An evaluation of thermodynamic models for the prediction of drug and drug-like molecule solubility in organic solvents

Prediction of solubility of active pharmaceutical ingredients (API) in different solvents is one of the main issue for crystallization process design. Experimental determination is not always possible because of the small amount of product available in the early stages of a drug development. Thus, one interesting perspective is the use of thermodynamic models, which are usually employed for predicting the activity coefficients in case of Vapour–Liquid equilibria or Liquid–Liquid equilibria (VLE or LLE). The choice of the best thermodynamic model for Solid–Liquid equilibria (SLE) is not an easy task as most of them are not meant particularly for this. In this paper, several models are tested for the solubility prediction of five drugs or drug-like molecules: Ibuprofen, Acetaminophen, Benzoic acid, Salicylic acid and 4-aminobenzoic acid, and another molecule, anthracene, a rather simple molecule. The performance of predictive (UNIFAC, UNIFAC mod., COSMO-SAC) and semi-predictive (NRTL-SAC) models are compared and discussed according to the functional groups of the molecules and the selected solvents. Moreover, the model errors caused by solid state property uncertainties are taken into account. These errors are indeed not negligible when accurate quantitative predictions want to be performed. It was found that UNIFAC models give the best results and could be an useful method for rapid solubility estimations of an API in various solvents. This model achieves the order of magnitude of the experimental solubility and can predict in which solvents the drug will be very soluble, soluble or not soluble. In addition, predictions obtained with NRTL-SAC model are also in good agreement with the experiments, but in that case the relevance of the results is strongly dependent on the model parameters regressed from solubility data in single and mixed solvents. However, this is a very interesting model for quick estimations like UNIFAC models. Finally, COSMO-SAC needs more developments to increase its accuracy especially when hydrogen bonding is involved. In that case, the predicted solubility is always overestimated from two to three orders of magnitude. Considering the use of the most accurate equilibrium equation involving the ΔCp term, no benefits were found for drug predictions as the models are still too inaccurate. However, in function of the molecules and their solid thermodynamic properties, the ΔCp term can be neglected and will not have a great impact on the results

A Multiscale Approach for the Characterization and Crystallization of Eflucimibe Polymorphs: from Molecules to Particles

We present in this paper a generic multiscale methodology for the characterization and crystallization of eflucimibe polymorphs. The various characterization techniques used have shown that eflucimibe polymorphism is due to a conformational change of the molecule in the crystal lattice. In addition, the two polymorphs are monotropically related in the temperature range tested and have similar structures and properties (ie. interfacial tension and solubility). Consequently, it was found that for a wide range of operating conditions, the polymorphs may crystallize concomitantly. Induction time measurements and metstable zone width determination allow to infer the origin of the concomitant appearance of the polymorphs. A predominance diagram has been established which allows to perfectly control the crystallization of the desired polymorph. However, even if the stable form can be produced in a reliable way, the crystal suspension went toward a very structured gel-like network which limits the extrapolation process. Based on microscopic observation of the crystallization events performed in a microfluidic crystallizer, we propose a range of operating conditions suitable for the production of the stable form with the desired handling properties

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

Maîtrise du polymorphisme dans les procédés de cristallisation de produits d'intérêts pharmaceutiques : application à la cristallisation de l'Eflucimibe

Ces travaux de thèse portent sur l’étude de la cristallisation et du polymorphisme d’un produit organique pharmaceutique. L’éflucimibe est un principe actif pharmaceutique développé par les laboratoires Pierre Fabre. Les nombreuses techniques de caractérisation misen oeuvre ont permis d’identifier à température ambiante deux polymorphes de conformation, A et B. La cristallisation en solution de l’éflucimibe entraîne l’apparition concomitante des deux formes. Des études thermodynamiques, de détermination des diagrammes de phases des deux polymorphes, et cinétiques (nucléation, transitions) ont permis de déterminer les domaines de prédominance de chaque polymorphe. Le polymorphe souhaite (forme A), a pu être isolé en contrôlant rigoureusement les paramètres du procédé (concentration initiale, ensemencement, vitesse de refroidissement). Bien que ces résultats soient conservés lors d’un changement d’échelle, les études de cristallisation montrent que le système évolue vers un ensemble très structure qui prend en masse. Cet état est un frein pour l’extrapolation du procédé. Des études réalisées en rhéologie des suspensions ont permis de mettre en évidence qu’à partir d’une concentration en particules seuil, la suspension évolue vers arrangement fractal, de type gel, par un mécanisme d’agrégation DLCA. ABSTRACT : This thesis deals with the industrial crystallization of a pharmaceutical compound : Eflucimibe. Eflucimibe is a drug, developed by the Pierre Fabre Company, which exhibits two polymorphs. These polymorphs can crystallize concomitantly. The A form is the form of industrial interest. The main objectives of our study are the comprehension of the mechanism which governs the polymorphism and the control of the crystallization process. Specific polymorph characterization techniques (RX, DSC, and Spectroscopy) have been chosen and applied. The solubility curves of the two polymorphs have been measured experimentally and modelled (UNIQUAC). The solubility and the physcio-chemical properties of the two forms are very close. The determination of nucleation kinetics of the two polymorphs let us draw up a predominance diagram. The results show that, even in presence of seeds, the A form can only be obtain at low concentration and temperature. The study of the crystallization process shows that if the A form can be isolated ; the suspension went toward a very structured network, which limit the process extrapolation. The rheological behaviour of these suspensions shows that over a certain concentration the particles form a very structured gel

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

Applicability of Probabilistic Nucleation Modelling for the Analysis of Microfluidics Data

Microfluidics tools have been developing rapidly over the past decade, as they offer unparalleled ability for controlling nucleation and tracking crystallisation events inside very large numbers of individual nanolitre-size droplets. They have demonstrated a significant potential for screening protein crystallization conditions and for the direct determination of inorganic products solubility curves. The accepted basis for analysing microfluidics data is the probabilistic nucleation model originally proposed by Pound and La Mer (1952). Given the significance of this model for the purpose of analysing microfluidics data, the paper conducts a review of its hypotheses, usage and applicability. A step-by-step derivation of the model equations confirms that the time variation of the proportion of empty droplets which microfluidics experiments can provide with high accuracy is indeed the recommended method for estimation of nucleation kinetic parameters from microfluidics experiments. The paper shows that, depending on its implementation, the model predicts different rates of appearance of crystals inside individual droplets. The paper focuses on two distinct implementation modes, referred to as constant supersaturation and single nucleation event modes. By confronting model prediction with microfluidics measurements for eflucimibe in octanol, the paper finds that both modes yield different model predictions, shedding light on the potential and limits of the probabilistic nucleation model for the analysis of microfluidics data

Ammonium-controlled nano-fibrillar boehmite synthesis through electrolysis from aluminate solutions

International audienceThe synthesis of nano-fibrillar boehmite through electrolysis with a sacrificial aluminum anode in the presence of 0.1 mol/L sulfate electrolyte solutions at initial pH 9 and at 60°C has been investigated. The beneficial use of ammonium salt has been justified to maintain pH at a level compatible for the exclusive formation of boehmite during electrolysis from aluminate solutions. According to the experimental results and analyses inferred from XRD, TEM and EDS characterizations, the underlying mechanism has been described

An evaluation of COSMO-SAC model and its evolutions for the prediction of drug-like molecule solubility: part 1

COSMO-SAC model and its evolutions have been investigated for solubility prediction of six pharmaceutical ingedients (ibuprofen, paracetamol, benzoic acid, salicylic acid, 4-aminobenzoic acid, and anthracene) in 35 solvents. The aim is to check the relevancy of the last improvements of the COSMO-SAC method for solubility prediction. The performance of each COSMO-SAC version has been evaluated following different criteria: the mean quadratic error (mse), the predicted solubility order of magnitude, and the solubility temperature dependence. In addition, solubility predictions in mixed solvents have also been analyzed. The results obtained show that the model refinements are relevants for solid-liquid equilibrium predictions. Compared to the original model, the solubility prediction in polar solvents is more accurate, and the solubility temperature dependences are well-represented. Moreover, the refined models (especially the 2010 version) are also more able to predict the solubility maxima in mixed solvents. However, the methods still have problems in representing complex interactions (hydrogen bond and dipole-dipole) and weaker electrostatic ones

Effect of carboxymethylcellulose on potassium bitartrate crystallization on model solution and white wine

Instability in bottled wines refer to tartaric salts crystallization such as potassium bitartrate (KHT). It is not desirable as consumers see the settled salts as an evidence of a poor quality control. In some cases, it causes excessive gushing in sparkling wine. We investigate the effect of two oenological carboxymethylcellulose (CMC) for KHT inhibition in a model solution of white wine by studying the impact of some properties of CMC such as the degree of polymerization, the degree of substitution, and the apparent dissociation constant determined by potentiometric titration. Polyelectrolyte adsorption is used for determining the surface and total charge and for providing information about the availability of CMC charged groups for interacting with KHT crystal faces. The inhibitory efficiency of CMC on model solution is evaluated by measuring the induction time with the help of conductimetric methods. Crystals growth with and without CMC are studied by observation with MEB and by thermal analysis using DSC. The results confirm the effectiveness of CMC as an inhibitor of KHT crystallization in a model solution. The main hypothesis of the mechanism lies in the interaction of dissociated anionic carboxymethyl groups along the cellulose backbone with positively charged layers on KHT faces like the {0 1 0} face. Key factors such as pH, CMC chain length and total charge are discusse