Stable Crystalline Salt Forms of ALK2 Inhibitor

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

The free base of Compound (I), a potent inhibitor of ALK2, is physically unstable in humid environments and difficult to isolate on a production scale due to gumming when exposed to water, and existing salts like the hydrochloric acid and fumaric acid salts face issues with crystallinity, stability, and solubility.

Innovation Solution

The development of stable crystalline forms such as the 1.5:1 succinic acid salt (Sesqui-Succinate), 1:1 hydrochloric acid salt, and 1:1 fumaric acid salt of Compound (I), which are non-hygroscopic, highly soluble, and suitable for large-scale synthesis, providing a single polymorph with high melting points and thermal stability.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If the free base of Compound (I) is used, then it shows potent ALK2 inhibition activity, but it is physically unstable in humid environments and gums when exposed to water

Engineering Contradiction:

Improvestability of Compound (I)VSAvoidgumming when exposed to water

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent applies parameter changes by converting the free base of Compound (I) into different salt forms (hydrochloride, fumarate, and succinate salts) with specific stoichiometries. This chemical parameter change transforms the unstable free base into stable crystalline salts that do not gum when exposed to water, while maintaining the potent ALK2 inhibition activity. The succinate salt in particular provides enhanced stability and reduced hygroscopicity.

Inventive Principle:

Principle #35Parameter changes

2Productivity

If the free base of Compound (I) is prepared on production scale, then it can be synthesized, but it is difficult to isolate due to gumming

Engineering Contradiction:

Improveproduction scale synthesisVSAvoidisolation difficulty

Core Design Contradiction:

ProductivityVSEase of manufacture

Solution Approach 1:

The patent resolves the isolation difficulty by changing the chemical form from free base to crystalline salt forms. The succinate, hydrochloride, and fumarate salts exhibit well-defined crystalline structures that facilitate easy filtration, washing, and drying on production scale, eliminating the gumming problem that complicates isolation of the free base.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent utilizes phase transitions by forming crystalline solid salts from the compound. The crystalline nature of the salt forms provides distinct phase separation from solution, enabling straightforward isolation through filtration and crystallization techniques, thereby simplifying the manufacturing process at production scale.

Inventive Principle:

Principle #36Phase transitions

3Reliability

If existing salts like hydrochloric acid and fumaric acid salts are used, then they provide some stability, but they face issues with crystallinity, stability, and solubility

Engineering Contradiction:

Improvestability of salt formsVSAvoidcrystallinity and solubility properties

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent optimizes the balance between stability, crystallinity, and solubility by developing specific salt forms with defined stoichiometries. The 1:1 hydrochloride, 1:1 fumarate, and 1.5:1 succinate salts were specifically designed to achieve optimal crystallinity for manufacturing while maintaining adequate water solubility for formulation and absorption. The succinate salt in particular provides an excellent balance of these properties.

Inventive Principle:

Principle #35Parameter changes

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

These crystalline salt forms enhance the stability and solubility of Compound (I), facilitating its isolation and large-scale production, ensuring effective absorption and prolonged storage, thereby addressing the challenges of instability and isolation difficulties in humid environments.

Implementation Method 1

These three salts also have good solubility in water and in simulated gastric fluids (see Table 2), have high melting point onsets and are suitable for large scale synthesis. The 1.5:1 succinic acid salt has the additional advantage that it exists as a single polymorph and undergoes no thermal transitions below its melting point, indicating a high degree of form stability

Methodology Applied

Scientific EffectNon-hygroscopic property:

Implementation Method 2

These three salts also have good solubility in water and in simulated gastric fluids (see Table 2), have high melting point onsets and are suitable for large scale synthesis

Methodology Applied

Scientific EffectMelting: Melting

Data Source

PatentUS20220281879A1Salt and crystal forms of an activin receptor-like kinase inhibitor

Publication Date: 2022.09.08 BLUEPRINT MEDICINES CORP

AI summary

Various salt forms of Compound (I) represented by the following structural formula, and their corresponding pharmaceutical compositions, are disclosed. Particular single crystalline forms of 1:1.5 Compound (I) succinate, 1:1 Compound (I) hydrochloride salt, and 1:1 Compound (I) fumarate salt are characterized by a variety of properties and physical measurements. Methods of preparing specific crystalline forms are also disclosed. The present disclosure also provides methods of treating or ameliorating fibrodysplasia ossificans progressive in a subject.