How can a long-acting injectable release its drug predictably?
Process engineering for a slow-release microsphere medicine at Dr. Reddy's: sizing the particles, checking the mixing, controlling coacervation and removing solvent at scale.
Key findings
- If the drug diffuses four times more slowly, full release stretches from 30 to about 120 days
- The existing 11.12 kW motor is enough once baffles are fitted
- About 11,300 litres of silicone oil to extract 136 kg of solvent
An independent proposal, written in response to a competition brief. The organisation it addresses did not commission this work, and we do not suggest it has acted on our recommendations.
The challenge
Long-acting injectables use tiny polymer microspheres that release a drug slowly over weeks. Getting that release right depends on particle size and shape, on mixing, on pH and on how the solvent is removed. The finals brief set four process problems on these points.
Our approach
We modelled drug release from spherical microspheres with Fick's second law, solved as a series, and compared it with the simpler Higuchi model. We set out the process parameters that matter (polymer concentration of 15–20%, aqueous-to-organic phase ratio of 2.5–3.5, quench volume of 20–30 mL) and the quality targets (particles of 47–52 µm, 83–87% of the drug captured, 1–3% initial burst). For mixing we worked from Reynolds and Froude numbers and power-number curves; for solvent removal, from mass balances and how much solvent silicone oil can take up.
How we found the answer
The Higuchi model only holds early in release, while the concentration gradient is high, so we used the full diffusion solution to size particles for a steady daily release. Shape matters as much as size: irregular particles have more surface, release faster and give a bigger initial burst, so spherical particles give the controlled profile the product needs.
A Box-Behnken experimental design of 17 runs maps how each process variable moves the quality targets.
What we proposed
- Size the microspheres for the target daily release, and keep them spherical to limit the initial burst.
- If diffusivity falls to a quarter, plan for full release in about 120 days instead of 30.
- Keep the 11.12 kW motor sized for the unbaffled tank: with four baffles the power needed falls and mixing improves.
- A pH-controlled experiment in liposomes (pH 4 to 9, tracked by fluorescence) to study how stable the coacervates are, with uses in targeted and multi-drug delivery.
- Extract about 136 kg of dichloromethane with about 11,300 litres of silicone oil to take the polymer solution from 6% to 65%, controlling temperature, addition rate and agitation.
- Manage the solvent risks with closed-loop solvent recovery, scrubbed ventilation, fluoropolymer coatings and written operating procedures.
Potential impact
The work gives a modelling and experimental framework for tuning a controlled-release formulation. Its numbers are design calculations, and the formulation would need lab validation before its performance could be established.
Modelled in our analysis. These are estimates, not results measured in operation.
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