reviews research focus
19 October 2003
Solid-state analysis of the active
pharmaceutical ingredient in drug
products
Ann W. Newman and Stephen R. Byrn
The solid form of a drug substance is important when developing a new
chemical entity. The crystalline form used in development is significant
based on possible manufacturability, solubility, bioavailability and stability
differences between the solid forms. Regulatory issues require that the
form present in a solid dosage form or liquids containing undissolved drug
substance be identified. Drug product samples can be analyzed by a
variety of techniques to determine the crystal form present or changes
that occur during the manufacture of a drug product. The form present
will affect development, regulatory and intellectual property issues.
▼ The solid form of a drug substance, or ac-
Ann W. Newman
SSCI, West Lafayette tive pharmaceutical ingredient (API), is im-
IN 47906, USA portant when developing a new chemical en-
e-mail: anewman@ssci-inc.com tity (NCE). Crystalline organic solids are made
Stephen R. Byrn
Purdue University
up of molecules that are packed or ordered in
West Lafayette a specific arrangement. These molecules are
IN 47907, USA held together by relatively weak forces, such
e-mail: stephen.byrn@gte.net
as hydrogen bonding and van der Waals in-
teractions. The arrangement of the molecules
is defined by a unit cell, which is the smallest
repeating unit of a crystal. These different
arrangements determine the crystal form of
the material and can include solvates, hy-
drates and unsolvated materials. The term
polymorph describes multiple crystal forms
with the same molecular formula; for exam-
ple, two unsolvated forms are considered
polymorphs, just as two monohydrate forms
are considered polymorphs but an unsolvated
and a hydrated form are not considered poly-
morphs. A noncrystalline solid is called amor-
phous, where the molecules are not ordered
in a specific arrangement (Figure 1). The crys-
tal form used in development is important
based on possible manufacturability, solubil-
ity, bioavailability and stability differences
between the different solid forms [1].
898 www.drugdiscoverytoday.com 1359-6446/03/$ – see front matter ©2003 Elsevier Science Ltd. All rights reserved. PII: S1359-6446(03)02832-0
DDT Vol. 8, No.
Considerations for solid-state during
development
The delivery system to be targeted is an im-
portant consideration when considering solid-
state issues during development. A variety of
dosage forms are available for pharmaceutical
products (for examples see Box 1). The key
solid-state parameters for the drug substance
in a tablet formulation will be significantly
different than those for an oral suspension or
inhalation product.
Regulatory issues for solid dosage forms or
liquids containing undissolved drug substance
are outlined in an International Conference
on Harmonisation (ICH; http:// www.ich.org)
decision tree, as shown in Figure 2 [2,3]. The
polymorph or the crystal form used to
produce the dosage form must be known, as
should how crystal form changes might affect
the performance or stability of the drug prod-
uct. These are important questions that must
be answered during the drug development
process.
The information obtained from drug prod-
uct analysis is important in many areas. When
designing formulations, it is imperative to
know which crystal form of a drug is present
at the various stages of a process and at the
end of the process. A hygroscopic drug will
likely form a hydrate during a wet granu-
lation, but that hydrate could also convert or
partially convert to another form upon dry-
ing. A direct compression formulation might
be feasible but only under certain relative
humidity conditions. It is important to deter-
mine if there are phase transformations
occurring during processing, as well as what
crystal form is present in the final drug
product [4–7].
DDT Vol. 8, No. 19 October 2003
Another consideration is possible
crystal form transformations over time
or during solid-state (also known as
physical) stability testing. This is not
the same as chemical stability, which
deals with degradation; however, the
same samples can be used and analyzed
by different methods to determine
physical and chemical stability. In many Order (crystalline)
solid-state systems, two polymorphic
forms can exist that have different
thermodynamic stabilities. The more Figure 1. An illustration of the concept of molecular order in solids.
stable form is usually chosen for devel-
opment but a solubility advantage
could be obtained with the less stable form. In such
systems, the less stable form can transform to the more
stable form especially under the influence of heat,
mechanical stress, moisture or seeds. Establishing the solid-
state stability (no crystal form change) under various
conditions will help determine the shelf life of the drug
product or force the development of the more stable form
if the metastable form does not exhibit sufficient stability.
The importance of solid analysis of API in drug product
development will be discussed in the following sections,
including common techniques used to analyze solid
dosage forms, examples of drug product analysis and process-
induced transformations during formulation.
Techniques
Several analytical techniques are commonly used in form-
selection studies. Various publications [8–10] and books
[1,11] describe physical characterization of solid-state
pharmaceuticals. A brief description of common methods
will be presented here.
X-ray powder diffraction
X-ray diffraction techniques used for characterizing phar-
maceutical solids include the analysis of single crystals and
powders. The electrons surrounding the atoms diffract
X-rays in a manner described by the Bragg equation [11].
X-rays will be diffracted at an angle (defined as θ), and this
knowledge, together with knowledge of the X-ray wave-
length, can be used to calculate the spacing between the
planes.
X-ray powder diffraction (XRPD) is the analysis of a
powder sample with a typical output being a plot of inten-
sity versus the diffraction angle (2θ). The value 2θ is used
based on the configuration of the instrument. Such a plot
can be considered a fingerprint of the crystal structure and
is useful for determining the crystallographic similarity of
samples by pattern comparison. A crystalline material will
research focus reviews
Intermediate order Disorder (amorphous)
Drug Discovery Today
Box 1. Examples of pharmaceutical dosage
forms
Tablets Patches
Emulsions Capsules
Depot Inhalers
Solutions Implants
Suppositories Suspensions
Intravenous (IV) Soft gel capsules
exhibit peaks indicative of reflections from specific atomic
planes; these patterns are representative of the structure
but do not give positional information about the atoms in
the molecule. One peak will be exhibited for all repeating
planes with the same spacing. By contrast, an amorphous
sample will exhibit a broad hump in the pattern called an
amorphous halo. Representative XRPD patterns for lactose
are shown in Figure 3.
Qualitative analysis of powder patterns can be used to
determine if multiple samples are the same crystal form or
if multiple crystal forms have been developed. Mixtures of
samples can also be evaluated. When mixtures are ob-
tained, XRPD can also be used in a quantitative mode to
calculate the amount of each phase present.
Vibrational spectroscopy
Common techniques used to characterize drugs and excip-
ients are infrared (IR) and Raman spectroscopy, which are
sensitive to the structure, conformation and environment
of organic compounds. Because of this sensitivity, they are
useful characterization tools for pharmaceutical crystal
forms. Qualitative as well as quantitative analysis can be
performed with both techniques.
IR spectroscopy is based on the conversion of IR radi-
ation into molecular vibrations. For a vibration to be IR
active, it must involve a changing molecular dipole (asym-
metric mode). For example, vibration of a dipolar carbonyl
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reviews research focus DDT Vol. 8, No. 19 October 2003

crystal form determination because

minimal sample manipulation is re-
Monitor polymorph change on Can
No No need to set acceptance quired. Mulls can also be used for form
manufacture or stability of polymorph ratio criteria fpr polymorph
drug product change? content in drug product identification, but peaks that result
from the suspension medium could
interfere with the peaks of interest.
Yes Raman spectroscopy is based on the
inelastic scattering of laser radiation
Does
drug product
with loss of vibrational energy by a
performance No need to set acceptance sample. A vibrational mode is Raman-
testing provide Yes
criteria for polymorph active when there is a change in the
adequate control content in drug product
(e.g. polarizability during the vibration.
dissolution)?
Symmetric modes tend to be Raman
active; for example, vibrations about
No
bonds between the same atom, such as
Establish acceptance criteria
in alkynes, can be observed by this
that are consistent with technique.
safety and efficacy
Small amounts of samples can be
Drug Discovery Today
analyzed by Raman spectroscopy and
Figure 2. Regulatory decision tree for solid dosage forms or liquids containing a variety of sample holders are avail-
undissolved drug substances (adapted from Ref. [3]). able, ranging from stainless steel hold-
ers to glass NMR tubes. The samples
are analyzed neat, eliminating the
need for sample preparation proce-
dures that might induce solid form
changes. A laser is used, therefore, only
a small portion of the sample is in the
beam during analysis.
Both IR and Raman microscopes are
available for imaging drug product
samples [12–14]. Several methods of
analysis, such as spot mode, line scan
or area mapping, can be used to look at
the distribution of a crystal form in a
dosage form, such as a tablet, or to find
minor levels of a form. Recently, NIR
microscopy has been introduced as a
powerful new method for drug product
analysis by imaging [13].

Drug Discovery Today

NMR spectroscopy
Figure 3. XRPD patterns of crystalline anhydrous lactose (top) crystalline lactose NMR spectroscopy probes atomic
monohydrate (middle) and amorphous lactose (bottom). environments based on the different
resonance frequencies exhibited by
nuclei in a strong magnetic field.
group is detectable by IR spectroscopy. Whereas IR has Many different nuclei are observable by NMR but those of
been traditionally used as an aid in structure elucidation, hydrogen and carbon atoms are the most frequently stud-
vibrational changes also serve as probes of intermolecular ied. NMR spectroscopy of solutions is commonly used for
interactions in solid materials. structure elucidation. However, solid-state NMR measure-
Sampling techniques for IR include pellets, mulls and ments are extremely useful for characterizing the crystal
diffuse reflectance. Diffuse reflectance is the best choice for forms of pharmaceutical solids.

900 www.drugdiscoverytoday.com
DDT Vol. 8, No. 19 October 2003
Table 1. Summary of quantitative methods
Quantitative method Scope of assay
Limit test A limit of detection for a technique is
determined (such as 2%)
Specification assay An assay limit is determined for a
technique (such as 95%)
Full quantitative method A minimum quantifiable limit (MQL) (such
as 2%) and linear range (such as 2–25%)
is determined
Nuclei that are typically analyzed with this technique in-
clude those of 13C, 31P, 15N, 25Mg and 23Na. Different crystal
structures of a compound can result in perturbation of the
chemical environment of each nucleus, resulting in a
unique spectrum for each form. Once resonances have been
assigned to specific atoms of the molecule, information on
the nature of the polymorphic variations can be obtained.
This can be useful early in drug development when the sin-
gle crystal structure might not be available. Long data acqui-
sition times are common with solid-state NMR, so it is often
not considered for routine analysis of samples. However, it is
usually a sensitive technique and sample preparation is min-
imal. NMR spectroscopy can be used either qualitatively or
quantitatively, and can provide structural data, such as the
identity of solvents bound in a crystal.
Qualitative versus quantitative analysis
Different levels of analysis are used at different stages of
the development process. At the early formulation and
process evaluation stage, early Good Manufacturing
Practices (GMP) method development and validation ap-
proaches are used. Qualitative or visual determinations can
be made at this stage instead of full quantitative analyses.
These measurements are used to guide the development of
the drug and might not be applicable to the final chosen
form. During Phase II, stronger GMP method development
and validation are needed. These methods are developed
in preparation for end-of-Phase II meetings where ques-
tions about method accuracy and suitability could arise.
Quantitative or limit test methods are usually in place to
aid early process validation. By the product launch, final-
ized methods and full validation of methods and the
process are required. ICH Q2B Guidelines are available for
quantitative methods [15].
There are several quantitative approaches for solid-state
testing. For all assays, specificity needs to be determined for
the technique being used for method development. As an ex-
ample, Form A is the form chosen for development and Form
B is a contaminating form. Possible choices for quantitation
research focus reviews
Result
Result is specified as ’2% Form B present’
Result is specified as ’95% Form A present’
'X% of Form B' if within the quantitation range of
2–25% or ‘2% Form B' if below MQL or '25% Form
B' if above linear range
are outlined in Table 1. Various levels of validation are re-
quired for the different methods. Methods become more
complex as the number of contaminating forms increases.
Analysis of the drug product
There have been several reports on the analysis of solid
dosage forms [16–28]. A variety of techniques, such as
XRPD [16–23], NMR [24–27], Raman [28–29] and IR [30]
have been used to identify the crystal form in a wide
selection of dosage forms, including tablets, capsules, oint-
ments, suppositories and microspheres. A small selection
of the available literature will be discussed here.
X-ray powder diffraction
XRPD is a common choice for pharmaceutical dosage form
analysis because it is a direct measure of the crystal form of
a material. Overlap of the crystalline API peaks with crys-
talline excipients is a common problem when analyzing
drug product samples. However, when the excipients are
amorphous, or there is a high loading of the drug in the
formulation, XRPD can be an effective technique in identi-
fying crystalline API. Qualitative or quantitative [16,17]
determinations can be performed using this technique.
Tablets and capsules are common dosage forms to ana-
lyze. An example is the analysis of marketed ampicillin cap-
sules [17] where the anhydrous or trihydrate forms were
readily identified by XRPD at a drug loading of ~83% w/w
ampicillin. Dosage forms with multiple active ingredients
can also be effectively analyzed, as demonstrated using
marketed Excedrin® tablets. Identification of acetamino-
phen and aspirin was readily performed; however, further
data analysis using pattern subtraction was required to
identify caffeine. Quantitation of clinical trial samples of
dOTC, an antiviral drug in the nucleoside analog class of
drugs, which was previously in development, was per-
formed at SSCI (http://www.ssci-inc.com) using XRPD. The
method was developed and validated from 3–30% for the
metastable Form A in the desired stable Form B formulation
and amounts up to 50% were estimated with a second
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reviews research focus
calibration curve. Large amounts of Form A (up to 38%)
were measured for the samples. It was found that over a six
month time period, the amount of Form A decreased from
~38% to ~30%. This was important information for the
clinical scientists when reviewing the bioavailability data.
The lack of crystalline API peaks when a dosage form is
analyzed could indicate that the material is amorphous or
that the loading is too low to detect using the parameters
chosen. Synchrotron radiation can be used to increase sen-
sitivity and measure much lower levels of different forms
in the drug product, as evidenced by data collected on
ranitidine HCl and Children’s Advil© [18]. Different data
analysis methods, such as spectral subtraction [17],
Rietveld analysis [18,19], whole pattern matching software
[20,21] and partial least-square (PLS) methods [22], can
also be used to obtain lower detection levels or quantitate
materials with significant overlap.
Analysis of other dosage forms using XRPD has also been
reported. The amount of crystalline tolnafate was deter-
mined in ethylcellulose microspheres [23]. Acetaminophen
suppositories containing hydrogenated vegetable oil, poly-
oxyethylene stearate, glycol monostearate and preserva-
tives were examined [17]. Interference with the excipients
was evident between ~15°2θ and 25°2θ, however, aceta-
minophen peaks were clearly present. Pattern subtraction
was again used to unequivocally identify the aceta-
minophen. In the case of a zinc oxide ointment, the
crystalline inorganic peaks attributed to zinc oxide were
observed above 30°2θ, eliminating overlap with the amor-
phous halo observed below 20°2θ [17].
Solid-state NMR spectroscopy
Solid-state NMR spectroscopy has become a popular
method of analyzing dosage forms [24–26]. The technique
offers little interference from many excipients but the data
acquisition can be complicated and lengthy. Quantitation
can also be performed with NMR spectroscopy [25,27]. A
number of parameters need to be determined for each sys-
tem for the signal intensities to be representative of the
number of nuclei being measured.
Several marketed tablets and capsules were analyzed by
NMR to determine the feasibility of using this technique for
solid dosage form analysis [24]. Samples of enalapril maleate
(Vasotec®) and ibuprofen (Nuprin®, Haltran®) tablets readily
exhibited peaks due to the drug substance, showing that
NMR can easily be used to differentiate between drug prod-
uct and placebo samples. Analysis of lovastatin tablets
(Mevacor®) resulted in interference from the excipients,
therefore a determination of form using this technique was
not possible. Two prednisolone products analyzed by NMR
were found to contain Form I in one case and Form II in
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DDT Vol. 8, No. 19 October 2003
another. The dose of 5mg in a 100 mg tablet demonstrates
the levels that are detectable using this technique.
Raman and IR spectroscopy
Raman spectroscopy has also been used to investigate API
present in tablets [28,29]. The benefits of Raman spectroscopy
include minimal, if any, sample preparation, as well as less
overlap with common excipients when compared to IR spec-
troscopy. The shortcomings include possible fluorescence, a
small sampling area due to the size of the laser beam used for
excitation, and possible sample heating during data collection.
Raman spectroscopy has been used to try to identify
counterfeit drug products and was found to be more effec-
tive than IR for the cases presented [29]. In another study,
tablets of various marketed products were analyzed to
specifically look at the crystal form present in various sam-
ples [30]. In the case of a 2.5 mg prednisolone tablet
(~1.4% of drug), the peaks for Form II prednisolone were
clearly evident. Warfarin sodium exists as an amorphous
solid or crystalline clathrate of the drug and isopropyl al-
cohol. A 2.1% loading in a 2.5 mg tablet was analyzed and
found to contain the crystalline clathrate and not the
amorphous solid. In the case of ranitidine HCl, tablets
from different manufacturers were found to contain different
crystal forms. Artonil tablets contained Form I ranitidine
HCl and Zantac® tablets contained Form II. Raman was
also used to distinguish the anhydrous and monohydrate
forms of theophylline in tablets stored at 75% relative hu-
midity (RH) for up to 12 days. It was found that the anhydrous
form readily converts to the monohydrate form over time.
A near infrared (NIR) method was developed and vali-
dated to determine the amount of crystalline miokamycin
in the presence of the desired amorphous material in mar-
keted tablets. A PLS method was developed to quantitate
crystalline material in the range of 1–9%.
Chemical imaging
Chemical imaging is a powerful method for the analysis of
drug products. Most Raman studies involve microtoming or
using some other technique to obtain a smooth surface. It
is possible to image an entire tablet by successively micro-
toming and collecting data in that plane. An NIR imaging
system has been developed that is faster than the Raman
procedure and requires less sample handling [13]. NIR
imaging has also been used to analyze blend homogeneity
and particle size changes in tablets. Chemical imaging pro-
vides another powerful method for drug product analysis.
Changes during processing
The presence of different physical forms in various dosage
formulations could be a result of the initial API that was
DDT Vol. 8, No. 19 October 2003
used to manufacture the drug product
or to changes that occurred during pro- Wetting
cessing. Form changes can occur at vari-
ous stages of the formulation process,
including wet granulation, drying (in-
cluding lyophilization), compression,
handling and storage (including stabil-
ity testing) [4,6,7]. Examples of possible
changes that could occur during Stable
Hydrate
form
the formulation process are shown
schematically in Figure 4 [6].
A change in crystal form to a more
stable, less soluble form can have dire
consequences in the formulation. A re-
cent example is the semisolid capsule
formulation of ritonavir [31]. During
development, only one form of riton-
Figure 4. Possible form changes during a wet granulation process. (Reproduced, with
avir (Form I) was known even though
permission, from Ref. [6]).
attempts were made to find other
forms. The semisolid formulation was
nearly saturated with respect to Form I ritonavir and ended
up being supersaturated with respect to Form II ritonavir,
resulting in crystallization of the more stable Form II in the
marketed capsules. This change in form resulted in a mar-
ket crisis until a new formulation with the much less solu-
ble Form II was produced. It should be noted that Form II
was not observed during development of the API or formu-
lation or for two years after the launch of the product.
Common steps in the formulation process where form
changes can occur will be discussed here; however, it
should be noted that form changes can occur at almost any
point in the process.
Wet granulation and drying: the influence of moisture
and heat
Wet granulation is a frequent way of creating new forms,
especially if hydrated forms are already known for the drug
substance. Testing materials in the presence of water or
aqueous solvents can help determine the feasibility of
using wet granulation. In the case of cimetidine, anhy-
drous Form A was found to convert to hydrated Form B in
water over a period of up to 12 months [32]. A mixture of
anhydrous Forms A and D were found to convert to hydrate
Form C in water but to Form D in a 50:50 ethanol:water
solution. It was postulated that in a high shear mixer other
mechanisms would likely increase the solid form transfor-
mations. In the case of an HMG-CoA reductase inhibitor
(SQ33600), dry blending the formulation resulted in no
change in crystal form; however, wet granulation trans-
formed the crystalline material into amorphous [33].
When the amorphous formulation was exposed to 33%
research focus reviews
Drying Processing/storage
(moisture/stress/time)
Meta-
stable
form
Stable
form
Stable
form
Hydrate
Isomorphic
desolvate
Meta-
Amorphous
solid stable
form
Drug Discovery Today
and 75% RH conditions, the material converted back to
crystalline form. It was found that dissolution of capsules
containing crystalline material in the formulation was the
same as capsules containing the amorphous formulation.
Based on XRPD data, it appears that contact with water at
the dissolving surface of the crystalline form results in
amorphous or liquid crystalline material.
Several studies with theophylline have shown a conver-
sion of anhydrous Forms I and II to the monohydrate in
the presence of water [34,35]. A significant decrease in dis-
solution is observed when the hydrate material is present.
Other studies have shown that wet granulation and fluid-
bed drying will result in a third unsolvated polymorph of
theophylline with different dissolution characteristics
[6,35]. Phase transformations to metastable forms can also
occur. In the case of fosinopril sodium, rapid drying from a
granulation fluid containing alcohol showed conversion
to the metastable unsolvated Form B instead of the stable
unsolvated Form A. The amount of conversion depended
on the drying conditions used [6,36]. It is important to an-
alyze samples at various stages of a wet granulation and
drying process to investigate any form changes occurring
under these conditions.
Compression: the influence of mechanical force
Tablets are one of the most common dosage forms used in
pharmaceuticals and form changes upon compression is
an active area of study [32,37–39]. Several investigations
have been performed on chlorpropamide [40–42]. It is pos-
tulated that chlorpropamide Form A and C will partially
convert to a highly unstable amorphous material upon
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reviews research focus
compression and a form change occurs from the amor-
phous material. It was observed that the stable Form A will
convert to the metastable Form C upon compression.
Compressing the material at elevated temperatures will
produce more of Form C. Compression of Form C at ambi-
ent temperatures results in the formation of Form A;
however, at elevated temperatures, Form C is maintained.
Compression pressures will also affect the conversion to
another form [38]. In the case of sulfabenzamide stable
Form A, higher compression pressures resulted in greater
formation of the metastable Form B material. Maprotiline
HCl exists as a stable Form II as well as metastable Forms I
and III. Upon compression, Form III will convert to stable
Form II, however, Form I will remain as Form I under the
same conditions. Cimetadine Forms A, B, C and D will not
change upon compression but the amorphous material
will crystallize under similar pressure conditions [32].
Storage
Storage conditions can have a crucial role in form stability
[5]. The effects of moisture and temperature can readily
cause transformation between hydrated and anhydrous
species but temperature alone can also induce solid trans-
formations between unsolvated polymorphic forms.
Recent studies at Purdue University (http://www.purdue.
edu), as well as published reports [31], have shown that
seeding also accelerates transformations. Suspensions are
also at risk for form transformations due to possible disso-
lution and recrystallization phenomenon, especially at
elevated temperature conditions.
For theophylline, it was found that the tabletting pres-
sure significantly affected the hydration kinetics in the
tablet [43]. Hydration was found to significantly decrease
with an increase in tabletting pressure. The data suggested
that the hydration of the tablets does not depend on the
hydration mechanism of the bulk powder but on the struc-
ture of the dosage form. In another study, the conversion
to the monohydrate was manifested as distinct needles on
the surface of the tablets after storage [44]. A significant
decrease in the rate of theophylline release was observed in
tablets containing the monohydrate needles. The exam-
ples given here deal with crystalline and hydrated species
and it should be noted that amorphous materials might
also readily convert upon storage. Attempts to prepare a
fast-dissolving form of nifedipine involved using 2-hydrox-
ypropyl-β-cyclodextrin to stabilize the amorphous material
[45]. When the mixture was heated to low temperatures,
crystalline nifedipine Form A was produced, however at
high temperatures, Form B was produced. Significant con-
trol of storage conditions is sometimes needed to maintain
the desired solid state form.
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DDT Vol. 8, No. 19 October 2003
Aerosol formulations are also at risk. A nedocrimal
sodium aerosol formulation was stored at various RH condi-
tions [46]. From 12–76% RH, the trihydrate form remained
unchanged and there was no change in the in vitro aerosol
performance of the drug. When stored at 86% RH, the trihy-
drate converted to the heptahemihydrate and a significant
decrease in the deaggregation performance was observed.
Process analytical technology (PAT)
Industry and regulatory agencies are seeking ways to im-
prove manufacturing efficiency by increasing throughput,
reducing costs and improving product quality. New meas-
urement technologies have been developed to acquire, in
real time, information rich data on process performance
using on-line or in-line sensors. Process Analytical Tech-
nology (PAT) is a new initiative to enable effective in-
process control during routine manufacture [47,48]. The
goals are to reduce waste, shorten manufacturing time, de-
liver significant improvements in quality consistency and
reduce costs. The data collected real-time during the manu-
facturing steps will decrease post-production analysis
through an improved understanding of the manufacturing
processes. PAT methods are sensitive to hydration, such as
determining the drying endpoint for a granulation in a
fluid dryer with NIR, and sensitive to solid form, such as de-
termining a form change during a wet granulation process.
Chemical stability
Chemical stability in dosage forms is also a concern
and initial excipient compatibility studies are usually per-
formed during development of the dosage form [49]. It
should be recognized that different forms can have differ-
ent chemical stabilities. It is often the case that amorphous
materials will not only be less physically stable (prone to
crystallization), but also less chemically stable. The glass
transition temperature and how it changes with moisture
content, related to mobility, is an important factor for the
stability and formulation of amorphous materials [50].
Formulation can accelerate chemical degradation as a re-
sult of: (1) interaction with excipients, (2) processing
effects and (3) induction by excipients (but not involving
chemical reactions with the excipients) [51]. Various
reactions, such as oxidation, cyclization and hydrolysis,
are common degradation pathways and excipient interac-
tions, such as acid and Maillard reactions, also need to be
considered during formulation development.
Conclusions
Solid-state analysis of API in drug products covers a wide
variety of topics, ranging from the form present in the final
dosage form to possible changes that can occur upon
DDT Vol. 8, No. 19 October 2003
processing. It is important to note that form changes can
occur at almost any stage during formulation depending on
your solid-state system. Several analytical techniques are
available for determining the crystal forms present in the
drug product. These techniques can be used for qualitative
or quantitative testing. It is important from a regulatory, as
well as an intellectual property, perspective to know the
crystal form(s) present in the marketed drug product.
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3 Q6A Specifications, Test procedures and acceptance criteria for new
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Fed. Reg. 62, 62889–62910
4 York, P. (1983) Solid-state properties of powders in the formulation and
processing of solid dosage forms. Int. J. Pharm. 14, 1–28
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6 Morris, K.R. et al. (2001) Theoretical approaches to physical
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manufacturing processes. Adv. Drug Deliv. Rev. 48, 91–114
7 Brittain, H.G. and Fiese, E.F. (1999) Effects of pharmaceutical processing
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