Crystalline Macitentan Form I for Tropical Stability
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Solution Overview
Problem
Existing pharmaceutical compositions of Macitentan for treating pulmonary arterial hypertension face challenges in chemical stability, storage stability, and dissolution properties, particularly when exposed to tropical conditions, and are limited by the choice of excipients which can be allergenic or poorly tolerated.
Innovation Solution
A pharmaceutical composition comprising crystalline Macitentan free base form I, characterized by specific X-ray powder diffraction patterns, combined with suitable excipients, which enhances chemical and polymorphic stability, flexibility in excipient choice, and improved disintegration characteristics, even in high humidity environments.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If conventional Macitentan formulations are used, then chemical stability is compromised, but using alternative excipients to improve stability is limited by allergenicity and patient tolerance
Solution Approach 1:
The patent changes the physical state parameter of Macitentan from amorphous to crystalline form. This parameter change fundamentally alters the chemical stability profile, allowing the use of broader excipient ranges without compromising stability, thereby resolving the contradiction between stability and excipient flexibility
Solution Approach 2:
The patent creates a composite system by combining crystalline Macitentan with specific excipients (microcrystalline cellulose, crospovidone, magnesium stearate) in defined proportions. This composite formulation achieves both chemical stability and excipient flexibility, as the crystalline structure provides stability while the composite nature allows selective excipient choice
2Reliability
If amorphous Macitentan is used in formulations, then dissolution properties are satisfactory, but storage stability deteriorates under tropical conditions
Solution Approach 1:
The patent changes the physical state parameter from amorphous to crystalline form. This transformation dramatically improves storage stability under tropical conditions while maintaining acceptable dissolution properties, resolving the contradiction between reliability and ease of manufacture
Solution Approach 2:
The patent utilizes the phase transition from amorphous to crystalline state of Macitentan. This phase transition confers enhanced polymorphic stability and chemical stability during storage, while the crystalline form can still be processed into tablets with satisfactory dissolution characteristics
3Stability of the object's composition
If Macitentan formulations are designed for immediate release, then dissolution rates are improved, but chemical stability upon storage is reduced
Solution Approach 1:
The patent develops a composite tablet formulation containing crystalline Macitentan with specific excipients in optimized ratios. The composite structure maintains immediate release characteristics for rapid dissolution while the crystalline API provides enhanced chemical stability during storage
Solution Approach 2:
By changing the API form to crystalline while maintaining immediate release tablet design, the patent achieves both chemical stability and satisfactory dissolution rates, resolving the contradiction between stability and speed
4Stability of the object's composition
If conventional excipients are used to maintain stability, then chemical stability is improved, but patient tolerance deteriorates due to allergenicity
Solution Approach 1:
The patent changes the API physical state to crystalline form, which fundamentally improves chemical stability. This parameter change eliminates the need for conventional stabilizing excipients that may be allergenic, thereby resolving the contradiction between stability and harmful factors
Solution Approach 2:
The patent extracts or eliminates the need for problematic stabilizing excipients by using crystalline Macitentan itself as the stability-providing element. This removes the source of allergenicity while maintaining chemical stability
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 composition exhibits significantly higher chemical and polymorphic stability, improved dissolution rates, and flexibility in excipient selection, making it suitable for tropical climates and various packaging materials, while maintaining bioavailability and safety.
Implementation Method 1
crystalline Macitentan free base form I, which comprises macitentan free base characterized by an X-ray powder diffraction pattern showing peak maxima at 2 theta/° values of 11.4±0.2, 13.0±0.2, 16.1±0.2, and 25.4±0.2
Implementation Method 2
characterized by an X-ray powder diffraction pattern showing peak maxima at 2 theta/° values of 11.4±0.2, 13.0±0.2, 16.1±0.2, and 25.4±0.2 when a radiation wavelength of 0.15419 nm is used
Data Source
AI summary
The present invention relates to an oral solid dosage form, in particular a tablet, comprising macitentan free base polymorphic form I.