Quality by design
PharmTech: Quality by design (QbD) is an overarching consideration in drug development. With respect to solubility enhancement, what
are the critical quality attributes and/or critical process parameters important in excipient selection?
Morgen (Bend Research): Recently, pharmaceutical companies, excipient providers, and CRDMOs (contract research/development/manufacturing organizations)
have launched significant initiatives to bring QbD principles to the selection and design of the polymer, the formulation,
and the process space. With respect to the polymer, critical quality attributes might include molecular-weight distribution
and chemistry attributes, such as the ratio and sequence of different monomeric units and/or the number and substitution pattern
of hydrophobic groups on the polymer backbone. There are instances in which relatively small differences in chemistry can
significantly affect the performance of the polymer and the formulation. In some cases, the impurity profile of the polymer
can also be critical to the performance.
Typically, a number of critical parameters on the process side will influence the choice of excipients. Depending on the process,
solvents, and solution temperatures may be selected based on solubility of API or its compatibility with the solvent, which
can in turn influence the choice of the polymer. Likewise, process- time–temperature profiles can be critical process parameters,
particularly for the choice of HME excipients, to ensure adequate mixing for complete dispersal and dissolution of the API
into the heated polymer matrix if a solid solution is desired.
Koblinski (Dow): Selecting the right excipient with control of the critical quality attributes is crucial to a robust formulation. A QbD approach
to drug development helps the final drug product to have the desired therapeutic effect on a consistent basis. In solubility
enhancement, excipients play the role of stabilizing the drug and keeping it in the desired state to achieve the maximum drug
release and concentration sustainment. A QbD study with an excipient, for example HPMCAS, will look at characteristics of
the polymer, such as acetyl and succinyl substitution using a design of experiment study to cover the experimental space to
find the enhanced substitution levels for solubilization of the specific drug. Through studies done at Dow, we have found
some drugs, such as phenytoin, are very sensitive to changes in polymer substitution levels and, therefore, require tight
control around the enhanced values for consistent performance. Other less sensitive drugs can tolerate a wider range of substitution
values while maintaining performance. A QbD program, in cooperation with the excipient manufacturer, can help formulators
develop a robust and therapeutically efficient drug product.
Asgarzadeh (Evonik): When selecting excipients for solubility enhancement, excipient physicochemical properties such as morphological characteristics,
aqueous/pH solubility, molecular weight, crystalline structure, porosity, density, and viscosity are amongst the critical
quality attributes (CQAs) that should be evaluated. The impact of selected CQAs based upon the risk-assessment survey on the
properties of the final product should be studied and well understood. Excipients in a solubility-enhanced formulation should
not be considered as fillers or part of the binding matrix anymore because they contribute to the performance of API that
otherwise does not have any absorption and bioavailability. The critical process parameters (CPPs) are process specific attributes.
For solubility-enhancement applications, melt extrusion and spray drying are the most commonly used technologies. The CPPs
for melt extrusion are the screw speed, extrusion temperature, feed rate, glass-transition temperature of the drug-polymer
mixture, and melt viscosity. For spray drying however, parameters such as spray rate, percent solids content, size, and scale
of the spray dryer, nozzle size and temperature in the expansion chamber should be considered.