DE202007019054U1 - Spirapril hydrochloride and polymorphic forms thereof - Google Patents

Abstract

Anhydrous spirapril hydrochloride.

Description

The present invention relates to novel polymorphic spirapril hydrochloride forms, these containing drugs and their therapeutic uses.

Spirapril hydrochloride is used chemically [8S- [7 [R * (R *)], 8R *]] - 7- [2 - [[1- [ethoxycarbonyl] -3-phenylpropyl] amino] -1-oxopropyl] -1,4 called dithia-7-azaspiro [4,4] nonane-8-carboxylate hydrochloride and can be represented by the following structural formula:

spirapril is a prodrug of a non-sulfhydryl angiotensin converting enzyme (ACE) inhibitor (ACE: angiotensin non-converting enzyme), which after administration to the active diacetic metabolite spiraprilat is converted. It may be used in the treatment and prevention of cardiovascular disorders, including hypertension, decompensated heart failure and left ventricular dysfunction. It can also be at the Treatment and prevention of neuropathy in diabetes mellitus be used.

polymorphic Forms of a drug substance may be different chemical and physical properties, including Melting point, chemical reactivity, apparent solubility, Dissolution rate, optical and mechanical properties, Vapor pressure and density. These properties can a direct effect on the processing and / or manufacturing ability a drug substance and a drug product, as well as the drug product stability, dissolution and bioavailability exhibit. Consequently, the polymorphism can affect the quality, Influence the safety and efficiency of a drug product.

• (i) Kristalline Formen weisen unterschiedliche Anordnungen und/oder Konformationen der Moleküle im Kristallgitter auf.
• (ii) Amorphe Formen bestehen aus ungeordneten Anordnungen von Molekülen, die kein erkennbares Kristallgitter aufweisen.
• (iii) Solvate sind Kristallformen, die entweder stöchiometrische oder nicht-stöchiometrische Mengen eines Lösungsmittels enthalten. Ist das eingebrachte Lösungsmittel Wasser, ist das Solvat allgemein als Hydrat bekannt.

Polymorphic forms may include, as referred to herein, crystalline and amorphous forms, as well as solvate and hydrate forms, which may be further characterized as follows:

• (i) Crystalline forms have different arrangements and / or conformations of the molecules in the crystal lattice.
• (ii) Amorphous forms consist of disordered arrangements of molecules that have no recognizable crystal lattice.
• (iii) Solvates are crystal forms containing either stoichiometric or non-stoichiometric amounts of a solvent. If the solvent introduced is water, the solvate is commonly known as hydrate.

Lies a drug substance in polymorphic forms, is considered to be Polymorphism shows.

It There are a number of methods used to characterize polymorphs a drug substance can be used. A Demonstration of a non-equivalent structure by single-crystal X-ray diffraction is currently considered definitive proof of a polymorphism considered. An X-ray powder diffraction can also be used for Confirmation of the presence of polymorphs can be used. Other methods, including microscopy, thermal analysis (eg differential scanning calorimetry, thermogravimetric analysis and hot stage microscopy) and spectroscopy (eg infrared (IR) and near-infrared (NIR), Raman, and solid-state nuclear magnetic resonance [ssNMR]) are also useful for further characterizing polymorphic forms helpful.

Polymorphic forms of a drug substance may, as mentioned above, exhibit different chemical, physical and mechanical properties, including water solubility and dissolution rate, hygroscopicity, particle shape, density, flowability and compactness, which in turn may affect the processing of the drug substance and / or production of the drug product. Polymorphs can also have different stabilities. The most stable polymorphic form of a drug substance is often used during drug development on the minimum potential basis Conversion to another polymorphic form and their greater chemical stability selected. However, alternatively, for various reasons, including better bioavailability, a metastable form may be selected.

Therefore are now polymorphic forms of the pharmaceutical by the present invention compatible spirapril salt spirapril hydrochloride with advantageous properties provided. The benefits are depending on the selected form selected from elevated physical stability, improved resolution, improved morphology, improved post-formulation properties and improved properties during storage.

It it was surprisingly found that certain polymorphic Spirapril hydrochloride forms advantageous properties and in particular Advantages over commercially available spirapril hydrochloride exhibit.

Especially are anhydrous spirapril hydrochloride by the present invention and the polymorphic spirapril hydrochloride forms I, II, III, IV and V provided.

The crystalline structure of an anhydrous spirapril hydrochloride according to the invention is characterized in that it comprises an X-ray powder diffractogram or substantially the same X-ray powder diffractogram as in 1 has shown.

Inventive, anhydrous spirapril hydrochloride is further characterized that it selects characteristic peaks (2θ) one or more of the following: 8.1 ± 0.2 °, 9.7 ± 0.2 °, 14.2 ± 0.2 °, 16.3 ± 0.2 °, 18.4 ± 0.2 ° and 19.3 ± 0.2 °. Further peaks (2θ) associated with the invention, anhydrous spirapril hydrochloride are selected one or more of the following: 15.4 ± 0.2 °, 20.5 ± 0.2 °, 21.4 ± 0.2 °, 23.0 ± 0.2 ° and 26.9 ± 0.2 °.

The crystalline structure of anhydrous spirapril hydrochloride of the present invention is further characterized by an orthorhombic space group and by unit cell parameters comprising crystal axis lengths of a = 10.45 ± 0.01 Å, b = 13.23 ± 0.01 Å, c = 19.23 ± 0 , 01 Å. The properties of the crystalline structure of anhydrous spirapril hydrochloride according to the invention can be summarized as follows: crystal system orthorhombisch space group P2 ₁ 2 ₁ 2 ₁ Einheitszellmaß: α 10.45 ± 0.01 Å B 13.23 ± 0.01 Å C 19.23 ± 0.01 Å Unit cell volume: V 2659.8 (2) Å ³ Density, ρ 1.25 g cm ^-3

The crystalline structure of the polymorph I of spirapril hydrochloride according to the invention is characterized in that it contains an X-ray powder diffractogram or substantially the same X-ray powder diffraction pattern as in FIG 2 has shown.

The polymorph I of spirapril hydrochloride according to the invention is further characterized in that it has characteristic X-ray powder diffraction peak (2θ) selected from one or more of the following has: 6.5 ± 0.2 °, 8.1 ± 0.2 °, 16.2 ± 0.2 °, 20.4 ± 0.2 °, 24.3 ± 0.2 °. Further characterizing X-ray powder diffraction peak (2θ), with the polymorph according to the invention I of spirapril hydrochloride are selected one or more of the following: 9.3 ± 0.2 °, 13.2 ± 0.2 °, 17.4 ± 0.2 °, 19.3 ± 0.2 ° and 26.5 ± 0.2 °.

The crystalline structure of the polymorph II of spirapril hydrochloride according to the invention is characterized in that it contains an X-ray powder diffractogram or substantially the same X-ray powder diffractogram as in FIG 3 has shown.

The polymorph II of spirapril hydrochloride according to the invention is further characterized by having characteristic X-ray powder diffraction peak (2θ) selected from one or more of the following: 7.6 ± 0.2 °, 8.6 ± 0.2 °, 9.4 ± 0.2 °, 14.1 ± 0.2 °, 16.4 ± 0.2 ° and 17.3 ± 0.2 °. Further characterizing X-ray powder diffraction peak (2θ) obtained with the polymorph II of Spi rapril hydrochloride are selected from one or more of the following: 12.5 ± 0.2 °, 19.2 ± 0.2 °, 20.2 ± 0.2 °, 23.8 ± 0.2 ° and 29 , 7 ± 0,2 °.

The crystalline structure of the polymorph III of spirapril hydrochloride according to the invention is characterized in that it contains an X-ray powder diffractogram or substantially the same X-ray powder diffractogram as in FIG 4 has shown.

The polymorph III of spirapril hydrochloride according to the invention is further characterized in that it has characteristic X-ray powder diffraction peak (2θ) selected from one or more of the following has: 6.2 ± 0.2 °, 7.6 ± 0.2 °, 14.1 ± 0.2 °, 16.4 ± 0.2 ° and 17.3 ± 0.2 °. Further characterizing X-ray powder diffraction peak (2θ), with the polymorph according to the invention III of spirapril hydrochloride are selected one or more of the following: 10,2 ± 0,2 °, 12.5 ± 0.2 °, 19.2 ± 0.2 °, 20.3 ± 0.2 °, 23.8 ± 0.2 ° and 24.2 ± 0.2 °.

The crystalline structure of the polymorph IV of spirapril hydrochloride according to the invention is characterized in that it has an X-ray powder diffractogram or substantially the same X-ray powder diffractogram as in FIG 5 has shown.

The polymorph IV of spirapril hydrochloride according to the invention is further characterized in that it has characteristic X-ray powder diffraction peak (2θ): 7.6 ± 0.2 °, 8.1 ± 0.2 °, 14.1 ± 0.2 °, 16.4 ± 0.2 ° and 17.4 ± 0.2 °. Further characterizing X-ray powder diffraction peak (2θ) coincident with the polymorph IIV of spirapril hydrochloride according to the invention are selected from one or more of the following: 5.7 ± 0.2 °, 12.5 ± 0.2 °, 13.3 ± 0.2 °, 19.3 ± 0.2 ° and 20.4 ± 0.2 °.

The crystalline structure of the polymorph V of spirapril hydrochloride according to the invention is characterized in that it contains an X-ray powder diffractogram or substantially the same X-ray powder diffraction pattern as in FIG 6 has shown

The polymorph V of spirapril hydrochloride according to the invention is further characterized in that it has characteristic X-ray powder diffraction peak (2θ) selected from one or more of the following has: 7.1 ± 0.2 °, 10.2 ± 0.2 °, 18.7 ± 0.2 °, 19.8 ± 0.2 ° and 22.3 ± 0.2 °. Further characterizing X-ray powder diffraction peak (2θ), with the polymorph according to the invention IV of spirapril hydrochloride are selected one or more of the following: 7.6 ± 0.2 °, 8.6 ± 0.2 °, 9.3 ± 0.2 °, 13.6 ± 0.2 ° and 17.2 ± 0.2 °.

It are also methods of preparation by the present invention of polymorphs substantially as hereinbefore described Spirapril hydrochloride forms described.

In certain embodiments of the present invention Invention described method is essentially as polymorphic spirapril hydrochloride form described hereinabove formed by solvent crystallization.

typically, The method may include dissolving spirapril hydrochloride in a suitable solvent such. Dioxane, anhydrous Dioxane, acetonitrile, 1,2-propylene carbonate or the like or mixtures and forming crystals of the polymorphic form.

In In one embodiment, a solution becomes an anti-solvent added to the solubility for a given Compound to reduce, resulting in a precipitate. Antisolvents may, for. B. n-amyl acetate, anhydrous Octane, anhydrous benzene, anhydrous tert-butyl methyl ether or anhydrous tetrachloromethane or mixtures thereof.

• (i) Lösen von Spiraprilhydrochlorid in einem geeigneten Lösungsmittelmedium, typischerweise unter Erwärmen;
• (ii) Erwärmen der durch Schritt (i) erhaltenen Lösung;
• (iii) Wahlweise Zusetzen von Molekularsieb zum Entfernen von überschüssigem Wasser und dann Abfiltrieren dessen;
• (iv) Kristallisation einer im Wesentlichen wie hier vorstehend beschriebenen polymorphen Form durch Mittel wie Kühlen, Eindampfung, Zugabe eines Antilösungsmittels, Keimen oder eine Kombination von beliebigen dieser Techniken; und wahlweise
• (v) Filtrieren und/oder Waschen und/oder Trocknen der erhaltenen Kristalle.

Preferably, a polymorphic spirapril hydrochloride form substantially as hereinbefore described is prepared by the following steps:

• (i) dissolving spirapril hydrochloride in a suitable solvent medium, typically with heating;
• (ii) heating the solution obtained by step (i);
• (iii) optionally adding molecular sieve to remove excess water and then filtering it off;
• (iv) crystallizing a polymorphic form substantially as hereinbefore described by means such as cooling, evaporation, addition of an anti-solvent, germination, or a combination of any these techniques; and optionally
• (v) filtering and / or washing and / or drying the resulting crystals.

polymorphic Spirapril hydrochloride forms as by the present invention provided are prodrugs of angiotensin converting enzyme (ACE) inhibitors. They are therefore in the treatment and prevention of cardiovascular disorders, including hypertension, decompensated heart failure and left ventricular dysfunction, useful. You can also in the treatment and prevention of neuropathy in diabetes mellitus be used.

The The present invention therefore further provides pharmaceutical compositions which a therapeutically effective dose of an inventive polymorphic spirapril hydrochloride form together with a pharmaceutically acceptable Carriers, diluents or excipients therefor include. Excipients are made according to the pharmaceutical Form and the desired mode of administration selected.

As As used herein, the term "therapeutically effective Amount "an amount of an inventive polymorphic spirapril hydrochloride form which is capable of Disease condition for which administration of a Angiotensin converting enzyme (ACE) inhibitor is indicated to prevent, too alleviate or eliminate.

Of the Term "pharmaceutically acceptable" means that the carrier, diluent or excipient with a polymorphic spirapril hydrochloride form of the invention compatible and for a recipient thereof is not harmful.

In the medicaments of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal or rectal administration becomes a polymorphic spirapril hydrochloride form of the invention Animals and humans in dosage unit forms mixed with conventional pharmaceutically acceptable carriers for the prophylaxis or treatment of the above disorders or diseases. These are suitable dosage unit forms include forms for oral administration such as tablets, Gelatin capsules, powders, granules and oral solutions or suspensions, forms for sublingual, buccal, intratracheal or intranasal administration, forms of subcutaneous, intramuscular or intravenous administration and forms for rectal Administration. For topical administration, an inventive polymorphic spirapril hydrochloride form in creams, ointments or lotions be used. Oral administration is preferred.

To the Achieve the desired prophylactic or therapeutic Effect can be the dose of a polymorphic spirapril hydrochloride form between 0.01 and 50 mg per kg body weight per day vary. Each dose unit can 0.1 to 1000 mg, preferably 1 to 500 mg of an inventive polymorphic spirapril hydrochloride form in combination with a pharmaceutical Carrier included. This dosage unit can be taken 1 to 5 times a day be administered so that a daily dose of 0.5 to 5000 mg, preferably 1 to 2500 mg is administered.

Becomes a solid composition prepared in the form of tablets is a polymorphic spirapril hydrochloride form of the invention with a vehicle such as gelatin, starch, lactose, magnesium stearate, talc, Mixed gum arabic or the like. The tablets can coated with sucrose, a cellulose derivative or other suitable substances or otherwise treated so that they extend one or delayed activity and a predetermined In principle release the amount of active ingredient continuously.

One Preparation in the form of gelatin capsules can be by mixing a polymorphic spirapril hydrochloride form of the invention with a diluent and pouring the obtained Mixture can be obtained in soft or hard gelatin capsules.

One Preparation in the form of a syrup or elixir or for administration in the form of drops, an inventive polymorphic spirapril hydrochloride form typically with a preferably calorie-free sweetener, optionally antiseptics such as methylparaben and propylparaben, as well a flavor and a suitable color.

Water-dispersible granules or powders may be a polymorphic form of spirapril hydrochloride of the invention mixed with dispersants or wetting or suspending agents such as Po lyvinylpyrrolidone, as well as sweeteners or flavor correctors.

The rectal administration is effected using suppositories the binders melting at the rectal temperature, e.g. B. Polyethylene glycols are produced.

The Parenteral administration is carried out using aqueous Suspensions, isotonic saline or sterile, Injectable solutions that are pharmacologically acceptable Dispersants and / or wetting agents, e.g. For example, propylene glycol or Butylene glycol contained causes.

A polymorphic spirapril hydrochloride form of the invention can also be used as microcapsules with, according to fitness, one or more Carriers or additives are formulated.

It is also substantially the same as the present invention polymorphic spirapril hydrochloride form described hereinabove provided for therapeutic use.

The The present invention further provides a substantially as herein to the above-described polymorphic spirapril hydrochloride form Treatment of a disease state caused by the administration of a Angiotensin converting enzyme (ACE) inhibitor prevents, alleviates or eliminated, ready. In particular, the present invention Invention a substantially as described hereinabove polymorphic drug rapiril hydrochloride form for treatment and prevention a number of disorders, including cardiovascular disorders such as high blood pressure, decompensated heart failure and left ventricular dysfunction, and neuropathy in diabetes mellitus

The The present invention may be understood by the following figures and not by way of limitation Examples are further illustrated.

With Referring to the figures, these are as follows:

1 : X-ray powder diffractogram of anhydrous spirapril hydrochloride according to the invention, obtained using a Philips X'Pert PRO with CuKα radiation in the range 2θ = 3-40 °

2 : X-ray powder diffraction pattern of spirapril hydrochloride polymorph I, obtained using a Philips X'Pert PRO with CuKα radiation in the range 2θ = 3-40 °.

3 : X-ray powder diffraction pattern of spirapril hydrochloride polymorph II, obtained using a Philips X'Pert PRO with CuKα radiation in the range 2θ = 3-40 °.

4 : X-ray powder diffraction pattern of spirapril hydrochloride polymorph III obtained using a Philips X'Pert PRO with CuKα radiation in the range 2θ = 3-40 °.

5 : X-ray powder diffraction pattern of spirapril hydrochloride polymorph IV obtained using a Philips X'Pert PRO with CuKα radiation in the range 2θ = 3-40 °.

6 : X-ray powder diffraction pattern of spirapril hydrochloride polymorph V, obtained using a Philips X'Pert PRO with CuKα radiation in the range 2θ = 3-40 °.

The The following examples are for illustrative purposes only of the invention and are not intended to limit the scope of the present invention restrict.

Spirapril hydrochloride monohydrate may be prepared according to the methods described in US 4470972 See Example 4, and US 5403593 See Example 1.

XRPD analysis was performed on a Philips X'Pert PRO diffractometer using CuKα1 radiation Test conditions: Sample holder preparation Samples were powdered with a mortar and pestle directly onto the zero-background PW1817 / 32 silicon holder device Philips X'Pert PRO goniometer PW3050 / 60 generator PW3040; 45 kV, 40 mA X-ray tube PW3373 / 00; Cu anode LFF focus Linear sample stage PW3072 / 60 or PW3064 Scan angle range (2Θ) 4-40 ° scan mode Continuous absolute scan Step size (2Θ) 0.016 ° Time per step 100 seconds X-rays λ (CuKα ₁ ) = 1.540598 Å First Soller slot 0.04 rad PDS Fixed, divergence 1/2 ° First mask 10 mm Second Soller slot 0.04 rad monochromator Inc. beam α ₁ Cu / Co for reflection mode detector X'Celerator (2,022 ° 2Θ) control program X'Pert Data Collector temperature 293 ± 3K

The Single-crystal study was conducted using a CCD diffractometer Bruker Nonius FR591 / Kappa type with CuKα radiation a temperature of 293 (3) K performed.

EXAMPLES

EXAMPLE 1

Preparation of anhydrous spirapril hydrochloride

50 mg of spirapril hydrochloride monohydrate were dissolved in 3 ml of dioxane with warming dissolved, and 5 ml of n-amyl acetate was added dropwise. The obtained Product was filtered off to give 54 mg of white crystals receive.

EXAMPLE 2

Preparation of anhydrous spirapril hydrochloride

50 mg of spirapril hydrochloride monohydrate were dissolved in 3 ml of acetonitrile Heating solved. Molecular sieve was added to remove excess water, and then filtered off. The solution was cooled to the Crystallization to take place. for single X-ray diffraction suitable crystals were obtained. These were filtered off and washed with acetonitrile.

EXAMPLE 3

Preparation of spirapril hydrochloride form I

50 mg of spirapril hydrochloride monohydrate were dissolved in 3 ml of 1,2-propylene carbonate solved. Molecular sieve was added to excess Remove water, and then filtered off. The crystallization took place at room temperature. The product was filtered off and with 1,2-propylene carbonate washed to obtain 11 mg of white crystalline product.

EXAMPLE 4

Preparation of spirapril hydrochloride form II

50 mg of spirapril hydrochloride monohydrate were dissolved in 3 ml of anhydrous dioxane dissolved by heating. 2.5 ml of anhydrous octane were dropped, resulting in a precipitate of a product which was filtered off to 52 mg white to obtain crystalline product.

EXAMPLE 5

Preparation of spirapril hydrochloride form III

50 mg of spirapril hydrochloride monohydrate were dissolved in 3 ml of anhydrous dioxane dissolved by heating. 5 ml of anhydrous benzene were dropped, resulting in a precipitate of a product led, which was filtered off, to 44 mg of a white to obtain crystalline product.

EXAMPLE 6

Preparation of spirapril hydrochloride form IV

50 mg of spirapril hydrochloride monohydrate were dissolved in 3 ml of anhydrous dioxane dissolved by heating. 4 ml of anhydrous tert-butyl methyl ether were dropped, resulting in a precipitate of a product led, which was filtered off, to 41 mg of a white to obtain crystalline product.

EXAMPLE 7

Preparation of spirapril hydrochloride form V

50 mg of spirapril hydrochloride monohydrate were dissolved in 3 ml of anhydrous dioxane dissolved by heating. 4 ml of anhydrous tetrachloromethane were dropped, resulting in a precipitate of a product led, which was filtered off, to 37 mg of a white to obtain crystalline product.

QUOTES INCLUDE IN THE DESCRIPTION

This list The documents listed by the applicant have been automated generated and is solely for better information recorded by the reader. The list is not part of the German Patent or utility model application. The DPMA takes over no liability for any errors or omissions.

Cited patent literature

• US 4470972 [0054]
• US 5403593 [0054]

Claims (23)

Anhydrous spirapril hydrochloride. Anhydrous spirapril hydrochloride, characterized that there are characteristic X-ray powder diffraction peak (2θ): 8.1 ± 0.2 °, 9.7 ± 0.2 °, 14.2 ± 0.2 °, 16.3 ± 0.2 °, 18.4 ± 0.2 ° and 19.3 ± 0.2 °. Anhydrous spirapril hydrochloride according to claim 2, further characterized in that it has characteristic X-ray powder diffraction peak (2θ) selected from one or more of the following has: 15.4 ± 0.2 °, 20.5 ± 0.2 °, 21.4 ± 0.2 °, 23.0 ± 0.2 ° and 26.9 ± 0.2 °. Anhydrous spirapril hydrochloride, characterized in that it has an X-ray powder diffraction pattern as in 1 shown or has a substantially the same X-ray powder diffractogram. Polymorph I of spirapril hydrochloride, characterized that there are characteristic X-ray powder diffraction peak (2θ): 6.5 ± 0.2 °, 8.1 ± 0.2 °, 16.2 ± 0.2 °, 20.4 ± 0.2 ° and 24.3 ± 0.2 °. A polymorph according to claim 5, further characterized by X-ray powder diffraction peak (2θ) one or more of the following: 9.3 ± 0.2 °, 13.2 ± 0.2 °, 17.4 ± 0.2 °, 19.3 ± 0.2 ° and 26.5 ± 0.2 °. Polymorph I of spirapril hydrochloride, characterized in that it has an X-ray powder diffraction pattern as in 2 shown or has a substantially the same X-ray powder diffractogram Polymorph II of spirapril hydrochloride, characterized that there are characteristic X-ray powder diffraction peak (2θ): 7.6 ± 0.2 °, 8.6 ± 0.2 °, 9.4 ± 0.2 °, 14.1 ± 0.2 °, 16.4 ± 0.2 ° and 17.3 ± 0.2 °. A polymorph according to claim 8, further characterized by X-ray powder diffraction peak (2θ) one or more of the following: 12.5 ± 0.2 °, 19.2 ± 0.2 ° 20.2 ± 0.2 °, 23.8 ± 0.2 ° and 29.7 ± 0.2 °. Polymorph II of spirapril hydrochloride, characterized in that it has an X-ray powder diffraction pattern as in 3 shown or has a substantially the same X-ray powder diffractogram. Polymorph III of spirapril hydrochloride, by characterized in that it has characteristic X-ray powder diffraction peak (2θ): 6.2 ± 0.2 °, 7.6 ± 0.2 °, 14,1 ± 0,2 ° 16,4 ± 0,2 ° and 17.3 ± 0.2 °. A polymorph according to claim 12, further characterized by X-ray powder diffraction peak (2θ) one or more of the following: 10,2 ± 0,2 °, 12.5 ± 0.2 °, 19.2 ± 0.2 °, 20.3 ± 0.2 °, 23.8 ± 0.2 ° and 24.2 ± 0.2 °. Polymorph III of spirapril hydrochloride, characterized in that it has an X-ray powder diffraction pattern as in 4 shown or has a substantially the same X-ray powder diffractogram. Polymorph IV of spirapril hydrochloride, by characterized in that it has characteristic X-ray powder diffraction peak (2θ): 7.6 ± 0.2 °, 8.1 ± 0.2 °, 14.1 ± 0.2 °, 16.4 ± 0.2 ° and 17.4 ± 0.2 °. The polymorph of claim 14, further characterized by X-ray powder diffraction peak (2θ) one or more of the following: 5.7 ± 0.2 °, 12.5 ± 0.2 °, 13.3 ± 0.2 °, 19.3 ± 0.2 ° and 20.4 ± 0.2 °. Polymorph IV of spirapril hydrochloride, characterized in that it has an X-ray powder diffraction pattern as in 5 shown or has a substantially the same X-ray powder diffractogram. Polymorph V of spirapril hydrochloride, characterized that there are characteristic X-ray powder diffraction peak (2θ): 7.1 ± 0.2 °, 10.2 ± 0.2 °, 18.7 ± 0.2 °, 19.8 ± 0.2 ° and 22.3 ± 0.2 °. Polymorph according to claim 17, further characterized by X-ray powder diffraction peak (2θ) one or more of the following: 7.6 ± 0.2 °, 8.6 ± 0.2 °, 9.3 ± 0.2 °, 13.6 ± 0.2 ° and 17.2 ± 0.2 °. Polymorph V of spirapril hydrochloride, characterized in that it has an X-ray powder diffraction pattern as in 6 shown or has a substantially the same X-ray powder diffractogram. A pharmaceutical composition comprising a therapeutically effective Dose of a polymorphic spirapril hydrochloride form according to one of Claims 1 to 19 together with a pharmaceutically acceptable Carriers, diluents or excipients therefor. Polymorphic spirapril hydrochloride form after one of claims 1 to 19 for therapeutic use. Polymorphic spirapril hydrochloride form after one of claims 1 to 19 for use in the treatment a disease state caused by the administration of an ACE inhibitor prevented, alleviated or eliminated. Polymorphic spirapril hydrochloride form according to claim 22, wherein the disease state is selected from the Group consisting of cardiovascular disorders, including Hypertension, decompensated heart failure and left ventricular dysfunction, and neuropathy in diabetes mellitus.