| Solid crystals of organic pharmaceuticals can exhibit polymorphism,i.e.for the same molecule,under varied physical and chemical conditions of crystallization,it can form crystals of different polymorphs that have different internal structure.Different crystal polymorphs could have significantly different physical and chemical properties,such as stability,solubility,and dissolution rate.Research in the literature has focused on polymorph prediction as well as polymorph screening such as via high-throughput experiments using parallel reactors.Challenges remain for many complicated crystallization processes on how to find process condition to obtain pure target polymorph at the same time achieve optimum in multiple other objectives including crystal size and yield,such as the process studied in this work i.e.azithromycin crystallization that involves coordinated manipulation of cooling and addition of an anti-solvent and transformation between the two hydrates.In this study,by reference to a commercial pharmaceutical,Azithromycin,Process Analytical Technology(PAT)was studied for a systematic investigation on the mechanism and kinetics of polymorphic transformation and the phenomena and causes of concomitant nucleation during the crystallization of the polymorphic drug.As a broad-spectrum antibiotic,azithromycin was reported to crystallize two possible hydrates in an acetone-water solution.From the perspective of crystallization thermodynamics and kinetics,the causal relationship between the multiple variables including the amount of the anti-solvent,temperature and supersaturation and the crystal form and crystal size distribution(CSD)of the final product was investigated.Subsequently,each elementary step of the transformation process,i.e.,the dissolution and growth kinetics of the metastable form,the growth kinetics of the stable form and the nucleation kinetics of both forms were examined in detail and were correlated to the key process variables.Furthermore,the mechanism of concomitant nucleation was interpreted by nucleation kinetics.Using Attenuated Total Reflection Fourier Transformed Infrared Spectroscopy(ATR-FTIR)and partial least squares method model building algorithm,multi-component concentration prediction models for azithromycin crystallization in acetone-water solution were established.The PAT platform composed of ATR-FTIR and on-line microscope imaging system allows real-time observation of solution mediated polymorphic transformation and crystal growth behavior during azithromycin antisolvent/cooling crystallization.Key factors affecting the crystal form and size distribution of the final product were revealed and quantified,including the amount of first portion of water addition,the feed rate of the second portion of water,the initial temperature and the cooling rate etc.Based on the insights obtained into the causal relationships between the multiple variables and crystal growth behavior,the operational spaces leading to the three desired CSDs were defined,including <180 ?m,180 – 425 ?m and 425 – 850 ?m,and were successfully implemented in the 1 L laboratorial scale,25 L pilot scale and industrial scale.With different water content(10 – 25%),relative undersaturation(0.25 – 0.55)and relative supersaturation(0.2 – 0.8),the dissolution and growth rates of a azithromycin monohydrate seed crystal in the acetone-water solution were measured,and the effects of water content on the rate and the control mechanism in the corresponding process were investigated and quantified.The theoretical and empirical models were used concurrently to fit the data and derive the corresponding kinetic parameters,and empirical expressions relating the water content to the dissolution and growth kinetics were established.At different temperature(293.15 – 313.15 K),with different water content(10 – 25%)and relative supersaturation(0.04 – 0.35),the growth rates of the two defined characteristic dimensions of a azithromycin seed crystal were measured,and the differences in the effect of temperature and water content on the growth rate and control mechanism of the two characteristic dimensions were investigated.An empirical equation of growth rate relating multiple parameters including water content,temperature,and relative supersaturation was presented.The main controlling factors for the polymorphic transformation were analyzed by comparing the dissolution kinetics of the monohydrate and the growth kinetics of the dihydrate.The polymorphic nucleation behavior in azithromycin acetone-water solution with different water content(10 – 25%)and relative supersaturation(0.50 – 1.80)was observed in real time and the induction time of the two hydrates was determined.According to the classical nucleation theory,the nucleation kinetic parameters such as interfacial tension,critical free energy,nuclei critical radius and pre-exponential factor of the two hydrates in these solutions were fitted,and the effect of water content on the polymorphic nucleation behavior and interfacial tension of the two hydrates was discussed.By estimating the supersaturation region formed by the intersection of the nucleation rates of the two hydrates and the intersection of the critical free energy of the two hydrates,the reason for the occurrence of concomitant nucleation was explained and the polymorphic domain of azithromycin crystallization was plotted,and thus the nucleation behavior of azithromycin under different solution conditions was predicted.Based on the concentration plateaus during the polymorphic transformation processes monitored by ATR-FTIR in real-time,and the nucleation,dissolution and growth kinetics of monohydrate and dihydrate investigated,the effects of supersaturation and water content on the polymorphic transformation and its rate controlling step was discussed.In addition,using hot stage microscope and off-line particle size analysis,the effects of the presence of monohydrate crystals and polymorphic transformation on the product particle sizes were investigated.The above research content not only provides basic data for the characterization and mathematical simulation of polymorphic transformation process,but also provides good demonstration for the development and optimization of the complex pharmaceutical crystallization processes involving the cooling/anti-solvent coupling process and polymorphic transformation. |
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