Anhydrous crystalline free base form of 6-{2-[1 -(6-methyl-3-pyridazinyl)-4-piperidinyl]ethoxy}-3-ethoxy-1,2-benzisoxazole
Inventors
Lee, Edward • MCALLISTER, David • TRIGWELL, Andrew • TUOHY, III, Robert Vincent • SNYDER, JR., Peter • FRASSETTO, Christa Leisa
Assignees
Publication Number
US-9802926-B2
Publication Date
2017-10-31
Expiration Date
2035-06-19
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Abstract
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.
Core Innovation
The invention provides an anhydrous, non-hydrate, free base crystalline form of 6-{2-[1-(6-methyl-3-pyridazinyl)-4-piperidinyl]ethoxy}-3-ethoxy-1,2-benzoxazole, also known as vapendavir. This form is specifically characterized by a needle-like crystal habit and is distinguished from prior salt forms, such as the bis-dihydrogenphosphate salt, which suffered from process-induced transformations, water-induced phase changes, poor flow properties, and difficulties in manufacturing reproducible and stable pharmaceutical compositions.
The patent addresses the recurring problems encountered with previous crystalline forms of vapendavir, including instability to water during large-scale manufacture, poor flow and compressibility due to plate-like crystal habits, and the inability to achieve consistent particle size for reliable pharmaceutical formulation. Such limitations hindered the reproducible formulation of oral tablets and suspensions and increased manufacturing costs and variability, particularly affecting pediatric suspensions and solid oral dosage forms.
Through the development of the anhydrous crystalline vapendavir free base form with a needle-like crystal habit, the invention enables efficient, stable, and scalable manufacturing processes. The invention also includes methods for producing the crystalline form, optionally involving micronization to achieve uniform, small particle sizes suitable for suspensions and tablets. The new form is stable, resists hydration and phase changes during formulation, and is more suitable for pharmaceutical compositions such as tablets, capsules, suspensions, and resuspendable powders for oral or other administration.
Claims Coverage
The patent contains a single independent claim, which defines a compound as an anhydrous crystalline free base form of vapendavir having a needle-like crystal habit. Several dependent claims further specify XRPD patterns and other characteristics.
Anhydrous crystalline free base form of vapendavir with needle-like crystal habit
The invention covers a compound comprising an anhydrous (non-hydrate) crystalline free base form of 6-{2-[1-(6-methyl-3-pyridazinyl)-4-piperidinyl]ethoxy}-3-ethoxy-1,2-benzoxazole (vapendavir). - The crystalline free base form exhibits a needle-like crystal habit. - The form is distinguished from prior art by its anhydrous nature and its crystal morphology. - Dependent claims further specify XRPD peaks and patterns as distinguishing features, but the core inventive feature is the compound's specific crystalline free base form and crystal habit.
In summary, the claims cover the specific anhydrous crystalline free base form of vapendavir characterized by its needle-like crystal habit, with dependent claims directed to XRPD peak patterns confirming the unique physical structure.
Stated Advantages
Allows for more stable, efficient, and less expensive large-scale manufacture of pharmaceutical compositions containing vapendavir.
Provides improved properties in terms of stability and flowability compared to prior salt forms, especially due to its needle-like crystal habit.
Is anhydrous, resisting water absorption and phase changes (i.e., avoids process-induced transformations) during formulation and manufacturing.
Can be micronized to small, uniform particle sizes, enabling the preparation of stable suspensions, particularly useful for pediatric treatments.
Enables the formation of solid oral dosage forms (such as tablets) with smaller size for equivalent dose, potentially improving patient adherence.
Does not undergo hydrate formation or change form in aqueous solvent systems, offering robustness during pharmaceutical processing.
Demonstrates chemical stability and low hygroscopicity, with no significant change in properties under typical storage and processing conditions.
Documented Applications
Treatment of infections caused by Picornaviridae, including human rhinovirus (HRV) and enterovirus infections.
Treatment, alleviation, prevention, or reduction of symptoms or exacerbations of asthma and/or chronic obstructive pulmonary disease (COPD).
Treatment, alleviation, and/or prevention of hand, foot, and mouth disease.
Use in pharmaceutical compositions such as tablets, capsules, suspensions, resuspendable sachets or powders, and other oral dosage forms.
Formulations suitable for pediatric administration, including suspensions and suppositories.
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