Published Apr 14, 2026

A practical framework for comparing amorphous dispersions, nanocrystals, lipid systems, salts, and co-crystals based on how each approach changes the development profile for poorly soluble oral drugs.

The Solubility Problem in BCS Class II and IV Drug Development

Most new chemical entities entering development pipelines today have poor aqueous solubility. Within the Biopharmaceutics Classification System, these compounds fall into two categories that matter most for oral drug development. BCS Class II compounds have low solubility but adequate permeability. If they can dissolve, they will absorb. BCS Class IV compounds have both low solubility and low permeability, which means that even when you solve the dissolution problem, absorption remains uncertain.

That distinction sounds straightforward, but it has large consequences for formulation strategy. A solubility enhancement approach that works well for a Class II molecule may produce the same in vitro improvement for a Class IV molecule without delivering proportional oral exposure. The toolbox is the same, but the value of each tool is different depending on what is actually limiting absorption.

In this blog, we focus on the development levers each method is pulling and why the same lever carries different weight depending on whether the compound is Class II or Class IV. In practice, the central question is not just whether a compound is poorly soluble, but whether the dominant limitation is dissolution rate, equilibrium solubility, permeability, or a combination of all three.

Three Levers That Determine Developability

Every solubility enhancement strategy works by changing something about how the drug interacts with aqueous media. But not all of them change the same thing. There are three distinct levers, and understanding which one a given approach is pulling is the first step in evaluating whether it fits the molecule.

Lever 1: Changing the solubility itself. 

Salt formation and co-crystals modify the crystal lattice to increase the equilibrium solubility of the solid form. The improvement ensures thermodynamic stability, meaning it persists under storage and does not depend on the formulation maintaining a metastable state. This makes salts and co-crystals relatively straightforward from a stability and regulatory standpoint. The limitation is that not every molecule is ionizable (ruling out salts) and not every compound forms viable co-crystals.

Lever 2: Generating temporary supersaturation. 

Amorphous solid dispersions and certain lipid-based systems do not change the equilibrium solubility. Instead, they create a supersaturated state where the dissolved concentration temporarily exceeds the thermodynamic limit. This can produce dramatic apparent solubility improvements in screening, sometimes 10 to 50-fold or higher. But supersaturation is inherently unstable. The drug will eventually precipitate or recrystallize unless the formulation actively maintains the supersaturated concentration long enough for absorption. The development consequence is significant: these approaches require more extensive stability testing, more complex analytical characterization, and tighter process control.

Lever 3: Accelerating dissolution rate without changing solubility. 

Nanocrystals and micronization increase the surface area of the crystalline drug, which accelerates how quickly it dissolves. The equilibrium solubility remains the same, but the drug reaches that concentration faster. This preserves the thermodynamic stability of the crystalline form, which simplifies the development path. The limitation is equally clear: if the equilibrium solubility ceiling is too low to drive adequate absorption, getting there faster does not solve the problem.

These three levers build on each other logically. The first question is whether the molecule needs a higher solubility ceiling or just faster access to the existing one. The second question is whether the improvement needs to be thermodynamically stable or whether a transient supersaturation is acceptable given the absorption window. The answers determine which strategies are worth evaluating further.

Why the Same Lever Carries Different Value in BCS II Versus BCS IV

For a BCS Class II compound, permeability is not a barrier. The molecule will absorb efficiently once it is in solution. This means all three levers can contribute to improved oral exposure. Increasing equilibrium solubility through a salt or co-crystal, generating supersaturation through an amorphous dispersion, or accelerating dissolution through nanocrystals can each be effective, because the rate-limiting step is getting the drug dissolved.

For a BCS Class IV compound, the situation is different. Even when the drug is fully dissolved, the intestinal membrane limits how much can cross. These compounds tend to show high variability in absorption and poor overall bioavailability. [1] A strategy that only pulls Lever 3 (faster dissolution) is unlikely to deliver meaningful improvement, because the solubility ceiling may still be too low to drive adequate permeation. A strategy that pulls Lever 1 or 2 has a better chance, but only if the resulting dissolved concentration is high enough and sustained long enough to overcome the permeability barrier.

This is why the same formulation approach can produce a successful outcome for a Class II molecule and an underwhelming one for a Class IV molecule. The lever was pulled correctly. It was just the wrong lever for the problem.

Two Examples That Illustrate the Framework

Vemurafenib (BCS Class II). 

Vemurafenib is a B-Raf kinase inhibitor with aqueous solubility near 1 µg/mL. Its permeability is adequate, making dissolution the clear rate-limiting step. In crystalline form, even doses as high as 1600 mg twice daily could not achieve the target plasma exposure. The development team used Lever 2: an amorphous solid dispersion with HPMCAS, produced through a solvent-controlled coprecipitation process. The result was a four to fivefold increase in bioavailability, enabling approval as Zelboraf. [2] This is a case where the lever matched the limitation. The compound needed supersaturation, the polymer system maintained it, and the process was controllable at scale.

Ritonavir (BCS Class II/IV). 

Ritonavir, an HIV protease inhibitor, was originally formulated in a semisolid capsule to address its poor crystalline solubility. Two years after launch, a previously unknown polymorph appeared that was less than half as soluble as the original form. The product had to be withdrawn and reformulated. [3,4] This case is less about which solubility lever was chosen and more about what was missed: the solid form landscape was not fully characterized before the formulation strategy was locked in. The solubility enhancement worked until the underlying solid form changed. It is a reminder that any solubility strategy is only as durable as the solid-state understanding behind it.

How to Evaluate Which Strategy Fits

When comparing solubility enhancement options for a given molecule, the evaluation should focus on how well each approach matches the compound's specific limitation:

• What is the rate-limiting step? Is the primary barrier dissolution rate, equilibrium solubility, permeability, or a combination? This determines which lever needs to be pulled.

• Is a thermodynamic or kinetic improvement needed? If the molecule needs a permanently higher solubility, salt or co-crystal approaches are the natural starting point. If transient supersaturation is sufficient given the absorption window, amorphous dispersions or lipid systems may be appropriate.

• Can the improvement be maintained? For supersaturation-based strategies, the key question is whether the formulation can sustain the dissolved concentration long enough for absorption and whether the solid form will remain stable through manufacturing, storage, and shelf life.

• Does the approach match the BCS class? A dissolution rate strategy (Lever 3) may be sufficient for Class II but inadequate for Class IV. A supersaturation strategy (Lever 2) may work for both, but only if the resulting concentration exceeds the permeability threshold for the Class IV compound.

The goal is not to find the approach that produces the largest solubility number in screening. It is to find the one where the type of improvement matches the type of limitation, and where the improvement can be maintained reliably through development.

References

1. 1. Dahan A, Miller JM, Amidon GL. Prediction of solubility and permeability class membership: provisional BCS classification of the world’s top oral drugs. AAPS J. 2009;11(4):740–746.

2. 2. Shah N, Iyer RM, Mair HJ, et al. Improved human bioavailability of vemurafenib, a practically insoluble drug, using an amorphous polymer-stabilized solid dispersion prepared by a solvent-controlled coprecipitation process. J Pharm Sci. 2013;102(3):967–981.

3. 3. Bauer J, Spanton S, Henry R, et al. Ritonavir: an extraordinary example of conformational polymorphism. Pharm Res. 2001;18(6):859–866.

4. 4. Chemburkar SR, Bauer J, Deming K, et al. Dealing with the impact of ritonavir polymorphs on the late stages of bulk drug process development. Org Process Res Dev. 2000;4(5):413–417.