Omecamtiv Mecarbil Dihydrochloride Hydrate for Solubility and Stability
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current cardiac muscle myosin activators, such as omecamtiv mecarbil, face challenges with stability, solubility, and in vivo pharmacology, necessitating the development of new or purer salts, hydrates, and polymorphic crystalline forms to improve their efficacy and safety.
Innovation Solution
The development of a dihydrochloride hydrate salt of omecamtiv mecarbil, characterized by specific crystalline forms (Form A, B, and C) with improved solubility and stability, achieved through a synthesis process involving the crystallization of omecamtiv mecarbil in the presence of aqueous hydrochloric acid and an alcohol solvent.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If omecamtiv mecarbil is developed as a cardiac muscle myosin activator, then cardiac contractility is improved, but stability and solubility are insufficient
Solution Approach 1:
The patent applies parameter changes by converting omecamtiv mecarbil into different salt forms (dihydrochloride, hemisulfonate) and crystalline polymorphs (Forms I, II, III). These parameter changes in molecular arrangement and crystal structure directly improve stability and solubility while preserving the cardiotonic activity, resolving the contradiction between reliability and stability
Solution Approach 2:
The patent creates composite crystalline structures by forming specific polymorphic forms with defined molecular packings and intermolecular interactions. These composite arrangements at the molecular level provide enhanced stability and solubility properties while maintaining the pharmacological activity of the parent compound
2Reliability
If omecamtiv mecarbil is developed as a cardiac muscle myosin activator, then cardiac contractility is improved, but solubility is insufficient
Solution Approach 1:
The patent applies parameter changes by converting omecamtiv mecarbil into different salt forms (dihydrochloride, hemisulfonate) and crystalline polymorphs (Forms I, II, III). These parameter changes in molecular arrangement and crystal structure directly improve stability and solubility while preserving the cardiotonic activity, resolving the contradiction between reliability and stability
Solution Approach 2:
The patent utilizes phase transitions by developing different crystalline polymorphs with distinct melting points, densities, and solubility characteristics. The transition between different polymorphic forms allows optimization of solubility properties for pharmaceutical formulation while maintaining the active pharmaceutical ingredient's efficacy
3Reliability
If current positive inotropic agents increase intracellular calcium concentration, then cardiac sarcomere contractility is increased, but velocity of contraction increases and systolic ejection time shortens causing side effects
Solution Approach 1:
The patent takes out the calcium-dependent pathway and extracts the essential function of increasing contractility through a different mechanism. By developing direct cardiac myosin activators that work independently of intracellular calcium concentration, the invention eliminates the harmful side effects associated with calcium-based positive inotropes while preserving the beneficial contractility enhancement
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 dihydrochloride hydrate salt of omecamtiv mecarbil exhibits enhanced solubility (greater than 40 mg/mL at pH 3.5), stability under accelerated conditions, and minimal hygroscopicity, making it suitable for pharmaceutical formulations and treatments for heart failure.
Implementation Method 1
crystallizing the omecamtiv mecarbil in the presence of aqueous hydrochloric acid and an alcohol solvent to form the omecamtiv mecarbil dihydrochloride hydrate salt
Data Source
Figure 1
Figure 2
Figure 3
AI summary
Provided are omecamtiv mecarbil dihydrochloride salt forms, compositions and pharmaceutical formulations thereof, and methods for their preparation and use. Omecamtiv mecarbil (AMG 423, CK-1827452), having the structure: