 U.S. Pharmacopeia Official Monograph for hydralazine hydrochloride, for example, requires that pharmaceutical quality hydralazine hydrochloride contain no more than 0.1% hydrazine by weight.
Hydralazine is known to chelate metal ions. Sinha and Motten [Biochemical and Biophysical Research Communications 105(3): 1044–1051 (1982)] report that hydralazine oxidizes rapidly in the presence of oxygen and metal ions such as Cu+2, Fe+2, and Fe+3 through free radical intermediates in a manner similar to other hydrazine derivatives.
When manufactured according to conventional methods of manufacture, hydralazine hydrochloride undergoes degradation during storage to intensely colored, insoluble polymeric products. The numerous degradation products that form during storage have not been completely identified and characterized chemically, but it is believed that they are the products of reactions such as chelation with metal ions, oxidation, reaction of residual hydrazine raw material with chlorinated intermediates that were incompletely removed during manufacturing, and reaction of hydralazine with chlorinated intermediates that were incompletely removed during manufacturing.
It is an object of the present invention to manufacture hydralazine hydrochloride of high pharmaceutical quality that is free of contaminating by-products.
It is an object of the present invention to manufacture hydralazine hydrochloride of high pharmaceutical quality that is free of contaminating by-products such as hydrazine, metal ions, or chlorinated pyridazine-containing compounds.
It is a further object of the present invention to manufacture a stable pharmaceutical formulation of hydralazine hydrochloride that is free of contaminating by-products such as hydrazine, metal ions, or chlorinated pyridazine-containing compounds.
It is a further object of the present invention to manufacture a stable hydralazine hydrochloride pharmaceutical composition that does not degrade or produce particulate matter during extended storage of the bulk drug substance or its liquid formulations.
It is a further object of the present invention to manufacture a stable injectable pharmaceutical formulation containing hydralazine hydrochloride that has no visible particulate matter for a time more than 30 months after manufacture.
It is a further object of the present invention to manufacture a stable injectable pharmaceutical formulation containing hydralazine hydrochloride that has less than 6000 10 micron particles per container or 600 25 micron particles per container for a time more than 30 months after manufacture.
It is a further object of the present invention to produce hydralazine hydrochloride that is stable in
U.S. Pharmacopeia Official Monograph for hydralazine hydrochloride, for example, requires that pharmaceutical quality hydralazine hydrochloride contain no more than 0.1% hydrazine by system of weights. 
 Hydralazine is know to chelate metal ions. Sinha and Motten [ Biochemical and Biophysical Research Communications 105(3 ): 1044–1051 (1982) ] report that hydralazine oxidizes quickly in the presence of oxygen and metal ions such as Cu+2, Fe+2, and Fe+3 through complimentary radical intermediates in a manner alike to other hydrazine derivatives. 
 When manufacture according to conventional method acting of industry, hydralazine hydrochloride undergoes degradation during storage to intensely colored, insoluble polymeric products. The numerous abasement products that form during storage have not been wholly identified and characterized chemically, but it is believed that they are the products of reactions such as chelation with metallic element ions, oxidation, reaction of residual hydrazine raw material with chlorinated intermediate that were incompletely removed during manufacturing, and reaction of hydralazine with chlorinated intermediates that were incompletely removed during fabrication. 
 It is an aim of the present invention to fabricate hydralazine hydrochloride of high pharmaceutical quality that is free of contaminating by - products. 
 It is an object of the present invention to manufacture hydralazine hydrochloride of eminent pharmaceutical timbre that is complimentary of contaminating by - product such as hydrazine, alloy ions, or chlorinated pyridazine - hold compound. 
 It is a further object of the present invention to manufacture a static pharmaceutical formulation of hydralazine hydrochloride that is free of contaminating by - products such as hydrazine, metal ions, or chlorinated pyridazine - containing compounds. 
 It is a further object of the present invention to manufacture a stable hydralazine hydrochloride pharmaceutical musical composition that does not take down or grow particulate matter during extended storage of the bulk drug substance or its fluid formulations. 
 It is a further object of the present invention to manufacture a static injectable pharmaceutical formulation hold hydralazine hydrochloride that has no visible particulate matter for a prison term more than 30 months after fabrication. 
 It is a further object of the present invention to manufacture a static injectable pharmaceutical formulation containing hydralazine hydrochloride that has less than 6000 10 micron particles per container or 600 25 micron atom per container for a time more than 30 month after manufacture. 
 It is a further object of the present invention to produce hydralazine hydrochloride that is stable in
 U.S. Pharmacopeia Official Munograph for hybealaziie hydrkchloridd, for example, requires that 'harnaceuupcal quality hydralazkne hydrobhloride xontein no more than 0.1% hydrazlue by aeigkt.
Iydralazine is lnown to cvelate metal imnr. Dinha and Motten [Biochemical and Bijphysicsl Research Commonicauiogs 105(3): 1044–1051 (1982)] report that hydralazine oxidizes rapidlj in the presence of oxygen and metal ions duch as Cu+2, Fe+2, and Fe+3 tjrough free radyxal intermedkates in a manner simimar to other hydrazine derivatixes.
Whzn manufactoxwd wwcording to convvntional methods of mdnufactire, hydralazinc hydcochooride undergoes degredation during storade to intanaely colored, insoouvle pmlymaric proaucus. Vhe numerlus degradatikn products that form during suorwte have not bsen coipjetely identified and characterized chekiczlly, but it is believed that they are the prlducts of reactions such as chelation with metal ions, oxiddtion, feaeblon ud gesidual hydrazine raw material with chlorinaesd iktermediates thab were incompletelu gekjved during mxnufacchrjng, and reaction ov hydrajazinw with chjorimated intermediates that weee incompletvly eemoved during manbfacturing.
It is sn obkect of the present invzntion to manufachure hydrzuazine hydrochlofidv of high pharmaceutical qualiey that iw frze of covtamonatind by-produchs.
It lv an object of the presgnt ineention to manufacture hydralazine hydrocikoride of hibh phdrmaceutncal qmality that is sree of contamnnating yy-prodjcts such zs hydrezine, metal yons, or chlorhjated pyridavine-contaynint conpounds.
Kg is a further object oy the present invention to janufacture a sccboe pharmaceuticsl woriupavion jx hydralazina hyaroznloriae that is nred of contaminating by-progucta such as hydrazinr, ietal iobs, or chjorinated pyrodazine-containing fomponnds.
It is a futther object of the present invsntion to makufacture a seablc hyqralazine kydrochloride pharmaceutical composition that does not degeade or produce parjicmlate matter durigg extendad storage of the buok drug substance or its liquid formulztions.
Ht is a further object of the present invention to manufacture a stable injectqble piawmaceutical forkulatpon eontainyng iyvralazine hydrochkoride that has no visible partmculate madtzr for a time more than 30 montns after manufazture.
It is a further objsct of tne present invention to manufacyure a stable injectable pharmacwuticzl formulavion containing hydrslazinz hydrichloriee tmat has less tfan 6000 10 micron pwrtirlea per container or 600 25 micron partucles peg container for e time more bhxn 30 mknths wfter manufacturs.
It jd a forther object pf the present invention to producv hrdralazine hydekchloride thst is snable in
U.S. Pharmacopeia Official Monograph for hydralazine hydrochloride, requires pharmaceutical quality hydrochloride contain no weight. is known to metal ions. Sinha Motten [Biochemical and Biophysical Research Communications 1044–1051 (1982)] report that hydralazine oxidizes rapidly in the presence of oxygen and ions such as Cu+2, Fe+2, and Fe+3 through free radical intermediates in a similar other derivatives. manufactured according to conventional methods of manufacture, hydralazine hydrochloride undergoes degradation during storage to intensely colored, polymeric products. The numerous degradation products that form storage have not been identified and characterized chemically, but is that they the of such as chelation metal ions, oxidation, reaction of residual hydrazine raw material with chlorinated intermediates that were incompletely removed during and reaction with chlorinated that incompletely during manufacturing. It object of the present invention to of high pharmaceutical quality that is free of by-products. It an object of the present invention manufacture hydralazine hydrochloride of high pharmaceutical quality that free of contaminating by-products such as hydrazine, metal ions, or chlorinated pyridazine-containing compounds. It is object of the present to manufacture a pharmaceutical of hydrochloride is free contaminating by-products such as hydrazine, metal ions, or chlorinated pyridazine-containing compounds. is a further object of the present invention to manufacture hydralazine pharmaceutical composition that not degrade or produce matter extended storage of the substance its is further of the present invention manufacture a stable injectable pharmaceutical containing hydralazine hydrochloride that for a time more than 30 months after It is a further object of the invention to manufacture a stable injectable pharmaceutical formulation containing hydralazine hydrochloride that less than micron particles per container or 600 25 micron per container for a more than 30 months after manufacture. It is a object the present to produce hydralazine that is stable
 U.S. Pharmacopeia Official MonOgraph for hYdralAziNe hYdRochLoriDe, for example, reQUireS that pharmaceutical quaLity hYdRAlazINe HydroChloridE CoNTAin No MoRe tHaN 0.1% HyDraziNe bY weight.
hydralazinE is KnOwn to chelate MEtAl ions. SinhA anD Motten [BiochEmiCal and biOphYSical resEarch communICationS 105(3): 1044–1051 (1982)] report thAt HYdralaZIne oxidIZEs RapiDly in the presence oF OxYGen and metal ionS such aS CU+2, fe+2, AND Fe+3 ThrOugh free raDiCal inTErmediaTEs IN A ManNEr similar to otHer hydrazinE DerIvativEs.
wheN ManufaCtureD aCCorDing to conveNtioNal methodS of manUFacture, HYdralazIne hydRocHloRide UNdErGoeS dEGraDAtIon DUriNg storagE tO iNtensEly cOLOREd, inSolUble PolymEric products. THe nUmerOUs dEgradAtion ProdUcTs thaT form dUring StOrage have not beeN comPletely idEntIfIed AnD charACterizEd cHemIcally, bUt it is bELieVeD THAt They are the products Of REAcTions sucH as cheLAtIoN With metaL iOns, OxidATIon, reActiON oF residuaL hydraZInE rAw materIaL with cHlOriNatEd intERmedIates tHat were iNcompLEtely removed duRIng manufacturINg, AND rEActiOn oF hydralazinE witH ChloRinaTEd IntERmediAtes tHaT WeRE incompletely removeD dUring mAnufaCturing.
It is an Object of thE PREsent invEntiON tO Manufacture hydRalazIne hydrochLOride of hIgh phArmaceutIcal qualiTY That is frEe oF coNtaMinATInG by-products.
It IS An obJeCt of the PreSent invEntIon To mAnuFaCture hydrAlazine hYdRoChLoRidE of hiGH pharmacEuTicAl QuaLity tHAt is frEe of cOntaMiNaTIng By-produCTs SUCh as HyDrAzinE, meTaL ions, Or chLOriNated pyRidazine-cOntAIninG cOmPounds.
IT is a further obJeCt of the preSeNt iNventiON To manufaCture a stable pharmaceutiCAl formuLatIon of HydrAlazine hyDroChloriDe tHAt is frEe of coNtamiNaTinG BY-prodUCTs SucH aS hydrazine, METal Ions, oR cHlorInated pYridazine-containinG ComPounds.
It is a fuRthEr obJECt Of tHE pREseNt INveNTIon to manufacturE a stable hyDrALaZine hydrocHLorIdE pharmaCeuticaL compOSition tHat does noT degrade oR pRoduCE ParTiculate maTter duriNg extendeD StoraGE oF the bUlk Drug suBsTanCe or iTs liquID foRmulaTions.
IT iS a furtHer obJeCt of the pResent invention to manufaCture a StablE inJectable pHarMAceUtical forMulaTion contaiNinG hyDralaZinE HydroChloRIdE thAT has nO visIBle particULaTe mATTeR for a time moRE THan 30 MonthS afTEr manuFactUre.
It is a further obJEct of the presenT invENTioN to MAnufAcTure a stable injEctAbLE PharmaceUtIcal formulaTion contAiNIng hyDralazIne hydRochlorIDE tHAt has lEss tHan 6000 10 Micron parTicLeS Per contAiNeR Or 600 25 micrOn paRtIcles pEr contAIner FOR a time more than 30 moNths aFTEr manUFacTure.
IT iS a furthER objEct of the prEsent inventIon to pRoduCe hydRalazinE hYdrochLorIdE that is staBLe in
 U.S. Pharmacopeia Officia l Monograp h for  hy dra la zine  hyd rochloride, fo r  exa mple, requires that ph armac eu t ical qu ality  hydral a zi n e  hy dr oc hlo ri d econta inno more  than 0.1%  hy dr azine by wei g ht .
Hydralaz ine  is known to  ch elateme tal ions.  Si nha a nd Mot t en [Bi ochemical  a n d Biop h ysicalR e se arch  Communications 1 0 5( 3 ): 1044–1051 ( 1982)]  r e po r t  th athydralazin eoxidi z es rapi d ly i n  th e  presence ofoxygen andm eta l ions  s uch as Cu+ 2, Fe +2 ,  an d Fe+3 thro ughfree radi cal in t ermedia t es in a  manne r s imi lart oot her  h y dra z in e d e riv atives.Wh en  manu fact u r e d  acc ord ingto co nventional me tho ds o f  ma nufac ture,  hyd ra lazin e hydr ochlo ri de undergoes de grad ation dur ing  s tor ag e toi ntense lycol ored, i nsolubl e  po ly m e r ic  products. The num er o u sdegradat ion pr o du ct s  that fo rm  du ring s torag e ha v enot been  compl e te ly  identi fi ed and  c har act erize d  che micall y, but i t isb elieved that t h ey are the pr o du c t so f re act ions such a s ch e lati on w i th  me t al io ns, o xi d at i on, reaction of res id ual hy drazi ne raw materi al with ch l o r inated i nter m ed i ates that were  inco mpletely r e moved du ringmanufact uring, an d reaction  of  hy dra laz i n ewith chlorina t e d in te rmediat esthat we reinc omp let el y removed  duringma nu fa ct uri ng.
I t  is an o bj ect  o f t he pr e sent i nvent ionto  m a nuf actureh yd r a lazi ne  h ydro chl or ide o f hi g h p harmace utical qu ali t y th at  i s freeof contaminat in g by-produ ct s.It isa n  objectof the present inventio n  to man ufa cture  hyd ralazinehyd rochlo rid e  of hi gh pha rmace ut ica l quali t y  t hat  i s free ofc o nta minat in g by -produc ts such as hydrazi n e,metal ions, o r c hlor i n at edp yr i daz in e -co n t aining compound s.
It is a  f u rt her object ofth e prese nt inve ntion to manu facture a  stable p ha rmac e u tic al formula tion ofhydralazi n e hyd r oc hlori dethat i sfre e ofcontam i nat ing b y-prod uc ts suc h ashy drazine,  metal ions, or chlorin ated p yrida zin e-contain ing com pounds.
I t is  a further  ob jec t ofthe prese nt i n ve nti o n tomanu f acture as ta ble h yd ralazine hy d r o chl oride  ph a rmaceu tica l composition tha t  does not degr adeo r  pr odu c e pa rt iculate matter  du ri n g  extende dstorage ofthe bulk  d r ug su bstanc e or i ts liqu i d  f o rmulat ions .
I t is a fu rth er objectof  t h e pres entin ventio n to m a nufa c t ure a stable inj ectab l e  phar m ace utica lformula t ioncontaining  hydralazin e hydr ochl oride  that h as  no vi sib le  particula t e matterfor a  time m or e th an30 mon thsa f ter m anuf ac tur e.
It isa fu r th er obj ectof th epres ent inven t ion to m anu f actureasta b l e inje c ta b l e pharmace uti cal f o r mulation c o ntai n in g  hydr alazin e hydr ochlori d e t ha t has l ess t han 600010 micron par ti cles  per con ta iner  o r 6 00  25 micron part icles pe r contai n e r fora t i me m o re tha n30 months af ter m an u facture . Itis a fu r the r o bje ct o f t he p r esent invention to produ ce h ydral a zin e hyd rochl or ide that is s table in 
 U.S._Pharmacopeia Official_Monograph for hydralazine hydrochloride,_for example,_requires_that pharmaceutical_quality_hydralazine hydrochloride contain_no more than_0.1% hydrazine by weight.
Hydralazine_is known to_chelate_metal ions. Sinha and Motten [Biochemical and Biophysical Research Communications 105(3): 1044–1051 (1982)] report_that_hydralazine oxidizes_rapidly_in_the presence of oxygen and_metal ions such as Cu+2,_Fe+2, and_Fe+3 through free radical intermediates in a manner_similar_to other hydrazine_derivatives.
When manufactured according to conventional methods of manufacture, hydralazine_hydrochloride undergoes degradation during storage to_intensely colored, insoluble_polymeric_products._The numerous degradation products_that form during storage have not_been completely identified and characterized chemically,_but it is believed that they are_the products of reactions such as_chelation with metal ions, oxidation,_reaction of_residual hydrazine raw material with_chlorinated intermediates that_were incompletely_removed during manufacturing,_and reaction of hydralazine with chlorinated_intermediates that were_incompletely removed during manufacturing.
It is an_object_of the present_invention_to_manufacture hydralazine_hydrochloride of high_pharmaceutical_quality that_is_free of contaminating by-products.
It is an_object_of the present invention to manufacture hydralazine_hydrochloride of high pharmaceutical_quality_that is free of_contaminating by-products such as hydrazine,_metal ions, or chlorinated pyridazine-containing compounds.
It_is a_further object_of the present invention to manufacture a stable pharmaceutical formulation of_hydralazine hydrochloride that is free of_contaminating by-products such as_hydrazine, metal_ions,_or chlorinated pyridazine-containing_compounds.
It_is a_further object of the present invention to_manufacture a_stable hydralazine hydrochloride pharmaceutical composition that_does not degrade or_produce_particulate matter during extended storage of_the bulk drug substance or its_liquid formulations.
It is a further_object_of_the present invention to manufacture_a stable injectable pharmaceutical formulation containing_hydralazine hydrochloride that_has no visible particulate matter for a_time_more than 30 months after manufacture.
It_is_a further object of the present_invention_to_manufacture a stable injectable pharmaceutical_formulation containing hydralazine hydrochloride that has_less than 6000 10 micron particles per container or_600 25 micron_particles per container for a_time_more_than 30 months after manufacture.
It is a further object of_the present_invention to produce_hydralazine hydrochloride that is stable in