Tadalafil Co-precipitates for Enhanced Dissolution and Bioavailability
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Solution Overview
Problem
Tadalafil's low solubility in solvents and aqueous solutions leads to challenges in industrial-scale synthesis, bioavailability, and pharmaceutical formulation, including high solvent requirements, poor in vivo absorption, and issues with particle size and agglomeration, which affect its efficacy and processing.
Innovation Solution
A process for preparing co-precipitates of tadalafil with pharmaceutically acceptable excipients, specifically hydroxypropyl methylcellulose phthalate, involves dissolving tadalafil and excipients in an organic solvent, adding the solution to a precipitation medium at controlled temperature and pressure, and isolating the co-precipitate, which enhances dissolution rates and bioavailability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If tadalafil is synthesized and crystallized at industrial scale using conventional methods, then the desired product is obtained, but large quantities of solvents are required which have unwanted technological, environmental and economical impact
Solution Approach 1:
The patent applies parameter changes by modifying the crystallization conditions - specifically using a slurry process in methanol at controlled temperature (0-25°C) with specific pH adjustment (pH 2-4 using hydrochloric acid). This changes the physical-chemical parameters to achieve crystallization with reduced solvent volume compared to conventional methods, directly addressing the contradiction between solvent quantity and manufacturing ease
Solution Approach 2:
The patent creates a composite crystalline structure by co-crystallizing tadalafil with specific excipients (such as hydroxypropyl methylcellulose phthalate or polyvinyl acetate phthalate) to form a stable co-precipitate. This composite approach allows the active ingredient to be recovered in a pre-formulated state that maintains stability while reducing the overall solvent requirements for the process
2Reliability
If tadalafil is used in pharmaceutical formulations, then the drug can be administered, but poor solubility in aqueous solutions results in poor in vivo absorption and bioavailability
Solution Approach 1:
The patent forms a composite co-precipitate of tadalafil with pharmaceutically acceptable excipients (hydroxypropyl methylcellulose phthalate or polyvinyl acetate phthalate) that have improved solubility characteristics. This composite material maintains the pharmacological activity of tadalafil while significantly improving its aqueous solubility and in vivo absorption, directly resolving the contradiction between bioavailability and aqueous solubility
Solution Approach 2:
The co-precipitate structure created in the patent exhibits porous characteristics with increased surface area and porosity compared to conventional tadalafil formulations. This porous structure facilitates enhanced dissolution rates and improves the drug's solubility in aqueous media, thereby improving bioavailability without compromising the active ingredient's efficacy
3Speed
If particle size is reduced to less than 10 μm to improve dissolution, then dissolution rate increases, but chargeability and secondary agglomeration occur due to increased surface energy
Solution Approach 1:
The patent creates a composite co-precipitate where tadalafil particles are stabilized within a matrix of excipient materials (hydroxypropyl methylcellulose phthalate or polyvinyl acetate phthalate). This composite structure prevents chargeability and agglomeration of fine particles by providing a protective coating, allowing the maintenance of small particle sizes (d90 < 40 μm) without the stability issues that would normally occur, thus resolving the contradiction between dissolution rate and particle stability
Solution Approach 2:
The patent applies local quality by creating a heterogeneous structure where the excipient material is distributed throughout the particle matrix, providing localized stabilization at critical interfaces. This ensures that the surface properties of individual particles are modified to prevent agglomeration while maintaining the overall small particle size necessary for rapid dissolution
4Reliability
If starch is used as carrier with weight ratio 15:1 to improve solubility, then dissolution is enhanced, but the formulation requires large amounts of carrier material
Solution Approach 1:
The patent creates a composite co-precipitate with excipients that have high compatibility and synergistic effects with tadalafil, achieving effective dissolution enhancement at lower carrier ratios (1:1 to 1:3 weight ratio). This composite approach maximizes the efficiency of the carrier material, providing superior dissolution enhancement compared to starch while requiring significantly less carrier quantity
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 process reduces solvent requirements, improves tadalafil's bioavailability by increasing its dissolution rate, and produces co-precipitates with optimal particle size and surface area, suitable for handling and processing, achieving comparable dissolution profiles to reference drug products like CIALIS.
Implementation Method 1
dissolving tadalafil and hydroxypropyl methylcellulose phthalate in organic solvent
Implementation Method 2
adding the solution into precipitation medium...isolating the co-precipitate
Implementation Method 3
adding the solution into precipitation medium at temperature from 0°C to 40°C and at pressure from normal atmospheric pressure to pressure of 0.6MPa
Data Source
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AI summary
The present invention relates to an improved process for preparation of tadalafil and crystallization and/or purification thereof, wherein the processes are conducted at increased pressure. The invention relates also to a process for preparation of tadalafil co-precipitates and to a solid pharmaceutical composition comprising tadalafil co-precipitates and at least one water soluble diluent and/or water insoluble non-swellable diluent, wherein the composition is substantially free of water insoluble swellable diluents.