Application-oriented Crystallization of Pharmaceutical Products

Thomas Bruun Hansen

Research output: ThesisPh.D. thesis


The purpose of this PhD thesis is to investigate various options for controlling the crystallization process of pharmaceutical products, both with regards to polymorphic control and crystal morphology.
During this process, several model compounds were used, depending on the goal of the studies. Initially procaine was used to investigate the transformation from salt to free base both during titration with NaOH and during wet massing with various excipients that could influence the micro environmental pH and induce transformation. The study was able to show the apparent reversal in pH change during titration that others have also noticed, one the drug starts to change form. The wet massing experiments also found that the presence of water allowed for excipients to impact the polymorphic nature of the product.
The majority of the work used piroxicam as a model compound. The initial work was focused on determining the details of how the transformation from form I or II into the monohydrate form occurred. This was achieved by using an inline Raman probe to monitor the transformation, and the use of multivariate curve resolution MCR to quantify the rate of change as well as determine the pathway of the transformations.
As part of the next step of investigating additive effects, acetone was decided on as a suitable solvent and the crystal landscape of piroxicam in acetone/water mixtures were mapped out. This in itself showed some interesting effects where the concentration of the Active Pharmaceutical Ingredient (API) looked to have a greater impact on polymorphism than cooling rate, and by changing concentration of API and water content of solvent, two forms and a hydrate could be produced. This was all achieved within a concentration range from 15 to 45 mg/g and water content from 0 to 10 wt%. As it was found that specific areas of this landscape would have two forms competing, it was decided to try out several additives in those specific systems to see how this would impact polymorphism. This helped determine which additives had an impact on the process and also if this was done by promoting a form or inhibiting another.
During the environmental stay at Purdue University, piroxicam was also used for various experiments using process analytical tool. This involved anti-solvent crystallization in order to have both forms I and II available as seed crystals. Once enough seed crystals were produced, cooling crystallizations were performed at fixed cooling rates, but also using Supersaturation control SSC and direct nucleation control DNC, to determine the temperature set point of the reactor. The impacts on crystal size, especially from the DNC experiments were quite impressive and clearly showed the advantages of feedback control for a crystallization process.
Finally the model compound Isonicotinamide INA was used in a similar fashion to the initial studies of the crystal landscape of piroxicam. This was done partly to investigate if INA would exhibit similar tendencies as there are similarities in the hydrogen bonding behavior of the two compounds, but also to build the foundation for further studies using a compound that would allow for better monitoring using FT-IR. In this study the solubility of INA in several solvents have been determined, furthermore the crystallization of different polymorphs during cooling crystallization at various concentrations has been investigated.
Original languageEnglish
Publication statusPublished - 2017

Bibliographical note

Finalised in April 2017
Supervisor:Haiyan Qu

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