PHARMACEUTICALS
Another trend has been a growth in the number of products on an accelerated development pathway, typically due to the needs of a particular patient group being unmet by current therapeutics. This accelerated trajectory poses a burden on those planning for success because a significant amount of data relating to manufacture, stability, solid form landscape and formulation are required early in the development timeline to support safe and rapid progression.
For these projects a well-integrated and iterative development pathway is required. This is particularly the case in the field of pre-formulation and solid form development, which remains a challenging yet critical part of the development process.
Challenging small molecule development
Despite advances in the science of drug design, an increasing number of small molecules enter development facing challenges to their progress. These most commonly manifest as sub-optimal physicochemical characteristics, particularly inadequate or very low solubility and poor permeability.
The effort involved in maintaining an appropriate level of efficacy for molecules that demonstrate such issues can be significant and remains a constant battle for those involved in the production and manufacture of the API and drug product.
At least 70 % of new chemical entities( NCEs) fall within the BCS Class II category, those with very poor solubility, but manageable permeability( Figure 1). 4 It will be interesting to track how AI and ML impact upon these figures and reflect upon their ability to improve lead optimisation over the next five to ten years.
Pre-formulation for challenging molecules
Effective pre-formulation is vital and more so for compounds that sit within BCS Class II / IV. Having a well-
Category Solid Form Screening
Bulk Powder Properties
Solubility and Performance
Critical Stability Studies
Table 1 – Selection of essential pre-formulation studies
characterised batch, solubility data and a pH solubility profile in aqueous, biorelevant and common formulation solvent and excipients can make the choice of development candidate less of a challenge for very little material cost.
Butler and Dressman derived an extension of the BCS termed the Developability Classification System( DCS) to better enable development choices. 5 Figure 2 illustrates this system for oral immediate-release compounds and addresses the question of via the dose-solubility ratio, whether solubility, dissolution rate, and / or permeability would limit the oral absorption of a drug and at what particle size dissolution rate is absorption limiting.
It can be used to help identify the critical quality attributes( CQAs) of the drug substance for a preferred route of formulation. These CQAs will be the target deliverables from the integrated solid form and chemical development process to feed into formulation. 5 From the perspective of those active within development, CDMO or Big Pharma, partnerships between internal working groups and / or the customer are essential.
Preformulation Elements- Salt versions- Polymorphism- Developable solvates or hydrates- Amorphous developability- Cocrystal versions- Crystal morphology- Particle size- Surface properties- Hygroscopicity- Flowability- pKa and pH solubility- Log P( partition coefficient) and Log D- Solubility- Biorelevant solubility- Dissolution kinetics- Solid state stability- Solution phase stability- Inclusive of mechanical, process, chemical stress- Excipient compatibility( inclusive of the above)
The basis for robust preformulation requires a strategy and investigation that should consider the critical elements listed in Table 1. This process is iterative and wellintegrated development is preferred, with the understanding that all parts will not be in place until key decisions, such as version selection, have been made.
One of the primary routes to enhancing solubility and performance is to produce a viable salt. The Handbook of Pharmaceutical Salts neatly defines that the selection of an optimal salt form for a novel drug candidate is an opportunity to modulate its characteristics to improve dissolution rate, bioavailability, stability, manufacturability, and patient compliance. 6
Not all molecules can form salts, due to their structure, the lack of an ionisable atom or inappropriate delta pKa values. Size reduction via a process such as jet milling is another common approach to impact upon dissolution rate, producing particles within a specific size range e. g. Dv90 5-10 micron and a uniform distribution curve. Figure 3 gives a
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