Defense Date

1996

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Pharmaceutical Sciences

First Advisor

Peter R. Byron

Abstract

The feasibility of producing inhalable microparticles of sugars and protein-sugar molecular mixtures using spray drying was investigated as an alternative to conventional micronization techniques. Four sugars; lactose (L), trehalose (T), sucrose (S) and mannitol (M) were spray dried using a commercial bench-top spray dryer and their physicochemical stability, with respect to particle size, moisture uptake and crystallinity changes, investigated after storage at 23%, 52%, 75% and 93% relative humidity (RH) and 25 °C for 30 days. Two crystalline size fractions (“coarse” = 125-212 μm and “fine” = 44-74 μm) of each sugar, were also characterized, as possible replacements for lactose as carriers for admixture with drugs in dry powder inhalers (DPIs). Sieve fractions of lactose, trehalose and mannitol failed to show significant moisture uptake at RHs ≤ 93% and 25 °C indicating their thermodynamic stability under most realistic storage conditions. While sucrose failed to show moisture uptake at ≤ 75% RH, it dissolved in sorbed moisture at 93% RH. Spray dried sugars were collected successfully in particle sizes suitable for inhalation. Spray dried lactose, trehalose and sucrose were amorphous and remained in this state after storage at 23% RH. At higher RHs, however, they recrystallized completely in ≤ 30 days. Spray dried mannitol was completely crystalline after collection from the spray dryer. It did not show moisture uptake or physical state changes at all RHs.

A fine particle collection apparatus incorporating a nebulizer and a wire-in-tube type electrostatic precipitator (EP), built and characterized for particle collection efficiency, was used to review protein activity following spray drying with or without the four sugars as stabilizers. Bacterial (BAP) and bovine intestinal alkaline phosphatase (BIAP) were used as model proteins. Sugar free BAP solutions (apparent protein concentration ~120 μg/ml) lost 23% of initial enzyme specific activity after spray drying at ~63 °C and collection in the EP. Protection offered by the sugars to BAP during drying, was however statistically indistinguishable from the sugar-free protein solution (dried from the same protein concentration solution). When BIAP was dried from sugar free solutions (apparent protein concentration ~1 mg/ml), it lost 31% of its initial specific activity; activity which could be completely recovered when BIAP was co-dried with L, T or S (ANOVA, p < 0.05). However, M which crystallized during spray drying failed to protect the enzyme from this loss of activity. These results implied that the physical state of sugar (amorphous or crystalline) in the final dried product may be an important determinant for offering protection to proteins during spray drying and storage. Even so, multiple factors could potentially influence the selection of a sugar to form inhalable microparticles with a protein. These factors are described and discussed in this thesis, whether or not they appeared to be important with respect to the drying and stability of particular proteins selected for experimental investigation.

Comments

Scanned, with permission from the author, from the original print version, which resides in University Archives.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

8-1-2017

Share

COinS