Palbociclib Acetic Acid Adduct Crystalline Form
Solution Overview
Problem
Current forms of palbociclib, such as Form A, have limitations including low solubility, hygroscopicity, and stability issues, as well as toxicological concerns with certain salt forms, necessitating the development of a more effective and safer solid state form for pharmaceutical applications.
Innovation Solution
The creation of a palbociclib acetic acid adduct, specifically in crystalline forms characterized by distinct X-ray powder diffraction patterns, which offers enhanced solubility, improved hygroscopicity, and reduced toxicity, achieved through a process involving the reaction of palbociclib with acetic acid in controlled ratios and conditions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If palbociclib is formulated as known salts (hydrochloride, dihydrochloride, 2-hydroxyethylsulfonate), then water solubility is improved, but toxicological safety deteriorates or manufacturing quality worsens
Solution Approach 1:
The patent uses acetic acid, a common and safe pharmaceutical excipient, to form an adduct that provides the desired solubility enhancement without the toxicological concerns of other salt forms. The acetic acid adduct serves as a safe, short-term solution that dissolves appropriately without leaving harmful residues
Solution Approach 2:
The patent changes the chemical form of palbociclib from free base or traditional salt forms to an acetic acid adduct form. This parameter change in the chemical structure maintains or improves solubility while eliminating the toxicological issues associated with other salt forms, achieving a safer pharmaceutical formulation
2Quantity of substance
If palbociclib hydrochloride is used, then water solubility is improved, but crystallinity deteriorates
Solution Approach 1:
The patent transforms palbociclib from its hydrochloride salt form to an acetic acid adduct form. This chemical parameter change restores good crystallinity properties while maintaining adequate water solubility, overcoming the defect of poor crystallinity exhibited by the hydrochloride form
3Quantity of substance
If palbociclib dihydrochloride is used, then water solubility is improved, but hygroscopicity deteriorates
Solution Approach 1:
The patent employs acetic acid adduct formation using a safe, commonly accepted pharmaceutical excipient. This approach provides the necessary solubility enhancement without the excessive hygroscopicity problem of dihydrochloride, creating a formulation that is both soluble and stable in normal storage conditions
Solution Approach 2:
The patent changes the salt/adduct form parameter from dihydrochloride to acetic acid adduct. This modification maintains the solubility benefit while eliminating the harmful hygroscopicity effect, achieving a more stable pharmaceutical formulation
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 palbociclib acetic acid adduct exhibits significantly improved solubility in both water and organic solvents, superior crystallinity, and is toxicologically uncritical, addressing the drawbacks of existing forms while maintaining a straightforward and cost-effective preparation process.
Implementation Method 1
The palbociclib acetic acid adduct exhibits significantly improved solubility in both water and organic solvents
Implementation Method 2
specifically in crystalline forms characterized by distinct X-ray powder diffraction patterns
Data Source
AI summary
The present invention relates to an adduct of palbociclib, a method of preparing the preparing the same, and a pharmaceutical composition comprising the same. More particularly, the invention provides a crystalline form of palbociclib, a method of preparing the same, as well as a pharmaceutical composition comprising the same.