Pharmaceutical grade phthalazinediones, process for their preparation and pharmaceutical compositions containing them

Abstract

The present invention comprises methods of manufacturing a highly purified, pharmaceutical grade phthalazinedione for administration to a human or animal. The manufacturing methods identify and isolate starting materials, and prepare intermediate products, which are suitable for the commercial batch process production of highly purified and high-yielding intermediate products and final phthalazinedione products.

1 . A process for the reproducible preparation of a highly purified pharmaceutical grade phthalazinedione comprising the steps of:
 identifying and isolating a starting material suitable for the preparation of a highly purified pharmaceutical grade final phthalazinedione product;   chemically treating the starting material to form a pharmaceutical grade final phthalazinedione product such that the final phthalazinedione product has a purity of at least 90%;   wherein the process complies with GMP reproducibility standards.   
   
   
       2 . The process of  claim 1  for preparing a pharmaceutical-grade phthalazinedione, further comprising the steps of:
 chemically treating the starting material to form a highly purified intermediate product suitable for the preparation of the pharmaceutical grade final phthalazinedione product; and   chemically treating the highly purified intermediate product to form the pharmaceutical grade final phthalazinedione product.   
   
   
       3 . The process of  claim 1 , wherein the starting material is at least 90% pure as determined by HPLC. 
   
   
       4 . The process of  claim 2 , wherein the starting material is a highly purified form of 3-nitrophthalic acid. 
   
   
       5 . The process of  claim 2 , wherein the intermediate product is at least 90% pure as determined by HPLC. 
   
   
       6 . The process of  claim 5 , wherein the intermediate material is a highly purified form of 3-nitrophthalhydrazide. 
   
   
       7 . The process of  claim 1 , wherein the final phthalazinedione product is at least 90% pure as determined by HPLC. 
   
   
       8 . The process of  claim 1 , wherein the final phthalazinedione product meets the standard GMP requirements. 
   
   
       9 . The process of  claim 1 , wherein the final phthalazinedione product is capable of crossing the human blood-brain barrier. 
   
   
       10 . The process of  claim 9 , wherein the final phthalazinedione product has a molecular weight of less than 500 grams-mol −1 . 
   
   
       11 . The process of  claim 9 , wherein the final phthalazinedione product has a molecular weight of 199.14 grams-mol −1 . 
   
   
       12 . The process of  claim 1 , wherein the process is a commercial batch process. 
   
   
       13 . The process of  claim 1  or  2 , wherein the intermediate product has a product yield of at least 20 wt %. 
   
   
       14 . The process of  claim 1  or  2 , wherein the intermediate product has a product yield of at least 30 wt %. 
   
   
       15 . The process of  claim 1  or  2 , wherein the intermediate product has a product yield of at least 40 wt %. 
   
   
       16 . The process of  claim 1 , wherein the highly purified form of 3-nitrophthalic acid starting material is at least 95% pure as determined by HPLC analysis. 
   
   
       17 . The process of  claim 1 , wherein the highly purified form of 3-nitrophthalic acid starting material is at least 99.9% pure as determined by HPLC analysis. 
   
   
       18 . The process of  claim 2 , wherein the 3-nitrophthalhydrazide intermediate product is at least 95% pure as determined by HPLC analysis. 
   
   
       19 . The process of  claim 2 , wherein the 3-nitrophthalhydrazide intermediate product is at least 99.9% pure as determined by HPLC analysis. 
   
   
       20 . The process of  claim 1 , wherein the final phthalazinedione product has a purity of at least 95% as determined by HPLC analysis. 
   
   
       21 . The process of  claim 1 , wherein the final phthalazinedione product has a purity of at least 99.6% as determined by HPLC analysis. 
   
   
       22 . The process of  claim 2  for preparing a highly purified pharmaceutical grade phthalazinedione, wherein
 the identified and isolated highly purified starting material is 3-nitrophthalic acid having a purity of at least 99% as determined by HPLC analysis, and   the highly purified intermediate product is 3-nitrophthalhydrazide having a purity of at least 99% as determined by HPLC analysis, and wherein   the pharmaceutical grade final phthalazinedione product is monosodium luminol having a product yield of at least 20% and a purity of at least 99.6% as determined by HPLC analysis.   
   
   
       23 . A process for identifying a starting material suitable for use in preparation of a highly purified pharmaceutical grade phthalazinedione product, the process comprising:
 performing an HPLC analysis of a composition including the starting material so as to identify a starting material suitable for preparation of a pharmaceutical grade phthalazinedione; and   isolating the highly purified starting material, under conditions such that the identified and isolated starting material is at least 90% pure.   
   
   
       24 . The process of  claim 23 , wherein the starting material is a highly purified form of 3-nitrophthalic acid. 
   
   
       25 . The process of  claim 24 , wherein the 3-nitrophthalic acid has a purity of at least 95% as determined by HPLC analysis. 
   
   
       26 . The process of  claim 2 , wherein the  3 -nitrophthalic acid has a purity of at least 99% as determined by HPLC analysis. 
   
   
       27 . A process for reproducibly preparing a highly purified intermediate product suitable for use in preparing a highly purified pharmaceutical grade final phthalazinedione product, the process comprising the steps of:
 identifying and isolating a highly purified starting material suitable for the preparation of a pharmaceutical grade final phthalazinedione product; and   chemically treating the identified and isolated highly purified starting material to form a highly purified intermediate product having a purity of at least 90% and being suitable for the preparation of the highly purified pharmaceutical grade final phthalazinedione product.   
   
   
       28 . The process of  claim 27 , wherein the step of identifying and isolating the starting material is according to  claim 23 . 
   
   
       29 . The process of  claim 27 , wherein the highly purified intermediate product is at least 99% pure as determined by HPLC analysis. 
   
   
       30 . The process of  claim 27 , wherein the intermediate product has a product yield of at least 20 wt %. 
   
   
       31 . The process of  claim 27 , wherein the intermediate product has a product yield of at least 30 wt %. 
   
   
       32 . The process of  claim 27 , wherein the intermediate product has a product yield of at least 40 wt %. 
   
   
       33 . The process of  claim 27 , wherein the highly purified intermediate product is at least 99% pure as determined by HPLC analysis. 
   
   
       34 . A pharmaceutical composition comprising, a phthalazinedione having a purity of at least 99% as determined by HPLC analysis. 
   
   
       35 . A pharmaceutical composition comprising the highly purified pharmaceutical grade phthalazinedione product of  claim 1  or  2 . 
   
   
       36 . The pharmaceutical composition of  claim 35 , wherein the phthalazinedione product is at least 99% pure. 
   
   
       37 . The pharmaceutical composition of  claim 35 , wherein the phthalazinedione product is at least 99.6%. 
   
   
       38 . The pharmaceutical composition of  claim 35 , wherein the phthalazinedione is monosodium luminol.