Mixed Solvents for Spray Drying Amorphous Solid Dispersions
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing methods for preparing spray dried amorphous solid dispersions of active pharmaceutical ingredients (APIs) face challenges with limited solubility in conventional solvents, leading to inadequate API concentrations, chemical degradation, and inefficient processing, especially when using volatile solvents that are costly, toxic, or poorly compatible with equipment.
Innovation Solution
A method involving the use of a mixed solvent comprising a C1-2 alkanol and a C1-2 carboxylic acid C1-2 alkyl ester, which exhibits synergistic dissolution behavior, allowing for higher API solubility and stability, enabling spray drying at modest temperatures without chemical degradation, and potentially improving manufacturing throughput and particle characteristics.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If conventional volatile solvents (methanol, acetone) are used for spray drying, then the process is simple and fast, but the API solubility is limited and chemical degradation occurs
Solution Approach 1:
The patent uses a composite solvent system combining a C1-2 alkanol (methanol or ethanol) with a C1-2 carboxylic acid C1-2 alkyl ester (methyl acetate or ethyl acetate) in specific ratios. This composite solvent provides synergistic dissolution behavior, achieving higher API solubility (up to 5-10 times higher than individual solvents) while maintaining API stability through moderate temperatures and reduced chemical degradation.
Solution Approach 2:
The patent optimizes the solvent composition parameters by varying the ratio of alkanol to carboxylic acid ester (from 10:90 to 90:10 w/w) and selecting specific chain lengths (C1-2 for both components). These parameter changes enable tuning of solubility, volatility, and stability characteristics to achieve optimal spray drying conditions for different APIs.
2Productivity
If higher API concentrations are used in spray solution, then manufacturing throughput increases, but solubility limitations and chemical degradation worsen
Solution Approach 1:
The composite solvent system of C1-2 alkanol and C1-2 carboxylic acid C1-2 alkyl ester enables significantly higher API solubility, allowing concentrations of 5-10% w/w or higher in the spray solution. This increases the amount of API processed per batch, thereby improving manufacturing throughput while the moderate temperature conditions prevent chemical degradation.
3Reliability
If modest temperatures are used for spray drying, then API stability is maintained, but evaporation efficiency decreases
Solution Approach 1:
The patent selects solvents with specific volatility parameters - C1-2 alkanols and C1-2 carboxylic acid C1-2 alkyl esters have appropriate boiling points and vapor pressures that enable efficient evaporation at moderate temperatures (below ambient pressure boiling point). The synergistic combination maintains rapid evaporation kinetics while allowing spray drying at temperatures that preserve API stability.
4Quantity of substance
If non-volatile or less volatile solvents are used, then API solubility increases, but spray drying efficiency and equipment compatibility worsen
Solution Approach 1:
The patent optimizes the volatility parameter of the solvent system by using C1-2 chain length alkanols and carboxylic acid esters. These short-chain solvents provide an optimal balance: sufficient solubility enhancement while maintaining high vapor pressure for efficient evaporation during spray drying, and compatibility with standard spray drying equipment.
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 method achieves higher API concentrations and improved stability of amorphous solid dispersions, enhancing manufacturing efficiency and particle characteristics while avoiding the drawbacks of conventional volatile solvents.
Implementation Method 1
a mixture of a C1-2 alkanol with a C1-2 carboxylic acid C1-2 alkyl ester shows synergistic, also called non-linear, dissolution behaviour, i.e. a mixture provides for higher solubility compared to the, by linear extrapolation from the solubilities of the pure solvents, expected solubilities
Implementation Method 2
spray drying is done with a solution of the active agent and of the dispersion polymer in a solvent comprising a mixture of a C1-2 alkanol with a C1-2 carboxylic acid C1-2 alkyl ester
Data Source
AI summary
A method for preparing an amorphous solid dispersion by spray drying a spray solution comprising a) a mixed solvent, the mixed solvent comprising i. a solvent 1 selected from the group consisting of methyl acetate, methyl formate, ethyl acetate, ethyl formate and mixtures thereof; ii. a solvent 2 selected from the group consisting of methanol, ethanol and mixtures thereof; with the ratio (w:w) of solvent 1 to solvent 2 being from 10:90 to 90:10; b) an active agent; c) a dispersion polymer, wherein: c1) said dispersion polymer is HPMC; or c2) said dispersion polymer is PVP, provided that said mixed solvent does not consist of a mixture of methanol and ethyl acetate; or c3) said dispersion polymer is selected from the group consisting of: hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl cellulose (HPC), cellulose acetate phthalate (CAP), carboxymethyl ethyl cellulose (CMEC), poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA), polymethacrylates such as poly(methacrylic acid-co-methyl methacrylate) (PMMAMA) or poly(methacrylic acid-co-ethyl acrylate), [acetic acid ethenyl ester, polymer with 1-ethenylhexahydro-2H-azepin-2-one and .alpha.-hydro-.omega.-hydroxypoly(oxy-I,2-ethanediyl), graft], or a combination thereof.