Article

Cite This: Mol. Pharmaceutics 2018, 15, 40−52

Impact of Solid-State Form on the Disproportionation of Miconazole

Mesylate
Mitulkumar A. Patel,† Suman Luthra,‡ Sheri L. Shamblin,§ Kapildev Arora,§ Joseph F. Krzyzaniak,§
and Lynne S. Taylor*,†
†
Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, West Lafayette, Indiana 47907, United
States
‡
Pfizer Inc, Worldwide Research and Development, Cambridge 02139, Massachusetts, United States
§
Pfizer Inc, Worldwide Research and Development, Groton 06340, Connecticut, United States
See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

*
S Supporting Information
Downloaded via PURDUE UNIV on June 15, 2020 at 13:42:24 (UTC).

ABSTRACT: Approximately 50% of solid oral dosage forms utilize salt forms of the active pharmaceutical ingredient (API). A
major challenge with the salt form is its tendency to disproportionate to produce the un-ionized API form, decreasing the
solubility and negatively impacting product stability. However, many of the factors dictating the tendency of a given salt to
undergo disproportionation remain to be elucidated. In particular, the role of the solid-state properties of the salt on the
disproportionation reaction is unknown. Herein, various solid forms of a model salt, miconazole mesylate (MM), were evaluated
for their tendency to undergo disproportionation when mixed with basic excipients, namely tribasic sodium phosphate
dodecahydrate (TSPd) and croscarmellose sodium (CCS), and exposed to moderate relative humidity storage conditions. It was
observed that the rate and extent of salt disproportionation were significantly different for the various solid forms of MM. As
expected, the amorphous salt was highly susceptible to disproportionation, while the dihydrate salt form was resistant to
conversion under the conditions tested. In addition, binary excipient blends of amorphous and anhydrous forms exhibited a
reduced extent of disproportionation at a higher relative humidity storage condition. This was due to the competitive kinetics
between disproportionation to the free base and conversion to the dihydrate salt form. The results of this study provide
important insights into the impact of solid-state form on susceptibility to disproportionation that can be utilized for rationally
designing robust pharmaceutical formulations.
KEYWORDS: salt disproportionation, pharmaceutical excipient, stability, amorphous, solid form

■ INTRODUCTION
The pharmaceutical industry has achieved great success in
hence bioavailable, is one of the biggest challenges for
pharmaceutical scientists.7 To improve solubility, many
discovering new drug candidates by employing high throughput approaches are employed including the use of cyclodextrins,
screening, leading to molecules which possess better target cosolvents, surfactants, cocrystals, polymorphs, amorphous
binding and have higher efficacy.1,2 However, many of these forms, salts, and lipid-based systems.8 Among these techniques,
newly discovered drug molecules have poor aqueous solubility.3 the use of salts is a common approach for commercial
Nearly 90% of emerging drug candidates are poorly soluble, formulations, due to the ease of manufacture. Approximately
falling into Class II or Class IV of the Biopharmaceutical 50% of marketed small-molecule medicines are available as the
Classification System (BCS) which categorizes them based on salt form according to the Food and Drug Administration’s
their permeability and solubility.3−5 Depending on the origin of (FDA) orange book database.9 Salt forms are possible for either
the poor solubility, compounds have been termed “brick dust”
or “greaseballs”.6 The former compounds are very insoluble, Received: August 11, 2017
crystalline compounds with high melting points, while the later Revised: November 2, 2017
compounds are extremely lipophilic and often have lower Accepted: December 4, 2017
melting points. Rendering these compounds water-soluble, and Published: December 4, 2017

© 2017 American Chemical Society 40 DOI: 10.1021/acs.molpharmaceut.7b00694

Mol. Pharmaceutics 2018, 15, 40−52
Molecular Pharmaceutics Article

Figure 1. Chemical structures of MM, TSPd, and CCS.

acidic or basic drugs. As the majority of drugs are weak bases, modeling approach was developed for the disproportionation
their salt forms have been the main focus of investigations into process and implemented to select pharmaceutical salts using
salt properties. quality by design.22 The pH of the maximum solubility (pHmax)
The major advantage of utilizing salts is the enhancement of for the salt/neutral form pair is considered an important
aqueous solubility. In addition, they often have improved solid- parameter for indicating the stability of salt form.12,23 For the
state properties relative to the free base form, leading to salt of a weakly basic drug, if pH is below pHmax then the salt
enhanced stability.10,11 However, many studies have shown that form is stable, while for pH values above pHmax, the free base is
when the salt form of a weakly basic drug is mixed with certain stable.12,23 Therefore, in a pharmaceutical formulation, any
basic excipients, the counterion can dissociate from the salt, a excipient which leads to a microenvironmental pH greater than
phenomenon commonly termed disproportionation.12−16 pHmax could encourage disproportionation.16,23 In addition, it
Understanding the risk for this transformation is of utmost has been established that various physicochemical parameters
importance since the partial formation of the free base in the such as particle size, storage relative humidity (RH), counterion
drug product can lead to a decrease in dissolution rate and selection, and temperature play a major role in governing the
hence bioavailability.16,17 A recent example where this process rate and extent of the disproportionation.12,24 However, the
occurred is exemplified by prasugrel HCl, a platelet aggregation effect of different solid-state forms of the same salt complex on
inhibitor drug. The partial salt-to-free base conversion of this the physical stability of the salt in the presence of excipients has
drug during product manufacturing had consequences in not been studied to date. Specifically, there is no reported study
patients with elevated gastric pH, where a decrease in which compares the rate and extent of disproportionation
bioavailability was observed.17 In addition, the formation of among various solid-state forms of a given pharmaceutical salt
free acid/base can also cause undesirable stability problems such as amorphous, anhydrous, and hydrated forms. Typically,
with formulations. Unfortunately, commonly used pharmaceut- during early stages of drug development, a salt could be
ical disintegrants and lubricants such as croscarmellose sodium formulated either as amorphous or crystalline anhydrous
and magnesium stearate, when combined with salts of weakly material. Importantly, the use of an amorphous salt form as
basic drugs, have been shown to generate significant amounts of an API has also been seen in commercial products such as
free base (∼10%) form upon storage (10 days).12 Therefore, it Crestor, Viracept, and Accupril. In addition, even if the
is of utmost importance to understand the underlying crystalline salt form is used, during the manufacturing unit
mechanism of disproportionation. Liquid chromatography, operations such as milling and wet granulation, there is a
the most commonly used analytical technique for pharmaceut- chance for partial amorphization or other solid-state form
ical analysis, cannot be used to distinguish between salt or free conversions. Given that different solid-state forms of a
base in solid form since it is a solution state analysis method. particular salt could have different physical and chemical
However, solid-state analytical techniques such as X-ray powder properties, it is important to understand which solid forms are
diffraction as well as Raman and infrared (IR) spectroscopy can more prone to disproportionation versus those which are
be used to differentiate between the ionized and nonionized resistant. Solid forms that show a lower propensity to undergo
state of the drug in crystalline solid systems and thus enable disproportionation reactions are desirable for further drug
detection of disproportionation.18−20 development.
When developing formulations for a pharmaceutical salt, it is The goal of this study was to evaluate the link between
critical to identify and mitigate the risk of disproportionation different solid-state forms of the same salt and their
and therefore extensive research is ongoing in this field.16 For disproportionation propensity in the presence of excipients.
example, a strategy of making crystalline solid dispersions has Miconazole mesylate (MM) is the salt of a weakly basic drug,
been used to reduce the occurrence of disproportionation, and has been noted previously to undergo disproportionation.24
whereby the salt and the excipient that is responsible for Therefore, MM was selected as a model salt as different solid-
physical instability are physically isolated.21 In addition, a state forms of MM can be readily prepared. Specifically,
41 DOI: 10.1021/acs.molpharmaceut.7b00694
Mol. Pharmaceutics 2018, 15, 40−52
Molecular Pharmaceutics Article

amorphous (AMO), anhydrous (AH), and dihydrate (DH) diffractometer. The instrument was equipped with a Micro-
forms of MM were prepared and their disproportionation Max002+ high-intensity copper X-ray source (Cu Kα radiation,
tendency in the presence of basic excipients were evaluated. λ = 1.54184 Å) along with the confocal optics. The diffraction
The hypothesis under evaluation was that the higher the data were obtained at −173 °C. Detailed information regarding
solubility difference between a metastable salt form and the free single crystal data processing is provided in the Supporting
base (relative to the solubility difference between the stable salt Information.
form and free base), the greater the tendency to convert to the Attenuated Total Reflectance Fourier Transform Infrared
free base form of the drug when mixed with basic excipients. Spectroscopy (ATR-FTIR). ATR-FTIR spectra were collected
Powder blends of MM with either tribasic sodium phosphate using a Bruker Vertex 70 instrument (Bruker Co., Billerica,
dodecahydrate (TSPd, a model highly basic excipient) or the MA) equipped with a Golden Gate attenuated total reflectance
commonly used pharmaceutical excipient, croscarmellose (ATR) sampling accessory with a diamond crystal (Specac Ltd.,
sodium (CCS) were prepared. Raman spectroscopy, in Orpington, UK), as described previously.25 OPUS software
combination with chemometric modeling of the spectroscopy (Bruker Co., Billerica, MA) was used for data collection and
data, were utilized to monitor disproportionation/phase analysis. FTIR spectra were generated by placing samples in
transformations between different solid-state forms of MM. contact with the diamond crystal of the ATR accessory,
Additionally, the effect of RH on differences in rate and extent followed by accumulating 64 scans between 650 and 3950 cm−1
of disproportionation among various solid forms of MM salt at a resolution of 4 cm−1.
was also analyzed.

■
Polarized Light Microscopy (PLM). A few particles of each
solid form of MM were placed onto a microscope slide, which
EXPERIMENTAL SECTION was then mounted onto the stage. The images were obtained by
Materials. Miconazole (MCZ) was obtained from Alfa an Eclipse E600 POL microscope in combination with a DS Fi1
Aesar (Haverhill, MA). Methanesulfonic acid (MSA) was camera (Nikon Corporation, Tokyo, Japan) using cross-
purchased from Acros Organics (Fair Lawn, NJ). Trisodium polarized light in transmittance mode. The diameters of 100
phosphate dodecahydrate (TSPd) and croscarmellose sodium particles were then measured manually using ImageJ software
(CCS) were obtained from Mallinckrodt (Saint Louis, MO) (Version 1.8, developed by the National Institutes of Health) to
and FMC (Philadelphia, PA), respectively. Tetrahydrofuran obtain the particle size distribution.
(THF) was purchased from Macron. Ultrapure water was Sample Preparation for Disproportionation Study. Each
obtained using a Millipore ultrapure water system (Billerica, solid form of MM (AMO, AH, and DH) was mixed with model
MA). All chemicals were >99% of purity. The molecular excipients (CCS or TSPd) to produce binary mixtures at a 50%
structures of miconazole mesylate (MM) and the excipients are (w/w) ratio. Prior to blending, AMO and AH powders were
shown in Figure 1. individually stored in desiccators over calcium sulfate (W. A.
Anhydrous MM was prepared by acid−base reaction. In a Hammond Drierite Co. Ltd., Xenia, OH) for a week at 25 °C,
glass vial, 5 g of MCZ free base was dissolved in 4 mL of THF while the DH powder was stored in a tightly closed container to
with a magnetic stirrer (700 rpm) at 25 °C. To the same vial, prevent dehydration. 50 mg of each solid form was geometri-
795 μL of MSA (1:1 molar ratio) was added dropwise with cally mixed with 50 mg of the excipient using a spatula. All the
continuous stirring (with slight ∼2 mol % excess of MSA). The samples were prepared in a controlled environment of ∼20%
resultant reaction mixture was stirred continuously at 5 °C until
RH. Each binary mixture was prepared in triplicate. Samples
MM crystallized (∼2 h). The solids were then vacuum filtered
were then stored in open vials and exposed to 33, 43, or 57%
and washed with 4 mL of THF, which resulted in formation of
RH and 25 °C. In addition, reference AMO, AH, and DH
a THF solvate of MM. The obtained crystals were subsequently
powders were stored under similar conditions. The Raman
dried in a desiccator at 65 °C for 24 h followed by storage with
desiccant at 25 °C. Amorphous MM (AMO) was prepared by spectra of all samples were taken periodically to monitor the
melt quenching. The obtained glassy material was stored in a progress of disproportionation (conversion to MCZ) or phase
desiccator. To obtain MM dihydrate (DH), AH powder was transformation (conversion to DH).
exposed to 75% RH and 25 °C for 2 days in order to reach Raman Spectroscopy. Raman spectra of the samples were
equilibrium. The resulting powder was collected and stored in collected using a RamanRxn2 Analyzer (Kaiser Optical
an airtight container. Systems, Inc., Ann Arbor, MI) with a PhAT probe. A 785
Methods. X-ray Powder Diffraction (XRPD). Diffraction nm high power NIR diode laser (Invictus) was used as the light
patterns were recorded using a Rigaku SmartLab (XRD 6000) source. The laser spot size was 6 mm and back scattered
diffractometer (The Woodlands, TX) using Bragg−Brentano radiation was delivered to the base unit via the fiber bundle of
mode using Cu Kα radiation (λ = 1.5405 Å). Samples (∼40 the PhAT probe. The instrument was calibrated using ASTM
mg) were placed onto a glass sample holder. Diffraction data standards for the laser excitation wavelength (cyclohexane),
were recorded at room temperature between 10° to 40° 2θ spectrograph wavelength (neon atomic lines), and instrument
with a step size of 0.02°, and a scan time of 8 min per sample. spectral response (white-light source). To obtain reproducible
Single Crystal X-ray Diffraction (SCXD). To obtain the results from PhAT Raman measurements, a specially designed
single crystals of DH, a vial containing 100 mg of AH were sample holder with a controlled thickness was used. To reduce
exposed to 95% RH and 40 °C until the solid underwent the offset in the baseline, the CCD detector (charge coupled
deliquescence. The resultant clear solution of MM was then device) was cooled to −40 °C and a dark subtraction was
used to obtain the crystals of DH by simultaneous cooling and automatically applied to each spectrum. A laser power of 400
evaporation at 25 °C. A crystal suitable for single crystal X-ray mW was used and 6 scans were accumulated at an exposure
diffraction was mounted on the Mitegen loops or micromesh. time of 10 s each to obtain the Raman spectra. Grams AI
This sample was then placed on the stage and the data were (Thermo, Inc. Waltham, MA) was used for visually monitoring
collected utilizing a Rigaku R-axis curved image plate the data, while, for chemometric analyses, the multivariate
42 DOI: 10.1021/acs.molpharmaceut.7b00694
Mol. Pharmaceutics 2018, 15, 40−52
Molecular Pharmaceutics Article

Figure 2. Crystal structure of DH. The circle indicates the presence of four water molecules per two molecules of miconazole mesylate.

analysis software SIMCA v13 (Umetrics AB, Umeå, Sweden) 1000 and 125 mg/mL respectively. A precalibrated VWR
was used for subsequent data processing. Symphony pH meter equipped with Symphony pH probe
Determination of the Weight Gain (% w/w). About 50 mg (VWR Scientific, Radnor, PA) was used to measure the pH
of AMO powder was weighed before and after exposure to 33, potentiometrically.
43, and 57% RH. The samples were exposed to these humidity Determination of Intrinsic Dissolution Rate (IDR). The IDR
conditions for 5 h to avoid crystallization to the DH. All of various solid forms of MM was determined using a Sirius
samples were analyzed in triplicate. The weight gain (% w/w) InForm instrument (Sirius Analytical, Forest Row, UK). A UV
was then obtained by subtracting the initial weight of the dip probe with 2 mm path length was utilized to monitor the
sample from the final weight of the sample after exposure to concentration of MM as a function of time. The experiment
various RH conditions. was carried out using water as a medium at 25 °C with a stirring
Differential Scanning Calorimetry (DSC) Analysis. To speed of 300 rpm. About 20 mg powder of each solid form of
obtain the thermal profile of various solid forms of MM, a MM was filled in a die with 3 mm diameter. The disk for IDR
Q2000 DSC (TA Instruments, New Castle, DE) was used. The was prepared by compressing the power in a Carver press
instrument was equipped with a refrigerated cooling accessory (Carver Inc., Summit, NJ) at 150 psi for 3 s. The disk
(RCS) (TA Instruments, New Castle, DE) purged with containing the sample was immersed into the solution and UV
nitrogen gas. About 10 mg of sample was sealed into a Tzero spectra were obtained periodically. The amount of MM release
pan with a hermetic Tzero lid (TA Instruments, New Castle, at each time point was calculated using a predetermined
DE). The samples were heated using a heating rate of 10 °C/ calibration curve.
min. The glass transition temperature (Tg) and the onset of Determination of pHmax. The pHmax for various solid forms
melting temperature were determined using the TA Analysis of MM can be calculated based on the following equation.4,26
software (TA Instruments, New Castle, DE). S0
Determination of Solubility. The thermodynamic solubility pH max = pK a + log
of the DH was obtained in triplicate, using the slurry method.25 K sp (1)
An excess amount of DH was allowed to slurry in water for 48
h at 25 °C in a jacketed beaker. Next, the excess solids were Where, the pKa is related to the acid dissociation constant (Ka)
separated utilizing an Optima L-100 XP ultracentrifuge of the protonated drug, S0 is the intrinsic solubility of the free
(Beckman Coulter, Inc., Brea, CA) at 35 000 rpm for 25 min. base, and Ksp is the solubility product for the salt. The
An Agilent 1290 Infinity Series high performance liquid previously reported pKa value of 6.9 for MCZ was used to
chromatography (HPLC) system (Agilent Technologies, calculate pHmax.24
Santa Clara, CA) was then used to determine the concentration
in the supernatant. An Inertsil ODS-3 C18 5 μm, 4.6 × 100 mm
column (GL Sciences Inc., Rolling Hills Estates, CA) was used
■ RESULTS AND DISCUSSION
Preparation and Characterization of Various Solid
with a mixture of 0.1% trifluoroacetic acid in water (50%) and Forms of MM. To check the solid-state purity of the AH salt
acetonitrile (50%) as the mobile phase. A flow rate of 1 mL/ form of MM and the free base form of miconazole (MCZ), X-
min and an injection volume of 10 μL were used. Ultraviolet ray powder diffraction (XRPD) and Fourier transform infrared
detection at 220 nm was used to monitor the elution of the spectroscopy (FTIR) were performed. The X-ray diffraction
compound. The concentration of each sample was obtained by patterns (Figure S1) and FTIR spectra (Figure S2) indicated
applying a calibration curve (R2 value of 0.997). Samples were that the AH salt is present in the pure form without detectable
diluted with mobile phase to obtain concentration values within free base. AH was then used to prepare various solid forms of
the range of the calibration plot. MM. The DSC data on AH revealed a sharp endotherm with
The kinetic solubilities of various solid forms of MM were onset temperature of ∼100 °C. This corresponded to the
also determined visually by adding small quantities of known melting event of the anhydrous salt form of MM. (Figure S3A).
amounts of material to a fixed volume of water until dissolution Therefore, for preparing AMO by the melt quench method, a
ceased. temperature of 115 °C was used to ensure complete melting of
Determination of Saturated Solution pH. The pH of a AH. This newly obtained AMO showed a Tg with midpoint of
saturated solution of CCS, TSPd, and DH was obtained by ∼38 °C, indicating successful formation of the amorphous form
slurrying excess solid in water for 2 days (10% w/v slurry). For of MM (Figure S3B). The XRPD data was in agreement with
AMO and DH, the pH was measured at a concentration of the DSC data, showing a halo, a characteristic feature for an
43 DOI: 10.1021/acs.molpharmaceut.7b00694
Mol. Pharmaceutics 2018, 15, 40−52
Molecular Pharmaceutics Article

Figure 3. Overlay of (A) XRPD patterns and (B) Raman spectra for (a) AMO stored with TSPd at 25 °C 57% RH for 2 days, (b) AH stored with
TSPd at 25 °C 57% RH for 2 days, (c) DH stored with TSPd at 25 °C 57% RH for 2 days, (d) DH only, and (e) MCZ only. In both (A) and (B),
the dotted (2θ = 11.7° or cm−1 = 1506) and dashed (2θ = 15.3° or cm−1 = 1268) lines indicate the position of the unique peak for MCZ and DH,
respectively.

amorphous material. The amorphous material was found to be characteristic to MCZ could be observed either by XRPD or
stable when stored under dry conditions (Figure S4A). Raman spectroscopy. (Figure 3A and B). These results indicate
However, when AMO was exposed to 57% RH and 25 °C that both AMO and AH are prone to disproportionation, while
for 2 days, it gave an XRPD pattern that was different from that the DH appears to be resistant. In addition to undergoing
obtained from either the AH or MCZ forms (Figure S4B). partial disproportionation, both AMO and AH also show some
Similarly, when AH was exposed to 75% RH and 25 °C for 2 conversion to DH. Having established that both AMO and AH
days, it also converted to this unknown form (Figure S4C). The undergo both disproportionation and DH formation, the next
unknown form was suspected to be a hydrated crystal of MM step was to quantitatively determine the kinetics and extent of
that formed at high humidity conditions. To identify the exact these phase transformations. Raman spectroscopy, as the more
nature of this crystalline form, single crystal X-ray diffraction sensitive technique, was selected for quantitative kinetic studies.
analysis was performed on crystals grown from water as a Chemometric Models and Calibration Curves. Raman
solvent system. The hydrated form of MM was identified as a spectroscopy has previously been used to quantitatively study
dihydrate (DH) (Figure 2) and the calculated XRPD pattern disproportionation in powder blends as well as tablets.27 In the
from the single crystal was consistent with that observed for current study, multiple solid-state forms are present during
AMO and AH following storage at 57% RH and 75% RH, disproportionation and/or phase transformation. Therefore,
respectively (Figure S4D). Raman spectroscopy together with a chemometric model were
The particle size distribution analysis of different salt forms utilized to quantify the amount of MCZ produced as a result of
indicated that AH and DH have very similar distributions, while disproportionation and the amount of DH produced as a result
particles of AMO MM are slightly larger (Figures S5 and S6). of phase transformation of either AMO or AH. The calibration
Previous studies have indicated that particle size can impact curves for systems starting with AMO MM (group 1, AMO−
disproportionation.24 Since the observed distribution was DH−MCZ) or AH MM (group 2, AH−DH−MCZ) samples
similar, no special measures were taken for particle size control were prepared separately. First, Raman spectra of the various
in this study. solid forms and excipients were obtained to identify unique
Disproportionation of Different Solid-State Forms. peaks to develop chemometric models for groups 1 and 2. For
After obtaining the AMO, AH, and DH forms of MM and group 1, unique peaks at 1421 cm−1, 1268 cm−1, and 1506 cm−1
performing initial characterization, the next step was to evaluate were found to correspond to AMO, DH, and MCZ respectively
their rate and extent of disproportionation. To qualitatively (Figure 4A), while for group 2, unique peaks at 854 cm−1, 1268
observe the tendency of various solid-state forms of MM to cm−1, and 1506 cm−1 corresponded to AH, DH, and MCZ,
undergo disproportionation, the salt forms were mixed with respectively (Figure 4B). To generate calibration curves,
TSPd followed by storage at 57% RH for 2 days and were various samples with different known molar ratios of AMO−
analyzed by both XRPD and Raman spectroscopy. The XRPD DH−MCZ or AH−DH−MCZ were prepared (Table 1).
patterns for the AMO and TSPd blend upon storage showed For the preparation of calibration curves, each sample was
peaks corresponding to both MCZ and DH. This indicates that freshly prepared in triplicate and stored in an airtight vial prior
AMO mixed with TSPd disproportionates to form crystalline to Raman measurements. For each spectrum, the baseline was
MCZ, but also undergoes phase transformation to crystalline corrected and the second derivative was calculated. For group
DH (Figure 3A). For the AH samples, peaks characteristic of 1, the ratio of peak intensity at 1421 cm−1, 1268 cm−1, and
the DH are clearly visible by XRPD, however MCZ peaks, 1506 cm −1 , corresponding to AMO, DH, and MCZ
although present, are of low intensity. Note that these samples respectively, to that of the 1589 cm−1 peak was determined.
were also characterized using Raman spectroscopy, which For group 2, the ratio of peak intensities at 854 cm−1, 1268
provided orthogonal evidence of MCZ formation in both AMO cm−1, and 1506 cm−1, corresponding to AH, DH, and MCZ,
and AH samples. In contrast, storage of the DH:TSPd blend respectively, to that of the 1589 cm−1 peak (corresponds to
did not result in disproportionation and no evidence of peaks aromatic CC stretching 28 and is not impacted by
44 DOI: 10.1021/acs.molpharmaceut.7b00694
Mol. Pharmaceutics 2018, 15, 40−52
Molecular Pharmaceutics Article

Figure 4. Raman chemometric model development for group 1 (left panel-A, C, and E) and group 2 (right panel-B, D, and F) calibration models. (A
and B) Raman spectra showing unique peak of each solid form and excipients used in group 1 and group 2, for (a) MCZ, (b) AMO (group 1), or
AH (group 2), (d) DH, (d) CCS, and (e) TSPd. (C and D) PCA models for calibration standards. (E and F) Representative PLS models of MCZ
mole% calibration standards showing validation samples (identified by prefix “V’) along with the important statistical parameters.

disproportionation or phase transformation) was determined. transformation.18 Furthermore, the PLS calibration curves
Respective calibration curves for groups 1 and 2 were then were also cross-validated (Figure 5C) utilizing group samples
established by plotting the intensity ratio as a function of their with a similar mole percent ratio as that of the standards in
mole percentage in the mixtures. This data was then subjected triplicate. The reasonable values of root-mean-square error of
to principal components analysis (PCA). The result of the PCA estimation (RMSEE) and root mean squares error of cross
analysis for groups 1 and 2 indicated that combination of first validation (RMSECV) for both group 1 and 2 (Table 2)
principal component (PC1) with the second principal indicates that there is a balance between fitting of the model
component (PC2) captures 96.6% and 99.2% spectral and its predictive power.18,29 The points for calibration and
variations, respectively. In addition, for both groups 1 and 2, validation are consistent indicating the robustness of PLS
no outliers were detected in the Hotelling’s T2 ellipse at 95% models generated. These PLS models were then utilized to
confidence regions in the score plot of PC1-PC2 (Figure 5C quantify both disproportionation and phase transformation of
and D). A PLS calibration was then performed using both PC1 various solid forms of MM.
and PC2 for both groups 1 and 2 (Figure 4E and F). The values Quantitative Disproportionation Study. To study the
of R2Y and Q2 were also found to be appropriate for effect of various solid forms of MM on disproportionation rate
quantifying the amount of disproportionation and phase and extent, binary mixtures of AMO, AH, and DH with TSPd
45 DOI: 10.1021/acs.molpharmaceut.7b00694
Mol. Pharmaceutics 2018, 15, 40−52
Molecular Pharmaceutics Article

Table 1. Mole % Ratio of Various Group 1 and Group 2 Samples Used To Prepare Chemometric Calibration Curve
sample ID mole %
AMO−DH−MCZ (group 1) or AH−DH−MCZ (group 2) AMO (group 1) or AH (group 2) DH MCZ
0−0−100 0 0 100
100−0−0 100 0 0
0−100−0 0 100 0
50−0−50 50 0 50
0−50−50 0 50 50
50−50−0 50 50 0
16−16−68 16 16 68
68−16−16 68 16 16
16−68−16 16 68 16
33.4−33.4−33.4 33.4 33.4 33.4
10−10−80 10 10 80
80−10−10 80 10 10
10−80−10 10 80 10
20−20−60 20 20 60
60−20−20 60 20 20

Figure 5. Disproportionation and phase transformation of various solid forms of MM as a function of time at 57% RH and 25 °C with (A) TSPd and
(B) CCS.

Table 2. Values of Root Mean Square Error of Estimation (RMSEE) and Root Mean Square Error of Cross Validation
(RMSECV) for Calibration Groups 1 and 2
group 1 group 2
component RMSEE RMSECV component RMSEE RMSECV
MCZ mole % 2.5 2.6 MCZ mole % 2.7 2.8
AMO mole % 2.9 3.1 AH mole % 2.9 3.2
DH mole % 2.4 2.5 DH mole % 3.1 3.4

or CCS in a 1:1 ratio (w/w) were prepared. It is known from underwent a much higher extent of disproportionation
previous studies that higher RH will increase the rate and extent compared to AH. The DH form was resistant to disproportio-
of the disproportionation reaction.24 Therefore, to test nation over the period of the study, or the level of
disproportionation at accelerated storage conditions, samples disproportionation was lower than the detection limit (<
were exposed to 57% RH and 25 °C for 25 days. The samples ∼3%). The amount of disproportionation for AMO was about
were analyzed by Raman spectroscopy and the chemometric six times higher when mixed with TSPd as compared to CCS.
models were applied to determine the amount of MCZ Similarly, the amount of disproportionation for AH was also
produced as a result of disproportionation and extent of higher (∼three times) with TSPd as compared to CCS. It is
formation of DH as a result of phase transformation. The expected that, in the presence of moisture, the excipient with
observed mole % of MCZ and DH formed with TSPd and CCS the higher saturated solution pH will lead to a higher
are shown as a function of time in Figure 5A and B, microenvironment pH in a powder blend.12 This increase in
respectively. the microenvironmental pH is known to affect the rate and
The data show that at 57% RH, both AMO and AH extent of disproportionation.12 To understand why the TSPd
underwent disproportionation with TSPd and CCS. AMO blends showed a higher rate and extent of disproportionation
46 DOI: 10.1021/acs.molpharmaceut.7b00694
Mol. Pharmaceutics 2018, 15, 40−52
Molecular Pharmaceutics Article

Figure 6. Disproportionation and phase transformation of various solid forms of MM as a function of time at 43% RH and 25 °C with (A) TSPd and
(B) CCS.

Figure 7. Disproportionation and phase transformation of various solid forms of MM as a function of time at 33% RH and 25 °C with (A) TSPd and
(B) CCS.

for all samples, saturated solution pH of TSPd and CCS were a function of time. This shows that phase transformation of
analyzed. The result indicated that the TSPd has a very high AMO and AH to DH occurs during the disproportionation
saturated solution pH of 12.2 ± 0.1 compared to that of the study. Further, due to the resistance of the DH form to
CCS which was found to be 5.4 ± 0.2. In addition, the proton disproportionation, rapid conversion of AMO and AH to the
accepting (buffering) capacity of the excipients can also impact DH at higher humidity conditions would hinder disproportio-
their ability to cause API disproportionate.13 The proton nation. If this is true, then counterintuitively, the extent of
accepting capacity of the excipients used in this study depends disproportionation might be higher at a lower RH where DH
on the amount of Na ions available for exchange with the formation is expected to be slower. To test this hypothesis, we
proton from the API salt. In case of the CCS, according to the also monitored disproportionation of AMO, AH, and DH at
manufacturer,30 the Na content is 6.34% w/w. Therefore, in 50 43% RH and 25 °C with results summarized in Figure 6A (with
mg of CCS there will be 3.2 mg of Na, which corresponds to TSPd) and Figure 6B (with CCS).
0.138 mM of Na. For TSPd, the corresponding amount of Na is Similar to the results at 57% RH, the AMO showed a higher
0.914 mM of Na. Consequently, TSPd has a far greater proton extent of disproportionation with either TSPd or CCS than the
accepting capability as compared to CCS, although both AH form. DH did not show any detectable disproportionation
excipients have sufficient proton accepting capacity to with either TSPd or CCS. The data also showed that, for both
completely convert MM to the free base form. Thus, the the TSPd and CCS, the extent of disproportionation at 43%
higher saturated solution pH and proton accepting capacity are RH is higher than that obtained at 57% RH. To check if
consistent with the observation that the TSPd blends showed a lowering of the storage RH would further increase the extent of
higher extent of disproportionation. disproportionation, the study was also performed at 33% RH
The chemometric analysis also indicated that the amount of and 25 °C (Figure 7). Interestingly, the data revealed that the
DH in binary mixtures of TSPd with AMO and AH increases as extent of disproportionation was lower than that observed at
47 DOI: 10.1021/acs.molpharmaceut.7b00694
Mol. Pharmaceutics 2018, 15, 40−52
Molecular Pharmaceutics Article

Figure 8. Disproportionation and phase transformation of pure solid forms of MM as a function of time at 25 °C monitored at (A) 57% RH, (B)
43% RH, and (C) 33% RH.

Figure 9. Extent of disproportionation and DH formation from AMO and AH at various % RH after 48 h. Extent of MCZ formation for samples
with (A) TSPd and (B) CCS. Extent of DH formation for samples with (C) TSPd and (D) CCS. (E) Extent of DH formation for pure AMO and
AH.

43% RH, but higher as compared to 57% RH. In addition, both as compared to 43% RH, the extent of disproportionation was
AMO and AH showed phase transform to DH, indicating that found to be lower at 33% RH. This could be due to lower
the critical water activity for conversion from AH to DH mobility in the system at lower % RH, or simply a consequence
formation is less than 33% RH. Despite slower DH formation of the lower water availability.
48 DOI: 10.1021/acs.molpharmaceut.7b00694
Mol. Pharmaceutics 2018, 15, 40−52
Molecular Pharmaceutics Article

To confirm the crystalline nature of the free form, MCZ, This is further exemplified by considering that the extent of DH
produced as a result of disproportionation of AMO and AH, formation was highest for the powders with no excipients where
XRPD analysis was performed for selected samples. Character- there was no disproportionation, intermediate for samples with
istic reflections of both MCZ and DH were observed and no CCS, and lowest for samples with TSPd, where greater
evidence of an intermediate amorphous free base form was disproportionation is occurring. However, TSPd samples
detected (Figure S7A−C). It can be noted that the plateau undergo disproportionation to a higher extent than CCS
values for the extent of conversion differ when starting with the samples, even though CCS is an amorphous excipient, and
AMO form versus the AH form, even though the final products therefore might be expected to be more reactive. Clearly, the
in both cases are a mixture of DH and MCZ. This suggests that more basic nature and higher proton accepting capacity of
the systems are not at true thermodynamic equilibrium at the TSPd outweigh the amorphous nature of CCS. For the specific
end of the experiment. Factors that limit the extent of case of the AMO:TSPd sample, disproportionation is very fast
conversion leading to the different plateau values are not leading to substantial conversion to MCZ, consequently there is
currently well understood but could include: (1) formation of a less residual AMO available for conversion to DH. Switching to
MCZ layer on the salt particles, which acts as a barrier CCS results in a slowing of disproportionation and hence more
preventing further proton transfer; (2) accessible excipient conversion to the DH. The competition between disproportio-
groups are fully neutralized by protons from MM; and (3) all nation and DH formation provides an explanation for the
remaining AMO or AH solid state forms have transformed to observations that the extent of disproportionation was highest
the nonreactive DH form and hence no more AMO/AH is at 43% RH. This is readily explained by the lower amount of
available for disproportionation. DH formation at 43% RH compared to 57% RH (Figure 9C
Control samples consisted of MCZ or MM alone (AMO, and D), allowing more opportunity for conversion to the free
AH, or DH), and a 50:50 blend of MCZ and MM DH stored at base, rather than forming the disproportionation-resistant DH.
25 °C and 57% RH, 43% RH, or 33% RH. Based on the Raman These results differ from those of Hsieh et al., who showed that
spectroscopy analyses, AMO, AH, and DH did not show any greater disproportionation of anhydrous MM occurred at 57%
disproportionation at any condition up to 25 days. However, RH, followed by 43% RH and 33% RH.24 This discrepancy
both AMO and AH converted to the DH form (Figure 8) most likely arises because the solid state form of anhydrous
which was confirmed by XRPD analysis (Figure S7D). Neither MM used in the current study was not the same as that used in
DH nor MCZ or their blend showed any changes in solid state previous studies.12,24 Upon further investigation, we found that
form following storage (Figures S8 and S9). In addition, the MM desolvation at room temperature (previous studies) versus
XRPD data also showed that there were no changes in the 65 °C (current study) resulted in different anhydrous forms
powder pattern for the neat TSPd stored at different MM. Raman spectra and PXRD patterns of these two forms are
conditions, indicating the stability of TSPd (Figure S7E). shown in Figure S10.
A comparison of the extent of disproportionation and phase Interestingly, even though the DH formation is lower at 33%
transformation i.e. DH formation, after 48 h of storage at RH than at 43% RH, the extent of disproportionation is also
various humidity conditions (Figure 9) indicated that the extent decreased. At low % RH, due to a low water content, the
of disproportionation for AMO systems was much higher than molecular mobility of the amorphous salt is expected to be
observed for AH in binary mixtures containing TSPd or CCS at reduced, hindering the process of disproportionation. To
all storage conditions (Figure 9A and B). Similarly, the extent monitor the effect of water on the mobility, AMO was stored
of DH formation was also higher for AMO as compared to AH at different RHs and the weight gain and Tg were measured.
for all conditions, except in the binary mixture of AMO:TSPd, The results indicated that, due to the lower water content at
where the extent of DH formation was lower than that of 33% RH, the Tg of AMO was higher than for the sample stored
AH:TSPd, for all storage conditions (Figure 9C−E). These at 43% RH, indicating lower mobility for the former sample
results suggest that the AMO form is more prone to undergo (Figures 10 and S11). However, the Tg of the salt is low
disproportionation and also phase transformation to DH. This relative to the storage temperature for all RH storage
result is consistent with previous research which indicates that conditions and therefore mobility is probably not the limiting
the rate of the reaction, in general, will be faster in amorphous factor in dictating the extent of disproportionation. Rather, the
systems compared to its crystalline phase under a given set of lower water content of the sample at 33% RH is probably
conditions.31 responsible for the lower observed extent of disproportionation.
The effect of relative humidity on extent of DH formation
and disproportionation was also evaluated. The analysis
confirms that the extent of disproportionation for all samples
(AMO and AH with TSPd or CCS) was highest at 43% RH,
while they were similar at 57% RH and 33% RH (Figure 9A
and B). In contrast, extent of DH formation was highest at 57%
RH, and slowest at 33% RH (Figure 9C−E).
A comparison of the extent of DH formation and
disproportionation revealed that the extent of DH formation
for AMO:TSPd was lower than the extent of disproportiona-
tion at all storage conditions (Figure 9A and C). In contrast,
the extent of DH formation for AH:TSPd, AMO:CCS, and
AH:CCS was higher than their extent of disproportionation
(Figure 9B and D). This inverse relation between the extent of
DH formation and disproportionation indicates that there is a Figure 10. Tg and weight gain of AMO as a function of relative
competition between DH formation and disproportionation. humidity.

49 DOI: 10.1021/acs.molpharmaceut.7b00694
Mol. Pharmaceutics 2018, 15, 40−52
Molecular Pharmaceutics Article

Solubility and pHmax. Disproportionation is a type of These trends in IDR follow the same order as for the kinetic
acid−base reaction that is assumed to occur between species solubility experiments.
mobilized in an adsorbed surface layer of water present on The results of the solubility study are consistent with the
particles. It is well-known that solution-state reactions are disproportionation data which showed that AMO form has the
typically faster than solid-state reactions and indeed, we observe highest amount of disproportionation, followed by AH, while
that disproportionation is very rapid. If we assume that the DH was found to be resistant disproportionation. Based on
disproportionation occurs in an adsorbed surface layer of the kinetics solubility values obtained, the values of pHmax were
water, then for a given salt, it would be anticipated that a more calculated using eq 2. Results are shown in Table 3, and a
soluble solid-state form would have a higher tendency to schematic pH solubility profile for each solid-state form is
convert to the free base. Therefore, we expect to see trends shown in Figure 11B. Because of the different apparent
between the solubility of the solid form and the observed extent solubility values, each solid-state form yields a different
of disproportionation. To better evaluate this hypothesis, the apparent pHmax. AMO has the lowest apparent pHmax followed
solubility of various solid forms of MM was measured. by AH and DH. It is known that the lower the value of pHmax,
Both the thermodynamic and kinetic solubilities of various the greater the driving force for disproportionation. Thus, the
solid forms of MM were determined and are presented in Table difference in the kinetic solubility values of the different solid-
3. When the DH was slurried in water, no change in solid form state forms helps explain why AMO undergoes a greater extent
of disproportionation than AH, and why AH in turn shows an
Table 3. Thermodynamic and Kinetic Solubilities of Various increased tendency to convert to the free base relative to DH.
Solid Forms of MM However, the lack of detectable disproportionation of DH
cannot be explained based on consideration of pHmax values.
solid kinetic
form of thermodynamic solubility calculateda solid form Thus, even though the pHmax of the DH was found to be 2.02,
MM solubility mg/mL mg/mL pHmax after 48 h which is very low compared to the saturated pH of both TSPd
AMO 1125 ± 25 0.65 ± 0.01b dihydrate and CSS, the DH form did not show any disproportionation.
AH 115 ± 10 1.64 ± 0.06b dihydrate There could be multiple reasons behind this phenomenon. It is
DH 48 ± 1 50 ± 2 2.02 ± 0.01 dihydrate possible that solvation of surface DH molecules followed by
a
Calculated utilizing the pKa = 6.9 and Solubility of free base = 9.98 × disproportionation results in a layer of free base on the outer
10−04 mg/mL.32 bThese values are apparent pHmax values as they were surface of DH particles that can prevent further reaction
calculated from kinetic solubility data. whereby this low extent of disproportionation is undetected.
Alternatively, if the DH is not a salt, then also it might not
disproportionate. However, the crystal structure clearly
was observed (Figure S12). The thermodynamic solubility of indicates the hydrogen from the MSA is transferred to the
DH was found to be 48 mg/mL. The AH was found to convert nitrogen of the MCZ molecule (Figure 12), confirming that
to the DH when slurried in water. To evaluate differences in the DH is indeed a salt. A detailed analysis of crystal structure of
solubility of the different forms, kinetic solubility measurements DH reveals that the MCZ molecule does not directly form a
were also performed. In line with expectations, AMO has the salt bridge with the mesylate ion (Figure 12). The MCZ
highest apparent solubility, while the DH form has the lowest molecule forms a hydrogen bond with a water molecule, which
solubility. The apparent solubility of AMO is about an order of forms a second hydrogen bond with another water molecule
magnitude higher than that of AH, while the thermodynamic and this water molecule then forms a hydrogen bond with
solubility of DH is about half of the apparent solubility of AH. mesylate ion. Consequently, the MCZ molecule is connected to
Intrinsic dissolution rate (IDR) measurements were also MSA by intermediate water molecules. Due to this unique and
performed to confirm trends seen with the kinetic solubility stable crystal lattice arrangement, it is possible that proton
measurements. The data indicated that AMO had the highest transfer is limited by structural features, preventing dispro-
IDR of 15 μg/s/cm2, followed by AH and DH which have IDR portionation from occurring to a detectable amount. Clearly the
of 3 μg/s/cm2 and 2 μg/s/cm2, respectively (Figure 11A). role of crystal structure in disproportionation reactions needs to

Figure 11. (A) Intrinsic dissolution rate (IDR) for various solid forms of MM measured at 25 °C and (B) schematic pH solubility profile indicating
pHmax of various solid forms along with pKa of MCZ and saturated solution pH of excipients.

50 DOI: 10.1021/acs.molpharmaceut.7b00694
Mol. Pharmaceutics 2018, 15, 40−52
Molecular Pharmaceutics Article

Detailed methods, experimental details, XRPD patterns ,

FTIR spectrum, DSC traces, polarized light microscopic
images, particle size distribution, and Raman spectra
(PDF)
Accession Codes
CCDC 1568272 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; Fax: + 44 1223 336033.

■ AUTHOR INFORMATION
Corresponding Author
*Phone: 765-496-2775; Fax: 765-494-6545; E-mail: lstaylor@
Figure 12. Hydrogen bonding pattern in DH form of MM. Hydrogen purdue.edu.
bonds of interest are represented by a dotted blue line along with their
respective bond distances. ORCID
Mitulkumar A. Patel: 0000-0002-9309-6288
be further investigated given this interesting observation around Lynne S. Taylor: 0000-0002-4568-6021
DH resistance to conversion.

■
Notes
The authors declare no competing financial interest.

■
CONCLUSIONS
Using miconazole mesylate as a model pharmaceutical salt, we ACKNOWLEDGMENTS
have demonstrated that different solid forms have varying
This research was supported by Pfizer Inc. The authors wish to
susceptibilities to disproportionation when mixed with basic
thank Marcus Ewing for his help in the preparation of the
excipients and stored at moderate relative humidity conditions.
miconazole mesylate. In addition, we would like to acknowl-
Importantly, the amorphous salt was found to show a higher
edge Parag Mukhopadhyay and Pankaj Doshi for providing
amount of disproportionation than crystalline salts. Interest-
their suggestions to improve the manuscript. Matthias Zeller is
ingly, the crystalline anhydrate salt underwent conversion to the
thanked for assistance with the single crystal determination.

■
free base, albeit to a lower extent than the amorphous form,
whereas the crystalline dihydrate salt did not show any
detectable disproportionation. This observation cannot be REFERENCES
explained based on pHmax differences between the anhydrate (1) Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J.
and dihydrate, since solubility differences were relatively minor. Experimental and computational approaches to estimate solubility and
It is thought that the structure of the dihydrate renders this permeability in drug discovery and development settings. Adv. Drug
solid-state form less susceptible to disproportionation. In Delivery Rev. 2012, 64, 4−17.
(2) Bleicher, K. H.; Böhm, H.-J.; Müller, K.; Alanine, A. I. Hit and
addition to partial disproportionation, both the amorphous lead generation: beyond high-throughput screening. Nat. Rev. Drug
and anhydrate salts also converted into the dihydrate salt Discovery 2003, 2, 369.
crystal. The competition between dihydrate formation and (3) Thayer, A. M. Finding Solutions. Chem. Eng. News 2010, 88, 13−
disproportionation led to a nonintuitive relationship between 18.
the extent of free base formation and storage relative humidity. (4) Serajuddin, A. T. M. Salt formation to improve drug solubility.
This work highlights the need to consider the impact of salt Adv. Drug Delivery Rev. 2007, 59, 603−616.
solid-state form when considering salt stability to conversion to (5) Amidon, G. L.; Lennernäs, H.; Shah, V. P.; Crison, J. R. A
the free base form. During manufacturing, any processing theoretical basis for a biopharmaceutic drug classification: the
operations that create amorphous content in a nominally correlation of in vitro drug product dissolution and in vivo
crystalline salt, e.g. surface disordering, render the salt more bioavailability. Pharm. Res. 1995, 12, 413−420.
(6) Mü l ler, C. E. Prodrug approaches for enhancing the
susceptible to disproportionation in the presence of basic bioavailability of drugs with low solubility. Chem. Biodiversity 2009,
excipients. Furthermore, amorphous salts need to be evaluated 6, 2071−2083.
not only for crystallization tendency, but also for susceptibility (7) Savjani, K. T.; Gajjar, A. K.; Savjani, J. K. Drug solubility:
to conversion to the free form. By understanding role of the importance and enhancement techniques. ISRN Pharm. 2012, 2012,
various solid forms and excipient properties, together with a 1−10.
mechanistic understanding of disproportionation, rationally (8) Williams, H. D.; Trevaskis, N. L.; Charman, S. A.; Shanker, R. M.;
designed and robust formulations of pharmaceutical salts can be Charman, W. N.; Pouton, C. W.; Porter, C. J. Strategies to address low
produced. drug solubility in discovery and development. Pharmacol. Rev. 2013,

■
65, 315−499.
ASSOCIATED CONTENT (9) Paulekuhn, G. S.; Dressman, J. B.; Saal, C. Trends in active
pharmaceutical ingredient salt selection based on analysis of the
*
S Supporting Information
orange book database. J. Med. Chem. 2007, 50, 6665−6672.
Supporting Information is available free of charge via the (10) Hsieh, Y.-L.; Yu, W.; Xiang, Y.; Pan, W.; Waterman, K. C.;
Internet at The Supporting Information is available free of Shalaev, E. Y.; Shamblin, S. L.; Taylor, L. S. Impact of sertraline salt
charge on the ACS Publications website at DOI: 10.1021/ form on the oxidative stability in powder blends. Int. J. Pharm. 2014,
acs.molpharmaceut.7b00694. 461, 322−330.

51 DOI: 10.1021/acs.molpharmaceut.7b00694
Mol. Pharmaceutics 2018, 15, 40−52
Molecular Pharmaceutics Article

(11) Bastin, R. J.; Bowker, M. J.; Slater, B. J. Salt selection and (31) Shalaev, E. Y.; Zografi, G. How does residual water affect the
optimization procedures for pharmaceutical new chemical entities. Org. solid-state degradation of drugs in the amorphous state? J. Pharm. Sci.
Process Res. Dev. 2000, 4, 427−435. 1996, 85, 1137−1141.
(12) Guerrieri, P.; Taylor, L. S. Role of Salt and Excipient Properties (32) Hsieh, Y.-L.; Merritt, J. M.; Yu, W.; Taylor, L. S. Salt Stability −
on Disproportionation in the Solid-State. Pharm. Res. 2009, 26, 2015− The Effect of pHmax on Salt to Free Base Conversion. Pharm. Res.
2026. 2015, 32, 3110−3118.
(13) John, C. T.; Xu, W.; Lupton, L. K.; Harmon, P. A. Formulating
weakly basic HCl salts: relative ability of common excipients to induce
disproportionation and the unique deleterious effects of magnesium
stearate. Pharm. Res. 2013, 30, 1628−1641.
(14) Thakral, N. K.; Behme, R. J.; Aburub, A.; Peterson, J. A.; Woods,
T. A.; Diseroad, B. A.; Suryanarayanan, R.; Stephenson, G. A. Salt
Disproportionation in the Solid State: Role of Solubility and
Counterion Volatility. Mol. Pharmaceutics 2016, 13, 4141−4151.
(15) Christensen, N. P. A.; Rantanen, J.; Cornett, C.; Taylor, L. S.
Disproportionation of the calcium salt of atorvastatin in the presence
of acidic excipients. Eur. J. Pharm. Biopharm. 2012, 82, 410−416.
(16) Stephenson, G. A.; Aburub, A.; Woods, T. A. Physical stability of
salts of weak bases in the solid-state. J. Pharm. Sci. 2011, 100, 1607−
1617.
(17) Unger, E. F. Weighing benefits and risksthe FDA’s review of
prasugrel. N. Engl. J. Med. 2009, 361, 942−945.
(18) Nie, H.; Xu, W.; Ren, J.; Taylor, L. S.; Marsac, P. J.; John, C. T.;
Byrn, S. R. Impact of Metallic Stearates on Disproportionation of
Hydrochloride Salts of Weak Bases in Solid-State Formulations. Mol.
Pharmaceutics 2016, 13, 3541−3552.
(19) Wray, P. S.; Sinclair, W. E.; Jones, J. W.; Clarke, G. S.; Both, D.
The use of in situ near infrared imaging and Raman mapping to study
the disproportionation of a drug HCl salt during dissolution. Int. J.
Pharm. 2015, 493, 198−207.
(20) Skrdla, P. J.; Zhang, D. Disproportionation of a crystalline citrate
salt of a developmental pharmaceutical compound: Characterization of
the kinetics using pH monitoring and online Raman spectroscopy plus
quantitation of the crystalline free base form in binary physical
mixtures using FT-Raman, XRPD and DSC. J. Pharm. Biomed. Anal.
2014, 90, 186−191.
(21) Nie, H.; Xu, W.; Taylor, L. S.; Marsac, P. J.; Byrn, S. R.
Crystalline solid dispersion-a strategy to slowdown salt disproportio-
nation in solid state formulations during storage and wet granulation.
Int. J. Pharm. 2017, 517, 203.
(22) Merritt, J. M.; Viswanath, S. K.; Stephenson, G. A.
Implementing Quality by Design in Pharmaceutical Salt Selection: A
Modeling Approach to Understanding Disproportionation. Pharm. Res.
2012, 30, 203−217.
(23) Hsieh, Y.-L.; Merritt, J. M.; Yu, W.; Taylor, L. S. Salt stability−
the effect of pHmax on salt to free base conversion. Pharm. Res. 2015,
32, 3110−3118.
(24) Hsieh, Y.-L.; Taylor, L. S. Salt Stability - Effect of Particle Size,
Relative Humidity, Temperature and Composition on Salt to Free
Base Conversion. Pharm. Res. 2015, 32, 549−561.
(25) Patel, M. A.; Kaplan, K.; Yuk, S. A.; Saboo, S.; Melkey, K.;
Chadwick, K. Utilization of Surface Equilibria for Controlling
Heterogeneous Nucleation: Making the “Disappeared” Polymorph of
3-Aminobenzensulfonic Acid “Reappear. Cryst. Growth Des. 2016, 16,
6933−6940.
(26) Bogardus, J. B.; Blackwood, R. K. Solubility of Doxycycline in
Aqueous Solution. J. Pharm. Sci. 1979, 68, 188−194.
(27) Nie, H.; Liu, Z.; Marks, B. C.; Taylor, L. S.; Byrn, S. R.; Marsac,
P. J. Analytical approaches to investigate salt disproportionation in
tablet matrices by Raman spectroscopy and Raman mapping. J. Pharm.
Biomed. Anal. 2016, 118, 328−337.
(28) Gupta, A.; Kar, H. K. Solid state compatibility studies of
miconazole using thermal and spectroscopic methods. Advances in
Analytical Chemistry 2015, 5, 51−55.
(29) Taday, P. F. Applications of terahertz spectroscopy to
pharmaceutical sciences. Philos. Trans. R. Soc., A 2004, 362, 351−364.
(30) FMC-biopolymer Sodium content of Ac-Di-Sol. http://www.
fmcbiopolymer.com/Portals/Pharm/Content/Docs/
ADS%20Bulletin%20Sodium%20DS.pdf.

52 DOI: 10.1021/acs.molpharmaceut.7b00694
Mol. Pharmaceutics 2018, 15, 40−52