Solid state control of active pharmaceutical ingredients using supercritical fluid technology

Low bioavailability of drug candidates due to poor water solubility accounts for one of the greatest obstacles facing the pharmaceutical industry. Poorly soluble compounds represent 40% of the top 200 oral drugs marketed in the US and 90% of new chemical entities in development, highlighting the importance of establishing comprehensive methodologies to improve the bioavailability of these compounds. Supercritical fluid (SCF) technologies have been used as alternative manufacturing methods to overcome this property, mostly through solid-state control and particle size reduction. Supercritical CO2 (scCO2), the most common SCF, allows for a wide range of methods to be developed for the production of pharmaceutical materials due to its ability to act as a solvent, antisolvent and/or additive/spray enhancer. This thesis investigates the development of batch and continuous supercritical CO2 methodologies which can induce precipitation of active pharmaceutical ingredients (APIs). Different approaches and strategies have been investigated in this thesis to control the solidstate of APIs, specifically, polymorphic control and the generation of pharmaceutical cocrystals. An introduction to the topics and technologies that are employed to address the most common concerns in the pharmaceutical industry are described in Chapter 1 and a detailed description of the characterization techniques employed in this thesis is described in Chapter 2. The experimental chapters are arranged as research articles with introductory summaries at the beginning of each. The first phase of this thesis (Chapter 3) describes the control over the polymorphism of carbamazepine (CBZ), a highly polymorphic BCS class II drug, using anionic additives in a gas antisolvent (GAS) method. A design of experiments (DoE) approach was performed to assess the impact of CO2 antisolvent processing variables such as pressure, temperature and CO2 addition rate when anionic additives (sodium stearate or sodium dodecyl sulfate) were employed on the outcome of CBZ polymorphism. Statistical analysis revealed that the combination of temperature and CO2 addition rate show statistically significant impact (p < 0.05) on the final CBZ polymorphic form obtained when no additive was present during short hold studies. However, when 5% w/w of additives sodium stearate (SS) or sodium dodecyl sulfate (SDS) were used, CBZ form II and III were obtained, respectively, regardless of the processing condition used. An additional investigation into the polymorphic stability of these CBZ samples was undertaken, allowing the precipitated CBZ to remain immersed in the supercritical media (scCO2 and methanol) for a prolonged period (sixty hours) which demonstrated moderate conversion for metastable forms (form II) and minimal conversion for stable forms (form III) of CBZ, which occurred close to the transition temperature between stable and metastable forms of this API (CBZ). The second phase of this thesis (Chapter 4) investigates if the results produced in the batch GAS method could be reproduced using a supercritical-CO2-assisted spray drying method (SASD). A DoE approach was used to investigate the impact of (1) additive quantity and (2) solution flow rate, which changes the ratio between drug solution and scCO2 antisolvent, on the polymorphic form of CBZ. The results of this investigation show a similar effect caused by the anionic additives SS and SDS, presented in the previous chapter, using the SASD method with minimal influence caused by the processing variables investigated. Additionally, the SASD method offers a greater degree of control with respect to particle size evidenced by the production of CBZ particles in the submicron/nano sized range (0.5-5 µm). Similar experiments using a conventional spray dryer (Büchi B-290) were completed but did not exhibit the polymorphic control achieved using the SASD method, suggesting that the antisolvent effect was the governing crystallization mechanism. The final phase of this thesis (Chapter 5) reports the use of two SCF methods (GAS and cocrystallization with supercritical solvent [CSS]) to generate a recently reported cocrystal of the poorly soluble API, posaconazole (PSZ) using 4-aminobenzoic acid (4AMB) as a coformer. A DoE approach is applied to investigate the impact of critical processing variables (pressure, temperature and stirring rate) on PSZ-4AMB formation. This study highlights that both methods can be employed to form PSZ-4AMB, however, samples produced by the GAS method were of a higher purity than those produced by the CSS method. Reaction time was investigated as an opportunity to improve the purity of the cocrystal samples produced by the CSS method but did not appear to play an influencing role. The low purity of CSS samples is likely caused by the low solubility of PSZ and 4AMB in scCO2. Further optimization, potentially by using a co-solvent, may be required for the CSS method, while the GAS method displayed that higher purity samples (compared to the CSS method) can be obtained across a wide range of processing parameters.