Solid-state characterization of novel active pharmaceutical ingredients: Cocrystal of a salbutamol hemiadipate salt with adipic acid (2:1:1) and salbutamol hemisuccinate salt

Article abstract of DOI:10.1002/jps.22569

The production of salt or cocrystalline forms is a common approach to alter the physicochemical properties of pharmaceutical compounds. The goal of this work was to evaluate the impact of anion choice (succinate, adipate, and sulfate) on the physicochemic

Full text of DOI:10.1002/jps.22569

Solid-State Characterization of Novel Active Pharmaceutical
Ingredients: Cocrystal of a Salbutamol Hemiadipate Salt with
Adipic Acid (2:1:1) and Salbutamol Hemisuccinate Salt
KRZYSZTOF J. PALUCH,1 LIDIA TAJBER,1 CURTIS J. ELCOATE,2 OWEN I. CORRIGAN,1 SIMON E. LAWRENCE,2
ANNE MARIE HEALY1
1School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, College Green, Dublin 2, Ireland
2Department of Chemistry, Analytical and Biological Chemistry Research Facility, University College Cork, Cork, Ireland
Received 27 December 2010; revised 21 February 2011; accepted 14 March 2011
Published online 6 April 2011 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.22569
ABSTRACT: The production of salt or cocrystalline forms is a common approach to alter
the physicochemical properties of pharmaceutical compounds. The goal of this work was to
evaluate the impact of anion choice (succinate, adipate, and sulfate) on the physicochemical
characteristics of salbutamol forms. Novel crystals of salbutamol were produced by solvent
evaporation: a cocrystal of salbutamol hemiadipate with adipic acid (salbutamol adipate, SA),
salbutamol hemisuccinate tetramethanolate (SSU.MeOH), and its desolvated form (SSU). The
crystalline materials obtained were characterized using thermal, X-ray, nuclear magnetic reso-
nance, Fourier transform infrared spectroscopy, dynamic vapor sorption (DVS), and elemental
analysis. The crystal forms of SA and SSU.MeOH were determined to be triclinic, (P¯i), and
monoclinic, (P21/n), respectively. DVS analysis confirmed that SSU and SA do not undergo hy-
dration under increased relative humidity. Both thermal and elemental analyses confirmed the
stoichiometry of the salt forms. The aqueous solubilities of SA and SSU were measured to be
82 2 mg/mL (pH 4.5 0.1) and 334 13 mg/mL (pH 6.6 0.1), respectively. Measured values
corresponded well with the calculated pH solubility profiles. The intrinsic dissolution rate of
cocrystallized SA was approximately four times lower than that of SSU, suggesting its use as
an alternative to more rapidly dissolving salbutamol sulfate. © 2011 Wiley-Liss, Inc. and the
American Pharmacists Association J Pharm Sci 100:3268–3283, 2011
Keywords: cocrystals; crystal structure; desolvation; dissolution rate; solubility; solvate;
thermal analysis; water sorption; X-ray powder diffraction
INTRODUCTION
Sepracor Inc., Marlborough, Massachusetts, USA).
Although some other salbutamol salts have been re-
ported in the literature, that is, ethanolated salbu-
tamol adipate and salbutamol stearate,2 to date only
two crystal structures are reported in the Cambridge
Structural Database (CSD): salbutamol base (SB)3
and SS.4 Information about the solid-state nature of
other forms of salbutamol is sparse.
From a pharmaceutical point of view, different
solid-state characteristics of salt forms can result in
different in vitro solubility and dissolution proper-
ties, which, in turn, can result in an alteration of
the in vivo activity of the active pharmaceutical in-
gredient (API). In particular, for pulmonary delivery,
possibilities for modification of the dissolution profile
of the API from a formulation point of view are lim-
ited due to restrictions in terms of excipients that are
regarded as safe for pulmonary use, and may result
Salbutamol is a $2-mimetic used as a bronchodilator,
which is presented as a ( ) racemic mixture in phar-
maceutical inhalers (propellant based and dry pow-
der), nebules, injections, syrups, and tablets, includ-
ing controlled-release forms.1 The hemisulfate salt
[commonly referred to as salbutamol sulfate (SS)] is
the most common form of salbutamol used in phar-
maceutical products; however, the (R) salbutamol hy-
drochloride form is also available in the market as
an inhalation solution (XopenexTM , manufactured by
Additional Supporting Information may be found in the online
version of this article. Supporting Information
Correspondence to: Anne Marie Healy (Telephone: +353-1-896-
1444; Fax: + 353-1-896-2783; E-mail: healyam@tcd.ie)
Journal of Pharmaceutical Sciences, Vol. 100, 3268–3283 (2011)
© 2011 Wiley-Liss, Inc. and the American Pharmacists Association
3268
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SOLID-STATE CHARACTERIZATION OF NOVEL APIS
3269
in additional costs and regulatory obstacles associ-
ated with the development of a new drug product.
This may be avoided by the direct production of alter-
native crystalline forms of the API with the desired
solubility and dissolution profiles. The marketed solid
dosage forms contain only SS, which is freely soluble
in water.5 The advantage of prolonged-release tablets
containing SS was reported in clinical studies.6 New
prolonged-release oral dosage forms containing SS in-
clude hard capsules, VentmaxTM (Chiesi Ltd., Cheadle,
UK), and tablet forms: Volmax CRTM (GlaxoSmithK-
line plc, London, UK) and Vospire ERTM (Teva Phar-
maceuticals, North Wales, Pennsylvania, USA).7 Both
prolonged-release capsules and tablets containing SS
acid is currently used to produce salts of piper-
azine (EntacylTM ) and spiramycine (RovamycineTM
injectable form).11 Succinic acid is used to form salts of
benfurodil, bamethan, chloramphenicol, cibenzoline,
deanol, doxylamine, ergotamine, loxepine, metopro-
lol, oxaflumazine, sumatriptan, and iron (FeII).11
MATERIALS
Salbutamol base was obtained from CHEMOS GmbH
(Regenstauf, Germany). Adipic acid and succinic
acid (both 99%+ grade) were obtained from Sig-
ma–Aldrich (Dublin, Ireland). High-performance liq-
uid chromatography (HPLC) grade methanol was
obtained from Fischer Scientific (Dublin, Ireland).
Deionized water was obtained from a Purite Prestige
Analyst HP water purification system (Purite Ltd.,
Thame, UK). Potassium bromide (KBr, FTIR grade)
was obtained from Sigma–Aldrich (Dublin, Ireland).
Deuterated dimethyl sulphoxide (DMSO-d6) was ob-
tained from Apollo Scientific Limited (Stockport, UK),
and paraffin wax was obtained from BDH Laboratory
Supplies (Poole, UK). All other chemicals were of an-
alytical grade and used without further purification.
have monographs in the British Pharmacopeia.8
A
transdermal delivery patch of SS was also developed.9
In this study, we investigated the impact of re-
placing the sulfate anion in the SS salt structure by
an organic dicarboxylic acid: either the four-carbon
chain, succinic (butanedioic) acid, or the six-carbon
chain, adipic (hexanedioic) acid, on the physicochemi-
cal characteristics of the API. These two organic acids
were chosen in order to investigate the impact of small
changes in the chemical structure of the coformer
on the physicochemical properties of the resulting
salbutamol forms. A reasonable correlation between
the melting points of organic coformers and the re-
sulting salts was previously reported for diclofenac.10
The authors also observed a trend between the salt
melting point and the logarithm of the solubility. The
reported melting points of adipic and succinic acids
are approximately 151◦C–154◦C and approximately
185◦C–187◦C, respectively11; hence, it may be hypoth-
esized that the succinate would have a lower solubility
than the adipate. On the contrary, increasing the hy-
drophilicity of the counterion as a means of increasing
the water solubility of the resultant salt has been pro-
posed and investigated for a series of erythromycin
salts.12 The calculated log Ps of adipic and succinic
acid are 0.356 and −0.655 respectively,13 indicating
that a salt of adipic acid may be less soluble than that
of succinic acid. The study performed by Li et al.14 suc-
cessfully investigated the possibility of forming ionic
(salts) or neutral (cocrystals) complexes of a hetero-
cyclic base (an ErbB2 inhibitor for the treatment of
cancer) with dicarboxylic acids comprising succinate,
malonate, and maleate coformers. The acids (adipic
and succinic) used in the current study have similar
pKa values. The pKa1 and pKa2 for succinic acid are
4.21 and 5.64, respectively,11 and for adipic acid these
are 4.44 and 5.44, respectively.11 As pKa values of
salbutamol are 9.1 and 10.4,15 it was expected that
the new forms of the API would be novel 1:1 salts of
salbutamol.
METHODS
Crystallization Studies
Attempts were made to crystallize salbutamol with
adipic acid and succinic acid by solvent evaporation
from ethanol, methanol, and water. The tested mo-
lar ratios of salbutamol to the acid were: 1:2, 1:1, and
2:1 for each solvent, respectively. It was observed that
successful crystallization was achieved only for salbu-
tamol mixed with adipic acid in 1:1 molar ratio using
methanol or water as the solvent, and for salbuta-
mol and succinic acid mixed in 2:1 molar ratio using
methanol (details of the procedure are described be-
low). Other combinations resulted in either crystal-
lization of one or two of the components separately or
in the production of a glassy/amorphous material.
The crystals subsequently used for single-crystal
X-ray and other analyses were prepared from satu-
rated solutions, which were obtained by introducing
an excess of raw material into the appropriate sol-
vent at ambient conditions and shaking for 1 h on a
R
WhirliMixerꢀ (Fisons Scientific Equipment, Lough-
borough, UK). Ten milliliters of the suspension ob-
tained was filtered through a 0.22-:m membrane fil-
ter into a glass vial, which was kept in a glove box
(Clean Sphere CA 100, Safetech Ltd.) under constant
nitrogen flow at room temperature (20◦C–23◦C). The
moisture content in this controlled environment was
less than 1% of relative humidity (RH).
Dry nitrogen flow and temperature control were
provided to maintain reproducible conditions of
solvent evaporation. Crystallization of salbutamol
Both acids are generally recognized as safe16,17
by the US Food and Drug Administration and
listed in the European Pharmacopeia.5 Adipic
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PALUCH ET AL.
adipate (SA) from methanol resulted each time in
a very rapid nucleation of the crystals. Modifica-
tion of the environmental conditions, including slow-
ing down the evaporation rate of methanol and de-
creasing the temperature, did not retard the crystal
growth. Very small crystals with crystal defects (in-
clusions) were not of sufficiently good quality to be
analyzed by single-crystal X-ray analysis. A change of
the solvent to water resulted in slow crystal growth
and good quality crystals of SA, with a powder X-ray
diffraction (PXRD) pattern consistent with that ob-
tained for crystals produced from methanol; hence,
the SA crystals obtained from water were later used
for single-crystal X-ray analysis.
CCDC 801059 (SA) and 801060 (SSU.MeOH) con-
tain the supplementary crystallographic data for this
paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Center
via www.ccdc.cam.ac.uk/data request/cif.
Powder X-Ray Diffraction
Powder X-ray diffraction analysis was conducted us-
ing a Rigaku Miniflex II desktop X-ray diffractometer
(Rigaku, Tokyo, Japan) fitted with an Ilaskris cooling
unit operating at 30 kV and 15 mA. Ni-filtered Cu K"
radiation (λ = 1.5408 Å) was used. Room temperature
measurements were recorded for the range 5◦–40◦ 2θ
at a step size of 0.05◦/s.20
Differential Scanning Calorimetry
Preparation of Salbutamol Adipate and Succinate
Differential scanning calorimetry (DSC) experiments
were performed using a Mettler Toledo DSC 821e
(Mettler Toledo, Greifensee, Switzerland) with a re-
frigerated cooling system, LabPlant RP-100. Nitrogen
was used as the purge gas. Aluminum sample holders
were sealed with a lid and pierced to provide three
vent holes. Sample volume was sufficient to provide
proper contact between the powder and the bottom of
the pan, and sample weight was at least 5 mg. DSC
measurements were carried out at a heating/cooling
rate of 10◦C/min.21 The DSC system was controlled by
Mettler Toledo STARe software (version 6.10) work-
ing on a Windows NT operating system. The unit was
calibrated with indium and zinc standards.
A stoichiometric mixture of salbutamol and adipic
acid in a 1:1 molar ratio was dissolved in methanol
at 0.05 g/mL concentration of solid at 25◦C. Methanol
was evaporated under forced air flow at an evapora-
tion rate of 0.4 g/min (monitored using a balance ev-
ery 5 min) while stirring. The white precipitate was
filtered close to the end of the methanol evaporation.
The precipitate was dried for 1 h under constant air
flow at 25◦C. The dry powder was subjected to ele-
mental analysis, and was determined to be salbuta-
mol monoadipate (SA). It was obtained with a 95%
yield.
A stoichiometric mixture of salbutamol and suc-
cinic acid in a 2:1 molar ratio was dissolved in
methanol at 0.05 g/mL concentration of solid at 25◦C.
Methanol was evaporated under forced air flow at
an evaporation rate of 0.4 g/min (monitored using a
balance every 5 min) while stirring. After nucleation
of the salt, the temperature was dropped to 20◦C,
and the evaporation rate of methanol was kept con-
stant (0.4 g/min) until the concentration of the solid in
methanol reached 0.1 g/mL. The white precipitate was
filtered and dried at 25◦C. Elemental analysis of the
white crystalline powder determined it to be salbu-
tamol hemisuccinate tetramethanolate (SSU.MeOH).
It was obtained with a 80% yield. Further drying of
the precipitate under constant air flow at 25◦C for
24 h resulted in formation of desolvated salbutamol
hemisuccinate (SSU).
Thermogravimetric Analysis
Thermogravimetric analysis (TGA) was performed
using a Mettler TG 50 module (Mettler Toledo,
Greifensee, Switzerland) linked to a Mettler MT5 bal-
ance (Mettler Toledo, Greifensee, Switzerland). Sam-
ples were placed into open aluminum pans (5–12 mg).
A heating rate of 10◦C/min was implemented in all
measurements.21 Analysis was carried out in the fur-
nace under nitrogen purge and monitored by Mettler
Toledo STARe software (version 6.10) with a Windows
NT operating system.
Solid-State Fourier Transform Infrared Spectroscopy
Infrared spectra were recorded on a Nicolet Magna IR
560 E.S.P. spectrophotometer equipped with MCT/A
detector, working under Omnic software version 4.1.
Single-Crystal X-Ray Diffraction
A spectral range of 650–4000 cm−1, resolution 2 cm−1
,
X-ray diffraction measurements were made on a
Bruker APEX II DUO diffractometer (Bruker, Biller-
ica, Massachusetts, USA) using graphite monochro-
matized Mo K" radiation (λ = 0.7107 Å), and an Ox-
ford Cryosystems COBRA (Oxford Cryosystems Ltd.,
Oxford, UK) fitted with a N2 generator. All calcula-
tions were made using the APEX2 software (APEX2
v2009.3-0, Bruker AXS, 2009; SHELX)18 and the dia-
grams were prepared using Mercury.19
and accumulation of 64 scans were used in order to
obtain good quality spectra. A KBr disk method was
used with a 0.5%–1% sample loading. KBr disks were
prepared by direct compression under 8 tonne pres-
sure for 1 min.22 The sample preparation did not affect
the spectra, as confirmed with an attenuated total re-
flectance spectrometer (data not shown). The Omnic
4.1TM –FTIR spectra analysis with baseline auto cor-
rection software was used to analyze the data.
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SOLID-STATE CHARACTERIZATION OF NOVEL APIS
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Nuclear Magnetic Resonance (1H NMR, 13C NMR)
Saturation pressure P0 was determined prior to the
measurement of each sample.
A Bruker Avance 400 NMR (Bruker, Billerica, Mas-
sachusetts, USA) with a four-nucleus (1H, 13C, 31P,
and 19F) probe was used for NMR studies. Deuterated
DMSO-d6 was used to prepare the samples. Sample
concentration was in the range 20–40 mg/mL. Spec-
trometer frequency was 400 MHz with an acquisition
time of 2 s. The number of scans was appropriate
to gain good quality spectra. Standard pulse se-
Particle Size
Measurements of particle size and particle size distri-
butions were obtained using a laser diffraction par-
ticle sizer Mastersizer 2000 (Malvern Instruments
Ltd., Malvern, UK). Particles were dispersed using a
Scirocco dry feeder instrument (Malvern Instruments
Ltd., Malvern, UK) with 2 bar pressure. An obscura-
tion rate of 0.5%–6% was obtained under a vibration
feed rate of 50%.
1
quence supplied by Bruker was used for H, DEPT-
90, DEPT-135, 13C, and two-dimensional CH-COSY
experiments. The TopSpin 2.1TM software was used to
evaluate 1H NMR and 13C NMR results.
Solubility Studies
Powdered SA, SSU, and SB were added in excess (ap-
proximately three times the expected saturated con-
centration of salbutamol) directly to 2 mL of water
in an Eppendorf vial at 37◦C.24 In addition, the SA
powder was suspended in an NaOH solution to in-
vestigate its solubility at a pH value other than that
measured for the sample in pure water. The Eppen-
dorfs were placed horizontally in a water bath and
shaken at 100 cpm. Suspensions were filtered through
a 0.22-:m membrane filter. The content of salbutamol
in the saturated solutions was assayed by ultravio-
let (UV) spectrophotometry at 276 nm (Shimadzu UV
1700 Pharmaspec). SB, SA, and SSU aliquots were
diluted with water to obtain the appropriate concen-
tration range. Samples were withdrawn and analyzed
after 10, 11, and 12 h, and as equilibrium appeared to
be reached after 10 h, the values were averaged over
these three time points.
The content of adipic and succinic acids in SA and
SSU aliquots was determined by HPLC. The HPLC
system used was a Shimadzu HPLC Class VP series
with a LC-10AT VP pump, autosampler SIL-10AD
VP, and SCL-10AVP system controller. The mobile
phase was filtered through a 0.45-:m membrane filter
(Supor-450, Gelman, North Hempstead, New York,
USA) before use. The HPLC method used for the anal-
ysis of the dicarboxylic acids was modified by Thoma
and Ziegler25 and Kordis-Krapez et al.26 The ana-
lytical column used was a LiChrosorb RP-10 column
(250 mm length, internal diameter 4 mm, and particle
size 10 :m). UV detection was carried out at a wave-
length of 210 nm and the injection volume was 20 :L.
Separation of adipic acid was carried out isocrat-
ically at ambient temperatures with a flow rate of
1 mL/min. The mobile phase consisted of methanol
and phosphoric acid solution [(pH 2.1); 20:80 (v/v)].
Separation of succinic acid was carried out using
a gradient method with a flow rate of 1 mL/min. The
mobile phase consisted of two eluents: (a) phosphoric
acid solution (pH 2.1) and (b) methanol and phospho-
ric acid solution [(pH 2.1); 20:80 (v/v)]. The following
gradient was used: a linear gradient from 0% to 50%
B over 7 min, and then a linear gradient from 50%
Elemental Analysis
Elemental analysis was carried out using an Exeter
Analytical CE440 CHN analyzer (Exeter Analytical
Ltd., Coventry, UK). The molar amount of carbon as
carbon dioxide, nitrogen as nitrogen oxide, and hydro-
gen as water was determined by oxidation of the sam-
ple (around 10 mg) and thermal conductivity analysis
of the gases obtained.23
Dynamic Vapor Sorption
Vapor sorption experiments were performed on a Dy-
namic Vapor Sorption (DVS) Advantage-1 automated
gravimetric vapor sorption analyzer (Surface Mea-
surement Systems Ltd., London, UK). The tempera-
ture was maintained constant at 25.0 0.1◦C. Around
10 mg of powder was loaded into a sample net basket
and placed in the system. The samples were equili-
brated at 0% of RH until the dry, reference mass was
recorded. The samples were exposed to the following
percentage of RH profile: 0%–90% in 10% steps and
the same for desorption. At each stage, the sample
mass was equilibrated (dm/dt ≤ 0.002 mg/min for at
least 10 min) before the change of RH. An isotherm
was calculated from the complete sorption and des-
orption profile. Amount of water was expressed as a
percentage of the reference mass.
Specific Surface Area Analysis by Brunauer, Emmett,
and Teller Isotherm
Samples were dried prior to analysis under nitro-
gen flow at 50◦C for 12 h using a Gemini SmartPrep
drying station (Micromeritics, Norcross, Georgia,
USA). To determine the bulk specific surface area, a
Micromeritics Gemini VI surface area analyzer (Mi-
cromeritics, Norcross, Georgia, USA) was used. Com-
pressed nitrogen was used as an adsorptive gas. Each
measurement consisted of six steps, determining the
amount of gas adsorbed at six relative pressure points
in the range of 0.05–0.3 of relative pressure P/P0, with
an equilibration time of 10 s. Free space was deter-
mined separately for each sample using helium gas.
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PALUCH ET AL.
to 100% B over 1 min; this composition was main-
tained for 7 min. Then, again a linear gradient from
100% to 0% B over 10 min was applied, and the final
mobile phase composition was continued further for
5 min. Under these conditions, the retention times of
adipic acid and succinic acid were 4.3 and 6.5 min,
respectively.
Data Analysis
ACD/Chem SketchTM freeware was used to calculate
theoretical element contributions for elemental anal-
ysis and partial polarizability volumes.29
RESULTS AND DISCUSSION
Single-Crystal X-Ray Analysis
Intrinsic Dissolution Studies
Single-crystal analysis of SA and salbutamol suc-
cinate (SSU.MeOH) was undertaken, the details of
which are shown in Table 1. Crystals of SA are cen-
trosymmetric, with both enantiomers present in the
lattice. Figure 1a presents the atomic labeling in the
unit cell of the adipate system, which has a 1:1 ra-
tio of SB and adipic acid. The adipate exists in the
lattice in both protonated [O(5)] and ionized [O(6),
O(7)] forms, as shown by the C–O distances: 1.322(2)
Å for the protonated form, and C(17)–O(6): 1.265(1)
Å and C(17)–O(7): 1.261(2) Å for the ionized form. In
addition, there is some disorder in the hydroxyl group
on the stereogenic centre, C(8). Further views of the
crystal packing are depicted in Figures 2a and 2b.
Crystals of SSU.MeOH (Fig. 1b) are also centrosym-
metric and were determined to be solvated with
methanol molecules (Figs. 2c and 2d). This was subse-
quently confirmed by DSC, TGA, elemental analysis,
and 1H NMR spectroscopy. The succinate was found in
its ionized form, with C−O bond distances of 1.274(1)
and 1.253(2) Å. The SSU.MeOH stoichiometry was
2:1:4.
Disks of SS, SSU, and SA were prepared by compress-
ing 300 mg of the given material in an IR hydraulic
press (PerkinElmer, UK). The 13-mm diameter disks
had a 1.33 cm2 top surface area. The bottom and side
surfaces of the disks were coated with paraffin wax
and mounted at the center of the bottom of a standard
dissolution vessel.27 Each dissolution experiment was
performed in triplicate, as long as the dissolving disk
kept a visibly constant surface area.
Intrinsic dissolution studies were performed with
a type 2 dissolution test apparatus (VanKel VK7000
dissolution test station) equipped with VK650 heater/
circulator.5 The rotation speed of the paddle was
set to 100 rpm. Nine hundred milliliters of deion-
ized, degassed water was used as the dissolution
medium, equilibrated at 37◦C. To sample the dis-
solution medium, a standard dissolution vessel was
equipped with a medium recirculation system. The
dissolution medium was constantly circulated using a
LSMatec peristaltic pump fitted with a 0.45-:m filter,
through a 2 mm flow-through UV cuvette placed in a
Cecil CE2020 UV-spectrophotometer set to 276 nm.28
The rate of medium circulation was set to 25 mL/min,
and the pH of the aqueous medium was monitored
using a Thermo Orion 420+ pH meter.
Analysis of Hydrogen Bond Network
Analysis of the hydrogen bonds in SA (Table 2) reveals
that the vast majority of these bonds occur between
the hydroxyl groups on salbutamol and the ionized
adipic carboxylate. This carboxylate is also hydrogen
bonded to the secondary amine group of salbutamol.
The protonated adipic acid does not play a crucial
role in the creation of the hydrogen bond network,
with only one hydrogen bond to a hydroxyl group of
the salbutamol molecule.
Statistical Analysis
Statistical analysis was carried out using MinitabTM
statistical software, version 14 (Minitab Inc.). Two-
sample t-tests were carried out at a significance level
of 0.05, with a p-value of less than 0.05 taken as sig-
nificant, indicating that the observed difference be-
tween the means was statistically significant, that is,
rejecting the null hypothesis.
Interestingly, analysis of the hydrogen bonds in
methanolated salbutamol succinate (Table 3) reveals
the crucial role of methanol in the formation of the
Table 1. Crystallographic Data for SA and SSU.MeOH
SA
SSU.MeOH
Crystal system
Triclinic
Monoclinic
Space group, Z
P¯i, 2
P 21/n, 4
Unit cell dimensions (◦) and (Å)
a = 9.733(3), α = 66.354(5)
b = 10.700(3), β = 86.080(6)
c = 10.926(3), γ = 67.906(5)
961.2(4)
a = 10.3934(5)
b = 20.2011(10), β = 114.5300(10)
c = 10.3962(5)
Volume (Å3)
1985.76(17)
R1 [I > 2F(I)], wR2 (all data)
0.038, 0.090
0.039, 0.104
SA, salbutamol adipate; SSU.MeOH, salbutamol hemisuccinate tetramethanolate.
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SOLID-STATE CHARACTERIZATION OF NOVEL APIS
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Figure 2. (a) Unit cell of SA, (b) extended packing dia-
gram of SA along c axis, (c) unit cell of SSU.MeOH, and (d)
extended packing diagram of SSU.MeOH along b axis.
lattice, and no significant interaction with the ion-
ized succinate. Two molecules of methanol are hydro-
gen bonded together. There is an O−H···O interac-
tion with the hydroxyl group of salbutamol, as well
as O−H···O hydrogen bonding between the methanol
hydroxyl group and salbutamol. In addition, the car-
boxylate of the succinate interacts with the secondary
amine and a hydroxyl group of salbutamol.
A comparison of the crystal packing of SA (Figs. 2a
and 2b) with SSU.MeOH (Figs. 2c and 2d) indicates
why SA contains an “additional” protonated molecule
of adipic acid. It can be seen that SA molecules pack-
ing along the c axis (Fig. 2b) consists of channels made
of salbutamol molecules. These channels are placed
centrally around the molecules of adipic acid. Adipic
acid molecules are placed one below the other, where
Figure 1. (a) SA and (b) SSU.MeOH showing the atomic
labeling. The solvent molecules in SSU.MeOH are omitted
for clarity. Probability ellipsoids are shown at the 50% level.
Table 2. Hydrogen Bonding in SA
D−H···A
D−H (Å)
H···A (Å)
D···A (Å)
D−H···A (◦)
N1−H1A···O7
N1−H1B···O1B
N1−H1B···O6a
O1A−H1C···O7a
O1B−H1D···O6a
O1B−H1D···O7a
O2−H2A···O6b
O3−H3A···O4a
O5−H5···O3c
0.951(19)
0.96(2)
0.96(2)
0.84
0.84
0.84
0.84
0.84
0.88(3)
0.95
0.99
1.845(19)
2.404(18)
1.88(2)
1.93
2.46
1.79
1.81
1.92
1.76(3)
2.50
2.54
2.7945(18)
2.808(5)
2.8353(18)
2.7619(19)
2.816(5)
175.6(14)
105.0(12)
172.2(16)
169
106
166
165
167
172(2)
101
154
2.609(5)
2.6327(17)
2.7437(18)
2.6314(18)
2.8470(19)
3.457(2)
C6−H6···O3
C8−H8B···O2d
C16−H16A···O1Ba
0.99
2.29
3.148(5)
144
Symmetry codes: a1 − x, −y, 1 − z; b1 − x, −y, 2 − z; c1 + x, 1 + y, −1 + z; d −x, −y, 2−z.
SA, salbutamol adipate.
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Table 3. Hydrogen Bonding in SSU.MeOH
forms of adipic acid were found. The same report indi-
cated the occurrence of only nine salts of succinic acid,
indicating that both forms of salbutamol presented
here are rare in terms of their solid-state structures.
The SA reported in the current work should be classi-
fied as a cocrystal of the salbutamol hemiadipate salt
with adipic acid, in contrast to the previously reported
ethanolated salt of salbutamol hemiadipate.2
Previously, a cocrystal of the salt of the API with
an unionized counterion was reported for the anti-
convulsant drug valproic acid, wherein the API com-
prised cocrystalline form of sodium valproate salt
with valproic acid.31 The use of cocrystals in a sim-
ilar manner to salts in order to alter the physico-
chemical properties of API has been comprehensively
investigated,32–38 although only one paper published
so far reports on the coexistence of dianions and an
unionized form of the acid in the same crystal lattice;
similar to what we have determined for SA; it was a
hydrated crystal of escitalopram oxalate with oxalic
acid.39
D
H···A
D
H···A
D
H (Å) H···A (Å)
0.84 1.79
D···A (Å)
2.6297 (14)
(◦)
O1 H1···O5a
173
N1 H1A···O4a 0.929 (18) 1.852 (19) 2.7786 (15) 175.0 (13)
N1 H1B···O1b 0.912 (16) 1.924 (17) 2.7953(13) 159.1 (17)
O2 H2A···O7c
O3 H3A···O4d
O6 H6A···O3e
O7 H29···O6f
C2 H2···O5g
0.84
0.84
0.84
0.84
0.95
0.95
0.99
0.98
1.80
1.85
1.84
1.81
2.53
2.56
2.38
2.57
2.6312(16)
2.6721(13)
2.6754(13)
2.6523(15)
3.4744(14)
2.8788(14)
3.3068(15)
3.5145(15)
171
165
174
176
177
100
155
162
C6 H6···O3
C8 H8A···O2d
C11 H11B···O2h
Symmetry codes: a1 + x, y, z; b2 − x, 2 − y, 2 − z; cx, 1 + y, z; d1 − x, 2
− y, 1 − z; ex, −1 + y, z; f−1/2 + x, 1/2 − y, 1/2 + z g1 − x, 2 − y, 2 − z; h3/2
− x, −1/2 + y, 3/2 −z.
SSU.MeOH, salbutamol hemisuccinate tetramethanolate.
ionized and protonated molecules are placed alter-
nately in each layer. The ionized carboxylic groups of
adipic acid face toward the secondary amine moieties
of salbutamol molecules, whereas protonated groups
are placed in close proximity to methoxyls of the ben-
zene ring of salbutamol molecules. This indicates that
the ionized acid stabilizes more polar parts of the
salbutamol molecule, where partial polarizability (α)
of R–NH–Me–MeOH molecule fragment was calcu-
lated to be 15.68 0.5 Å3, whereas the protonated
molecule is responsible for interaction with less po-
lar parts of salbutamol, where partial polarizability
(α) of HOMe–Ar part was calculated to be 12.96 0.5
Å3. The interaction is promoted by the close proxim-
ity of carboxylic acid groups to the channels formed
by salbutamol molecules. This is due to the length of
adipic acid being similar to the length of the channel,
with the O(5)-O(5) distance being approximately 8 Å.
Succinic acid is much shorter than adipic acid; the
O(5)–O(4) distance is approximately 5 Å and forms
a different arrangement to SA along the c axis. De-
spite the fact that the pKa(s) 1,2 of succinic acid (4.21
and 5.64 at 25◦C)11 and adipic acid (4.44 and 5.44
at 25◦C)11 are only slightly different, this difference
seems to be large enough to allow ionized succinic
acid to stabilize the amine group and neighboring hy-
droxyl of salbutamol simultaneously. In SSU.MeOH,
each salbutamol molecule is stabilized, as described,
by a succinic acid from one side and a second molecule
of salbutamol; in that, the amine group of SB(A) in-
teracts with the hydroxyl next to the amine group of
SB(B). The solvated nature of SSU.MeOH arises from
the interaction of H-bond dimers (as later described
in hydrogen bond network analysis) of methanol with
hydroxyls of salbutamol.
Hirshfeld Surfaces Analysis
Hirshfeld surfaces analysis (Fig. 3) allowed visualiza-
tion and comparison of reciprocal interactions among
atoms in crystal lattices of SB and SS as compared
with salbutamol adipate and succinate. The visual-
ization is based on a three-dimensional surface sur-
rounding a single molecule of salbutamol.
Noticeably, the same chemical structure of salbu-
tamol may present different intensities of reciprocal
interactions externally and internally to the Hirsh-
feld surface. Red places named “hot spots” indicate
areas of salbutamol molecules wherein the interac-
tions are the strongest, and the distance between at-
tracting atoms is shorter than the attraction caused
by van der Waals forces (corresponding to white color
on Hirshfeld surface). In all derivatives of salbutamol,
the most involved areas in the formation of hot spots
include hydroxyl groups, wherein hydrogens and oxy-
gens generate separate, independent crystallographic
hot spots, and the secondary amine group. Hirsh-
feld surface analysis also confirmed that hydrogens of
methyl groups of the butyl moiety, secondary methyl
group, and hydrogens of the benzene ring are able
to form weak hot spot interactions. It is evident that
the molecule of salbutamol in the crystal structure
of SB forms an intensive hot spot interaction close to
O(1)−H(1), the same as in cocrystalline form of SA,
whereas this interaction is visibly weaker for salbuta-
mol molecules forming crystal structures of salt forms
SS and SSU.MeOH. The intensity of hot spot interac-
tion also differs in the case of the methoxyl group
O(3)−H(3) attached to the benzene ring of salbuta-
mol. Involvement in the strongest (the most intense
red color) interaction was for O(3) of SB, a slightly
weaker interaction was demonstrated by H(3) in
Haynes et al.30 presented a review, reporting the
occurrence of pharmaceutically acceptable anions and
cations in the CSD. No examples of a cocrystal of a salt
of adipic acid were reported and only 23 cocrystalline
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Figure 3. Hirschfield surfaces of: (a) SB, (b) SS, (c) SA, and (d) SSU.MeOH
crystal structures of SA and SSU.MeOH, whereas
O(3) contact lost its intensity. The SS structure pre-
sented two weak hot spots, one from oxygen and the
other from hydrogen atom. The weakest intensity and
distribution on Hirshfeld surface of hot spot interac-
tions was for SB and its cocrystalline form. The hot
spot interactions identified corresponded well with
the detected H-bond interactions for SA and SSU
shown in Tables 3 and 4.
The bulk material consisted of colorless, transpar-
ent, rhomboidal, thin, and plate-like crystals.
Results of PXRD analysis of SSU.MeOH (Fig. 5b)
are also consistent with the theoretical PXRD pat-
tern (Fig. 5a). Again, small differences between the
two patterns can be attributed to the different temper-
atures used for the experiments. Figure 8c presents
the PXRD pattern of desolvated SSU. Broadening and
lowering intensities of the Bragg peaks may be indica-
tive of the damage to the crystal lattice.
Results of PXRD Analysis
NMR Results
The theoretical powder pattern of SA generated from
the single-crystal X-ray analysis at 100 K (Fig. 4a) is
consistent with the PXRD pattern of the bulk mate-
rial determined at ambient conditions (Fig. 4b). There
are small differences between the two patterns, which
most likely can be attributed to thermal anisotropic
expansion of the lattice.
1
Table 4 compares H NMR data recorded for SB and
the following salts: SS, SA, SSU.MeOH, and SSU. Re-
sults obtained for SB are consistent with data previ-
ously reported by Regla et al..40 1H NMR confirmed
the presence of methanol in the crystal structure due
to the methyl group (3.18 ppm), which was absent in
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Table 4. 1H NMR Analysis of SB, SS, SA, SSU.MeOH, and SSU
SB
SB (Regla et al.40
)
SS
SA
SSU.MeOH
SSU
Peak
ν(F1) (ppm) Integral
ν(F1) (ppm)
ν(F1) (ppm) ν(F1) (ppm) ν(F1) (ppm) ν(F1) (ppm)
C(10,11,12) H(10,11,12)
C(8)H(8/AB)
C(7)H(7)
C(13)H(13/AB)
C(2)H(2)
1.02
2.54
4.40
4.48
6.69
6.99
7.27
–
9.08
2.79
1.09
1.99
1.00
1.02
1.04
–
1.02
2.55
4.42
4.47
6.69
6.99
7.27
–
1.22
2.78
4.69
4.50
6.75
7.08
7.34
–
1.21
2.84
4.70
4.48
6.74
7.07
7.32
2.11
1.16
2.74
4.61
4.59
6.755
7.04
7.31
2.28
1.16
2.71
4.59
4.49
6.75
7.04
7.31
2.28
C(3)H(3)
C(6)H(6)
C(15,18) H(15,18/AB)
C(15) H(15/AB)
C(16,19)
C(16) H(16/ABC) C(17)
H(29-31)
–
–
–
–
–
–
–
–
1.49
–
–
3.18
–
–
SB, salbutamol base; SS, salbutamol sulfate; SA, salbutamol adipate; SSU.MeOH, salbutamol hemisuccinate tetramethanolate; SSU,
salbutamol hemisuccinate.
Figure 4. Comparison of SA PXRD patterns: (a) theoretical pattern and (b) experimental
diffractogram.
Figure 5. Comparison of PXRD patterns: (a) SSU.MeOH theoretical pattern, (b) SSU.MeOH
experimental diffractogram, and (c) SSU experimental diffractogram.
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SOLID-STATE CHARACTERIZATION OF NOVEL APIS
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Table 5. 13C NMR Analysis of SB, SS, SA, SSU.MeOH, and SSU
SB
SB (Regla et al.40
)
SS
SA
SSU.MeOH
SSU
Peak
ν(F1) (ppm)
ν(F1) (ppm)
ν(F1) (ppm) ν(F1) (ppm) ν(F1) (ppm) ν(F1) (ppm)
C(10,11,12) H(10–12/ABC)
C(9)
C(8)H(8/AB)
C(13)H(13/AB)
C(7)H(7)
C(2)H(2)
C(3)H(3)
C(6)H(6)
C(1,4,5)
C(1,4,5)
C(1,4,5)
C(14,17)
C(15,18)
C(16,19)
C(17,16)
28.9
49.6
50.8
58.3
72.4
114.0
124.8
125.0
127.9
134.6
153.1
–
28.74
49.8
50.7
58.3
72.3
114.0
124.9
125.1
127.9
134.5
153.1
–
26.7
49.7
49.6
58.7
70.3
114.6
125.5
125.6
128.6
133.4
153.9
–
26.4
49.1
49.6
58.8
69.9
114.7
125.3
125.5
128.6
133.3
154.0
176.7
35.9
25.6
–
27.4
50.1
27.4
50.2
50.0
58.8
71.1
114.6
125.4
125.5
128.6
133.8
153.9
176.2
32.9
–
49.98
58.73
71.11
114.60
125.40
125.54
128.61
133.79
153.90
176.18
32.92
–
–
–
–
–
–
–
–
–
–
49.06
–
SB, salbutamol base; SS, salbutamol sulfate; SA, salbutamol adipate; SSU.MeOH, salbutamol hemisuccinate tetramethanolate; SSU,
salbutamol hemisuccinate.
the desolvated form. Slight shifts in peak positions be-
tween SB and salbutamol salt forms may be ascribed
to the interactions of molecules of dissolved APIs with
DMSO.
material have greater variation due to solvate insta-
bility at ambient conditions and methanol evapora-
tion. Results of elemental analysis confirm that the
molar ratio of salbutamol to succinic acid in SSU
is 2:1.
Results of 13C NMR analysis are shown in Table 5.
The number and position of the carbon peaks cor-
relate well with the data reported by Regla et al.40
for SB. The carbons of adipic acid appeared as three
peaks corresponding to six symmetrical carbons, and
the carbons of succinic acid showed as two peaks
corresponding to four symmetrical carbons. The 13C
NMR also detected the carbons (17,16) of methanol in
the solvated form of SSU.MeOH, and their absence in
the desolvated form SSU.
Thermal Analysis
Thermogravimetrical analysis of SA did not indicate
a significant mass loss on drying at the beginning of
the scan. Overall mass loss recorded during the TGA
scan (Fig. 6a) up to 100◦C was 0.94 0.03% of the ini-
tial mass of the sample. DSC analysis of the material
showed a single strong endothermal event (Fig. 6d)
related to melting with decomposition at 181.00
0.04◦C, correlating with the beginning of significant
further mass loss in the TGA. The melting point of
adipic acid was measured to be 150.93 0.10◦C.
Differential scanning calorimetry analysis of
SSU.MeOH (Fig. 6e) indicated a large broad en-
dotherm with an onset at 69.97 0.30◦C and an en-
thalpy of 139.43 J/g. These endothermal events corre-
lated well with the sample mass loss due to liberation
of methanol (Fig. 6b) of 17.26 1.20%. The theoretical
Stoichiometry and Elemental Analysis
Elemental analysis confirms the molar ratio of salbu-
tamol and adipic acid in SA to be 1:1 (Table 6).
Elemental analysis of SSU.MeOH correlates well
with the single-crystal X-ray analysis data suggesting
a ratio of two molecules of salbutamol to one molecule
of succinic acid to four molecules of methanol, the
presence of which in the crystallized material was
confirmed by NMR analysis. Results for the solvated
Table 6. Comparison of Theoretical Values and Experimental Results of Elemental Analysis of
Carbon, Nitrogen, and Hydrogen contents in Salbutamol Salts
Sample Content (%, w/w):
C %
H %
N %
SA
Theory 1:1
Experimental
Theory
Experimental
Theory 2:1
Experimental
59.20
59.00 0.01
56.34
56.53 0.37
60.38
8.11
8.20 0.08
8.90
8.19 0.18
8.11
3.63
3.68 0.07
3.86
3.59 0.53
4.69
SSU.MeOH
SSU
60.275 0.05
8.01 0.07
4.61 0.01
SA, salbutamol adipate; SSU.MeOH, salbutamol hemisuccinate tetramethanolate; SSU, salbutamol
hemisuccinate.
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Figure 6. Thermal analysis: (a) TGA scan of SA, (b) TGA scan of SSU.MeOH, (c) TGA scan of
SSU, (d) DSC of SA, (e) DSC scan of SSU.MeOH, and (f) DSC scan of SSU.
content of solvated methanol was calculated to be
17.68%.
be concluded that the new forms and SS have similar
thermal stability.
The onset of thermal decomposition after desolva-
tion was recorded to be at 179.23 0.10◦C and cor-
responded with further significant mass loss. In con-
trast, succinic acid melted at 185.90 0.21◦C. There
was a 0.80 0.02% overall mass loss up to 100◦C in
the TGA determined for SSU (Figs. 6c and 6f), indi-
cating very slight drying. The onset of thermal decom-
position was recorded at 182.83 0.15◦C.
FTIR Analysis
The FTIR patterns of SA (Fig. 7c) and SSU (Fig. 8d)
differ in comparison with the spectra of the parent
compounds (Figs. 7a, 7b, and 7e). The main difference
between SA, SSU, and SB is the strong suppression
of conjugated C=C stretching vibrations of the ben-
zene ring of salbutamol just above 1600 cm−1, and
changes in the intensity of the carboxylic acid C=O
stretch peaks. The stretching vibration of the N−H
The onsets of thermal decomposition of the new
salbutamol forms were consistent with the onset of
decomposition of about 180◦C41 for SS. Thus, it can
Figure 7. FTIR spectra of: (a) adipic acid, (b) succinic acid, (c) SA, (d) SSU, and (e) SB.
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SOLID-STATE CHARACTERIZATION OF NOVEL APIS
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Figure 8. Dynamic vapor sorption of: (a) SA (squares), (b) SSU (triangles), and (c) SS (dia-
monds).
group of salbutamol (Fig. 7e) recorded at 3300 cm−1
for SB was nearly completely suppressed and slightly
shifted toward longer wavelengths in SSU (Fig. 7d),
indicating a complete ionization of the secondary
amine group.In contrast, the N−H stretching vibra-
tion of the secondary amine group in SA (Fig. 7c) is
and 8.73 0.09 :m for SS, SA, and SSU, respectively.
It is possible, therefore, that the higher propensity of
SA to adsorb moisture may be due to the different par-
ticle size but cannot be explained by the difference in
the surface area. It is likely that other surface prop-
erties, such as surface energy, contribute to this effect
and will be the subject of further studies.
relatively noticeable with a strong shift to 3450 cm−1
.
These observations agree with the single-crystal X-
ray data, suggesting a cocrystal form of SA, wherein
one out of two adipic acid molecules per two molecules
of SB remains unionized, but strongly H-bonded to
the secondary amine group of salbutamol. The cocrys-
tal versus salt forms of salbutamol are clearly dis-
tinguishable by FTIR, wherein the broad stretching
vibration of C=O of the acid in SSU has been com-
pletely suppressed, whereas the acidic carbonyl group
vibration in SA remained highly visible with a slight
shift toward longer wavelengths.
Solubility and Dissolution Studies
The estimated aqueous solubilities of SA, SSU, and
SB were found to be 82 2 mg/mL (equivalent to
0.231 0.001 M of salbutamol) at pH 4.5 0.1, 334
13 mg/mL (equivalent to 1.183 0.045 M of salbuta-
mol) at pH 6.6 0.1, and 2.63 0.09 mg/mL (equiva-
lent to 0.0110 0.0004 M of salbutamol) at pH 10.0
0.1, respectively. Thus the improvement in solubil-
ity, compared with SB, was 21- and 108-fold for the
drug presented as SA and SSU, respectively, indi-
cating that SSU has a fivefold greater solubility
than SA.
Dynamic Vapor Sorption
Both SSU and SA do not adsorb more than 2% of mois-
ture, and under the conditions of DVS analysis, do not
tend to form hydrates (Fig. 8). Results of equilibration
of SSU at any given RH %, regardless of whether as-
sessed in the sorption or desorption stage, are similar
to SS, and in both cases, the amount of adsorbed liq-
uid does not exceed 0.3% of the initial sample mass at
90% RH. In the case of the SA sample, less than 1.6%
of the initial mass was adsorbed at 90% RH.
Because the moisture sorption behavior may be at-
tributed to the powder surface area, the samples sub-
jected to the DVS analysis were also characterized in
terms of their specific surface area and particle size.
The specific surface area (TBET) of SS was measured
to be 1.53 0.02 m2/g, that of SA was 1.81 0.02 m2/
g, and TBET of SSU was 2.26 0.06 m2/g. The median
particle size determined was 8.09 0.18, 19.26 0.07,
As the new forms of salbutamol are composed of the
drug and coformer that are able to ionize in solution,
it is expected that the pH of the saturated medium
may have a profound effect on the solubility of the
compounds.11 This was investigated for SA, as it was
easier to change the pH for this compound due to the
lower solubility in comparison with SSU. When the
pH of medium was adjusted to 5.3, the solubility of
SA was measured to be 60 1 mg/mL.
Equations describing the solubility of gabapentin/
3-hydroxybenzoic acid cocrystal,42 carbamazepine,
and itraconazole cocrystals have been reported.43
These models allow relationships between the pH and
cocrystal solubility to be predicted knowing only the
solubility product constant (Ksp) and acid dissocia-
tion constants of the cocrystal constituents (pKas).
Although the theoretically derived models neglect
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nonidealities due to complexation and other specific
interactions, very good agreements between the cal-
culated and experimental values were observed.42,43
This approach was employed in this work as the
authors suggest that cocrystal solubility and its
pH relationship may be estimated from a sin-
gle measurement.43 Similar mathematical equations
were therefore developed for the new salbutamol
forms to predict their solubility–pH dependence and
estimate the solubility difference in relation to the
pure drug. The coformers and the drug have acidic
and amphoteric characteristics, respectively, there-
fore the previously reported equations were adapted,
taking into consideration that each of the species has
two pKa values and that the stoichiometry of the suc-
cinate form is 2:1.
[S−] are concentrations of protonated and monobasic
salbutamol species.
Combining the total acid and drug concentrations,
the solubility of SA can be expressed as (Eq. 7):
S
=
cocrystal
ꢀ
ꢁ
ꢂ
K
K
× K
a1,H2A
[H+]
a2,H2A
a1,H2A
Ksp
×
1 +
+
[H+]2
ꢀ
ꢁ
ꢂ
[H+]
Ka1,S
Ka2,S
[H+]
× 1 +
+
(7)
where Scocrystal is cocrystal solubility, Ka1,H2A and
Ka2,H2A are the first and second dissociation constants
for the acid, respectively, and Ka1,S and Ka2,S are the
first and second dissociation constants for the drug,
respectively.
Using a similar approach, the equation for SSU,
considering the 2:1 stoichiometry, is as follows (Eq. 8):
SA has a molar ratio of 1:1, hence the equation
for equilibrium reaction describing dissociation of the
cocrystal in solution is as follows:
S − H2A ↔ Ssolution + H2Asolution
(1)
S
=
salt
where S-H2A is the cocrystal/salt in the solid phase,
Ssolution and H2Asolution are equilibrium solubilities of
the drug and acid, respectively, thus
ꢀ
ꢁ
ꢂ
Ksp
4
K
K
× K
a1,H2A
[H+]
a2,H2A
a1,H2A
3
1 +
+
[H+]2
ꢀ
[S][H2A]
[S − H2A]
ꢁ
ꢂ
2
[H+]
Ka2,S
[H+]
Ksp
=
× 1 +
+
(8)
Ka1,S
and with S-H2A in the solid phase, the Ksp can be
presented as
The pKsp constants for salbutamol adipate and suc-
cinate, calculated using the aqueous solubility values,
were 6.3 and 8.6, respectively. Substituting in pKa
values as follows: pKa1 = 4.44, pKa2 = 5.44 for adipic
acid,11 pKa1 = 4.21, pKa2 = 5.64 for succinic acid,11
and pKa1 = 9.1, pKa2 = 10.4 for salbutamol,17 the
pH–solubility profiles derived from Eqs. 8 and 9 are
shown in Figure 9. The theoretical models suggest
that a minimum SA solubility occurs at pH around
5.0 and that of SSU at pH 7.0.
The comparison of intrinsic dissolution rates
(IDRs) of salbutamol from SA [4.18 mg/(cm2 min), R2
of 0.999] and SSU [14.94 mg/(cm2 min), R2 of 0.997]
with that of salbutamol sulfate [15.47 mg/(cm2 min),
R2 of 0.999] (Fig. 10) reveals that the rate of salbu-
tamol release from SA is lower than that from SS or
SSU. The IDR of salbutamol from SA is approximately
four times lower and significantly different (p < 0.05)
than that of the other salt forms, consistent with the
approximately fivefold difference in salbutamol solu-
bility. There was no significant difference (p = 0.865)
between the IDRs of salbutamol in SS and SSU. Our
results for the cocrystal of the salbutamol hemiadi-
pate salt with adipic acid (SA) contrasts with that
of Jashnani et al.2 who obtained a salbutamol hemi-
adipate diethanolate, which had an IDR equivalent
to SS.
Ksp
[S]
Ksp = [S][H2A] ⇒ [H2A] =
(2)
Equilibrium reactions for adipic acid and salbuta-
mol are presented in Eqs. 3 and 4 (for the acid) and
Eqs. 5 and 6 (for the drug).
[H+][HA−]
H2A ↔ HA− + H+
HA− ↔ A2− + H+
SH+ ↔ S+ H+
S ↔ S− + H+
Ka1,H A
=
(3)
(4)
(5)
(6)
2
[H2A]
[H+][A2−
[HA−]
]
Ka2,H A
=
2
[S][H+]
Ka1,S
=
[SH+]
[S−][H+]
=
[S]
Ka2,S
where [HA−], [A2−] are concentrations of the monodis-
sociated and fully dissociated acid species and [SH+],
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SOLID-STATE CHARACTERIZATION OF NOVEL APIS
3281
Figure 9. Theoretical profiles describing pH–solubility dependence for SA (dashed line), SSU
(dotted line), and SB (solid line). Empty squares indicate experimental solubility values for SA,
the triangle for SSU, and the circle shows the experimental solubility of SB. The inset shows a
correlation (y = x) between the experimental and predicted data points.
Interestingly, the difference in the IDR values ob-
tained reflect the different acid solubilities, that is,
the saturated solubility of succinic acid at 20◦C is re-
ported to be 7.7% (w/v) and that of adipic acid to be
1.8% (w/v) 11; therefore, it may be expected that the
solubility of salbutamol adipate is lower than that of
salbutamol succinate.
cantly different. For the first time, we reported the
involvement of adipic acid molecule in the formation
of a cocrystal of a salt. Salbutamol succinate is a rare
example of the succinate constituting a solvated salt
form with API molecule. The IDR of salbutamol in
SSU was around fourfold greater than that of SA,
consistent with the approximately fivefold difference
in aqueous solubility of salbutamol in SA and SSU,
thus the difference in the IDRs was comparable to
the solubility trend. Both materials presented simi-
lar thermal stability and did not undergo hydration
under increasing humidity. The effectiveness of anion
choice as a modification of in vivo bioavailability of
CONCLUSIONS
Despite the chemical similarity of succinic and adipic
acid, the solid-state properties of their salbutamol
salts when made by the same methods are signifi-
Figure 10. Intrinsic dissolution profiles of SA (diamonds), SSU (squares), and SS (triangles).
DOI 10.1002/jps
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 100, NO. 8, AUGUST 2011

3282
PALUCH ET AL.
salbutamol needs further investigations, as the con-
cept of retarding dissolution of an API by the for-
mation of an appropriate salt/cocrystal is a promising
approach, which may alleviate some issues associated
with formulation of extended-release dosage forms
such as component compatibility and regulatory ap-
proval for the use of excipients.
Results described here show that salt and/or cocrys-
tal formation remains largely unpredictable and
requires predominantly empirical screening. The ar-
rangement of molecules in the crystal lattice is de-
pendent on the geometry of the molecules involved
and their potential for forming chemical interactions.
Even the careful choice of similar counterions can
have a profound effect on the observed crystalline
lattice and further work in this area is required.
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ACKNOWLEDGMENTS
The authors wish to acknowledge the funding for
this research from the Irish Research Council for Sci-
ence and Engineering Technology and the Solid State
Pharmaceutical Cluster, supported by Science Foun-
dation Ireland under grant number [07/SRC/B1158].
Authors would like to thank Mrs. Ann Connolly,
Department of Chemistry, University College Dublin,
Ireland, for elemental analysis.
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