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Abstract(s)
Dispersões sólidas amorfas e sistemas co-amorfos emergiram como estratégias de formulação de sistemas promissores para a melhoraria da biodisponibilidade de fármacos pouco solúveis em água. Nas dispersões sólidas amorfas, congruência na libertação do fármaco e do polímero é fundamental para assegurar um bom desempenho da dissolução dos componentes da formulação. O limite de congruência é definido como a maior fração do fármaco que permite esta congruência. Um limite de congruência elevado é desejável, de forma a reduzir a carga de comprimidos dos pacientes e, dessa forma, melhorar a adesão ao tratamento. Os fatores que parecem influenciar o limite de congruência são as interações intermoleculares entre o fármaco e o polímero e a hidrofilia do sistema a que dão origem.
A presente Tese teve como objetivo determinar a existência de uma correlação entre as interações intermoleculares entre os componentes de uma formulação e/ou a sua hidrofilia e a sua dissolução num meio aquoso. A caracterização das interações intermoleculares (FTIR) e a hidrofilia (DVS) foi efetuada para dispersões sólidas amorfas e para sistemas co-amorfos contendo um de dois fármacos modelo BCS Class II – o API 1 e o API 3 – ou um fármaco modelo BCS Class IV – o API 2 – e um polímero ou um aminoácido.
Os resultados obtidos mostram uma relação direta entre as interações intermoleculares dos componentes nos sistemas estudados e os seus comportamentos durante a dissolução num meio aquoso. Para além disso, observou-se que a hidrofilia dos sistemas estudados estava diretamente relacionada com a Cmáx obtida durante o ensaio de dissolução. Esta correlação não se observou na ausência de interações intermoleculares entre os componentes de uma formulação, particularmente quando existia uma disparidade significativa entre as hidrofilias dos componentes quando considerados individualmente. Tal pode ter ocorrido com a formação de um sistema bifásico amorfo-amorfo devido à formação de uma fase rica em fármaco consequente de uma libertação rápida (não congruente) do polímero. Os sistemas co-amorfos exibiram uma libertação de fármaco quase completa, devido a interações intensas entre o fármaco e o aminoácido e ao aumento da hidrofilia do sistema.
Amorphous solid dispersions (ASD) and co-amorphous systems (CAS) have emerged as promising formulation strategies to improve the bioavailability of poorly soluble drugs. In ASDs, congruency between the release rates of the drug and polymer is key to ensure maximum API release upon dissolution. The highest drug load which allows for congruent release of both components is known as the limit of congruency (LoC). A high LoC is desirable, in order to reduce patient pill burden, and thus improve patient compliance. The factors that are thought to affect the LoC are the intermolecular interactions between the drug and the polymer and the hydrophilicity of the formulation. This Thesis aimed to determine if a correlation could be found between the intermolecular interactions occurring between the components of a formulation and/or its hydrophilicity and its dissolution performance. As such, characterization of the intermolecular interactions by Fourier-transform infrared spectroscopy (FTIR) and of the hydrophilicity through Dynamic Vapor Sorption (DVS) was performed for ASDs and CAS containing two BCS Class II drug models – API 1 and API 3 – and one BCS Class IV drug model – API 2 – and commonly used polymers and aminoacids. The results showed that the extent of intermolecular interactions occurring between the components of a formulation was related to the dissolution performance of both ASD and CAS, probably due to a higher sustained release effect of the components in those systems. Similarly, it was observed that the hydrophilicity of a formulation was positively correlated with the Cmax observed upon dissolution. This correlation was lost when drug and polymer did not interact and a high water-solubility disparity between the two compounds was observed. This was possibly due to the occurrence of amorphous-amorphous phase separation (AAPS), which results from the formation of a drug-enriched phase, caused by the fast dissolution of the polymer. Co-amorphous systems exhibited almost complete drug release due to extensive drug-aminoacid interactions and improvement of the formulation’s components wetting properties.
Amorphous solid dispersions (ASD) and co-amorphous systems (CAS) have emerged as promising formulation strategies to improve the bioavailability of poorly soluble drugs. In ASDs, congruency between the release rates of the drug and polymer is key to ensure maximum API release upon dissolution. The highest drug load which allows for congruent release of both components is known as the limit of congruency (LoC). A high LoC is desirable, in order to reduce patient pill burden, and thus improve patient compliance. The factors that are thought to affect the LoC are the intermolecular interactions between the drug and the polymer and the hydrophilicity of the formulation. This Thesis aimed to determine if a correlation could be found between the intermolecular interactions occurring between the components of a formulation and/or its hydrophilicity and its dissolution performance. As such, characterization of the intermolecular interactions by Fourier-transform infrared spectroscopy (FTIR) and of the hydrophilicity through Dynamic Vapor Sorption (DVS) was performed for ASDs and CAS containing two BCS Class II drug models – API 1 and API 3 – and one BCS Class IV drug model – API 2 – and commonly used polymers and aminoacids. The results showed that the extent of intermolecular interactions occurring between the components of a formulation was related to the dissolution performance of both ASD and CAS, probably due to a higher sustained release effect of the components in those systems. Similarly, it was observed that the hydrophilicity of a formulation was positively correlated with the Cmax observed upon dissolution. This correlation was lost when drug and polymer did not interact and a high water-solubility disparity between the two compounds was observed. This was possibly due to the occurrence of amorphous-amorphous phase separation (AAPS), which results from the formation of a drug-enriched phase, caused by the fast dissolution of the polymer. Co-amorphous systems exhibited almost complete drug release due to extensive drug-aminoacid interactions and improvement of the formulation’s components wetting properties.
Description
Tese de mestrado, Engenharia Farmacêutica, 2022, Universidade de Lisboa, Faculdade de Farmácia.
Keywords
Amorphous solid dispersions Co-amorphous systems Fourier-transform infrared spectroscopy Hydrophilicity Intermolecular interactions. Teses de mestrado - 2022