Abstract
Design and development of efficient processes for continuous manufacturing of solid dosage oral formulations is of crucial importance for pharmaceutical industry in order to implement the Quality-by-Design paradigm. Supercritical solvent-based manufacturing can be utilized in pharmaceutical processing owing to its inherent operational advantages. However, in order to evaluate the possibility of supercritical processing for a particular medicine, solubility measurement needs to be carried out prior to process design. The current work reports a systematic solubility analysis on decitabine as an anti-cancer medicine. The solvent is supercritical carbon dioxide at different conditions (temperatures and pressures), while gravimetric technique is used to obtain the solubility data for decitabine. The results indicated that the solubility of decitabine varies between 2.84 × 10–05 and 1.07 × 10–03 mol fraction depending on the temperature and pressure. In the experiments, temperature and pressure varied between 308–338 K and 12–40 MPa, respectively. The solubility of decitabine was plotted against temperature and pressure, and it turned out that the solubility had direct relation with the pressure due to the effect of pressure on solvating power of solvent. The effect of temperature on solubility was shown to be dependent on the cross-over pressure. Below the cross-over pressure, there is a reverse relation between temperature and solubility, while a direct relation was observed above the cross-over pressure (16 MPa). Theoretical study was carried out to correlate the solubility data using several thermodynamic-based models. The fitting and model calibration indicated that the examined models were of linear nature and capable to predict the measured decitabine solubilities with the highest average absolute relative deviation percent (AARD %) of 8.9%.
Highlights
Design and development of efficient processes for continuous manufacturing of solid dosage oral formulations is of crucial importance for pharmaceutical industry in order to implement the Qualityby-Design paradigm
Either EoS or semi-empirical approaches can be employed in order to predict the solubility of active pharmaceutical ingredients (APIs) in supercritical CO2 (SC-CO2) at different conditions, semi-empirical approach is easier to implement and can be fitted using simple regression techniques[4,11,16]
Solubility of decitabine as an anti-cancer drug in supercritical CO2 using gravimetric method was reported in this work
Summary
Design and development of efficient processes for continuous manufacturing of solid dosage oral formulations is of crucial importance for pharmaceutical industry in order to implement the Qualityby-Design paradigm. The solvent is supercritical carbon dioxide at different conditions (temperatures and pressures), while gravimetric technique is used to obtain the solubility data for decitabine. Different techniques and processes have been developed and studied to assess the applicability of supercritical CO2 (SC-CO2) as green solvent in pharmaceutical industry such as rapid expansion[7,8] and anti-solvent process[9,10] These processes are mainly based on dissolution of a drug candidate in the supercritical solvent, and removal of solvent from the solution to obtain sub-micron sized drug particles with enhanced dissolution properties. Pishnamazi et al.[13] reported the measured and modelled solubilities of an anti-cancer drug (busulfan) in wide range of temperature and pressure in supercritical carbon dioxide. Either EoS or semi-empirical approaches can be employed in order to predict the solubility of APIs in SC-CO2 at different conditions, semi-empirical approach is easier to implement and can be fitted using simple regression techniques[4,11,16]
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