Strategies of solubility enhancement and perspectives in solubility measurements of pharmaceutical compounds
Special issue guest edited by Christel Bergström and Antonio Llinas
About two-thirds of the compounds in the drug discovery pipeline are very poorly soluble in water posting tremendous challenges in development. Poor solubility could lead to many pharmacokinetic problems, such as incomplete absorption following oral administration, poor bioavailability for both oral and inhaled drugs, fed/fasting effects and difficulties to establish the maximum tolerated dose.
For many low soluble drugs, the rate-limiting step in absorption is often dictated by the kinetics of dissolution of the active pharmaceutical ingredient from the solid form. The dissolution rate is a function of a number of factors, foremost being the aqueous solubility of the drug, which, for ionizable molecules, can be affected by the pH of the medium. Also, depending on the drug that has been introduced, the dissolution may overshoot the saturation concentration and produce a supersaturated solution. The supersaturation is typically achieved when the API is introduced in its amorphous form or in a charged form as a salt. In such a supersaturated solution, drug molecules may self-associate as sub-micellar aggregates/clusters, particularly if they are surface-active or polarizable. In the case of inhaled drugs the composition of the lung fluid, where the drug lands after inhalation, plays a critical role on the rate and extent of the solubility and dissolution rate and hence on the absorption and lung PK profiles.
To increase solubility, oral drugs are often formulated as salts. However, there are numerous other strategies which have been successfully implemented such as cocrystals, nano-formulations, solid dispersions, self-emulsifying systems, to name just a few. Lately with the increased focus of the biopharmaceutical industry on developing drugs bRoF (Beyond Rule of five) or “new modalities” the delivery landscape has become even more exciting and complex, and what was previously considered difficult or even impossible has now become a reality with new and creative approaches.
This special issue of ADMET and DMPK is guest edited by Christel Bergström, Uppsala University, Sweden and Antonio Llinas, AstraZeneca, Sweden. It will critically address solubility methods, strategies for the solubility improvement and the different needs in pharmaceutical research, spanning from drug discovery to drug development. Both, oral and inhaled drugs will be covered. The topics of the special issue include but are not limited to:
- Novel strategies for improving the solubility of drug compounds,
- Solubility determination challenges and measurement methods
- Interpretation of solubility data,
- The importance of solid-state characterization in solubility measurements
- Solubility prediction and in silico models
- Dissolution testing of oral and inhaled drugs
- Formulations of the poorly soluble drugs.
The special issue is planned for June 2020. The deadline for manuscript submission is May 01, 2020. During article submission please select “Solubility special issue” as a section.
1. C. A.S. Bergström and A. Avdeef. Perspectives in solubility measurement and interpretation. ADMET and DMPK 7(2) (2019) 88-115.
2. C.A.S. Bergström, R. Holm, S.A. Jørgensen, S.B.E. Andersson, P. Artursson, S. Beato, A. Borde, K. Box, M. Brewster, J. Dressman, K.-I. Feng, G. Halbert, E. Kostewicz, M. McAllister, U. Muenster, J. Thinnes, R. Taylor, A. Mullertz. Early pharmaceutical profiling to predict oral drug absorption: Current status and unmet needs. Eur. J. Pharm. Sci. 57 (2014) 173-199.
3. A. Avdeef, E. Fuguet, A. Llinàs, C. Ràfols, E. Bosch, G. Völgyi, T. Verbić, E. Boldyreva, K. Takács-Novák. Equilibrium solubility measurement of ionizable drugs – consensus recommendations for improving data quality. ADMET & DMPK 4 (2016) 117-178.
4. C.A. Lipinski, F. Lombardo, B.W. Dominy, P.J. Feeney. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Delivery Rev. 23 (1997) 3-25.