# US 8,772,294 B2 · Crystalline forms for 5-amino-2, 3-dihydrophthalazine-1, 4-dione sodium salt, pharmaceutical preparations containing the same and method for the production of said forms

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- Number: US 8,772,294 B2
- Document ID: US8772294B2
- Status: Granted
- Kind: B2
- Application number: 13/582,522
- Filed: 2011-03-01
- Published: 2012-12-27
- Granted: 2014-07-08
- Earliest claimed: 2010-03-01
- Assignees: MetrioPharm AG
- Applicants: Josef Breu; Wolfgang Brysch; Astrid Kaiser; Beate Ludescher; Gerrit Maass; Thomas Martin; Wolfgang Milius; Michael Niedermaier
- Inventors: Josef Breu; Wolfgang Brysch; Astrid Kaiser; Beate Ludescher; Gerrit Maass; Thomas Martin; Wolfgang Milius; Michael Niedermaier
- Web page: https://patentgrep.com/patent/US8772294B2

## CPC

- C07D 237/32: with oxygen atoms directly attached to carbon atoms of the nitrogen-containing ring
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 5/14: of the thyroid hormones, e.g. T3, T4
- A61P 5/18: of the parathyroid hormones
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 7/04: Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
- A61P 7/06: Antianaemics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 13/02: of urine or of the urinary tract, e.g. urine acidifiers
- A61P 13/12: of the kidneys
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61P 21/04: for myasthenia gravis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/04: Antibacterial agents
- A61P 31/12: Antivirals
- A61P 31/14: for RNA viruses
- A61P 31/16: for influenza or rhinoviruses
- A61P 31/18: for HIV
- A61P 31/20: for DNA viruses
- A61P 31/22: for herpes viruses
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 35/04: specific for metastasis
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/02: Immunomodulators
- A61P 37/04: Immunostimulants
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The invention relates to the provision of two novel crystalline forms I and II for 5-amino-2,3-dihydrophthalazine-1,4-dione sodium salt. Surprisingly, it was discovered that form I and form II have differing immunological effects. This advantageous property is useful for immunospecific applications. In addition, both forms have advantageous physicochemical properties, which are useful in the production, further processing and/or use of a pharmaceutical preparation of form I or form II or a mixture of both.

## Claims

### Claim 1

A crystalline polymorph form of a 5-amino-2,3-dihydrophthalazine-1,4-dione alkali salt, wherein said crystalline polymorph form is either form I or form II which are characterized by the following crystallography values determined by means of x-ray powder diagrams:
form I:
d values: 13.5; 6.9; 5.2; 4.6; 3.9; 3.5; 3.4; 3.3; 3.1; 3.0 and/or
2-theta values: 6.5; 12.7; 16.9; 19.3; 22.8; 25.8; 26.6; 27.2; 28.7; 30.3 and
form II:
d values: 12.9; 7.9; 7.1; 6.5; 5.3; 4.0; 3.7; 3.6; 3.3; 3.2 and/or
2-theta values: 6.8; 11.2; 12.5; 13.7; 16.7; 22.4; 24.3; 24.9; 27.2; 27.8.

### Claim 2 (depends on 1)

The crystalline polymorph form according to claim 1, wherein said crystalline polymorph form has a content of water of crystallization ≦0.4%.

### Claim 3 (depends on 1)

The crystalline polymorph form according to claim 1, wherein said form is form I.

### Claim 4 (depends on 1)

The crystalline polymorph form according to claim 1, wherein said form is form II.

### Claim 5 (depends on 1)

A pharmaceutical composition comprising a crystalline polymorph form according to claim 1 and at least one pharmaceutically suitable auxiliary substance.

### Claim 6 (depends on 5)

The pharmaceutical composition according to claim 5, wherein said composition further contains one or more other active ingredients.

### Claim 7 (depends on 1)

A method for producing the crystalline polymorph form according to claim 1, said method comprising:
mixing 5-amino-2,3-dihydrophthalazine-1,4-dione with sodium hydroxide solution and adding a low-molecular liquid alcohol, thereby reducing the solubility product of the generated 5-amino-2,3-dihydrophthalazine-1,4-dione sodium salt such that the latter precipitates, and
separating and drying the precipitated crystalline product, wherein crystalline form I can be suspended several times in ethanol, stirred, rewashed with ethanol and again dried.

### Claim 8 (depends on 7)

The method according to claim 7, wherein said polymorph form is form I, and the added low-molecular alcohol is ethanol having a degree of purity ≧98%, and said ethanol is added at room temperature within 10-40 min.

### Claim 9 (depends on 7)

The method according to claim 7, wherein said polymorph form is form II, and the added low-molecular alcohol is 2-propanol having a degree of purity ≧98%, and said 2-propanol is added at room temperature within 10-40 min.

### Claim 10 (depends on 1)

A method for producing the crystalline polymorph form I according to claim 1, said method comprising:
a) Producing a mixture of 1.0-1.4 equivalents sodium hydroxide, with 4-7 equivalents (vol/m) water;
b) Adding 1 equivalent luminol to said mixture and stirring until complete dissolution is achieved;
c) Adding 50-70 equivalents (vol/m) ethanol with a degree of purity ≧98%, at room temperature (25° C. ±5° C.) within 10-40 min;
d) After complete addition of the ethanol, restirring the reaction mixture at room temperature for maximum 20 h, and filtering this mixture;
e) Washing the resultant filter cake with 10-15 equivalents (vol/m) ethanol having a degree of purity ≧98%; and
f) Drying the resultant product in a vacuum compartment drier at 50-90° C./1-3 mbar or in a rotary evaporator at 20±10 mbar and 50° C.-90° C., until constant masses are obtained.

### Claim 11 (depends on 1)

A method for producing crystalline polymorph form II according to claim 1, said method comprising:
a) Producing a mixture of 1.0-2.0 equivalents sodium hydroxide with 6-7.5 equivalents (vol/m) water;
b) Adding 0.5-1 equivalent luminol and stirring the mixture until complete dissolution is achieved;
c) Adding 60 equivalents (vol/m) 2-propanol with a degree of purity >98% within 20±10 min, at room temperature (25° C. ±5° C.);
d) Stirring the resultant suspension at room temperature (25° C. ±5° C.) for at least 1 h;
e) Filtering and washing the resultant filter cake with 13-15 equivalents (vol/m) 2-propanol with a degree of purity ≧98%; and
f) Drying the resultant product in a vacuum compartment drier at 85° C.-120° C./1-3 mbar or in a rotary evaporator at 20±10 mbar and 85° C.-120° C., until constant masses are obtained.

### Claim 12 (depends on 11)

The method according to claim 11, wherein in d) the stirring time is 1-5 h, or the stirring time is at least 10 h if the added luminol quantity is at least 200 g.

### Claim 13 (depends on 8)

The method according to claim 8, wherein said ethanol has a degree of ≧99.

### Claim 14 (depends on 9)

The method according to claim 9, wherein said 2-propanol has a degree of purity ≧99%.

### Claim 15 (depends on 10)

The method for according to claim 10, wherein:
said ethanol has a degree of purity ≧99%;
after complete addition of the ethanol, the reaction mixture is restirred for 2-8 h;
the filter cake is washed with ethanol having a degree of purity ≧99%; and
the product is dried in a vacuum compartment drier at 70° C.-90° C./1-3 mbar, or in a rotary evaporator at 20±10 mbar and 50 70° C.-90° C.

### Claim 16 (depends on 11)

The method for according to claim 11, wherein:
said 2-propanol has a degree of purity ≧99%;
the filter cake is washed with ethanol having a degree of purity >99%; and
the product is dried in a vacuum compartment drier at 90° C.-100° C./1-3 mbar, or in a rotary evaporator at 20±10 mbar and 90° C.-100° C.

### Claim 17 (depends on 12)

The method according to claim 12, wherein in d) the stirring time is 1-5 h, and the added luminol quantity is at least 300 g.