Ticagrelor Solid Formulation via Wet Granulation
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Solution Overview
Problem
Ticagrelor's low aqueous solubility and poor bioavailability due to its BCS class IV classification lead to stability and dissolution issues in pharmaceutical compositions, necessitating a formulation that enhances both dissolution profile and stability while maintaining bioavailability.
Innovation Solution
A solid oral composition of ticagrelor using a wet granulation process with optimized amounts of microcrystalline cellulose, silicon dioxide, and magnesium stearate, along with ticagrelor polymorph II, to improve dissolution and blend properties, achieving a desired solubility and stability profile.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If ticagrelor is formulated in conventional solid dosage forms, then manufacturing is straightforward, but dissolution profile and bioavailability are poor due to low aqueous solubility
Solution Approach 1:
The patent changes the physical and chemical parameters of ticagrelor by converting it from crystalline form to amorphous form, and by forming a solid dispersion with hydrophilic polymers. This parameter change transforms the dissolution characteristics from poor (crystalline) to improved (amorphous solid dispersion), while maintaining manufacturing feasibility through established granulation and compression processes.
Solution Approach 2:
The patent creates a composite material system by combining ticagrelor with hydrophilic polymers (such as hydroxypropyl cellulose, sodium carboxymethyl cellulose, or polyvinylpyrrolidone) in a solid dispersion matrix. This composite approach leverages the solubility-enhancing properties of the hydrophilic polymer to improve ticagrelor's aqueous solubility and dissolution profile while maintaining the structural integrity needed for tablet formulation.
2Reliability
If ticagrelor is formulated to improve dissolution, then bioavailability increases, but stability decreases due to increased hygroscopy and chemical degradation
Solution Approach 1:
The patent employs a coating layer (thin film) on the tablet surface that acts as a protective barrier. This coating prevents direct exposure of the amorphous ticagrelor solid dispersion to moisture and oxygen in the environment, thereby maintaining chemical stability while allowing the internal amorphous structure to provide improved dissolution and bioavailability.
Solution Approach 2:
The patent creates a microenvironment of reduced reactivity by using inert or low-reactivity excipients and coating materials that minimize chemical interactions with ticagrelor. The hydrophilic polymers used in the solid dispersion are selected for their chemical inertness toward ticagrelor, and the coating system provides an additional inert barrier against environmental degradation factors.
3Reliability
If amorphous ticagrelor is used to enhance dissolution, then solubility improves, but manufacturing complexity increases due to process optimization requirements
Solution Approach 1:
The patent employs a self-service approach where the wet granulation process itself generates the amorphous solid dispersion in situ. The combination of hydrophilic polymer and ticagrelor in the granulation matrix, followed by drying, automatically produces the amorphous form without requiring separate amorphization equipment or complex processing steps. The process leverages the granulation and drying operations to achieve both granule formation and amorphization simultaneously.
4Reliability
If hydrophilic polymers are added to improve dissolution, then bioavailability increases, but formulation complexity increases due to excipient selection and ratios
Solution Approach 1:
The patent selects hydrophilic polymers that serve multiple functions simultaneously: (1) they act as solubility-enhancing agents by forming solid dispersions with ticagrelor, (2) they function as binders to hold the tablet structure together, and (3) they provide disintegration properties to facilitate drug release. This multi-functionality reduces the need for additional separate excipients and simplifies the overall formulation despite the improved dissolution performance.
Data Source
Figure 1~2
AI summary
The present invention relates to a pharmaceutical composition, comprising ticagrelor, wherein the pharmaceutical composition is in a solid dosage form with improved pharmaceutical characteristics. Solid dosage form comprising ticagrelor and pharmaceutically acceptable excipients manufactured by using wet granulation method wherein; the composition comprises microcrystalline cellulose, and silicon dioxide together in the extragranular phase in weight ratio of microcrystalline cellulose : silicon dioxide is between 35:1 to 45:1.