Pharmaceutical formulation is often overlooked in its criticality for delivering therapeutic dosages of medicines to the public. Because there are so many different formulation types, it’s not simply an exercise in deploying a New Molecular Entity (NME) into a “standard” payload of excipients for final dosing to the patient, but instead is a multivariate problem to be solved with each new drug that enters clinical trials.

More traditional formulations include tablets and capsules, though even they have great differentiation now for greater uptake and patient adherence (morphology of the dosage form) as well as variable-disintegration characteristics (overcoating, multi-layer, etc.) to allow for more advanced and targeted dosing to the consumer. Along the modernization of this spectrum, there are more patient-centric, or “patient-friendly,” dosing forms, such as oral disintegrating forms (including films), oral suspensions, injections, transdermals, etc. There has also been great development in personalized dose approaches based on individual needs of the patient, and formulation has played an enormous role in their broad acceptance and applicability.

Formulation Design and Quality Control

Over the decades, we’ve also seen paradigm shifts from empirical design, trial-and-error experiments, and Quality by Test (QbT) migrating to Design of Experiments (DoE), Process Analytical Technologies (PAT), and Quality by Design (QbD) methodologies, which have provided much more scientifically rigorous and methodologically-sound approaches to approach formulation development. Newer approaches include digital design formulation, much greater reliance on modeling and simulation, and approaches involving (of course) Big Data and Artificial Intelligence (AI) and Machine Learning (ML).

Of course, the more we offload the statistical “heavy lifting” to computing technologies, the more algorithmic opacity becomes a salient topic, so that we can justify the models used for promoting newer formulation designs.

But formulation is never a “one-and-done” endeavor; there are formulations (often differing) through clinical trials, for different dosages, and routes of administration. For this reason, formulation is often considered the “alchemy of pharmaceuticals,” but not meant to be a pejorative—instead to call attention to the fact that it takes a multidisciplinary and multi-factored approach to handle an incredible number of competitive characteristics for each drug’s design.

Pharmaceutical Manufacturing and Formulation

Likewise, formulation development and advancement has brought with it paradigm shifts in manufacturing approaches, from large-scale batch manufacturing with traditional unit operations, to continuous processes, emerging unit operations, and flow API synthesis. This has led to advances in on-demand manufacturing, additive manufacturing approaches, and even more advanced pharmacy compounding. Personalized medicine is, at the same time, harnessing the promise of some of these nimbler manufacturing efforts to radically approach the treatment and chain of custody of patient samples, biobanking, and discrete manufacturing techniques.

Formulation must keep in mind consistency (i.e., lack of variability) from dose-to-dose (one tablet to the next, etc.), as well as particle size, pH, dose range, polymorphism, availability, and solubility in aqueous solutions and lipids and so on. Of course, the manufacturing itself is done with an additional end goal in mind, and that is what the final form and packaging will be, so that interactions between the drug and container (blister pack, bottle, vial, pre-filled syringe, etc.) is assessed and found to be appropriate.

The End Patient

Pharmaceutical formulation is always strictly controlled and is a superlatively critical part of the final resulting dosage form for drugs intended for (or which have garnered) regulatory approval. The route of administration of a drug has direct and profound effects on the pharmacokinetics and pharmacodynamics in the human body. In fact, consistency in bioavailability is necessarily and intricately related to dissolution characteristics and solubility of the matrix of the dose of medicine.

When the public picks up an OTC formulation, or a prescription for a medicine, the above attributes couldn’t be further from their minds—and that’s probably a good thing. We know that the science of formulation works, and the regulatory pathway that medicines flow through ensure that safe, effective, and consistent dosages make it to the patient-consumer. If formulation goes awry, it’s generally easy to assess that something has occurred, but the fact that so many medicines exist without wholesale issues stemming from formulation problems is testament to the absolute expertise that formulation as a discipline has empirically manifested.