Pharmaceutical Compositions Inhibiting NDMA Formation
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Solution Overview
Problem
Pharmaceutical compositions often contain harmful levels of N-nitrosodimethylamine (NDMA), which can exceed acceptable daily intake limits, leading to product withdrawals and patient access issues, with unclear root causes and uncertain NDMA levels in drug products.
Innovation Solution
Incorporating non-antioxidant acidic components into pharmaceutical compositions, such as those containing metformin, valsartan, and losartan, to inhibit NDMA formation below acceptable daily intake limits, using ingredients like hydrochloric acid, fumaric acid, and disodium edetate, which are combined with active pharmaceutical ingredients through processes like high shear wet granulation and tablet compression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If certain ingredients are used during drug manufacturing, then the manufacturing process can be simplified or cost reduced, but NDMA formation increases to harmful levels
Solution Approach 1:
The patent introduces an intermediary substance (acidic component) that mediates between the manufacturing process and NDMA formation. This acidic component reacts with or inhibits the formation of NDMA during manufacturing, allowing the use of certain ingredients while preventing harmful NDMA accumulation to levels below acceptable daily intake limits.
Solution Approach 2:
The patent changes the chemical parameter (pH level) of the pharmaceutical composition by incorporating acidic components. This parameter change creates an environment that inhibits NDMA formation while maintaining manufacturing simplicity and ingredient flexibility, thereby resolving the contradiction between ease of manufacture and harmful factor generation.
2Object-affected harmful factors
If NDMA levels are reduced below acceptable limits, then patient safety is improved, but product stability or efficacy may be compromised
Solution Approach 1:
The patent converts the potentially harmful effect of certain manufacturing ingredients into a beneficial outcome by using acidic components that inhibit NDMA formation. The acidic environment created by these components transforms what would be a harmful condition into a protective mechanism that ensures both low NDMA levels and product stability throughout shelf life.
Solution Approach 2:
The acidic components used in the patent are stable, non-antioxidant substances that do not compromise product longevity. These components serve as temporary inhibitors during the critical storage period, effectively managing NDMA formation without requiring complex long-term stabilization systems, thus maintaining product reliability while reducing harmful factors.
3Object-generated harmful factors
If acidic ingredients are added to inhibit NDMA formation, then NDMA levels are reduced, but formulation complexity increases
Solution Approach 1:
The acidic components incorporated into the pharmaceutical composition serve multiple functions: they inhibit NDMA formation, maintain appropriate pH levels for drug stability, and do not interfere with the active pharmaceutical ingredient's efficacy. This multi-functionality reduces the need for additional separate additives, thereby limiting the increase in formulation complexity while achieving effective NDMA inhibition.
Solution Approach 2:
By adjusting the pH parameter through the addition of acidic ingredients, the patent achieves NDMA formation inhibition with a single parameter change rather than requiring multiple complex formulation modifications. This approach simplifies the overall formulation strategy while effectively addressing the harmful NDMA formation issue.
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 use of acidic ingredients effectively reduces NDMA formation in pharmaceutical products, ensuring administration of less than 40 ng of NDMA per day, even at maximum daily doses, thereby addressing the contamination issue and maintaining product availability.
Implementation Method 1
the use of acidic ingredients effectively reduces NDMA formation in pharmaceutical products
Data Source
AI summary
A Pharmaceutical composition for inhibiting N-nitrosodimethylamine (NDMA) formation, and a method. In a pharmaceutical composition containing a selection of metformin, valsartan, irbesartan, losartan, sumatriptan, diltiazem, tetracycline, doxylamine, Chlorpheniramine, carbinoxamine, and/or any salt thereof, a non-antioxidant acidic component is added, causing N-nitrosodimethylamine content within an effective period of the pharmaceutical to be suppressed to lower than an acceptable daily intake limit therefor.