Hydrophilic polymers in a swellable matrix tablet hydrate quickly to form a hydrogel layer on the exterior of the dosage once in contact with water or biologic fluid. The resultant hydrogel serves as a barrier to regulate water permeation into the matrix and drug diffusion from the preparation. It is therefore important to understand how the polymer is hydrated and what mechanism exists between hydrogel formation and drug dissolution from a swellable matrix tablet. In this thesis, a TA texture analyzer was utilized to monitor and characterize matrix swelling properties during dissolution process. Multiple regression models were employed to analyze the quantitative relationship between drug dissolution or hydrogel thickness and major formulation factors (polymer ratio, drug solubility). Modified release matrix tablets were prepared using four APIs with a range of aqueous solubility, i.e., acetaminophen (ACE), chlorpheniramine (CHL), ibuprofen (IBU), and pseudoephedrine hydrochloride (PSE). Two hydrophilic polymers, polyethylene oxide (PEO) and hydroxypropyl methylcellulose (HPMC) were selected and tested as primary matrix polymers for the formulations. It was found from the experiments that multiple regression model was capable of estimating drug dissolution for both PEO and HPMC matrix preparations. Based on major formulation factors the regression models provide satisfactory prediction of drug release, which could further aid in formulation development and optimization.

Hydrophilic polymers in a swellable matrix tablet hydrate quickly to form a hydrogel layer on the exterior of the dosage once in contact with water or biologic fluid. The resultant hydrogel serves as a barrier to regulate water permeation into the matrix and drug diffusion from the preparation. It is therefore important to understand how the polymer is hydrated and what mechanism exists between hydrogel formation and drug dissolution from a swellable matrix tablet. In this thesis, a TA texture analyzer was utilized to monitor and characterize matrix swelling properties during dissolution process. Multiple regression models were employed to analyze the quantitative relationship between drug dissolution or hydrogel thickness and major formulation factors (polymer ratio, drug solubility). Modified release matrix tablets were prepared using four APIs with a range of aqueous solubility, i.e., acetaminophen (ACE), chlorpheniramine (CHL), ibuprofen (IBU), and pseudoephedrine hydrochloride (PSE). Two hydrophilic polymers, polyethylene oxide (PEO) and hydroxypropyl methylcellulose (HPMC) were selected and tested as primary matrix polymers for the formulations. It was found from the experiments that multiple regression model was capable of estimating drug dissolution for both PEO and HPMC matrix preparations. Based on major formulation factors the regression models provide satisfactory prediction of drug release, which could further aid in formulation development and optimization.

A intensificação de processos é importante na busca de equipamentos e reações menos nocivos e seguros, um exemplo é a aplicação de microrreatores. A indústria farmacêutica é a maior beneficiária dessa tecnologia, pois os microrreatores, dispositivos com microcanais de até 100 µm, podem reduzir em anos o tempo necessário para desenvolver e produzir um novo fármaco e podem ser montados em unidades industriais extremamente pequenas e compactas. O aumento de casos de diabetes no Brasil na última década vem incentivando a busca por novos fármacos. Neste trabalho, a aplicação de microrreatores capilares é estudada na síntese do (Z)-5-(4-hidroxi-3-metoxibenzilideno)2,4-tiazolidinadiona (HMTZD) e do (Z)-5-(3-hidroxi-4-metoxibenzilideno)2,4-tiazolidinadiona (MHTZD), obtidos da reação de 2,4-tiazolidinediona (TZD) com 4-hidroxi-3-metoxibenzaldeído (Vanilina) e com seu isômero, 3-hidroxi-4-metoxibenzaldeído (Isovanilina), que podem ser utilizados na síntese de moléculas com atividade biológica. Foram obtidos rendimentos máximos do produto HMTZD, 98% em 480 min de reação e do produto MHTZD, 73% em 120 min de reação, contrariando a literatura que apresenta um tempo de reação para essa síntese de 20 h a 40 h. Na síntese em fluxo no microrreator, ficou evidente que quanto maior a temperatura maior a conversão de TZD e o rendimento do produto, chegando a valores de 100%, para a temperatura de 160°C em etanol. A produção no processo batelada e no microrreator foram calculadas e, quando comparadas, mostraram que apenas dois microrreatores de 1 mL em sua melhor condição de operação são capazes de produzir três vezes mais que um reator batelada de 60 mL. Pelo estudo de cinética, a reação utilizando etanol não favorece a formação de reações em paralelo ou em série. As análises qualitativas comprovaram que os produtos esperados foram formados e com alto grau de pureza. / The process intensification is important in the search for less harmful and safe equipment and reactions, an example is the application of microreactors. The pharmaceutical industry is the largest beneficiary of this technology because microreactors, devices with microchannels up to 100 µm, can reduce the time required to develop and produce a new drug in years and can be mounted in extremely small and compact industrial units. The increase in diabetes cases in Brazil in the last decade has been encouraging the search for new drugs. In this work, the application of capillary microreactors is studied in the synthesis of (Z)-5-(4-hydroxy-3-methoxybenzylidene)2,4-thiazolidinedione (HMTZD) and (Z)-5-(3-hydroxy-4- methoxybenzylidene)2,4-thiazolidinedione (MHTZD), obtained from the reaction of 2,4-thiazolidinedione (TZD) with 4-hydroxy-3-methoxybenzaldehyde (Vanillin) and its isomer, 3-hydroxy-4-methoxybenzaldehyde (Isovanillin), which can be used in the synthesis of molecules with biological activity. Maximum yields of 98% in 480 min, for the product HMTZD, and 73% in 120 min, for the product MHTZD, were obtained, contradicting literature that shows a reaction time for this synthesis of 20 h to 40 h. In the flow synthesis in the microreactor, it was evident that the higher the temperature the higher the conversion of TZD and the yield of the product, reaching 100%, in ethanol working with the temperature of 160°C. The production in the batch process and the microreactor were calculated and, when compared, showed that only two 1 mL microreactors in their best operating condition are able to produce three times more than a 60 mL batch reactor. By the study of kinetics, the reaction using ethanol does not favor the formation of reactions in parallel or in series. The qualitative analyzes showed that the expected products was formed and with a high degree of purity.

A intensificação de processos é importante na busca de equipamentos e reações menos nocivos e seguros, um exemplo é a aplicação de microrreatores. A indústria farmacêutica é a maior beneficiária dessa tecnologia, pois os microrreatores, dispositivos com microcanais de até 100 µm, podem reduzir em anos o tempo necessário para desenvolver e produzir um novo fármaco e podem ser montados em unidades industriais extremamente pequenas e compactas. O aumento de casos de diabetes no Brasil na última década vem incentivando a busca por novos fármacos. Neste trabalho, a aplicação de microrreatores capilares é estudada na síntese do (Z)-5-(4-hidroxi-3-metoxibenzilideno)2,4-tiazolidinadiona (HMTZD) e do (Z)-5-(3-hidroxi-4-metoxibenzilideno)2,4-tiazolidinadiona (MHTZD), obtidos da reação de 2,4-tiazolidinediona (TZD) com 4-hidroxi-3-metoxibenzaldeído (Vanilina) e com seu isômero, 3-hidroxi-4-metoxibenzaldeído (Isovanilina), que podem ser utilizados na síntese de moléculas com atividade biológica. Foram obtidos rendimentos máximos do produto HMTZD, 98% em 480 min de reação e do produto MHTZD, 73% em 120 min de reação, contrariando a literatura que apresenta um tempo de reação para essa síntese de 20 h a 40 h. Na síntese em fluxo no microrreator, ficou evidente que quanto maior a temperatura maior a conversão de TZD e o rendimento do produto, chegando a valores de 100%, para a temperatura de 160°C em etanol. A produção no processo batelada e no microrreator foram calculadas e, quando comparadas, mostraram que apenas dois microrreatores de 1 mL em sua melhor condição de operação são capazes de produzir três vezes mais que um reator batelada de 60 mL. Pelo estudo de cinética, a reação utilizando etanol não favorece a formação de reações em paralelo ou em série. As análises qualitativas comprovaram que os produtos esperados foram formados e com alto grau de pureza. / The process intensification is important in the search for less harmful and safe equipment and reactions, an example is the application of microreactors. The pharmaceutical industry is the largest beneficiary of this technology because microreactors, devices with microchannels up to 100 µm, can reduce the time required to develop and produce a new drug in years and can be mounted in extremely small and compact industrial units. The increase in diabetes cases in Brazil in the last decade has been encouraging the search for new drugs. In this work, the application of capillary microreactors is studied in the synthesis of (Z)-5-(4-hydroxy-3-methoxybenzylidene)2,4-thiazolidinedione (HMTZD) and (Z)-5-(3-hydroxy-4- methoxybenzylidene)2,4-thiazolidinedione (MHTZD), obtained from the reaction of 2,4-thiazolidinedione (TZD) with 4-hydroxy-3-methoxybenzaldehyde (Vanillin) and its isomer, 3-hydroxy-4-methoxybenzaldehyde (Isovanillin), which can be used in the synthesis of molecules with biological activity. Maximum yields of 98% in 480 min, for the product HMTZD, and 73% in 120 min, for the product MHTZD, were obtained, contradicting literature that shows a reaction time for this synthesis of 20 h to 40 h. In the flow synthesis in the microreactor, it was evident that the higher the temperature the higher the conversion of TZD and the yield of the product, reaching 100%, in ethanol working with the temperature of 160°C. The production in the batch process and the microreactor were calculated and, when compared, showed that only two 1 mL microreactors in their best operating condition are able to produce three times more than a 60 mL batch reactor. By the study of kinetics, the reaction using ethanol does not favor the formation of reactions in parallel or in series. The qualitative analyzes showed that the expected products was formed and with a high degree of purity.

<p>De stora läkemedelsbolagen har sedan mitten på 1990-talet fått en ökad press på att optimera sina försörjningskedjor på grund av att patent på olika mediciner gått ut. När patentet gått ut kan generiska konkurrenter börja sälja liknande mediciner, de kan sälja dem till lägre pris eftersom de inte har forsknings och utvecklingskostnader att täcka. AstraZeneca tog i slutet av 1990-talet beslutet att implementera en ny strategi för deras försörjningskedja i deras produktion. Detta gjordes för att sänka deras produktionskostnader för att kunna konkurrera mot generiska konkurrenter. En konsultfirma togs in och Demand Driven Supply (DDS) implementerades. Syftet med denna uppsats är att definiera Demand Driven Supply och att utvärdera om denna implementering gett de resultat som eftersträvades. Vi presenterar en teoretisk referensram som behövs för att få en förståelse över de metoder och verktyg som behövs för att optimera varuförsörjningskedjan och därigenom kunna sänka kostnaderna. Dessa teorier står till grund för den implementering som skedde hos AstraZeneca. Den huvudsakliga anledningen till att DDS implementerades var att AstraZeneca ville gå mot sugande produktionsstyrning för att därmed korta ledtiden, sänka kostnader och sänka kapitalbindningen och höja marginalerna på sin försäljning för att få kapital till att återinvestera i företaget.</p>

De stora läkemedelsbolagen har sedan mitten på 1990-talet fått en ökad press på att optimera sina försörjningskedjor på grund av att patent på olika mediciner gått ut. När patentet gått ut kan generiska konkurrenter börja sälja liknande mediciner, de kan sälja dem till lägre pris eftersom de inte har forsknings och utvecklingskostnader att täcka. AstraZeneca tog i slutet av 1990-talet beslutet att implementera en ny strategi för deras försörjningskedja i deras produktion. Detta gjordes för att sänka deras produktionskostnader för att kunna konkurrera mot generiska konkurrenter. En konsultfirma togs in och Demand Driven Supply (DDS) implementerades. Syftet med denna uppsats är att definiera Demand Driven Supply och att utvärdera om denna implementering gett de resultat som eftersträvades. Vi presenterar en teoretisk referensram som behövs för att få en förståelse över de metoder och verktyg som behövs för att optimera varuförsörjningskedjan och därigenom kunna sänka kostnaderna. Dessa teorier står till grund för den implementering som skedde hos AstraZeneca. Den huvudsakliga anledningen till att DDS implementerades var att AstraZeneca ville gå mot sugande produktionsstyrning för att därmed korta ledtiden, sänka kostnader och sänka kapitalbindningen och höja marginalerna på sin försäljning för att få kapital till att återinvestera i företaget.

NRs are enzymes that catalyze the reduction of nitroaromatics to their corresponding nitroso, hydroxylamine, and, in limited cases, amine They have gathered interest in many scientific communities, and are currently actively researched bioremediation and prodrug activation. Here we attempt to utilize them for the purpose of synthesizing substituted aromatic amines that are found in a number of active pharmaceutical ingredients (APIs). As NRs described in the literature have varying product distribution ranges (from those that produce hydroxylamine to others that yield amine) several similar and different NRs were studied for their selectivity. Additionally, a quantitative structure-activity relationship (QSAR) was determined to characterize the substrate specificity of NRs. To employ the use of flavoenzymes in synthesis, multiple reaction- and protein-engineering approaches were devised. One scheme was to establish an enzymo-chemical synthesis where NRs were paired with reducing agents for a chemical reduction. Another method was to create a monomeric NR through directed evolution from ER scaffolds for future immobilization applications. Protein engineering techniques were also utilized on NADH oxidases which we characterized and developed for nicotinamide cofactor regeneration. As a whole, this dissertation expands our current understanding on NRs and demonstrates the possibility of using several flavoenzymes in the synthesis of organic molecules.

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

Yes / The use of near infra red spectroscopy to predict the concentration of two pharmaceutical co-crystals; 1:1 ibuprofen – nicotinamide (IBU-NIC) and 1:1 carbamazepine – nicotinamide (CBZ-NIC) has been evaluated. A Partial Least Squares (PLS) regression model was developed for both co-crystal pairs using sets of standard samples to create calibration and validation data sets with which to build and validate the models. Parameters such as the root mean square error of calibration (RMSEC), root mean square error of prediction (RMSEP) and correlation coefficient were used to assess the accuracy and linearity of the models. Accurate PLS regression models were created for both co-crystal pairs which can be used to predict the co-crystal concentration in a powder mixture of the co-crystal and the active pharmaceutical ingredient (API). The IBU-NIC model had smaller errors than the CBZ-NIC model, possibly due to the complex CBZ-NIC spectra which could reflect the different arrangement of hydrogen bonding associated with the co-crystal compared to the IBU-NIC co-crystal. These results suggest that NIR spectroscopy can be used as a PAT tool during a variety of pharmaceutical co-crystal manufacturing methods and the presented data will facilitate future offline and in-line NIR studies involving pharmaceutical co-crystals.

Made available in DSpace on 2015-08-19T13:52:55Z (GMT). No. of bitstreams: 2 13.pdf: 7121518 bytes, checksum: a7c8e7a7bd443ccd7df30b5090abf1e0 (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) Previous issue date: 2013 / Fundação Oswaldo Cruz. Instituto de Tecnologia em Fármacos/Farmanguinhos. Rio de Janeiro, RJ, Brasil. / O presente estudo teve por objetivo investigar e avaliar a possível contribuição que a obrigatoriedade do registro de Insumos Farmacêuticos Ativos (IFAs), estabelecida pela Resolução da Diretoria Colegiada da ANVISA (RDC) n° 57/2009, a partir de 2010, teve no estabelecimento da isonomia regulatória entre o fabricante do IFA no Brasil e o fabricante internacional e que efetividade essa isonomia teve no restabelecimento da produção local de IFAs quando aliada à implementação de outras ações demandadas pela indústria farmoquímica brasileira, como a isonomia tributária, os incentivos fiscais, as parcerias para o desenvolvimento produtivo e o poder de compra do Estado. A pesquisa foi do tipo bibliográfica, documental e longitudinal. Constatou-se que, passados dois anos desde o início da exigência do registro de IFA, esta se mostrou efetiva na obtenção da isonomia regulatória. Porém, o tempo de análise não foi suficientemente longo para assegurar que a mesma, conjugada com outras ações do governo para o incentivo à produção local de IFAs, tenha sido capaz de promover o aumento, via substituição das importações desses produtos, apesar de haver sinalizações de que isso acontecerá. Como consequência espera-se que traga um aumento da produção do IFA e a redução da dependência do Brasil ao fornecimento externo, possibilitando o aumento da oferta interna desses insumos aos laboratórios farmacêuticos instalados no país, sejam eles públicos ou privados, além de melhorar a qualidade e o acesso dos medicamentos disponibilizados à sociedade brasileira. / The present study had as objectives to investigate and evaluate the possible contribution that the requirement of registration of Active Pharmaceutical Ingredients (APIs), established by the Resolução da Diretoria Colegiada of ANVISA Nr. 57/2009, as of 2010, had on the establishment of the regulatory isonomy between the producer of the API in Brazil and the international producer as well as the effectiveness this isonomy had in the reestablishment of the local production of APIs, when applied in parallel with the implementation of other actions demanded by the Brazilian pharmochemical industry, like the tax isonomy, the fiscal incentives, the partnerships for the productive development and the State buying power. The investigation involved bibliographic, documental and longitudinal analysis of the material available. It was concluded that, after two years since the beginning of the registration requirement, it turned out to be effective in bringing up the desired regulatory isonomy. However, the space of time used for the analysis was not sufficiently long to ensure that the registration, coupled with other governmental actions to promote the local production of APIs, could have been capable to promote the increase, via substitution of importations, of these products, although there are some signs that this will happen. As a consequence it is expected that it will bring an increase of the API production and the reduction of the Brazilian dependence of external supply, giving space to the internal offer of these products to the pharmaceutical laboratories located in Brazil, either public or private, besides improving the quality and the access of the medicines made available to the Brazilian society.