Mitapivat Crystalline Forms for Stability, Solubility, and Bioavailability
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Solution Overview
Problem
There is a need for additional solid state forms of Mitapivat, including Mitapivat hemisulfate, to improve processing, stability, and bioavailability for the treatment of Inborn errors of metabolism such as Pyruvate kinase deficiencies and sickle cell disease.
Innovation Solution
The development of crystalline polymorphs of Mitapivat, Mitapivat hemisulfate, Mitapivat HCl, Mitapivat phosphate, Mitapivat hemisulfate: ascorbic acid, and Mitapivat hemisulfate: adipic acid, along with their pharmaceutical compositions, to enhance properties like stability, solubility, and handling characteristics.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If additional solid state forms of Mitapivat are developed, then chemical and physical stability is improved, but manufacturing complexity increases
Solution Approach 1:
The patent applies parameter changes by developing multiple solid state forms (polymorphs, salts, co-crystals) of Mitapivat with different crystal structures and physical properties. Each form represents a change in the physical parameters of the compound, allowing optimization of stability while managing manufacturing complexity through systematic exploration of solid state variations.
Solution Approach 2:
The patent utilizes composite materials by creating salt forms (e.g., Mitapivat hemisulfate, Mitapivat HCl, Mitapivat phosphate) and co-crystal forms (e.g., Mitapivat hemisulfate: ascorbic acid, Mitapivat hemisulfate: adipic acid) that combine Mitapivat with other compounds. These composite solid state forms enhance stability while providing diverse manufacturing pathways.
2Quantity of substance
If additional solid state forms of Mitapivat are developed, then solubility is enhanced, but processing complexity increases
Solution Approach 1:
The patent applies parameter changes by systematically varying the solid state form of Mitapivat to optimize solubility. Different polymorphs, salts, and co-crystals exhibit different solubility characteristics, allowing selection or development of forms with enhanced solubility while managing processing complexity through controlled crystallization and formulation methods.
Solution Approach 2:
The patent uses intermediary approaches by developing salt forms and co-crystals that act as intermediaries between Mitapivat and the formulation system. These intermediate forms (e.g., hemisulfate salts, co-crystals with ascorbic acid or adipic acid) can facilitate improved solubility and processing characteristics compared to the base compound.
3Reliability
If additional solid state forms of Mitapivat are developed, then bioavailability is improved, but formulation complexity increases
Solution Approach 1:
The patent applies parameter changes by exploring different solid state forms to optimize bioavailability. By varying crystal structure, salt form, or co-crystal composition, the patent seeks to enhance the absorption and bioavailability of Mitapivat while managing formulation complexity through systematic development and characterization of each form.
Solution Approach 2:
The patent uses copying approaches by creating multiple versions (polymorphs, salts, co-crystals) of Mitapivat that replicate the core therapeutic activity while varying physical properties to optimize bioavailability. Each form is characterized and evaluated to determine its suitability for formulation, allowing selection of the optimal form without requiring complete redesign of the formulation system.
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 polymorphs provide improved chemical and physical stability, enhanced solubility, and better processing characteristics, leading to more effective pharmaceutical formulations for treating Inborn errors of metabolism.
Implementation Method 1
The present disclosure encompasses solid state forms of Mitapivat, Mitapivat salts and Mitapivat co-crystals, in embodiments crystalline polymorphs of Mitapivat
Implementation Method 2
Different salts and solid state forms (including solvated forms) of an active pharmaceutical ingredient may possess different properties... changing the dissolution profile in a favorable direction
Data Source
AI summary
Solid state forms of Mitapivat, Mitapivat hemisulfate, Mitapivat HCl, Mitapivat phosphate, Mitapivat hemisulfate: ascorbic acid and Mitapivat hemisulfate: adipic acid, processes for preparation thereof, pharmaceutical compositions thereof, and uses thereof are disclosed.