Purpose: Currently there are limited publications investigating the solubility of poorly water soluble drugs within a phospholipid carrier. A systematic method allowing identification of drug solubility in a range of lipids would therefore be extremely useful. A drug-lipid phase diagram constructed via the application of the Flory-Huggins theory can be used to predict solubility and miscibility between the components, it will prediction of maximum drug loading along with thermodynamic stability and providing the systematic method required.
Methods: Felodipine, Naproxen and Ketoconazole were selected as model drugs representing neutral, weak acidic and weak basic compounds while phosphatidylcholines of varying chain lengths were chosen as the lipid system HSPC (18/16), DMPC (18), DPPC (16) and DSPC (14). Initial screening was carried out on the three drugs in the lipid carriers at one ratio (70% drug: 30% lipid) to ascertain if chain length had any bearing on solubility. Differential Scanning Calorimetry (DSC) was used to investigate the impact of chain length on drug interaction in order to select one lipid for further studies. The physical mixtures of drug and lipid where first ball milled before DSC was used to measure the crystalline drug melting depression at a scanning rate of 5C/min. Following this study HSPC was selected for the lipid phase in construction of phase diagrams due to minimal differences between the drug interaction with varying lipid chain lengths and economic reasons. In order to produce a phase diagram analysis of depression in the drugs melting point, as the concentration of drug was reduced, first needed to be investigated. Drug was mixed with HSPC at differing ratios using the ball milling method described above. DSC was then used to analyse melting depression over the range of ratios at a rate of 5 C/min and from this data a Flory Huggins Interaction plot was derived. This allowed the interaction parameter to be calculated at any temperature using the equation of the line. The Flory-Huggins equation was then applied to the results and a phase diagram was able to be constructed.
Results: Initial screening showed chain length did not have a significant impact on drug solubility after reviewing the melting point depression data, HSPC was therefore chosen as the lipid phase for the completion of phase diagrams due to availability and cost. Following the chain length study the interaction parameter was calculated at each ratio of drug to lipid and used to predict the solubility at lower drug to lipid ratios which could not be investigated during the DSC melting depression study due to lack of sensitivity. A Flory Huggins interaction plot was constructed using the interaction parameters calculated and gave an early insight into drug-lipid interaction using the equation of the line where a more negative x value demonstrated a better interaction. From the data obtained in the Flory Huggins interaction plot, the Flory Huggins equation could be solved at any temperature, through use of the equation of the line, which allowed construction of a phase diagram by relating temperature to drug weigh fraction. The liquid-solid curve was calculated allowing prediction of drug solubility within the lipid carrier. Above the liquid solid line the drug will be soluble in the carrier and a single phase system while below the line crystallisation of the drug out of the lipid carrier is more favourable. Comparisons between the three drugs selected suggested a weak acidic drug to interact more favourably with phosphatidylcholines than the weak base or neutral drug, this can be seen when comparing the phase diagrams for each drug.
Conclusion: The construction of a drug-lipid thermodynamic phase diagram has provided a simple and effective approach to predicting drug solubility within a lipid system. This systematic method will be significantly beneficial to formulation development due to the rising number of potent and poorly water-soluble drugs currently being developed and lack of techniques available to predict the solubility of these drugs in a lipid system, such as solid lipid nanoparticles or liposomes. The solubility of the drug in the lipid carrier may further be used when investigating the drug loading of a lipid based carrier formulation, the phase diagram provides details of the maximum loading capacity that could be achieved with the system being developed.