Tenofovir Alafenamide Monofumarate Crystalline Forms
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Solution Overview
Problem
Tenofovir alafenamide monofumarate exhibits thermodynamic instability and hygroscopicity, leading to issues with chemical degradation, dissolution behavior, and manufacturing challenges, necessitating the development of a stable and non-hygroscopic crystalline form for improved pharmaceutical formulations.
Innovation Solution
The development of crystalline forms II and III of tenofovir alafenamide monofumarate, characterized by specific X-ray powder diffraction patterns, which are thermodynamically stable and non-hygroscopic, along with a solvate form S, allowing for improved handling, storage, and manufacturing processes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If the known solid form of tenofovir alafenamide monofumarate is used, then the pharmaceutical can be formulated, but the solid form is thermodynamically unstable and hygroscopic, leading to chemical degradation and poor shelf-life
Solution Approach 1:
The patent applies parameter changes by discovering and characterizing new polymorphic forms (Forms II, III, and IV) of tenofovir alafenamide monofumarate with different crystal structures. Each polymorph exhibits distinct thermodynamic stability and hygroscopicity characteristics, allowing selection of the most stable form for pharmaceutical formulation. The X-ray powder diffraction patterns and differential scanning calorimetry data confirm these are distinct polymorphic modifications with improved stability profiles.
2Ease of manufacture
If the known solid form of tenofovir alafenamide monofumarate is used, then the pharmaceutical can be manufactured, but the hygroscopic nature causes water absorption, leading to chemical degradation via hydrolysis and altered dissolution behavior
Solution Approach 1:
The patent utilizes parameter changes by identifying polymorphic forms with reduced hygroscopicity. Forms II, III, and IV exhibit different water sorption characteristics compared to the known Form I, allowing selection of a form that minimizes water absorption during manufacturing and storage. The gravimetric moisture sorption measurements provide quantitative data on the reduced hygroscopicity of the new polymorphs.
3Manufacturing precision
If different solid state forms are used, then formulations with improved dissolution profile and stability can be achieved, but the sudden appearance or disappearance of polymorphs during processing presents problems
Solution Approach 1:
The patent applies preliminary action by thoroughly characterizing the thermodynamic stability relationships between different polymorphic forms before pharmaceutical manufacturing. The differential scanning calorimetry and X-ray powder diffraction analyses establish which polymorph is the most stable under various conditions, allowing formulators to pre-select the appropriate polymorph and implement measures to prevent unwanted polymorphic transformations during processing and storage.
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
These crystalline forms provide enhanced stability and reduced water interaction, ensuring consistent bioavailability and ease of manufacturing, thereby addressing the limitations of the existing thermodynamically unstable and hygroscopic forms.
Implementation Method 1
characterized by having an X-ray powder diffraction (XRPD) pattern comprising reflections at 2-theta angles of (7.3 ± 0.2)°, (9.4 ± 0.1)° and (10.1 ± 0.1)°
Implementation Method 2
X-ray powder diffraction pattern comprising reflections at 2-theta angles
Data Source
Figure 1
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AI summary
The present invention relates to crystalline forms of tenofovir alafenamide monofumarate and methods for their preparation. Furthermore, the invention relates to the use of one or more of the crystalline forms of tenofovir alafenamide monofumarate of the present invention for the preparation of pharmaceutical compositions as well as to pharmaceutical compositions comprising an effective amount of one or more of said forms. The pharmaceutical compositions of the present invention can be used as medicaments, in particular for the treatment and/or prophylaxis of viral infections such as HIV infections.