Crystalline T-Type Calcium Channel Modulator for Stable Formulation
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Solution Overview
Problem
Existing treatments for neurological and psychiatric disorders associated with aberrant T-type calcium channel function, such as essential tremor and mood disorders, lack effective and stable formulations of T-type calcium channel blockers.
Innovation Solution
Development of a novel crystalline form of N-((1-(2-(tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3-chloro-5-fluorobenzamide hydrochloride salt trihydrate (Compound 1) characterized by specific X-ray powder diffraction peaks and a melting point onset, which acts as a selective T-type calcium channel blocker.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If amorphous forms of T-type calcium channel blockers are used, then the compound can be synthesized and tested, but the formulation lacks stability and bioavailability
Solution Approach 1:
The patent applies parameter changes by transforming the compound from an amorphous state to a crystalline state, fundamentally altering the physical form parameter. This phase transition enables the formation of stable crystalline polymorphs with defined melting points and XRPD patterns, directly resolving the stability and bioavailability issues mentioned in the technical contradiction.
Solution Approach 2:
The patent utilizes phase transitions to convert the amorphous compound into crystalline forms through controlled crystallization processes. This phase change from amorphous to crystalline state provides the stability and reproducible properties required for effective pharmaceutical formulations, addressing the reliability concerns in the technical contradiction.
2Reliability
If existing T-type calcium channel blocker formulations are used, then treatment can be provided, but the formulations lack effective stability and bioavailability
Solution Approach 1:
The patent changes the physical state parameter from amorphous to crystalline, creating formulations with defined melting points and characteristic XRPD patterns. This parameter change enables improved stability and bioavailability while maintaining treatment effectiveness for neurological and psychiatric disorders.
Solution Approach 2:
The patent creates composite crystalline structures through the formation of salt forms and hydrates (e.g., hydrochloride salt trihydrate). These composite crystalline materials exhibit enhanced stability and bioavailability compared to simple amorphous forms, while maintaining the desired pharmacological 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 crystalline form provides a stable and effective treatment for neurological and psychiatric disorders by blocking abnormal neuron burst firing, offering improved stability and bioavailability compared to amorphous forms.
Implementation Method 1
T-type calcium channels are low-voltage activated ion channels that mediate the influx of calcium into cells. Compounds that selectively modulate T-type calcium channel in mammals may be useful in treatment of such disease states.
Implementation Method 2
characterized by an x-ray powder diffraction (XRPD) pattern comprising at least one peak at the diffraction angle (° 2θ) selected from the group consisting of: a peak at approximately 12.0°; a peak at approximately 15.6°; a peak at approximately 16.7°; a peak at approximately 19.8°; a peak at approximately 21.2°; a peak at approximately 24.1°; a peak at approximately 25.2°; and a peak at approximately 27.3°
Implementation Method 3
the crystalline form has a melting point onset as determined by differential scanning calorimetry (DSC) at about 75.2° C.
Data Source
AI summary
The present disclosure provides Pattern D, i.e., a crystalline form of N-((1-(2-(tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3-chloro-5-fluorobenzamide hydrochloride salt trihydrate (Compound 1). The present disclosure also provides pharmaceutical compositions comprising Compound 1 in the form of Pattern D, as well as methods of treating neurological and psychiatric disorders by administering to a subject in need thereof Compound 1 in the form of Pattern D or a pharmaceutical composition comprising Compound 1 in the form of Pattern D.