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Leveraging atomization strategies towards the production of composite particles
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A secagem por atomização é amplamente utilizada para preparar partículas compósi-
tas encapsuladas para inalação. No entanto a maioria dos excipientes para inalação são solúveis em água, enquanto os ingredientes ativos API não são. Tal é um desafio no desenvolvimento de formulações para inalação, já que é necessário dissolver o IA e excipientes no mesmo solvente, potencialmente causando incompatibilidades entre API/excipientes e solvente e também solubilidade limitada do API. Um atomizador de três fluidos (3FN) é uma alternativa interessante para este desafio, ao permitir utilizar duas soluções independentes. Assim, este estudo visa produzir partículas compósitas encapsuladas utilizando o 3FN, estabelecendo assim uma metodologia de desenvolvimento de processo aplicável desde a escala laboratorial à industrial. A utilização do 3FN foi extensamente estudada empregando uma formulação modelo com Leucina, como agente de encapsulação. Adotando uma abordagem de qualidade por design, o trabalho incluiu um desenho de experiências combinado com desenvolvimento de modelos empíricos. Assim é possível determinar os potenciais parâmetros críticos de processo e correlacioná-los com os atributos críticos
de qualidade. Foi demonstrado que o 3FN é uma estratégia de atomização eficiente para produzir partículas inaláveis (𝐷𝑣50 < 5 𝜇m) e fração de finos entre 38 e 53 %. A análise detalhada dos parâmetros de processo revelou que o caudal de atomização desempenha um papel fundamental na determinação do tamanho de partícula e consequentemente fração de finos. Para além disso, a metodologia aplicada é adaptável para encapsular outros API, tendo sido determinado que a Leucina é o aminoácido hidrofóbico que confere um processo de encapsulação mais simples.Este trabalho comprovou a aplicabilidade do 3FN para a produção de partículas compósitas encapsuladas bem como permitiu aumentar o conhecimento sobre o processo, dentro do contexto estudado. Para além disso, a metodologia seguida constitui uma ferramenta robusta para desenvolvimento de processo com aplicabilidade em diversas fases do desenvolvimento farmacêutico
Encapsulated composite particles designed for inhalation are commonly prepared by spray drying. However, a challenge arises as common inhalation excipients are water soluble whereas most commercial active pharmaceutical ingredients (APIs) are not. This creates an obstacle for inhalation formulations manufactured by spray drying, wherein the traditional approach requires excipients to be dissolved in the same solvent, leading to limitations such as incompatibilities between the API/ excipient and the solvent and limited solubility. The utilization of a three-fluid nozzle (3FN) as atomizing tool arises as an interesting alternative to overcome the mentioned challenges, enabling the use of two independent solutions. Therefore, the present work aims at preparing encapsulated composite particles using the 3FN enabling the definition of a process development methodology from lab scale to manufacturing scale. The use of a 3FN was extensively investigated using a model inhalation formulation containing Leucine as shell forming agent. Aligning with a quality-by-design approach, this study comprised a design of experiments combined with empirical model development, to determine the potential critical process parameters and link them to the investigated critical quality attributes. It was demonstrated that the 3FN is an efficient atomization strategy to prepare particles within the inhalable range (𝐷𝑣50 < 5 𝜇m) and with fine particle fraction between 38 and 53%. The thorough study of process parameters revealed that atomization flow rate is of paramount importance in defining the particle size and consequently aerosol performance. Furthermore, this methodology is demonstrated to be adaptable for encapsulating different APIs, with Leucine emerging as the hydrophobic amino acid with most potential for encapsulation. This work established the feasibility of using the 3FN towards the manufacture of encapsulated particles and advanced process knowledge within this specific context. Furthermore, the methodology whereby followed constitutes a robust process development tool with applicability across multiple phases of pharmaceutical development.
Encapsulated composite particles designed for inhalation are commonly prepared by spray drying. However, a challenge arises as common inhalation excipients are water soluble whereas most commercial active pharmaceutical ingredients (APIs) are not. This creates an obstacle for inhalation formulations manufactured by spray drying, wherein the traditional approach requires excipients to be dissolved in the same solvent, leading to limitations such as incompatibilities between the API/ excipient and the solvent and limited solubility. The utilization of a three-fluid nozzle (3FN) as atomizing tool arises as an interesting alternative to overcome the mentioned challenges, enabling the use of two independent solutions. Therefore, the present work aims at preparing encapsulated composite particles using the 3FN enabling the definition of a process development methodology from lab scale to manufacturing scale. The use of a 3FN was extensively investigated using a model inhalation formulation containing Leucine as shell forming agent. Aligning with a quality-by-design approach, this study comprised a design of experiments combined with empirical model development, to determine the potential critical process parameters and link them to the investigated critical quality attributes. It was demonstrated that the 3FN is an efficient atomization strategy to prepare particles within the inhalable range (𝐷𝑣50 < 5 𝜇m) and with fine particle fraction between 38 and 53%. The thorough study of process parameters revealed that atomization flow rate is of paramount importance in defining the particle size and consequently aerosol performance. Furthermore, this methodology is demonstrated to be adaptable for encapsulating different APIs, with Leucine emerging as the hydrophobic amino acid with most potential for encapsulation. This work established the feasibility of using the 3FN towards the manufacture of encapsulated particles and advanced process knowledge within this specific context. Furthermore, the methodology whereby followed constitutes a robust process development tool with applicability across multiple phases of pharmaceutical development.
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Spray drying 3-fluid nozzle Composite particles Encapsulation Empirical modeling