Trilaciclib Dihydrochloride Dihydrate for Stable IV Solubility
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Solution Overview
Problem
Trilaciclib, a cyclin-dependent kinase inhibitor, is not highly soluble in water and becomes less soluble at physiological pH, leading to challenges in delivering a therapeutic dose effectively and potentially causing drug deposition and loss of activity when administered intravenously.
Innovation Solution
Formulating trilaciclib as a dihydrochloride, dihydrate crystalline form (Pattern 1) for intravenous administration, which maintains stability and solubility, allowing for quick delivery in a concentrated form.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If trilaciclib is formulated for intravenous administration, then therapeutic delivery is enabled, but drug precipitation and loss of activity occur due to low solubility at physiological pH
Solution Approach 1:
The patent applies parameter changes by converting trilaciclib to its dihydrochloride salt form, which fundamentally alters the chemical parameters (pH, solubility characteristics) of the compound. This transformation enables the drug to maintain stability and solubility in aqueous intravenous formulations at physiological pH, preventing precipitation while enabling reliable therapeutic delivery
Solution Approach 2:
The dihydrochloride salt acts as an intermediary form that mediates between the insoluble free base form and the required aqueous solution for IV administration. This intermediate chemical form provides the necessary solubility and stability characteristics for intravenous delivery while maintaining the therapeutic activity of the original compound
2Productivity
If trilaciclib is administered in concentrated form, then rapid administration is achieved, but drug deposition occurs at injection site
Solution Approach 1:
By changing the chemical form to dihydrochloride, the patent modifies the solubility parameters to enable concentrated formulations that remain stable in solution. This allows rapid IV administration at high concentrations without the harmful deposition effect that would occur with the less soluble free base form
3Stability of the object's composition
If trilaciclib is administered in dilute form, then solubility is maintained, but administration time increases and therapeutic efficacy decreases
Solution Approach 1:
The dihydrochloride salt form fundamentally changes the solubility parameters, enabling the drug to be formulated at high concentrations that remain stable in aqueous solution. This eliminates the need for dilute formulations, allowing both maintenance of solubility and achievement of rapid administration for 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 dihydrochloride, dihydrate form of trilaciclib ensures effective and stable delivery, maintaining therapeutic efficacy by preventing drug precipitation and ensuring rapid administration.
Implementation Method 1
Formulating trilaciclib as a dihydrochloride, dihydrate crystalline form (Pattern 1) for intravenous administration, which maintains stability and solubility
Data Source
AI summary
An advantageous isolated morphic form of trilaciclib which is 2′-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-7′,8′-dihydro-6′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidin]-6′-one, for example in the form of a dihydrochloride salt or a dihydrochloride, dihydrate.