# Simple Quantification of Sticking Propensities of Pharmaceuticals with Mechanochemistry

## TL;DR

This paper introduces a simple, lab-friendly method to measure how likely pharmaceutical materials are to stick during tablet manufacturing.

## Contribution

A novel mechanochemical method using ball mill grinding to quantify sticking propensities with minimal material and equipment.

## Key findings

- The method effectively classifies materials into low, medium, and high sticking propensities based on adherence to a stainless-steel substrate.
- Materials like p-nitrobenzoic acid and ibuprofen showed low sticking, while D-mannitol exhibited high sticking (>100 g/m2).
- The method is versatile, robust, and suitable for early-stage pharmaceutical development.

## Abstract

Punch sticking poses
significant challenges in tablet
manufacturing
and the need for effective solutions is ever-growing. Direct sticking
assessment methods often rely on bulky, material-consuming equipment
such as compactor emulators, only available in manufacturing sites,
and thus inaccessible for most research labs. Consequently, there
only exists limited data on sticking propensities of pharmaceuticals
in the literature, significantly limiting our understanding of the
issue and how it impacts drug manufacturing. A novel, easy, material-sparing,
and lab-friendly method to evaluate sticking trends across diverse
systems is presented here. The method employs a mechanochemical technique
(ball mill grinding) to measure the materials’ adherence to
a stainless-steel substrate (milling ball). After optimization of
the operating parameters such as relative humidity pretreatment of
materials, a best practice protocol was developed. We measured the
sticking propensities of 19 diverse molecular crystalline systems
consisting of active pharmaceutical ingredients (APIs), API precursors,
and common excipients. The method was effective at differentiating
and quantifying the sticking ability of our diverse set of systems,
which were classified into low sticking (<30 g/m2),
medium sticking (30–60 g/m2), and high sticking
(>60 g/m2) propensities. For example, p-nitrobenzoic
acid
and (R,S)-ibuprofen were found to stick with low propensities to the
milling ball (<30 g/m2), while D-mannitol was found
to stick significantly (>100 g/m2). Formulations of
the
pure materials with microcrystalline cellulose (MCC) were also tested
and can be extensively explored with this method. Crucially, the operating
parameters of the method (such as the milling times, relative humidity
pretreatment of materials, or the material of the milling ball) can
be easily adjusted to suit the systems and problem of interest. Our
method is robust, nondestructive, and highly versatile and allows
for fast quantification of sticking propensities of many systems with
small quantities of material. The method has the potential to transform
the way we study sticking tendencies of pharmaceuticals, enabling
the assessment of sticking propensities significantly early in the
development pipeline before manufacturing problems arise.