Darunavir Polymorphs Enhancing Stability and Bioavailability

Solution Overview

Problem

There is a need for additional solid state forms of darunavir with improved physicochemical properties and bioavailability for effective treatment of retroviral infections, particularly HIV, as existing forms may have limitations in stability, solubility, and bioavailability.

Innovation Solution

New polymorphic forms, including crystalline tetrahydrofuran and dimethylsulfoxide solvates, and an amorphous form of darunavir are developed, characterized by specific X-ray diffraction patterns and improved stability, solubility, and bioavailability, which can be incorporated into various pharmaceutical formulations.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If existing solid state forms of darunavir are used, then the treatment of retroviral infections is achieved, but the stability, solubility, and bioavailability are limited

Engineering Contradiction:

ImprovestabilityVSAvoidbioavailability

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The patent applies parameter changes by developing new polymorphic forms and solvates of darunavir with different crystal structures and solvent associations. These structural parameter changes result in improved physicochemical properties including enhanced stability, solubility, and bioavailability while maintaining the therapeutic efficacy for retroviral infections

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent employs composite materials by creating solvate forms where darunavir molecules are associated with solvent molecules (ethanol, water, acetonitrile, etc.) in the crystal lattice. These composite crystalline structures combine the active pharmaceutical ingredient with solvent molecules to achieve superior stability and dissolution profiles compared to anhydrous forms

Inventive Principle:

Principle #40Composite materials

2Reliability

If existing solid state forms of darunavir are used, then the treatment of retroviral infections is achieved, but the solubility is limited

Engineering Contradiction:

ImprovestabilityVSAvoidsolubility

Core Design Contradiction:

ReliabilityVSStability of the object's composition

Solution Approach 1:

The patent applies parameter changes by developing new polymorphic forms and solvates of darunavir with different crystal structures and solvent associations. These structural parameter changes result in improved physicochemical properties including enhanced stability, solubility, and bioavailability while maintaining the therapeutic efficacy for retroviral infections

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent uses solvent molecules as intermediaries by forming solvate crystals where ethanol, water, acetonitrile, or other solvent molecules are incorporated into the crystal lattice with darunavir. These intermediary solvent molecules mediate the interaction between the hydrophobic drug molecule and the aqueous environment, enhancing solubility and dissolution rate

Inventive Principle:

Principle #24Intermediary (Mediator)

3Reliability

If existing solid state forms of darunavir are used, then the treatment of retroviral infections is achieved, but the intrinsic dissolution profile is limited

Engineering Contradiction:

ImprovestabilityVSAvoiddissolution rate

Core Design Contradiction:

ReliabilityVSSpeed

Solution Approach 1:

The patent applies parameter changes by developing new polymorphic forms and solvates of darunavir with different crystal structures and solvent associations. These structural parameter changes result in improved physicochemical properties including enhanced stability, solubility, and bioavailability while maintaining the therapeutic efficacy for retroviral infections

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent exploits phase transitions by creating solvate forms that undergo more favorable phase transitions during dissolution. The solvate crystals, with their incorporated solvent molecules, exhibit enhanced dissolution behavior as the crystal lattice breaks down more readily, releasing the active drug molecule into solution at improved rates

Inventive Principle:

Principle #36Phase transitions

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 new forms exhibit enhanced bioavailability, stability, and improved intrinsic dissolution profiles, making them suitable for effective treatment of retroviral infections, including HIV, with potential for improved patient outcomes and prolonged stability during storage.

Implementation Method 1

having an X-ray powder diffraction pattern with diffraction peaks at 2-theta values of about 22.8±0.1 and 16.4±0.1

Methodology Applied

Scientific EffectX-ray diffraction: X-Ray

Data Source

PatentUS8921415B2Polymorphs of darunavir

Publication Date: 2014.12.30 MAPI PHARMA LTD

AI summary

The present invention provides new pseudopolymorphic forms of darunavir as well as a novel amorphous form of darunavir, pharmaceutical compositions comprising these compounds, methods for their preparation and use thereof in treating retroviral infections, in particular, HIV infection.