Thienopyrimidine Salt and Crystal Forms for Stable Oral GnRH Antagonists
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Solution Overview
Problem
Existing GnRH receptor antagonists face challenges with oral absorbability, dosage form, drug stability, sustained action, and metabolic stability, and the crystal form and salt form of these compounds significantly impact their clinical efficacy.
Innovation Solution
Development of specific crystal forms (e.g., form A) and pharmaceutically acceptable salts (e.g., hydrochloride, fumarate, L-malate, methanesulfonate) of the thienopyrimidine compound, characterized by distinct X-ray diffraction peaks, and a method involving mixing with acids and solvents for crystallization, enhancing stability and bioavailability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If amorphous drug products are used, then manufacturing is easier, but product stability is poor
Solution Approach 1:
The patent applies parameter changes by transforming the physical state of the drug from amorphous to crystalline form. Specifically, it identifies and characterizes multiple crystal forms (Form A, Form B, Form C, etc.) with distinct X-ray diffraction patterns, thereby changing the structural parameters of the drug substance to achieve both manufacturability and stability.
Solution Approach 2:
The patent creates composite material systems by forming salts of the thienopyrimidine compound with various counterions (hydrochloride, sulfate, phosphate, maleate, tartrate, fumarate, citrate, malate, hippurate, lactate, succinate, acetate, p-toluenesulfonate, methanesulfonate, benzenesulfonate, oxalate, malonate, gentisate, or benzoate). These salt forms combine the active pharmaceutical ingredient with pharmaceutically acceptable ions to achieve desired stability and processing characteristics.
2Adaptability or versatility
If different crystallization conditions are used, then crystal form structure changes, but this leads to formation of other crystal forms and reduced stability
Solution Approach 1:
The patent applies preliminary action by establishing specific, optimized crystallization conditions for each crystal form before production. The patent provides detailed preparation methods with controlled parameters (solvents, temperatures, pH values, addition rates) that pre-establish the desired crystal form structure, preventing transformation to other forms during storage and handling.
Solution Approach 2:
The patent implements feedback mechanisms by using X-ray powder diffraction (XRPD) analysis to characterize and identify crystal forms. The diffraction patterns serve as feedback to confirm the formation of the desired crystal form and to detect any transformations to other forms, allowing for quality control and stability assurance.
3Reliability
If peptide compounds are used for GnRH receptor antagonism, then biological activity is achieved, but oral absorbability and metabolic stability are poor
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure from a peptide compound to a small-molecule thienopyrimidine derivative. This fundamental structural parameter change transforms the compound's properties, achieving both GnRH receptor antagonistic activity and improved oral absorbability and metabolic stability characteristic of small molecules.
Solution Approach 2:
The patent substitutes the peptide-based molecular structure with a small-molecule structure. This replacement changes the fundamental nature of the compound from a large, polar peptide that requires injection to a smaller, more lipophilic molecule that can be administered orally, thereby improving bioavailability and metabolic stability while maintaining biological activity.
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 new crystal forms and salts provide improved chemical stability, better flowability, and enhanced biological activity, suitable for industrial production and clinical use as GnRH receptor antagonists.
Implementation Method 1
GnRH receptor antagonists bind to the GnRH receptor; therefore, they are expected to exert an inhibitory effect rapidly without gonadotropin secretion
Implementation Method 2
having, in an X-ray powder diffraction pattern using Cu-Kα radiation, characteristic diffraction peaks at the following 2θ angles
Implementation Method 3
X-ray powder diffraction pattern
Implementation Method 4
Different crystallization conditions and storage conditions may lead to changes in the crystal form structure of the compound
Data Source
Figure 1-1~1-3
Figure 2-1~2-3
Figure 2-4~3-2
AI summary
The present disclosure relates to a salt form and crystal form of a thienopyrimidine compound, and a preparation method therefor and the use thereof. Specifically, provided are a salt form and crystal form of the compound of formula I, a preparation method therefor, and the use thereof in the preparation of a drug as a GnRH receptor antagonist.