Formulation pre-screening of inhalation powders using computational atom-atom systematic search method.
The synthonic modeling approach provides a molecule-centered understanding of the surface properties of crystals. It has been applied extensively to understand crystallization processes. This study aimed to investigate the functional relevance of synthonic modeling to the formulation of inhalation powders by assessing cohesivity of three active pharmaceutical ingredients (APIs, fluticasone propionate (FP), budesonide (Bud), and salbutamol base (SB)) and the commonly used excipient, α-lactose monohydrate (LMH). It is found that FP (-11.5 kcal/mol) has a higher cohesive strength than Bud (-9.9 kcal/mol) or SB (-7.8 kcal/mol). The prediction correlated directly to cohesive strength measurements using laser diffraction, where the airflow pressure required for complete dispersion (CPP) was 3.5, 2.0, and 1.0 bar for FP, Bud, and SB, respectively. The highest cohesive strength was predicted for LMH (-15.9 kcal/mol), which did not correlate with the CPP value of 2.0 bar (i.e., ranking lower than FP). High FP-LMH adhesive forces (-11.7 kcal/mol) were predicted. However, aerosolization studies revealed that the FP-LMH blends consisted of agglomerated FP particles with a large median diameter (∼4-5 μm) that were not disrupted by LMH. Modeling of the crystal and surface chemistry of LMH identified high electrostatic and H-bond components of its cohesive energy due to the presence of water and hydroxyl groups in lactose, unlike the APIs. A direct comparison of the predicted and measured cohesive balance of LMH with APIs will require a more in-depth understanding of highly hydrogen-bonded systems with respect to the synthonic engineering modeling tool, as well as the influence of agglomerate structure on surface-surface contact geometry. Overall, this research has demonstrated the possible application and relevance of synthonic engineering tools for rapid pre-screening in drug formulation and design.
Institute of Particle Science and Engineering, Institute of Process Research and Development, School of Chemical and Process Engineering, University of Leeds , Leeds LS2 9JT, U.K.
Vasuki
V
Ramachandran
Darragh
D
Murnane
Robert B
RB
Hammond
Jonathan
J
Pickering
Kevin J
KJ
Roberts
Majeed
M
Soufian
Ben
B
Forbes
Sara
S
Jaffari
Gary P
GP
Martin
Elizabeth
E
Collins
Klimentina
K
Pencheva
D000280:Administration, Inhalation; D000336:Aerosols; D000420:Albuterol / Q000737:chemistry; D000730:Androstadienes / Q000737:chemistry; D019819:Budesonide / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D002849:Chromatography, Gas; D003198:Computer Simulation; D003460:Crystallization; D016503:Drug Delivery Systems; D005079:Excipients / Q000737:chemistry; D000068298:Fluticasone; D006860:Hydrogen Bonding; D007785:Lactose / Q000737:chemistry; D007834:Lasers; D008962:Models, Theoretical; D010316:Particle Size; D011208:Powders / Q000737:chemistry*; D055672:Static Electricity; D013499:Surface Properties
D000336:Aerosols; D000730:Androstadienes; D005079:Excipients; D011208:Powders; D019819:Budesonide; D000068298:Fluticasone; D007785:Lactose; D000420:Albuterol
budesonide; de-agglomeration; fluticasone propionate; in silico formulation design; inhalation drug delivery; inter-particle interaction; laser diffraction; molecular and synthonic modeling; powder dispersion analysis; salbutamol; α-lactose monohydrate