What an amorphous solid dispersion is

Why a drug needs help to dissolve

A drug has to be dissolved before it can cross the intestinal membrane, and many drugs are poorly soluble in water. In a crystal the molecules are held in a regular lattice, and the solution in contact with that crystal reaches only the crystalline solubility. If that level is too low, little drug is available for absorption.

An amorphous form has no lattice and a higher free energy than the crystal, so its solubility is higher. The factor between the two was measured as 63.6 for atazanavir, 28.5 for telaprevir, about 600 for pazopanib and 2.5–5.9 for ibuprofen.

The amorphous form is metastable and may crystallize during storage or dissolution. Dispersing it in a polymer is the way to slow that: the polymer has to be in the same amorphous phase as the drug to be effective, which a physical mixture is not. Polymers used often in these papers are PVP, PVPVA, HPMC and HPMCAS. The dispersions are made by dissolving drug and polymer in a common solvent and removing it, as in rotary evaporation and spray drying, or by melt extrusion.

Evidence amorphous solid dispersion · amorphous solubility advantage · taylor1997 C1, C2; kestur2010a C2; rumondor2009a C3; indulkar2017a R4, R6; lu2017b R2, R1; sugihara2018 R4; ueda2022 R16

What it does in solution

Three concentrations of dissolved drug explain most of what a dispersion does.

• Crystalline solubility: the level the solution holds in contact with crystals.
• Supersaturation: any concentration above the crystalline solubility. This is what a dispersion produces.
• Amorphous solubility: the highest supersaturation a solution can hold without crystals. Past it the solution splits into a water-rich phase and a drug-rich phase, a process called liquid–liquid phase separation (LLPS).

Above the amorphous solubility, added drug only makes more drug-rich phase. The free drug and the flux across a membrane stop rising. For telaprevir, dissolved drug levelled at about 81–90 µg/mL beyond about 92 µg/mL added; flux rose linearly to about 0.97 µg/min at 90 µg/mL and reached only about 1.07 µg/min at 130 µg/mL.

A formulation therefore aims to reach the amorphous solubility quickly and to hold it until the dose is absorbed. It loses that benefit if crystals form: the solution then falls towards the crystalline solubility.

Evidence supersaturation · amorphous solubility · C. Amorphous solubility and LLPS F8 · Taylor and Zhang 2016, step 10 · mosqueragiraldo2015 R10, R12

Does it work in an animal?

In rats, enzalutamide dispersions that reached the amorphous solubility gave several times the exposure of the crystalline drug. One dispersion crystallized and gave less than the crystals. This is one drug with three to six animals per arm.

Evidence Overview F1 · wilson2018 R16, R17, R18, R6, C47

Three ways it can fail

1. It crystallizes in storage. Water taken up from the air can split a mixed dispersion into drug-rich and polymer-rich amorphous phases. At 94% RH, drug–PVP dispersions that separated showed crystals after 22 h to 6 days, and those that stayed mixed after 46 and 125 days.

2. It does not release the drug. Above a limiting drug loading, called the limit of congruency, the polymer leaves first and a drug-rich layer remains. Ritonavir–PVPVA tablets released ≈97% of their drug in 60 min at 25% loading, ≈29% at 30% and at most ≈2% at 35–50%.

3. It crystallizes on wetting or in solution. Crystals already present remove most of the protection from a polymer. A posaconazole–HPMCAS extrudate with 0.3% crystals fell to about 18.5 µg/mL by 150 min after a pH shift, while the crystal-free one held about 125 µg/mL at 300 min. A dispersion can also crystallize inside its own wetted solid: a crystal-free bicalutamide–PVPVA extrudate never exceeded about 38–40 µg/mL against an amorphous solubility of 150 µg/mL.

Evidence Solid state stability F8 · Dissolution F7 · Overview F6 · Overview F10 · rumondor2009c R7, R9, R12, R14, R16; indulkar2019a R11, C2, C31; shah2024 R12, R14; moseson2021 R12, R13, R14, R17, R18, R19, R25

What a formulator chooses

• The polymer. No polymer was best at every stage. PVP and PVPVA released fastest at low loading, while HPMCAS stayed congruent to higher loading and often inhibited crystallization longer.
• The drug loading. Storage, release and absorption each have a loading threshold, and these thresholds are different quantities. They need not coincide for one drug and polymer.
• The conditions of testing. Near the amorphous solubility total drug misleads, so free drug or flux has to be read. Whether a sample counts as amorphous depends on the method that looked.

Evidence Overview F11 · Overview F8 · Overview F3 · Overview F7 · saboo2020a R15, R14, C55; tian2016 R17; jackson2015 R2, R9; moseson2021 R17

How far this page can be trusted

Every statement comes from a paper in this wiki: 207 research papers from one group. The library holds exposure data for three drugs in animals and none for a dispersion in humans. Manufacture at scale is not covered here.

Evidence Overview: scope · Overview F14