Novel Dry Particle Layering for Drug Delivery to the Lungs

Abstract

Formulation of dry powder based delivery system using existing technologies such as high shear blending and TURBULA® mixing lacks predictability, scalability and involves extensive trial and improvement to achieve uniform powder blends. This challenge is compounded when dealing with drugs that are heat and moisture sensitive, fracture during blending, which requires extensive modifications such as temperature jackets and product quarantine respectively. Following the successful development of a novel aerosolized and isothermal dry particle coating device (iDPC) for the formation of composite particles by a previous work in this research group, this work aimed to develop a mechanistic understanding of the iDPC and explore its use in the formulation of dry powders for inhalation. There are three main sub-divisions in this work; the mechanistic understanding of the novel iDPC device, to develop a scientific rationale for its processes, determination of changes to carrier surface properties by particle surface characterisation techniques, and a Quality by design approach based on the mechanistic understanding obtained to develop dry powders for inhalation for pulmonary drug delivery.

The capability of the novel iDPC device to produce composite particles were directly linked to its centrifugal force and micro fluidization technique, which provide the blending energy input. The stages of dry particle coating as already established in literature i.e. deagglomeration, dispersion and redistribution were identified in the novel iDPC device along with the periods at which they commence. The use of the micro fluidization technique was found to hasten these processes, although they still occurred in its absence.

Carrier particle properties such as particle size, powder flow, thermal and surface properties, determined by a range of characterisation techniques such as laser diffraction, FFC, SEM, CLSM, BET SSA, DSC, XRD and IGC show that most carrier properties are retained post-processing in the iDPC. Changes in surface energy were observed especially when different inert gases were used to achieve micro fluidization. The observed changes particularly in the acid-base component of the surface energy was attributed to changes in the orientation of lactose water of crystallisation post blending. More evidence to support this was later obtained.

The established method of incorporating fine lactose to a coarse lactose based DPI formulation was investigated using the iDPC. Similar to optimal fines concentration of 10% reported in literature, the addition of 9.4% fine lactose was optimal to DPI formulation performance. In the same chapter, the possibility of a fines-free formulation with the added advantage of better flow, which is beneficial for formulation preparation, handling and dosing, was also explored, through pre-conditioning the lactose carrier in the iDPC. This approach also increased FPF although, to a lesser extent than the fines-coarse carrier system.

Surface interaction dynamics were determined through surface energy measurements of the lactose carrier, using inert gases of different densities i.e. helium, nitrogen and argon to generate the air blade for micro fluidization. Processing induced differences especially in the specific surface energy component of lactose surface energetics were revealed. Reduced acid-base surface energy observed was attributed to possible reorientation of the molecules of lactose water of crystallisation, increasing interaction between polar probes and particle surface, and resulting in increased polar surface energy, corroborating findings from chapter 3.

In conclusion, the findings from this work is an advancement towards using scientific rationale of dry coating device mechanistic understanding, a quality by design approach and carrier selection to leverage particle interaction dynamics for early formulation prediction of product performance.

Date of Award	Sept 2021
Original language	English
Supervisor	Afzal-Ur-Rahman Mohammed (Supervisor) & Ali Al-Khattawi (Supervisor)