Dolutegravir Sodium Polymorphs via De-solvation

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Solution Overview

Problem

Current forms of dolutegravir sodium lack stability and predictable solubility profiles, which are crucial for effective HIV-1 treatment, necessitating the discovery of new polymorphic forms with improved physical and chemical properties.

Innovation Solution

Development of novel polymorphic forms of dolutegravir sodium, specifically Form-L9 and Form-L12, characterized by unique X-ray diffraction patterns, differential scanning calorimetry, and thermo gravimetric analysis, achieved through de-solvation of dolutegravir sodium 1-pentanol solvate at controlled temperatures and processing conditions, resulting in stable and high-dissolution-rate forms.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If existing crystalline forms of dolutegravir sodium are used, then the drug can be manufactured, but the stability and solubility profiles are unpredictable and insufficient for effective HIV-1 treatment

Engineering Contradiction:

Improvestability and solubility predictabilityVSAvoideffectiveness in HIV-1 treatment

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The patent applies parameter changes by discovering and characterizing multiple polymorphic forms (Form-I through Form-XI, plus additional forms) of dolutegravir sodium, each with distinct crystal structures, solubility profiles, and stability characteristics. By systematically varying crystallization conditions and identifying novel polymorphs, the invention provides predictable solubility and stability parameters that enable effective HIV-1 treatment while maintaining manufacturability

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent utilizes phase transitions by examining and comparing different solid-state crystalline phases of dolutegravir sodium. Each polymorphic form represents a distinct phase with unique properties, and the patent provides methods to control transitions between these phases through specific crystallization conditions, thereby achieving predictable solubility and stability for therapeutic effectiveness

Inventive Principle:

Principle #36Phase transitions

2Reliability

If multiple polymorphic forms are discovered and characterized, then stability and dissolution rates are improved, but the complexity of identifying and selecting the appropriate form increases

Engineering Contradiction:

Improvestability and dissolution rateVSAvoidpolymorph identification and selection process

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent applies preliminary action by providing comprehensive pre-characterization of each polymorphic form including PXRD patterns, DSC thermograms, TGA data, and solubility profiles. This advance characterization allows form selection to be made more easily based on predetermined criteria without requiring complex real-time analysis during drug development

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The patent replaces complex mechanical/physical identification methods with characteristic spectral signatures. Each polymorphic form has unique PXRD patterns, DSC profiles, and TGA characteristics that serve as fingerprints for identification, simplifying the selection process from complex structural analysis to comparing characteristic spectral data

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

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 polymorphic forms, Form-L9 and Form-L12, exhibit enhanced stability and dissolution rates compared to existing forms, maintaining chemical and polymorphic identity under accelerated conditions and demonstrating improved pharmaceutical performance.

Implementation Method 1

achieved through de-solvation of dolutegravir sodium 1-pentanol solvate at controlled temperatures and processing conditions

Methodology Applied

Scientific EffectDe-solvation:

Implementation Method 2

characterized by one or more analytical methods such as X-ray powder diffraction (XRPD) patterns

Methodology Applied

Scientific EffectX-ray diffraction: X-Ray

Implementation Method 3

dolutegravir sodium Form-L9, characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 1

Methodology Applied

Scientific EffectPowder X-ray diffraction: Bragg Diffraction

Implementation Method 4

dolutegravir sodium Form-L9, characterized by a differential scanning calorimetry (DSC) substantially in accordance with Figure 2

Methodology Applied

Scientific EffectDifferential scanning calorimetry: Calorimetry

Implementation Method 5

dolutegravir sodium Form-L9, characterized by a thermo gravimetric analysis (TGA) substantially in accordance with Figure 3

Methodology Applied

Scientific EffectThermo gravimetric analysis:

Data Source

PatentEP3337479B1Novel polymorphs of dolutegravir and salts thereof

Publication Date: 2023.12.13 LAURUS LABS

Figure 1
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Figure 3

AI summary

The present invention relates to novel crystalline forms of dolutegravir, process for its preparation and pharmaceutical composition comprising them.