Drug Nanocrystals: Theoretical Background of Solubility Increase and Dissolution Rate Enhancement

Regardless of the administration route, the key factor for the success and reliability of any formulation is drug bioavailability, defined as the rate and extent at which the active drug is absorbed from a pharmaceutical form and becomes available at the site of drug action.1 Although metabolism and physiological factors highly affect drug absorption by living tissues, bioavailability is strongly dependent on drug permeability through cell membranes and on drug dissolution in physiological fluids. In particular, dissolution becomes the most important factor in terms of bioavailability for poorly water-soluble – highly permeable drugs (class II drugs according to the Amidon classification2). This aspect is of paramount importance if we know that, at present, about 40 % of the drugs being in the development pipelines are poorly soluble, up to 60 % of synthetized compounds are poorly soluble,3 and 70 % of the potential drug candidates are discarded due to low bioavailability related with poor solubility in water.4 Examples of commonly marketed drugs that are poorly soluble in water (less than 100 mg cm–3) include analgesics, cardiovasculars, hormones, antivirals, immune suppressants and antibiotics.5 Since it is well known that solubility increases with drug nanocrystal size decrease,5 this paper focuses on the theoretical relation existing between nanocrystal size, solubility and dissolution rate. To this end, a thermodynamic model relating to nanocrystal dimensions (radius), melting temperature/ enthalpy and solubility will be presented and discussed.