Cabozantinib Crystalline Forms for Solubility and Storage Stability
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Solution Overview
Problem
Existing forms of N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide exhibit low solubility and stability issues, making them unsuitable for solid oral dosage development, necessitating the discovery of new crystalline solid forms with improved properties for pharmaceutical applications.
Innovation Solution
Development of novel crystalline solid forms, including free base and solvate forms such as dihydrate, anhydrous forms, and solvates, characterized by specific x-ray powder diffraction patterns and thermal stability, to enhance solubility and stability for cancer treatment.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If the free base form of Compound 1 is used, then the chemical structure is simple and synthesis is straightforward, but the solubility is low and it is unsuitable for solid oral dosage development
Solution Approach 1:
The patent applies parameter changes by converting the free base form into various salt forms (sulfonate salts, carboxylate salts, phosphate salts, etc.) with different solubility characteristics. This chemical modification changes the physical and chemical parameters of the compound while maintaining its pharmacological activity, thereby resolving the contradiction between ease of manufacture and solubility.
Solution Approach 2:
The patent creates composite material systems by forming salts of Compound 1 with various counterions (e.g., tosylate, mesylate, fumarate, malate). These composite salt forms combine the active pharmaceutical ingredient with suitable anions to achieve both manufacturability and improved solubility properties required for oral dosage forms.
2Reliability
If early crystalline forms were developed, then initial therapeutic efficacy was achieved, but stability and processing properties were insufficient for commercial manufacturing
Solution Approach 1:
The patent systematically evaluates and optimizes crystalline forms by changing physical parameters such as hydration state (anhydrous vs. solvates), polymorphic form, and salt composition. These parameter changes enable the selection of forms with optimal stability profiles for long-term storage while maintaining therapeutic efficacy.
Solution Approach 2:
Instead of attempting to improve unstable early forms, the patent inverts the approach by deliberately developing alternative salt forms and crystalline structures that inherently possess superior stability and processing properties, thereby replacing the problematic early forms rather than trying to fix them.
3Reliability
If hygroscopic salts are selected to improve solubility, then dissolution is enhanced, but moisture sensitivity and storage stability deteriorate
Solution Approach 1:
The patent applies parameter changes by selecting salt forms with different hygroscopicity characteristics. Some salts are chosen for their high solubility despite moderate hygroscopicity, while others are selected when low moisture sensitivity is prioritized. The patent provides guidance on selecting the appropriate balance based on the specific therapeutic application and storage conditions.
Solution Approach 2:
The patent introduces coating materials and excipients as intermediary substances that protect hygroscopic salt forms from moisture exposure during storage and handling. These intermediaries allow the use of highly soluble salts without suffering from their moisture sensitivity, as the coating barrier prevents direct interaction with environmental humidity.
Data Source
AI summary
The invention relates to novel crystalline solid forms of the chemical compound N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1), and solvates thereof, including hydrates, that are useful for the treatment of cancer. Also disclosed are pharmaceutical compositions comprising the crystalline solid forms and processes for making the crystalline solid forms, as well as methods of using them for the treatment of cancer, particularly thyroid cancer, prostate cancer, hepatocellular cancer, renal cancer, and non-small cell lung carcinoma. The crystalline solid forms can be used to make the L-malate salt of cabozantinib.