1. Overview of HPC Polymer

1.1 Structure

HPC (hydroxypropyl cellulose) is an ether derivative of cellulose, where some hydroxyl groups on the cellulose backbone are substituted with hydroxypropyl groups. These hydroxypropyl groups can further undergo etherification during HPC synthesis, extending the polymer chain. The typical molecular substitution (MS) level for HPC is around 4, meaning that four hydroxypropyl groups are substituted per anhydroglucose unit,

The characteristics of cellulose derivatives are often compared based on the following indices:

• • Percentage by mass of substituent groups attached to the polymer backbone.
  • Degree of Substitution (DS) per anhydroglucose unit: This refers to the number of hydroxyl groups on each anhydroglucose unit that have been substituted. Since each anhydroglucose unit has a maximum of three hydroxyl groups (at C2, C3, and C6), the highest possible DS value is 3.
  • Molar Substitution (MS) per anhydroglucose unit: This represents the total number of substituent groups (including oligomerized ones) per anhydroglucose unit. Unlike DS, MS is not constrained by the number of original hydroxyl positions, as the substituents can oligomerize and form longer chains.

These indices can be used interchangeably, but the selection depends on the application and whether the substituents form “oligomeric branched chains.” In the case of such branching, DS alone cannot fully represent the total amount of substituents on the polymer chain.

Theoretically, the total MS derived from an oligomerized functional group is not limited by the number of reactive hydroxyl sites on the cellulose backbone. However, steric constraints and polymer synthesis efficiency impose practical limits. HPC, with an MS value typically reaching around 4, is one of the highest-substituted cellulose derivatives. Each hydroxypropyl addition generates a secondary hydroxyl group, increasing the MS beyond the DS value.

1.2. Solubility and Applications

Native cellulose has a tightly packed crystalline structure, which restricts its solubility in water. Substituting hydroxypropyl groups disrupts this crystalline structure, enhancing polymer solubility. To achieve optimal solubility, HPC requires an MS of around 4.

A high degree of substitution increases HPC’s solubility in both water and organic solvents. HPC is widely used in the pharmaceutical industry as a binder, film-coating agent, controlled-release excipient, and extrusion aid.

2. Polymer Solubility in Water

Several factors influence the solubility of polymers, including:

2.1. Effect of Molecular Weight on Free Energy of Dissolution

Polymers with higher molecular weights contain fewer molecules per mole compared to small-molecule solutes. As a result, the entropy change (ΔS) during dissolution is relatively small, leading to a lower Gibbs free energy (ΔG), which makes the dissolution process more challenging.

2.2. Homogeneity of Chemical Composition (copolymer):

Most polymers are copolymers, in which monomer units have varying degrees of intrinsic solubility. For example, in HPC:

• • Unsubstituted anhydroglucose units are hydrophilic.
  • Hydroxypropyl-substituted anhydroglucose units are relatively hydrophobic.

In practical polymer samples, compositional distribution may vary between different polymer chains (interchain heterogeneity) and even within a single chain (intrachain heterogeneity). As a result, when dissolved in a given solvent, some polymer fractions may dissolve completely while others may not, or specific segments of a chain may dissolve unevenly.

2.3. Polarity of Polymer and Solvent

The fundamental solubility principle “like dissolves like” applies to polymers, similar to small-molecule solutes. That is, substances with similar polarity, chemical structures, and functional groups tend to dissolve in each other. For example, water dissolves highly polar polymers.

However, the solubility of copolymers becomes more complex when constituent monomers have widely varying solubility. In such cases, using binary solvent mixtures or ternary solvent mixtures can improve polymer solubility.

2.4. Unique Solubility Behavior of Polymers in Water – Cloud Point

Polymer solubility also depends on Upper Critical Solution Temperature (UCST) and Lower Critical Solution Temperature (LCST) in aqueous solutions.

LCST – Lower Critical Solution Temperature:

• • Below this temperature, two liquids are completely miscible at any ratio. Above LCST, the mixture separates into two distinct phases due to changes in intermolecular interactions. For example, at low temperatures, the molecules can bond with each other through hydrogen bonds, allowing them to dissolve. As the temperature increases, these bonds weaken, leading to phase separation.
  • A classic example involves aqueous polymer solutions: at low temperatures, the polymer is soluble in water, but above LCST, it precipitates, turning the solution cloudy.

UCST – Upper Critical Solution Temperature:

• • In contrast to LCST, UCST is the temperature above which two liquids are completely miscible. When the temperature drops below UCST, phase separation occurs. This phenomenon is typically related to changes in the system’s entropy. At high temperatures, the system’s entropy increases, promoting solubility. As the temperature decreases, entropy decreases, making phase separation more thermodynamically favorable. The polymer aggregates into a polymer-rich phase, while the solvent forms a polymer-lean phase.
  • Some organic solvent-polymer systems exhibit UCST behavior, such as polyacrylamide or polystyrene in specific solvents.

The LCST value can be observed from the cloud point by conducting an inverse experiment—starting with a homogeneous solution in a single-phase region and gradually increasing the temperature until phase separation occurs. This phenomenon occurs uniformly throughout the entire solution volume, typically forming small droplets of the “polymer-rich” phase dispersed in the “polymer-lean” phase. This results in strong light scattering, causing the solution to appear turbid—hence the term “cloud point”

A study on the cloud point of HPC (Hydroxypropyl Cellulose) and HPMC (Hydroxypropyl Methylcellulose) was conducted by preparing a 1% solution in water. The results showed a significant difference in cloud points between these two derivatives (HPC at approximately 40–45°C and HPMC at around 60–70°C). This difference can be explained by the considerable variation in hydrophilicity and the balance between polymer-water and polymer-polymer interactions

• HPC: More hydroxyl groups create strong hydrogen bonding with water at low temperatures, but enhanced polymer-polymer interactions lead to phase separation as temperature rises, lowering the cloud point.
• HPMC: Fewer hydroxyl groups and additional hydrophobic methoxy groups reduce water interaction while limiting polymer-polymer interactions, maintaining solubility at higher temperatures.

Adding electrolytes lowers the cloud point via a “salting-out” effect, reducing polymer solubility in water. Similarly, increasing the hydroxypropyl content in HPC/HPMC or the methoxyl content in HPMC decreases the cloud point.

References

https://youtu.be/hIh95xS85y4?si=iRflw-c2YLwxCUS8

Yihong Qiu, Yisheng Chen, Geoff G.Z. Zhang, Lawrence Yu, Rao V. Mantri (eds.) – Developing Solid Oral Dosage Forms_ Pharmaceutical Theory and Practice-Academic Press (2016)