See all › See all › See all › Download citation Recruit

Share
Search for publications, researchers, or questions or Discover by subject area researchers Download full-text
Join for free PDFLogin
2 Citations 163 References 7 Figures

Sticking and Picking in Pharmaceutical Tablet Compression: Advertisement

An IQ Consortium Review
Article (PDF Available) in Journal of Pharmaceutical Sciences 107(9) · May 2018 with 2,784 Reads
DOI: 10.1016/j.xphs.2018.04.029
Cite this publication

Sayantan Chattoraj
Patrick Daugherity
18.15 · GlaxoSmithKline plc. Upper Providence

Todd McDermott +2 Angela Olsofsky

Show more authors

Abstract

Sticking and picking during tablet manufacture has received increasing interest recently, as it causes tablet defects, downtime in
manufacturing and yield losses. The capricious nature of the problem means that it can appear at any stage of the development
cycle, even when it has been deemed as low risk by models, tests and previous experience. In many cases, the problem manifests
when transferring the process from one manufacturing site to another. Site transfers are more common than in previous times due
to the multinational nature of drug product manufacture and the need for redundancy in manufacturing networks.

Discover the world's research

15+ million members

118+ million publications
700k+ research projects

Join for free

Figures - uploaded by Mike Tobyn Author content

Content may be subject to copyright.

+4

Picking in a tablet logo. The disastrous effects of tablet sticking Photomicrograps of tools with steel
when observed in manufacturing process. inclusions.

Advertisement

Download and Play for Free DOWNLOAD

Flexible control with mouse and keyboard Tencent Gaming Buddy

Content uploaded by Mike Tobyn Author content

Download full-text PDF
Content may be subject to copyright.

Journal of Pharmaceutical Sciences xxx (2018) 1-16

Contents lists available at ScienceDirect

Journal of Pharmaceutical Sciences

journal homepage: www.jpharmsci.org

Review

Sticking and Picking in Pharmaceutical Tablet Compression: An IQ

Consortium Review
Sayantan Chattoraj 1, Patrick Daugherity 2, Todd McDermott 3, Angela Olsofsky 4,
Wyatt J. Roth 5, Mike Tobyn 6, *
1
Drug Product Design and Development, GlaxoSmithKline Pharmaceuticals R&D, Collegeville, Pennsylvania 19426
2
Pfizer Inc., Worldwide Research & Development, Pharmaceutical Sciences Small Molecules, Drug Product Design, Groton, Connecticut 06340
3
Process Engineering Sciences, AbbVie, 1 North Waukegan Road, North Chicago, Illinois 60064
4
Drug Product Technologies, Amgen Inc., 1 Amgen Center Dr, Thousand Oaks, California 91320
5
Small Molecule Design and Development, Lilly Research Laboratories, Indianapolis, Indiana 46225
6
Drug Product Science and Technology, Bristol-Myers Squibb, Reeds Lane, Moreton, CH48 4DU, UK

a r t i c l e i n f o a b s t r a c t

Article history: Sticking and picking during tablet manufacture has received increasing interest recently, as it causes
Received 6 March 2018 tablet defects, downtime in manufacturing, and yield losses. The capricious nature of the problem means
Revised 23 April 2018 that it can appear at any stage of the development cycle, even when it has been deemed as low risk by
Accepted 27 April 2018
models, tests, and previous experience. In many cases, the problem manifests when transferring the
process from one manufacturing site to another. Site transfers are more common now than in previous
times because of the multinational nature of drug product manufacturing and the need for redundancy
Keywords:
tableting in manufacturing networks. Sticking is a multifactorial problem, so one single “fix” is unlikely to solve it
tablet(s) completely, and “solutions” addressing one problem may exacerbate another. A broad-based strategy
physical characterization involving the API, formulation, tablet tooling, and the manufacturing process is the most likely approach
excipient(s)
to provide a robust and lasting solution. When faced with a sticking problem for the first or subsequent
process analytical technology (PAT)
processing time, the formulator should address, in a structured way, a range of possible causes and remedies. In this
article, we focus on current research and practice; on some of the common causes of sticking; mitigation
and resolution strategies and solutions; and possible future directions in research.
© 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Introduction polytetrafluoroethylene-tipped punches were proposed as a solu-

When sticking and picking are encountered for the first time
in a tablet development program or during manufacture, it is
often at an inopportune moment and may be time-critical for the
development and manufacture of the product or batch. Produc-
tion may need to be slowed or stopped to resolve the issues,
resulting in an increase in the cost of goods, burdening both the
industry and payers. Knowledge and planning can reduce the
instance of sticking and provide the appropriate solutions when
it arises. The necessity of dealing with sticking and picking
resulted in the formation of an IQ Consortium in this field. This
article reflects a view on the current state of research and
knowledge in this field.
Sticking during tablet manufacture has been a problem since
tableting technology was invented. As early as in the 1960s,
* Correspondence to: Mike Tobyn (Telephone: þ44 (0) 151 552 1654).
E-mail address: mike.tobyn@bms.com (M. Tobyn).
tion to mitigate sticking.1 However, literature references in this
field were infrequent until around 2000, when the number of
literature references began to increase. Since 2010, the number of
reports of problems and potential ways to study the problem have
been significantly higher and represent a peak of interest since this
field has been studied.
This explosion of interests leads to the question of why there has
been such an increase. Is the increased interest in sticking pro-
pensity in part due to changes in preferred manufacturing methods,
for example, dry granulation versus wet granulation, or is the
increased focus on the topics purely a result of organizations being
willing to share precompetitive information and be open about
issues that may have been hidden previously? Has the pharma-
ceutical industry unwittingly contributed to these problems by
requesting nonstandard tablet shapes and complex logos?
It is interesting to note the changes in manufacturing and drug
and formulation practice that have occurred parallel to the increase
in interest of this topic. Although it may notbe possible to develop a
causative relationship between these changes in manufacturing

https://doi.org/10.1016/j.xphs.2018.04.029
0022-3549/© 2018 American Pharmacists Association ®. Published by Elsevier Inc. All rights reserved.

2 S. Chattoraj et al. / Journal of Pharmaceutical Sciences xxx (2018) 1-16

and formulation practices, it could be that a combination of these

factors has made the issue more prevalent.
One obvious point is, as expectations for tablet appearance are
increasing, “minor” flaws may no longer be acceptable to patients,
professionals, and caregivers. Most tablet formulations are now
film coated (for identification and safety reasons), and the film
coating process can make tablet flaws appear more pronounced.
Sugar coating, which had the potential to “hide” minor flaws, is not
now widely used and rarely used at all for new products. Some
markets (most notably Japan), who traditionally placed a higher
emphasis on the appearance of tablets, have come up with
particularly innovative solutions to deal with, or avoid, potential
sticking and appearance issues.
In the R&D and manufacturing environments, several themes
have been developing at the same time as sticking is gaining a
greater focus among organizations.
An increasing proportion of drugs in development and reaching
the market are now placed under Biopharmaceutics Classification
System class 2.2-9 These drugs are generally hydrophobic and, in
many cases, require aggressive milling to allow timely dissolution
from the dosage form. This milling may expose even more hydro-
phobic surfaces (or just more surface), with high surface energy
imparted by the milling process, and this may exacerbate sticking Figure 1. Sticking of formulation to an unembossed punch.
issues. It has been shown that both an increase in surface area
(caused by milling)10 and surface energy can contribute to sticking
issues. monitoring of tableting, and more automatic, programmable logic
One of the major shifts in manufacturing since the late 1990s controllerecontrolled changes may have contributed to greater
has been an increasing focus on dry granulation by roller sticking issues. The loss of tacit knowledge and the elimination of
compaction. Although roller compaction was initially posited as a “risky,” but beneficial, actions (e.g., turning up pressure beyond
dry granulation method for pharmaceuticals in the 1960s, it was recommendations) may have resulted in safer and more reliable
not widely adopted until the late 1980s/1990s. Since then, for some practice, but it also removed from the armory some techniques to
organizations, it has become a preferred route of manufacture (and deal with sticking as it arises.
part of the arsenal for others), supplanting both wet granulation In the remainder of the review, we will deal with some of these
and previous dry granulation (e.g., slugging) approaches. Granules topics in depth, along with the ways of studying and ameliorating
(and the presence of free drug) from dry granulation by roller the problems.
compaction differ from those that came from wet granulation, and
this may have worsened the sticking issue faced by the industry. Definitions and Effects of Sticking and Picking
In addition, it is possible that attrition and fragmentation of
active pharmaceutical ingredient (API) occurs during the roller Definitions
compaction feeding and transmission processes before compaction
into the ribbon.11 This, along with the loss of a hydrophilic binder, Multiple definitions and usages for sticking terminology are
and the strong bonds formed after drying of liquid bridges created prevalent throughout the literature, making it at times confusing to
during wet granulation may have contributed to a greater pro- distinguish between sticking, picking, and filming. Therefore,
pensity of sticking in roller compaction formulations. It is also sticking will be used here as a general term for picking and filming.
important to note that tablets made by roller compaction tend Filming is a term given to the buildup of a monolayer of material
either to be weaker for a given compression force or to require on the tablet punch and should be avoided as it can lead to the
higher pressures to make tablets in a particular strength range (due production of tablets with a dull unappealing appearance.12
to the work loss in the plastic component in the formulation). Thus, Sticking, an extension of filming, occurs when multiple layers of
the cohesion/adhesion balance between the formulation and the material adhere to the punch. In this text, we will use sticking to
punch is changed, favoring adhesion to the die and punches rather address all the areas where unwanted adherence of material to the
than beneficial cohesive strength. punch occurs. Sticking and filming are not specific to the tooling's
In addition to changes in formulation route and strategy, there embossing as it can occur on any area of the tooling's face, whereas
have been a number of other changes in manufacturing which may picking is generally related to tooling's embossing and occurs
have contributed to sticking. Tablet presses are of higher capacity mostly within the logo and island areas. Examples can be seen in
(of up to 1,000,000 tablets per hour), resulting in shorter dwell Figures 1 and 2.
times in the die and new paradigms in feeding, to achieve die filling
in reduced times. These changes in the tablet press coupled with Impact on a Process and Yield
changes in compression tooling, for example, “unique” designs of
shape and logos, may have exacerbated the problem if the novel Sticking, when it arises, is a significant problem in production.
designs were implemented with an allowance for sticking. Taking a tablet machine out of service for several hours to clean
Furthermore, because of timeline and cost constraints (and, punches is a very expensive process, as is losing tablets with un-
perhaps, a preference for uniformity), not all punches are hand acceptable appearance. The effects can be seen in Figure 3. As the
finished, and this may have resulted in punch performance changes. technology exists, and is now in use, to allow 100% inspection of
Although these changes were ongoing, there was a gradual tablets, yield losses are inevitable at the tablet production stage
transition from operator-led tableting decision to instrumented when faults are detected.

S. Chattoraj et al. / Journal of Pharmaceutical Sciences xxx (2018) 1-16 3

Figure 2. Picking in a tablet logo.

Manufacture of Tablet Tooling
Steel Selection
The manufacture of tablet tooling starts with selection of the
correct steel. The steel needs to have the ability to be conditioned to
allow the correct tensile strength and toughness. These 2 properties
are key as they will together improve the ability of the punches and
dies to resist fracture and allow the maximum possible compres-
sion force to be applied. Some tooling manufacturers offer steel that
have undertaken a secondary refining process as standard. This
process not only increases the steel's ability to withstand fracture
but also has a great effect on the structure of the compression faces
of the punches. If the steel has been refined, then the carbide
structures within the steel will be more homogeneous, and the
surface will be polished to a more consistent finish.
There are thousands of types of steels available in the market
today. However, because of the nature of the cyclic loading placed on
the tooling during powder compaction and manufacturing pro-
cesses, such as cold forming, the number of steel options is reduced
to only a handful. In general, tooling manufacturers will maintain a
number of steels, with specific properties, that may have specifically
advantageous properties in some situations, taking into account tip
wear, strength, and suitability for common processes, such as wash
in place, among other characteristics. Consultation with a tooling
manufacturer to identify the most suitable steel for the tooling for a
specific application is a key step in development.13,14
Although other materials have been investigated as possible
bases for tooling,15 it is likely that steel tooling will remain the only
viable option for the foreseeable future.

Tooling Manufacturing Process

Tooling manufacturing techniques, such as computer numeri-

cally controlled machine tools, have allowed the more rapid pro-
duction of tooling. It has also allowed the potential range of tools
that could be made to widen considerably. However, not all the
“possible” tools will be suitable for large-scale production and may
exacerbate sticking.
From the selected tooling steel, a tool is manufactured by the
tooling manufacturer to the correct dimensions, and any shape,
impression, or embossing is given to the tool via a precision-
engineered “Master Hob” that is pressed onto the tool surface. All
aspects of this process can make a difference to the overall char-
acteristics of the tool.

Finishing of Tooling

The finish of tooling is an important determinant of the overall

performance and thus the sticking potential. There are preferred
levels of “roughness” which are acceptable for manufacture. Final
polishing of a tool is required to achieve this specification, and this
can be achieved by machine, although some significant manufac-
turers of tooling still manually polish as a final step of manufacture.
The aim is to achieve a roughness specifically. For pharmaceutical
tooling, a roughness (R )a value of <0.15 mm is typical, and some
vendors can reproducibly achieve Ra values of <0.10 mm. However,
as noted in the following, this may not apply across the whole tool,
Figure 3. The disastrous effects of tablet sticking when observed in manufacturing as it is both difficult to achieve and measure Ra in some sections of a
process. tool, such as the base of the lettering.

4 S. Chattoraj et al. / Journal of Pharmaceutical Sciences xxx (2018) 1-16

Figure 4. Photomicrograps of tools with steel inclusions.

Causes of Sticking production problems such as capping. Subtle changes, such as

Tooling
Steel Inhomogeneity
The cleanliness of steel is an important factor in terms of the
molecular attraction and, in turn, sticking. “Dirty” and cheap steels
with high nonmetallic inclusion counts can have voids and im-
perfections that not only cause tooling breakages but can also allow
granules to penetrate and then build upon themselves, “keying”
into the surface of a material. The distribution of elements in a piece
of steel can also influence sticking, as polar attractions between
elements with high surface energies can attract some particles
more readily than in a homogeneous steel, where the distribution
of elements is finer and more uniform. An American Society for
Testing Materials E45 Method D test will show the concentration
and distribution of inclusions in a steel to verify if the steel can be
considered “dirty” or “clean.” The effect of inclusions on steels can
be seen in Figure 4.
Tooling Design
Shape. The shape of a tablet tool is a key component of sticking in a
formulation.16-18 The shape of a tablet is only restricted by the
imagination, at least in theory (or in the minds of colleagues from
marketing). The shape is very important for functional reasons,
such as the ease of swallowing by the patient and alignment for
tablet printing and packaging. Apart from the more popular round
or caplet shapes, all other standard geometric shapes can be used,
such as oval, elliptical, square, diamond, rectangle, polygon, and so
forth. In addition to these standard geometric shapes, designer
shapes can also be employed to add to the product's functionality
and brand identity or for ease of recognition (animal shapes, fruit
shapes, or even shapes representative of the ailment being treated,
such as heart-shaped tablets for cardiac treatments). Not all shapes
are equally suitable for large-scale production of tablets, and this
should be taken account of in developing a tablet shape.
The tablet profile produces the 3-dimensional shape of the
tablet and significantly adds to the appearance and distinctiveness
of its shape. Apart from appearance, the tablet profile has a func-
tional relevance, and consideration must be given to both the pa-
tient friendliness attributes, such as swallowability and
breakability, as well as the impact on the subsequent stages in
processing, such as coating and printing (for instance, some tablet
shapes/profiles will coat better than others). Automated tablet
packaging, such as blister packaging, relies on the tablet shape and
profile for the correct presentation of the tablets to the packaging.
Also, the durability of the tablet is important for transportation and
packaging. An incorrect profile can lead to sticking and other
changing the edge of the punch, can lead to improvements in the
properties of tablets.19 It is clear that an overall approach to the
design of the punch, which takes into account commercial needs
and production realities, is the key to the development of a suc-
cessful formulation, which does not stick to the tooling.
Concavity. It is well known that the deeper the tablet profile, the
less consistent the tablet hardness.20,21Keeping the tablet profile as
flat as possible will help reduce the possibility of a softer core
forming in the center of the tablet. This, in turn, would keep the
cohesive forces within the tablet as consistent as possible, thereby
reducing the possibility of sticking because cohesion in the tablet
reduces adhesion of the material to the punch surface. A tablet with
high concavity can also be difficult to remove from the lower punch,
leading to capping or sticking if insufficient lubrication is present.
Logos/Lettering and Embossing. Brand identity and the requirement
to have logos on tablets can lead to difficulty in adapting the design
of a tablet so that the embossing on the tool creates a good tablet
with a clearly defined logo. Some brand logos are very large and
require large surface areas to fit the lettering, which influences the
shape and profile of the tablet. Lettering with details, such as
angular fonts or numbers and characters with holes in their de-
signs, such as O, A, R, 6, and 8, can create a perfect void for powder
to fill and accumulate. This would lead to tablets being rejected and
the need for time-consuming polishing processes to free the
powder from the embossing. There are potential changes that can
be made to the embossing so that the buildup of formulation in
these areas is minimized. These can be in the form of what are
known as reduced counters or prepicking, in which the depth of the
center of a character can be raised, or a tapered peninsular inwhich
lettering can be designed without as many voids for the powder to
accumulate, creating a less troublesome logo for tableting while
keeping the lettering defined. The understanding of the impact of
embossing on sticking can be based on a range of factors, some of
which are gradually being better understood.22 It has been
demonstrated, for instance, that the cut angles of a logo can make a
difference to sticking.23 Other factors may come into play. This
should be part of the development of the tooling selection.
Roughness
The roughness of tooling is an important determinant in the
performance with respect to sticking. Factors, such as finishing
method, will determine the final roughness of a material. A coating
or treatment applied to a tool, for any reason, can influence the final
roughness. The preparation for the coating method may actually
roughen a material (e.g., by removing steel inclusions), but the

S. Chattoraj et al. / Journal of Pharmaceutical Sciences xxx (2018) 1-16 5

Figure 6. Worn-out embossing due to excessive polishing.

to lower sticking, as it may lead to an increased contact area be-

tween the formulation and the tool, particularly during compac-
tion. Of particular difficulty are situations when a tool has both
rough and smooth areas, which may mean that there is an area
where sticking can commence. Different roughness levels, as seen
in Figure 5, could lead to sticking at different parts of the punch or
near the logo, leading to picking or sticking.

Atmospheric (Relative Humidity) Effects

Humidity can be highly detrimental to formulations that attract

water. Atmospheric water can be absorbed by powder and can
cause the formulation to bind to itself and other surfaces by
creating capillary bridges, leading to sticking. Moisture sorption by
formulations can be a significant contributory factor to sticking.25
Many tablet manufacturers will invest in humidity-controlled en-
vironments when compressing problematic formulations that
attract water to keep the compression suite as dry as possible and
minimize the effects of humidity and consequently reduce sticking.
It is an underestimated factor in the transfer of formulations from
site to site that the humidity conditions can be different. Even if the
manufacturing rooms are under controlled conditions, the tooling
and intermediates may be exposed to different conditions during
storage, maintenance, or transport, and this may influence sticking
outcomes as well.

API Properties

Based on the principles of Material Science Tetrahedron,26 the

Figure 5. Profilometry and microscopy images of the surface of tablet tooling, indi-
cating regions of roughness on the tool. A range of roughness on different areas of a
punch could predispose certain areas to sticking and especially picking. (a) Optical
profileometry image of an unembossed chromium-coated tablet tool. (b) Microscopy
image of an unembossed chromium-coated tablet tool. (c) Image of an embossed tool
taken from a Taylor Hobson Talysurf Interferometer. The roughness at the base of the
lettering may form the initiation of sticking (or picking, in this case).
application of the coat may lead to a smoothing or roughening of a
surface. It has recently been shown that the roughness and the
coating of a tool cannot be considered as being independent, when
assessing the sticking of formulations, and so a comprehensive
assessment of both the factors is required when assessing the
suitability of a tool to mitigate sticking.24
For a given formulation, there will be levels of roughness that
promote sticking or mitigate it. The granules (or any fines) may
stick preferentially at a particular roughness level. Unfortunately, it
is not possible to state that a smoother surface will universally lead
molecular and particle structure of a material directly influences
the properties and manufacturing performance of materials.
The impact of API properties on sticking potential may be
categorized as follows:
(1) The effect of the intrinsic chemical and molecular structure
of the drug (e.g., polar surface area)
(2) How the molecules assemble in a solid form (e.g., crystalli-
zation characteristics, relative proportion of particular moi-
eties exposed, and molecular packing)
(3) Effect of particle properties (surface area and surface energy,
particle size, and shape distribution)
(4) Bulk drug properties, such as particle size distribution and
flow.
All these factors have been examined with respect to their
contribution to sticking. However, none in isolation can explain the
phenomenon. It is worth noting that chemists, chemical engineers,
and formulators have limited control over the choice of API (which

Load more

Citations (2) References (163)

Manufacturing Classification System in the real world: factors influencing manufacturing process choices for
filed commercial oral solid dosage formulations, case studies from industry and considerations for continuou…

Article Full-text available Oct 2018 · PHARM DEV TECHNOL

Michael M Leane · Kendal Pitt · Gavin Kenneth Reynolds · Rafaela Dall Agnol

View Show abstract

A novel pharmaceutical excipient: Coprecipitation of calcium and magnesium silicate using brine-seawater in
date palm cellulose as an absorbing host

Article Full-text available Sep 2017

Mayyas Al-Remawi · Amani M. Elsayed · Ibrahim Abdullah Maghrabi · Nisrein Jaber

View Show abstract

Show more

Recommendations Discover more publications, questions and projects in Tablet

Project Project

TIMERx Machine Learning for Cheminformatics

Mike Tobyn Chris Morris · Rebecca Mackenzie · Jose C Menezes ·
[...] · Ana Patricia Ferreira

We are delivering a course 5-9 Feb 2018: https://eventbooking.stfc.ac.uk/news-

events/machine-learning-for-cheminformatics-404

View project View project

Project Project

Multivariate Analysis Sticking and Picking

Mike Tobyn · Jose C Menezes · Ana Patricia Ferreira Mike Tobyn

View project View project

Article Article

Co Processed Excipients for Tabletting: Critical Excipient Attributes Relevant to

Review Article Solid Dosage Formulation Manufacturing
July 2017 · Research Journal of Pharmacy and Technology January 2019 · Journal of Pharmaceutical Innovation

Amol Main · Bhushan A. Bhairav · R. B. Saudager Naseem Charoo

This main aim of the current review article is to provide a complete overview on
recent development in excipient technology and the approaches involved in
development of such excipients. Formulation scientists recognized that single
component excipients do not always provide the requisite performance to allow
certain active pharmaceutical ingredients to be formulated or manufactured
adequately ... [Show full abstract]
Purpose The objective of this article is to review the critical material attributes of
pharmaceutical excipients employed in solid dosage manufacturing and link
them to critical quality attributes (CQAs). Material attributes can have a profound
impact on CQAs of product. Methods The importance of particle size, particle
morphology, density, moisture content, and polymorphism to product CQAs is ...
[Show full abstract]

Read more Read more

Article Article Full-text available

Application and research situation of direct A REVIEW ON CO-PROCESSED

powder tableting technology and excipients EXCIPIENTS: CURRENT AND FUTURE
November 2015 TREND OF EXCIPIENT TECHNOLOGY
J.-Z. Li · J.-R. Feng · T. He · X. Lin January 2019 · International Journal of Pharmacy and Pharmaceutical Sciences

Kai Bin Liew · Anand Gaurav · Uttam Kumar Mandal

Compared to the other production technologies of tablets, direct powder
compaction technique has remarkable advantages, such as simplicity, energy
and time saving, low production cost and stable production quality, etc. It is
increasingly used in pharmaceutical companies worldwide. However, this
technique has relatively high requirements on excipients, such as good
flowability, compressibility, ... [Show full abstract]
Read more
There is no single-component excipient fulfills all the requisite performance to
allow an active pharmaceutical ingredient to be formulated into a specific
dosage form. Co-processed excipient has received much more attention in the
formulation development of various dosage forms, specially for tablet
preparation by direct compression method. The objective of this review is to
discuss the ... [Show full abstract]
View full-text

Discover more

About Support Business solutions

News Help center Recruiting

Company FAQ Advertising

Careers

© ResearchGate 2019. All rights reserved. Imprint · Terms · Privacy