Crystalline form of 5-amino-2,3-dihydrophthalazine-1,4-dione

Abstract

A new 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. Crystalline Form II of 5-amino-2,3-dihydrophthalazine-1,4-dione of the following formula: ##STR00002## wherein the crystalline Form II is characterized by a powder X-ray diffraction pattern comprising diffraction peaks at angles (° 2θ) of 7.5°, 12.6°, 13.1°, 13.4°, 25.9°, and 27.2°.

2. The crystalline Form II according to claim 1, wherein the crystalline Form II is further characterized by a powder X-ray diffraction pattern comprising additional diffraction peaks at angles (° 2θ) of 10.2°, 10.9°, and 26.7°.

3. A pharmaceutical composition comprising the crystalline Form II according to claim 1 and at least one pharmaceutically acceptable excipient.

4. The pharmaceutical composition according to claim 3, wherein the at least one pharmaceutically acceptable excipient is selected from the group consisting of an acidifier, an antioxidant, an aromatic substance, a binding agent, a buffer, a carrier, a consistency enhancer, a colorant, a diluent, a disintegrant, an emulsifier, a fatiquor, a flavoring substance, a glidant, a hydrotope, a lubricant, a pH regulator, a permeation enhancer, a preservative, a solubilizing agent, a solvent, a sweetener, and a thickening agent, or a combination thereof.

5. The pharmaceutical composition according to claim 3, wherein the pharmaceutical composition is administered topically.

6. The pharmaceutical composition according to claim 3, wherein the pharmaceutical composition further comprises at least one additional pharmaceutically active agent.

7. A process for producing the crystalline Form II according to claim 1, wherein the process comprises the following steps: (a) providing a solution of 5-amino-2,3-dihydrophthalazine-1,4-dione sodium salt dissolved in demineralized water; (b) adding a 10%-38% v/v hydrochloric acid solution to the solution provided in step (a) at a temperature in the range of 5° C. to 50° C. for a period of 1 second to 3600 seconds, to provide a precipitate; (c) filtering the precipitate provided in step (b); (d) washing the precipitate provided in step (c) at least one time with demineralized water; and (e) drying the precipitate provided in step (d) at room temperature for a period of 6 hours to 48 hours, to produce the crystalline Form II according to claim 1.

8. The process according to claim 7, wherein the process comprises the following steps: (b) adding a 17% v/v hydrochloric acid solution to the solution provided in step (a) at room temperature for a period of 1800 seconds, to provide a precipitate; (c) filtering the precipitate provided in step (b); (d) washing the precipitate provided in step (c) three times with demineralized water; and (e) drying the precipitate provided in step (d) at room temperature for a period of 12 hours, to produce the crystalline Form II according to claim 1.

9. The process according to claim 7, wherein step (e) of the process comprises: (e) drying the precipitate provided in step (d) in a vacuum dryer at a pressure in the range of 5 mbar to 1100 mbar, to produce the crystalline Form II according to claim 1; or (e) drying the precipitate provided in step (d) in a lyophilizer and removing any residual solvent content by sublimation at 0.1 mbar, to produce the crystalline Form II according to claim 1; or (e) drying the precipitate provided in step (d) in a rotary evaporator at a pressure in the range of 1 mbar to 1050 mbar, to produce the crystalline Form II according to claim 1.

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 Å2.

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

Example 2: Crystallization Method of Crystalline Form II of Luminol

(8) A phase-pure powder of good crystallinity could be obtained by neutralization of Na-luminolate. Slow addition of 5 mL hydrochloric acid (17%) to a stirred solution of 2 g Na-luminolate (MetrioPharm) in 500 mL demineralized water yielded a microcrystalline powder.

(9) The precipitate was filtered and then washed three times with demineralized water before allowing it to dry at room temperature for 12 h.

(10) 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

(11) Simultaneous thermogravimetry (TG) and differential scanning calorimetry (DSC) prove the thermal stability of the new crystalline Form II of luminol up to 320±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

(12) 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.

(13) FIG. 2: Upper trace: XRPD diagram of the crystalline Form II of 5-amino-2,3-dihydro-1,4-phthalazinedione. Lower trace: The difference (A) to the XRPD diagrams from Exp. 1. Indicated are also the 2-theta reflections from the crystalline Form II of 5-amino-2,3-dihydro-1,4-phthalazinedione and of NaCl.

(14) 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

(15) B: Space-filling model of the molecular packing of the crystalline Form II of 5-amino-2,3-dihydro-1,4-phthalazinedione top: along a axis; center: along b axis; bottom: 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 II of 5-Amino-2,3-dihydro-1,4-phthalazinedione

(18) FIG. 5: TG-DSC diagram of crystalline Form II of 5-amino-2,3-dihydro-1,4-phthalazinedione. 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 DMSO dimethyl sulfoxide DPI dry powder inhaler DSC differential scanning calorimetry ECL electrogenerated chemiluminescence of luminol EDTA ethylenediaminetetraacetic acid GMP Good Manufacturing Practice I/lo (rel) relative intensities I/lo (%) 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