Erlotinib Hydrochloride Form-P Crystallization Stability
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Solution Overview
Problem
Existing polymorphic forms of Erlotinib Hydrochloride lack stability and require hazardous, expensive solvents for preparation, making them unsuitable for large-scale industrial production and storage.
Innovation Solution
A novel stable crystal form, Form-P, is developed using inexpensive solvents like isopropanol and methylene chloride, where Erlotinib base is treated with dry HCl gas in methylene chloride to produce a crystalline powder that is stable at various temperatures, characterized by a specific Powder XRD pattern.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If polymorphic forms A or B of Erlotinib HCl are prepared using conventional methods, then the product can be obtained, but the stability is insufficient and hazardous expensive solvents are required
Solution Approach 1:
The patent changes the chemical parameters by selecting isopropanol and methylene chloride as solvents instead of conventional hazardous solvents. This parameter change enables the formation of a new polymorphic form (Form-P) with superior stability while eliminating the use of hazardous expensive solvents, directly resolving the technical contradiction between reliability and harmful factors
Solution Approach 2:
The patent employs inexpensive commercially available solvents (isopropanol and methylene chloride) that can be easily handled and disposed of, replacing hazardous expensive solvents. This principle addresses the contradiction by using cheap, safe solvents that achieve the desired polymorphic form without the harmful effects of conventional solvents
2Reliability
If polymorphic form B is prepared to achieve thermodynamic stability, then stability is improved, but the process requires hazardous expensive solvents and complex preparation methods
Solution Approach 1:
The patent changes the solvent parameters to isopropanol and methylene chloride, which fundamentally alters the crystallization process to yield Form-P. This parameter change simplifies the manufacturing process by using safe, inexpensive solvents while achieving superior stability, making the process easier to manufacture at scale compared to conventional methods
Solution Approach 2:
The patent employs a self-service approach where the selected solvent system (isopropanol/methylene chloride) automatically directs the crystallization toward the desired polymorphic form (Form-P) under reflux conditions. This eliminates the need for complex multi-step processes or hazardous solvents, allowing the system to self-organize into the stable polymorphic form through simple filtration and drying
3Reliability
If polymorphic form E is prepared in (α,α,α)-trifluorotoluene to achieve improved stability, then stability is enhanced, but the solvent is highly flammable, dangerous for environment, and expensive
Solution Approach 1:
The patent replaces the hazardous solvent (α,α,α)-trifluorotoluene with inexpensive, safe, and environmentally friendly solvents (isopropanol and methylene chloride). These solvents are commercially available, non-flammable or low-flammability, and easy to handle, directly eliminating the harmful factors while maintaining the ability to produce a stable polymorphic form
Solution Approach 2:
The patent fundamentally changes the solvent parameters from (α,α,α)-trifluorotoluene to an isopropanol/methylene chloride system. This parameter change eliminates the flammability and environmental dangers associated with the conventional solvent while still achieving the desired polymorphic form (Form-P) with improved stability through controlled crystallization
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
Form-P is highly stable at room and elevated temperatures, easily scalable, and reproducible, eliminating the need for costly and hazardous solvents, ensuring consistent production without chromatographic methods.
Implementation Method 1
Dissolving Erlotinib base (prepared according to the process given in International Publication No. : WO. 2007/060691) in dry methylene chloride
Implementation Method 2
The crystals of Erlotinib HCl are filtered and dried and designated as Form-P
Data Source
Figure 1
AI summary
The present invention relates to three novel crystalline forms of Erlotinib hydrochloride and method of preparation thereof. Erlotinib hydrochloride is N-(3-ethynylphenyl)-6,7-bis(2-methoxy ethoxy)-4-quinazolinamine hydrochloride of formula-(I). The present invention provides stable novel crystalline forms of Erlotinib hydrochloride designated as Form-M, Form-N and Form-P, and processes for the preparation of the same. Erlotinib hydrochloride can be used as medicament for the treatment of hyperproliferative disorders, such as cancers, in humans.