Methhod for producing a crystalline form of 5-amino-2,3-dihydrophthalazine-1,4-dione

Abstract

A new method for producing a crystalline form of 5-amino-2,3-dihydro-1,4-phthalazinedione (luminol) is provided. Advantageous uses for this crystalline form as a detecting agent or as an agent for forensic purposes are disclosed, as well a pharmaceutical composition containing said crystalline form.

Claims

1. A method for producing a crystalline form of 5-amino-2,3-dihydrophthalazine-1,4-dione comprising the following steps: a) Dissolving 5-amino-2,3-dihydrophthalazine-1,4-dione in a refluxing ethanol-water solution having a range from 5:1 to 1:1 (v/v) at 50 to 100° C., b) cooling the solution of step a) to room temperature over a period of 60 to 240 min to afford a precipitated crystalline product, c) separating the precipitated crystalline product provided in step b), d) drying the precipitated crystalline product provided in step c) at room temperature over a period of 6 to 48 hours, and e) optionally, resuspending the precipitated crystalline product provided in step d) one to three times in ethanol, stirring, rewashing with ethanol and drying again, the resulting crystalline form being characterized by the following crystallography values determined by means of powder X-ray diffraction: D values: 11.4; 11.2; 6.9; 6.8; 6.4; 5.6; 3.6; 3.5; 3.5; 3.3; 3.2 and 2-theta values: 7.8; 7.9; 12.8; 13.0; 13.9; 15.7; 24.9; 25.7; 25.7; 27.2; 27.5.

2. The method according to claim 1, wherein the resulting crystalline form has a crystal water content ≤0.4%.

3. The method according to claim 1, wherein the ethanol of step e) has a degree of purity ≥98%.

4. The method according claim 1, wherein the method comprises the following steps: a) Dissolving 5-amino-2,3-dihydrophthalazine-1,4-dione in a refluxing ethanol-water solution (3:1, v/v) at 80° C. b) cooling the solution of step a) to room temperature over a period of 120 min to afford a precipitated crystalline product, c) separating the precipitated crystalline product provided in step b), and d) drying the precipitated crystalline product provided in step c at room temperature for 12 hours.

Description

EXAMPLES

(1) All standard chemicals were purchased from Sigma-Aldrich.

Example 1: PXRD Analysis of Commercially Available Luminol

(2) 1 g of commercially available luminol (Merck) were analyzed by means of PXRD. Measurements were performed in transmission geometry using a STOE STADI P diffractometer with CuK.sub.α1 radiation equipped with a fast, high resolution silicon strip detector (DECTRIS Mythen1K). The samples were prepared in glass capillaries (diameter 0.5 mm). Instrumental parameters for Rietveld refinements were determined applying a Si standard. (n=3)

(3) Crystal structure determination: TOPAS Academic (A. A. Coelho, TOPAS-Academic, version 5.0, Coelho Software, Brisbane, Australia, 2007) was used for indexing, determination of the Laue group, structure solution, and Rietveld refinement.

(4) Structure solution was accomplished by a simulated annealing method in TOPAS Academic applying a rigid body model of a luminol molecule of the amide-hydroxyimine tautomeric form. The molecular structure of the rigid body was obtained by DFT geometry optimization with the DMol3 module applying the generalized-gradient approximation (GGA) with the Perdew-Burke-Ernzerhof (PBE) functional as implemented in the Materials Studio software.

(5) For structure solution six parameters were globally optimized in the simulated annealing run: Three positional and three angular parameters for the luminol.

(6) Rietveld refinements of the resulting structure models were performed using a fundamental parameters approach for describing the peak profiles. A conjoint isotropic temperature factor for all heteroatoms was refined. Temperature factors for hydrogens were fixed to Uiso=1.27 A2.

(7) Experiments with luminol purchased from Applichem yielded qualitatively the same results.

Example 2: Crystallization Method of Luminol

(8) To obtain a phase-pure powder luminol (1 g, Merck) was dissolved in 80 mL of a refluxing (80° C.) ethanol-water mixture (3:1, vol %:vol %). After complete dissolution the mixture was allowed to cool slowly to room temperature within a period of 2 h. The microcrystalline powder was recovered by suction filtering and was allowed to dry at room atmosphere for 12 h.

(9) The resulting powder was analyzed by means of PXRD, as described in Ex. 1. Also the crystal structure determination and Rietveld refinements were performed as in Ex. 1. (n=3)

Example 3: Thermal Stability of the Crystalline Form Produced by the Method According to the Invention

(10) Simultaneous thermogravimetry (TG) and differential scanning calorimetry (DSC) prove the thermal stability of the crystalline form of luminol produced by the method according to the invention up to 328±1° C. Furthermore, no solid state transformation to other forms is observed until thermal degradation of the crystalline compound sets in (FIG. 5).

SHORT DESCRIPTION OF THE FIGURES

(11) FIG. 1: XRPD diagrams of commercially available 5-amino-2,3-dihydro-1,4-phthalazinedione. Upper trace: 5-amino-2,3-dihydro-1,4-phthalazinedione purchased from Merck. Lower trace: 5-amino-2,3-dihydro-1,4-phthalazinedione purchased from AppliChem.

(12) FIG. 2: Upper trace: XRPD diagram of the crystalline form of 5-amino-2,3-dihydro-1,4-phthalazinedione produced by the method according to the invention. Lower trace: The difference (A) to the XRPD diagrams from Exp. 1. Indicated are also the 2-theta reflections from the crystalline form of 5-amino-2,3-dihydro-1,4-phthalazinedione produced by the method according to the invention.

(13) FIG. 3: A: Space-filling model of the molecular packing of the crystalline form of 5-amino-2,3-dihydro-1,4-phthalazinedione, calculated according to the values published by Paradies

(14) B: Space-filling model of the molecular packing of the crystalline form of 5-amino-2,3-dihydro-1,4-phthalazinedione produced by the method according to the invention

(15) Upper traces: along a axis; medium traces: along b axis; lower traces: along c axis, respectively.

(16) FIG. 4: A: Trimer stacking model of the molecular packing of the crystalline form of 5-amino-2,3-dihydro-1,4-phthalazinedione, calculated according to the values published by Paradies

(17) B: Trimer stacking model of the molecular packing of the crystalline form of 5-Amino-2,3-dihydro-1,4-phthalazinedione produced by the method according to the invention

(18) FIG. 5: TG-DSC diagram of crystalline form of 5-amino-2,3-dihydro-1,4-phthalazinedione produced by the method according to the invention. Upper trace: Mass loss determined by TG. Lower trace: Heat flow determined by DSC

ABBREVIATIONS

(19) COPD chronic obstructive pulmonary disease D (or: d) interplanar distance DFT discrete Fourier transform DPI dry powder inhaler DSC differential scanning calorimetry ECL electrogenerated chemiluminescence of luminol EDTA ethylenediaminetetraacetic acid GMP Good Manufacturing Practice I/Io (rel) relative intensities I/Io (%) relative intensities in percent ICD-10 10th revision of the International Statistical Classification of Diseases and Related Health Problems IMIDs immunomodulatory agents mbar millibar MDI metered-dose inhaler min minutes NSAIDs non-steroidal anti-inflammatory drugs PEG polyethylene glycol PXRD powder X-ray diffraction SDS-PAGE sodium dodecyl sulfate polyacrylamide gel electrophoresis TG thermogravimetry Uiso isotropic atomic displacement parameters v/v volume concentration θ Bragg angle theta % by weight percentage by weight