Ozonation of NOM/HS in reject water results in higher purity of the recovered products during CaP crystallization.

Antisolvent crystallization of indomethacin (IMC), a nonsteroidal anti-inflammatory drug, from a ternary solvent system (acetone–methanol–water) has been investigated in this work. The acetone–methanol (66.5–33.5 wt %) binary mixture was selected as a solvent on the basis of the solubility of IMC reported earlier. Water was selected as an antisolvent on the basis of the solubility of IMC measured in acetone–methanol–water mixtures at 25 °C. Unseeded and seeded antisolvent crystallization was carried out for two initial concentrations of IMC (C0,1 and C0,2) with the stepwise addition of antisolvent. The acetone solvate of IMC was crystallized during the unseeded experiments, while the desired γ-IMC was obtained with a bimodal particle size distribution (PSD) during the experiments seeded with γ-IMC. A significant increase in the productivity was observed because of increased crystal yield and faster crystallization kinetics as compared to those of the crystallization processes reported earlier for the production of γ-IMC. Finally, the feasibility of IMC particle size tuning through the solvent–antisolvent (dissolution–growth) addition cycles was demonstrated successfully.

Background: Pharmaceutical industry is witnessing increased pressure to introduce innovative and efficient processes for manufacturing of Active Pharmaceutical Ingredients (APIs) in order to be competitive as well as to meet the stringent product quality requirements set by regulatory authorities. Crystallization with its ability to engineer the final product to the desired qualities such as purity, polymorphic form, particle size and shape is one of the most important steps involved in manufacturing of APIs. Therefore, development of crystallization processes with better understanding of process parameters and their impact on quality of APIs and subsequently the drug products assume great significance for pharmaceutical industry. Methods: This review paper focuses on application of PAT tools, an integral part of Quality by Design (QbD) approach, for better understanding, control, and design of crystallization processes in manufacturing of APIs. Results: Firstly, various steps involved in the drug development process are introduced briefly with emphasis on crystallization as one of the most important steps in manufacturing of drug products. Secondly, Critical Quality Attributes (CQAs) of drug products, their dependence on material attributes of APIs and role of crystallization in manipulating material attributes of APIs has been discussed. Finally, application of PAT tools such as advanced process analyzers for continuous monitoring, chemometric methods for multivariate data analysis, and control strategy for APIs crystallization processes has been reviewed along with some examples. Conclusion: Application of PAT in crystallization of APIs facilitates development of robust processes that works within the design space to produce the drug products of consistent quality. Furthermore, it opens up the opportunities for continuous improvement of the process by generating knowledge base of existing processes.

BACKGROUND:Pharmaceutical industry is witnessing increased pressure to introduce innovative and efficient processes for manufacturing Active Pharmaceutical Ingredients (APIs) in order to be competitive as well as to meet the stringent product quality requirements set by regulatory authorities. Crystallization with its ability to engineer the final product to the desired qualities such as purity, polymorphic form, particle size and shape is one of the most important steps involved in the manufacturing of APIs. Therefore, development of crystallization processes with better understanding of process parameters and their impact on quality of APIs and subsequently the drug products assume great significance for the pharmaceutical industry.METHODS:This review paper focuses on the application of PAT tools, an integral part of Quality by Design (QbD) approach, for better understanding, control, and design of crystallization processes in the manufacturing of APIs.RESULTS:Firstly, various steps involved in the drug development process are introduced briefly with emphasis on crystallization as one of the most important steps in manufacturing of drug products. Secondly, Critical Quality Attributes (CQAs) of drug products, their dependence on material attributes of APIs and role of crystallization in manipulating material attributes of APIs has been discussed. Finally, application of PAT tools such as advanced process analyzers for continuous monitoring, chemometric methods for multivariate data analysis, and control strategy for APIs crystallization processes has been reviewed along with some examples.CONCLUSION:Application of PAT in crystallization of APIs facilitates development of robust processes that works within the design space to produce the drug products of consistent quality. Furthermore, it opens up the opportunities for continuous improvement of the process by generating knowledge base of existing processes.

In this work, the effect of crystallization parameters, i.e., supersaturation, seeding, and temperature, on the polymorphism and crystal size of a nonsteroidal anti-inflammatory drug, indomethacin (IMC), was investigated. First, several crystallization solvents (ethanol, methanol, ethyl acetate, acetone, acetonitrile, and dichloromethane) were screened through the measurement of IMC solubility at different temperatures. This was followed by the investigation of IMC nucleation through measurement of induction times in selected solvents at two supersaturations. Finally, seeded cooling crystallization of IMC in ethanol was performed with different process parameters to investigate the influence on the polymorphism and crystal size distribution. Remarkably long induction times were observed for IMC in ethanol and ethyl acetate solutions, while a shorter induction time was observed in acetone. Cooling crystallization of IMC from ethanol confirmed that supersaturation, operating temperature, and seeding do affect the polymorphism as well as crystal size distribution of IMC. Fine needle-shaped crystals of metastable α-IMC were obtained at 5°C with high supersaturation even in the presence of γ-IMC seeds, while rhombic platelike crystals of thermodynamically stable γ-IMC were obtained in the remaining experiments. The seed loading only marginally influenced the crystal growth rate and median particle diameter. Particle size analysis of the crystals obtained showed a bimodal distribution in all experiments, and a larger median particle diameter was observed at 15°C with high supersaturation.

Natural products are defined as secondary metabolites produced by plants and form a vast pool of compounds with unlimited chemical and functional diversity. Many of these secondarymetabolites are high-value-added chemicals that are frequently used as ingredients in food, cosmetics, pharmaceuticals, and other consumer products. Therefore, process technology toward industrial-scale production of such high value chemicals from plants has significant importance. This chapter discusses a process synthesis methodology for recovery of natural products fromplants at the conceptual level. Themethodology generates different process flowsheet alternatives consisting of multiple separation techniques. Decision making is supported by heuristics as well as basic process information already available from previous studies. A process analytical technology (PAT) framework, part of the quality by design approach, has been included at various steps to obtain molecular-level information on process streams and, thereby, support rational decision making. The formulated methodology has been used to isolate and purify artemisinin, an antimalarial drug, from dried leaves of the plant Artemisia annua. A process flowsheet is generated consisting of maceration, flash column chromatography, and crystallization unit operations for extraction, partial purification, and final purification of artemisinin, respectively. PAT tools such as high-performance liquid chromatography, liquid chromatography-mass spectroscopy, and chemometric methods have been used extensively to characterize the process streams at the molecular level. The generated process information is used to further optimize the process flowsheet.

Solubility is one of the most basic chemical phenomena. It has a key role in understanding of major unit operations such as crystallization, solid-liquid extraction, and dissolution. In addition, solubility data is crucial for design, development, and operation of these processes. Therefore, solubility measurement of solid solutes in different solvents or solvent mixtures as a function of temperature can be of great significance to the university students and researchers. In this article, comparatively inexpensive apparatus for solubility measurement of solid solutes in pure or mixture of solvents, which can be easily assembled by using readily available equipment in the laboratory, is demonstrated.The proposed apparatus uses classical isothermal technique for measurement of solubility. Solubility of the naturally occurring antimalarial drug artemisinin was measured in n-hexane-ethyl acetate mixtures of varying composition at different temperatures to demonstrate the suitability and reliability of the proposed solubility measurement apparatus. The proposed apparatus has been used to conduct laboratory exercises in the course "Industrial Separation Technology" offered to undergraduate students of chemical engineering program at University of Southern Denmark. The exercises included solubility measurement and cooling crystallization of salicylic acid from five different organic solvents and extraction of artemisinin from the leaves of the plant Artemisia annua by using different solvents. Performance of the apparatus during laboratory exercises was evaluated through the survey among students. The results showed the general positive feedback from students and revealed enhanced interest among students to understand the exercises through the simple design of the apparatus. (C) 2016 Institution of Chemical Engineers. Published by Elsevier B.V. All rights reserved.

Crystallization is an inevitable step in the purification of artemisinin either from the plant Artemisia annua or from reaction mixtures of semisynthetically produced artemisinin. Rational design of crystallization process requires knowledge about the solid liquid equilibrium in a given solvent system and effect of impurities on it. In the present work, a crystallization process was designed to purify artemisinin from fractions of a flash chromatography column effluent collected after injecting extracts of Artemisia annua leaves. The fractions from chromatography containing artemisinin were combined together into one fraction, and the impurities present in this fraction were identified. The solubility of artemisinin in the mobile phase used for chromatography, i.e., n-hexane-ethyl acetate mixture of varying compositions, was measured at 25, 15, and 5 degrees C, respectively. The collective effect of impurities present in the combined fraction on the solid liquid equilibrium of artemisinin was evaluated by measuring the solubility of artemisinin in the combined fraction at same temperatures. The results show that the impurities present in the combined fraction increase the solubility of artemisinin. Finally, the crystallization of artemisinin from the combined fraction designed on the basis of artemisinin solubility data was carried out in two steps by adding an antisolvent and cooling crystallization. The yield of artemisinin obtained in the process was 50%, and it was found that the impurities present in the combined fraction at a given concentration do not affect the crystallization of artemisinin.

In this work, to understand the separation behavior of the flash column chromatography during purification of artemisinin from the crude extract of Artemisia annua, multivariate data analysis technique PARAFAC (Parallel factorization) is used to mine the relevant chemical information from analytical chromatograms of 9 artemisinin containing fractions. The size of three way dataset obtained from chromatogram measurements in sample, retention time, and spectral mode is 9 × 1981 × 82. Prior to the application of PARAFAC, the dataset is preprocessed to remove baseline drift and peak misalignment caused by retention time shifts due to matrix effects. Due to the complicated nature of chromatograms, the preprocessed HPLC data were divided into intervals containing analytical signals and then PARAFAC modeling was performed on individual intervals. Loadings from the PARAFAC analysis provided pure elution profiles and pure UV spectra even for co-eluting peaks, thus enabling the identification of chromatographically unresolved components. Also, loadings were used to determine the number of components and their relative concentrations in the fractions containing artemisinin which are the most important information of the flash column performance.

Phycocyanobilin (PCB) is an important linear tetrapyrrolic molecule for food as well as pharmaceutical industry. It is obtained from blue-green algae, where it is attached covalently to phycobiliproteins (C-PC and APC) present in the light harvesting complexes. In this work, cleavage of PCB from phycobiliproteins present in the extract of Arthrospira platensis by methanolysis is investigated. Different initial concentrations (25 mg/mL, 10 mg/mL, and 5 mg/mL) of proteins are used in order to investigate the effect of protein aggregation on process yield. A kinetic model is developed by fitting the experimental data for methanolysis. Results show that the kinetics follows a pseudo first order kinetics and remains unaffected due to the different initial concentration of phycobiliproteins. Moreover, yield of PCB in the cleavage process is found to be proportional to the initial concentration of phycobiliproteins.

The sesquiterpene lactone artemisinin is recommended by WHO against drug resistant malaria in combination with other antimalarial drugs [1]. Artemisinin is obtained from dried leaves of Artemisia annua L. The process for production of artemisinin includes purification of artemisinin from A. annua extracts by stand-alone crystallization or crystallization in combination with other purification techniques. Extraction can have wide implications on the downstream purification of artemisinin due to the quality of the extract that depends on solvent, temperature, and extraction technique. It is known that the yield of artemisinin depends on the composition of extract or fractions in terms of impurities because they influence the crystallization of artemisinin [2]. Understanding the role of impurities is therefore essential for the design of an optimal process for recovery of artemisinin. The aim of this study was to investigate the effect of impurities in extracts on the overall recovery of artemisinin. Dried leaves of A. annua were extracted with n-hexane, ethyl acetate, acetone and methanol, respectively. Yield of artemisinin was as follows: methanol (1.47 wt %), ethyl acetate (1.13 wt %), acetone (1.02 wt %), and n-hexane (0.34 wt %). HPLC and LC-MS analysis of the extracts revealed that methanol extracted large number of impurities compared to the other solvents used. Impurities consisted of flavonoids (e.g., casticin), coumarin and artemisinin derivatives such as artemisitene, dihydroartemisinic acid, and artemisinic acid [3]. Purification of artemisinin from the extracts was performed by combination of chromatography and crystallization (see figure). Maximum yield of artemisinin in the overall process was obtained with acetone (0.29 wt %) followed by ethyl acetate (0.26 wt %), methanol (0.18 wt %), and n-hexane (0.15 wt %). The results show that the composition of extracts obtained with different solvents has a significant influence on the purification of artemisinin.

In this work, to understand the separation behavior of the flash column chromatography during purification of artemisinin from the crude extract of Artemisia annua, multivariate data analysis technique PARAFAC (Parallel factorization) is used to mine the relevant chemical information from analytical chromatograms of 9 artemisinin containing fractions. The size of three way dataset obtained from chromatogram measurements in sample, retention time, and spectral mode is 9 x 1981 x 82. Prior to the application of PARAFAC, the dataset is preprocessed to remove baseline drift and peak misalignment caused by retention time shifts due to matrix effects. Due to the complicated nature of chromatograms, the preprocessed HPLC data were divided into intervals containing analytical signals and then PARAFAC modeling was performed on individual intervals. Loadings from the PARAFAC analysis provided pure elution profiles and pure UV spectra even for co-eluting peaks, thus enabling the identification of chromatographically unresolved components. Also, loadings were used to determine the number of components and their relative concentrations in the fractions containing artemisinin which are the most important information of the flash column performance.

In the present work, anti-solvent crystallization of artemisinin from four different organic solvents (methanol, ethanol, acetonitrile, and acetone) was studied. Water was used as anti-solvent. The effect of an impurity (quercetin) on the performance of anti-solvent crystallization of artemisinin was investigated. The fundamental process data such as solubility of artemisinin in pure organic solvents and their binary mixtures with varying composition water were measured at room temperature. The solubility of quercetin was measured only in pure organic solvents at room temperature. Anti-solvent crystallization experiments were designed based on the fundamental process data determined. Firstly, the anti-solvent crystallization of artemisinin without impurity was performed from all four organic solvents and then the experiments were repeated with addition of an impurity (quercetin) while keeping all other process parameters constant. Two different concentrations of impurity, i.e., 10% and 50% of its solubility, in the respective organic solvents at room temperature were used. The effect of impurity on performance of anti-solvent crystallization was evaluated by comparing the yield and purity of the artemisinin obtained with those in the absence of impurity. Results of the present work demonstrated that the presence of quercetin in the solution does not affect the final yield of artemisinin from the solution of each of four organic solvents used. However, the purity of artemisinin crystals were reduced when quercetin concentration was 50% of its solubility in all solvents studied.

A systematic method based on conceptual process synthesis for recovery of natural products from their biological sources is presented. The proposed methodology divides the task into two major subtasks namely, isolation of target compound from a chemically complex solid matrix of biological source and purification of the target compound from the crude extract. This methodology consists of three major separation techniques to achieve the task and provides a platform to generate different process alternatives by employing different combinations of separation units and with different set of key process variables. Decision making about the different combinations of separation units as well as key process variables is based upon the process information collected at every step with the help of process analytical techniques ( PAT) and heuristics. The optimal combination of different separation units and set of key process variables is determined in an iterative approach. In the present work, this methodology is applied to isolate and purify artemisinin, an anti-malarial drug from the plant Artemisia annua.