Combining crystalline and polymeric excipients in API solid dispersions - Opportunity or risk?

Area of Science:

• Pharmaceutical Sciences
• Materials Science
• Physical Chemistry

Background:

• Amorphous solid dispersions (ASDs) are metastable and prone to crystallization, impacting drug product stability.
• Low molecular weight excipients stabilize amorphous active pharmaceutical ingredients (APIs) in co-amorphous systems.
• The potential of low molecular weight excipients to enhance polymeric ASD stability is largely unexplored.

Purpose of the Study:

• To investigate the stabilizing effect of combined low molecular weight excipient/polymer formulations on ASDs.
• To predict and validate the impact of excipients on critical quality attributes like phase separation, API crystallization driving force (CDF), and molecular mobility.
• To assess the long-term stability of carbamazepine/polyvinylpyrrolidone ASDs with various excipients.

Main Methods:

• In-silico modeling to predict ASD stability.
• Long-term stability testing of selected ASD formulations.
• Analysis of amorphous phase separation, API CDF, and molecular mobility.
• Case study using carbamazepine/polyvinylpyrrolidone ASDs with fructose, lactose, sucrose, trehalose, saccharin, tryptophan, and urea.

Main Results:

• In-silico predictions were validated by long-term stability tests.
• Saccharin emerged as the most promising excipient among those tested, despite all excipients negatively impacting ASD stability.
• ASDs containing saccharin or tryptophan showed accelerated API crystallization compared to reference ASDs.
• The addition of crystalline excipients can introduce risks to polymeric ASD long-term stability.

Conclusions:

• Excipient selection for polymeric ASDs must consider the thermodynamic phase behavior of the entire API/polymer/excipient mixture.
• Pure-component excipient properties are insufficient for predicting their effect on ASD stability.
• In-silico tools can significantly reduce the number of experimental screening tests required for excipient selection.