acceptable carriers, excipients, diluents or adjuvants in accordance with known and established practice. Suitable excipients and the amounts to use may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field, e.g., the buffering agents, sweetening agents, binders, diluents, fillers, lubricants, wetting agents and disintegrants described hereinabove.
  • Capsule dosages will contain the novel perindopril erbumine in polymorph
  • the enteric coated powder forms may have coatings containing at least phthalic acid cellulose acetate, hydroxypropylmethyl cellulose phthalate, polyvinyl alcohol phthalate, carboxy methyl ethyl cellulose, a copolymer of styrene and maleic acid, a copolymer of methacrylic acid and methyl methacrylate, and like materials, and if desired, they may be employed with suitable plasticizers and/or extending agents.
  • a coated capsule or tablet may have a coating on the surface thereof or may be a capsule or tablet comprising a powder or granules with an enteric coating.
  • compositions of the present invention may contain diluents such as cellulose-derived materials like powdered cellulose, microcrystalline cellulose, microfine cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose salts and other substituted and unsubstituted celluloses; starch; pregelatinized starch; inorganic diluents such calcium carbonate and calcium diphosphate and other diluents known to one of ordinary skill in the art.
  • diluents such as cellulose-derived materials like powdered cellulose, microcrystalline cellulose, microfine cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose salts and other substituted and unsubstituted celluloses
  • starch pregelatinized starch
  • Suitable diluents include waxes, sugars (e.g., lactose) and sugar alcohols like mannitol and sorbitol, acrylate polymers and copolymers, as well as pectin, dextrin and gelatin.
  • the tablets can be prepared according to known tableting procedures, e.g., wet granulation, dry granulation, etc.
  • Actual dosage levels of the novel polymorph of perindopril erbumine of the present invention may be varied to obtain an amount of the novel polymorph of perindopril erbumine of the present invention that is effective to obtain a desired therapeutic response for a particular composition and method of administration.
  • the selected dosage level therefore depends upon such factors as, for example, the desired therapeutic effect, the route of administration, the desired duration of treatment, and other factors.
  • the total daily dose of the compounds of this invention administered to a host in single or divided dose and can vary widely depending upon a variety of factors including, for example, the body weight, general health, sex, diet, time and route of administration, rates of absorption and excretion, combination with other drugs, the severity of the particular condition being treated, etc.
  • the pharmaceutical compositions herein can be formulated in any release form, e.g., immediate release, sustained release, controlled release, etc.
  • the novel polymorph of perindopril erbumine disclosed herein for use in the pharmaceutical compositions of the present invention can have a D 50 and D90 particle size of less than about 300 microns, preferably less than about 200 microns, more preferably less than about 100 microns, still more preferably less than about 50 microns and most preferably less than about 20 microns.
  • D x means that X% of the particles have a diameter less than a specified diameter D.
  • a D50 of about 300 microns means that 50% of the micronized particles in a composition have a diameter less than about 300 microns.
  • micronization used herein means any process or methods by which the size of the particles is reduced.
  • the particle sizes of the novel polymorph of perindopril erbumine of the present invention can be obtained by any milling, grinding, micronizing or other particle size reduction method known in the art to bring the solid state form of the novel polymorph of perindopril erbumine of the present invention into any of the foregoing desired particle size range.
  • Tube anode Cu
  • Tube current 40 mA
  • Probe 7.5 mm MAS probe
  • Perindopril erbumine in polymorph Form Theta ( ⁇ ) was stored for 5 months under normal storage conditions known to one skilled in the art. After 5 months, the XRD pattern of perindopril erbumine in polymorph Form Theta ( ⁇ ) was recorded and set forth in Figure 3. As the figure shows, the XRD pattern of perindopril erbumine in polymorph Form Theta ( ⁇ ) after 5 months of storage is substantially the same as the XRD pattern of perindopril erbumine in polymorph Form Theta ( ⁇ ) ( Figures 1 and 4) prior to storage indicating the stored perindopril erbumine in polymorph Form Theta ( ⁇ ) is stable.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Indole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un nouveau polymorphe stable de la périndopril erbumine, appelé polymorphe de Forme Thêta (ϑ). L'invention porte également sur un procédé permettant de le préparer et sur les compositions pharmaceutiques le contenant.
PCT/IB2007/000364 2006-10-26 2007-02-16 Nouveaux polymorphes de la périndopril erbumine Ceased WO2008050185A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1769/MUM/2006 2006-10-26
IN1769MU2006 2006-10-26

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WO2008050185A2 true WO2008050185A2 (fr) 2008-05-02
WO2008050185A3 WO2008050185A3 (fr) 2011-04-07

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PCT/IB2007/000364 Ceased WO2008050185A2 (fr) 2006-10-26 2007-02-16 Nouveaux polymorphes de la périndopril erbumine

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012044189A1 (fr) 2010-09-29 2012-04-05 Instituto Superior Técnico Forme cristalline hydratée inédite de l'erbumine de périndopril, ses procédés de préparation et son utilisation dans des préparations pharmaceutiques
CN103822996A (zh) * 2014-03-20 2014-05-28 东英（江苏）药业有限公司 一种培哚普利叔丁胺盐含量的测定方法
CN112697935A (zh) * 2020-12-10 2021-04-23 湖南泰新医药科技有限公司 同时测定人血浆中培哚普利和培哚普利拉浓度的方法

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2811319B1 (fr) * 2000-07-06 2002-08-23 Adir Nouvelle forme cristalline beta du sel de tert-butylamine du perindopril, son procede de preparation et les compositions pharmaceutiques qui la contiennent
WO2004113293A1 (fr) * 2003-06-24 2004-12-29 Les Laboratoires Servier Nouvelles formes cristallines de perindopril erbumine
BR0318561A (pt) * 2003-10-21 2006-10-10 Lupin Ltd processo seletivo para a preparação de erbumino perindopril cristalino
SI21704A (en) * 2004-01-14 2005-08-31 Lek Farmacevtska Druzba Dd New crystal form of perindopril, procedure of its preparation, pharmaceutical preparations containing this form and their application in treatment of hypertensia
JP4547245B2 (ja) * 2004-12-16 2010-09-22 株式会社パーマケム・アジア ペリンドプリルエルブミンのｉ型結晶、及びその製造方法

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012044189A1 (fr) 2010-09-29 2012-04-05 Instituto Superior Técnico Forme cristalline hydratée inédite de l'erbumine de périndopril, ses procédés de préparation et son utilisation dans des préparations pharmaceutiques
CN103822996A (zh) * 2014-03-20 2014-05-28 东英（江苏）药业有限公司 一种培哚普利叔丁胺盐含量的测定方法
CN112697935A (zh) * 2020-12-10 2021-04-23 湖南泰新医药科技有限公司 同时测定人血浆中培哚普利和培哚普利拉浓度的方法

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