Glasdegib Dimaleate Salt Crystallization for Solubility and Stability
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Solution Overview
Problem
Current solid-state forms of glasdegib, a Smo inhibitor used in treating cancers like acute myeloid leukemia, exhibit varying physicochemical properties that affect dissolution rate, solubility, stability, and handling, necessitating an improved form for enhanced pharmaceutical compositions.
Innovation Solution
A crystalline dimaleate form of glasdegib is obtained through specific crystallization conditions, characterized by improved properties such as dissolution rate, solubility, stability, and handling, achieved by characterizing the form using PXRD and DSC, and formulated into a pharmaceutical composition with pharmaceutically acceptable excipients.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Speed
If existing solid-state forms of glasdegib are used, then the pharmaceutical composition can be formulated, but the dissolution rate and solubility are insufficient
Solution Approach 1:
The patent applies parameter changes by transforming glasdegib from its free base form into a dimaleate salt form. This chemical parameter change (forming a salt with maleic acid) fundamentally alters the physicochemical properties of the compound, resulting in improved dissolution rate and solubility while maintaining the therapeutic activity of the active moiety.
Solution Approach 2:
The patent creates a composite material by combining glasdegib with maleic acid to form a dimaleate salt. This composite approach integrates two different chemical entities (the active pharmaceutical ingredient and the acid component) into a single crystalline structure that exhibits superior dissolution and solubility characteristics compared to the free base form.
2Reliability
If existing solid-state forms of glasdegib are used, then the compound can be handled, but physical stability and chemical stability are compromised
Solution Approach 1:
The patent employs parameter changes by converting glasdegib into a salt form, which stabilizes the molecular structure. The dimaleate salt form exhibits enhanced physical and chemical stability compared to the free base, while the crystalline nature of the salt form improves handling properties such as flowability and compressibility for tablet formulation.
3Reliability
If glasdegib is converted to different salt forms, then solubility improves, but the complexity of the formulation process increases
Solution Approach 1:
The patent applies parameter changes by selecting maleic acid as the counterion to form the dimaleate salt. This specific parameter choice (maleic acid) optimizes the balance between improved solubility and formulation simplicity. The resulting dimaleate form provides enhanced solubility without introducing excessive complexity into the formulation and manufacturing process.
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 crystalline dimaleate form of glasdegib demonstrates improved physicochemical properties, leading to enhanced bioavailability, stability, and processing advantages, making it suitable for improved pharmaceutical formulations and cancer treatment.
Implementation Method 1
The inventors of the present invention have surprisingly found that when applying very specific crystallization conditions, a crystalline dimaleate form of glasdegib can be obtained.
Data Source
Figure 1
AI summary
The present invention relates to a dimaleate form of 1-((2R,4R)-2-(1H-benzo[d]imidazol-2-yl)- 1-methylpiperidin-4-yl)-3-(4-cyanophenyl)urea (INN: glasdegib) and a process of producing the same. Furthermore, the invention relates to a pharmaceutical composition comprising the dimaleate form of glasdegib and at least one pharmaceutically acceptable excipient. The pharmaceutical composition of the present invention can be used as a medicament, in particular for the treatment and/or prevention of cancers such as acute myeloid leukemia.