✕
☰

Maximising limited drug substance to developing optimised formulations

Lisa Caralli, Science and Technology director, Pharmaceutics, Catalent, discusses the methods that formulation scientists can undertake on small quantities of API to achieve the greatest possible results to progress through drug product development.

Key insights:

At the beginning of an oral drug delivery development programme, it is not uncommon for the quantity of active pharmaceutical ingredient (API) available to formulation scientists to be limited, which can make it difficult to gather sufficient meaningful data to select the most promising candidates to advance into in vivo studies.

Any formulation ultimately progressed through to clinical studies must demonstrate adequate and consistent drug-to- patient exposure, to collect high quality data. Through an iterative process, numerous prototypes during initial animal pharmacokinetic (PK) studies may be needed to determine the ideal formulation, requiring multiple formulation adjustments that not only take time, but also use greater quantities of API material.

Using in silico modelling, that can predict a compound’s absorption, distribution, metabolism and excretion (ADME) parameters using the molecular structure gives initial information to act as a starting point for formulation studies, and optimise API usage for in vivo studies. Data from these studies can then be fed back into the models to enhance and refine output.

Insights into metabolic susceptibility by human liver CYP450 enzymes can be gained by testing using liver microsomes and/or a hepatocyte cell line. Compound solubility in biorelevant media along with an estimation of the intestinal permeability from Caco-2 cells, provide data on oral absorption potential. The biorelevant solubility measurements and predicted permeability can be inputted into the Developability Classification System (DCS) to provide an estimate of oral formulation development risk, and guide formulation development.

The three key factors that determine oral API bioavailability are the molecule’s solubility, metabolism and permeability, and candidates that have the greatest potential to be orally delivered are inherently resistant to hepatic metabolism and/or display high permeability. Solubility is where formulators can be most impactful, and if enhancement is necessary, there are a number of in vitro techniques that can be used on limited quantities of API to ensure the correct formulation for further studies, including small volume dissolution, two-stage dissolution, liquid-liquid phase separation, polymer screening studies, film casting, crystallising tendency and flux measurements. Deciding upon the appropriate technique to use may depend on API availability, timescales, and enhancing technologies under evaluation.

Small volume dissolution

Small volume dissolution is useful where kinetic or equilibrium solubility is an issue, for example in micronised materials or amorphous solid dispersions (ASDs) of crystalline drugs. Experimental apparatus is commercially available, and uses small vessels, monitored using fibre optic probes with small amounts of API. The setup measures API concentrations every few seconds rather than minutes during typical full-scale dissolution experiments.

Two-stage dissolution

The API’s solubility can be very sensitive to pH and the nature of the dissolution media. In the acidic stomach, weakly basic APIs are typically very soluble, but when exposed to the higher pH in the small intestine, can precipitate. Two-stage dissolution experiments can be used to investigate the behaviour of the API during this pH shift. Ideally, an API will remain supersaturated in the small intestine for sufficient time to allow for absorption, but if precipitation occurs at a high pH, follow-up two-stage dissolution experiments should be conducted to screen for polymers that can maintain the API supersaturation following the pH shift.

Liquid-liquid phase separation and polymer screening studies

Liquid-liquid phase separation (LLPS) occurs when the concentration of the API exceeds its amorphous solubility, and is characterised by the formation of drug-rich colloidal species within a supersaturated aqueous solution of a poorly soluble API. The concentration at which LLPS occurs can be influenced by the biorelevant media used, and the presence/absence of polymers within it. Additional experiments are necessary to identify which polymers can successfully maintain supersaturation of the API, and will need to be incorporated into any final amorphous drug dispersion.

Small volume dissolution apparatus can only be used for polymer screening with small quantities of API, and additional experiments can investigate the optimal API-polymer ratio to provide an estimate of the drug loading feasibility for an ASD formulation. Figure 1. shows the theoretical dissolution behaviour of a poorly soluble compound as a crystalline drug, an amorphous drug and an ASD. The crystalline drug displays low solubility, whereas the amorphous drug shows peak solubility but quickly drops. The ASD achieves the spring seen with the amorphous drug, and helps maintain supersaturation in solution (parachute effect).

Figure 1: Spring and parachute concept to achieve high apparent solubility for insoluble drugs.

Film casting

Film casting also screens for suitable polymers, and estimates the drug loading for an ASD formulation and the physical stability of API-polymer mixtures. In a typical experiment, the API and potential polymer are dissolved in a solvent and an aliquot of the solution is added onto either a slide, or into wells of a 96-well plate where the solvent evaporates, leaving a film. Phase separation or API crystallisation of the film is then investigated using polarised light microscopy (PLM), differential scanning calorimetry and/or powder X-ray diffraction.

Crystallising tendency

PLM can also be used to study the crystallising tendency of an API, and this requires little API material. Molecules that exhibit a low crystallisation tendency are often good candidates for ASD formulation.

Small volume dissolution – flux measurements

In the small intestine, the jejunum is between the duodenum and the ileum. Permeability across a jejunal-like membrane can be studied by measuring the concentration of an API in solution across donor and acceptor compartments. The rate of flux across the membrane can be calculated, and although this does not predict tin vivo PK specifically, formulations can be ranked with respect to their expected in vivo performance. These studies are most useful when investigating complex lipid formulations, where movement across membranes may be more directly impacted by the formulation.

Maximising API resources

Time pressures and the amount of API available for early development programmes mean that formulation scientists need to capture as much data as possible with both careful planning and resource management. In silico tools are invaluable in guiding starting points for development, and advances in rapid experimental techniques that use little API material can mitigate these challenges and yield the information necessary to choose the most promising formulation candidates to move on to in vivo studies.

Back to topbutton