How to Synthesize PLGA Ended with Carboxylix Groups?

Poly(lactic-co-glycolic acid) (PLGA) is a copolymer of lactic acid and glycolic acid. Normally, PLGA has three end groups: ester group, carboxylic Acid-ended and Hydroxyl-ended PLGA. Each has their unique properties.

In this post, we will explain the process about how to synthesize PLGA polymer carboxylix group end group, the difference among the three end group types.

Table of Contents

Why End PLGA with Carboxylic Groups?

End-functionalizing PLGA (Poly(lactic-co-glycolic acid)) with carboxylic groups offers several advantages for drug delivery applications, enhancing its utility as a versatile biomaterial in the pharmaceutical and medical fields. Below are the reasons why PLGA is often end-functionalized with carboxylic groups:

Enhanced Solubility and Dispersion

Carboxylic groups on the PLGA polymer increase its solubility in water and various organic solvents. This characteristic is essential for the delivery of drugs that are typically insoluble or only slightly soluble in water, enabling a wider range of drugs to be encapsulated and delivered using PLGA.

Meanwhile, the presence of carboxylic groups assists in creating more stable dispersions or emulsions, which is crucial when preparing nanoparticles or microparticles for drug delivery.

Surface Functionalization Opportunities

Terminal carboxylic groups provide reactive sites for the conjugation of drugs, targeting ligands, or other functional moieties. This enables the construction of more complex and multifunctional drug delivery systems.

Controlled Drug Release

The introduction of carboxylic groups allows for the alteration and fine-tuning of the polymer’s drug release kinetics. This helps in achieving controlled and sustained drug release profiles, which are crucial for maintaining therapeutic drug concentrations over time.

Terminal carboxylic groups can offer protection to encapsulated drugs, enhancing their stability and prolonging their shelf-life.

Steps to Synthesize PLGA Ended with Carboxylic Groups

The synthesis of PLGA with carboxylic end groups involves a carefully controlled process, typically through ring-opening polymerization. Below is a general overview of the steps involved in synthesizing carboxylic acid-terminated PLGA.

PLGA polymer Synthesize

1. Selection of Monomers

The first step is choosing high purity monomers, including dl-lactide and glycolide. They can be used in different ratios to achieve polymers with different characteristics.

2. Incorporating Initiator Molecules

The next is adding the initiator to the monomer mixture. The initiator’s carboxylic acid group will form the end group of the resulting polymer.

You can use A carboxylic acid-containing initiator in the process. The common choices are acetic acid or propionic acid.

3. Ensuring controlled polymerization

You can heat the mixture to initiate polymerization. The temperature and other conditions should be carefully controlled to ensure the reaction proceeds smoothly and predictably.

You need to constantly monitor the reaction process, checking the molecular weight and viscosity of the polymer as it forms. This monitoring helps ensure the polymerization is controlled and results in PLGA with the desired properties. 

Once the polymer reaches the desired molecular weight, the reaction will be terminated.

4. Purification and Isolation:

After the polymerization, it’s the purification process. You need to remove unreacted monomers, initiators, and other impurities.

According to the requirements of the pharmacopoeia, we need to control the residual monomer in very small proportion, so you need to spend a lot time in this process.

5. Characterization

Once synthesized, it’s crucial to characterize the polymer to confirm the presence of the carboxylic end groups. Techniques such as FTIR (Fourier Transform Infrared Spectroscopy), NMR (Nuclear Magnetic Resonance), and GPC (Gel Permeation Chromatography) can be employed for this purpose.

Comparison with Other PLGA End Groups

PLGA can be end-functionalized with different groups, and each variant has its distinct properties and applications. Here’s a comparison between carboxylic acid-ended PLGA, hydroxyl-ended PLGA, and ester-ended PLGA:

Carboxylic Acid-ended PLGA

Carboxylic Acid-ended PLGA


  • Enhanced Solubility: Carboxylic end groups can improve the solubility of PLGA, especially in polar solvents.
  • Surface Functionalization: Provides reactive sites for the attachment of various molecules, enhancing its utility in targeted drug delivery or surface modification.
  • Increased Stability: Offers stable conjugation with various drugs or molecules.


  • Potentially Acidic Degradation Products: The degradation can result in a slightly more acidic microenvironment, which might not be ideal for all applications.

Hydroxyl-ended PLGA


  • Neutral Degradation Products: Degradation of hydroxyl-ended PLGA is less likely to result in an acidic environment compared to carboxylic acid-ended PLGA.
  • Versatility in Functionalization: Hydroxyl groups are reactive and can be utilized for further functionalization or modifications.
  • Compatibility: Often compatible with a wide range of solvents and drugs.


  • Less Reactive Than Carboxyl or Amine Groups: While hydroxyl groups are reactive, they might require more stringent conditions for certain reactions compared to carboxylic acid or amine groups.

Ester-ended PLGA

ester ended PLGA


  • Rapid Degradation: Ester linkages can be more susceptible to hydrolysis, leading to faster degradation. This can be advantageous for applications where rapid drug release or polymer resorption is desired.
  • Synthetic Flexibility: Ester end groups offer flexibility in synthesizing block copolymers with other polyesters.


  • Potential for Uncontrolled Degradation: Faster degradation might not be ideal for applications requiring prolonged drug release or structural support.
  • Susceptibility to Hydrolysis: Ester linkages might make the polymer more susceptible to premature degradation during storage, especially in humid conditions.


Why is carboxylic-ended PLGA preferable in some applications?

They are majorly used in drug delivery and tissue engineering due to enhanced surface attachment properties.

How is the formation of carboxylic end groups confirmed?

You can analysis the end-group with techniques like NMR.

What is the shelf life of carboxylic-ended PLGA?

The shelf life of carboxylic-ended PLGA can vary depending on storage conditions and how it has been handled. Generally, carboxylic-ended PLGA has a shelf life of 1-2 years if stored properly in a dry and cool environment. 

How does the presence of carboxylic groups impact the physical properties of PLGA?

The carboxylic groups allow for the formation of intermolecular hydrogen bonding, resulting in increased crystallinity and higher melting temperature of the polymer. This enhanced crystallinity leads to a higher degree of stiffness and rigidity in PLGA. 

Additionally, the carboxylic groups also make PLGA more hydrophilic, thereby increasing its water absorption capacity. 


Carboxyl-terminated PLGA is an exciting variant of the traditional PLGA, offering added functionalities. Its synthesis, while slightly more complex than regular PLGA, opens doors to a range of biotechnological applications.

As with any chemical procedure, it’s imperative to work under controlled conditions, ensuring safety and optimal results.