Pharmaceutical Outsourcing Q3 2023 - 28

CONTRACT MANUFACTURING
The Power of Solubilization -
How CDMOs Help Low Solubility
Drug Candidates Reach Their
Full Potential
Dr. Robert W. Lee
President
Lubrizol Life Science Health - CDMO Division
Water solubility is a key factor in determining the extent of a drug
molecule's therapeutic effect. There is a clear relationship between
poor water solubility and bioavailability, as drug uptake may be
variable and insufficient to provide the desired therapeutic effect.1
However, the molecular targets that exhibit physiological responses
are often receptive to hydrophobic molecules, as they can
cross membranes and fit into target active sites - leading to the
development of active pharmaceutical ingredients (APIs) with poor
water solubility. It is estimated that approximately 40% of existing
market drugs and 90% of newly developed APIs suffer from poor
water solubility.2
Historically, potential drug candidates were discarded in the
early stages of drug development if they exhibited poor water
solubility, giving rise to an increase in water soluble APIs with poor
pharmacokinetic properties. But today, there exist a variety of
techniques to enhance molecules with poor water solubility, allowing
developers to create more efficacious medicines with improved
delivery routes. This ultimately brings substantial benefits to patients,
not only by accelerating the development of new treatments, but also
enabling patient-centric dose forms including less invasive delivery
routes such as oral and topical delivery, as well as benefits like smaller
tablet size. These solutions are however not without challenge, and
developers must navigate the complexity faced in their design,
implementation and scale up.
Solubility Enhancement Techniques -
A Breakdown
Drug developers and formulators can employ several techniques
to increase the uptake of APIs with poor water solubility. These
can be specific drug delivery systems, excipients, or size reduction
techniques, to help increase the bioavailability of the API.
Size reduction techniques, such as nanomilling, can increase the
drug particles rate of dissolution. By reducing particle size using
mechanical energy to form nanosuspensions, the exposed surface
area of the API is increased, allowing greater interaction with water.
These suspensions ultimately result in the drug particles dissolving
more quickly. Nanomilling is widely used as a method of solubility
enhancement for APIs as it is a highly scalable and reproducible
process with a proven track record, which is highly compatible with
most dosage forms.
In amorphous solid dispersions (ASDs), the solubility of the drug
substance is improved by disarranging its crystalline lattice to produce
a higher energy state in amorphous form. ASDs require less energy for
dissolution, therefore overcoming solubility barriers and providing
increased uptake at the target site via a higher concentration gradient
compared to its crystalline counterpart.
Inclusion complexes and novel excipients can also be used to enhance
the uptake of a low-solubility API. In an aqueous environment, the
Pharmaceutical Outsourcing | 28 | July/August/September 2023
Pharmaceutical Outsourcing Q3 2023

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