Valsartan Co-Amorphous Dispersion for Solubility and Stability
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current solid dispersions of valsartan, an angiotensin II receptor antagonist, face challenges with poor water solubility leading to low bioavailability and stability issues, limiting their effectiveness as antihypertensive agents and potential treatments for COVID-19.
Innovation Solution
A solid co-amorphous dispersion of valsartan is developed, comprising valsartan, a low molecular weight co-former like nicotinamide, and an amphiphilic solvent such as ethanol, with a valsartan content exceeding 40 mol% and 65 wt%, enhancing water solubility and stability through a synthesis method involving mixing, homogenization, and solvent evaporation at controlled temperatures.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If amorphization is used to improve solubility of valsartan, then water solubility increases, but the amorphous solid tends to recrystallize resulting in loss of homogeneity and stability
Solution Approach 1:
A co-former molecule acts as an intermediary between valsartan molecules, forming heteromeric interactions that prevent direct homomeric interactions and thus prevent crystallization. The co-former stabilizes the amorphous state by creating a molecular network that locks valsartan in an disordered arrangement.
Solution Approach 2:
The invention creates a composite amorphous system combining valsartan with a co-former in specific molar ratios (1:1 or 2:1). This composite structure leverages the complementary properties of both components, where the co-former provides structural stabilization while valsartan maintains its therapeutic function, achieving both solubility enhancement and stability.
2Stability of the object's composition
If polymer-based solid dispersions are used to stabilize valsartan, then stability improves, but poor miscibility and phase separation occur
Solution Approach 1:
The invention changes the molecular weight parameter of the co-former from high (polymer) to low (small molecule, MW < 900 g/mol). This parameter change fundamentally alters the interaction characteristics, enabling complete miscibility and homogeneous amorphous formation while maintaining stability, avoiding the phase separation issues inherent in polymer systems.
3Use of energy by moving object
If low molecular weight co-formers are used to improve miscibility, then miscibility improves, but the resulting formulation becomes hygroscopic
Solution Approach 1:
The invention selects co-formers with specific local molecular characteristics - small molecules with appropriate functional groups that can form heteromeric interactions with valsartan. This local quality control at the molecular level enables miscibility while the specific molecular structure of the co-former-resin complex reduces hygroscopicity compared to other small molecule co-formers.
4Stability of the object's composition
If polymer co-formers are used, then stability is achieved, but the total weight of the tablet increases due to dead mass
Solution Approach 1:
The invention fundamentally changes the molecular weight parameter of the co-former from high (polymer) to low (small molecule). This enables achieving stability with minimal co-former content (1-4 equivalents per valsartan), dramatically reducing the dead mass and tablet weight compared to polymer-based systems where large amounts of polymer are required for stabilization.
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 co-amorphous dispersion achieves a significant 25-fold increase in water solubility and stability, improving bioavailability and therapeutic efficacy, allowing for lower drug doses and reduced production costs, while also providing dual activity in treating hypertension and COVID-19.
Implementation Method 1
at least one non-toxic amphiphilic solvent that solvates valsartan and co-former molecules
Implementation Method 2
low molecular weight co-former capable of forming hydrogen bonds with valsartan molecules
Implementation Method 3
excess of the solvent used is evaporated
Data Source
AI summary
A solid co-amorphous dispersion of valsartan according to the invention is characterized in that in the amorphous solid phase it contains valsartan, at least one non-toxic low molecular weight co-former capable of forming hydrogen bonds with valsartan molecules, an d at least one non-toxic amphiphilic solvent that solvates valsartan and co-former molecules, wherein the content of valsartan exceeds 40 mol % and 65 wt %, and the dispersion exhibits an increased water solubility—with respect to valsartan contained therein, in comparison with the solubility of pure valsartan. A method for synthetizing a solid co-amorphous dispersion of valsartan by mixing valsartan with a co-former, pouring a solvent over the mixture and evaporating the solvent, wherein the physical mixture of valsartan, at least one non-toxic low molecular weight co-former capable of forming hydrogen bonds with valsartan molecules, and at least one non-toxic amphiphilic solvent is formed and subjected to mixing and homogenization in a condensed-phase, at the temperature range of 20-100° C., preferably 45-100° C., whereby excess of the solvent used is stripped off at the temperature range of 20-100° C., preferably 45-100° C., to give a final product in form of a solvated solid co-amorphous dispersion of valsartan, co-former and the solvent, which dispersion exhibits an increased water solubility—with respect to valsartan contained therein, in comparison with the solubility of pure valsartan. The use of solvated solid co-amorphous dispersions of valsartan as described above, obtained as described above, in medicine and pharmacy, especially for treatment of hypertension and COVID-19 disease caused by SARS-CoV-2 virus, as a ternary formulation of valsartan, nicotinamide and a non-toxic amphiphilic solvent, preferably ethanol, n-propanol or i-propanol, characterized by increased water solubility—with respect to valsartan contained therein, in comparison with the solubility of pure valsartan, and having a dual action, resulting from the synergy of ingredients supporting the therapeutic effect of valsartan. The disclosed solid dispersion according to the invention is characterized by higher solubility in comparison with that of pure valsartan, and therefore an increased bioavailability of this drug. A number of benefits results therefrom for patients (lower amount of active substance ingested), the pharmaceutical industry (lower effective dose of the active substance in preparations, resulting in reduction of production costs) and the environment (less amount of the active substance and its metabolites not absorbed by patients and released into the environment). The appropriate selection of excipients allows for the use of the dispersion according to the invention as a drug of dual-activity, in treatment of hypertension and in treatment of SARS-CoV-2 coronavirus infection causing COVID-19 disease.