Technical Brief 2012 Volume 5
Solid State Characterization
Introduction
Characterization of solid active pharmaceutical ingredients
(APIs) continues to be an area
of great interest. This is particularly true when a solid drug is
delivered in tablets or capsules,
but also relevant to other dosage
forms such as suspensions and
powders.
Solubility and Permeability
These characteristics dictate
bioavailability and thus dosage
form efficacy. The Biopharmaceutical Classification System
(BCS) classifies compounds on
the basis of solubility and membrane permeability, and guides
formulation development1,2. A
first step in any strategy is to obtain a pH solubility profile. For
compounds that are weakly acidic or weakly basic, these results
establish the relationship between charge state and pH; the
ionization constant (pKa) gives
some insight as to a compound’s
absorption and distribution in
vivo. Another useful property
is the partition coefficient logP,
which describes drug partitioning between aqueous and organic phase. Knowledge of pKa
value(s) and logP are critical to
assessing the ability of an ionized molecule to permeate biological membranes3.
Many newer APIs are poorly
water soluble, adding to the
challenge of designing an optimal formulation4. There are
various ways to improve API
solubility, such as chemical
modification of APIs (e.g., prodrugs), use of co-solvents or
other excipients (surfactants,
phospholipids), and manipulation of particle size/morphology. Reduction of particle size
through milling or micronization
increases specific surface area,
leading to enhanced dissolution
and improved homogeneity of
the bulk material. Acids or bases can also be converted to salts,
offering an additional option to
improve solubility. Salt screening
causing its withdrawal from the
market5. In recent years, high
throughput screening has facilitated form selection at an early
stage. However, this does not replace the need for more detailed
investigations of form stability.
There are many techniques used
to confirm polymorphic form, including optical microscopy, XRD,
differential scanning calorimetry
Stability
(DSC), Fourier Transform infraBesides solubility, physical red (FTIR), near infrared (NIR),
and chemical stability of solid Raman, and solid-state nuclear
drug forms must be adequately magnetic resonance (NMR).
characterized. To accomplish
this, solids are subjected to Hydrates/Solvates
stresses (heat, humidity, light)
In addition to polymorphs,
and analyzed. Chemical stabil- solvated or hydrated drug crystal
ity evaluates susceptibility to forms can exist, sometimes reoxidation, reduction, hydrolysis, ferred to as pseudopolymorphs.
decomposition, photochemical In “channel” hydrates such as
reactions, and thermal rearrange- the antibiotic cephalexin, solments, and is investigated in so- vent or water molecules can
lution as well as in solid-state. comprise an integral part of the
With respect to the latter, physi- crystal structure, which is prone
cal stability knowledge is equally to collapse when the stabilizing
important. Some common physi- solvent molecules are removed6.
cal forms of solid drugs are sum- While API solvates and hydrates
marized below.
are generally prepared by recrystallization, they may also occur
Polymorphs
during formulation, e.g., a stable
Many compounds can exist hydrate can result from wet granin multiple crystal forms, i.e., ulation of an anhydrous drug7.
chemically identical but physi- DSC, thermogravimetric analysis
cally distinct. The existence of (TGA), and XRD are especially
drug polymorphs has important useful for confirmation of hydratimplications for patent claims; ed or solvated species, while Rait can also impact formulation man and NIR are well suited to
strategies and bioavailability. monitor hydrate formation during
Early polymorph screening identi- processing.
fies and selects the best forms(s)
for further evaluation. Screening Co-crystals
involves recrystallization of the
Unlike solvates and hydrates,
drug from a variety of solvents these materials are designed
under different conditions. It through crystal engineering, i.e.,
is generally desirable to iden- two crystalline solids interact
tify and develop the most stable to form a new crystalline enpolymorph, bypassing forms that tity. The new structure is stabimay be more soluble but meta- lized through hydrogen bonding
stable. This goal is not always modes, which can be confirmed
possible, resulting in eventual with various techniques (FTIR,
complications. An extreme ex- DSC, XRD, X-ray crystallograample is the drug ritonavir, where phy)8. Co-crystals have generlate stage appearance of a new, ated considerable interest over
more stable polymorph com- the last decade for their potential
promised product performance to improve API solubility while
(i.e., capsule dissolution failure), maintaining acceptable stability.
is frequently done in discovery
to identify the best form(s) for
development. Counterions and
crystallization solvents are exposed to a number of preparation
conditions. Products are typically analyzed by powder X-ray
diffraction (XRD) and/or Raman
spectroscopy, to confirm “hits”
for further study and scale-up.
©2012 Particle Sciences, Inc. All rights reserved.
The ability of compounds to form
co-crystals will be significantly
influenced by structural factors
such as the type and number of
substituents.
Amorphous
There is increasing interest in
the non-crystalline (amorphous)
API form as drug substance and
product. There are many ways
of preparing amorphous materials, including hot melt extrusion
and spray drying9. Amorphous
drugs are attractive for solubility enhancement, but are inherently unstable and pose special
challenges for formulation due
to chemical reactivity and hygroscopicity.
Understanding
and preventing crystallization of
amorphous solid formulations
(e.g., through use of crystallization inhibitors) is key to their successful development. Detection
and quantification of crystalline
content in an amorphous matrix
requires appropriate methods;
XRD is a common technique,
along with spectroscopic methods
(FTIR, NIR, Raman, solid-state
NMR), isothermal microcalorimetry,
and
dynamic
vapor
sorption.
The glass transition temperature (Tg) which
can be measured by DSC, signifies conversion of amorphous or semi-crystalline
material to a glassy state and is often used
to predict amorphous form stability. In
general, the Tg value of amorphous
material should be as high as possible
to maintain adequate physical stability. Tg
decreases significantly in the presence
of moisture, leading to crystallization.
In some cases this problem can be minimized by storage of the amorphous
material at low humidity and/or by use of a
desiccant.
Formulation Considerations
During manufacture, a solid
drug is exposed to multiple processes on its way to a finished
product. In the case of a tablet, the
drug is in combination with a
variety
of
excipients;
drug-excipient incompatibility can com-
Case Studies
Selected case studies are presented as examples of solid drug
characterization. These studies also highlight a few of the
techniques available for sample
analyis.
1) Solubility Enhancement
(Amorphous)
Drug substance:
a poorly
soluble crystalline drug was converted to the amorphous form by
spray drying. Conversion was
was very stable in the absence of
moisture. The amorphous form
also demonstrated significant
enhancement of solubility and
intrinsic dissolution rate compared to the crystalline form.
Drug product: An amorphous
drug product was deliberately
produced by injection molding,
resulting in a solid dispersion.
In these systems, an excipient
carrier stabilizes the amorphous
drug within the formulation matrix, helping to retard crystallization. Such interactions frequently involve hydrogen bonding
between the drug and excipient,
which were readily confirmed by
characteristic spectral shifts in
the Raman spectrum.
spective FTIR spectra (Figure 2).
DSC also provided evidence that
the precipitate corresponded
to the base form. Clearly the
amount of base in the API salt
batches required strict control
to avoid solution precipitation.
Fortunately, techniques such as
FTIR, Raman, DSC, and XRD
were available to monitor the
presence of the undesirable
solid form.
API BASE,
BASE, AND UNKNOWN
API
UNKNOWN SOLID
SOLIDPRECIPITATE
PRECIPITATE.
5. J Bauer, S Spanton, R Henry,
J Quick, W Dziki, W Porter, and
J Morris, Pharm. Res. 18, 859
(2001).
Figure 1
POLARIZED LIGHT
MICROSCOPY
Showing conversion of crystalline drug substance starting
material (a) to amorphous drug
substance (b).
(a)
Conclusion
Properties of solid drugs impact on all stages of drug de(b)
velopment, from synthesis to
production of clinical supplies.
Appropriate analytical methods
are needed not only to generate
information during form screen2) Solubility Enhancement
ing, but also for troubleshooting
(Conversion to Salt)
unexpected problems with solid
Particle Sciences
Insoluble material isolated drug substance and product.
confirmed by polarized light opti- from API salt solution: API salt
References
cal microscopy and XRD; Figure screening led to selection of a
1 illustrates the visual difference phosphate salt. This salt dem- 1. Particle Sciences Technibetween crystalline starting mate- onstrated good water solubility, cal Brief 2011 Volume 9,
rial and amorphous product where but on occasion haziness was Biopharmaceutical Classificathe crystalline material (a) shows observed when the drug sub- tion System and Formulation
typical birefringence, or double stance powder was reconstituted Development.
refraction, which is not present in in aqueous solution. Isolation 2. GL Amidon, H Lennernas, VP
the amorphous material (b). As of the precipitate revealed that Shah, and JR Crison, Pharm.
measured by DSC, the Tg of the it was the much less soluble Res. 12, 413 (1995).
dry product was above 200 ˚C, in- base form of the drug; this was
3. A Avdeef, Absorption and
dicating this amorphous material evident from comparing the reDrug Development, John Wiley
& Sons, Hoboken, NJ (2003).
Figure 2
Figure 2
4. CA Lipinski, F Lombardo, BW
Dominy, and PJ Feeney, Adv.
COMPARISON OF FTIR
COMPARISON
FTIR SPECTRA
SPECTRAFOR
FORAPI
APISALT,
SALT, Drug Del. Rev. 46, 3 (2001).
API salt
2
1729
1363
1653
1
Absorbance
Absorbance
promise physical and chemical
stability of the API10. Rational
choice of excipients for solid
dosage formulation is critical,
and is supported through compatibility experiments conducted
during preformulation.
Other
characteristics of the solid drug
(such as moisture content) may
influence formulation behavior,
particularly in tabletting processes such as compression or
granulation. These can lead to
physical defects and dissolution
problems, culminating in product failure.
There is considerable interest
in combination tablets as a way
to overcome the incompatibility
between certain drugs. As an example, atorvastatin is acid labile
while aspirin undergoes alkaline hydrolysis. A bilayer tablet
limits contact between the two
actives, preventing degradation
and allowing treatment of multiple therapeutic indications with
one dosage form. Coating of one
or both actives affords additional
protection from degradation.
Granulation and compression
steps may also require adjustment to preserve stability of both
APIs, e.g., reducing mechanical
shear during the latter process.
Finally, properties of the solid drug can influence how it is
packaged and stored (i.e., desiccant to prevent moisture uptake
or amber glass containers to minimize light exposure). Sensitivity
of the API to high temperature,
high humidity, light, and other
potentially harmful conditions
must be controlled to maintain
product integrity, particularly
during transport.
6. AR Kennedy, MO Okoth, DB
Sheen, JN Sherwood, SJ Teat,
and RM Vrcelj, Acta Crystallogr.
C 59, 650 (2003).
1534
0
-1
API Base
1347
-2
-3 Precipitate
1682
-4
-5
1800
1700
1528
1600
1500
Wavenumber
Wavenumber
We Deliver ®
1258
1538
1682
1344
1400
1258
1300 1200
ParticleSciences
Sciences
Particle
3894 Courtney St.,
Bethlehem, PA 18017-8920, USA
Phone: +1 610 861 4701
Email: [email protected]
www.particlesciences.com
7. AD Gift, PE Luner, LL Luedeman, and LS Taylor, J. Pharm.
Sci. 98, 4670 (2009).
8. O Almarsson and MJ
Zaworotko, Chem. Commun.,
1889 (2004).
9. L Yu, Adv. Drug Del. Rev. 48,
27 (2001).
10. SS Bharate, SB Bharate,
and AN Bajaj, J. Excipients
Food Chem. 1, 3 (2010).
Particle Sciences is a leading integrated
provider of formulation and analytic services
and both standard and nanotechnology
approaches to drug development and delivery.
3894 Courtney Street, Suite 180
Bethlehem, PA 18017
610-861-4701 phone
www.particlesciences.com
For over 15 years Particle Sciences has been developing innovative drug delivery solutions
for our clients. We are a full service CRO providing complete formulation, GMP/GLP analytic,
bioanalytic and clinical trial material manufacturing. We specialize in nanoparticulate,
semisolids and combination products.
Unique Capabilities
Integrated Process
Fine-particle and nanoscale systems have been
a focus of Particle Sciences since its inception in
1991. We work with all dosage forms and offer unique
expertise in topical and mucosal therapeutics.
By structuring a program of pre-formulation,
formulation, analytic, bioanalytic and manufacturing
services, Particle Sciences provides clients with a
powerful, integrated solution to most efficiently take a
drug from discovery to the clinic. Each project has a
dedicated team and leader to manage the project from
start to finish.
Technology
Our staff has extensive experience in drug delivery
formats including micro- and nano-particulates,
emulsions, suspensions, encapsulated API’s and
polymeric controlled release dosage forms. Particle
Sciences has all the necessary instrumentation
and in-house expertise to produce and characterize
these systems. Additionally we have a dedicated
combination-product team with full compounding
and injection molding capabilities.
Exceptional Staff
Our talented staff come from a variety of backgrounds
and includes physicians, engineers, and doctoratelevel surface, analytic, material science and polymer
scientists. Combined, the senior management
team at Particle Sciences has well over 150 years
experience in innovative drug development.
Facilities
Particle Sciences is equipped with state-of-the art
formulation equipment, analytic and bioanalytic
instrumentation. Housed in 15,000 sqft, Particle
Sciences provides complete services from API
characterization through to clinical trial material
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products.
Problem-solving
With years of experience to draw from, Particle Sciences
can confidently handle difficult APIs, complicated
intellectual property terrains and challenging delivery
goals to arrive at the simplest, most efficient solution to
our client's needs.
Efficient
Clients with demanding performance requirements and
timelines will benefit from the speed, efficiency and
quality that Particle Sciences delivers.
Collaborative
Particle Sciences maintains an "open door policy" with
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expert extension of their in-house development team.
Client-focused
Each project receives individualized attention. Particle
Sciences prefers to take a consultative approach to
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levels of client satisfaction. Projects are overseen
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conjunction with a cross-functional team.
3894 Courtney Street, Suite 180
Bethlehem, PA 18017
610-861-4701 phone
www.particlesciences.com
[email protected]