Compound A Tartrate Dihydrate for Solubility and Storage Stability
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Solution Overview
Problem
Existing N-(pyrimidinophenyl)acrylamide compounds, particularly Compound A, face challenges with low water solubility and stability, which affect their suitability for oral administration and long-term storage, necessitating the development of stable and highly soluble forms for effective pharmaceutical use.
Innovation Solution
The development of a 1:1 salt of Compound A with L-(+)-tartaric acid (Compound A-TA), specifically in a crystalline dihydrate form, enhances water solubility and stability, allowing for the formulation of pharmaceutical compositions that are stable for long-term storage and effective in treating conditions associated with EGFR and BTK activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If Compound A is used in its free base form, then the compound can be synthesized and stored, but water solubility is poor and stability is insufficient for long-term storage
Solution Approach 1:
The patent changes the chemical form of Compound A from free base to salt form (specifically L-(+)-tartrate salt), which fundamentally alters its solubility and stability parameters. This parameter change enables the compound to achieve both improved water solubility and stability simultaneously, resolving the technical contradiction between these two properties.
2Reliability
If Compound A is formulated for oral administration, then therapeutic effect can be achieved, but poor water solubility reduces bioavailability
Solution Approach 1:
By converting Compound A to its L-(+)-tartrate salt form, the patent fundamentally changes the solubility parameter, enabling adequate water solubility for oral administration. This parameter change directly improves bioavailability by allowing sufficient dissolution and absorption of the compound in the gastrointestinal tract.
3Duration of action of stationary object
If Compound A is stored for long-term use, then pharmaceutical supply is maintained, but degradation occurs reducing efficacy
Solution Approach 1:
The patent changes the physical and chemical parameters of Compound A by forming a salt with L-(+)-tartaric acid, which significantly improves stability parameters. This enables the compound to maintain its efficacy over extended storage periods, resolving the contradiction between storage duration and stability.
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 L-(+)-tartrate salt of Compound A (Compound A-TA) provides improved water solubility and stability, enabling effective oral administration and long-term storage, thereby enhancing bioavailability and efficacy in treating conditions such as cancer and autoimmune diseases.
Implementation Method 1
The development of a 1:1 salt of Compound A with L-(+)-tartaric acid (Compound A-TA), specifically in a crystalline dihydrate form, enhances water solubility and stability
Implementation Method 2
specifically in a crystalline dihydrate form, enhances water solubility and stability, allowing for the formulation of pharmaceutical compositions that are stable for long-term storage
Data Source
AI summary
The invention relates to solid forms of certain N-(pyrimidinyloxy)acrylamide derivatives that are useful in the treatment of proliferation and immunological disorders and other diseases related to the dysregulation of kinases including EGFR (including HER), Alk, PDGFR, BLK, BMX/ETK, BTK, FLT3 (D835Y), ITK, JAK1, JAK2, JAK3, TEC and TXK. The invention provides methods of making these materials and their salts and polymorphs, and intermediates for preparing these materials, as well as pharmaceutical compositions comprising these materials. The solid forms and pharmaceutical compositions comprising them are useful to treat conditions including a proliferation disorder, a tumor, an inflammatory disease, an autoimmune disease, psoriasis, dry eye, rheumatoid arthritis, or lupus.