Academic literature on the topic 'Active pharmaceutical ingredient (API) crystallization'

Co-crystals play a significant role in the pharmaceutical sector. Medicinal co crystals are multicomponent systems with at least one active therapeutic ingredient and the rest of the constituents being pharmaceutically acceptable. Co crystallization of a medicinal material with a coformer is a potential and growing method for improving pharmaceutical performance in areas such as solubility, dissolution profile, pharmacokinetics, and stability.. A key barrier to developing novel API compounds is poor bio availability and water solubility, which can limit the effectiveness of new drugs or prevent their approval for the market. In terms of the significant enhancement in solubility profiles compared to the single- active pharmaceutical ingredients, co-crystals provide a distinct and competitive edge over other traditional approaches.

API (Active Pharmaceutical Ingredient) means the active ingredient which is contained in medicine. For example, an active ingredient to relieve pain is included in a painkiller. Developing and producing Active Pharmaceutical Ingredients (APIs) includes various processing steps, such as reaction, crystallization, separation and purification, solvent swap, and solvent exchange. Active Pharmaceutical Ingredients or APIs are also known as bulk drugs and a term that is often heard in business news. An active ingredient is the ingredient in a pharmaceutical drug or pesticide that is biologically active. The similar terms active pharmaceutical ingredient and bulk active are also used in medicine, and the term active substance may be used for natural products. Active Pharmaceutical Ingredients are the active ingredients contained in a medicine. The issue of disposal of wastes from these API companies, as well as the development and implementation of efficient collection strategies, is an important concern. This research looks into the factors that have an impact on the disposition of wastes from these companies, and how are these addressed by local government bodies. The pharmaceutical industry discovers, develops, produces, and markets drugs or pharmaceutical drugs for use as medications to be administered to patients with the aim to cure them, vaccinate them, or alleviate symptoms. Pharmaceutical companies may deal in generic or brand medications and medical devices. They are subject to a variety of laws and regulations that govern the patenting, testing, safety, efficacy using drug testing and marketing of drugs.

The expansion of a novel product is constrained by an active medicinal ingredient's poor solubility in aqueous solutions and limited oral bioavailability. A novel strategy to improve the physicochemical characteristics of the active medicinal ingredient is co-crystal formation. The pharmacological action of the API is unaffected by co-crystallization with pharmaceutically acceptable molecules, although it can enhance the physical characteristics like solubility, stability, and dissolution rate. Cocrystals are multi-component systems comprising active medicinal ingredients that also contain a stoichiometric amount of a coformer that is acceptable to the pharmaceutical industry. The pharmaceutical business has a significant chance to create new medicinal products since producing pharmaceutical co-crystals can enhance a drug's physicochemical qualities.The most major benefit of co-crystals is their ability to produce novel medications with improved solubility, which increases the effectiveness and safety of the treatment. The thermodynamic stability of the co-crystal preparation is the key influencing factor. Co-crystal screening provides information on the chemical composition and connection between the active medicinal ingredient and the coformer. This review discusses the many co-crystal synthesis techniques, including hot-melt extrusion, slurrying, antisolvent, grinding, and spray drying. Here is a quick explanation of the characteriszation methods frequently employed for co-crystals, as well as their uses in medicine. Here are some quick summaries of reported research on co-crystals that were evaluated in order to better grasp the notion of co-crystals.

Active pharmaceutical ingredient (API) particle size distribution is important for both downstream processing operations and in vivo performance. Crystallization process parameters and reactor configuration are important in controlling API particle size distribution (PSD). Given the large number of parameters and the scale-dependence of many parameters, it can be difficult to design a scalable crystallization process that delivers a target PSD. Population balance modeling is a useful tool for understanding crystallization kinetics, which are primarily scale-independent, predicting PSD, and studying the impact of process parameters on PSD. Although population balance modeling (PBM) does have certain limitations, such as scale dependency of secondary nucleation, and is currently limited in commercial software packages to one particle dimension, which has difficulty in predicting PSD for high aspect ratio morphologies, there is still much to be gained from applying PBM in API crystallization processes.

Integrated API and drug product processing enable molecules with high clinical efficacy but poor physicochemical characteristics to be commercialized by direct co-processing with excipients to produce advanced multicomponent intermediates. Furthermore, developing isolation-free frameworks would enable end-to-end continuous processing of drugs. The aim of this work was to purify a model API (sodium ibuprofen) and impurity (ibuprofen ethyl ester) system and then directly process it into a solid-state formulation without isolating a solid API phase. Confined agitated bed crystallization is proposed to purify a liquid stream of impure API from 4% to 0.2% w/w impurity content through periodic or parallelized operations. This stream is combined with a polymer solution in an intermediary tank, enabling the API to be spray coated directly onto microcrystalline cellulose beads. The spray coating process was developed using a Design of Experiments approach, allowing control over the drug loading efficiency and the crystallinity of the API on the beads by altering the process parameters. The DoE study indicated that the solvent volume was the dominant factor controlling the drug loading efficiency, while a combination of factors influenced the crystallinity. The products from the fluidized bed are ideal for processing into final drug products and can subsequently be coated to control drug release.

The word excipient is derived from the Latin excipere meaning to except, which is simply explained as other than. Pharmaceutical excipients are basically everything other than the active pharmaceutical ingredient. Ideally, excipients should be inert, however, recent reports of adverse reactions have suggested otherwise. Pharmaceutical excipients are substances other than the active pharmaceutical ingredient (API) that have been appropriately evaluated for safety and are intentionally included in a drug delivery system. Solubility, which defines the liquid /solid equilibrium, is a key parameter to control a crystallization process. 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. Keywords: Solubility, API, Impurity, Ph

Crystal morphology plays a critical role in the processability and physicochemical behavior of active pharmaceutical ingredients. Manipulating crystal morphology involves consideration of crystallization conditions such as temperature, supersaturation, and solvent choice. Typically, experimental screenings on a small scale are conducted to find targeted crystal morphologies. However, results from such small-scale experiments do not assure direct success at a larger scale, particularly if the small-scale setup differs significantly from a conventional stirred crystallizator. In this study, we successfully validated the morphologies observed in the small-scale experiments of an exemplary API, Bitopertin, when scaled up by a factor of 200, through the maintenance of identical process conditions and geometrical vessel relations. This successful scalability highlights the significant potential of small-scale crystallization studies to provide a reliable foundation for further exploration in large-scale endeavors.

Co-crystals comprising the active pharmaceutical ingredient 1,4-bis(4-pyridyl)-2,3-diaza-1,3-butadiene, C12H10N4, and the chiral co-formers (+)-, (−)- and (rac)-camphoric acid (cam), C10H16O4, have been synthesized. Two different stoichiometries of the API and co-former are obtained, namely 1:1 and 3:2. Crystallization experiments suggest that the 3:2 co-crystal is kinetically favoured over the 1:1 co-crystal. Single-crystal X-ray diffraction analysis of the co-crystals reveals N—H...O hydrogen bonding as the primary driving force for crystallization of the supramolecular structures. The 1:1 co-crystal contains undulating hydrogen-bonded ribbons, in which the chiral cam molecules impart a helical twist. The 3:2 co-crystal contains discrete Z-shaped motifs comprising three molecules of the API and two molecules of cam. The 3:2 co-crystals with (+)-cam, (−)-cam (space groupP21) and (rac)-cam (space groupP21/n) are isostructural. The enantiomeric co-crystals contain pseudo-symmetry consistent with space groupP21/n, and the co-crystal with (rac)-cam represents a solid solution between the co-crystals containing (+)-cam and (−)-cam.

Abstract The supercritical antisolvent (SAS) recrystallization process is one of the most promising recrystallization techniques for the particle formation of pharmaceutical compounds. In this process, a solution of active pharmaceutical ingredient (API) is sprayed into the supercritical carbon dioxide (SC CO2) environment. The mass transport of both the solvent and the antisolvent results in supersaturation followed by the crystallization of the API. In this work, a model is developed to estimate the supersaturation profile of solute in a droplet falling in the SC CO2 environment. The droplet consists of paracetamol as a solute and ethanol as a solvent. It moves down in the antisolvent (supercritical CO2) environment. Interestingly, the present model predicts a rise in supersaturation followed by a fall for a while and then a sharp increase. The competing phenomena of nucleation and growth mechanisms are used to justify this variation in the supersaturation.

Pharmaceutical co-crystals are novel class of pharmaceutical substances, which possess an apparent probability of advancement of polished physical properties offering stable and patentable solid forms. These multi-component crystalline forms influence pertinent physicochemical parameters like solubility, dissolution rate, chemical stability, physical stability, etc. which in turn result in the materials with superior properties to those of the free drug. Co-crystallization is a process by which the molecular interactions can be altered to optimize the drug properties. Co-crystals comprise a multicomponent system of active pharmaceutical ingredient (API) with a stoichiometric amount of a pharmaceutically acceptable coformer incorporated in the crystal lattice. By manufacturing pharmaceutical co-crystals, the physicochemical properties of a drug can be improved thus multicomponent crystalline materials have received renewed interest in the current scenario due to the easy administration in the pharmaceutical industry. There is an immense amount of literature available on co-crystals. However, there is a lack of an exhaustive review on a selection of coformers and regulations on co-crystals. The review has made an attempt to bridge this gap. The review also describes the methods used to prepare co-crystals with their characterization. Brief description on the pharmaceutical applications of co-crystals has also been incorporated here. Efforts are made to include reported works on co-crystals, which further help to understand the concept of co-crystals in depth.

Les entreprises pharmaceutiques ont progressivement adopté le concept de Process Analytical Technology (PAT) afin de contrôler et d'assurer en temps réel la qualité des produits pharmaceutiques au cours de leur production. Le PAT et un composant central du concept plus général de Quality-by-Design (QbD) promu par les agence régulatrices et visant à construire la qualité des produits via une approche scientifique et la gestion des risques.Une méthode basée sur la spectroscopie proche infrarouge (PIR) a été développée comme un outil du PAT pour contrôler en ligne la cristallisation d'un principe actif pharmaceutique. Au cours du procédé les teneurs en principe actif et en solvant résiduel doivent être déterminées avec précision afin d'atteindre un point d'ensemencement prédéfini. Une méthodologie basée sur les principes du QbD a guidé le développement et la validation de la méthode tout en assurant l'adéquation avec son utilisation prévue. Des modèles basés sur les moindres carrés partiels ont été construits à l'aide d'outils chimiométriques afin de quantifier les 2 analytes d'intérêt. La méthode a été totalement validée conformément aux requis officiels en utilisant les profils d'exactitude. Un suivi du procédé en temps réel a permis de prouver que la méthode correspond à son usage prévu.L'implémentation de cette méthode comme à l'échelle industrielle au lancement de ce nouveau procédé permettra le contrôle automatique de l'étape de cristallisation dans le but d'assurer un niveau de qualité prédéfini de l'API. D'autres avantages sont attendus incluant la réduction du temps du procédé, la suppression d'un échantillonnage difficile et d'analyses hors ligne fastidieuses
Pharmaceutical companies are progressively adopting and introducing the Process Analytical Technology (PAT) concept to control and ensure in real-time product quality in development and manufacturing. PAT is a key component of the Quality-by-Design (QbD) framework promoted by the regulatory authorities, aiming the building of product quality based on both a strong scientific background and a quality risk management approach.An analytical method based on near infrared (NIR) spectroscopy was developed as a PAT tool to control on-line an API (active pharmaceutical ingredient) crystallization. During this process the API and residual solvent contents need to be precisely determined to reach a predefined seeding point. An original methodology based on the QbD principles was applied to conduct the development and validation of the NIR method and to ensure that it is fitted for its intended use. Partial least squares (PLS) models were developed and optimized through chemometrics tools in order to quantify the 2 analytes of interest. The method was fully validated according to the official requirements using the accuracy profile approach. Besides, a real-time process monitoring was added to the validation phase to prove and document that the method is fitted for purpose.Implementation of this method as an in-process control at industrial plant from the launch of this new pharmaceutical process will enable automatic control of the crystallization step in order to ensure a predefined quality level of the API. Other valuable benefits are expected such as reduction of the process time, and suppression of a difficult sampling and tedious off-line analyzes

Les entreprises pharmaceutiques ont progressivement adopté le concept de Process Analytical Technology (PAT) afin de contrôler et d'assurer en temps réel la qualité des produits pharmaceutiques au cours de leur production. Le PAT et un composant central du concept plus général de Quality-by-Design (QbD) promu par les agence régulatrices et visant à construire la qualité des produits via une approche scientifique et la gestion des risques.Une méthode basée sur la spectroscopie proche infrarouge (PIR) a été développée comme un outil du PAT pour contrôler en ligne la cristallisation d'un principe actif pharmaceutique. Au cours du procédé les teneurs en principe actif et en solvant résiduel doivent être déterminées avec précision afin d'atteindre un point d'ensemencement prédéfini. Une méthodologie basée sur les principes du QbD a guidé le développement et la validation de la méthode tout en assurant l'adéquation avec son utilisation prévue. Des modèles basés sur les moindres carrés partiels ont été construits à l'aide d'outils chimiométriques afin de quantifier les 2 analytes d'intérêt. La méthode a été totalement validée conformément aux requis officiels en utilisant les profils d'exactitude. Un suivi du procédé en temps réel a permis de prouver que la méthode correspond à son usage prévu.L'implémentation de cette méthode comme à l'échelle industrielle au lancement de ce nouveau procédé permettra le contrôle automatique de l'étape de cristallisation dans le but d'assurer un niveau de qualité prédéfini de l'API. D'autres avantages sont attendus incluant la réduction du temps du procédé, la suppression d'un échantillonnage difficile et d'analyses hors ligne fastidieuses
Pharmaceutical companies are progressively adopting and introducing the Process Analytical Technology (PAT) concept to control and ensure in real-time product quality in development and manufacturing. PAT is a key component of the Quality-by-Design (QbD) framework promoted by the regulatory authorities, aiming the building of product quality based on both a strong scientific background and a quality risk management approach.An analytical method based on near infrared (NIR) spectroscopy was developed as a PAT tool to control on-line an API (active pharmaceutical ingredient) crystallization. During this process the API and residual solvent contents need to be precisely determined to reach a predefined seeding point. An original methodology based on the QbD principles was applied to conduct the development and validation of the NIR method and to ensure that it is fitted for its intended use. Partial least squares (PLS) models were developed and optimized through chemometrics tools in order to quantify the 2 analytes of interest. The method was fully validated according to the official requirements using the accuracy profile approach. Besides, a real-time process monitoring was added to the validation phase to prove and document that the method is fitted for purpose.Implementation of this method as an in-process control at industrial plant from the launch of this new pharmaceutical process will enable automatic control of the crystallization step in order to ensure a predefined quality level of the API. Other valuable benefits are expected such as reduction of the process time, and suppression of a difficult sampling and tedious off-line analyzes

L’un des nombreux défis pour l’industrie pharmaceutique est de développer des procédés compétitifs pour produire des principes actifs de hautes qualités à bas coût. Pour ce faire, plusieurs sociétés se tournent vers la chimie en flux continu et les avantages qu’elle présente comparé au batch traditionnel. C’est pourquoi ces travaux de thèse se centrent sur le développement d’un procédé continu allant des matières premières au principe actif. La première étape pour parvenir à ce but fut de collecter des données sur le procédé batch industriel actuel. Il se compose de trois étapes de réactions chimiques, une de séparation chromatographique et une étape de cristallisation. A partir de là, la chimie de chaque réaction a été adaptée pour profiter au mieux des avantages du flux continu. La dissipation de chaleur étant plus efficace qu’en batch il fut possible de développer une réaction exothermique sans solvant à haute température. Une étude cinétique a été réalisée afin de modéliser cette réaction. Ensuite, cet outil fut utilisé pour déterminer les conditions opératoires optimales théoriques de la réaction et en guider l’optimisation ainsi que la conception du futur réacteur. La deuxième partie de ce travail se focalise sur la cristallisation en continu du principe actif avec la technique des jets impactant. Il est nécessaire d’avoir un contrôle précis sur la distribution de taille de particules (DTP) et la morphologie des cristaux. En effet, le principe actif peut cristalliser sous deux formes compétitives : cristaux cubiques ou en forme d’aiguilles. Les cubes sont la forme désirée. La technique des jets impactant a été sélectionnée car c’est un procédé continu qui permet la génération de fines particules avec une DTP resserrée. La sursaturation est généralement crée en impactant un jet de solution de principe actif avec un jet d’anti-solvant. Ici, le solvant et l’anti-solvant sont les mêmes. Seule une large différence de température entre les deux jets génère la sursaturation. En testant différentes conditions opératoires, une « zone cubique » a été définie, où seuls des cristaux de forme désirée sont générés. Une fois la nucléation maîtrisée, le murissement et la séparation solide-liquide furent étudiés pour développer un procédé complet de cristallisation. En combinant les recherches sur le développement des réactions chimiques et l’étape de cristallisation, un procédé continu complet fut proposé et comparé au procédé batch actuel afin d’évaluer les bénéfices apportés par la transposition en flux continu à la production du principe actif
One of the many challenges in the pharmaceutical industry is to develop competitive processes to generate high quality active pharmaceutical ingredient (API) at low cost. To achieve this goal, many companies are looking towards flow chemistry and the advantages it affords, compared to traditional batch production. It is why this PhD work is focused on developing a continuous process from the raw materials to the API. The first step to achieve this goal was to collect data on the actual industrial batch process. It is composed of five steps, three steps of chemical reactions, one chromatographic separation and a crystallization step. From this starting point, the chemistry of each reaction was adapted to better use the advantages of flow chemistry. Thus, as the heat recovery in a continuous reactor is more efficient than in batch, it was possible to develop an exothermal reaction in neat conditions and at high temperature. A kinetic study was undertaken to gather knowledge on the reaction and develop a reaction model. This tool was used to find theoretical optimal operating conditions (temperature, residence time…) to guide the optimisation of the reaction and to design the future industrial reactor. The second part of this work is focused on the continuous crystallization of the API using the two impinging jets technology. It is required to have a tight control upon the morphology of the crystals and the particle size distribution (CSD). Indeed, the targeted API may crystallize under two competitive forms: cubic and needle crystals. The cubic form is the desired one. The two impinging jets technique was selected, since it is a continuous process able to generate small particles with a narrow CSD. The supersaturation is traditionally generated by impacting a jet of API solution with an anti-solvent one. Here, the solvent and the antisolvent are identical and only a large temperature difference between both streams is used to create the supersaturation. By screening different operating conditions, a “cubic zone” could be defined. Within this zone, only the desired crystal form is generated. Once the nucleation was under control, crystal growth and solid-liquid separation were studied to develop a complete crystallization process. By combining the research on the development of the chemical reactions and the crystallization step a full continuous process was proposed and was compared to the current batch one in order to evaluate the benefits brought by the flow chemistry to the API production

Thesis: M.B.A., Massachusetts Institute of Technology, Sloan School of Management, in conjunction with the Leaders for Global Operations Program at MIT, 2018.
Thesis: S.M., Massachusetts Institute of Technology, Department of Mechanical Engineering, in conjunction with the Leaders for Global Operations Program at MIT, 2018.
Cataloged from PDF version of thesis.
Includes bibliographical references (pages 92-95).
This thesis presents work that was done to improve the effectiveness of cleaning processes at an active pharmaceutical ingredient (API) manufacturing site that was in the phase of engineering trials and cleaning cycle development. Cleaning cycles executed on the site prior to the project were found to be inconsistent in cleaning the equipment to the desired specifications. Lack of repeatability of cleaning processes was hypothesized to be a resultant of inadequate process control and monitoring. Statistical Process Control (SPC) implemented using process automation was found to improve the success rate of cleaning processes significantly. SPC introduction required breaking down the cleaning operation into component steps, identifying critical process parameters (CPPs) and calculation of control limits using Shewhart Control Charts for these CPPs. Significant modifications were done to the automation controls for the recipe to ensure deviations from recipe are captured and appropriate actions are taken by the system or the operator to bring the process back in control. The success rate of cleaning processes improved from 38% to 72% post the implementation of Phase I of SPC with the newer non-conformances being associated to special external causes outside the control of the process. Real-time Multivariate Statistical Process Monitoring (RT-MSPM) was also introduced and piloted as a future opportunity for enhanced control and continuous quality improvement. Multivariate statistical process control eliminates the need to monitor multiple control charts (one for each variable) at the same time accounting for the correlations among process variables.
by Rajkumar aka Rahul Shankarlal Nechlani.
M.B.A.
S.M.

La cristallisation en solution est une opération unitaire essentielle du génie chimique. Les conditions opératoires dans lesquelles cette opération est menée déterminent sa productivité et la qualité des cristaux produits, par le biais de l’influence qu’elles ont sur les cinétiques de germination et de croissance. De nombreuses études ont mis en évidence que les conditions d’écoulement influencent significativement ces deux cinétiques. Néanmoins, une compréhension profonde de la nature de cette influence n’a, à l’heure actuelle, pas encore été atteinte. Ceci cause bien souvent des problèmes tant au niveau du procédé que du produit et a également pour conséquence que l’effet des conditions d’écoulement sur les cinétiques de cristallisation est rarement exploité de manière à en tirer le meilleur avantage.La première partie de ce travail a été consacrée à l’étude de l’effet des conditions d’écoulement sur les cinétiques de cristallisation en solution (germination et croissance), avec pour cas pratique la cristallisation d’hydrates de dioxyde de carbone (CO2), une solution émergeante pour la capture et la séquestration du CO2 (gaz à effet de serre majeur).De manière à étudier l’impact des conditions d’écoulement sur le taux de formation des hydrates de CO2, des expériences de formation d’hydrates de CO2 ont été réalisées dans un réacteur de type cuve agitée de 20 L mis en œuvre de manière semi-continue dans des conditions d’écoulement variées, produites à l’aide de trois mobiles d’agitations différents (une turbine à pales inclinées, un MaxblendTM et un DispersimaxTM) opérés à différentes vitesses de rotations. Un modèle mathématique original de l'ensemble du processus de formation des hydrates de CO2 attribuant une résistance à chacune de ses étapes constitutives a été établi. Pour chaque condition expérimentale, le taux de formation est mesuré et l’étape limitante est déterminée sur base de la valeur des différentes résistances. Les trois mobiles d’agitations étudiés sont comparés relativement à leur efficacité et, pour chaque mobile, l’influence de la vitesse de rotation sur l’étape limitante est discutée. En l’occurrence, il est montré que des limitations dues aux transferts de chaleur peuvent se produire à l'échelle relativement petite utilisée dans cette étude.L’étude de l’impact des conditions d’écoulement sur la cinétique de germination des hydrates de CO2 s’est concentrée sur la caractérisation de l’effet du taux de cisaillement sur le temps d’induction associé à cette formation (proportionnel à cette cinétique). Cette étude a été basée sur la réalisation de mesure de temps d’induction au cours d’expériences de formation d’hydrates de gaz, utilisant le système CO2-H2O-tetrahydrofuran comme système modèle, réalisées dans un réacteur de type Couette-Taylor. L’application, à la phase liquide dans laquelle prend place la formation des hydrates de gaz, de différents taux de cisaillement (entre 50 et 300 s-1), maintenus constants tout au long de l’expérience de formation, a révélé que le temps d’induction moyen diminuait significativement lorsque le taux de cisaillement appliqué à la phase liquide augmentait. Il a été montré que cette diminution peut être principalement attribuée à une diminution du temps nécessaire à l’apparition de germes stables d’hydrates et à leurs croissances jusqu’à une taille macroscopiquement détectable. Il a également été montré que le temps d’induction moyen peut également être significativement réduit par l’application, à la phase liquide, d’un haut taux de cisaillement (900 s-1) durant une période relativement courte et définie.La seconde partie de ce travail a été dédiée au développement d’une stratégie permettant d’améliorer le contrôle des procédés de cristallisation de substances pouvant cristalliser sous plusieurs formes cristallines, et ce, relativement à la forme cristalline générée au cours et à l’issue de ces procédés. Le cas pratique de cette partie du travail est le développement d’un procédé de cristallisation en solution par refroidissement en mode batch d’un principe actif, récemment développé par la société pharmaceutique UCB, présentant deux formes cristallines connues. La robustesse et la reproductibilité de ce procédé vis-à-vis de la production de la forme cristalline d’intérêt et de la prévention de l’occurrence d’un phénomène de prise en masse, dû à une formation massive de cristaux de la forme cristalline indésirable, sont deux impératifs ayant guidés son développement.Le procédé qui a été envisagé dans le cadre de la deuxième partie de ce travail est basé sur la production de semences cristallines de forme I (la forme d’intérêt) par germination primaire au sein d’un réacteur tubulaire suivie d’une croissance de ces semences en milieu agité contrôlé en température. Les propriétés particulières de l’écoulement mis en œuvre au sein du réacteur tubulaire permettent d’y contrôler finement l’allure des champs de température et de concentration (et donc de sursaturation) et, de manière inédite, de circonscrire l’apparition de cristaux à la partie centrale de l’écoulement (afin de prévenir tout risque d’incrustation de la paroi interne du réacteur). Les expériences réalisées dans ce travail montrent que, associé aux conditions expérimentales utilisées, ce dispositif permet de produire des semences cristallines de forme I de manière reproductible. Elles montrent également qu’un contrôle adéquat des conditions initiales dans lesquelles les semences cristallines de forme I sont amenées à croitre ainsi que du taux de refroidissement utilisé pour entretenir cette croissance permet de garantir que celle-ci se déroule sans que le phénomène de prise en masse ne prenne place. Il est mis en évidence que ce contrôle repose sur la prévention de toute formation indésirable de cristaux de forme II par un maintient, en tout temps, d’un niveau de sursaturation ne dépassant pas une valeur critique donnée. Enfin, ces expériences montrent aussi que le type d’agitation utilisée dans ce travail n’a pas d’influence sur l’occurrence de la prise en masse mais a une influence majeure sur l’état de surface, la taille moyenne et la distribution en taille des cristaux produits.
Solution crystallization is an essential unit operation in the chemical engineering field. Through their effect on the nucleation and growth kinetics, the operating conditions of such an operation determine its productivity and the quality of the produced crystals. An important number of studies have shown that the flow conditions have a significant influence on these two kinetics. Nonetheless, a deep understanding of the nature of this effect is still lacking, which often leads to severe difficulties in the development and operation of crystallization processes and impedes the emergence of positive applications of this effect.The first part of this work has been dedicated to the study of the effect of the flow conditions on the solution crystallization kinetics (nucleation and growth). Carbon dioxide (CO2) hydrate crystallization, an emerging method for the separation and capture of CO2, was used as a practical case.CO2 hydrate formation experiments have been performed in a 20 L semi-batch stirred tank reactor using three different impellers (a down-pumping pitched blade turbine, a Maxblend™, and a Dispersimax™) at various rotational speeds to examine the impact of the flow conditions on the CO2 hydrate formation rate. An original mathematical model of the CO2 hydrate formation process that assigns a resistance to each of its constitutive steps has been established. For each experimental condition, the formation rate is measured and the rate-limiting step is determined on the basis of the respective values of the resistances. The efficiencies of the three considered impellers are compared and, for each impeller, the influence of the rotational speed on the rate-limiting step is discussed. For instance, it is shown that a formation rate limitation due to heat transfer can occur at the relatively small scale used to perform our experiments.The investigation of the impact of the flow conditions on the nucleation kinetics of CO2 hydrates was focused on the characterization of the effect of the fluid shear rate on the induction time of gas hydrate formation (proportional to this kinetics). This study was based on induction time measurements during gas hydrate formation experiments, using the CO2-H2O-tetrahydrofuran system as model system, realized in a Couette-Taylor reactor. The investigation of the effect of the application of a constant shear rate (50 to 300 s-1) to the liquid phase from which the hydrates are formed revealed that the mean induction time decreases significantly as the applied shear rate increases. This could primarily be attributed to a decrease in the time required for stable gas hydrate nuclei to be generated and to grow to a macroscopically detectable size. The induction time could also be significantly reduced by the application of a high shear rate (900 s-1) to the liquid phase for a relatively short, defined period of time.The second part of this work has been dedicated to the development of a strategy for the improvement of the control of crystallization processes involving compounds able to crystallize under several crystalline forms, relatively to the crystalline form generated during and at the end of these processes. The strategy examined in this work was applied to the development of a batch cooling solution crystallization process of an active pharmaceutical ingredient, recently developed by the pharmaceutical company UCB, exhibiting two known crystalline forms. The robustness and the reproducibility of this process relatively to production of the desired crystalline form produced and the prevention of caking, due to the massive formation of crystals of the undesired crystalline form, were the two main priorities that have driven its development.The process considered in the second part of this work is based on the production of form I (the desired form) crystalline seeds through nucleation in a tubular reactor followed by the growth of these seeds in an agitated medium controlled in temperature. The particular properties of the flow conditions in the tubular reactor enable the temperature and the concentration fields, and therefore the supersaturation field, to be finely tuned and, in an original manner, to confine the emergence of new crystals in the center part of the flow (to prevent any fouling of the inner surface of the reactor). The experiments performed in this work showed that, coupled to the experimental conditions used, this device enables to reproducibly generate form I crystalline seeds. The experiments also revealed that a proper control of the initial conditions in which these seeds are brought to grow and of the cooling rate used to sustain this growth allows ensuring that this growth takes place without caking. It is shown that such a control lies on the inhibition of the formation of undesired form II crystals by keeping, at all times, the supersaturation level under a defined critical value. Finally, the experiments showed that the type of agitation used in this work does not influence the occurrence of caking but has a significant impact on the crystals surface quality, mean size, and size distribution.
Doctorat en Sciences de l'ingénieur et technologie
info:eu-repo/semantics/nonPublished

Protein pharmaceuticals is one of the fastest growing class of therapeutics today. However, they pose a lot of challenges in production lines due to their poor stability. Protein aggregation is one of the most common results of protein instability and is a risk factor regarding the quality of therapeutics. This master thesis at RISE focused on validating the techniques Dynamic Light Scattering (DLS) and multi angle DLS (MADLS) with respect to detection of aggregation. The model protein B-lactoglobulin was used to assess the robustness and accuracy of DLS. A comparison between two instruments from Malvern, Zetasizer Nano (2006) and Zetasizer Ultra (2018) was done with respect to DLS. It was determined that they were in many ways equivalent, but the newer model Ultra was favourable due to reduced noise and its ability to detect a lower concentration of aggregates. MADLS produced more precise results which is reflected in narrower distributions and has a higher sensitivity than DLS with regards to separating particles near in size. Both techniques proved sensitive enough to differentiate between aggregates and native protein. Experimental trials were performed with an active pharmaceutical ingredient, API. The experimental trials with the API aimed to investigate what conditions and surface-interfaces that might pose a risk for aggregation. Despite efforts put in creating an environment where aggregation could be monitored, aggregation could not be established. Measurements with the API generated less reliable results due to noisy data and a lack of reproducibility between individual measurements.

This project focus on investigating the dissolution of low water-soluble intermediate organic compounds called active pharmaceutical ingredients (API) and organic substances that are manufactured by a pharmaceutical company, Cambrex Karlskoga in Sweden. Several dissolution methods were used and evaluated using methods including total organic carbon (TOC), chemical oxygen demand (COD), biochemical oxygen demand (BOD) and Microtox toxicity test. The selection of solvents were based on previous studies and specifications from the Swedish Institute of Standards, SIS.The performance of eight solvents for different organic substances were evaluated using the above mentioned methods. Solvents that are highly volatile and have low solubility in water were excluded. Therefore, dimethyl sulfoxide (DMSO), dimethylformamide (DMF) and Pluronic F-68, that had highest water solubility, low acute toxicity and not degradable by microorganisms, were further used to dissolve four organic substances. Furthermore, DMSO and DMF were then also used to dissolve four censored chemicals with addition of physical treatment and solvent mixtures (DMF:DMSO with ratio 1:2).Results from each method were discussed and statistical tests were also performed in order to compare different dissolution methods. In addition, quality control and quality assurance were made in order to ensure the quality of measured values from analytical methods. Four organic substances were dissolve in DMSO, DMF and Pluronic F-68 with dissolution ≥79% using six ratios of DMSO and DMF and five ratios of Pluronic F-68 which were analyzed using TOC. Physical treatment increased dissolution of two APIs with 40%. Using BOD, para-aminobenzonic acid (PABA) and 5-nitroisophthalic acid (5-NIPA) had values higher than the guideline values, which indicate high biodegradability of these organic substances. PABA, 5-NIPA and bupivacaine base were acute toxic where PABA showed EC50 values of 27.9 mg/L using DMSO and 36.0 mg/L using DMF, and EC50 values of 5-NIPA were 102 mg/L using DMSO and 84.0 mg/L using DMF, and bupivacaine base had EC50 value of 174 mg/L using solvent mixture (DMF:DMSO with ratio 1:2). With increasing amount of Pluronic F-68, 5-NIPA had increased values of EC50, thereby Pluronic F-68 was not appropriate to use.In conclusion, DMSO and DMF were most appropriate solvents to use in order to dissolve APIs and organic substances with analyte: DMSO ratio of 1:0.5 and analyte: DMF ratio of 1:0.25. In addition, physical treatment could be used in order to increase dissolution of the APIs.

The production of stable solid crystalline material is an important issue in the pharmaceutical industry and the challenge to control the desired active pharmaceutical ingredient (API) with the specific chemical and physical properties has led to more development in the drug industry. Increasing the solubility and the dissolution of the drug will increase its bioavailability; therefore the solubility can be improved with the change in the preparation method. The formation of co-crystals has emerged as a new alternate to the salts, hydrates and solvate methods since the molecules that cannot be formed by the usual methods might crystallise in the form of co-crystals. Co-crystals are multicomponent crystals which can be known as supramolecules and are constructed by the non covalent bonds between the desired former and co-former. Therefore the synthon approach was utilised to design co-crystals with the specific properties, this involves the understanding of the intermolecular interactions between these synthons. These interaction forces can be directed to control the crystal packing in the design of the new crystalline solid with the desired chemical and physical properties. The most familiar synthon was the amide group with its complementary carboxylic group, in this work isonicotinamide and benzoic acid were chosen to design co-crystal and much literature exist that introduce the determination of co-crystal growth from these two compounds. The growth of co-crystals was carried out in water, ethanol and ethanol / water mixed solvent (30 - 90 % ethanol) by utilising the Cryo-Compact circulator. Co-crystals (1:1) and (2:1) were grown in ethanol and water respectively and a mixture of both phases were grown in the mixed solvent. All the phases were examined by powder X-ray diffraction (PXRD), Raman, Infrared and 1H-NMR spectroscopy. The solubility of isonicotinamide, benzoic acid, co-crystals (1:1) and (2:1) in water, ethanol and ethanol/water mixed solvent (30 - 90 % ethanol) were determined at 25 °C, 35 °C and 40 °C by utilising the React-Array Microvate. It was important to understand some of the thermodynamic factors which control the formation of these polymorphs such as the change in the enthalpy and the change in the entropy. Also it was important to study the pH behaviour during dissolution of the former, co-former and co-crystals in water, ethanol and ethanol/water mixed solvent (30 - 90 % ethanol) in-order to examine the affect of the solvent composition on the solubility and to identify if some ions were formed during the dissociation and how this could affects the formation of co-crystals. A discussion has been introduced in this research of how similar solubility of the compounds maps the formation of the typical ternary phase diagram of the mixture of 1:1 while compounds with different solubility maps the formation of skewed phase diagram as shown in section 1.6.2.3. In this project an isotherm ternary phase diagram at 20 °C and 40 °C was constructed to map the behaviour of benzoic acid and isonicotinamide and to show all possible phases formed and the regions where all phases are represented in the ternary phase diagram were determined by the slurry method. The ternary phase diagram was used to design a drawn out and cooling crystallisation at 100 cm3 solution of 50 % ethanol / water mixed solvent and a study of the impact of seeds of co-crystals 1:1 on the cooling crystallisation method.

Die Kristallisation ist ein wichtiger Teilprozess bei der industriellen Herstellung vieler Materialien und Medikamente. Es ist jedoch ein vielschichtiger, physikalischer Vorgang, der noch nicht vollständig aufgeklärt ist. Der Schwerpunkt dieser Arbeit liegt auf der Kristallisation von organischen, polymorphen Verbindungen aus unterschiedlichen Lösungsmitteln. Die Kristallisationsstudien wurden in einem akustischen Levitator mit Klimakammer, der den Einfluss von Temperatur, Feuchtigkeit und festen Oberflächen steuert, durchgeführt. Verschiedene analytische in-situ-Methoden und deren Kopplung kamen für die Analyse der Kristallisationsabläufe zum Einsatz. Als Unterstützung für die Interpretation der beobachteten Phänomene wurden unter äquivalenten Bedingungen Moleküldynamik-Simulationen vorgenommen. Die Kristallisation der Modellverbindungen zeigte verschiedene spezifische Kristallisationspfade, die nicht dem klassischen Kristallisationsmodell entsprachen. Zunächst verdampfte das Lösungsmittel, was mit einer Konzentrationszunahme der Lösung und der Ausbildung von charakteristischen amorphen Phasen (Polyamorphismus) einherging, und schließlich trat die Kristallisation ein. Durch die oberflächenfreie Kristallisation wurde ausschließlich nur ein Polymorph ein- und derselben Verbindung als Kristallisationsprodukt isoliert. Die gezielte Wahl der Ausgangskonzentration und eines Lösungsmittels ermöglichte die Steuerung des Kristallisationsverlaufs hin zu einer gewünschten Kristallstruktur des untersuchten Materials. Die Ergebnisse dieser Arbeit unterstützen das Verständnis über den komplexen Ablauf des Kristallisationsvorgangs, gleichzeitig zeigen sie weitere Ansätze auf, die Kristallisation zu untersuchen. Die neuen Erkenntnisse sind hilfreich bei der Optimierung der Herstellungsprozesse verschiedener Materialien.
Crystallization is a complex process, which is used in different processes in the industrial production of various materials. The limited understanding about its fundamental mechanisms challenges the control of crystallization and influences the quality of the materials. The research of this work concentrates on the crystallization studies of organic model systems (active pharmaceutical ingredients) from different organic solvents in an acoustic levitator. This specific sample environment regulates the influence that solid surfaces, temperature, and humidity have on the crystallization process. The investigations were performed with in situ analytical techniques and theoretical simulations to gain a comprehensive insight into processes, occurring intermediates, and required reaction conditions. The results show that the model systems follow specific crystallization pathways different than those predicted by the classical nucleation theory. The crystallization proceeded via the evaporation of the solvent and the formation of characteristic amorphous phases (polyamorphism) into one crystalline structure of the compound. The targeted choice of the solvent and the concentration enabled the guidance of the pathways, therefore, resulting in the isolation of one desired crystalline structure. The findings are of great interest and they help explain the crystallization mechanisms on a molecular level, which is a fundamental contribution for the optimization of manufacturing processes.

The oral drug delivery is widely used and accepted routes of administration, but it fails to provide the therapeutic effectiveness of drugs due to low solubility, poor compression and oral bioavailability. Crystal engineering is the branch where the modification of API is of great importance. Co-crystallization of API using a co-former is a hopeful and emerging approach to improve the performance of pharmaceuticals, such as micromeritic properties, solubility, dissolution profile, pharmacokinetics and stability. Pharmaceutical co-crystals are multicomponent systems in which one component is an active pharmaceutical ingredient and the others are pharmaceutically acceptable ingredients that are of GRAS category. In multidrug co-crystals one drug acts as API and other drug acts as coformer. This chapter illustrates the guidance for more efficient design and manufacture of pharmaceutical co-crystals with the desired physicochemical properties and applications.

A relevant area of research in the preformulation phase for the development of new dosages is active pharmaceutical ingredient (API)-excipient compatibility. The possibilities of chemical and physical interaction of API and the excipients may affect how efficient and effective it is, while displaying an impact on the nature, stability and availability of API. The most common signs of deterioration of an API are changes in the color, taste, odor, polymorphic form, or crystallization (pharmaceutical incompatibility). These changes arise from chemical reactions with the excipient, leading to degradation of the API. The active components are usually more stable than solid dosage forms, and although testing the compatibility of API-excipients is essential, no protocol has yet been accepted to evaluate their interactions. Fourier Transform Infrared Spectroscopy (FT-IR), Differential Scanning Calorimetry (DSC), Isothermal Stress Testing-High Performance Liquid Chromatography (IST-HPLC), Hot Stage Microscopy (HSM), Scanning Electron Microscopy (SEM), Solid state Nuclear Magnetic Resonance Spectroscopy (ssNMR) and Power X-ray Diffraction (PXRD) are commonly used as screening techniques for assessing the compatibility of an active pharmaceutical ingredient (API) with some currently employed excipients. The potential physical and chemical interactions between drugs and excipients can affect the chemical nature, the stability and bioavailability of drugs and, consequently, their therapeutic efficacy and safety. Once the solid-state reactions of a pharmaceutical system are understood, the necessary steps can be taken to avoid reactivity and improve the stability of drug substances and products. In this chapter, we summarize the techniques to investigate the compatibility between APIs and excipients.

Nutraceuticals is an umbrella term for therapeutic leads derived from plants, animals and/or microbial species. Being synthesized in nature’s own laboratory a nutraceuticals have structural and functional features for interacting with an array of physiological targets. However, because of this very structural complexity and diversified nature, nutraceuticals often suffer from diminished gastrointestinal (GI) absorption and limited systemic bioavailability. Thus, in-spite of having an obvious edge over synthetic molecules, pharmaceutical applicability of nutraceuticals play second fiddle in the present pharmaceutical prospective. In this regard, co-crystallization of nutraceuticals have evolved as an attractive prospect. Co-crystallization causes stoichiometric non-covalent binding between nutraceutical API (active pharmaceutical ingredient) and a pharmaceutically acceptable co-former creating a single-phase crystalline material. Nutraceutical co-crystals thus created possess excellent absorption and bioavailability attributes. The principal aim of the current chapter is to highlight co-crystallization as the means of nutraceutical ascendancy over toxic synthetic drugs currently dominating the pharmaceutical market. In the current chapter the authors provide a detail exposition on the methods and application of co-crystallization in context of nutraceutical absorption and bioavailability. Herein, we discuss in detail about the constituents, characteristics, mechanism of action and protocol for preparation of nutraceutical co-crystals with relevant references from current and past studies.

Co-crystals are multicomponent molecular materials held together through non-covalent interactions that have recently attracted the attention of supramolecular scientists. They are the monophasic homogeneous materials where a naturally occurring pharmaceutical active ingredient (API) and a pharmaceutically acceptable co-crystal former are bonded together in a 1:1 via non-covalent forces such as H-bonds, π–π, and van der Waals forces. Co-crystallization is a promising research field, especially for the pharmaceutical industry, due to the enormous potential of improved solubility and bioavailability. Co-crystals are not the only multicomponent molecular materials, as there are many other forms of multicomponent molecular solids such as salts, hydrates, solvates, and eutectics. The formation of co-crystals can roughly be predicted by the value of ∆pKa, that is, if the ∆pKa is more than 3, then this monophasic homogeneous material usually falls in the category of salts, whereas if the ∆pKa is less than 2, then co-crystals are usually observed. A number of methods are available for the co-crystal formation, broadly classified into two classes established on state of formation, that is, solution-based and solid-based co-crystal formation. Similarly, a number of techniques are available for the characterization of co-crystals such as Fourier transforms-infrared spectroscopy, single-crystal and powder X-ray diffraction, etc. In this chapter, we will discuss the available methods for co-crystallization and its characterization.

Malaria is a complex disease associated with a variety of epidemiology and clinical symptoms worldwide. Despite the availability of a variety of antimalarial medications, national policies of many countries advocate for a single-medication first-line therapy for the majority of clinical malaria symptoms. However, the studies revealed that using multiple first-line medicines against malaria works more effectively. In this scenario, single-target monotherapy approaches have difficulties since malaria symptoms are seldom caused by single molecular entities. The current work is based on the critical literature review and primary sources as well as secondary databases. The chapter outline is as follows: (1) main antimalarial plant-derived active pharmaceutical ingredients (APD-APIs), (2) limitations of single APD-APIs and shift to multiple first-line therapies in malaria treatment, (3) techniques in the development and properties of APD-APIs co-crystals. The search for novel plant-derived antimalarial medicines and the development of antimalarial co-crystals are essential in the fight against antimalarial drug resistance.

Abstract The application of three-dimensional printers can be revolutionary as a tool for the customization and personalization of pharmaceutical dosage forms. The areas of 3D printing applicable to pharmaceutical manufacturing can be segregated into three categories: extrusion technologies, powder-bed fusion, and stereolithography. Common extrusion-based technologies are fused deposition modeling and pressure-assisted microsyringe; powder-bed fusion is separated by binder jet and selective laser sintering. The synergies between pharmaceutical, or active pharmaceutical ingredient (API), and polymer printing are discussed in this article, with particular attention to how the incorporation of small-molecule APIs changes the material selection, design considerations, processing parameters, and challenges associated with each technology.

This chapter discusses drug product degradation caused by the interaction between the active pharmaceutical ingredient (API) and components other than the API, including counter ions (if the API is an acid or base), excipients, impurities and degradants of excipients, and leachable impurities. In the first category of direct drug-excipient interaction, the mechanisms of the Maillard reaction including the Amadori rearrangement are discussed, followed by several examples involving secondary amine drugs and excipients containing reducing-end sugars. This chapter also examines a number of case studies where drug degradation is caused by impurities (hydrogen peroxide, formaldehyde, etc.) and degradants of excipients.

Pharmaceutical development of solid-state formulations requires testing for uniformity and active pharmaceutical ingredient stability. We demonstrate fast chemical imaging by epi-detected sparse spectral sampling stimulated Raman scattering to quantify API and excipient degradation and distribution.

Abstract Dry powder inhalers (DPIs), used as a means for pulmonary drug delivery, typically contain a combination of active pharmaceutical ingredient (API) and significantly larger carrier particles. The micro-sized drug particles — which have a strong propensity to aggregate and poor aerosolization performance — mixed with significantly large carrier particles that are unable to penetrate the mouth-throat region to deagglomerate and entrain the smaller API particles in the inhaled airflow. The performance of a DPI, therefore, depends on entrainment the carrier-API combination particles and the time and thoroughness of the deagglomeration of the individual API particles from the carrier particles. Since DPI particle transport is significantly affected by particle-particle interactions, very different particles sizes and shapes, various forces including electrostatic and van der Waals forces, they present significant challenges to Computational Fluid Dynamics (CFD) modelers to model regional lung deposition from a DPI. In the current work, we present a novel high fidelity CFD discrete element modeling (CFD-DEM) and sensitivity analysis framework for predicting the transport of DPI carrier and API particles. The work integrates exascale capable CFD-DEM and sensitivity analysis capabilities by leveraging the Department of Energy (DOE) laboratories libraries: Multiphase Flow Interface Flow Exchange (MFiX) for CFD-DEM, and Trilinos for leading-edge portable/scalable linear algebra. We carried out a sensitivity analysis of various formulation properties and their effects on particle size distribution with Dakota, an open source software designed to exploit High-Performance Computing (HPC) capabilities of a massively parallel supercomputer. We developed wrappers to exchange information among these state-of-the-art tools for DPI.