Published Jun 29, 2026

A high-drug-loading case study: how spray drying enabled bioavailability of a compound with 8 µg/mL solubility from 34% to 100%.

Yes — the oncology small molecule has 8 µg/mL solubility in FaSSIF and only 34% oral bioavailability for an API suspension. The Crystal Pharmatech team screened six spray-dried intermediates (SDIs) through three gateways — solubility, physical stability, and animal PK. HPMCAS was able to hold the API in an amorphous state at an ultra-high 67% drug loading (DL), while other ASD systems with similar kinetic solubility showed recrystallization at such DL. Thus, the 67% DL SDI was selected for IND tablet formulation development. The 200 mg FIH tablet formulation, with only a 750 mg tablet weight, achieved 100% relative bioavailability at 20 mg/kg in a dog PK study. 

Why High Dose, Not Solubility, Is the Hard Part?

Amorphous solid dispersion is the established route for solubility-limited absorption, and at 8 µg/mL it was the obvious choice. The harder problem is the dose. At a proposed 200–400 mg strength, the constraint shifts from “can we make it amorphous” to “can we make it amorphous at a drug loading that still fits in a swallowable tablet.”

Conventional spray-dried dispersions run modest loadings — often 15–40% API — because the polymer must keep the molecule amorphous and suppress recrystallization on storage [1]. The arithmetic is unforgiving: at 25% loading, a 200 mg dose means 800 mg of dispersion (or intermediate) before adding more excipients to formulate it into a tablet/capsule dosage form. In general, the ASD consists of no more than 40% of the overall composition, meaning that the tablet weight will be 2000 mg, which is impossible to swallow. Thus, the CFS team had only one choice — making the DL in the ASD as high as possible while achieving high bioavailability (>=34%). The following is our formulation development roadmap: 

The ASD Formulation Screening

Using film casting, six polymers and three surfactants at two DLs (35% and 67%) were screened for recrystallization (by XRPD) and kinetic solubility (in biorelevant media). Three ASD formulations with high kinetic solubility were selected for physical stability evaluation. Under accelerated storage (40 °C/75% RH closed with desiccant), two ASD formulations recrystallized, while only the HPMCAS system with 67% DL stayed fully amorphous under both open and closed conditions for eight weeks. A similar recrystallization inhibition effect by HPMCAS was also reported elsewhere [1][4].

Confirming the Pick in Vivo — What the Dog Study Showed

The in vitro biorelevant dissolution ranking does not reliably predict in vivo exposure: supersaturation is metastable, so the screen narrows the field, but PK decides it [3]. The 67% DL SDI was then dosed in beagle dogs at 20 mg/kg in both a normal capsule and an enteric-coated capsule form, along with a low-DL HPC SDI, against the crystalline API suspension.

The PK data show that the 67% SDI, both in normal and enteric-coated capsules, far outperformed the API suspension, demonstrating the strong enhancement by ASD technology. The enteric-coated SDI showed similarly low exposure as the API suspension, indicating that drug absorption is likely focused in the narrow upper GI region, while the enteric coating delayed capsule rupture and the release of the API from the ASD particles. The low-DL ASD exhibited slightly higher exposure than the 67% DL formulation; however, this cannot outweigh the high-DL, small-tablet-weight benefit.

From Intermediate to Tablet — Balancing Loading, Exposure, and Disintegration

With the 67% DL SDI selected, the tablet used 40% SDI and 60% excipients, giving a total tablet weight of just 750 mg for this 200 mg dose. The risk at a high SDI fraction is disintegration: HPMCAS gels in water and can slow it enough to blunt the absorption gain [4]. Balancing SDI loading against the disintegrant is critical to keep disintegration fast, ensuring fast drug release and reaching supersaturation in vivo.

The tablet formulation achieved 100% relative bioavailability at 20 mg/kg in a dog PK study (vs. 34% from the suspension). The IND was approved by the FDA, and the Phase I study is ongoing.

Common Questions on High-Dose ASDs

Can amorphous solid dispersion work for high-dose poorly soluble drugs (200–300 mg)?

Yes, it is possible. However, for certain ASD systems, the dissolution rate drops dramatically with the increase in DL, which could cause issues when trying high-DL ASD formulations. In our case, a high-loading SDI — say 67% API in HPMCAS — can carry a 200 mg dose in a sub-1 g tablet; here, a 200 mg, 750 mg tablet reached 100% relative bioavailability.

What drug loading is achievable in a spray-dried dispersion?

Conventional SDDs run ~15–40% API, but 50–67% is achievable for suitable API/polymer pairs. Higher loading reduces tablet weight but must be validated against both oral exposure and physical stability.

How do you enhance bioavailability without an oversized tablet?

Fix tablet weight as a ceiling first, then screen loading and polymer against PK exposure, not solubility alone — the highest-loading ASD could still possibly deliver target exposure. Here, 67% DL gave near-100% relative bioavailability in 750 mg.

Does the most soluble amorphous dispersion make the best formulation?

Not necessarily. The most soluble intermediates here — the surfactant-containing ones — recrystallized on storage. Solubility, stability, drug loading, and in vivo exposure are separate axes; the best formulation clears all of them.

What to Evaluate in Your Own High-Dose ASD Program

• Set the tablet-weight ceiling first. The ceiling divided by the dose sets the minimum drug loading you must achieve — decide it before screening.

• Screen drug loading against exposure, not only solubility. The highest-solubility option may not be the one carried forward; only PK separated the arms.

• Score stability and solubility together. The interplay of drug loading, kinetic solubility, and stability can be complex. Run open and closed XRPD stability alongside dissolution, and weight stability heavily for clinical programs.

• Choose polymer and loading in vivo. HPMCAS vs. HPC and enteric vs. non-enteric changed exposure materially at the same dose.

• Protect disintegration at high SDI fraction. Gelling polymers can slow it and erase the gain — design the tablet to keep disintegration fast.

• Build scale-up into the screen. A robust, well-characterized dispersion enabled one-attempt scale-up; one that screens well but scales poorly costs more than it saved.

  
  

How Crystal Pharmatech Can Help

Crystal Pharmatech develops high-drug-loading amorphous solid dispersions for poorly soluble, high-dose compounds where tablet size is a real constraint — spray drying and SDI development, PK-guided polymer and loading screening, First-in-Human tablet formulation, and clinical-batch GMP manufacturing, following the path this case took from 8 µg/mL to an IND-approved 750 mg tablet. For teams weighing whether an ASD can carry a 200–300 mg dose, we run the loading-versus-exposure screen that answers it with data.

References

1. Baghel S, Cathcart H, O'Reilly NJ. Polymeric amorphous solid dispersions: a review of amorphization, crystallization, stabilization, solid-state characterization, and aqueous solubilization of BCS class II drugs. J Pharm Sci. 2016;105(9):2527–2544. doi:10.1016/j.xphs.2015.10.008

2. Singh A, Van den Mooter G. Spray drying formulation of amorphous solid dispersions. Adv Drug Deliv Rev. 2016;100:27–50. doi:10.1016/j.addr.2015.12.010

3. Brouwers J, Brewster ME, Augustijns P. Supersaturating drug delivery systems: the answer to solubility-limited oral bioavailability? J Pharm Sci. 2009;98(8):2549–2572. doi:10.1002/jps.21650

4. Friesen DT, Shanker R, Crew M, Smithey DT, Curatolo WJ, Nightingale JAS. Hydroxypropyl methylcellulose acetate succinate-based spray-dried dispersions: an overview. Mol Pharm. 2008;5(6):1003–1019. doi:10.1021/mp8000793

5. Curatolo W, Nightingale JA, Herbig SM. Utility of HPMCAS for initiation and maintenance of drug supersaturation in the GI milieu. Pharm Res. 2009;26(6):1419–1431. doi:10.1007/s11095-009-9852-z