Afatinib Dimaleate Form Alpha Stability

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Solution Overview

Problem

There is a need for additional solid state forms of Afatinib di-maleate to improve processing properties, stability, and bioavailability, as existing forms may have limitations in handling, dissolution profiles, and shelf-life.

Innovation Solution

The development of Afatinib di-maleate Form Alpha, characterized by specific X-ray powder diffraction patterns and thermal properties, which can be used to prepare pharmaceutical compositions and other Afatinib salts, enhancing thermodynamic stability and bioavailability.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If existing solid state forms of Afatinib di-maleate are used, then the basic therapeutic function is achieved, but processing properties and stability are limited

Engineering Contradiction:
ImprovestabilityVSAvoidprocessing properties
Core Design Contradiction:
ReliabilityVSEase of manufacture

Solution Approach 1:

The patent applies parameter changes by discovering and characterizing multiple polymorphic forms (Forms A, B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, Q, R, S, T, U, V, W, X, Y, Z) of Afatinib di-maleate, each with distinct crystal structures, X-ray diffraction patterns, and physical properties. This allows selection of the optimal polymorphic form based on desired processing properties and stability requirements for specific pharmaceutical applications

Inventive Principle:
Principle #35Parameter changes

2Reliability

If existing solid state forms of Afatinib di-maleate are used, then the formulation is achieved, but dissolution profile and bioavailability are limited

Engineering Contradiction:
ImprovebioavailabilityVSAvoiddissolution profile
Core Design Contradiction:
ReliabilityVSEase of manufacture

Solution Approach 1:

The patent utilizes parameter changes by providing a comprehensive set of polymorphic forms with varying dissolution characteristics. Each polymorphic form exhibits different solubility and dissolution rates, enabling formulation scientists to select the optimal form to achieve target bioavailability and dissolution profiles for specific dosage forms and therapeutic indications

Inventive Principle:
Principle #35Parameter changes

3Duration of action of stationary object

If existing solid state forms of Afatinib di-maleate are used, then the basic formulation is achieved, but shelf-life is limited

Engineering Contradiction:
Improveshelf-lifeVSAvoidhandling characteristics
Core Design Contradiction:
Duration of action of stationary objectVSEase of manufacture

Solution Approach 1:

The patent applies parameter changes by characterizing multiple polymorphic forms with distinct thermal behaviors, melting points, and stability profiles. This enables selection of polymorphic forms with optimized shelf-life characteristics and handling properties, such as improved flowability, compressibility, and resistance to polymorphic transformation during storage and processing

Inventive Principle:
Principle #35Parameter changes

Data Source

PatentEP3089976B1Crystalline forms of afatinib dimaleate
Publication Date: 2019.08.14 TEVA PHARMACEUTICALS INTERNATIONAL GMBH
  • EP3089976B1 patent drawingFigure 1
  • EP3089976B1 patent drawingFigure 2
  • EP3089976B1 patent drawingFigure 3

AI summary

The present disclosure encompasses crystalline forms of Afatininb di-maleate and methods of their use.