14 BASF SkinDelivery PDF

Trends and
Formulation
Strategies
for Topical
Drugs M AY 2 0 1 8
Optimizing Semisolid Dosage Forms

Quality by design, in-vitro release testing, and modern analytical methods
are improving understanding and control of these complex formulations.
Formulation Trends for Topical Dosage Forms

Topical dosage forms include a range of skin delivery
systems with unique advantages and formulation challenges.
Excipient Selection to Enable the

Performance of Skin Delivery Dosage Forms
Semisolids like ointments, gels, and creams benefit from functional
ingredients that improve product performance and ensure delivery.
Excipient Selection for Topical Formulations

Case studies that illustrate how formulators can
use excipients as tools to improve drug products
This custom ebook

Semi-Solid Dosage Forms is sponsored by BASF
The advantages and the key considerations Pharma Solutions S p o n s o r e d b y
in developing topical formulations. and presented in
partnership with
Pharmaceutical
Technology.
Semisolid Topical
Functional Excipient Formulation
Optimizing Semisolid
Dosage Formulation
Forms Trends
Excipients Selection Development Dosage Forms
Images under license from Shutterstock.com

Dosage Forms
Quality by design, in-vitro release
testing, and modern analytical methods
are improving understanding and control
of these complex formulations.
Agnes Shanley
Y
ears ago, when excipients Another problem is the fact that every
were called “fillers” or “inac- formulation is different, says Alyn Mc-
tive ingredients,” drug-product Naughton, director of analytical and product
quality testing was simple. The development, Encap Drug Delivery, a divi-
traditional approach, however, often sets sion of Capsugel Dosage Form Solutions.
the stage for process variability and manu- “Excipients are used functionally to achieve
facturing and quality problems. different objectives, including bioavailability
Today, more is known about the poten- enhancement, dose homogeneity for low-
tial interactions that can occur between dose drugs, high-potency safety, and abuse
excipients and active ingredients, as well resistance. As such, each product must be
as the impact of raw-material variability considered individually within the lens of its
on the final drug-product quality. Quality specific function and desired outcome.”
assurance is evolving to a multidisciplinary A simple “cream” may contain several
approach that requires an understanding excipients, solubility enhancers, and par-
of materials properties on the molecular tially dissolved API, and may distribute the
and physical level, and of critical quality drug in a potentially complex or dynamic
attributes (CQAs) and potential product way. Sameersingh (Sam) Raney, scientific
failure modes. lead for topical and transdermal drug prod-
Taking a quality-by-design (QbD) ap- ucts at FDA’s Office of Generic Drugs, and
proach can be difficult when dealing with former professor of pharmaceutics at the
semisolid dosage forms because of their North Dakota State University, reminded
complex flow behavior. Some semisolids attendees of the challenges at a special
can act like a liquid and a solid within the session on October 2015, at the 2015
same formulation at different times and American Association of Pharmaceutical
under different conditions. Scientists’ (AAPS) meeting in Orlando, FL
2 M AY 20 1 8 | P H A R M T E C H
Semisolid Topical
Dosage Formulation
Forms Trends
(1). Given the complexity of creams, he stat digestion testing is typically used to
said, several different attributes may be quantify solubility improvement for lipidic
crucial to product quality, and several fail- bioavailability-enhancement projects, while
ure modes may be possible. Approaches x-ray powder diffraction and differential
will need to take multiple factors into scanning calorimetry are usually applied
account. Excipient selection can have to characterize amorphous dispersion and
a significant impact on performance at- crystalline suspensions, he says.
tributes, as Norman Richardson, Global DPT scientists are focusing on micro-
Technical Marketing Manager, Skin Deliv- structure, Bhatia says, which is directly
ery at BASF Pharma Solutions, explained related to factors and conditions on the
at the meeting. Research is under way manufacturing floor. Understanding mi-
to help clarify some of these issues. This crostructure allows processes to be opti-
article reviews some of the work going mized, according to Bhatia.
on in this area. Scientists use microscopy and laser
diffraction to analyze microstructure, and
Traditional Testing Cannot then take mechanical measurements us-
Address Variability ing a micelle counter (typically, a Clemex
Traditional quality testing for semisolid image analyzer or laser diffraction device
dosage forms typically focuses on viscos- attached to a computer).
In addition, rheology, which observes
ity, the effects of changes in temperature,
how stress affects product flow, is being
and flow. Although these test methods
used to study the compounds. Plotting
may be indispensible, when used alone, sheer stress vs. sheer rate results in a
they are not sufficient in examining poten- curve that can be used to help predict
tial for variability, says Kuljit Bhatia, vice- product behavior under different condi-
president of research and development tions, Bhatia says.
at DPT Labs and a North Dakota State “We are taking a step-by-step process to
alumnus. “These compounds contain examine emulsification, chemical stress, me-
emulsions, composed of an oil phase chanical stress, process development, and
and a water phase, with surfactants and other factors including cooling and the impact
of changes in temperature,” Bhatia says. One
emulsifiers. We keep all these ingredients
goal, he adds, is to ensure that laboratory ma-
together on a shelf for two years during
terials are the same as scale-up materials and
stability testing, but how can we ensure that such factors as globule and micelle size
they are stable?” he asks. are uniform from batch to batch.
Test selection usually depends on the Michael Lowenborg, DPT Labs’ senior
target product profile (TPP) of the dosage manager of R&D formulation and process
form and the formulation composition, development, explained the “microstruc-
explains McNaughton. For example, pH- ture” approach to studying emulsions
3 M AY 20 1 8 | P H A R M T E C H
Semisolid Topical
Dosage Formulation
Forms Trends
at the AAPS session (2), and gave an in microstructure can affect nonphysical
example of how this approach was used attributes such as in-vitro release.
to optimize the formulation and process Capsugel is also applying QbD principles
development for an emulsion, working to semisolid dosage forms, from the very
back from results in the lab to process de- start of the design process through to
sign and equipment selection. Part of the clinical and commercial manufacture, says
work involved optimizing the hydrophilic- McNaughton. “The understanding and con-
lipophilic balance (HLB) and mixing and trol of CQAs and CPPs, from the concept
temperature of emulsification. stages of dosage form design, helps mini-
Applying design-of-experiments (DOE) mize any impact of manufacturing later in
and scale-up studies offers insights into the process,” he explains. “It is important
the critical process parameters (CPPs) to determine both the tolerances of for-
and CQAs at each process phase. Future mulation and excipient ratios and combina-
work, he said, will focus on how variation tions and the processing parameters used
A SIMPLE MODEL FOR A COMPLEX PROCESS
Unlike homogeneous systems, where was varied, and the ointment structure
final product attributes depend solely studied under cross-polar microscopy,
on quantitative and qualitative at- bright regions showed less crystalline
tributes, creams, ointments, and gels areas. Rheological studies then revealed
are heterogeneous, and depend on ad- the impact of viscosity and shear thin-
ditional factors such as temperature, the ning. In studies of product stability, the
order in which ingredients are added, amount of one of the glycols was varied
shear, packaging conditions, excipient and evaluated with cross-polar micros-
source and grade, and storage time, copy. At 5%, fluid weeping occurred
explains Norman Richardson, Global immediately. At 20%, it took seven days.
Technical Marketing Manager, Skin De- Formulations with 25–30% of the glycol
livery at BASF Pharma Solutions. Tests were found to be the most stable.
have been done on simple ointment
systems containing two different poly- REFERENCE
ethylene glycols and solvent to better
1. N. Richardson, Controlling the
understand issues (1). The best sensory
Physical Properties and Performance
properties were achieved by balancing of Semisolid Formulations Through
fluid, gel, and solid states. When the Excipient Selection, Pharmaceutical
molecular weight of one of the glycols Technology webcast, June 10, 2015.
4 M AY 20 1 8 | P H A R M T E C H
Semisolid Topical
Dosage Formulation
Forms Trends
during manufacture at a small scale, and Addressing Unpredictable Changes

how these factors can change during scale In-vitro testing provides the only practical
up. It is also critical to know the perfor- means of demonstrating shelf life and
mance and limitations of the excipients and identifying potential changes in product at-
materials that are being used, particularly tributes from unpredictable sources such
those that are functional,” he says. as raw materials change or manufacturing
The fact that two companies that support impacts, explains McNaughton. “As we
contract development and manufacturing develop a greater understanding through
work are using more modern quality tools the characterization of both materials
reflects a change in and processes,
thinking within the it is likely that
industry. “The use “Multi-disciplinary teams the QbD process
will allow for a
of QbD has gone are a key component of more relaxed ap-
mainstream in the
past five years, and our formulation approach proach to standard
in-vitro stability
led to a ‘debunking’ of to customer projects, testing,” he says.
the traditional process
for semisolid dosage
regardless of problem “However, the
form development,” statement, TPP, or finished development of
more sophisticated
says Bhatia. product presentation.” dosage forms
At the same time,
could also result
more manufactur- – Alyn McNaughton, director of analytical and
in an increase of
ers are now using product development, Encap Drug Delivery, a
division of Capsugel Dosage Form Solutions more specialized
in-vitro release
testing until we
testing (IVRT) for
develop an under-
semisolid dosage standing of their
form manufacturing. A few years ago, the performance characteristics.”
method was used only in some research Whatever directions this work may
projects, Bhatia says, but it, too, has gone take in the future, the industry requires a
mainstream, and more companies are new approach to semisolid dosage form
even using it to submit new drug applica- development, and to staffing and training,
tions (NDAs). Two years ago, the United Bhatia says. “FDA asks for specifics on
States Pharmacopeia (USP) published an rate of release to control processes and re-
entire chapter on the method (3), aligned duced variability batch to batch, requiring a
with FDA guidance from 1997 (4). The goal clear understanding of rate of release, risk
was to standardize testing equipment and assessment, CQAs, and the design space,”
procedures. he adds, noting that his company tends to
5 M AY 20 1 8 | P H A R M T E C H
Semisolid Topical
Dosage Formulation
Forms Trends
hire mainly PhDs in formulation, but also course, more pharmaceutical sponsors are
more professionals with advanced semisol- proactively demanding that QbD methods
ids experience using rheology and IVRT. be used for their projects. As a result,
“Multi-disciplinary teams are a key compo- convergence is being seen between
nent of our formulation approach to customer name-brand and generic-drug sponsors,
projects, regardless of problem statement, Bhatia says. “NDA clients tend to ask
TPP, or finished product presentation,” says for QbD explicitly, while generic-drug
McNaughton. Such teams are mainly com- manufacturers may not ask for it at first,”
prised of fundamental scientists, including he explains. “Given FDA’s mandate to use
materials scientists. They often complement question-based review (QbR), however,
customers’ teams, which are generally ap- more companies see they are going to
plied science-focused, he says. need QbD-type data anyway, so they real-
While both companies recommend a ize they will need to use newer methods
QbD approach to clients as a matter of to evaluate their products and processes.”
EXCIPIENTS FOR SPONSORED CONTENT Modular PAT Approaches

DRUG FORMULATION Likely in the Future
The future may see the application of pro-
cess analytical technology (PAT) more rou-
tinely in semisolid formulations develop-
ment labs. Typically, the approach is used
for larger batches and continuous process-
ing, but there may be a need for built-in
endpoints (e.g., micelle size changes) that
Equipped with an in-depth under-
can ensure the best microstructure to en-
standing of multiple industries, sure rate of release in the lab, says Bhatia.
technologies and applications, we “PAT would allow R&D teams to build in
have the skills and resources to that endpoint,” he says.
make drug manufacturing more R&D groups are already developing probes
efficient, robust, and cost-effective. and taking samples and measurements
Whether you want to make your at the plant. “Evaluated on a case-by-case
medicine more effective, safer, or basis, PAT would be the logical next step,”
more patient-friendly, BASF has the Bhatia says. PAT approaches can be used
solution you need. Find the right to characterize materials and processes
answers to your pharmaceutical during development and control materials
formulation challenges.
and processes during manufacturing, and
can result in a reduction in in-process test-
Click here to learn more
ing while helping reduce finished product
testing, says McNaughton, noting that PAT
6 M AY 20 1 8 | P H A R M T E C H
Semisolid Topical
Dosage Formulation
Forms Trends
can be used at various stages in the manu- FDA is funding a number of research
facture of semisolid dosage forms, including projects focused on semisolid dosage form
raw material identification testing using measurement and assessment. DPT is
near infrared (NIR); assay and homogeneity working on some research that is funded
evaluation; and particle-size measurement by FDA under the Generic Drug User Fee
or performance testing during milling of dry Amendment of 2012 (GDUFA). FDA is also
powders or in suspension. funding research by Michael Roberts and
Currently, he says, these testing approach-
his team in Queensland, Australia, that aims
es are usually best-suited for dedicated
to identify and define CQAs and potential
product equipment, where they can target
failure modes for semisolid products. FDA
specific CQAs required for a particular prod-
uct. As PAT system designs become more wants to relate CQAs of drug products to
modular, he says, they will likely become in-vitro and in-vivo performance.
standard for many areas within a manufac- Research will examine the properties
turing process. While not quite the same of APIs, excipients, and the interaction of
approach, similar techniques can also be ap- product with the skin. The team will compare
plied to characterize performance attributes bioavailability, and use tools such as atomic
during formulation development, he says. force microscopy, confocal Raman, and multi-
Examples would be dissolution rates and photon microscopy to study the effects of
concentrations, where solubility-dependent excipients and formulation in-vitro and in-vivo.
absorption is being improved through formu-
lation development. This would allow more Agnes Shanley is the senior editor
rapid product development, he says, and of Pharmaceutical Technology.
improve the potential for success through
increased in-vitro screening. References
USP plans to launch a collaborative 1. S. Raney, “Considerations Relating to Product
study that will involve equipment vendors, Quality Characterization for Topical Semisolid
contract laboratories, and pharmaceutical Dosage Forms,” presentation at the AAPS Annual
Meeting (Orlando, FL, October 2015).
companies that have expertise on the per-
formance tests for semisolid dosage forms. 2. M. Lowenborg, “Effect of Process Development
The goal is to gain a better understanding of on Emulsion Microstructure,” presentation at the
AAPS Annual Meeting (Orlando, FL, October 2015).
possible sources of variability when running
these tests, and to better describe the test 3. V. Shah et al., Topical Drug Bioavailability, Bio-
equivalence and Penetration, Second Edition, p.
conditions in the USP General Chapter 1724, 65, (Springer, January 2015).
Semisolid Drug Products—Performance
4. FDA, Guidance for Industry SUPACSS: Nonsterile
Tests (4), says Margareth R. C. Marques, Semisolid Dosage Forms (Rockville, MD, May 1997).
principal scientific liaison, US Pharmacopeial
Convention’s Science Division, Chemical This article first appeared in Pharmaceutical
Medicines General Chapters. Technology 39 (12): 42–44 (2015).
7 M AY 20 1 8 | P H A R M T E C H
Semisolid Topical
Formulation Trends for
Dosage Formulation
Forms Trends
Excipients Selection Development Topical Dosage Forms
S P ONS OR E D C ONTE NT
Formulation
Trends for Topical
Dosage Forms
Topical dosage forms include
a range of skin delivery
systems with unique advantages
and formulation challenges.
S
kin is the largest organ of the hu- with advantages and disadvantages, and
man body. The primary functions specific formulation challenges. A suf-
of skin are to act as a barrier to ficiently broad excipient portfolio allows
external pathogens, toxins and flexibility and freedom in formulating.
pollutants and to act as a barrier to retain The overall global market size for topi-
water in the body. Due to cal formulations was just
its design and function, the under $95 billion in 2016,
skin offers both opportunity The overall global and is expected to grow to
and challenges to the topi- over $122 billion in the next
cal delivery of therapeutics. market size for five years, with ointments
Depending on the indication topical formulations and gels making some-
and the drug, the formulator what more rapid gains
of a topical product may was just under than other dosage forms
wish to accomplish one or $95 billion in 2016. in certain global regions,
more of the following: (1) said Amy Ethier, a scientist
Deliver drug only to the skin in the Global Skin Delivery
surface, (2) deliver drug into the skin layers Lab at BASF Pharma Solu-
and/or (3) deliver drug through the skin for tions, during a presentation delivered at
systemic activity. CPhI North America 2017.
More than 40 distinct skin delivery dos- Ethier pointed out that some drivers in
age forms are listed in the FDA’s NDC the growth of the topical formulation mar-
(National Drug Code) Directory. Some of ket include generics expansion in emerging
the most common are creams, ointments, markets. Population shifts toward older
gels, and liquids. Some other notable forms consumers leading to a greater incidence
are foams, solid sticks, balms, sprays, and of diabetes related needs (wound care) as
patches. Each topical dosage form comes well as more emphasis on home care.
9 M AY 2 0 1 8 | P H A R M T E C H SPON SO R ED CO N TEN T
Semisolid Topical
Dosage Formulation
Forms Trends
Skin delivery presents unique challenges of those functions include solubilizers,

compared to other dosing routes, Norman emollients, penetration enhancers, emulsi-
Richardson, Global Technical Marketing fiers, viscosity modifiers, film formers,
Manager, Skin Delivery at BASF Pharma So- spreading agents, foaming agents, and
lutions, noted during the same presentation. more. Excipients are used to enhance the
Where required, the drug product must pen- functionality of each dosage form, as well
etrate the stratum corneum, the outermost as overcome some of its challenges.
layer of the epidermis. The stratum corneum “When we think about our excipients,
is a thin layer of flattened skin cells, dense we think about functionality first,” Richard-
with crosslinked protein and embedded in son said. “What
a complex matrix do you need to
of highly organized do? What are
lipids. At the same Formulation of a successful the tools that
time, the product you are looking
must also be mild skin delivery system typically for when you’re
enough not to irritate requires the use of one or formulating?
the sensitive, living For instance,
skin cells under that more specialized excipients that you may need
layer. In developing provide functionality to achieve a hydrophilic or
a dosage form, a a hydrophobic
formulator considers the product design objective. solubilizer to
an array of factors dissolve some-
including: thing.”
• indication or disease He pointed out
that poloxamers can be used to solubilize,
• application site
and they are multifunctional. A poloxamer is
• patient compliance a nonionic triblock copolymer composed of a
• drug delivery profile hydrophobic block and two hydrophilic blocks.
• ease of application “They also can be used to emulsify or make
gels—all of that with one product,” he stated,
• API compatibility and stability adding that poloxamer 188 or poloxamer 407
in the formulation can have many other functions.
Excipients Creams and Lotions
Formulation of a successful skin delivery
An emulsion is a two-phase system com-
system typically requires the use of one
prised of at least two immiscible liquids, one
or more specialized excipients that provide
of which is dispersed as droplets within the
functionality to achieve the product design
other liquid, stabilized by one or more emul-
objective, Richardson explained. Some
sifying agents. A cream is generally defined
Semisolid Topical
Dosage Formulation
Forms Trends
as a semisolid dosage emulsion form con- unstable because they are not at a ther-
taining more than 20% water and volatiles modynamic minimum energy. Effective
and less than 40% hydrocarbons, waxes, or formulation, through the careful selection
polyols, Ethier explained. of excipients, allows for the slowing of for-
One advantage of emulsions is the soft, mulation instability, and thus extends the
spreadable consistency that encourages life of the product.
high patient compliance, she noted. In “Emulsions or creams are complex
addition, the water and oil phases of the systems. That gives us an opportunity to
emulsion allow for maximization of active tailor the formulation to achieve the desired
pharmaceutical ingredient (API) solubility. properties, but it also means there are a
On the other hand, formulations for creams lot of interactions that are occurring at the
and lotions can be complicated. First, skin macroscopic scale, the microscopic scale,
type and environmental conditions present through various chemistries” said Ethier in a
variables that can influence many aspects of discussion with Pharmaceutical Technology.
delivery with creams or lotions. For example, The interplay between the excipients, the
compromised skin and humid conditions vehicle, and the active ingredient ultimately
could affect the performance properties of influence the thermal and rheological be-
the product, Ethier explained. havior of the product. Figure 1 shows the
Creams and lotions are relatively components of a model cream formula-
Example of a Cream Formulation
n Formulation
FIGURE components are dependent
1: Example on application
of a Cream Foundation site, API and targeted dermal delivery and
sensory properties.
Item Description Purpose Wt%
Kollisolv® PG Propylene glycol Solvent 5%
Kollicream® OA Oleyl alcohol Emollient 5%
Kollicream® OD Octyldodecanol Emollient 5%
Kolliphor® CS 20 Polyoxyl 20 cetostearyl ether Emulsifier 3%

Consistency
Kolliwax® CSA 50 Cetostearyl alcohol 50 9%
factor
API - API 1%
Water - Solvent 72%
Preservative - Preservative drop
Semisolid Topical
Dosage Formulation
Forms Trends
tion. It contains a solvent (propylene gly- Ointments

col), a lipid-based emollient, an emulsifier, In contrast to creams, ointments are typi-
and a co-emulsifier for maximum stability. cally less than 20% water and more than
According to Richardson, the properties 50% hydrocarbons, waxes, or polyols as
of a cream can be enhanced through the the vehicle, according to CDER Data Stan-
inclusion of lipophilic solubilizers, penetra- dards Manual Definitions for Topical Dosage
tion enhancers, agents that stiffen the Forms. They are defined as a semi-solid dos-
formulation, and use of excipients that age form generally intended for external ap-
minimize residue. plication to the skin or mucous membranes.
Richardson covered Ointments fall into
how excipients can one of four classes:
mix together, par- The interplay between hydrocarbon base, ab-
ticularly emulsifiers
and fatty alcohols, to
the excipients, the vehicle, sorption base, water-
removable base, and
organize into complex and the active ingredient water-soluble base.
microstructures. “The Ointments offer the
molecules organize on ultimately influence the opportunity to fine-
a microscopic scale thermal and rheological tune many aspects
to build structure in of the formulation.
the formulation,” he behavior of the product. Viscosity, for example,
stated. “What hap- can vary from a thin to
pens, then, is you a very thick ointment.
build viscosity. So, this is how you can Ointment formulations also have the versatil-
take something that’s pourable and very ity to optimize incorporation of the API and
fluid and make it into a creamy consis- maximize stability of the formulation. Oint-
tency so you can pick it up and apply it on ments can be greasy, which is sometimes
your skin.” a disadvantage. However, the oily film can
He added that this interaction of also increase hydration of the skin, and en-
excipients and the formation of other courage retention of the product on the skin
microstructures drives the product’s per- because it doesn’t easily wash off.
formance. “Things like the viscosity, the An ointment formulation is suitable for a
physical stability, even the drug delivery hydrolytic API, targeted penetration, and a
out of the formulation is impacted by the long-acting formula. It is typically applied to
microstructure,” Richardson stated. This dry skin.
is an area of intense investigation now
as product developers and regulators are Gels
learning that the microstructure has a A gel is a solution or colloidal dispersion
critical role to play in topical product criti- form that contains a gelling agent. A gel
cal quality attributes and bioequivalence. may also contain suspended particles.
Semisolid Topical
Dosage Formulation
Forms Trends
Example of a Cream Formulation
n Formulation components are dependent on application site, API and targeted dermal delivery and
Thesensory
marketproperties.
for gels is highly dependent A disadvantage in marketing gels is that
on region (see Figure 2). In 2016, gels consumers don’t always associate gels
Wt%
occupied a significant Item Description Purpose
with efficacy. Creams
market share in North
Kollisolv ® PG Propylene glycol and ointments are
Solvent 5%
The market for gels is
America. Growth is
Kollicream ® OA Oleyl alcohol more visible 5%
Emollient and heavi-
Kollicream® ODhighly dependent
projected in all regions on
Octyldodecanol erEmollient
and those5% sensory
through 2021, butKolliphor® CS 20region. Gels are
Polyoxyl well- ether cues
20 cetostearyl signal efficacy
Emulsifier 3% for
growth will be greater many consumers.
Consistency
9%
Kolliwax® CSA 50
in North America and suited to hot, humid
Cetostearyl alcohol 50
Infactor
terms of formula-
1%
the Asia-Pacific API
region climates.
-
tion,API
gels may offer
72%
than Europe andWater
the - Solvent
less flexibility in solu-
rest of the world, said
Preservative - Preservative drop
bilizing the API, due
Ethier. to the general lack of an oil phase. Gels
One factor influencing regional varia- often contain alcohol, which can aid in
tions is climate. Gels are lighter formula- penetration, but also may have a drying
tions well-suited to hot, humid climates. effect on the skin.
FIGURE 2: Gel Market Size
Semisolid Topical
Dosage Formulation
Forms Trends
An example gel formulation (see Figure 3) Foams

uses a poloxamer (Kolliphor® P 407) as a A foam dosage form is an emulsion that
gelling agent. Formulations with poloxamers has been aerosolized to incorporate air.
may be customized by using polymers of The incorporation of air gives foams sev-
different molecular structures. Poloxam-
eral positive attributes. They can easily be
ers have advantageous qualities for gel
applied to a large surface, and they rub
formulations. They have the ability to
into the skin well (see Figure 4).
protect cells in the area of a wound or
Some disadvantages of foams are that the
compromised skin and may also impart
solubilization functionality. stability can sometimes be difficult to moni-
When the poloxamer is at least 15% of tor after the propellant is introduced to the
the formulation, solvents like alcohol and system. The propellant has the potential to
propylene glycol can be included. In this interact with the formulation, and foams are
case, glycerin is included as a solvent and dynamic systems that may be dependent
humectant, as well, and water makes up the on external energy such as shaking to create
balance of the solvent phase. “This creates a suitable system prior to dispensing.
a really nice gel on the skin,” said Ethier. “It A challenge in introducing air into the
has beautiful sensory properties and the formulation is that an excipient that has a
ability to incorporate a number of APIs.” functionality in the liquid formulation such
FIGURE 3: Gel Formulation with Poloxamers

Gel Formulation with Poloxamers
n Kolliphor® P 188 and Kolliphor ® P 407 are mild, thermoreversible gelling agents that do not
require pH adjustment.
Kollisolv® PG Propylene glycol Solvent 10%
Ethanol Ethanol Solvent 10%

Solvent /
Glycerin Glycerin 5%
Humectant
Kolliphor® P 407 Poloxamer 407 Gelling agent 16%
API - API 5%
Water - solvent 54%
Semisolid Topical
Dosage Formulation
Forms Trends
as aiding drug delivery used for products like

might actually also be sunscreen and poison
an anti-foaming agent. Sprays present a ivy remedies. Sprays
“You’re further com- are formed by gen-
plicating the formula-
challenge in maintaining erating droplets of a
tion. However, you API solubilization and a solution containing dis-
are also introducing solved drug. They are
homogenous solution. typically used on skin
another opportunity to
achieve the targeted or mucous membrane.
profile,” said Richard- Sprays can present a
son. “You have a new challenge in maintain-
space for understanding the microstruc- ing API solubilization and a homogenous
tures or some of the species that might solution. Safety is also a consideration be-
form as a result of incorporating air.” cause droplets can potentially be inhaled.
A relatively short dry time is desirable in a
Aerosols and Pump Sprays spray formulation, and it can be difficult to
Aerosols and pump sprays are often accomplish while achieving other formula-
simple formulations. They are commonly tion considerations.
aming Technology Including Aerosol Foams
The definition
FIGUREof a medicated
4: Foamingfoam is ‘an emulsion
Technology Usingcontaining one or more active ingredients,
Aerosol Foams
surfactants, aqueous or non-aqueous liquids and propellants.
Air bubble
Skin surface
Solvent /
Surface
emollient
active agent
er for Drug Evaluation and Research
Semisolid Topical
Dosage Formulation
Forms Trends
Sticks and Patches you can really start to feel that when you’re
A stick is a solid dosage form applied by applying the stick to the skin,” said Ethier.
rubbing on the skin. It typically provides A patch is a drug delivery system that
an occlusive barrier. Sticks are a simple usually includes an adhesive backing. It is
formulation generally not intended for applied to an external site on the body, and
large areas of skin. the ingredients either passively diffuse from
A very simple example of a stick formula- the patch, or are actively transported into
tion (see Figure 5) combines a fatty alcohol the skin. The intended target tissue may be
(Kolliwax® CSA the skin, a location
50/cetostearyl under the skin, or
alcohol 50) with A broad range of excipients general circulation
an emollient in the body. Extend-
(Kollicream® OD/ offers options for developing ed release films are
octyldodecanol) a variety of dosage forms to a common type of
and active ingredi- meet many formulation needs. patch dosage form.
ent. The stick can Patches can be
be adjusted for single-layer or
consistency and multi-layer. In a
properties of the oil, as desired. “We have single-layer patch, the drug and adhesive are
some oils that are very fast-spreading and sandwiched between the backing and the
liner. The backing layer protects the API and
FIGURE 5: Dosage Form: Stick

Dosage Form: Stick
n A stick is defined as a dosage form prepared in a relatively long and slender, often cylindrical form.

Consistency
Kolliwax® CSA 50 Cetostearyl alcohol 50 50%
builder
Kollicream® OD Octyldodecanol Solvent/Emollient 49%
API API API 1%
n Provides occlusive barrier n Simple formulation
n Convenient application n Not suitable for a large

surface
Semisolid Topical
Dosage Formulation
Forms Trends
excipients from evaporation and anchors the However, patches can sometimes be diffi-
formulation. The drug/adhesive layer adheres cult to remove from the skin or inconvenient
to the skin and holds the API. The liner layer to dispose of. Some active ingredients and
protects the formulation during storage and indications require a larger surface area.
is removed prior to application.
In a multi-layer formulation, layers of drug Conclusion
and adhesive are separated by a membrane The broad range of dosage forms available,
that reinforces the system and mediates including, but not limited to, lotions, creams,
sustained release. The lower drug layer con- ointments, gels, foams, sprays, sticks, and
tacts the skin initially and provides an initial
patches, have the potential to deliver many
burst of drug upon contact with skin. The up-
active ingredients on and through the skin.
per drug and adhesive layer contributes to an
Choices for skin delivery dosage forms de-
enhanced API release rate (see Figure 6).
pend on the indication or disease, the state
Patches are typically very adaptable for
the type of delivery desired. For example, of the skin, and patient compliance. A broad
they can be tailored for immediate release or range of excipients offers options for de-
extended release. The profile of the product veloping a variety of dosage forms to meet
is inconspicuous and discrete. many formulation needs.
FIGURE 6: Transdermal Patch Technologies

Transdermal Patch Technologies
Multi-Layer Patch Single-Layer Patch
BACKING
UPPER Drug in
Adhesive Outermost layer protects API
Reservoir that and excipients from
provides evaporation. Provides
enhanced API anchorage of the
release rate. formulation.
Backing
MEMBRANE
Upper Drug in Provides
Adhesive reinforcemen DRUG IN ADHESIVE Backing
t of the Adhere to the skin and
Membrane system and Drug in Adhesive
contains excipients and API
contributes to
Lower Drug in matrix.
sustained Liner
Adhesive API release
Liner LOWER Drug

in Adhesive LINER
Provides initial Serves to protect the
burst of API formulation during storage
release upon period. Release liner is
adhesion to the
skin.
removed prior to application.
Excipient Selection to
Semisolid
Dosage
Topical
Formulation
Functional Excipient Formulation Enable the Performance of
Forms Trends
Excipients Selection Development
Skin Delivery Dosage Forms
Enable the Performance of
Semisolids like ointments, gels, and creams
benefit from functional ingredients that improve
product performance and ensure delivery.
Norman Richardson and Amy Ethier
T
he global topical drug deliv- layers and make it to the correct biological
ery market was valued at compartment for activity. Third, once the
$92.4 billion in 2016, and API and excipients penetrate the stratum
is projected to expand at a corneum, formulators must ensure the
compound aggregate growth ingredients are mild and do not trigger
rate of 6.4% between 2016 and 2021 (1). inflammatory responses in the living cells.
Topical drug formulators have a large Finally, formulators must ensure the ac-
playing field of dosage form options such tives are delivered to the correct compart-
as ointments, creams, lotions, gels, trans- ment for efficacy and take effect in an
dermal patches, wipes, swabs, sprays, appropriate time period (see Figure 1).
and foams. Indeed, the US Food and Drug Topical drug developers are increasingly
Administration’s National Drug Code Direc- seeking novel or different dosage forms
tory includes more than 40 different types for a variety of reasons including:
of topical dosage forms. • Improved or safer drug
When deciding on the product design delivery routes;
and selecting an appropriate dosage form,
topical drug formulators consider many • Protection and stabilization
of sensitive reactive APIs;
challenges with regard to delivery method.
First is the need to apply drug product in • Increased solubilization
a clean, effective, and targeted way to of insoluble APIs;
the surface of the skin. Then, once the • Improvement of sensory
product is applied, active ingredients must properties, applicability
cross the stratum corneum into the living and patient acceptance;
Semisolid
Dosage
Topical
Formulation
Forms Trends
• Extension of the API and lotions, for instance, one could use wax
exclusivity or patent life; materials (e.g., cetyl alcohol, cetostearyl
• Cost savings; and alcohol or stearic acid) or polymers (e.g.,
Poloxamer 188, 407, and PVP K90) to achieve
• Replication of reference
the desired product consistency.
listed drugs.
Fluidity. Products must have the ability
Semisolid Attributes Are Driven to flow and spread onto the surface of the
by Functional Excipients skin. To achieve optimal fluidity, hydrophilic
While many attributes can be designed into a solvents such as propylene glycol, PEG 300,
topical drug, the following five characteristics PEG 400 and triacetin or hydrophobic materi-
can be improved with functional excipients. als (e.g., medium-chain triglycerides, oleyl
Solidity. Topical semi-solid products have a alcohol, and octyldodecanol) can be helpful.
certain degree of solidity or stiffness, which Physical stability. Topical products must
is often described as the elastic component remain consistent and stable throughout
of their viscoelastic nature. Formulators their shelf life. Physical stability requires
manage the stiffness or solidity of a semi- amphiphilic materials. Commonly used func-
solid formulation by the use of consistency tional excipients for emulsification include
EXCIPIENT are
factors. Higher melting point materials nonionics
SELECTION TO ENABLE such as Polyoxyl
THE PERFORMANCE 20 cetostearyl
OF SKIN DELIVERY DOSAGE FORMS
usually selected for this purpose. For creams ether, polysorbates, and poloxamers. Anion-
Major Concerns of Topical Drug
Major Concerns of Topical Drug
Formulators
Formulators
Figure 1: Major concerns of topical drug formulators.
Need to be able to apply the product

in an acceptableNeed
way to be able to
apply the product
Stratum corneum is difficult
in an acceptable way
Hypodermis Dermis Epidermis
to penetrate
Stratum corneum is
difficult to penetrate
Need mild ingredients to prevent
Irritation of living cells
Need mild ingredients
to prevent irritation of
living cells
Deliver drug to appropriate location
Deliver drug to
appropriate
location
Solidity. Topical semi-solid products have a certain degree

20 M AY 2 0 1 8 | P H A R M T E C H
For hydrophilic drugs, propylene glycol or triacetin could be
SPON SO R ED CO N TEN T
of solidity or stiffness, which is often described as the elastic considered; for a hydrophobic drug, enhancers such as oleyl
component of their viscoelastic nature. Formulators manage alcohol or isopropyl myristate are options. It is important to
Semisolid
Dosage
Topical
Formulation
Forms Trends
ics such as sodium lauryl sulfate and sodium (e.g., emulsifying waxes), and water-soluble
cetostearyl sulfate are also available and are bases (e.g., polyethylene glycols).
usually used at somewhat lower concentra- Advantages of the ointment dosage form
tions because they tend to cause irritation at include good physical stability, a barrier to
higher concentrations. bacteria, a low risk of phase separation, and
Drug delivery. As topical products are the need for fewer excipients, which can
released on or through the skin, drugs must lead to lower materials costs and simpler
perform as expected. A key consideration manufacturing processes.
is how to accelerate penetration through Mupirocin Ointment 2% USP is one ex-
the stratum corneum. For hydrophilic drugs, ample of a marketed ointment. It contains
propylene glycol or triacetin could be con- only three ingredients: mupirocin, polyeth-
sidered; for a hydrophobic drug, enhancers ylene glycol 400, and polyethylene glycol
such as oleyl alcohol or isopropyl myristate 3350. Polyethylene glycol 3350 has a higher
are options. It is important to note that melting point, so it tends to crystallize or
there is no single material that will be a mix with the polyethylene glycol 400 to form
penetration enhancer for all APIs. The choice rigid phases that build a consistency in the
of penetration enhancer is driven by the formulation. The polyethylene glycol is the
physical-chemical nature of the API and by fluid component that behaves like a solvent
the desired route or mechanism for acceler- and allows for spreadability.
ating penetration. To explore the impact of PEG 3350 on
Emolliency. This is driven by excipients microstructure and rheology, a series of
that soften the skin and provide a barrier placebo ointments, sans the active, contain-
that holds moisture for hydration (e.g., iso- ing a range of PEG 3350 concentrations
propyl myristate, and cocoyl caprylocaprate). were evaluated. Microscopy demonstrated
Ointment Dosage Form
The choice of excipients affects the micro-
structural arrangement, which in turn affects VISUALIZATION OF SPONSORED
CONTENT
the functionality and performance of the

OCTYLDODECANOL
semisolid dosage form, which is ointments
FLOW BEHAVIOR
Click here to view
in this case. Ointments usually contain less M8022 Visualization and Investigation of the Flow Behavior and Diffusion of Octyldodecanol
Inside Human Skin after Topical Application by Attenuated Total Reflectance Fourier
than 20% water and volatiles and more than Transform Infrared Imaging (ATR-FTIR Imaging) and Confocal Raman Spectroscopy
Amy Ethier1, Samuel Gourion-Arsiquaud2 and Norman Richardson1
50% hydrocarbons, waxes, or polyols as

1BASF Pharma Solutions 2 TRI Princeton
BASF Pharma Solutions, Tarrytown, NY . www.pharma.basf.com DEVELOPING SCIENCE. IMPACTING HEALTH.
the vehicle. This dosage form is generally

PURPOSE RESULTS RESULTS
The flow behavior and penetration of Kollicream® OD (octyldodecanol), on and through Additionally, 2D images of the penetration of octyldodecanol beyond the SC,
Complete understanding of the behavior of lipidic fluids and their functionality in
the layers of the SC was evaluated using ATR-FTIR imaging spectroscopy coupled with inside the epidermis, was evaluated by Confocal Raman Spectroscopy. Using
semi-solid formulations requires that the mechanism by which the excipient
tape stripping methodology. As shown in the spectra below, octyldodecanol can be this method, it is also possible to provide kinetic information concerning the
interacts with and influences the structures of the skin, both at the surface and
measured by tracking different IR markers, specifically noting peaks that are not delivery of neat Kollicream® OD in the different skin layers to better understand
inside the stratum corneum (SC) be evaluated. To achieve this understanding,
significantly influenced by the peak presence of the untreated skin. the time-dependent interaction with the structures of the skin.
intended for external application to the skin

vibrational imaging spectroscopy methods have been employed to study, 1080 to Phe peak Skin treated 30 min with
visualize and measure flow and penetration behavior of a representative long- area ratio Kollicream® OD
chain fatty alcohol, octyldodecanol.

.25
High OD
concentration Skin surface
Absorbance (AU)
.2
5 µm
Absorbance (AU)
.15
10 µm
or mucous membrane.
.1
15 µm
.05
20 µm
METHODS 0 25 µm
3500 3000 2500 2000 1500 1000

No OD
Wavenumber (cm-1) 30 µm
ATR-FTIR Imaging Spectroscopy ATR-FTIR spectra of human untreated skin (Black), skin treated with Kollicream® OD (Blue),
Single Beam / Microns
File # 3 : OD MINUS SKIN CONTROL

Overlay X-Zoom CURSOR
Res=None
Wavenumber (cm-1)
difference spectrum of treated and untreated skin (red) and neat Kollicream® OD (grey) Raman spectra of human skin (black) and Kollicream® OD (red) 35 µm
In this work, ATR-FTIR imaging spectroscopy is employed to visualize and It was necessary to first establish an approximate depth to which Kollicream® OD
Ointments may be classified into one of

40 µm
measure the penetration of Kollicream® OD (octyldodecanol) inside the SC and penetrates prior to completing more advanced spectroscopic techniques (Raman The penetration of Kollicream® OD extends beyond the stratum corneum and
evaluate the active penetration enhancement potential of this product for the spectroscopy). The confirmation of Kollicream® OD penetration may be observed from into the epidermis as shown by the Raman spectrum above. The vertical blocks
prospective delivery of actives into the SC in ex-vivo human skin. A comparison the FTIR-ATR spectroscopic imaging results below. It is clear from the scans of the tape indicate Kollicream ® OD concentrations at increasing depth into the epidermis
and visualization of Kollicream® OD deposition and penetration into the human stripped layers of ex-vivo human skin that the Kollicream® OD penetration has reached, and horizontal blocks differentiate multiple data collections.
skin was achieved by measuring levels of the excipient at the skin surface and in to a degree, up to layer 8 of the stratum corneum.
subsequent layers using ATR-FTIR imaging. Hyperspectral images were collected 2920 to Am1 area peak ratio 1465 to Am1 area peak ratio 1040 to Am1 area peak ratio Lipid Bilayer Organization
for each skin sample at the skin surface before treatment (control), on the skin
four general classes: hydrocarbon bases

surface after treatment (deposition) and then after eight sequentially tape strips Control
High OD (left)
Control
CONCLUSIONS
(penetration).The ATR-FTIR imaging system was used at Spectral Resolution: 4 Lipid disorganization (right) Through ATR-FTIR imaging and Confocal Raman Spectroscopy we have
cm-1, Pixel size: 6.25 & 6.25 microns; Accumulation Scans per Pixel: 4; Spectral After 1 hour After 1 hour
investigated and visualized the behavior of the lipidic fluid, Kollicream® OD
range: 4000-750 cm-1 (octyldodecanol) on and through the skin. This data ultimately provides insight
Layer 2
Layer 2 into the interaction between the structures of the skin and the simplistic chemistry
of long chain alcohols. Many lipidic fluids, when applied to the skin surface alter
(e.g., petrolatum), absorption bases (e.g.,

Layer 4 Layer 4
the lipid organization and in consequence, the skin barrier function. As a result,
there is an effect on the penetration of the vehicle and potentially the active
Layer 6 Layer 6 through the stratum corneum and epidermis. The results of ATR-FTIR
Confocal Raman Spectroscopy spectroscopic imaging and Raman spectroscopy indicate that Kollicream® OD is
Layer 8 No OD (left) Layer 8 interacting with the lipid bilayers of human skin; resulting in penetration through
Using a confocal Raman system, 2D images of the skin surface and inside the Lipid organization (right) the stratum corneum to a depth of 40 microns into the skin layers. These findings
epidermis of ex-vivo human skin were recorded to investigate active delivery and are significant in the selection and determination of excipient selection for
lanolin or beeswax), water-removable bases

distribution beyond the SC. The mechanism of penetration and flow of Kollicream® OD on human skin is evidenced effective formulation of semi-solids.
by the concentration variation in the x, y and z direction. The features of the skin surface
contribute to these patterns, and thus additional methodologies were employed to further
explore the behavior of Kollicream® OD on and through the skin. ATR-FTIR spectroscopic This work was jointly
techniques support the proposal that the presence of Kollicream® OD promotes the completed by BASF Pharma
temporary disordering of the lipid bilayers. This is shown in the ATR-FTIR spectroscopic Solutions, Skin Delivery Lab
image (above right) as an increase in lipid bilayer disordering as compared to the control. and TRI Princeton
EXCIPIENT SELECTION
SELECTION TO
TO ENABLE THE
THEPERFORMANCE OF
OFSKIN
SKINDELIVERY DOSAGE
DOSAGEFORMS
Semisolid EXCIPIENT
Dosage
Topical
Formulation
ENABLE
Functional PERFORMANCE
Excipient DELIVERY
Formulation FORMS Enable the Performance of
Forms Trends
ointment. It contains only three ingredients: mupirocin, polyeth- was studied and it was determined that by changing the
ointment. It contains only three ingredients: mupirocin, polyeth- was studied and it was determined that by changing the
ylene glycol 400, and polyethylene glycol 3350. Polyethylene amount of PEG 3350 in the formula, shear viscosity can be
ylene glycol 400, and polyethylene glycol 3350. Polyethylene amount of PEG 3350 in the formula, shear viscosity can be
glycol 3350 has a higher melting point, so it tends to crystallize tuned to a desirable level. (Figure 3).
that
glycolas 3350
or mix with thetheamount
has a higher melting
polyethylene ofglycol
PEG 3350
point,
400 decreased,
so it tends
to form
to crystallize tuned
rigid phases determined
In
to a desirable
this example, thethat by(Figure
level. changing
ointments
3). the amount of
were sheared from a rate of
or mix with the polyethylene glycol 400 to form rigid phases In this example, the ointments were sheared from a rate of
crystallinity
that build a consistencydecreased, which
in the formulation. in turn
The affected
polyethylene PEG
0.01 3350
reciprocal in
secondthe formula,
to 1,000
that build a consistency in the formulation. The polyethylene 0.01 reciprocal second to 1,000 reciprocal seconds. The data shear
reciprocal viscosity
seconds. The datacan
glycol is the fluid component that behaves like a solvent and collected showed that viscosity increases systematically with
the
glycolperformance
is the fluid component of thethat formulation.
behaves like aAt lower
solvent be tuned
and collected to athat
showed desirable level (Figure
viscosity increases 3). with
systematically
allows for spreadability. the amount of PEG 3350 in the formulation.
concentrations
allows for spreadability. of PEG 3350,
To explore the impact of PEG 3350 on microstructure and weeping oc- the amount of PEG 3350 in the formulation.
This Intells
thisus example,
that formulatorsthecanointments were prop-
tune the rheological
To explore the impact of PEG 3350 on microstructure and This tells us that formulators can tune the rheological prop-
curred
rheology, (Figure 2). The critical point at which
a series of placebo ointments,
rheology, a series of placebo ointments, sans the active, erties
sans the active, erties by
sheared selecting the
fromthe
by selecting
correct
a rate amount
ofamount
correct
of the
0.01 sof to
-1 higher
the 1,000
melting
s-1.
higher melting
containing a range of PEG 3350
the PEGa3350 crystals Effect of [PEG 3350] on Ointment
containing range of PEG 3350 Effect
Figure ofof[PEG
2: Effect [PEG 3350]3350] on Ointment
on ointment weeping.
concentrations were evaluated. Weeping
Figure 2: Effect of [PEG 3350] on ointment weeping.
packed
M i c ro s c otogether
concentrations py d e m o nand
were evaluated.
s tr a te d Weeping
M i c ro s c o py d e m o n s tr a te d
the
that PEG
that
as the400 amountfluidof filled
PEG Mupirocin Ointment 2% USP
3350 as the amount
decreased, of PEG
crystallinity Mupirocin Ointment 2% USP
the
3350 interspaces
d e c r edecreased,
be-
a s e d, w h i ccrystallinity
h in turn Ingredient UNII Function
Ingredient UNII Function
tween
d e c r e a s the
e d, crystals,
w h
affected the performance of thei c h i n so
t u r n Mupirocin D0GX863OA5 Active
affected the Atperformance of the Mupirocin D0GX863OA5 Active
that excess
formulation.
formulation. At
fluidconcentra-
lower
lower
does
concentra-
Polyethylene glycol 400 B697894SGQ Solvent, fluid
tions of PEG 3350, weeping Polyethylene glycol 400 B697894SGQ Solvent, fluid
Polyethylene glycol 3350 G2M7P15E5P Consistency factor
not
tions
occurred
leak
of PEG out3350,
(Figure of2).the The
oint-
weeping
critical Polyethylene glycol 3350 G2M7P15E5P Consistency factor
ment,
point at was
occurred (Figure
which 25–30%
the2). PEG
The critical
3350
Placebo ointments (BASF Skin Delivery Lab)
point
crystals at packed
which the PEG 3350
together and
PEG
crystals
3350.packed
Placebo ointments (BASF Skin Delivery Lab)
the PEG 400 fluid together
filled the inter-and
theAdditionally,
spacesPEG between
400 fluid filled the the inter-
the crystals,
rheology of the various
spaces
so that between
excess fluidthe crystals,
does not
so that excess fluid
leak out of the ointment, was does not
placebo ointments
Effect of [PEG3350] on Ointment
[PEG 3350] 35% 30% 25% 20% 10%
leak out of
25–30% PEG 3350. the ointment, was
was studied and it wasof
Effect of [PEG3350] on Ointment
[PEG 3350]
Weeping No 35% 30%
No 25%
Yes Yes20% 10%
Yes
25–30% PEG 3350.
Additionally, the rheology
Rheology
theAdditionally,
various placebo the rheology
ointments of Weeping No No Yes Yes Yes 11
Rheology
the various placebo ointments
Figure 3: Effect of [PEG3350] on ointment rheology.
11
Figure 3: Effect of [PEG3350] on ointment rheology.

40% PEG 3350 1.0E+05
35% PEG 3350
40% 3350 1.0E+05
30% PEG 3350
35% 3350
25%
30% PEG 3350
3350 1.0E+04
20% PEG 3350
25% 3350 1.0E+04
s) s)
15% PEG 3350

20% 3350
10% PEG 1.0E+03
15% PEG 3350
3350
(Pa
5% PEG
10% PEG3350
3350 1.0E+03
(Pa
5% PEG 3350
Viscosity
1.0E+02
Viscosity
1.0E+02
1.0E+01
1.0E+01
1.0E+00
1.0E+00
1.0E-01
1.0E-02 1.0E-01 1.0E+00 1.0E+01 1.0E+02 1.0E+03
1.0E-01
1.0E-02 1.0E-01 1.0E+00 1.0E+01 1.0E+02 1.0E+03
Shear rate (s-1)
Shear rate (s-1) 12
12
EXCIPIENT SELECTION TO ENABLE THE PERFORMANCE OF SKIN DELIVERY DOSAGE FORMS
EXCIPIENT SELECTION TO ENABLE THE PERFORMANCE OF SKIN DE
Semisolid
Dosage
Topical
Formulation
Forms Trends
point material. This technique can also be applied to creams most crystallinity and the lowest rate of diffusion through the
in which waxes are used. By changing pointthe material. This technique
concentration can also be
of membrane. The applied to creams
propylene most crystallinity
glycol formulation and and
was higher, the lowest rate o
wax, viscosity can be tuned. in which waxes are used. Bythe Poloxamer 124 had the highest rate of flux. Thus, there is glycol form
changing the concentration of membrane. The propylene
wax, viscosity can be tuned.
Also in these studies, solvent in the ointment was changed apparently a correlation between the theselection
Poloxamer 124 had the highest rat
of solvent,
The data collected showed that Alsoviscosity
in these studies, solvent Poloxamer 124
in the ointment washas solubilized
changed more
apparently of the itsbetween the
a correlation
to create three formulations, each containing 30% of a solvent impact on the micro-structure, and the diffusion through the
increases
and 2% mupirocinsystematically
(Figure 4). Thewith theimage
to create
middle amount showsofless stratum
three formulations, PEG.
each The other
containing
membrane.
30% oftwo images
a solvent show
impact more
on the crys-
micro-structure, and th
and 2% mupirocin (Figure 4).talline The middle image
structures. shows less stratum membrane.
PEG 3350indicating
crystallinity, in the formulation.
that solvent Poloxamer 124 has solu-
crystallinity, indicating that solvent Poloxamer 124 has solu-
bilized
Thismore
tellsofus thethat
PEG formulators
and the API. The other images Creams Are
two the Complex Heterogeneous onSystems
bilizedcan moretuneof the PEG and theWhat API. The effect
other does this have
two images Creams drug deliv- Heterogeneo
Are Complex
show more crystalline structures. Cream formulations are complex, two-phase systems that
rheological properties by selecting show more the cor- structures.
crystalline ery? A drug diffusion studyCream
What effect does this have on drug delivery? A drug diffusion center on effectively solubilizing and delivering an active
usingformulations
Franz cells are complex, tw
rect What effect does this have on drug delivery? A drug diffusion center on effectively solubilizing an
study amount
using Franzof the
cells withhigher
a modelmelting
skin membrane pointcompared
ma- with a while
ingredient model skin kinetics
balancing membrane compareddriving
with thermodynamic
study using Franz cells with a model skin membrane compared ingredient while balancing kinetics with
terial.
the threeThis technique
ointments (Figure 5)can
. Thealso beformulation
triacetin applied had to(Figure the three
the forces. ointments
This contributes (Figure
to the 5). The
complexities and triacetin
the impor-
Effect
creams
of
in which
Solventwaxes
Selection on
the three ointments Ointment 5). The triacetin formulation had the forces. This contributes to the comp
Effect of Solvent Selection on Ointment tance of understanding the role
tance of
Drug
Figure Solubilization
4: Effect
are used. By changing
of solvent selection on ointment drug solubilization.
Drug Solubilization
Figure 4: Effect of solvent selection on ointment drug
of excipients as the key driver to
solubilization. of excipie
deliver the active ingredient.
!  2% Mupirocin ointments wih different solvents at 30% deliver th
the concentration of !  2% Mupirocin ointments wih different solvents at 30% To b e t te r u n d e r s t a n d a
40x 40x 40x To b e
wax, viscosity can be 40x 40x cream’s
40x consistency, consider
cream’s
the emulsification, the solubi-
tuned. lization, and structure building
the emu
100x 100x 100x lization, a
Also in these studies, 100x 100x 100x
components. A simple cream
compone
solvent in the ointment formulation may include a fatty
formulati
400x alcohol, an emulsifier, and water.
was changed to create 400x 400x 400x
400x 400x changes to these alcohol, a
Systematic
three formulations, Systema
components provide a better
compon
each containing 30% understanding about the effect
understa
of a solvent (Figure 4). of excipient selection on the
of excipi
performance properties. These
The middle 30% image
PG 30% P124 30% GTA
properties are influenced by the
performa
30% PG 30% P124 30% GTA
propertie
shows less40%crystallinity,
PEG 400 40% PEG 400
40% PEG 400
40% PEG 400
40% PEG 400
selection of excipients,
40% PEG 400
quantity,
selection
indicating that solvent
30% PEG 3350 30% PEG 3350
30% PEG 3350
30% PEG 3350
30% PEG 3350
and the processing. Additionally,
30% PEG 3350 and the p
Kollisolv® PG = Propylene glycol Kollisolv® P124 = Poloxamer 124 Kollisolv® GTA = Triacetin changes can be visualized and changes
Kollisolv® PG = Propylene glycol Kollisolv® P124 = Poloxamer 124 Kollisolv® GTA = Triacetin
quantified in terms of differences quantified
Figure 5: Effect of solvent selection on ointment

Figure drug
5: Effect ofdelivery.
solvent selection on ointment drug delivery.

, &&1&'
, &&1&'
+ &&1&'
+ &&1&'
PG

* &&1&'
* &&1&'
) &&1&'
) &&1&'
( &&1&' ( &&1&'
P124
' &&1&' ' &&1&'
& &&1&& & &&1&&

& (& *& ,& -&& '&&
(& '(&
*& ,& -& '&& '(&

'(* '(*

GTA
Semisolid
Dosage
Topical
Formulation
Forms Trends
formulation had the most crystallinity and quantity, and the processing. Additionally,
the lowest rate of diffusion through the changes can be visualized and quantified
membrane. The propylene glycol formula- in terms of differences in viscosity or
tion was higher, and the Poloxamer 124 rheological profile when the composition
had the highest rate of flux. Thus, there of the formulation is modified.
is apparently a correlation between the Dermal drug delivery studies, in an in
selection of solvent, its impact on the vitro model system, were conducted with
micro-structure, and the diffusion through Clotrimazole cream formulations that dif-
the stratum membrane. fered only in the lipophilic fluids that were
used (e.g., mineral oil, isopropyl myristate,
Creams Are Complex cocoyl caprylocaprate or octyldodecanol).
Heterogeneous Systems Effects were evaluated based on each
Cream formulations are complex, two- component individually and their interac-
phase systems that center on effective contributions (Figure 6). The top left is
tively solubilizing and delivering an ac- an example of the release of Clotrimazole
tive ingredient from the formula-
while balancing Creams formulations are com- tion and penetration
kinetics with across a model
thermodynamic
plex, two-phase systems that membrane by indi-
driving forces. center on effectively solubilizing vidually changing
This contributes and delivering an active ingredi- the oil phase in the
to the com- particular formula-
plexities and the ent while balancing kinetics with tion. This modifi-
importance of thermodynamic driving forces. cation had a sig-
understanding nificant effect on the
the role of ex- Clotrimazole release
cipients as the key driver to deliver the and penetration across the membrane. In
active ingredient. this case, isopropyl myristate increased
To better understand a cream’s con- penetration of clotrimazole across the
sistency, consider the emulsification, membrane most significantly.
the solubilization, and structure-building The bottom left illustrates how fatty
components. A simple cream formula- alcohol content was systematically modi-
tion may include a fatty alcohol, an fied to understand the structuring effect
emulsifier, and water. Systematic and resulting influence on the viscosity or
changes to these components provide a rheological profile. It becomes clear that
better understanding about the effect of formulations containing stearyl alcohol
excipient selection on the performance have a lower viscosity than those contain-
properties. These properties are influ- ing cetyl alcohol or cetostearyl alcohol.
enced by the selection of excipients, This is critical because it not only affects
Semisolid
Dosage
Topical
Formulation
Forms Trends
the rheological pro- crease in crystal-

file, but also the mi-
Formulations with larger oil linity or a change
crostructures formed droplets might affect the re- in the lamellar
that contribute to sulting stability properties and spacing of the
the stability. phases that are
The cross-polarized even the delivery of the active. present in the
and bright-field im- formulation.
ages of different
formulations show clearly defined oil Formulating Gels
droplets. Formulations with larger oil Gels have several formulation compo-
droplets might affect the resulting stabil- nents that can contribute to the viscosity
ity properties and even the delivery of building and the efficacy or applicability
the active. of a topical dosage form. Poloxamers
Finally, x-ray diffraction illustrates how might contribute to the emulsification,
systematic changes
EXCIPIENT SELECTION to THE
TO ENABLE thePERFORMANCE
fatty alcohol the
OF SKIN DELIVERY solubilization,
DOSAGE FORMS and the gelling func-
might contribute to an increase or de- tionality when used in higher concentra-
Complexity and Tunability Increases with
Each Formulation Component
Figure 6: Complexity and tunability increases with each formulation component.
400x,
brightfield
400x, xpol
cream formulation
400x,
xpol
5-component
Properties of Poloxamer Gel Formulations

Figure 7: Properties of poloxamer gel formulations.
Gel Temperature as a Function of

EXCIPIENT SELECTION TO ENABLE THE PERFORMANCE OF SKIN DELIVERY DOSAGE FORMS Excipient Selection to
Complexity and
Semisolid
Dosage
Topical
Tunability
Functional
Formulation
Excipient
Increases
Formulation
withthe Performance of
Enable
Excipien
Forms Trends
Each Formulation Component
Figure 6: Complexity and tunability increases with each formulation component.
the Perfo
An Executive
tions. Poloxamers may protect living
400x,
Summary
the chemistry and the brightfield
Delivery
contributions of
400x, xpol
cells, and thus may be appropriate for excipients to these topical dosage forms,
application on compromised skin. Gel it’s possible to more efficiently andSemisolids effec- like o
formulations contain very simple ingredi- tively develop formulations. benefit from fun Excipient Selection to
cream formulation
400x,
ents, but understanding the functionality product perform
of these ingredients can help tune formu- Reference
An Executive
xpol
1. Topical Drug Delivery Market- Global
the Performance of S
lation properties.
Delivery Dosage For
5-component
Norman Richardson Overview: Topical Dru

Poloxamer 407 gels may be prepared SummaryForecast to 2021, by
published March 2017.
MarketsandMarkets,
Global Technical Marketing
Manager, Skin Delivery
The global topical drug d
BASF Pharma Solutions expand at a compound a
using Kolliphor P 407. Poloxamer gel sys-
®
Topical drug formulato
tems are quite nice because properties Semisolids like ointments, creams, lotions, gels, tra
gels, and cr
Food and Drug Administ
can be tuned by varying the component benefit from functional types ingredients thatf
of topical dosage
concentrations, as well as the chemistry product performance and ensure deliv When deciding on the
(Figure 7). drug formulators conside
to apply drug product in
Overview: Topical Drug Deliveryonce the product is appl
Summary Norman Richardson
Norman Richardson
Global Technical MarketingTheScientist,
Amy Ethier
Amy
Global Skin
global topical drug
Ethier
Delivery Lab market is valued at $92.4 b
delivery
Global Technical
Manager, Skin Delivery Scientist,
BASF Pharma layers and make it to th
Solutions Global
Functional excipients offer the ability BASF Pharma Solutions expand at a compound aggregate growth rate of 6.4%
and excipients betw
penetrate
Marketing Manager, Skin Delivery
Topical drug formulators Lab
have a large playing field of dosag
to tune formulations as an effect of the Skin Deliverycreams, lotions, gels, BASF Pharma
transdermal
mild and do not trigger
patches, wipes, swabs, s
ensure the actives are de
component behavior. By truly grasping BASF Pharma Solutions Solutions appropriate time period
Food and Drug Administration’s National Drug Code Directo
types of topical dosage forms.
Properties of Poloxamer Gel Formulations

Figure 7: Properties of poloxamer gel formulations.
When deciding on the product design
Topical and
drug formulators consider many challenges
drugselecting
developers
of reasons including: d
with regard
an
to
to apply drug product in a clean, effective, and targeted
• Improved or saferwad
Amy Ethier once the product is applied, active ingredients must cross th
Scientist,
Gel Temperature asGlobal Skin Delivery
a Function of Lab • Protection and stab
BASF Pharma Solutions layers and make it to the correct biological compartment
• Increased solubiliza
Kolliphor® P 407 Concentration
and excipients penetrate the stratum • corneum, formulators
Improvement of se
45 mild and do not trigger inflammatory • responses
40
Extensioninofthe
thelivin
AP
Gel Temperature (°C)
ensure the actives are delivered to the• correct compartmen

Cost savings; and
35
appropriate time period (see Figure 1)• . Replication of refer
30
25
20 Gel formulation Topical drug developers are increasingly seeking
Semisolid novel or diA
Attributes
15 of reasons including: While many attributes ca
10 Kolliphor P 407 + Water • Improved or safer drug delivery routes;
can be improved with fu
5 • Protection and stabilization of sensitive reactive APIs;
0 • Increased solubilization of insoluble APIs;
0 5 10 15 20 25 30
• Improvement of sensory properties, applicability and p
Kolliphor® P 407 Concentration • Extension of the API exclusivity or patent life;
• Cost savings; and SPONSORED BY
!  The rheology of the gel formulations were analyzed using• oscillatory measurements
Replication of reference listed drugs.
(ω=1 rad/s and γ=0.1%) while the temperature was increased at 1°C/minute
Semisolid Attributes Are Driven by Functional Excipie
!  The gel temperature was determined for each sample by evaluating
While G’can
many attributes andbe G” values
designed into a topical drug,
can be improved with
as a function of temperature and recorded as a function of concentration functional excipients.
!  To note is the shift in gel temperature as a result of added ethanol
29
SPONSORED BY
Case Studies: Excipient
Semisolid
Dosage
Topical
Formulation
Functional Excipient Formulation Selection for Topical
Forms Trends
Formulations
Case Studies:
Excipient Selection
for Topical
Formulations
T
opical drug products are a grow- livery, physical and chemical stability, as well
ing category, but the formula- as other attributes. Given the critical role that
tion of products like creams, excipients play, it is of utmost importance
ointments, and foams can be that formulators consider the many opportu-
extremely complex. Semi-solids often contain nities excipients have for modifying product
many components (or excipients) that inter- functionality and critical quality attributes.
act with each other and affect the functional The following case studies illustrate the many
Foam Formulations
properties of the end-product, including drug ways formulators can use excipients as tools
delivery onto and/or through the skin, mild- to improve drug products.
ness, aesthetic properties, and physical and
® = registered trademark of BASF SE

chemical stability.
When excipients and APIs are blended Case Study 1: Foam Formulations
Pharma Solutions.
together to prepare topical semi-solid formu- Topical foams are growing in popularity,
03_170701e-00
Focusing on your needs with platform solutions.
lations they organize in specific ways to yield and in some cases are preferred by panel-
Instant &certain
Modified microstructures.
Release | Solubilization These microstruc-
| Skin Delivery ists over creams. Foams provide ease of
| Softgels | Biologic Solutions
tures include phases and states of matter application, pleasing sensory properties,
that arise from the blending together of simplicity and effective drug delivery.
lipophilic material, emulsifiers, oils, solvents, Examples of topical pharmaceutical
Topical polymers,
foams are growing in popularity, and
water and APIs. It is becoming in some cases preferred by panelists over a cream.
foams include:
Foams provide ease of application, pleasing sensory properties, simplicity and effective drug delivery.
increasingly recognized
that these states of
Examples of topical pharmaceutical foams
include:
matter that comprise Gas
 Evoclinthe for semi-solid formula-

Gas
®
acne treatment (dynamic
foam, tion
contains will have an impact
alcohol) Gas
Solvent/Emollient
Surface active agent
 Olux-Eon®
forsensory attributes,
psoriasis and atopic dermatitis Gas Air
Gas
(incorporation of occlusive agents)
viscosity, emulsion
 Epifoam for minor pain, itching and
®
Gas
Gas
droplet
discomfort sizes, appear-
(dual functionality)
Air (dispersed phase) & Emulsion (continous phase)
ance, dermal drug de-
Material & Methods: Topical Foams

The foaming capability and properties of Ingredient Role A wt% B wt% C wt% D wt%
four topical aerosol foam formulations were ®
ormulations
ormulations
Semisolid
Dosage
Topical
Formulation
Selection for Topical
Formulations
SE SE
Forms Trends
trademark
trademark of BASF
of BASF
03_170701e-00
® = registered
platform solutions.
• Evoclin® for acne treatment (dynamic of varying ingredients (with and without
03_170701e-00
® = registered
platform solutions.
foam, contains alcohol)
ubilization | Skin Delivery | Softgels | Biologic Solutions Kolliphor® P188 and Kolliphor® CS 12 vs. CS
ubilization | Skin Delivery | Softgels | Biologic Solutions
• Olux-E® for psoriasis and atopic dermati- 20) on the foam properties (consistency, vis-
cosity and spreadability) were investigated.
tis (incorporation of occlusive agents)
R E S U LT S
• Epifoam
in popularity, for minor pain, itching and dis-
® cases preferred by panelists over a cream.
and in some
in popularity,
plication, and in
pleasing some properties,
sensory cases preferred by panelists
simplicity over adrug
and effective All formulations produced excellent foams
cream.
delivery.
comfort (dual functionality)
that retain shape when dispensed on the
plication, pleasing sensory properties, simplicity and effective drug delivery.
ical foams The Use of Excipients skin, spread easily over the desired area
ical foams
in Foam Formulations and dry quickly. Stiffness (G’) and viscosity
Gas
Gas
Gas
amic (η) of the foams were analyzed via rheolog-

Gas
amic M ATERIAL AND METHODS Solvent/Emollient
dermatitis
Gas
ical measurements
Solvent/Emollient
and summarized in the
The foaming capability and properties of Air
Gas Gas
ts)
dermatitis Gas
figure and tableAir below. Rheological analysis
Gas
four topical aerosol foam formulations

Gas
ts)
and revealed that stiffness and viscosity can be
Gas Gas
and
were evaluated. FormulationsAir consisted tailored
Gas
(dispersed phase) & Emulsion (continous phase) by the choice of foaming agents.
Gas
of all BASF pharma excipients. The effects Using Kolliphor® CS 12 as the foaming
Air (dispersed phase) & Emulsion (continous phase)
agent results in higher

Topical Foams
ties of Topical Foams
Ingredient Role A wt% B wt% C wt% D wt%
G’ and η values (i.e.,
ons were
ties of Ingredient
Kolliwax®
CSA 50 RoleStabilizer
Foam A wt%
3 B wt%3 C wt%
3 D wt%
3 thicker and creamier
of all
ons BASF
were
varying
of all BASF
Kolliphor
®®
CS 12
Kolliwax CSA 50 Foaming
Foam agent/emulsifier
Stabilizer 0
3 0
3 6
3 5
3
foams) than formula-
Kolliphor CS 20
®
12 Foaming agent/emulsifier 5
0 6
0 0
6 0
5
phor ®
varying P188
Kollicream
Kolliphor CS
® ®
3C20 Emollient/Solubilizer
Foaming agent/emulsifier 3
5 3
6 3
0 3
0
tions prepared with
n the® solu-
phor P188
nproperties
the solu-
Kolliphor P188
Kollicream
® ®
3C Foaming agent
Emollient/Solubilizer 1
3 0
3 0
3 1
3 Kolliphor® CS 20.
ability)
properties DI Water P188
Kolliphor
®
Solvent
Foaming agent 82
1 82
0 82
0 82
1
Additionally, po-
A
DI46
Water Propellant/Solvent
Solvent 6
82 6
82 6
82 6
82
ability)
A 46 Propellant/Solvent 6 6 6 6
loxomer can be added
to modify the viscosity
and sensory proper-
t foams ties, yielding richer/
A B C D
on the skin,
t foams A B C D creamier foams. Rheo-
on and
thedry
skin,
(η)
andofdry
the
logical and sensory
al(η)measure-
of the results indicate that
e and table
al measure-
vealed that
BASF excipients can
e and table
red by the
vealed that Resulting foams after aerosol packaging with propellant. be varied to obtain de-
olliphor CS
sired foam properties.
®
red by the Resulting foams after aerosol packaging with propellant.
higher
olliphorG’ ®
CS
10000
mier
higherfoams)
G’ η (Pa*s)
Case Study 2: Po-
A 
 B 
C 
D
lliphor ®
CS Formulation G’ (Pa) 10000
mier foams) (@0.01
η (Pa*s)1/s) 1000
A 
B 
C 
D
(Pa*s)(Pa*s)

Formulation G’ (Pa)
added® to
lliphor CS A 13.9 (@0.01
54.7 1/s) 1000
100 loxamers as Gelling
Viscosity
roperties,
added to
eological
B
A 130.6
13.9 428.9
54.7
100
Agents for Topical
Viscosity
roperties, C
B 189.8
130.6 113.8
428.9 10
ASF
eological
desired
ASF
D
C 173.8
189.8 756.6
113.8 10
1
Formulations
0.01 0.1 1 10 100
desired
D 173.8 756.6
1
0.01 0.1
Shear Rate (1/s)
1 10 100
Gelling agents are fre-
Summary of measured G’ and η for studied foam formulations. Rheological profiles of studied foam formulations (log-log plots).
Summary of measured G’ and η for studied foam formulations.
Shear Rate (1/s)
Rheological profiles of studied foam formulations (log-log plots).

quently utilized in topi-
.com | pharma.basf.com
.com 28| pharma.basf.com
M AY 2 0 1 8 | P H A R M T E C H SPON SO R ED CO N TEN T
03_171001e-
® = registere
Poloxamers, polyethylene-propylene glycol copolymers, may be Case
usedStudies: Excipient
in aqueous solu-
tions as a thermoreversible gelling agents for the efficacious formulation and delivery of
Semisolid
tgels | Biologic Topical
Solutions
Pharma
Dosage active
Solutions.
ingredients. Functional
Formulation
Excipient Formulation Selection for Topical
Forms Gelling
Focusing agents are frequently
Excipients utilized
Selection in
Trends on your needs with platform solutions. topical pharmaceutical
Development
Formulationsproducts to increase the v
Gelling
aqueousfunctionality may be achieved
formulations. through the
The chemistry use of:species imparts viscosity building properties
of these
Instant & Modified Release | Solubilization | Skin Delivery | Softgels | Biologic Solutions
structure,
Kolliphor® Ptemperature
188 and concentration.
Kolliphor® P 407
cal pharmaceutical
pharmaceutical
Poloxamers,products products to increase
to increase
polyethylene-propylene the viscosity
glycol Poloxamers,
thecopolymers,
of topical polyethylene-propylene
may be used in aqueous solu- gly-
tions as of
viscosity
pecies imparts a thermoreversible
topical building
viscosity
Phase Component aqueous gelling agents for
formulations.
properties
Chemical name athe
asFuction col copolymers,
efficacious
function of
wt% may be
formulation andused in aqueous
delivery of
active ingredients. solutions as a thermoreversible gelling
The chemistry
Ethanol 200ofproof
these species
Ethanol imparts solvent 10
IGelling agents
GellingKollisolv PG are
functionality mayfrequently
be achieved
Propylene utilized
through the
glycol
® in topical
of: pharmaceutical
useagents
solvent for Materials
10 the efficacious products and to increase
formulation Methods
and the v
viscosity-building properties as a function of
aqueous
Kolliphor
s, may be used
formulations.
Glycerol
in aqueous®
P 188
The chemistry solvent
Glycerol
solu- and concentration.
of these species
delivery5 imparts
of active viscosity building properties
ingredients.
structure, temperature Phase II and III were mixed and maintain
structure,
II
and®temperature
Kolliphor P 407
and concentration.
Poloxamer 407 gelling agent 15-20
®
Kolliphor
cious formulation P 407 of
delivery Gelling
until functionality
dissolved. maywas heated
The solution
III DI water Water solvent 53-58
be achieved
added through
with slow stirringthe
to not incorpora
Poloxamers,
IV Kollicreampolyethylene-propylene
IPM glycol tack
Isopropyl myristate®
copolymers,
reducer may
2 be used in aqueous solu-
with
use of:slow stirring.
Phase Component Chemical name Fuction wt%
tions as a thermoreversible gelling agents for the efficacious formulation and delivery of
Ethanol 200 proof
active ingredients. Ethanol solvent 10 • Kolliphor® P 188
Results
I Kollisolv ®
PG Propylene glycol solvent 10 Materials and Methods
Gelling functionality may be
Glycerol achieved through solvent
Glycerol the use of: 5 • Kolliphor P 407 ®
TheII rheology of
Kolliphor®the gel
P 407 formulations
Poloxamer 407was analyzed using
gelling agent oscillatory
15-20
Phase
measurements ω=1 mixed
II and III(were and γ=0.1%)
rad/s and maintained
w
Kolliphor
increased
®
P 188
at 1°C/minute. The gel temperature solvent
was determined for each Materials
until dissolved. The solution was
sample by evaluating G’ and G” valuesheated to
wt% III Kolliphor
rature
DI water
®
and recorded
Water
P 407 as a function of concentration (as shown
53-58
at left). added
To notewith slow
is the stirring in
increase to gelling
not incorporate
temperat
10 IV Kollicream® IPM Isopropyl myristate tack reducer 2 and
with Methods
slow stirring.
ethanol. A shear sweep of the gel (25 wt% poloxamer) at 32°C (shown below) demonstrates non-Newtonian b
10 Materials
Phase Component
and Methods
Chemical name Fuction wt%
Phase II and III were mixed
5
Results
Phase
45 II Ethanol
and III200
were mixed
proof and
Ethanol maintained at 2°C overnight
solvent or
10
and maintained
10000 at 2°C over-
15-20
IV was Materials and rad/sMethods
night or until dissolved. The
Gel Temperature (°C)
until
I dissolved.
40
Kollisolv The
PG solution was heated
Propylene glycol to 40°C
®
and Phase 10
solvent
53-58 The rheology
35 of the gel formulations was analyzed using oscillatory measurements
1000 ( ω=1 and γ=0.1%) while
added with slow stirring to not incorporate air. Phase I was added
Glycerol Glycerol solvent 5
solution was heated G’ to and
40°C
2 increased
30 at 1°C/minute. The gel temperature was determined for eachPhase sample by
II and evaluating
III were mixed andG” values as
maintained
with slow stirring.
Viscosity (Pa s)
II 25 Kolliphor P 407 Poloxamer 407 ®
gelling agent 15-20
rature and recorded as a function of concentration (as shown at left). To and
notePhase
is the IV was
increase added
in gelling
until dissolved. The solution was heated to
100 temperature
III 20 DIAwater
ethanol. shear sweep ofWater solvent
the gel (25 wt% poloxamer) 53-58
at 32°C (shownadded
below) demonstrates
15
with slow
with stirring
slow to non-Newtonian
stirring not beha
to not incorporate
IV Kollicream IPM
Gel formulation Isopropyl myristate ®
tack reducer 2 10
10
with slow stirring.
incorporate air. Phase I was
Kolliphor P 407 + Water ®
10000
545
scillatory measurements ( ω=1 rad/s and γ=0.1%) while the temperature was added with 1 slow stirring.
ned for eachResults
040
sample
350 by evaluating G’10and G” values as20a function 25 of tempe- 1000
Gel Temperature
5 15 30
wn at left). To note30is the increase in
The rheology
gelling
of the gelKolliphor
temperature
formulations
with the addition of
was analyzed using oscillatory measurements Results 0,1
0,01( ω=1 rad/s and γ=0.1%) while
Viscosity (Pa s)
®
P 407 Concentration 0,1 1 10
32°C (shown below) demonstrates non-Newtonian behavior of the formed gel. The rheology
25 100
of the gel
increased
20 at 1°C/minute. The gel temperature was determined for each sample by evaluating G’ and Shear
G” values
rate (s-1as
)
rature15and recorded
Formulation
10000 Gel as
formulation a function of concentration
Coefficient of (as
Friction shown at
400
left). formulations
To note is
10 the was
increaseanalyzed
in gelling temperature
10
ethanol.
With A shear

Kollicream IPM sweep
Kolliphor
® of the gel 0.38±0.00
P 407 + Water (25 wt% poloxamer) at 32°C (shownusing
® below)oscillatory
demonstrates non-Newtonian beha
measure-
5 350 1
1000
Without 0
Kollicream
45 0
®
IPM
5 10 15 20
0.71±0.07
25 300
30
ments10000
(ω=1 rad/s and
while the tempera-
Viscosity (Pa s)
Stress (Pa)
40
100 Kolliphor P 407 Concentration ® 250 γ=0.1%) 0,1
0,01 0,1 1 10
Although a suitable gel may be formed without the addition of 200
35
ture
a lipidic fluid, itwas
1000
has increased
been observedat 1°C/
(and measured u
Gel Temperature
30 Shear rate ®(s )-1
accessory 10 for the TA Instruments DHS-1 Rheometer with Vitro-Skin ®

) that the addition of 1% Kollicream IPM r
Viscosity (Pa s)
Formulation
25 Coefficient of Friction 150 minute.100 The gel temperature
friction and perceived tackiness. 0.38±0.00
20
With Kollicream
151
IPM ® 100
was determined for each
Gel formulation 50 10
Without Kollicream IPM 0.71±0.07 sample by evaluating G’ and
®
30 10
0,1 Kolliphor P 407 + Water ®
0
G” values as a function of
5
0,01 0,1 1 10 100 1000 1
0
Although0 a suitable 5 gel may 10 be formed 15 without
Shear rate (s )
20 the addition
25 -1
of a 30lipidic fluid, it has been and
temperature observed (and measured
recorded as ® usin
accessory for the TA Instruments DHS-1 Rheometer with Vitro-Skin®) that the0,1addition of 1% Kollicream IPM 10 red
Kolliphor P 407 Concentration
a function of concentration
®
0,01 0,1 1
friction and perceived tackiness.
(as shown at left). To noteShear rate (s ) -1
Formulation Coefficient of Friction

With Kollicream IPM ®
0.38±0.00
is the increase in gel tem-
Without Kollicream IPM 0.71±0.07
® perature with the addition of
of a lipidic fluid, it has been observed (and measured using the Tribo-Rheometry
ethanol. A shear sweep of
itro-Skin ) that the addition of 1% Kollicream IPM reduces the coefficient of
® ®
Although a suitable gel may be formed without the addition of a lipidic fluid, it has been observed (and measured usin
29 M AYaccessory for
2018 | PHARM H TA Instruments DHS-1 Rheometer with Vitro-Skin®) that the addition SPON
T E Cthe of 1%
SO RKollicream
ED CO N TEN T ® IPM red
friction and perceived tackiness.

Focusing on your needs with platform solutions.
03_171101e
® = register
| BiologicInstant
elsSemisolid & Modified Release | Solubilization | Skin Delivery | Softgels | Biologic Solutions
Solutions
Dosage
Topical
Formulation
Forms Trends
Formulations
Kolliwax
Kolliwax
ffectivelythe
build HCO
HCO,
formulation
gel (25 wt% whenas aused
High
viscosity
poloxamer)
® ®
atMelting
and
at 32°C low levelsPoint
enhance
(shown may effectively
stability
reduces build formulation
ofthe coefficient of friction andviscosity
per- and en
Consistency
topical
use in semi-solid
below) Factor
formulations.
formulations
demonstrates for
the Topical
Aissignificant
highbehav-
non-Newtonian Applications
advantage
melting point,of and
ceived use in semi-solid formulations is the high
tackiness.
® = registered trademark of BASF SE

efficient
ior multi-phase
of the formed gel. consistency building.
Although a suitable gel may be formed Case Study 3: Kolliwax HCO as a ®
In topical dermal applications, Kolliwax® HCO (hydrogenated castor oil) has
d castor oil) has
Pharma Solutions.
without functionsthe addition of aa lipidic fluid, it has High Melting Point Consistency Fac-
03_171101e-00
used at low various
levels on your needs across range of dosage forms. Generally used at low levels
Focusing
been andobserved
(0.1-2
or to (1) build wt.%), Kolliwax
with platform
(and measured
®
HCO mayusing
solutions.
the by the formulator
be utilized tor for Topical to (1) buildApplications
and
Instant & Modified Release | Solubilization | Skin Delivery | Softgels | Biologic Solutions ®
Tribo-Rheometry
stabilize
ase retention on viscosity accessory
due to a for
higher the TA
melting Instru-
point and (2) Kolliwax
increase HCO,
retention when
on used at low levels,
the
ments
ight and size skin, scalp or hair
and DHS-1 Rheometer with Vitro-Skin )surface through a higher
® molecular weight and size and
may effectively build formulation viscos-
hydrophobic chemistry.
that the addition of 1% Kollicream IPM ®
ity and enhance the stability of topical
Materials
Kolliwax® HCO, when andused Methods
at low levels may effectively build formulation viscosity and enhance stability of
formulations.
topical formulations. A significant advantage of use in semi-solid formulations is the high A melting
significantpoint, and
Phase Tradename Chemical Function % advantage of
efficient
% multi-phase consistency building.
I Di Water Water Solvent 72.6
t
72.6
In
5.0 topical Glycerin
dermal applications, Glycerin
Kolliwax ®
HCO (hydrogenated castor Humectant
oil) has 5.0 use in semi-solid
various
3.1 Kolliphor
functions acrossCS a20rangePolyoxyl
®
of dosage 20forms.
cetostearyl ether
Generally used at lowEmulsifier
levels 3.1 formulations is
(0.1-2
II
3.2 wt.%), Kolliwax IPM
Kollicream
Heat phaseHCO may
I
®®
and be utilized
Isopropyl
II by the formulator to (1) build
myristate
separately to 85-90 °C. Mix and
Emollient phase 3.2 Heat phase I and II separately to
stabilize viscosity
3.1 Kollicream due to OD a higher
® melting point and (2) increase retention
Octyldodecanol on
Emollient 3.1 the high melting
I and II, homogenize for 5 minut
the skin, scalp I or
and hair II,surface
homogenize
through for oil
a higher 5molecular
minutes at about
weight and size 5000
and rpm,
2.8 Mineral oil Light mineral Emollient 2.8 point
then and effi-
transfer to 4- blade impelle
cy factor
hydrophobic
1.9 then transfer
chemistry.
Kolliwax HCO ® to 4- blade impeller
Hydrogenated castor oil mixer at 200 rpm. Atfactor
Consistency 1.9
40and °CGMS add cient
40 °C multi-phase
add phase III, and continu
II phase III, monostearate
and continue toII)cool while stirring.
Consistency factor/
cy factor/ Materials
2.0 Kolliwax Methods
®
Glyceryl (type 2.0
Once the formulation reaches 30
fier Once the formulation reaches 30 °C, store in a sealed co-emulsifier consistency
cy factor 6.1 Kolliwax CSA 50 Cetostearyl alcohol Function
®
Consistency factor 6.1 glass container for a minimum o
Phase Tradename
IIII
glass container for a minimum of 24 hours prior to
Chemical
Preservative Water Preservative
Di Water Solvent
%
Preservative
72.6 0.2 building.
ve 0.2
Glycerinevaluation.
evaluation.
Kolliphor CS 20 ®
Glycerin
Polyoxyl 20 cetostearyl ether
Humectant
Emulsifier
5.0
3.1
In topical der-
FormulationKollicream IPM
Properties Emollient
Isopropyl myristate Emollient 3.2
mal applications,
Heat phase I and II separately to 85-90 °C. Mix phase
®
II
Kollicream OD Octyldodecanol
®
3.1 I and II, homogenize for 5 minutes at about 5000 rpm,
Mineral oil
Kolliwax HCO
Light mineral oil
Hydrogenated castor oil
Emollient 2.8
then transferKolliwax ®
HCOmixer
to 4- blade impeller (hydroge-
at 200 rpm. At
a rich cream Consistency factor 1.9
®
skin, The10000formulation produces that absorbs into the skin, 10000

40 °C add phase III, and continue to cool while stirring.
Kolliwax GMS II ®
Glyceryl monostearate (type II)
resulting in the formation of a thin occlusive
Consistency factor/
Increasing shear
barrier through the
co-emulsifier
2.0 rate nated castor
Once the formulation reaches 30oil) hasinvarious
°C, store a sealed
he Decreasing shear rateglass container for a minimum of 24 hours prior to
Kolliwax CSA 50 Cetostearyl alcohol Consistency factor 6.1
functions across a range
®
es functionality
III Preservativeof the
1000 lipids. Rheological evaluation
Preservative Preservative demonstrates
0.2
evaluation.
1000
lation. G’/G” values greater than one; indicative of structured formulation. of dosage forms. Generally
Viscosity (Pa s)
Viscosity (Pa s)
ntribu- Formulation
hear sweeps
100 Properties
indicate minimal hysteresis, in part from the contribu- used at 100
low levels (0.1–2
that tion of Kolliwax
The formulation ®
produces HCO ascream
a rich a consistency
that absorbs intobuilding
the skin,component that 10000
resulting10 in theformulation
formation of a robustness.
thin occlusive barrier through the and macroscopic wt.%), 10KolliwaxIncreasing
®
HCO shear may
rate
opic increases Microscopic Decreasing shear rate

functionality of the lipids. Rheological evaluation demonstrates
evaluations confirm theindicative
formulation remains stable at ambient
1000
be utilized by the formulator
nt G’/G” values greater than one; of structured formulation.
Viscosity (Pa s)
o- conditions
hear sweeps 1 and elevated
indicate temperature
minimal hysteresis, (40°C/75%
in part from the contribu-R.H.). Micro- 100 to (1) build 1 and stabilize vis-
tion of Kolliwax HCO as a consistency building component that
cosity due to a higher melt-
®
ty of scopic images evidence the consistency-building functionality of
increases formulation robustness. Microscopic and macroscopic 10
0,1
droplet Kolliwax 0,1 ® CSA 50 as well as Kolliwax® HCO through the interdroplet
evaluations 0,01 confirm the formulation remains ing point 0,01 and (2) increase
0,1 1 stable at ambient
10 100 1000 0,1 1
e structures
conditions and(left andtemperature
elevated center images) (40°C/75% and characteristic
R.H.). Micro- Maltese 1
scopic images
cross patterns evidence
in the the cross-polarized
consistency-building
Shear ratefunctionality
images
(s-1) (right of image).0,1
retention on the skin, scalp, Shear rate (s-
Kolliwax CSA 50 as well as Kolliwax HCO through the interdroplet 0,1or hair1 surface 10 through a 1000
® ®
0,01 100
structures (left and center images) and characteristic Maltese
cross patterns in the cross-polarized images (right400x Shear rate (s1000x
)
-1
image). 200x
1000x
400x x-pol 1000x 200x
x-pol
Semisolid
Dosage
Topical
Formulation
Forms Trends
Formulations
higher molecular weight and size and hy- robustness. Microscopic and macroscopic
drophobic chemistry. evaluations confirm the formulation re-
mains stable at ambient conditions and
Materials and Methods
elevated temperature (40°C/75% R.H.).
Heat phase I and II separately to
Microscopic images evidence the consis-
85–90 °C. Mix phase I and II, homogenize
for 5 minutes at about 5000 rpm, then tency-building functionality of Kolliwax®
Formulators consider numerous factors including

the indication, application site, patient compliance,
ease of application, and API compatibility and stability.
Accessing a broad excipient portfolio gives formulators
flexibility while developing gels, foams, creams and
other topical products.
transfer to 4-blade impeller mixer at 200 CSA 50 as well as Kolliwax® HCO through
rpm. At 40 °C add phase III, and continue the interdroplet structures (left and center
to cool while stirring. Once the formula- images) and characteristic Maltese cross
tion reaches 30 °C, store in a sealed glass patterns in the cross-polarized images
container for a minimum of 24 hours prior (right image).
to evaluation.
Summary
Formulation Properties As the market for topical drugs expands,
The formulation produces a rich cream
formulators are looking for options that
that absorbs into the skin, resulting in
are not only consumer friendly, but also
the formation of a thin occlusive barrier
solve formulation challenges. Formula-
through the functionality of the lipids.
Rheological evaluation demonstrates tors consider numerous factors including
G’/G” values greater than one; indicative the indication, application site, patient
of structured formulation. compliance, ease of application, and API
Shear sweeps indicate minimal hys- compatibility and stability. Accessing a
teresis, in part from the contribution of broad excipient portfolio gives formulators
Kolliwax® HCO as a consistency building flexibility while developing gels, foams,
component that increases formulation creams and other topical products.
Semisolid
Dosage
Topical
Formulation
Functional Excipient Formulation Semi-Solid
Forms Trends
Dosage Forms
Semi-Solid
Dosage Forms
Adeline Siew, PhD
M
atthias Springfelter, senior Transdermal delivery systems can be de-
formulation scientist at signed to offer prolonged and controlled-
Recipharm Pharmaceutical release absorption of certain drugs, which
Development AB, Solna, can be convenient for pain relief drugs,
Sweden, spoke to Pharmaceutical Technol- nicotine, and hormone products.
ogy about the advantages and the key con-
siderations in developing topical formulations. Drug Absorption
PharmTech: Can you tell us more about
Advantages the mechanisms of drug absorption across
PharmTech: What advantages do topical the skin barrier and how they affect the
formulations offer compared to other dos- development of topical drug products?
age forms?
Springfelter: The human skin functions
Springfelter: Perhaps the most obvious as an efficient barrier against the outside
advantage is that topical formulations environment. Achieving sufficient drug ab-
allow for local treatment of a number of sorption can, therefore, prove challenging
dermatological conditions with very little for many molecules. For a drug to reach its
systemic exposure. A high drug load can target site or to be absorbed into the blood
be applied on the actual site where the stream, a sufficient amount has to pass
drug is required, with a reduced risk of through the outer part of the epidermis,
unwanted side effects. Topical products the stratum corneum, and the epidermis.
are easy for the patient to apply and the Even though there are some passages,
moisturizing effect of topical formulations, such as the hair follicles, sweat glands,
such as creams and ointments, may also and active transportation mechanisms, the
be beneficial for several skin conditions. most important mechanism for drug ab-
Transdermal delivery systems offer an al- sorption is by passive diffusion. The rate of
ternative route for systemic administration diffusion will, to a large extent, depend on
of various drugs with the benefit of a re- the properties of the drug molecule itself.
duced risk of loss of potency or unwanted However, formulators can use a number of
variability due to first-pass metabolism. methods to optimize drug absorption.
32 M AY 20 1 8 | P H A R M T E C H
Semisolid
Dosage
Topical
Formulation
Forms Trends
Dosage Forms
In general, small-sized and relatively stance dissolved or dispersed in a semisol-

lipophilic molecules are most likely to be id ointment base made of paraffin or other
readily absorbed through the skin, and hydrocarbons. Emulsions are somewhat
this aspect must be considered when more complex because they consist of
selecting a drug candidate. Sometimes, it two liquid phases, one of which is dis-
is possible to modify the drug properties persed within the other, usually oil droplets
or alternatively, choose a pro-drug that is dispersed in water. A number of excipients
delivered in inactive form and that better are often necessary to achieve a physically
matches these criteria. The choice of vehi- and chemically stable emulsion. Water and
cle depends on the properties of the drug one or more organic compounds, such as
substance, such as the solubility profile mineral or vegetable oils, make up the two
and partition coefficient, so that the chem- liquid phases, and one or more emulsify-
ical potential of the drug is maximized. The ing agents will be needed to keep the
permeability of the skin is also an impor- phases apart. The stability of the emulsion
tant factor--the penetration rate could be can be further improved by the addition of
increased by an increase in skin hydration, polymers to increase the viscosity of the
for example, by choosing an occlusive water phase. Additional excipients such as
vehicle or patch. A number of penetration pH-buffers, antioxidants, and preservatives
enhancers that increase the absorption of are usually added as well.
a drug by temporarily increasing the per-
meability of the skin have been evaluated, Considerations in
but there are limitations because of skin Formulation Development
irritation or toxicity concerns. PharmTech: What are the key consider-
ations when designing a formulation for
PharmTech: What are the main compo- topical drug delivery?
nents of a topical formulation?
Springfelter: First of all, the choice of for-
Springfelter: The components of a mulation must be made based on the dis-
topical product will depend on the type ease or condition to be treated, the type
of formulation. It could be as simple as of skin upon which it is to be applied, and
an active ingredient dissolved in a solvent the properties of the drug substance. After
with suitable additives such as pH-buffers, that, one has to ensure that sufficient
co-solvent, and preservatives to achieve amount of the drug reaches its site of ac-
adequate solubility and stability for the tion, whether it is on the skin layer, or sys-
formulation. In a topical gel, viscosity temically. The drug absorption may have to
modifiers such as cellulose-based or syn- be optimized, for example by adjusting the
thetic polymers are added to achieve the vehicle or adding penetration enhancers. It
desired rheological properties. Ointments is also important to ensure that skin irrita-
are semi-solid preparations of a drug sub- tion and toxicity are minimized.
33 M AY 20 1 8 | P H A R M T E C H
Semisolid
Dosage
Topical
Formulation
Forms Trends
Dosage Forms
As always in formulation development, used as they provide a moisturizing effect

the physicochemical properties of the on dry and flaky skin due to their occlusive
drug product must be well controlled. The properties. In addition, the increase in
stability of the active ingredients and other hydration of the skin can also improve the
functional excipients, such as preservatives absorption of the drug. Ointments are
or antioxidants, will have to be monitored. also less irritating to sensitive skin than
Phase changes, such as separation or water-based formulations, but they have a
bleeding, must greasy feel that
be prevented in patients tend to
emulsions and The selection of a vehicle for a dislike.
ointments. The Emulsion-type
microbial quality
topical formulation is based on vehicles, such
control of the drug several factors, ranging from as oil-in-water
product needs to creams, are of-
be considered,
stability and compatibility, the ten preferred for
especially in water- type of disease and skin to be their improved
rich formulations; applied on, to biopharmaceuti- cosmetic prop-
in this case, it is erties because
often necessary to cal considerations. they are easy
add preservatives. to apply and
The viscosity and are less viscous
rheological behavior should be adjusted to and greasy. Achieving a stable emulsion,
fit the type of application and the overall however, can prove to be challenging in
cosmetic properties should be acceptable. some cases. Liquid vehicles such as solu-
tions or gels are convenient for application
Vehicle Selection on hairy skin areas such as the scalp and
PharmTech: Can you elaborate more on are sometimes preferred in dermal condi-
the selection of a vehicle for topical formu- tions for which a drying effect is desired. For
lations and how drug properties will affect transdermal applications, a suitable patch
the choice of a vehicle? or other device would have to be evaluated
together with the formulation.
Springfelter: The selection of a vehicle for a
topical formulation is based on several fac- Testing Drug Release
tors, ranging from stability and compatibility, and Drug Absorption
the type of disease and skin to be applied
PharmTech: How do you test drug release
on, to biopharmaceutical considerations.
and drug absorption?
In general, the lipophilic type of vehicles,
such as ointments and emulsions, are Springfelter: A number of methods are
preferred for conditions that involve dry available for the evaluation of the drug
skin. Ointment vehicles are commonly release and absorption of dermal and
34 M AY 20 1 8 | P H A R M T E C H
Semisolid
Dosage
Topical
Formulation
Forms Trends
Dosage Forms
transdermal products. There is, however, PharmTech: As the pharmaceutical land-

no gold standard and the method used scape becomes increasingly competitive,
will vary from case to case. drug developers are now focusing more
Some in-vitro methods are particularly on patient centricity and formulation for
useful for early studies and screening pur- specific populations. In your opinion, what
poses. For transdermal patches, the pad- is the future outlook for semi-solid drug
dle-over-disc meth- products and do you expect demand for
od described in this type of dosage
the United States form to increase?
Pharmacopeia New topical formulations
Springfelter: We
and the European using drugs that were have seen increased
Pharmacopoeia is a
reliable test to de- previously administered in interest in semi-solid
products in recent
termine the in-vitro another dosage form can
years and there may
dissolution rate.
For semi-solids, no
offer significant benefits, not be several reasons
for this trend. Where,
compendial meth- only therapeutic benefits, several years ago,
ods are available,
but the diffusion
but financial ones, as they the focus was on
blockbuster prod-
cell systems, such reduce development cost ucts, today there
as Franz or In-Line and risk. is a move toward
cells, are widely more niche applica-
used and may be tions. As demand
fitted with various for personalized
artificial or animal skin membranes, or even products increases, topical administration
excised human skin. Diffusion cell systems is gaining popularity. Another key driver
can provide useful information and guid- is the increasing interest in new products
ance, for example, when choosing the that use existing drug substances. New
vehicle for a topical product, but as always, topical formulations using drugs that were
caution should be taken when extrapolat- previously administered in another dosage
ing into more complex in-vivo conditions. form can offer significant benefits, not only
New in-vitro models and methods are also therapeutic benefits, but financial ones, as
being developed, and are becoming more they reduce development cost and risk.
useful in the characterization of topical
Adeline Siew, PhD, is the science
products. In-vivo studies in different spe-
editor of Pharmaceutical Technology.
cies of animals are often performed, but as
animal skin differs from human skin, results This article first appeared in Pharmaceuti-
should be extrapolated with caution. cal Technology 39 (3), 66–67 (2015).
35 M AY 20 1 8 | P H A R M T E C H

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Trends and

Optimizing Semisolid Dosage Forms

Formulation Trends for Topical Dosage Forms

Excipient Selection to Enable the

Excipient Selection for Topical Formulations

This custom ebook

Images under license from Shutterstock.com

A SIMPLE MODEL FOR A COMPLEX PROCESS

during manufacture at a small scale, and Addressing Unpredictable Changes

EXCIPIENTS FOR SPONSORED CONTENT Modular PAT Approaches

Skin delivery presents unique challenges of those functions include solubilizers,

Item Description Purpose Wt%

Kollisolv® PG Propylene glycol Solvent 5%

Kollicream® OA Oleyl alcohol Emollient 5%

Kollicream® OD Octyldodecanol Emollient 5%

Kolliphor® CS 20 Polyoxyl 20 cetostearyl ether Emulsifier 3%

Water - Solvent 72%

Preservative - Preservative drop

tion. It contains a solvent (propylene gly- Ointments

FIGURE 2: Gel Market Size

An example gel formulation (see Figure 3) Foams

FIGURE 3: Gel Formulation with Poloxamers

Item Description Purpose Wt%

Kollisolv® PG Propylene glycol Solvent 10%

Ethanol Ethanol Solvent 10%

Water - solvent 54%

as aiding drug delivery used for products like

er for Drug Evaluation and Research

FIGURE 5: Dosage Form: Stick

Item Description Purpose Wt%

API API API 1%

n Provides occlusive barrier n Simple formulation

n Convenient application n Not suitable for a large

FIGURE 6: Transdermal Patch Technologies

Liner LOWER Drug

Need to be able to apply the product

Solidity. Topical semi-solid products have a certain degree

the functionality and performance of the

Amy Ethier1, Samuel Gourion-Arsiquaud2 and Norman Richardson1

50% hydrocarbons, waxes, or polyols as

BASF Pharma Solutions, Tarrytown, NY . www.pharma.basf.com DEVELOPING SCIENCE. IMPACTING HEALTH.

the vehicle. This dosage form is generally

intended for external application to the skin

chain fatty alcohol, octyldodecanol.

3500 3000 2500 2000 1500 1000

File # 3 : OD MINUS SKIN CONTROL

Ointments may be classified into one of

four general classes: hydrocarbon bases

(e.g., petrolatum), absorption bases (e.g.,

lanolin or beeswax), water-removable bases

Figure 3: Effect of [PEG3350] on ointment rheology.

15% PEG 3350

Figure 5: Effect of solvent selection on ointment

& &&1&& & &&1&&

  '(*     '(*  

the rheological pro- crease in crystal-

Properties of Poloxamer Gel Formulations

Gel Temperature as a Function of

Norman Richardson Overview: Topical Dru

Properties of Poloxamer Gel Formulations

ensure the actives are delivered to the• correct compartmen

! To note is the shift in gel temperature as a result of added ethanol

® = registered trademark of BASF SE

'(* '(*

!  To note is the shift in gel temperature as a result of added ethanol