Pharmaceutical Dosage Form Using Microcrystalline Cellulose
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Solution Overview
Problem
The compound 4-[(5R)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl]-3-fluorobenzonitrile, particularly in its phosphate salt form, exhibits strong cohesion leading to aggregation, poor pharmaceutical processability, low bulk density, chemical instability, and hygroscopicity, making it difficult to design stable and commercially viable oral dosage forms.
Innovation Solution
Incorporating microcrystalline cellulose (MCC) as a filler in the pharmaceutical dosage form, along with colloidal silicon dioxide as a glidant, to improve processability and stability, transforming the cohesive drug substance into a well-blendable material and preventing chemical degradation and absorption issues.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If the drug substance is used in its pure form, then the dosage form contains 100% active ingredient, but the drug substance exhibits strong cohesion leading to aggregation and poor processability
Solution Approach 1:
The patent introduces microcrystalline cellulose (MCC) as an intermediary substance to mediate between the cohesive drug substance and the manufacturing process. MCC acts as a carrier that prevents direct contact between drug substance particles, reducing aggregation and improving flow properties during tableting without significantly reducing drug content.
Solution Approach 2:
The patent changes the physical parameters of the drug substance by converting it from phosphate salt form to free base form. This parameter change fundamentally alters the cohesive properties and aggregation tendency of the drug substance, making it more amenable to standard pharmaceutical processing while maintaining high drug content.
2Ease of manufacture
If the drug substance bulk density is increased to improve flow, then processability improves, but the drug substance requires special compaction steps and the dosage form size increases
Solution Approach 1:
MCC serves as a volumetric intermediary that provides flow assistance without requiring high compaction forces. The MCC matrix allows the drug substance to flow adequately at lower bulk densities, eliminating the need for special compaction steps and keeping tablet size manageable.
3Ease of manufacture
If lactose is used as filler, then the dosage form can be manufactured, but chemical degradation products appear after compression
Solution Approach 1:
The patent extracts lactose from the excipient list entirely, removing the source of chemical degradation. By eliminating lactose and replacing it with MCC-based fillers, the system avoids the chemical incompatibility between lactose and the drug substance during compression while maintaining manufacturability.
4Ease of manufacture
If mannitol is used as intragranular filler, then the dosage form can be manufactured, but stickiness issues and ribbon discoloration occur during compaction
Solution Approach 1:
The patent removes mannitol from the formulation, eliminating the stickiness and discoloration problems. The replacement MCC-based system provides equivalent manufacturability without generating these harmful effects during compaction.
5Ease of manufacture
If microcrystalline cellulose is used as filler, then the dosage form can be manufactured, but drug substance absorption effects occur due to amorphous regions
Solution Approach 1:
The patent converts the drug substance from phosphate salt to free base form, which fundamentally changes its interaction with MCC. The free base form does not exhibit cationic characteristics, eliminating the absorption effect into MCC's amorphous regions while preserving the manufacturability benefits of MCC.
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 use of MCC and colloidal silicon dioxide results in a pharmaceutically processable blend with improved flow and stability, eliminating capping issues and enhancing tablet hardness and drug availability, enabling the production of stable and commercially viable oral dosage forms.
Implementation Method 1
the use of MCC as filler for dosage forms of compound of formula (1) is possible. It was further surprisingly found that by blending compound of formula (1) together with MCC turned the problematically very cohesive drug substance into a very well pharmaceutically processable blend.
Implementation Method 2
The pharmaceutical dosage form according to present invention may further comprise a glidant, preferably it comprises a glidant, preferably said glidant is a silicon dioxide, more preferably said glidant is colloidal silicon dioxide
Data Source
AI summary
The present invention relates to pharmaceutical dosage forms for oral administration comprising the drug substance 4-[(5R)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl]-3-fluorobenzonitrile or any pharmaceutically acceptable salt thereof and to processes of making said solid pharmaceutical dosage forms.