Hemisulfate Salt Crystalline Forms for Oral Drug Bioavailability
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
The bioavailability of orally administered drugs like Compound (I) is affected by factors such as solubility, stability in the gastrointestinal tract, and pH variations, leading to variability in treatment efficacy, especially when coadministered with medications like antacids or proton pump inhibitors.
Innovation Solution
The development of a hemisulfate salt and crystalline forms of Compound (I), which provide consistent and enhanced bioavailability by stabilizing the drug and improving its dissolution rate across different pH levels, thereby reducing variability in treatment outcomes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If Compound (I) is administered orally, then the drug can be delivered to patients conveniently, but the bioavailability becomes variable due to pH changes in the gastrointestinal tract and interactions with other medications
Solution Approach 1:
The patent converts Compound (I) from its free base form to a hemisulfate salt form, fundamentally changing its chemical parameters. This salt formation modifies the dissolution characteristics and pH-dependent behavior of the compound, making bioavailability less sensitive to gastrointestinal pH variations and concurrent medication use.
Solution Approach 2:
The hemisulfate salt acts as an intermediary form between the original compound and its active state in the body. This intermediate salt form provides a buffer against pH fluctuations, mediating the release of the active compound in a more consistent manner regardless of stomach pH conditions.
2Speed
If the dissolution rate of Compound (I) is increased at low pH, then rapid treatment of migraine headaches can be achieved, but the dissolution rate decreases when stomach pH is raised by coadministered medications
Solution Approach 1:
By transforming Compound (I) into its hemisulfate salt, the patent alters its dissolution parameters to create a more flattened dissolution profile across different pH values. The salt form maintains adequate dissolution rates even at elevated pH levels where the original compound would fail to dissolve efficiently.
3Reliability
If a form of Compound (I) with high solubility and bioavailability is used, then treatment efficacy is improved, but the compound may convert to a less soluble form during manufacture, preparation, or storage
Solution Approach 1:
The patent performs the salt formation action in advance during the manufacturing process, converting Compound (I) to its hemisulfate salt form before storage and distribution. This preliminary conversion stabilizes the compound in a form that is less prone to spontaneous transformation, ensuring consistent bioavailability throughout the product lifecycle.
Solution Approach 2:
The patent converts the potential harm of form conversion during storage into a benefit by deliberately forming the hemisulfate salt, which has more stable dissolution characteristics. The salt formation process, which could be seen as an additional manufacturing step, actually protects against unwanted form conversions during storage.
Data Source
Figure 1~2
Figure 3~4
Figure 5
AI summary
Disclosed is a hemisulfate salt of Compound (I): and crystalline forms of the hemisulfate salt. Also disclosed are methods of using the hemisulfate salt of Compound (1) as a CGRP receptor antagonist, and pharmaceutical compositions comprising the hemisulfate salt of Compound (I). The hemisulfate salt of Compound (I) is useful in treating, preventing, or ameliorating disorders including migraine and other headaches, neurogenic vasodilation, neurogenic inflammation, thermal injury, circulatory shock, flushing associated with menopause, airway inflammatory diseases such as asthma, and chronic obstructive pulmonary disease (COPD).