Stable Hydralazine Hydrochloride Composition via Purification
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Solution Overview
Problem
Hydralazine hydrochloride pharmaceutical compositions are unstable during storage, leading to the formation of insoluble particles and contamination with by-products such as hydrazine, metal ions, and chlorinated pyridazine-containing compounds, limiting their therapeutic use and requiring a method for stable and purified production.
Innovation Solution
A method involving the reaction of phosphorous oxychloride with 1-phthalazinone to produce stable chlorinated heterocyclic compounds, followed by reaction with an alkane and tetrahydrofuran, and subsequent reaction with hydrazine hydrate to produce highly purified hydralazine hydrochloride, minimizing contamination and degradation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If conventional methods are used to manufacture hydralazine hydrochloride, then the product contains contaminating by-products such as hydrazine, metal ions, and chlorinated pyridazine-containing compounds, but the manufacturing process is simpler and more established
Solution Approach 1:
The patent extracts and removes contaminating by-products (hydrazine, metal ions, chlorinated pyridazine-containing compounds) from the manufacturing process through specialized purification steps, including filtration and chromatography, to achieve high purity hydralazine hydrochloride
Solution Approach 2:
The patent employs preliminary purification steps during the manufacturing process itself, rather than post-processing, to prevent contamination. This includes using purified starting materials and incorporating purification stages within the synthesis sequence to eliminate by-products before they can contaminate the final product
2Stability of the object's composition
If hydralazine hydrochloride is stored in sterile injectable formulations, then the drug maintains its therapeutic function, but it degrades and forms insoluble yellow-green particles within 1 to 2 months at 40°C and 6 to 9 months at 25°C
Solution Approach 1:
The patent introduces stabilizing agents and protective intermediaries in the formulation that prevent direct degradation of hydralazine hydrochloride. These intermediaries block the formation of insoluble particles and prevent reactions with contaminating by-products, thereby extending the shelf life and maintaining stability during storage
3Reliability
If hydralazine hydrochloride is used in pregnant women with severe pre-eclampsia and eclampsia, then blood pressure control is achieved, but the drug's instability during storage compromises its availability and reliability
Solution Approach 1:
The patent changes the formulation parameters of hydralazine hydrochloride, including pH adjustment, addition of stabilizing agents, and modification of excipients, to create a formulation that maintains stability during storage while preserving therapeutic efficacy for treating hypertension in pregnant women
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The method results in a stable, highly purified hydralazine hydrochloride composition free from significant degradation and particulate matter, maintaining pharmaceutical quality for extended storage periods with reduced levels of impurities like hydrazine and metal ions.
Implementation Method 1
heating a first mixture of 1-phthalazinone with phosphorous oxychloride thereby providing 1-chlorophthalazine
Implementation Method 2
contacting said 1-chlorophthalazine with an alkane having from about 5 to about 7 carbon atoms; removing said alkane from said 1-chlorophthalazine; contacting said 1-chlorophthalazine obtained in step c with tetrahydrofuran
Implementation Method 3
Hydralazine is extensively metabolized in the body to products that are excreted predominantly in the urine, and undergoes N-acetylation, oxidation, hydroxylation, hydrazone formation, and conjugation
Data Source
AI summary
The present invention relates to stable and highly purified stable hydralazine hydrochloride compositions and stable hydralazine-containing pharmaceutical compositions. A sterile aqueous injectable pharmaceutical composition suitable for parenteral administration is described comprising a therapeutically effective dose of hydralazine hydrochloride in a pharmaceutically acceptable carrier or diluent wherein the hydralazine hydrochloride is essentially free of phthalazines, hydrazine and metal ions. In addition, a stable sterile aqueous pharmaceutical composition comprising hydralazine hydrochloride in a pharmaceutically acceptable salt or diluent is described that is colorless and has no visible particulate matter.