In amorphous solid dispersions (ASD), polymers play a crucial role as carriers for active pharmaceutical ingredients. The characteristics of these carriers influence the amorphous stability of the drug, with some properties, such as low hygroscopicity or high viscosity, potentially conflicting with others necessary to enhance dissolution rates. Consequently, selecting the appropriate carrier involves a complex trade-off among various factors. This article provides an overview of the essential characteristics of polymers in ASDs, covering physicochemical properties and their roles in formulation development.

1. Key Characteristics for Selecting Polymers in ASD:

The table below outlines the importance of various polymer (carrier) characteristics in the formation of ASDs:

Carrier Characteristic	Relevance in ASD Formation
Molecular Weight	Significantly affects viscosity and drug dissolution rate. Generally, higher molecular weight polymers reduce drug dissolution rates. It also correlates with the glass transition temperature (Tg); polymers with higher molecular weights exhibit higher Tg values.
Glass Transition Temperature (Tg)	Influences molecular mobility, affecting crystallization tendencies and amorphous stability. High Tg polymers act as antiplasticizers, limiting drug molecular mobility in the amorphous state, thereby stabilizing the ASD.
Solubility Parameter	Predicts miscibility between the drug and polymer; systems with similar solubility parameters tend to be more miscible. However, in practice, this theoretical concept does not always yield reliable predictions.
Ionization Constant	Determines solubility, ionization state, drug-polymer interactions, and potentially the polymer morphology in aqueous environments, influencing drug release profiles..
Hydrophobicity	Affects hydrophobic interactions between the drug and polymer, drug solubility, polymer morphology, and crystallization inhibition ability.
Melt Viscosity	Strongly dependent on temperature and shear stress, impacting the deformability of the material during hot-melt extrusion.
Hygroscopicity	Greatly influences the Tg of the system and drug-polymer interactions. Highly hygroscopic polymers may lead to phase separation and increased crystallization tendencies.
Functional Groups	Dictate molecular interactions with the drug, such as hydrogen bonding, affecting physical state, solubility, supersaturation maintenance, and amorphous drug stability..
Morphology	Related to drug-polymer interactions, Tg, stabilization efficiency, and supersaturation maintenance.
Hydrogen Bonding Capability	Drug-polymer hydrogen bonding can stabilize amorphous drugs by preventing crystallization.
Gel Formation Ability	Some polymers form high-viscosity gels around drug particles, potentially limiting release rates but also helping maintain supersaturation.
Crystallization Inhibition Ability	The polymer should prevent drug crystallization both in the solid state and in supersaturated solutions. Some polymers, such as HPMCAS, exhibit superior crystallization inhibition compared to others.
Surface Activity	Surface-active polymers can improve solubility, miscibility, and the physical stability of amorphous drugs. They also enhance drug wettability and prevent precipitation from supersaturated solutions
Plasticizing Ability	Certain polymers act as plasticizers, lowering the Tg of the drug-polymer mixture. This is beneficial for ASD processing via hot-melt extrusion at lower temperatures, reducing drug and polymer degradation.

Selecting the appropriate polymer is critical, requiring careful balancing of these factors to achieve optimal drug stability and formulation performance.

The role of polymers in a successful ASD formulation

The role of polymers in a successful ASD formulation

2. . Strategies for Selecting Polymers in ASD

The optimal polymer carrier must stabilize high-energy amorphous drugs in the solid state while simultaneously enhancing dissolution rates and maintaining supersaturation in solution. The properties that promote amorphous stability, such as low hygroscopicity or high viscosity, often conflict with those that enhance dissolution rates, making polymer selection a complex trade-off.

Furthermore, there remains a gap in understanding the mechanisms by which carriers enhance drug solubility, improve stability, and maintain the supersaturation state. As a result, carrier selection is still largely empirical, requiring substantial resources and time. To develop a rational strategy for carrier selection that minimizes time and resource investment, various theoretical and experimental approaches have been explored. These include predicting drug-carrier miscibility and solubility using the Flory-Huggins theory, constructing thermodynamic phase diagrams, utilizing solubility parameters, computational docking methods, solubility in polymer monomers, solubility in polymer solutions, and thermal analysis. However, these methods exhibit limitations in predictive accuracy and reliability, restricting their practical applications. To compensate for the shortcomings of theoretical approaches, miniaturized high-throughput screening methods based on experimental techniques have been proposed. These include film casting, solvent shift, coprecipitation, melt-fusion, and freeze-drying. The most suitable drug-carrier combination identified through these miniaturized screening methods can be further expanded for in vitro and in vivo evaluation. A schematic workflow for carrier screening using the film casting method is illustrated in Figure 4.

3. Commonly Used Polymers in ASDs:

Advances in the development of amorphous solid dispersions: The role of polymeric carriers - ScienceDirect

3.1. Polyvinyllactam:

- PVP (Polyvinylpyrrolidone): A widely used polymer with high hygroscopicity, available in various molecular weights. The stability of ASDs with PVP can be influenced by humidity.

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Hydrogen bonding in rafoxanide-PVP solid dispersion

- PVP/VA (Copovidone): Less hygroscopic than PVP, with good processability; commonly used in hot-melt extrusion ASD production. However, its drug interaction and crystallization inhibition capabilities may be lower than PVP.
- Soluplus^®: An amphiphilic polymer that enhances the solubility of poorly water-soluble drugs and improves bioavailability.

3.2. Cellulosic polymers:

- HPMC (Hydroxypropyl methylcellulose): As a hydrophilic polymer, it has good compatibility with many types of drugs. However, HPMC has a high melting viscosity, which is not suitable for the melting method.
- HPMCAS (Hypromellose acetate succinate): Exhibits low hygroscopicity, strong drug interaction, and enhances supersaturation during dissolution. Suitable for hot-melt extrusion ASD manufacturing

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Two hydrogen bonds are formed between Posaconazole and HPMCAS

3.3. Acrylate and methacrylate (co-)polymers

- Eudragit^®: Available in various grades with different properties; commonly used for enteric coatings and controlled drug release. Eudragit® E can form ionic interactions with acidic drugs

3.4. Other Polymer:

- Poloxamer: Enhances drug solubility and dissolution rates; can also function as a surfactant in ASDs

Summary of some characteristics of polymers

Grouping	Chemical name	Main physical properties
Polyvinyllactam polymers	Polyvinylpyrrolidone (PVP)	High hygroscopicity There are different grades based on average molecular weight (KollidonR® 12 PF, KollidonR® 90F,…)
	Copovidone (PVP/VA)	High decomposition temperature Medium hygroscopicity
	Polyvinylcaprolactam–polyvinyl acetate–polyethyelne glycol graft copolymer (Soluplus^®)	Amphiphilic structure Low glass transition temperature (Tg) High decomposition temperature Low hygroscopicity
Cellulosic polymers	Hydroxypropyl methyl cellulose (HPMC)	Low hygroscopicity There are different types based on average molecular weight.
	Hydroxypropyl cellulose (HPC)	Low hygroscopicity Low glass transition temperature (Tg)
	Hypromellose acetate succinate (HPMCAS)	Modified from HPMC (hydroxypropyl methylcellulose) by esterification with acetic anhydride and succinic anhydride Insoluble at pH below 5.0
	Hydroxypropyl methylcellulose phthalat (HPMCP)	Contains phthalic acid Enteric coating material
	Cellulose acetate phthalate (CAP)	Soluble at higher pH (above 6) Contains phthalic acid group Enteric coating material
Acrylate and methacrylate (co-)polymers	Poly(butyl methacrylate-co- (2-dimethylaminoethyl) methacrylate-comethyl methacrylate) 1:2:1 (Eudragit^® E PO)	Dissolves at pH below 5.5 Low hygroscopicity
	Hetero block co-polymers of poly(methacrylic acidco-methyl methacrylate) 1:1 (Eudragit^® L 100)	Ionizes at pH above 6.0 Enteric-coated materials
	Hetero block co-polymers of poly(methacrylic acidco-methyl methacrylate) 1:2 (Eudragit^® S 100)	Ionizes at pH above 7.0 Enteric-coated materials
	Poly(methacrylic acid-co-ethyl acrylate) 1:1 (Eudragit^® L 100-55)	Ionizes at pH above 5.5 Enteric-coated materials
Polymer khác	Polyvinyl acetate phthalate (PVAP)	Ionizes at pH above 5,0 Contains phthalic acid group
	Poly(acrylic acid) (PAA)	pKa = 4,5 Has a high density of carboxylic acid groups
	Polyethylene glycol /polyethylene oxide (PEG/PEO)	Water soluble Low glass transition temperature (Tg)
	Poly-(ethylene oxide)−poly(propylene oxide)−poly(ethylene oxide) triblock copolymers (Polexamer)	Water soluble Low glass transition temperature (Tg)

Some polymers in commercial products

Commercial name	API	Manufacturing method	Polymer	Company	Approved year
Cesamet^®	Nabilone	Bay hơi dung môi	PVP	Valeant	1985
Isoptin^®	Verapamil	HME	HPC/HPMC	Abbott	1987
Sporanox^®	Itraconazole	Fluid-bed bead layering	HPMC	Janssen	1992
Prograf^®	Tacrolimus	Solvent evaporation	HPMC	Fujisawa	1994
KaletraR^®	Ritonavir/ Lopinavi	HME	PVP/VA64	Abbott	2007
Intelence^®	Etravirine	Spray drying	HPMC	Janssen	2008
Samsca^®	Tolvaptan	Spray drying	HPC	Otsuka	2009
Zortress^®	Everolimus	Spray drying	HPMC	Novartis	2010
Norvir^®	Ritonavir	HME	PVP/VA64	Abbott	2010

4. Conclusion

Polymers play a pivotal role in the success of ASDs, impacting stability, solubility, bioavailability, and manufacturing feasibility. Selecting the right polymer requires an in-depth understanding of physicochemical properties, drug-polymer interactions, and process requirements. Advances in analytical and computational techniques, along with the development of novel polymers, are expected to drive further innovations in ASD formulation