Anhydrous Vapendavir Free Base Crystals
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Solution Overview
Problem
There is a need for a stable and efficient pharmaceutical form of 6-{2-[1-(6-methyl-3-pyridazinyl)-4-piperidinyl]ethoxy}-3-ethoxy-1,2-benzoxazole that can effectively treat picornavirus infections, such as those caused by human rhinovirus or enteroviruses, while being safe, stable, and cost-effective for large-scale production, particularly in forms like tablets and suspensions, as previous crystalline forms suffer from variability in crystal shape, size, solubility, and stability issues.
Innovation Solution
An anhydrous, free base crystalline form of 6-{2-[1-(6-methyl-3-pyridazinyl)-4-piperidinyl]ethoxy}-3-ethoxy-1,2-benzoxazole is developed, which is manufactured through a process involving micronization to achieve uniform particle sizes suitable for pharmaceutical compositions, including tablets and suspensions, and is characterized by a needle-like crystal habit and specific XRPD patterns, enhancing stability and solubility.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If the bis-dihydrogenphosphate salt form of vapendavir is used, then desirable solubility and stability properties are achieved, but process induced transformation occurs leading to formation of other crystalline phases such as sesquiphosphate semihydrate
Solution Approach 1:
The patent changes the chemical form parameter from salt (bis-dihydrogenphosphate) to free base form, which eliminates the water-induced phase transformation problem while maintaining stability. This parameter change resolves the contradiction by selecting a different chemical state that is inherently more stable under manufacturing conditions.
Solution Approach 2:
The patent extracts the water molecule that causes the phase transformation problem. By developing an anhydrous free base form, the invention removes the source of process-induced transformation, thereby preventing the formation of hydrate phases while maintaining the desirable stability properties.
2Reliability
If the bis-dihydrogenphosphate salt form of vapendavir is used, then desirable solubility properties are achieved, but poor flow properties and agglomeration occur during manufacturing
Solution Approach 1:
The patent changes the physical form parameter from salt to free base, which fundamentally alters the crystal packing and intermolecular forces. This parameter change improves flow properties by eliminating the square-planar crystal habit that causes agglomeration, while the solubility is maintained through the inherent properties of the free base form.
3Productivity
If large-scale production is implemented, then manufacturing efficiency is improved, but variability in crystal shape and size increases
Solution Approach 1:
The patent changes the crystalline form parameter to anhydrous free base, which exhibits more consistent nucleation and growth characteristics during crystallization. This parameter change reduces variability in crystal shape and size even at large scale, allowing efficient manufacturing while maintaining precision.
4Ease of manufacture
If previous crystalline forms are used, then pharmaceutical compositions can be manufactured, but high costs and reduced patient adherence result
Solution Approach 1:
The patent changes the form from salt to anhydrous free base, which simplifies the manufacturing process by eliminating the need for controlled humidity environments and complex drying steps. This parameter change reduces manufacturing costs while maintaining the ability to produce pharmaceutical compositions, thereby improving patient adherence.
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 anhydrous free base crystalline form provides improved stability, solubility, and manufacturing efficiency, allowing for the production of stable and effective pharmaceutical compositions, such as tablets and suspensions, that are suitable for treating picornavirus infections with reduced costs and improved patient adherence.
Implementation Method 1
An anhydrous, free base crystalline form of 6-{2-[1-(6-methyl-3-pyridazinyl)-4-piperidinyl]ethoxy}-3-ethoxy-1,2-benzoxazole is developed
Data Source
AI summary
A crystalline form of 6-{2-[1-(6-methyl-3-pyridazinyl)-4-piperidinyl]ethoxy}-3-ethoxy-1,2-benzoxazole is provided which is useful in the treatment of infections caused by Picornaviridae such as human rhinovirus (HRV), and in particular the crystal form is an anhydrous crystalline free base form of 6-{2-[1-(6-methyl-3-pyridazinyl)-4-piperidinyl]ethoxy}-3-ethoxy-1,2-benzoxazole. In addition, a method of manufacturing the free base crystalline form is also provided, including a step of micronizing the compound particles, optionally using a wetting agent, as well as pharmaceutical compositions incorporating the free base crystalline form such as tablets or suspensions, and methods of therapeutic treatments using this form and pharmaceutical compositions thereof.