Impact of downstream processing on crystal quality during the precipitation of a pharmaceutical product

In pharmaceutical industries, active pharmaceutical ingredients (API) are made of crystals whose properties must be controlled because they influence the end-use properties of the drug. Even if crystal quality is mainly determined during the precipitation step, downstream processing also has an influence. In this study, the influence of washing on the crystal size and shape was analyzed. For the API being considered, different impurities have to be removed from the final suspension by filter cake washing. The efficiency of the washing steps was measured by different types of characterization on the solid phase (differential scanning calorimetry, scanning electron microscopy, and size distribution) and on the remaining filtrate (concentration of impurities). A second component also coprecipitates with the API. A specific study has been carried out on the withdrawal of this by-product and on its impact on the evolution of the crystalline form during washing steps. It was found that three filter cake washings allow us to remove all the impurities and to obtain a pure crystalline form

Influence of pH, Temperature and Impurities on the Solubility of an Active Pharmaceutical Ingredient (API)

Solubility, which defines the liquid /solid equilibrium, is a key parameter to control a crystallization process. This work is focused on the effects of pH, temperature and impurities on the aqueous solubility of an Active Pharmaceutical Ingredient (API).As the API is a weak acid (pKa = 3.7), its solubility increases with the pH. On the basis of the experimental curve of solubility, a model was defined to fit the evolution of the solubility as a function of pH. In the case of this compound, studies revealed a weak influence of the temperature in comparison with the pH. So, the solubility of the compound is slightly impacted by the temperature.Some experiments were carried out in order to compare the solubility of the API, at the same pH and temperature, for different concentrations of impurities found in the process. The results revealed a solubility increase in presence of acetic acid and a high solubility decrease in presence of sodium chloride. By carrying out experiments on common ions salts, the anion chloride Cl- has been identified as the cause of the solubility decrease

Characterization of the conglomerate form of acetyl-dl-leucine by thermal analysis and solubility measurements

Starting from a mixture of enantiomers in solution, crystallization can generate different types of crystals. In order to determine which type of crystal is obtained in the case of acetylleucine, an active pharmaceutical ingredient (API), analytical methods have been used to partially elucidate the binary and ternary phase diagrams of the system composed of the two enantiomers and water.The melting temperature phase diagram of this compound has been obtained by using differential scanning calorimetry (DSC) analyzes. The results show that it is characteristic of a conglomerate. This mode of crystallization has also been confirmed by X-ray powder diffraction analysis. Solubility measurements of enantiomerical mixtures in water enabled the determination of the ternary diagram of solubility. The empiric Meyerhoffer double solubility rule has been modified, due to the characterization of interactions between enantiomers

The understanding of silicon sequential elutriation behaviour

During the fluidization of broad PSD (Particle Size Distribution) powders, elutriation can not be avoided, but has to be process controlled. Batch elutriations of continuous PSD powders were studied in a laboratory scale fluidized bed. The reference sample was metallurgical-grade silicon powder, with non-spherical shape. The smallest elutriable fines, namely superfines (\u3c10 µm) are entrained first. However, the largest elutriable particles (Ut ~ Ug) do not begin to be entrained simultaneously, but only after a delay that is as long as the time required for the superfines to leave the bed, thus inducing sequential elutriation (Figures 1). When no superfines were present, the entrainment was not delayed. This peculiar phenomenon was observed at all of the tested gas velocities (0.05-0.2 m/s). The superfines thus seem to strongly limit the elutriation of the larger elutriable particles. This sequential behaviour is particularly interesting to separate particles according to a small and narrow PSD (Figure 2). These phenomena are related to interparticle interactions within the bed and/or the freeboard and confirm the importance of polydispersity in the elutriation behavior. Thanks to the elutriation mathematical models developed in this study, the behavior that was thought to be explained by Silicon attrition can now be explained by sequential elutriation. Please click Additional Files below to see the full abstract

Control of the properties of crystals of an active pharmaceutical ingredient in the process chain of precipitation - filtration - drying : toward a continuous process

Les travaux de cette thèse portent sur le développement d'une méthodologie permettant le passage au continu d'une production de cristaux d'un principe actif pharmaceutique : l'acétyl-L- leucine. Le travail est centré sur l'étape de précipitation et ses interactions avec les procédés en aval de filtration / lavage et séchage. La démarche adoptée fut donc d'abord d'acquérir un ensemble de données analytiques et thermodynamiques sur les produits, sous-produits et cristaux. L'impact de plusieurs paramètres opératoires sur la solubilité du produit fut ainsi mis en évidence. D'autre part, on a montré que l'acétyl-DL- eucine cristallise sous la forme d'un conglomérat. Des études ont ensuite été réalisées sur les procédés en discontinu, notamment sur les étapes de précipitation et de lavages, afin d'identifier les paramètres permettant de contrôler au mieux la qualité finale des cristaux. Enfin, à partir de ces résultats, des essais de précipitation en continu ont pu être réalisés à l'échelle du laboratoire, puis à l'échelle industrielle sur l'ensemble de la chaîne de production du principe actif.This study deals with the development of a methodology allowing to transform a batch precipitation process in a continuous one. The active substance considered is acetyl-L-leucine. The work is focused on the precipitation step but also considers the interactions with the downstream processes of filtration, washing and drying. In a first part, characterization methods of pure and impure solutions of active substance were developed as well as methods for determining the crystals properties (purity, size, size distribution, shape, ...). Then the solubility of the product was investigated and the influence of parameters such as temperature, pH, impurity concentration, was studied. The crystallization mode of the racemic mixtures was also determined . Finally, batch crystallization was carried out at the laboratory scale in order to determine nucleation kinetics and to understand the main operating parameters influencing the quality of the crystals. For the applied range of concentrations, the induction time was found very small and indicates that the control of the nucleation step is difficult and depends on the mixing of the reactants. The whole continuous process was finally designed and tested, from the initial reactive to the final dry ZPI powder, in industrial site to validate the feasibility of the continuous proces

Contrôle des propriétés des cristaux d'un principe actif pharmaceutique dans la chaîne précipitation - filtration - séchage : Vers un procédé continu

Les travaux de cette thèse portent sur le développement d'une méthodologie permettant le passage au continu d'une production de cristaux d'un principe actif pharmaceutique : l'acétyl-L- leucine. Le travail est centré sur l'étape de précipitation et ses interactions avec les procédés en aval de filtration / lavage et séchage. La démarche adoptée fut donc d'abord d'acquérir un ensemble de données analytiques et thermodynamiques sur les produits, sous-produits et cristaux. L'impact de plusieurs paramètres opératoires sur la solubilité du produit fut ainsi mis en évidence. D'autre part, on a montré que l'acétyl-DL- eucine cristallise sous la forme d'un conglomérat. Des études ont ensuite été réalisées sur les procédés en discontinu, notamment sur les étapes de précipitation et de lavages, afin d'identifier les paramètres permettant de contrôler au mieux la qualité finale des cristaux. Enfin, à partir de ces résultats, des essais de précipitation en continu ont pu être réalisés à l'échelle du laboratoire, puis à l'échelle industrielle sur l'ensemble de la chaîne de production du principe actif

Contrôle des propriétés des cristaux d'un principe actif pharmaceutique dans la chaîne précipitation - filtration - séchage (vers un procédé continu)

TOULOUSE-INP (315552154) / SudocSudocFranceF

The sequential elutriation behavior of wide particle size distributions

International audienc

Multi-scale chemical characterization of a ground metallurgical-grade silicon powder

International audienc