Abstract
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.
Highlights
The study of interaction forces between particles in pharmaceutical formulations (e.g., active pharmaceutical ingredients (APIs) and excipients) has increased in importance over the past 20 years with the emergence of very sensitive surface analytical techniques such as atomic force microscopy (AFM) and inverse gas chromatography (IGC)
The findings suggest that the interaction energy between mLMH and fluticasone propionate (FP) would be insufficient to break-up the strongest mLMH cohesive interactions, and segregation into FP-rich and mLMH-rich blend regions was predicted
The ability of the synthonic modeling approach to provide a molecular-level understanding of the surface properties of inhalation powders was demonstrated by assessing the cohesivity of three active pharmaceutical ingredients (API, fluticasone propionate (FP), budesonide (Bud), and salbutamol base (SB)) and the commonly used excipient, α-lactose monohydrate (LMH)
Summary
The study of interaction forces between particles in pharmaceutical formulations (e.g., active pharmaceutical ingredients (APIs) and excipients) has increased in importance over the past 20 years with the emergence of very sensitive surface analytical techniques such as atomic force microscopy (AFM) and inverse gas chromatography (IGC). Physical interaction between similar particles (e.g., API−API) is known as cohesive force,[1] and the interaction between heterogeneous particles (e.g., API−excipient) is known as adhesive force.[1] The ability to study adhesive or cohesive interactions between particles is beneficial in understanding or even predicting behaviors as diverse as blending operations[2] (and the resultant content uniformity) to tablet compaction[3,4] or disintegration,[5] where surface interactions dictate the strength of surface contacts. It is not straightforward to detect these interactions in a formulation by simple experimental techniques. There is not Received: May 6, 2014 Revised: October 31, 2014 Accepted: November 7, 2014 Published: November 7, 2014
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