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More flexible yet robust manufacturing solutions are needed in the pharmaceutical industry. Tablet compaction is no longer the obvious choice for commercial-scale processing of innovative drug delivery systems. Engineering solutions have gained wide attention in the pharmaceutical industry. Technical innovations within printing are considerable solutions for future product design. Printable medicinal products of a model compound are designed and an analytical approach for imaging the model compound in the printed medicinal products is investigated. The potential implications of using a unique combination of ink solution and carrier-substrate for designing a specific crystallization process and future directions towards continuous manufacturing of personalized medicinal products are discussed.

The mechanism of the salt-to-free form drug transformation was explored by investigating the pH-solubility profiles of a model drug in a salt form and the nucleation of the free base from the salt solution when its pH was increasing. The transformation of the salt to the free base during wet massing in the presence of pharmaceutical excipients with different pH was studied. The nucleation of the free base occurred when the pH of the salt solution reached a certain level pHmetastable, which was related to the free energy penalty associated with the creation of a new solid phase. The nucleation of the free base happened readily and thus, the salt-to-free base transformation occurred rapidly during wet massing with the excipients with a pH above the pHmetastable. These results can support robust formulation design of solid dosage forms containing salts by optimal excipient selection.

Polymorphic anhydrate systems have been well studied but until now little attention has been paid to polymorphic hydrate systems. The incorporation of water molecules can complicate the whole polymorphic system and thus impede the control of the crystallization process. In this work, nitrofurantoin monohydrate polymorphs which have the same chemical composition and molar ratio of water but different crystal packing arrangements, have been investigated. The metastable nitrofurantoin monohydrate was found to be difficult to crystallize, where both evaporative and cooling crystallization failed in its production. The possible phase conversion of the nitrofurantoin hydrate polymorphic system was also investigated in a liquid-assisted ball milling process. High-energy solids, e.g., amorphous and cocrystals, have often been created during high-energy ball milling. Metastable nitrofurantoin monohydrate, however, was again not observed during the whole milling process, in contrast to another polymorphic hydrate system, namely niclosamide. During milling of niclosamide anhydrate in ethyl acetate-water mixture the metastable niclosamide monohydrate was formed immediately upon milling (2 min). Under further milling, the metastable niclosamide hydrate started converting to the stable niclosamide hydrate (from 30 min onwards).

The feasibility of using a chromatography-crystallization hybrid separation process for isolation and purification of artemisinin from the herbal plant Artemisia annua was studied. After separating the crude extracts of Artemisia annua by flash column chromatography, a two-step antisolvent crystallization process was used for further isolation and purification. The two-step antisolvent crystallization process was designed based on the solubility of artemisinin in different solvents and solvent mixtures. The first step crystallization process was to remove impurities from the solution and the second step to isolate artemisinin. The crystallization behavior of the two polymorphs of artemisinin during the antisolvent crystallization process was also studied by performing crystallization in solutions of artemisinin in acetonitrile and acetone, respectively. It was observed that the formation of the two polymorphs of artemisinin in acetone solution follows the Ostwald's rule of stages. Fast feeding of the antisolvent (water) resulted in crystallization of the metastable triclinic form which then transformed to the stable orthorhombic form through a solvent-mediated transformation mechanism. The stable orthorhombic form crystallized out when water was fed slowly. Crystallization from acetonitrile always yielded the stable orthorhombic form regardless of the feeding rate of the antisolvent. Finally, a chromatography-crystallization hybrid separation process was proposed and tested. The results of the present work demonstrated the feasibility of combining the advantages of column chromatography and crystallization to improve efficiency of the isolation of artemisinin from Artemisia annua.

In polymorph screening it is imperative to maximize the physicochemical diversity of solvents used in crystallization experiments. This is done in order to increase the probability of finding as many crystal forms of the compound as possible. When setting up a complete solid form screening scheme it is common practice to work with solvent subsets of varying sizes, adequately spanning the chemical space. There exists a wide array of algorithms to perform this pre-experimental selection. Prior to the implementation of these methods, the impact on the physicochemical diversity observed in the selected subsets should be fully understood. In the current study subsets of 5, 10 and 20 solvents were selected from a database of 218 organic solvents times 24 property descriptors. For this purpose four mathematically different subset selection algorithms were tested and compared: Federov D-optimal selection, Kennard-Stone selection, Principal Properties selection and a Cluster-Based selection. Federov D-optimal, Kennard-Stone and the Cluster-Based selection primarily sampled in the outer regions of solvent space, whereas the Principal Properties approach represented more of a compromising solution selecting solvents closer to the centre. In conclusion, subset selection algorithms in crystallization experimental design should be used to guarantee physicochemical diversity, though it is recommended that the computed selection is supplemented with solvents selected based on chemical knowledge of the particular compound being screened. Copyright © 2008 John Wiley & Sons, Ltd.

The above article (DOI: 10.1002/cem.1107) was published online on 21 January 2008. An error was subsequently identified. Figures 2a, 2b and 2c should appear as below. The print publication will incorporate the amendment identified by this erratum notice.

Currently there is a great interest in new process analytical approaches to increase the process understanding of pharmaceutical unit operations. In the present study, the influence of the solvent composition on the material properties and, further, on the filtration characteristics, of different crystal suspensions obtained through an unseeded batch-cooling-crystallization process was studied. Sulphathiazole, which is an antibiotic agent with multiple polymorphic forms, was produced by performing laboratory-scale cooling crystallization experiments from five different mixtures of water and propan-1-ol (n-propanol). The size, shape and polymorphic composition of the crystals produced were characterized with a scanning electron microscope, with a novel automated image analyser and with an X-ray powder diffractometer. All of the monitored crystal properties were found to clearly differ between the samples obtained from different solvents. The crystals produced in the batch-cooling-crystallization experiments were separated from the crystallizing solvents using a batch-type pressure Nutsche filter, and the filtration characteristics of the suspensions were evaluated on the basis of average filter-cake porosities and average specific cake resistances, which were determined from the experimentally obtained filtration data. Comparison between the calculated filtration characteristics revealed that considerable differences existed between the different suspensions, and it could therefore be concluded that the pressure-filtration process was influenced by the composition of the crystallizing solvent. The filterability of all the studied sulphathiazole suspensions was considered to be rather good on the basis of the relatively low cake porosities (0.51-0.63), which were accompanied with low average specific cake resistances [(8.7 x 10(7))-(1.2 x 10(9)) m/kg].