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Oral Solid Dosage Forms: Science Inside! (Part 1)

Corden Connect Newsletter
29 Oct 24
Markus von Raumer, Preformulation & Galenical Development Scientific Expert, CordenPharma International

White medical pills or tablets with bottle on black background. Macro side view with copy space. [CordenPharma Photo] Oral Solid Dosage is the most preferred and abundant dosage form.

Understanding oral absorption and the desired exposure profile is key for designing the optimal Oral Solid Dosage (OSD) form

From the outside, any tablet / capsule just looks like any other tablet / capsule, small and convenient. Perceived differences are generally color, size, and shape. So apparently it should also be easy to make them – just mix the drug substance with some other powders and compress the blend into tablets. This is a very simplistic view because, in fact, OSDs are carefully designed requiring a variety of scientific concepts from various disciplines to develop and manufacture high-quality OSDs. It starts with the route of administration – once a tablet is swallowed its fate is similar to anything we ingest that gets exposed to the gastrointestinal (GI) environment. Residence time in the stomach and the (small and large) intestine, as well as the composition, properties, and volume of the GI content will depend mainly on the fasted / fed state, age, possible co-medications and disease state of the ingesting persons. For a drug to be absorbed it needs to be present at the right place and in the right amount in the solubilized state. Once solubilized, it still needs to cross the gut wall to reach the blood circulation system. In short, solubility (how much drug can be solubilized in aqueous media), dissolution (how fast a drug dissolves), and permeability (how fast a molecule crosses the relevant membrane) are key factors for oral absorption.

Solubility: How soluble is good enough?

When contemplating solubility, which is an equilibrium state between the solid-state form and the surrounding medium, the most pertinent of the many questions that arise is, what solubility is required for a given dose to be absorbed? The developability classification concept helps to classify molecules according to the dose, the solubility in fasted-state-simulated intestinal fluid, and their permeability. A large fraction of new molecules falls in the region where the solubility of the contemplated material is not sufficient, and the absorption is limited by solubility. Luckily, this is not the end of the story, as there are strategies to address insufficient solubility! The solubilized fraction of a material can be strongly influenced by the solid-state form of the drug substance, e.g., is it a free form or a multicomponent form (salts and co-crystals)? Is it crystalline or amorphous?

Understanding the pH dependent biorelevant solubility profile of crystalline species, be it as free form or as multicomponent crystals, including the apparent solubility of the amorphous, leads to an understanding of the relevant solid phases that will ultimately define the overall achievable solubilization. Any solubility value reached that is above the solubility of the most thermodynamically stable state at the considered condition is called “supersaturated”. Such a supersaturated state is metastable and can relax to the solubility of the most stable crystalline state. This entire concept is referred to as the spring-and-parachute principle and is the underpinning for the scientific rationale behind any bioavailability enhancement approach for OSD via the solid-state form or as an Amorphous Solid Dispersion (ASD).

Solubility Limited Absorption: Addressing the solid-state form

The simplest and most cost-efficient way of addressing insufficient solubility of a free form material is to search for alternative multicomponent solid-state forms like salts and co-crystals, which have the big advantage that conventional immediate release drug products can be designed using standard and widely used technologies. CordenPharma’s Solid State Centre of Excellence has established an efficient process to search for new salts and co-crystals. With a focus on pharmaceutical developability, new solid-state forms are characterized to identify optimal candidates for developing safe and efficacious OSD type formulations.

[CordenPharma Photo] Micrograph under crossed polars of a crystalline material
after hot stage microscopic experimentation.

Solubility Limited Absorption: Addressing the formulation technology

If no suitable multi-component crystal can be identified, or if the supersaturated state from salts or co-crystals is only of a very short nature, an enabling formulation approach is generally recommended. On multiple occasions, ASDs have demonstrated that performant formulations of otherwise not solubilized drug substances are achievable. The underlying idea is to solubilize the drug in a polymer to deliver a polymer-drug solid solution, with the polymer acting as a solid solution carrier and nucleation inhibitor once in the GI tract.

CordenPharma’s oral Drug Product Innovation Centre of Excellence has established an efficient small-scale and API-sparing process to screen for the best molecule-polymer combination and ratio. Once identified, such drug product intermediates are either made by spray drying or by hot melt extrusion, then further used to enter OSD development with pharmaceutical developability in mind.

[CordenPharma Photo] Feeding the hot melt extruder with an API/polymer blend to produce
an ASD for further performance testing.

Biopharmaceutics as Part of Developability Assessment: A holistic view on drug development

Developability assessments for OSD drug products consist of several aspects. In addition to reaching an acceptable shelf life, it needs to be manufacturable at scale without significant quality challenges, meet regulatory standards using accepted excipients and technologies, and perform in humans as expected. The latter requirement is covered by the biopharmaceutic assessment. Biopharmaceutics can be defined as the study of how the physicochemical properties of a drug (molecule and material, i.e., the drug substance), the dosage form (medicine, i.e., the drug product), and the route of administration affect the rate and extent of drug absorption. 

Most importantly, this is not only applicable for early phase and First In Human studies, but also applies to reformulations, or technical changes while advancing the clinical studies towards a marketed product. Generally bioequivalent formulation options are required, and the understanding of what biopharmaceutic factors are responsible to reach the desired exposure in the human body helps to design robust and scalable formulations and processes.

[CordenPharma Graphic]: A holistic view on developability combining
drug substance and drug product aspects

CordenPharma is your partner of choice for OSD formulation development and manufacturing

We can accompany you for the entire lifecycle of your products, from early-phase development, clinical supplies, late-stage registration and validation to commercial manufacturing and packaging. Additionally, we can handle APIs with OELs down to the picogram per cubic meter level.

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Get in touch with our team of experts to explore bespoke end-to-end CDMO support of your complete drug lifecycle
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