Mergers among leaders and mergers among followers

We are the first to confirm that sufficient cost convexity in a Stackelberg model generates profitable mergers between two leaders and between two followers. Moreover, the degree of convexity required for leaders to merge is generally far smaller than that required for followers. Most importantly, the structure of the stage game means that the convexity required for either two followers or two leaders to merge is less than that required for two Cournot competitors.

Batch to continuous organic salt crystallisation, model based design

Organic salt crystallisation is of great importance to the pharmaceutical industry as the majority of pharmaceutical products are sold as salts with salt formation being an essential step in drug development. In this research a solution speciation model was developed to predict pH and solution composition during salt crystallisation processes. This tool allows for the entire salt crystallisation design space to be explored in terms of process pathways in the concentration vs. pH phase diagram. This allows for greater process understanding to be obtained and for theoretical solid yields to be determined.The model compound used in this work is the polymorphic organic salt ethylenediammonium 3,5-dinitrobenzoate (EDNB) which is the 2:1 salt of 3,5-dinitrobenzoic acid (3,5-DNBA) with ethylenediamine. In this system one of the two EDNB polymorphs (monoclinic and triclinic) or the 3,5-DNBA starting material may crystallise. The solution speciation model was used to predict the crystallisation pathway for each solid form and to guide the development of semi-batch and fully continuous crystallisation processes. In addition, aqueous pH-solubility measurements of EDNB triclinic and 3,5-DNBA were made to better understand EDNB salt solubility in high ionic strength solutions and to establish the operating space where 3,5-DNBA crystallisation is avoided.In this study EDNB crystallisation was experimentally performed in semi-batch and fully continuous processes. The semi-batch experiments demonstrated the scale up of the EDNB crystallisation process to 400 ml compared to 50 ml in literature. The fully continuous processes demonstrated that continuous mixing approaches could be used to crystallise the EDNB salt with consistent yield and PSD. Control over which polymorphic form crystallised was successfully demonstrated in both semi-batch and continuous mixing processes.Organic salt crystallisation is of great importance to the pharmaceutical industry as the majority of pharmaceutical products are sold as salts with salt formation being an essential step in drug development. In this research a solution speciation model was developed to predict pH and solution composition during salt crystallisation processes. This tool allows for the entire salt crystallisation design space to be explored in terms of process pathways in the concentration vs. pH phase diagram. This allows for greater process understanding to be obtained and for theoretical solid yields to be determined.The model compound used in this work is the polymorphic organic salt ethylenediammonium 3,5-dinitrobenzoate (EDNB) which is the 2:1 salt of 3,5-dinitrobenzoic acid (3,5-DNBA) with ethylenediamine. In this system one of the two EDNB polymorphs (monoclinic and triclinic) or the 3,5-DNBA starting material may crystallise. The solution speciation model was used to predict the crystallisation pathway for each solid form and to guide the development of semi-batch and fully continuous crystallisation processes. In addition, aqueous pH-solubility measurements of EDNB triclinic and 3,5-DNBA were made to better understand EDNB salt solubility in high ionic strength solutions and to establish the operating space where 3,5-DNBA crystallisation is avoided.In this study EDNB crystallisation was experimentally performed in semi-batch and fully continuous processes. The semi-batch experiments demonstrated the scale up of the EDNB crystallisation process to 400 ml compared to 50 ml in literature. The fully continuous processes demonstrated that continuous mixing approaches could be used to crystallise the EDNB salt with consistent yield and PSD. Control over which polymorphic form crystallised was successfully demonstrated in both semi-batch and continuous mixing processes

Dendritic Cells The Tumor Microenvironment and the Challenges for an Effective Antitumor Vaccination

Many clinical trials have been carried out or are in progress to assess the therapeutic potential of dendritic-cell- (DC-) based vaccines on cancer patients, and recently the first DC-based vaccine for human cancer was approved by the FDA. Herewith, we describe the general characteristics of DCs and different strategies to generate effective antitumor DC vaccines. In recent years, the relevance of the tumor microenvironment in the progression of cancer has been highlighted. It has been shown that the tumor microenvironment is capable of inactivating various components of the immune system responsible for tumor clearance. In particular, the effect of the tumor microenvironment on antigen-presenting cells, such as DCs, does not only render these immune cells unable to induce specific immune responses, but also turns them into promoters of tumor growth. We also describe strategies likely to increase the efficacy of DC vaccines by reprogramming the immunosuppressive nature of the tumor microenvironment

Small-scale experiments supporting the MicroFactory

Small-scale crystallisation experiments allow for rapid screening and the minimisation of material use

Continuous cocrystallization of benzoic acid and isonicotinamide by mixing-induced supersaturation : exploring opportunities between reactive and antisolvent crystallization concepts

This study combines reactive and antisolvent crystallization concepts via mixing-induced supersaturation to demonstrate a wider range of options for solvent system selection in multicomponent crystallization. This approach was applied to investigate continuous crystallization of 1:1 and 2:1 cocrystals of benzoic acid and isonicotinamide. Design of Experiments was used to identify conditions where pure cocrystal phases are obtained and a continuous mixing-induced cocrystallization process was implemented to selectively produce either 1:1 or 2:1 cocrystals

Effect of process conditions on particle size and shape in continuous antisolvent crystallisation of lovastatin

Lovastatin crystals often exhibit an undesirable needle-like morphology. Several studies have shown how a needle-like morphology can be modified in antisolvent crystallisation with the use of additives, but there is much less experimental work demonstrating crystal shape modification without the use of additives. In this study, a series of unseeded continuous antisolvent crystallisation experiments were conducted with the process conditions of supersaturation, total flow rate, and ultrasound level being varied to determine their effects on crystal size and shape. This experimental work involved identifying acetone/water as the most suitable solvent/antisolvent system, assessing lovastatin nucleation behaviour by means of induction time measurements, and then designing and implementing the continuous antisolvent crystallisation experiments. It was found that in order to produce the smallest and least needle-like particles, the maximum total flow rate and supersaturation had to be combined with the application of ultrasound. These results should aid development of pharmaceutical manufacturing processes where the ability to control particle size and shape would allow for optimisation of crystal isolation and more efficient downstream processing

Modelling solution speciation to predict pH and supersaturation for design of batch and continuous organic salt crystallisation processes

Organic salt crystallisation is of great importance to the pharmaceutical industry as the majority of pharmaceutical products are marketed as salts. In this study a solution speciation model was developed and experimentally validated to predict pH and supersaturation during organic salt crystallisation processes when only the overall solution composition is known. By solving a particular system of equations simultaneously the full speciation and pH of the solution is calculated. Simply with knowledge of only the overall solution composition, dissociation constants and solubility products this model can be used to generate the design space for organic salt crystallisation and gain deeper understanding of the salt crystallisation process. In particular, the model can be used to calculate the maximum theoretical crystallisation yield and the corresponding mother liquor pH which would be impossible to determine otherwise without performing experiments. The case study used in this work is the polymorphic organic salt ethylenediammonium 3,5-dinitrobenzoate (EDNB) which is the 2:1 salt of 3,5-dinitrobenzoic acid (3,5-DNBA) with ethylenediamine. In this system three solid forms can be produced: EDNB monoclinic, EDNB triclinic and/or the 3,5-dinitrobenzoic acid (3,5-DNBA) starting material. The solution speciation model was used to investigate the crystallisation process for each solid form and test different feed molar ratios and different solution addition/mixing approaches for semi-batch and continuous processes

Investigation of metastable zones and induction times in glycine crystallisation across three different antisolvents

Experimental data on the effects that different antisolvents and antisolvent addition strategies have on nucleation behavior in antisolvent crystallization is very limited, and our understanding of these effects is sparse. In this work we measured the metastable zone width for the isothermal antisolvent crystallization of glycine from water utilizing methanol, ethanol, and dimethylformamide as antisolvents. We then investigated induction times for glycine crystallization across these metastable zones using the same three antisolvents. Supersaturated solutions were prepared by mixing of an antisolvent with undersaturated aqueous glycine solutions, either by batch rapid addition or using a continuous static mixer. Induction times were then recorded under agitated isothermal conditions in small vials with the use of webcam imaging and vary from apparently instant to thousands of seconds over a range of compositions and different mixing modes. Well-defined induction times were detected across most of the metastable zone, which shows that primary nucleation is significant at supersaturations much lower than those identified in conventional metastable zone width measurements. As supersaturation increases toward the metastable zone limit, crystal growth and secondary nucleation are likely to become rate-limiting factors in the observed induction times for antisolvent crystallization. Furthermore, the observed induction times were strongly dependent on the mode of mixing (batch rapid addition vs continuous static mixing), which demonstrates an interplay of antisolvent effects on nucleation with their effects on mixing, leading to crossover of mixing and nucleation time scales. This shows that appropriate mixing strategies are crucial for the rational development of robust scalable antisolvent crystallization processes