Citrate Salt Crystalline Stability for Pharmaceutical Formulations

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Solution Overview

Problem

The hydrochloride salt of 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,12(27),16,21,23-decaene exhibits significant polymorphism and hygroscopicity, leading to batch-to-batch inconsistencies and stability issues, making it unsuitable for commercial production and pharmaceutical formulations.

Innovation Solution

The development of a citrate salt, which exists as a single robust polymorph, characterized by specific X-ray diffraction peaks and showing stability under various conditions, including humidity and temperature stress, thereby addressing the stability and consistency concerns of the hydrochloride salt.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Ease of manufacture

If the hydrochloride salt form is used, then the compound can be formulated as a pharmaceutical substance, but it exhibits significant polymorphism and hygroscopicity leading to batch-to-batch inconsistencies

Engineering Contradiction:

Improvepharmaceutical formulation capabilityVSAvoidbatch-to-batch consistency

Core Design Contradiction:

Ease of manufactureVSManufacturing precision

Solution Approach 1:

The patent changes the chemical parameter by converting the hydrochloride salt to a citrate salt, which fundamentally alters the crystalline properties and hygroscopicity of the compound. This parameter change resolves the contradiction by providing a form that maintains pharmaceutical formulability while eliminating polymorphism and batch inconsistency issues

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention creates a composite salt form by combining the active pharmaceutical ingredient with citric acid in a specific stoichiometric ratio (1:1). This composite approach produces a new material with superior crystalline stability and reduced hygroscopicity compared to the original hydrochloride salt

Inventive Principle:

Principle #40Composite materials

2Productivity

If the hydrochloride salt is used, then the compound can be produced, but it shows polymorphism with multiple crystalline forms depending on manufacturing conditions

Engineering Contradiction:

Improveproduction capabilityVSAvoidcrystalline form stability

Core Design Contradiction:

ProductivityVSStability of the object's composition

Solution Approach 1:

By changing the salt form parameter from hydrochloride to citrate, the patent achieves a single stable crystalline form that does not exhibit polymorphism. This allows consistent production across different manufacturing conditions while maintaining compositional stability

Inventive Principle:

Principle #35Parameter changes

3Ease of manufacture

If the hydrochloride salt is used, then the compound can be manufactured, but moisture content and polymorph ratio vary from batch to batch

Engineering Contradiction:

ImprovemanufacturabilityVSAvoidbatch-to-batch reproducibility

Core Design Contradiction:

Ease of manufactureVSReliability

Solution Approach 1:

The conversion to citrate salt form changes the hygroscopicity parameter, resulting in a material that does not absorb moisture and maintains consistent polymorph ratios across batches, thereby improving reliability while preserving ease of manufacture

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent transforms the problematic hygroscopic nature of the hydrochloride salt into a beneficial property by using citrate salt formation, which inherently resists moisture absorption. This converts what was originally a harmful characteristic into a desirable feature for reliable manufacturing

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

4Ease of operation

If the compound is hygroscopic, then it can be handled, but it is almost impossible to reliably formulate into a drug due to varying hydration levels

Engineering Contradiction:

Improvehandling capabilityVSAvoidformulation reliability

Core Design Contradiction:

Ease of operationVSEase of manufacture

Solution Approach 1:

By changing the salt form parameter, the patent eliminates hygroscopicity while maintaining handling capabilities. The citrate salt form allows reliable formulation because it does not vary in hydration level, solving the contradiction between ease of operation and formulation reliability

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS9624242B211-2(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene citrate salt

Publication Date: 2017.04.18 SOBI INC

AI summary

The present invention relates to certain salts of a 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene (Compound I) which have been found to have improved properties. In particular the present invention relates to the citrate salt of this compound. The invention also relates to pharmaceutical compositions containing the citrate salt and methods of use of the citrate salt in the treatment of certain medical conditions.