Design of Experiments Approach to Assess the Impact of Api Particle Size on Freeze-Dried Bulking Agents

Abstract

The current work aimed at the thorough characterization of freeze-dried bulking agent structures loaded with different particle sizes of active pharmaceutical ingredient (API). Using Design of Experiments, a D-Optimal screening design was conceived in order to evaluate the influence of the formulation factors on the features of the obtained structures. The selected formulation factors were API particle size (X1), the type of the bulking agent (X2) and the ratio of the bulking agent (X3). The disintegration time, the dissolution profile and the texture characteristics were studied. The particle size of the API (ibuprofen) influenced the dissolution and the highest dissolution ratios were obtained for trehalose. The texture characteristics of the structures were influenced by the type and the ratios of bulking agents, by increasing the ratio of the bulking agent, the measured parameters were improved. Maltodextrin conducted to robust structures for which, according to the XRPD results, the particles are to a certain degree in an amorphous state. The obtained results represent a contribution to the actual knowledge in this area that can be further used in development of lyophilized pharmaceutical forms. RezumatScopul prezentei lucrări a fost caracterizarea în profunzime a structurilor obținute, prin liofilizare, în urma unui amestec format din substanță medicamentoasă și un diluant farmaceutic. Utilizând design-ul experimental a fost conceput un plan experimental de tip D-Optimal cu scopul de a evalua influența factorilor de formulare asupra caracteristicilor structurilor obținute. Factorii de formulare selectați au fost mărimea particulelor de API (X1), tipul (X2) și procentul formatorului de matriță (X3) și s-a studiat impactul acestora asupra timpului de dezagregare, dizolvării și a caracteristicilor mecanice obținute pentru structurile liofilizate. Mărimea particulelor ingredientului activ, respectiv ibuprofen, a influențat profilul de dizolvare al acestuia, cel mai mare procent de ibuprofen dizolvat în cel mai rapid timp s-a obținut pentru formulările cu trehaloză. Caracteristicile mecanice ale structurilor liofilizate au fost influențate de tipul și procentul formatorului de matriță, cel din urmă influențând direct proporțional rezultatele. Maltodextrina a condus la obținerea unor structuri robuste, care, conform rezultatelor XRPD, demonstrează un proces de amorfizare în urma liofilizării. Rezultatele obținute reprezintă o contribuție la cunoștințele din acest domeniu care pot fi utilizate ulterior în dezvoltarea formelor farmaceutice liofilizate.

Orally Dispersible Dosage Forms for Paediatric Use: Current Knowledge and Development of Nanostructure-Based Formulations

“…Bulking agents, intended to add heft to the lyophilisate, may also bring the further advantages of cryoprotection and tastemasking, as is the case of mannitol, one of the most frequently used excipients for this application [47,53]. Maltodextrin has been proven to be a suitable bulking agent as well, in the case of an ibuprofen OL formulation, leading to a sturdy product that could easily be manipulated, while keeping a sufficiently short disintegration time and a good dissolution profile [54]. Not only the excipients, but also the freeze-drying parameters, impact the final product.…”

Preparation and Characterization of Smartcrystals for Dissolution Enhancement of Poorly Water – Soluble Niflumic Acid

“…Freeze-dried nanocrystals with mannitol showed 406.55 nm, whereas nanocrystals of 276.55 nm were produced by freeze-drying with trehalose. The presence of cryoprotectants is significant to reduce aggregation and improve redispersion in water [29]. The sugar matrix provided a physical barrier that prevented the particles aggregation.…”

Development of a Mouthwash Using Freeze-Drying Technique: An Optimization Study

“…Mannitol, a compound with the structure-forming ability [23] and sweetening properties, was selected as a bulking agent since it favors efficient freeze-drying and the attainment of elegant matrices [25]. It gave freeze-dried compacts with appropriate strength even without matrix-forming polymers and it showed superior mechanical properties when compared to trehalose, and lower when compared to maltodextrin [26].…”