Linagliptin Metformin Granulation Stability

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Solution Overview

Problem

Existing pharmaceutical compositions of linagliptin and metformin hydrochloride face stability issues due to incompatibilities and degradation problems with certain excipients, and achieving a suitable content of linagliptin in the final dosage form is challenging.

Innovation Solution

A process involving the preparation of a granulation liquid with linagliptin, an acid, and optionally a binder, which is then sprayed onto metformin hydrochloride mixed with intragranular excipients to form granules, thereby stabilizing linagliptin and ensuring its complete dissolution.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Stability of the object's composition

If basic excipients (amino acids, magnesium oxide, meglumine) are used to stabilize linagliptin, then linagliptin stability is improved, but the compatibility and degradation problems with certain excipients worsen

Engineering Contradiction:

Improvelinagliptin stabilityVSAvoidincompatibility and degradation with excipients

Core Design Contradiction:

Stability of the object's compositionVSObject-affected harmful factors

Solution Approach 1:

The patent introduces an enteric coating as an intermediary layer between linagliptin and incompatible excipients (particularly metformin hydrochloride and nucleophilic/basic agents). This coating acts as a physical barrier that prevents direct interaction between linagliptin and harmful excipients during storage, while allowing drug release in the gastrointestinal tract where pH conditions differ. This resolves the contradiction by enabling the use of stabilizing excipients without their harmful degradation effects.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent changes the pH parameter by using enteric coating materials that are insoluble at gastric pH but soluble at intestinal pH. This parameter change allows linagliptin to be protected from incompatible excipients in the stomach while enabling drug release in the intestine. The pH-dependent solubility transformation resolves the stability-incompatibility contradiction by creating different chemical environments at different gastrointestinal locations.

Inventive Principle:

Principle #35Parameter changes

2Stability of the object's composition

If pre-treatment of metformin HCl by heating/drying is applied, then excessive volatile impurities are reduced and linagliptin stability is improved, but additional processing steps are required

Engineering Contradiction:

Improvelinagliptin stabilityVSAvoidprocessing steps

Core Design Contradiction:

Stability of the object's compositionVSDevice complexity

Solution Approach 1:

The patent applies pre-treatment to metformin hydrochloride by heating and drying it before mixing with linagliptin and other excipients. This preliminary action removes excessive volatile impurities (HCl and urea) from metformin HCl in advance, preventing these impurities from causing linagliptin degradation during formulation and storage. By performing this treatment beforehand, the patent simplifies the overall formulation process and eliminates the need for complex in-process controls.

Inventive Principle:

Principle #10Preliminary action

3Quantity of substance

If small dose of linagliptin is used, then the therapeutic efficacy is maintained, but achieving a suitable content of linagliptin in the final dosage form becomes difficult

Engineering Contradiction:

Improvelinagliptin contentVSAvoiddosage uniformity

Core Design Contradiction:

Quantity of substanceVSManufacturing precision

Solution Approach 1:

The patent uses a composite granulation system where linagliptin is combined with multiple excipients including binders (hydroxypropyl cellulose, hydroxypropyl methyl cellulose), fillers (microcrystalline cellulose), and disintegrants (sodium starch glycolate). This composite material approach allows the small dose of linagliptin (0.5-5 mg) to be uniformly distributed throughout a larger mass of compatible excipients, achieving both the required low dose and acceptable dosage uniformity. The composite granules ensure consistent drug distribution despite the small active ingredient amount.

Inventive Principle:

Principle #40Composite materials

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

This process effectively stabilizes linagliptin, prevents its loss due to sedimentation, and allows for the achievement of desired and even high contents of linagliptin in the final dosage form, enhancing the stability and efficacy of the pharmaceutical composition.

Implementation Method 1

an acid is added to the granulation liquid to lower its pH and in that way allow complete dissolution of linagliptin

Methodology Applied

Scientific EffectpH adjustment and dissolution: Solvation

Implementation Method 2

spraying thus prepared granulation liquid onto metformin HCl optionally mixed with intragranular excipients to prepare granules

Methodology Applied

Scientific EffectSpray granulation: Spray

Data Source

PatentEP4373482B1Process for preparing a pharmaceutical composition comprising linagliptin and metformin hydrochloride

Publication Date: 2025.04.30 KRKA D D NOVO MESTO

AI summary

The present invention relates to a process for preparing a solid pharmaceutical composition comprising linagliptin and metformin hydrochloride, as well as to the solid pharmaceutical composition obtainable by this process.