Lisinopril Torasemide Tablet Dissolution via Mannitol
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Solution Overview
Problem
Combination preparations of ACE inhibitor lisinopril and loop diuretic torasemide exhibit lower dissolution profiles when using common excipients from single active substance preparations, leading to reduced bioavailability.
Innovation Solution
A composition comprising torasemide modification I, lisinopril dihydrate, microcrystalline cellulose, starch, mannitol, and a glidant like magnesium stearate, formulated into a rapidly dissolving tablet through direct compression, with specific particle size distribution and pH-dependent solubility optimization, ensuring at least 85% dissolution of both active substances within 15 minutes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If common excipients from single active substance preparations are used in combination preparation, then manufacturing simplicity is maintained, but dissolution profile deteriorates
Solution Approach 1:
The patent changes the chemical identity parameter of the excipient from calcium hydrogen phosphate to mannitol, which fundamentally alters the dissolution behavior of the combination preparation. Mannitol provides pH-independent solubility that maintains high dissolution profiles across different gastrointestinal pH conditions, resolving the contradiction between manufacturing simplicity and dissolution performance.
Solution Approach 2:
Mannitol acts as an intermediary substance that mediates between the two active ingredients (lisinopril and torasemide) with conflicting solubility requirements. It provides a neutral, pH-independent dissolution environment that allows both drugs to dissolve effectively without interfering with each other's solubility characteristics.
2Ease of manufacture
If calcium hydrogen phosphate is used as excipient, then tablet compression is facilitated, but dissolution rate decreases
Solution Approach 1:
The patent changes the excipient from calcium hydrogen phosphate (which facilitates compression but reduces dissolution rate) to mannitol (which maintains compression capability while dramatically improving dissolution rate). This parameter change in excipient identity resolves the contradiction between compression ease and dissolution speed.
3Reliability
If torasemide is used in combination with lisinopril, then therapeutic efficacy is improved, but solubility compatibility deteriorates
Solution Approach 1:
The patent changes the pH dependence parameter of the formulation by using mannitol instead of pH-sensitive excipients like calcium hydrogen phosphate. This creates a pH-independent dissolution environment that accommodates both torasemide (pH-dependent solubility) and lisinopril (high solubility), maintaining solubility compatibility while preserving therapeutic efficacy.
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 solution achieves high bioavailability by ensuring that at least 85% of both torasemide and lisinopril are dissolved within 15 minutes in phosphate buffer at pH 4.5 or 6.8, significantly improving the dissolution profile compared to previous attempts.
Implementation Method 1
solubility of torasemide depends on the manufacturing parameters, polymorphic form, particle size and shape
Implementation Method 2
at least 85% of torasemide and at least 85% of lisinopril is dissolved in 15 minutes
Implementation Method 3
manufactured by direct compression
Implementation Method 4
glidant, e.g. magnesium stearate
Data Source
Figure 1~2
Figure 3~4
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AI summary
The invention refers to a pharmaceutical combination preparation of ACE inhibitor and loop diuretic, characterized in that it has a form of tablet comprising lisinopril and torasemide modification I in pharmaceutically effective amount, microcrystalline cellulose, starch, mannitol and glidant, whereby at least 85% of lisinopril and at least 85% of torasemide is dissolved from the tablet in 15 minutes in buffer of pH 4.5 using paddle apparatus at 75 rpm and 37.0 ± 0.5°C