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Submitted by: Bruce Rehlaender, Ph.D.

Background

Many new drug molecules have solubility problems with some having almost no aqueous solubility. This creates formulation development issues since many standard formulation techniques may not be successful in delivering a drug orally. A common approach to improving oral delivery is to use the amorphous form of an active pharmaceutical ingredient. The amorphous form will have higher apparent solubility compared to its crystalline counterpart. This improvement in apparent solubility can be a strategy to increase oral absorption and bioavailability when in-vivo dissolution is the rate-limiting step. In general, the increased surface area exposure of the amorphous form can decrease time for drug to solvate and be absorbed.

Benefits

The key benefit of the higher apparent solubility is a faster dissolution rate which may lead to higher bioavailability when poorly water soluble drugs can be enhanced with this technique. The higher dissolution can also improve exposure with a more rapid onset and some cases allow a lower dose than needed for a crystalline form of the drug.

Downsides

The major disadvantage of using an amorphous form is their enhanced properties are offset by the decreased physical and chemical stability relative to the crystalline form. Amorphous solids are metastable and may recrystallize during storage,. Another limitation occurs during dissolution where trace amounts of crystalline drug may act as nucleating agents when the drug is introduced to aqueous media. Another issue is when an amorphous solid is undergoing dissolution. The supersaturated solution generated in the dissolution media around this solid is thermodynamically metastable or unstable and may undergo a phase transformation to a lower free energy state. At supersaturation there will be a thermodynamic driving force for crystallization from solution to a more stable crystalline form. If this phase transition takes place rapidly, the actual supersaturation will be much lower than expected and the benefits of the amorphous form will be lost.

Techniques

A common technique to stabilize an amorphous form in solid state and to protect from phase transition during dissolution is to formulate the drug as a solid dispersion. This formulation is a mixture of the API in the amorphous form with a solid dispersion with a second component, such as a polymer. The stabilizing of amorphous APIs has been attributed to an antiplasticization effect since solid dispersions typically possess higher glass transition temperatures than the pure amorphous drug thus resulting in a lower molecular mobility that prevents phase transition. The stability may also be due to formation of specific drug-polymer interactions such as hydrogen bonds.

There are many cases where the addition of a polymer significantly delayed the onset of crystallization in the solid state. This physical stabilization has been attributed to several factors, such as reduction in molecular mobility, reduction in the thermodynamic driving force for crystallization, increase in the energy barrier for crystallization, disruption of molecular recognition necessary for drug crystallization, or a combination of these factors. Regardless of the specific mechanism, drug polymer blends are more resistant to drug crystallization than the amorphous drug alone. Polymers that are commonly used to stabilize the amorphous state during storage include HPMC, HPMCAS, HPMCP, CAP, Eudragit and Povidone.

An approach is to use an amorphous dispersion where there is an intimate mixture of a drug and a polymer in which the polymer disperses the drug and helps to maintain it in an amorphous form. In this system the drug is dispersed on a molecular level and its release is controlled by erosion of the polymer framework rather than by the dissolution of the drug. This can provide a dissolution pattern that is an independent mechanism of controlled release.

The formulation development team has a number of techniques available to stabilize amorphous drugs with polymers. In a dispersion processes, the API and polymer are heated until they melt or a molten drug or dissolved in a molten polymer. The melt is then extruded, cooled and milled. In a spray drying process, a solution of the drug and polymer in a common solvent is sprayed and dried thus forming a highly concentrated drug/polymer gel also known as a solid solution. The hot melt extrusion has gained popularity for preparing solid dispersion due to many advantages, such as free of solvents, simple procedures and uniform product quality. Co-crystallization is another solid state approach which improves the apparent solubility of the without compromising its structural integrity and bioactivity.

Conclusion

In the formulation development of poorly soluble compounds, forming and stabilizing the amorphous drug has become an important approach when attempting to produce a drug product that will perform consistently over time. These formulations can maintain the performance benefit of an amorphous form while preventing phase transitions during storage thus allowing for the development of viable pharmaceutical products containing a poorly soluble drug.

Look for more articles like this one by searching for “PharmaDirections Formulation Development Blog”.

About the Author: Bruce Rehlaender, Ph.D., Principal, Formulation Development at

PharmaDirections

, a pharmaceutical consulting and project management company specializing in

preclinical development

,

CMC

and

regulatory affairs

. We design and direct preclinical programs for biotech firms.

Source:

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