Mechanistic Formulation Design of Spray-Dried Powders

Abstract

Spray drying is gaining traction in the pharmaceutical industry as one of the processing methods of choice for the manufacture of solid dosage forms intended for pulmonary, oral, and parenteral delivery. This process is particularly advantageous because of its ability to produce engineered particles with improved efficacy and stability by combining active pharmaceutical ingredients or biologics with appropriate excipients. Moreover, due to its high throughput, continuous operation, and ability to produce thermostable solid powders, spray drying can be a manufacturing method of choice in the production of drugs and other formulations, including vaccines, for global distribution. Formulation design based on a mechanistic understanding of the different phenomena that occur during the spray drying of powders is complicated and can therefore make the use of available particle formation models difficult for the practitioner. This review aims to provide step-by-step guidance accompanied by critical background information for the successful formulation design of spray-dried microparticles. These include discussion of the tools needed to estimate the surface concentration of each solute during droplet drying, their times and modes of solidification, and the amount of glass stabilizers and shell formers required to produce stable and dispersible powders.

On the Physical Stability of Leucine-Containing Spray-Dried Powders for Respiratory Drug Delivery

“…Analysis of the primary particle size of the collected powder using an aerodynamic particle sizer in conjunction with a powder disperser, as described below, revealed a mass median aerodynamic diameter of 3.2 µm. Using a mass balance equation [ 4 ] and a particle density equal to 1580 mg/mL for amorphous trehalose [ 10 ], the mass median diameter of the atomized spray droplets was then back-calculated to be equal to about 9 µm. Because of the relatively high manufacturing yield of 83%, it was assumed that this initial median droplet size approximated the totality of the spray droplets.…”

“…Spray drying is a particle engineering technique that is used to manufacture respirable powders for inhaled delivery to the deep lung. Key attributes for successful delivery to the bronchi, bronchioles, and alveoli within the lung include a suitable aerodynamic particle size [ 1 , 2 ] and optimal dispersibility of the powders [ 3 , 4 ]. When delivered by a passive dry powder inhaler, about 1 to 50 mg of powder, typically contained in a capsule or blister, is dispersed by the patient’s own breath.…”

“…The formulation design of spray-dried pulmonary particles depends on the type of active ingredient, which can be categorized into three classes: (1) small-molecule drugs that tend to crystallize during spray drying, (2) small-molecule drugs that tend to dry into a glass, and finally, (3) large macromolecular biologics that are generally amorphous after spray drying [ 5 ]. Depending on the class of the drug, different excipients have frequently been included in formulations to improve the physicochemical properties and efficacy of the carrier-free product [ 4 ]. For example, glass stabilizers with high glass transition temperatures, such as trehalose, have been added to formulations, both to increase the storage stability of the powders and to reduce the risk of processing damage to biologics, such as proteins [ 6 , 7 ].…”

“…It has been explained elsewhere that leucine instantaneously nucleates and grows crystals on the surface of evaporating droplets once its local concentration reaches a critical supersaturation ratio, which can be predicted [ 10 ]. This information can be used in the formulation design of leucine-containing systems to achieve the goal of a fully crystalline shell on the surface of the particles for maximum effectiveness [ 4 ].…”

The Processing Space of the Spray-Dried Mannitol-Leucine System for Pulmonary Drug Delivery

“…In this instance, the short crystallization window, i.e., the time available for crystal growth between nucleation and complete evaporation of the solvent, can be insufficient for complete leucine crystallization [ 17 ], especially in the presence of other components in the formulation [ 19 ]. Thus, adjusting solvent ratios, leucine concentration, and changing drying temperatures play a large role in determining which excipient supersaturates and subsequently nucleates first [ 20 ].…”