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European Journal of Pharmaceutics and Biopharmaceutics 174 (2022) 131–143
Available online 9 April 2022
0939-6411/© 2022 Published by Elsevier B.V.
Combining enabling formulation strategies to generate supersaturated
solutions of delamanid: In situ salt formation during amorphous solid
dispersion fabrication for more robust release proles
Tu Van Duong
1
, Hanh Thuy Nguyen
1
, Lynne S. Taylor
*
Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, West Lafayette, IN 47907, United States
ARTICLE INFO
Keywords:
Solid dispersions
Salt formation
Amorphous
Delamanid
Sulfonates
Supersaturation
Stability
Release
ABSTRACT
Poor solubility is a major challenge that can limit the oral bioavailability of many drugs, including delamanid, a
weakly basic nitro-dihydro-imidazooxazole derivative used to treat tuberculosis. Amorphous solid dispersion
(ASD) can improve the bioavailability of poorly water-soluble compounds, yet drug crystallization is a potential
failure mechanism, particularly as the drug loading increases. The goal of the current study was two-fold: to
enhance the stability of amorphous delamanid against crystallization and to improve drug release by developing
ASDs containing the salt form of the drug. Various sulfonate salts of delamanid were prepared in amorphous form
and evaluated for their tendency to crystallize and undergo chemical degradation following storage at 40 ◦C/
75% relative humidity. Drug release was evaluated by a two-stage dissolution test consisting of an initial low pH
stage, followed by transfer to a higher pH medium. For ASDs of the free base, small amounts of crystallinity
during preparation were found to limit the drug release. Delamanid salts with sulfonic acids showed considerably
improved amorphous stability. Tosylate, besylate, edisylate, and mesylate salts had high glass transition tem-
peratures as well as good chemical and physical stability. In addition, a remarkable improvement in the drug
release was observed when ASDs were prepared with these salts in comparison to the free base form. Specically,
ASDs with hydroxypropyl methylcellulose phthalate (HPMCP) at 25% drug loading exhibited near-complete drug
release for all four sulfonate salts. These ndings suggest that the dual strategy combining salt formation with
ASD formation is a promising approach to alter the crystallization tendency and to improve drug release of
problematic poorly water-soluble compounds.
1. Introduction
Delamanid (DLM), a nitro-dihydro-imidazooxazole derivative, is
indicated for the treatment of multi-drug resistant tuberculosis [1] and is
marketed under the brand name Deltyba
TM
. The commercial product is
formulated as an amorphous solid dispersion with the enteric polymer,
hydroxypropyl methylcellulose phthalate (HPMCP). DLM is a weakly
basic compound with a reported pKa of 4.3 [2], and hence exhibits pH-
dependent solubility like other weak bases [3,4]. The drug is slightly
soluble at low pH and undergoes a substantial decrease in solubility
when the solution pH increases above the pKa [5]. Despite a fairly long
half-life, DLM requires twice daily dosing and must be taken with food to
ensure adequate bioavailability [6].
A high percentage of marketed drugs and drug candidates have low
aqueous solubility and consequently low bioavailability [7,8]. As a
result, there has been an increase in the number of amorphous solid
dispersion formulations being used in commercial products [9]. How-
ever, drug crystallization is always a risk factor for these formulations.
Whether or not crystallization occurs is a complex interplay of intrinsic
drug properties that impact the crystallization tendency, formulation,
Abbreviations: ASD, amorphous solid dispersion; DCM, dichloromethane; DL, drug loading; DLM, delamanid; DLS, dynamic light scattering; DMSO, dimethyl
sulfoxide; DSC, differential scanning calorimetry; Eud-L, Eudragit L-100; HPLC, high performance liquid chromatography; HPMC, hydroxypropyl methylcellulose;
HPMCAS, hydroxypropyl methylcellulose acetate succinate; HPMCP, hydroxypropyl methylcellulose phthalate; IR, infrared; MCC, microcrystalline cellulose; MeOH,
methanol; NMR, nuclear magnetic resonance; PBS, phosphate buffer solution; PVPVA, polyvinylpyrrolidone/vinyl acetate; PXRD, powder X-ray diffraction; RH,
relative humidity; UV, ultraviolet.
* Corresponding author.
E-mail address: lstaylor@purdue.edu (L.S. Taylor).
1
The authors contributed equally.
Contents lists available at ScienceDirect
European Journal of Pharmaceutics and Biopharmaceutics
journal homepage: www.elsevier.com/locate/ejpb
https://doi.org/10.1016/j.ejpb.2022.04.002
Received 14 January 2022; Received in revised form 1 April 2022; Accepted 7 April 2022
European Journal of Pharmaceutics and Biopharmaceutics 174 (2022) 131–143
132
processing, and storage conditions. Some drugs are simply inherently
fast crystallizers, while other compounds are much easier to make and
maintain in amorphous form.
Salt formation is a commonly employed strategy to alter the physi-
cochemical properties of ionizable active pharmaceutical ingredients,
including hygroscopicity, melting point and dissolution rate [8,10–12].
Salt formation to produce crystalline salts is an extremely common
approach to improve the developability of candidate drugs. The success
of this strategy is highlighted by the observation that almost 50% of
drugs marketed in 2007 were in the form of salts [11,13]. Salt formation
with acids that have a pKa at least 3 units lower than the base is
considered important to achieve proton transfer and formation of a
stable salt [14]. Widely used salts for weakly basic drugs include hy-
drochlorides, sulfonates and sulfates [11]. Between 2015 and 2019,
there were ve mesylate salts and eight tosylate salts in products
approved by the United States Food and Drug Administration, suggest-
ing that sulfonate salts are increasingly being utilized [15]. An impor-
tant, but not very widely investigated observation, is that salt formation
may alter the crystallization tendency of a drug [8,16,17]. Strong elec-
trostatic interactions between the drug and counterions likely contribute
to stabilizing the amorphous form of the drug via an enhanced glass
transition temperature (T
g
) and reduced molecular mobility [17–19].
Furthermore, bulky counterions may provide steric hindrance to
crystallization.
Combining salt formation with amorphous solid dispersions offers a
potential strategy to inhibit the crystallization of rapidly crystallizing
drugs, while maintaining the advantage of an amorphous formulation.
Salt formation between basic drugs and acidic polymers has been re-
ported in several studies [20–23]. There are fewer studies where a drug
salt is used in an amorphous solid dispersion formulation. Recently,
Haser et al. [24] reported the in situ formation of a meloxicam-
meglumine salt during hot melt extrusion. The same group has investi-
gated salt formation between naproxen and meglumine, also during hot
melt extrusion with polymers [25]. Given that salt formation can impact
the crystallization tendency of a drug, ASDs containing the salt of a drug
are of interest for compounds with a high propensity to crystallization.
The goal of the current study was to improve amorphous stability
and enhance the release of delamanid by developing amorphous solid
dispersions containing a drug salt in combination with a polymer that is
effective at inhibiting crystallization of the drug during preparation and
dissolution. It was hypothesized that delamanid salts with sulfonic acids
(Fig. 1) would be more resistant to solid-state crystallization than the
corresponding amorphous free base due to their higher glass transition
temperature. Moreover, by maintaining the amorphous nature of the
drug salt in the ASDs, improved release performance would be achieved.
Delamanid salts with the sulfonic acids shown in Fig. 1 were synthesized
and characterized by evaluation of thermal transitions, X-ray powder
diffraction patterns, hygroscopicity and chemical stability. Amorphous
solid dispersions of delamanid free base and delamanid salts with either
HPMCP or hydroxypropyl methylcellulose acetate succinate (HPMCAS)
were prepared at different drug loadings (DLs) and subjected to similar
characterization as for the neat amorphous salts. Release performance of
the ASDs were evaluated using a two-stage dissolution test consisting of
an initial low pH gastric stage followed by transfer to a higher pH me-
dium corresponding to intestinal pH conditions.
Fig. 1. Chemical structures of DLM, sulfonic acids, HPMCAS-LF and HPMCP HP-50.
T.V. Duong et al.
European Journal of Pharmaceutics and Biopharmaceutics 174 (2022) 131–143
133
2. Materials and methods
2.1. Materials
Delamanid (DLM) was obtained from Gojira Fine Chemicals, LLC
(Bedford Heights, OH). Hydroxypropyl methylmellulose phthalate
(HPMCP, HP-50 grade), hydroxypropyl methylcellulose acetate succi-
nate (HPMCAS, LF grade) and hydroxypropyl methylcellulose (HPMC,
substitution type 2910, grade 603) were procured from Shin-Etsu
Chemical Co., Ltd. (Tokyo, Japan). Polyvinylpyrrolidone/vinyl acetate
(PVPVA, Kollidon VA 64) was obtained from the BASF Corporation
(FlorhamPark, NJ). 1,2-Ethanedisulfonic acid dihydrate (edisylate) and
4-chlorobenzenesulfonic acid (closylate) were purchased from Tokyo
Chemical Industry Co. Ltd. (Tokyo, Japan). Methanesulfonic acid
(mesylate), benzenesulfonic acid (besylate), and (1S)-(+)-10-cam-
phorsulfonic acid (camsylate) were provided by Sigma-Aldrich (St.
Louis, MO). Ethanesulfonic acid (esylate) and 1,5-naphthalenedisulfonic
acid (napadisylate) were bought from Merck (Darmstadt, Germany). P-
toluenesulfonic acid (tosylate) was from Acros organic (Geel, Belgium).
Cros-carmellose sodium and microcrystalline cellulose pH 101 (MCC)
were sourced from FMC Biopolymer (Newark, DE). Magnesium stearate
was supplied by Spectrum (New Brunswick, NJ). Eudragit L100 (Eud-
L100) and silica, colloidal hydrated were from Evonik (Essen, Germany).
Sodium starch glycolate was obtained from JRS Pharma (Rosemberg,
Germany). Biorelevant simulated intestinal uid powders (FaSSIF/
FaSSGF and FaSSIF-V2) were purchased from Biorelevant (London, UK).
Phosphate buffer solution (PBS) pH 6.5 (29 mM) and maleate buffer pH
6.5 (19 mM) were used to prepare FaSSIF V1 and FaSSIF V2 media,
respectively. Dichloromethane (DCM), methanol (MeOH) and acetone
were supplied by Fisher-Scientic (Pittsburg, PA).
2.2. Determination of drug solubility
The equilibrium solubility of crystalline DLM was determined by
adding an excess amount of drug to the media of interest with stirring at
300 rpm at 37 ◦C for 48 h. The undissolved drug was removed by ul-
tracentrifugation at 35,000 rpm (37 ◦C, 30 min) by an Optima L-100 XP
ultracentrifuge (SW 41Ti rotor) (Beckman Coulter, Inc., Brea, CA). The
supernatant was diluted in methanol to an appropriate concentration.
The drug concentration was determined using an Agilent high perfor-
mance liquid chromatography (HPLC) system (Agilent Technologies,
Santa Clara, CA) with a C18 column (Zorbax Eclipse Plus, 4.6 ×250 mm,
5
μ
m, Agilent Technologies, Santa Clara, CA). The mobile phase
comprised acetonitrile and water (75:25 by volume) at a ow rate of 1.5
mL/min and an injection volume of 20 µL. DLM was detected by UV
absorbance at 320 nm.
The UV-extinction method [26] was used to determine the amor-
phous solubility of delamanid in fasted state simulated gastric uid
(FaSSGF), fasted state simulated intestinal uid (FaSSIF) version 1 (V1)
and version 2 (V2) (FaSSIF V1 and FaSSIF V2, respectively) and phos-
phate buffer solution (PBS) pH 6.5. The media pH ranged from 1.6 to 6.5
at 37 ◦C. Briey, a stock solution of DLM in dimethyl sulfoxide (DMSO)
was gradually added into the aqueous medium using a syringe pump
(Harvard Apparatus, Holliston, MA) at a speed of 50–100 µL/min. The
concentration of stock solution was adjusted to maintain the nal
organic solvent content below 1% (v/v). A 10 mm ultraviolet (UV) probe
was used to monitor light scattering at non-absorbing wavelengths
ranging from 400 to 450 nm by using a SI Photonics UV/vis spectrom-
eter (Tucson, Arizona). The drug amorphous solubility was considered
as the concentration where an abrupt increase in scattering was
observed [27].
2.3. Nucleation induction time measurement
The nucleation induction time was determined to evaluate the
impact of various polymers on the time until crystals could be detected.
A SI Photonics UV/vis spectrometer (Tuscon, Arizona), coupled with a
10 mm probe was used for the measurements as described previously.
[28] The increase in scattering resulting from the nucleation and growth
of crystals was monitored at 30 s intervals by measuring the extinction at
a non-absorbing wavelength (440 nm). The time until crystals were
detected was evaluated at 37 ◦C at a concentration corresponding to the
amorphous solubility of the drug in HCl solution, pH 1.6 or in PBS, pH
6.5. The ability to inhibit drug crystallization was determined with
various polymers added to the PBS at a concentration of 300
μ
g/mL.
2.4. Salt preparation and characterization
The salt form of DLM was prepared using a Buchi Rotavapor-R
(Newcastle, Delaware). DLM free base and sulfonic acid were added at
drug-acid 1:1 molar ratio in a mixture of DCM and acetone (1:1 v/v)
where alcoholic solvents were avoided to prevent the formation of alkyl
esters during salt synthesis [29]. Solvents were removed by rotary
evaporation at 40 ◦C. DLM salts were then kept under vacuum at room
temperature overnight to remove residual solvents. DLM salts were
characterized by
1
H-nuclear magnetic resonance (NMR) spectroscopy to
conrm salt formation. Their physical and chemical stability were
monitored following storage at 40 ◦C/75% relative humidity (RH) by
measuring several physicochemical properties, including crystallinity
(by powder X-ray diffraction, PXRD), impurities (by
19
F NMR spec-
troscopy), drug content (by HPLC as described above) and hygroscop-
icity (using dynamic vapor sorption analysis).
2.5. Dynamic light scattering
The size of DLM-rich droplets formed above the amorphous solubility
was measured by dynamic light scattering (DLS) using a Nano-Zetasizer
(Nano-ZS, Malvern Instruments, Westborough, MA). Nanodroplets were
generated by adding a stock solution of delamanid in acetonitrile (10
mg/mL) into PBS pH 6.5 at 37 ◦C with stirring at 300 rpm. To evaluate
the impact of polymers on nanodroplet stability, polymers were pre-
dissolved in solution at a concentration of 300
μ
g/mL and drug was
introduced at 50
μ
g/mL. Samples were monitored for up to 3 h after
liquid–liquid phase separation was initiated. The impact of select poly-
mers (HPMCAS and HPMCP) on nanodroplet formation was also eval-
uated as a function of drug concentration in the range of 2–100
μ
g/mL.
2.6. Preparation of DLM ASDs and DLM salt ASDs
ASDs of DLM free base and DLM salts were prepared using a Buchi
Rotavapor-R (Buchi, Newcastle, DE). ASDs of DLM free base with
HPMCAS and HPMCP were prepared by dissolving both components in
DCM-MeOH (1:1 v/v), followed by evaporation. The drug-to-polymer
ratio in the binary formulations is expressed as the mass ratio. DLM
salt ASDs were prepared in situ by dissolving drug, polymer and acid in a
mixture of DCM and acetone (1:1, v/v), avoiding MeOH to prevent the
esterication reaction between sulfonic acids and alcohols [30,31]. The
drug-counterion was kept at a 1:1 molar ratio. After removing solvents
using a rotary evaporator at 40 ◦C, ASD samples were kept under a
vacuum at room temperature overnight, cryo-milled, and sieved to
obtain the desired particle size fraction of 106–250
μ
m.
2.7. Powder X-ray diffraction (PXRD)
Crystallinity of ASDs and DLM salts was evaluated using a Rigaku
Smartlab diffractometer (Rigaku Americas, The Woodlands, TX) equip-
ped with a Cu–K
α
radiation source and a D/tex ultradetector. Samples
were added to glass sample holders, and powder patterns were recorded
over the range of 4-40◦2θ at a scanning speed of 4◦per min and a 0.02◦
step size with the voltage and current set to 40 kV and 44 mA,
respectively.
T.V. Duong et al.
European Journal of Pharmaceutics and Biopharmaceutics 174 (2022) 131–143
134
2.8. Differential scanning calorimetry (DSC)
The glass transition temperatures (T
g
) of drug, polymers and ASD
samples were determined using a TA Q2000 DSC equipped with an
RCS90 refrigeration unit (TA Instruments, New Castle, DE). The tem-
perature calibration was performed using indium and tin, while
enthalpy calibration was conducted with indium. Samples (5–10 mg)
were added to aluminum pans with a pinhole lid (Tzero pan, TA In-
strument, DE). The sample was equilibrated at 0 ◦C and then heated
from 0 to 210 ◦C at 10 ◦C/min and then cooled back down to 0 ◦C at
20 ◦C/min under a nitrogen ow of 50 mL/min. The heating and cooling
cycle was repeated 3 times to remove residual solvent and thermal
history, and the last cycle was used for analysis.
2.9. Infrared (IR) spectroscopy
The IR spectra of bulk polymers, drug and ASDs were collected in the
attenuated total reectance (ATR) mode using a Bruker Vertex 70 FTIR
spectrometer (Billerica, MA) equipped with a Golden Gate ATR acces-
sory (Specac, Orpington, Kent, UK). The spectrum of each sample was
the average of triplicate runs of 32 scans and a resolution of 4 cm
−1
. The
data were analyzed using OPUS software (version 7.2, Bruker, Billerica,
MA).
2.10. Water sorption analysis
Water sorption proles of DLM salts and ASDs were measured by
using a SGA-100 symmetrical gravimetric analyzer (TA Instrument, New
Castle, DE) at 37
◦
C. Samples (10–20 mg) were ushed with dry air for 3
h. After drying, samples were exposed to increasing relative humidity
(RH) steps from 5 to 95% with a maximum step time of 180 min. Vapor
sorption proles are recorded as the equilibrium value (the weight
change was below 0.001%/min over 5 min) at each RH.
2.11.
1
H NMR and
19
F NMR spectroscopy
Salt formation was conrmed by
1
H nuclear magnetic resonance
(NMR) spectroscopy and impurities in DLM salts following preparation
and storage were detected by
19
F NMR spectroscopy. Samples were
dissolved in dimethyl sulfoxide-d6 (Cambridge Isotope Laboratories,
Inc., Andover, MA) at a concentration of 20 mg/mL. All NMR spectra
were acquired on a Bruker DRX 500 MHz spectrometer (Karlsruhe,
Germany) equipped with a BBFO z-gradient probe operating at room
temperature. For
1
H NMR spectra, the spectral sweep width was 20 ppm,
acquisition time was 1.6 sec and number of scans was 16. For
19
F NMR
spectroscopy,
1
H was decoupled during acquisition, spectral sweep
width was 50 ppm, acquisition time was 1.4 sec and the number of scans
was 64.
2.12. Release testing
The ASDs were mixed with excipients and compressed to obtain
tablets containing 5 mg DLM with respect to the free base. The tablet
formulation is summarized in Table S1. All dissolution studies of DLM
tablets were conducted in triplicate in single-stage or two-stage pH-shift
condition using a Hanson Vision G2 Classic 6 dissolution system (Tele-
dyne Hanson Research, Chatsworth, CA). For single-stage testing, the
tablets containing the ASDs were added to 50 mL PBS, pH 6.5 and
monitored for 1 h at 37◦C, with 150 rpm of stirring. For pH-shift ex-
periments, release in the acidic stage was conducted in 45 mL HCl so-
lution pH 1.6 for 1 h, followed by addition of 5 mL concentrated PBS (pH
7.3) to adjust the pH of solution to pH 6.5 and drug release was moni-
tored for an additional 30 min. An in situ Rainbow ber optic ultraviolet
spectrometer coupled with 10 mm ber optic dip probes (Pion, Billerica,
MA, USA) was used to monitor drug concentration over time. Second
derivative analysis was applied to correct the spectral baseline and a
calibration curve of area under curve (AUC) of the range 330–350 nm
was used to calculate the drug concentration.
3. Results
3.1. Physicochemical properties of delamanid and delamanid ASDs
3.1.1. Physicochemical properties and solubility of DLM free base
Physical properties of delamanid are summarized in Table 1.
Delamanid is a weakly basic compound (pKa has been reported as 3.99
[32] or 4.3 [2]) and exhibits pH-dependent solubility (Table 1).
Delamanid has crystalline and amorphous solubility values in FaSSGF of
17.6 ±1.5 and 69.9 ±2.6 µg/mL, respectively (Table 1). However, the
drug is much less soluble at the higher pH value of the intestinal uids.
The crystalline and amorphous solubility values of DLM in PBS pH 6.5
were found to be 0.018 ±0.003 and 0.76 ±0.02 µg/mL, respectively.
Higher solubility was noted in biorelevant media (FaSSIF V1 and V2),
indicating that DLM undergoes solubilization in mixed bile salt/lecithin
micelles.
Delamanid has T
g
of 43.3 ◦C and shows a high tendency to crystallize
in both the solid state and from aqueous solution. Amorphous delamanid
could not be generated by cooling from the melt at a cooling rate as high
as 50 ◦C/min (Fig. S1). Fast nucleation and crystal growth were also
observed in both low and high pH environment with induction times
(t
ind
) of 2.4 ±0.5 and 10.7 ±1.2 min, respectively, for a supersaturation
corresponding to the amorphous solubility.
3.1.2. Impact of polymers on induction time and nanodroplet size stability
Some polymers have been demonstrated as effective drug crystalli-
zation inhibitors in solution, with effectiveness attributed to the for-
mation of intermolecular interactions with the drug [35,36]. In this
study, two neutral polymers (HPMC and PVPVA) and three weakly
acidic polymers (Eud-L100, HPMCP and HPMCAS) were evaluated for
their solution crystallization inhibition effectiveness at a polymer con-
centration of 300 µg/mL (Fig. 2A). Induction times were measured in
PBS pH 6.5 where both neutral and enteric polymers are soluble. At a
supersaturation corresponding to the amorphous solubility of delamanid
(0.76 ±0.02 µg/mL), the drug showed rapid nucleation and crystal
growth (induction time of 10.7 ±1.2 min). For the neutral polymers,
PVPVA showed good inhibition of drug crystallization where the su-
persaturation was maintained for more than 1000 min, whereas in the
presence of HPMC, crystallization commenced in about 50 min. For the
weakly acidic polymers, Eud-L100 was ineffective as the induction time
was similar to that observed in the absence of the polymer (10.2 ±3.1
min). In contrast, HPMCP and HPMCAS were highly effective at inhib-
iting crystallization of delamanid with no crystallization observed
within 1000 min.
Besides inhibiting crystallization, polymers can also stabilize the
drug-rich droplets formed when the amorphous solubility is exceeded
Table 1
Physicochemical properties and solubility of delamanid free base.
Parameter Value
Log P 5.67 [33]; 6.14 [34]*
pK
a
3.99 [32]
**
; 4.3 [2]
T
g
(◦C) 43.3 ±0.4
Melting temperature (◦C) 196.1 ±0.5
Solubility (µg/mL) Crystalline Amorphous
FaSSGF 17.6 ±1.5 69.9 ±2.6
FaSSIF V1 0.52 ±0.12 7.93 ±0.11
FaSSIF V2 0.086 ±0.009 3.11 ±0.11
PBS pH 6.5 0.018 ±0.003 0.76 ±0.02
Induction time (min)
FaSSGF (pH 1.6) 2.4 ±0.5
PBS (pH 6.5) 10.7 ±1.2
*
predicted log P calculated by ALOGPS.
**
predicted pKa.
T.V. Duong et al.
European Journal of Pharmaceutics and Biopharmaceutics 174 (2022) 131–143
135
[37]. At a concentration of 50 µg/mL (>50 times higher than delamanid
amorphous solubility), drug-rich nanodroplets were formed but crys-
tallized immediately in the absence of polymer. The polymers delayed
crystallization, allowing nanodroplet size to be probed. The initial size
of the nanodroplets in the presence of different polymers followed the
trend: HPMCP ~ PVPVA <HPMCAS <HPMC <Eud-L100 (Fig. 2B).
However, nanodroplets were short-lived in Eud-L100 and HPMC solu-
tions, where crystallization occurred at short time frames, with rapid
increase in the size of the scattering species. PVPVA inhibited crystal-
lization, but nanodroplets gradually ripened, increasing in size with
time. On the other hand, there was no notable change in the size of
nanodroplets in HPMCP and HPMCAS solutions over the 3-h period
monitored. Furthermore, these polymers were able to stabilize delam-
anid nanodroplets even when the drug concentration was increased to
100 µg/mL (Fig. 2C). Based on these observations, HPMCP and HPMCAS
were selected to prepare DLM ASDs.
3.1.3. Characterization of DLM free base ASDs
ASDs of DLM free base prepared with either HPMCAS or HPMCP by
rotary evaporation were found to contain residual crystallinity imme-
diately following preparation, for DLs >10–15%. PXRD data in Fig. 3A
shows evidence of drug crystallinity at 15% drug loading for HPMCAS
and 20% drug loading for HPMCP. Delamanid has a much lower T
g
(43.3 ◦C) than the polymers (121.0 ◦C and 120.1 ◦C for HPMCAS and
HPMCP, respectively) and DLM was an effective plasticizer; the T
g
values of the ASDs were lowered with increasing amounts of drug
(Fig. 3B). Crystalline delamanid free base was non-hygroscopic with
very low water sorption (Fig. 3C). In contrast, the neat polymers showed
higher water sorption with about 11–12% water being absorbed at 95%
RH. The hygroscopicity was reduced with increasing drug loading in the
ASDs. No specic intermolecular interactions between drug and poly-
mers were detected by infrared spectroscopy (Fig. S2).
3.1.4. Drug release from DLM free base ASDs
Initial release studies with ASD powders suggested wetting issues
with powder oating on the top of the dissolution vessel; therefore,
release studies were performed with tablets. No wetting issues were
observed with the tablets which showed rapid disintegration and
dispersion of the resultant particles. Due to the fact that similar release
proles were observed for biorelevant media versus buffer (Fig. S3), all
release tests were performed in buffer.
Drug release proles for DLM free base ASD tablets are summarized
in Fig. 4. The maximum theoretical drug concentration for 100% release
is 100 µg/mL, approximately 100 times the amorphous solubility and
the dissolution conditions are thus highly non-sink with respect to both
the crystalline and amorphous solubilities. For crystalline drug, no
release was detected in PBS pH 6.5, while a concentration of around 20
µg/mL was observed in the pH shift experiment, due to the initially
higher solubility in a low pH environment.
The ASD formulation with the enteric polymers considerably
Fig. 2. Impact of polymer on delamanid induction time and nanodroplet size stability: (A) Induction time in the presence of polymer at a concentration of 300 µg/
mL. For PVPVA, HPMCP, and HPMCAS, no crystallization was observed for up to 1000 min; (B) Nanodroplet size as a function of time at an initial drug concentration
of 50 µg/mL, and a polymer concentration of 300 µg/mL; (C) Droplet size as a function of drug concentration (polymer concentration of 1000 µg/mL, samples were
measured 1 h after preparation).
T.V. Duong et al.
European Journal of Pharmaceutics and Biopharmaceutics 174 (2022) 131–143
136
improved the drug release, especially at low drug loadings, where the
drug was maintained in the amorphous state in the ASD matrix following
preparation. Complete release was observed in both the single-stage test
and the pH-shift experiment when the drug loading was only 10%, for
ASDs with both polymers. Importantly, both enteric polymers were able
to prevent crystallization from the supersaturated solution formed
following drug release.
However, the higher drug loading ASDs, which contained residual
crystallinity, based on the PXRD analysis (Fig. 3A), performed poorly.
Presumably, the DLM crystals present in the ASD were able to grow
either in the hydrated matrix, or after release into solution, reducing the
achievable supersaturation and leading to poor release, as observed in
other systems [38,39]. For HPMCP, the drug release dropped to 50% for
the 20% DL ASD, which further decreased to 20% for the 25% DL. The
decrease in release on increasing the DL from 20 to 25% DL was
consistent with the greater extent of crystallinity in the latter sample
(Fig. 3A). Similarly, ASDs with HPMCAS also showed a notable decrease
of drug release when the drug loading increased from 10% to 20%,
corresponding the greater tendency of these ASDs to crystallize during
preparation. Interestingly, the drug release rate was rapid for all systems
Fig. 3. Physical properties of DLM ASDs with HPMCAS and HPMCP as a function of drug loading: (A) PXRD patterns; (B) DSC thermograms showing T
g
and (C) water
sorption proles.
T.V. Duong et al.
European Journal of Pharmaceutics and Biopharmaceutics 174 (2022) 131–143
137
and reached a plateau level within 5–10 min. In general, comparing
between the two polymers, HPMCP ASDs exhibited better release than
HPMCAS ASDs at comparable DLs.
3.1.5. Dissolution performance of Deltyba
TM
tablet
The marketed product (Deltyba
TM
) contains an ASD of delamanid
with HPMCP, prepared by spray drying. The estimated drug loading
relative to polymer is ~20–25%, based on the results of reverse engi-
neering experiments (as described in the Appendix A). Fig. 5 shows that
there is incomplete release from the reference product in both single
stage and pH-shift experiments. A maximum drug concentration of
about 20 µg/mL was obtained in PBS pH 6.5, which was similar to the
DLM ASD with HPMCP at a 25% DL (Fig. 4A). In the pH-shift dissolution
measurement, higher drug release was noted in the acid stage (about 45
µg/mL) followed by a small extent of additional release upon moving to
higher pH environment, although release was incomplete.
3.2. Salt formation and characterization of DLM salts
Salts of DLM with a variety of sulfonic acids (molecular properties of
counterions are summarized in Table S2) were evaluated to identify the
best candidates for incorporation into ASDs.
The solution-state
1
H NMR spectral comparison of DLM free base and
DLM edisylate reveals that salt formation has a substantial impact on the
1
H spectra of DLM. The peaks assigned to protons of the piperidine ring
Fig. 4. Drug release proles of DLM ASDs as a function of drug loading in (A) PBS pH 6.5 and (B) pH-shift experiment. Dashed line indicates the shifting of pH from
1.6 to 6.5.
Fig. 5. Dissolution prole of Deltyba
TM
tablet in PBS pH 6.5 (blue) or pH-shift
experiment (black). Dash line indicates pH shift from acidic into intestinal
environment. (For interpretation of the references to color in this gure legend,
the reader is referred to the web version of this article.)
T.V. Duong et al.
European Journal of Pharmaceutics and Biopharmaceutics 174 (2022) 131–143
138
of the free base signicantly shifted downeld in the salt due to the
protonation of the tertiary amine group following interaction with the
sulfonic acid that changed the electron density of the adjacent atoms
(Fig. S4). In contrast, almost no change was observed for protons near
the imidazole ring (Fig. S4). This suggested that the piperidine ring is
the site of ionization for salt formation. Further evidence of salt for-
mation, specically protonation of a nitrogen group, is provided in
Fig. S5, with the appearance of a very broad and intense infrared peak in
the range from 2770 to 2380 cm
−1
(maximum peak at 2519 cm
−1
) in
sulfonate salts, which was assigned to the characteristic tertiary N
+
-H
stretching vibration [40]. Methylene groups next to the nitrogen atom in
the tertiary amine group of the free base resulted in bands at 2816 cm
−1
which were absent from the salt spectra. The protonation of the tertiary
amine group increased the C-H binding constant, displacing these bands
to a higher frequency region, causing them to overlap with other bands
in this spectral range (such as C-H stretch aromatic and aliphatic)
[41–44].
Fig. 6A shows partial crystallization for the DLM-napadisylate salt
while all other DLM sulfonate salts could be readily produced in amor-
phous form. Salt formation resulted in an increased hygroscopicity
relative to DLM free base (Fig. 6B). The highest moisture sorption was
observed for the mesylate salt with approximately 21% water uptake at
95% RH. In addition, several salts appeared to undergo liquefaction
(presumably due to a high extent of plasticization by water) following
storage at 40 ◦C/75% RH including mesylate, esylate, tosylate, besylate
and closylate salts (Fig. 6B and Table 2). Less hygroscopicity was noted
for aromatic sulfonic salts, which can be attributed to the more lipo-
philic properties of these counterions.[45] Furthermore, excess coun-
terion in the DLM-edisylate (1:1) salt led to increased water sorption
(59% at 95% RH). The induction times (t
ind
) at the amorphous solubility
for the DLM salts and free base were similar as expected; around 2 min in
FaSSGF and less than 20 min in PBS pH 6.5 (Table 2).
Salt formation with sulfonic acids at a drug-counterion of 1:1 molar
ratio led to an increase in T
g
of DLM salts as compared with DLM free
base (Table 2). The highest T
g
compound was the DLM-edisylate (2:1)
salt (117.8 ◦C). However, the presence of excess counterion resulted in a
notable decrease in T
g
(53.9 ◦C for DLM-edisylate (1:1) salt).
The stability of DLM sulfonate salts was monitored for 2 weeks under
open dish accelerated storage conditions of 40 ◦C/75% RH. All initially
amorphous DLM salts were physically stable over this time period, and
no peaks were detected from the PXRD patterns (Fig. S6). Impurities and
drug content were evaluated by
19
F NMR spectroscopy and HPLC
analysis. Impurity peaks were observed in the
19
F NMR spectra of DLM-
closylate, DLM-camsylate, DLM-edisylate (2:1) and DLM-tosylate salts,
with DLM-closylate and DLM-camsylate salts showing the largest rela-
tive peak areas (2.3% and 2.0%, respectively) (Table 2 and Fig. S7A).
Similarly, drug content was found to decrease in these four salts, in
particular DLM-closylate and DLM-camsylate (Fig. S7B). Based on the
physicochemical properties and stability of the various salts, four salts
were selected for ASD formation, namely the besylate, edisylate (2:1),
mesylate and tosylate salts.
3.3. Characterization of DLM salt ASDs
3.3.1. Moisture sorption and T
g
of DLM salt ASDs
DLM salt ASDs were prepared in situ with HPMCAS-LF and HPMCP
HP-50 by rotary evaporation. In general, DLM salt ASDs showed higher
water sorption than ASDs containing DLM free base. For example, for a
20% DL HPMCAS ASD, the water content for the free base was about 8%
at 95% RH (Fig. 3C), while DLM salt ASDs had water contents in the
range of 10–14% (Fig. 7A). ASDs containing salts exhibited higher T
g
s
than ASDs with the corresponding free base. The T
g
of the 20% DL free
base ASD with HPMCAS was ~87 ◦C (Fig. 3B) while the T
g
s of DLM salt
ASDs were above 100 ◦C (Fig. 7B). The DLM-edisylate ASD yielded the
highest T
g
of 117.0 ◦C, which is consistent with the high T
g
of the neat
salt (Table 2).
3.3.2. Release proles of DLM salt ASDs
Drug release proles from ASDs as a function of drug loading were
evaluated with the DLM-edisylate salt. The neat DLM-edisylate showed
no release in PBS pH 6.5 (Fig. 8A). In an acidic medium, the release of
neat DLM-edisylate (Fig. 8B) was slightly higher than that observed for
DLM free base (Fig. 4B) but was lower than the drug amorphous
solubility.
DLM-edisylate ASDs with 10–40% DL showed enhanced release
relative to DLM free base ASDs (Fig. 4). In PBS pH 6.5, ASDs with
HPMCAS exhibited nearly complete release for DLs from 10 to 30%,
while the DL boundary of good release for ASDs of HPMCP was 25%
(Fig. 8A). For pH-shift experiments, HPMCAS ASDs were found to
release drug to a greater extent in the acidic media relative to the cor-
responding HPMCP ASDs (Fig. 8B). However, under fasted-state intes-
tinal pH conditions, drug release was better from HPMCP ASDs. For
HPMCAS ASDs, only the 10% DL system showed almost complete
release in the two-stage dissolution test, while for HPMCP ASDs with
DLM-edisylate, good release was observed for DLs as high as 25%. In
addition, stable drug-rich nanodroplets were generated in the
Fig. 6. Physical properties of DLM sulfonate salts (A) XRPD diffractograms and (B) Water sorption proles.
T.V. Duong et al.
European Journal of Pharmaceutics and Biopharmaceutics 174 (2022) 131–143
139
dissolution medium at various DLs (Fig. S8). In general, ASDs of HPMCP
yielded smaller drug-rich droplets than those with HPMCAS, similar to
ndings from the solvent-shift experiments (Fig. 2).
Fig. 9 provides a summary of the counterion impact on drug release,
at a 25% DL with HPMCP. All four sulfonate salts showed a similar
pattern with near-complete release in the single-stage test in PBS pH 6.5
medium (Fig. 9A). In acidic medium, the concentration released ranged
from 20 to 35 µg/mL, with the highest amount observed for the DLM-
edisylate ASD. Despite differences in the extent of drug release in the
gastric stage, all formulations exhibited rapid and essentially complete
release when the pH was increased from 1.6 to 6.5 (Fig. 9B).
4. Discussion
4.1. Salt formation and crystallization tendency
Delamanid is a poorly water-soluble compound with a high tendency
to crystallize. Several factors might impact glass forming ability and
crystallization tendency, including the free energy difference between
the crystalline and amorphous states, molecular mobility of the amor-
phous material, molecular weight and complexity, and differences in
intermolecular interaction patterns in the crystal versus amorphous
materials [46]. It has been proposed that the solubility difference be-
tween the amorphous (C
a
) and crystalline (C
s
) forms of a drug compound
at a given temperature (T) is directly related to the free energy difference
(ΔG) between the two forms: ΔG =-RT ln(C
a
/C
s
) (1), where R is the gas
constant.[47].
ΔG can be estimated from the Hoffman equation as following [48]:
ΔG= − ΔHf(Tm−T)T
T2
m
(2)
in which ΔH
f
is the enthalpy of fusion measured at the melting point
(T
m
).
By using the ΔH
f
and T
m
values obtained from the DSC thermogram
(Fig. S1), the solubility ratio of amorphous DLM relative to its crystal-
line counterpart at 37 ◦C was calculated to be 31.8, which is in
reasonable agreement with the experimental ratio of 42.3 (Table 2).
Delamanid crystallizes during cooling from the melt at 50 ◦C/min
and hence is a poor glass former (Class I compound).[46] Glassy
delamanid can be obtained by quenching the melt in liquid N
2
, yet de-
vitries upon heating to just above the T
g
(Fig. S9). The poor glass
stability of delamanid makes it challenging to prepare crystal-free ASDs
via rotary evaporation, for drug loadings >10%. The solvent evapora-
tion rate plays an important role in determining if material can be
trapped in a metastable state before nucleation and crystal growth can
occur [46,49]. Clearly, the solvent evaporation rate using rotary evap-
oration was not fast enough to prevent crystal nucleation and growth,
even in the presence of a polymer, for delamanid DLs of interest, leading
to ASDs with residual crystallinity (Fig. 3A). It is likely that ASD for-
mation methods that achieve faster evaporation rates, e.g. spray drying,
could lead to crystal-free ASDs at higher drug loadings.
Salt formation led to increased glass transition temperatures and
enhanced the stability of amorphous salts against crystallization. Neat
amorphous DLM salts could be readily prepared by solvent evaporation
and showed remarkable stability to crystallization when exposed to
harsh storage conditions, with the exception of the napadisylate salt.
Table 2
Physicochemical properties of DLM sulfonate salts.
Property Besylate Camsylate Closylate Edisylate (2:1) Esylate Mesylate Tosylate Napadisylate (2:1)
%DLM in the salt 77 70 74 85 83 85 76 79
Amorphous Y Y Y Y Y Y Y N
T
g
(
o
C) 85.1 97.9 90.1 117.8 83.7 86.2 90.2 N/A
t
ind
in FaSSGF (min) 1.1 1.3 1.1 0.6 1.0 1.1 1.0 N/A
t
ind
in PBS pH 6.5 (min) 16.6 14.7 14.1 16.0 19.7 15.7 18.5 N/A
Water sorption (%) at 95 % RH 7.1 8.1 5.8 11.6 16.2 21.1 6.1 N/A
Stability (2 weeks, 40 ◦C/RH 75%)
Liquefaction +– – – + + + N/A
Amorphous Y Y Y Y Y Y Y N/A
Impurity (
19
F NMR) (%) 0.5 2.0 2.3 1.0 0.7 0.3 1.0 N/A
Drug content reduction (%) 0.5 6.1 3.1 0.8 N/A 2.8 2.1 N/A
t
ind
induction time; N/A not applicable.
Fig. 7. (A) Water sorption proles and (B) glass transition temperature of DLM salt ASDs with HPMCAS at 20% drug loading.
T.V. Duong et al.
European Journal of Pharmaceutics and Biopharmaceutics 174 (2022) 131–143
140
This strategy was thus highly successful in enabling higher DL ASDs to
be prepared with no detectable residual crystallinity, demonstrating that
the low crystallization tendency of the salts translated to the ASD during
preparation and storage. Historically, salt formation has been used to
improve the crystallinity of a given drug. There are relatively few studies
on improving glass forming ability through salt formation [10,19,50],
Fig. 8. Drug release from DLM-edisylate ASDs as a function of drug loading in (A) PBS pH 6.5 and (B) pH-shift experiments. Dashed lines indicate the pH change from
pH 1.6 to pH 6.5.
Fig. 9. Release proles of DLM sulfonate salt ASDs with HPMCP at a 25% drug loading in (A) PBS pH 6.5 and (B) pH-shift experiment. Dashed lines indicate the pH
change from pH 1.6 to pH 6.5.
T.V. Duong et al.
European Journal of Pharmaceutics and Biopharmaceutics 174 (2022) 131–143
141
although just as counterions can promote formation of an ordered
crystal lattice, it can be anticipated that they can equally effectively
disrupt the lattice, depending on the nature of the counterion, and the
site of ionization. For delamanid, the site of ionization is the piperidine
ring. We can speculate that salt formation disrupts the ability the long,
thin delamanid molecules to line up to form an ordered crystal structure,
although unfortunately, the single crystal structure of this molecule has
not been obtained to date.
4.2. Factors impacting delamanid release from ASDs
Amorphous solid dispersions are an effective strategy to generate a
supersaturated solution of the drug [51,52]. The polymers used to form
the ASD matrix play a critical role in kinetically stabilizing the super-
saturated solution generated upon drug release and are thought to
inhibit drug crystallization via the formation of non-specic interactions
between the drug and polymers [35,36]. However, not all polymers are
equally effective at maintaining supersaturation. Herein, PVPVA,
HPMCAS and HPMCP were found to be effective solution crystallization
inhibitors, extending the induction time from a few minutes to up to
>12 h (Fig. 2A). However, size enlargement of DLM-rich droplets
occurred in presence of PVPVA, as observed for other systems [37].
Given that drug-rich nanodroplets are thought to be important in
improving oral bioavailability for some drugs [53,54], where nano-
droplet size may play a role [55], PVPVA shows disadvantages for ASD
formulations relative to HPMCAS and HPMCP. Indeed, the high sensi-
tivity of delamanid to the polymer used to form that ASD is highlighted
in Fig. S10, where the enteric polymers facilitate drug release to a much
greater extent than the two neutral polymers evaluated [56].
Although HPMCAS and HPMCP are very good at inhibiting crystal-
lization from highly supersaturated delamanid solutions, these polymers
are less effective at preventing crystallization of DLM free base during
ASD fabrication via solvent evaporation, leading to residual crystallinity
in ASDs above a threshold drug loading. Residual crystals directly result
in lost solubility advantage and, for some drugs, can act as seeds for
additional crystal growth during matrix hydration and drug release
[38,39]. For delamanid, once any level of residual crystallinity could be
detected in the ASD, release was incomplete during dissolution testing
(Fig. 3A). This can be explained by the growth of crystals formed during
the manufacturing process which competes with the dissolution of the
surrounding amorphous material [39]. Further, the low release indicates
that the polymers are unable to substantially delay crystal growth in
hydrated conditions, making residual crystallinity extremely detri-
mental to ASD performance. This is different from the case of indo-
methacin, where residual crystals were found to be effectively poisoned
by the ASD polymer [39], but similar to tacrolimus [38,57], and bica-
lutamide [58] dispersions with residual crystallinity, where trace crys-
tallinity substantially impacted release extent. Interestingly, HPMCAS
ASDs appeared to contain a higher extent of residual crystallinity than
the corresponding HPMCP ASDs at a comparable drug loading (20% DL,
Fig. 4), which in turn translated to a lower extent of release for the
former systems. Notably, the marketed product (Deltyba
TM
) contains a
spray dried ASD with HPMCP, with an estimated drug loading relative to
polymer of 20–25%. Higher drug release is observed in acidic medium,
relative to our formulation. However, following transfer to pH 6.5
media, the maximum extent of release is approximately 60% from both
Deltyba
TM
tablets (Fig. 5) and our 25% DL free base HPMCP ASD
formulation (Fig. 4). This may indicate a similar failure mechanism for
Deltyba
TM
ASDs as for the 25% DL ASD but would require further
investigation.
Preparation of amorphous solid dispersion of salts has been sug-
gested as a promising strategy to combine the benets of amorphization
and salt formation for improved dissolution and stability against crys-
tallization during storage [10]. For delamanid, using certain sulfonic
acid salts in the fabrication of ASDs led to a clear improvement in the
attainable drug loading where crystal-free systems could be obtained
immediately following preparation. The formation of completely
amorphous ASDs with the salts and HPMCP then translates into
improved release for both single-stage and two-stage dissolution (25%
DL, Fig. 8). As for the ASDs of free base, HPMCP solid dispersions with
the salts generally yield improved release proles relative to ASDs with
HPMCAS.
Interestingly, different patterns of release are observed for single-
stage and two-stage dissolution. Several salt ASDs show diminished
release performance when incubated in a low pH environment prior to
shifting to higher pH media. Due to the fact that the polymers are
insoluble at low pH, this observation may suggest physical instability of
the drug remaining in the ASD matrix during the acid immersion stage.
Given the expected variation in gastric pH within patients as a function
of fed and fasted state, and inter-patient pH variations arising from
factors such as age or concomitant mediations (e.g. proton pump in-
hibitors), as well as general variability, further studies of pH effects
should be carried out. Importantly, even higher drug solubility in bio-
relevant media was noted, although there was no difference in release
proles in buffer versus in FaSSIF (Fig. S3). The results presented herein
also suggest that ASD formulations should be subjected to biorelevant
dissolution testing conditions, at least in terms of pH changes, especially
for systems employing enteric polymers and ionizable drugs.
5. Conclusions
Crystallization is a major failure mechanism for ASDs. Herein, we
have demonstrated that drug crystallization tendency can be manipu-
lated via salt formation. Amorphous delamanid was difcult to prepare
and underwent rapid recrystallization. In contrast, several sulfonate
salts remained amorphous for extended periods of time when exposed to
stress storage conditions. By in situ salt formation during ASD manu-
facture, drug crystallization was prevented at higher drug loadings and
release proles were improved. In general, delamanid salt ASDs with
HPMCP outperformed those fabricated with HPMCAS during release
testing. Salt formation, combined with ASD formation, thus provides a
dual strategy to address dissolution and solubility challenges with
poorly soluble compounds that are difcult to formulate using a single
enabling strategy.
Declaration of Competing Interest
The authors declare that they have no known competing nancial
interests or personal relationships that could have appeared to inuence
the work reported in this paper.
Acknowledgements
The authors gratefully acknowledge the Bill and Melinda Gates
Foundation, Seattle, WA for funding this study through award number
OPP1159809. Under the grant conditions of the Foundation, a Creative
Commons Attribution 4.0 Generic License has already been assigned to
the Author Accepted Manuscript version that might arise from this
submission. Otsuka Pharmaceutical Co., Ltd., Tokyo, Japan is
acknowledged for providing DeltybaTM tablets. The authors also thank
Dr. Niraj S. Trasi for performing the reverse engineering experiment as
well as Dr. Huaping Mo and Dr. Qingqing Qi for assistance with NMR
spectroscopy and discussion of the data.
Appendix A. Supplementary material
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.ejpb.2022.04.002.
T.V. Duong et al.
European Journal of Pharmaceutics and Biopharmaceutics 174 (2022) 131–143
142
References
[1] A.H. Diacon, R. Dawson, M. Hanekom, K. Narunsky, A. Venter, N. Hittel, L.
J. Geiter, C.D. Wells, A.J. Paccaly, P.R. Donald, Early bactericidal activity of
delamanid (OPC-67683) in smear-positive pulmonary tuberculosis patients, Int. J.
Tuberc. Lung Dis. 15 (2011) 949–954.
[2] Y. Shimokawa, K. Sasahara, N. Koyama, K. Kitano, M. Shibata, N. Yoda,
K. Umehara, Metabolic mechanism of delamanid, a new anti-tuberculosis drug, in
human plasma, Drug. Metab. Dispos. 43 (2015) 1277–1283.
[3] T. Van Duong, Z. Ni, L.S. Taylor, Phase behavior and crystallization kinetics of a
poorly water-soluble weakly basic drug as a function of supersaturation and media
composition, Mol. Pharm. 19 (4) (2022) 1146–1159.
[4] H. Sugihara, L.S. Taylor, Evaluation of pazopanib phase behavior following pH-
induced supersaturation, Mol. Pharm. 15 (2018) 1690–1699.
[5] H. Sasabe, Y. Shimokawa, M. Shibata, K. Hashizume, Y. Hamasako, Y. Ohzone,
E. Kashiyama, K. Umehara, Antitubercular agent delamanid and metabolites as
substrates and inhibitors of ABC and solute carrier transporters, Antimicrob.
Agents Chemther. 60 (2016) 3497–3508.
[6] T. Mukherjee, H. Boshoff, Nitroimidazoles for the treatment of TB: past, present
and future, Future Med. Chem. 3 (11) (2011) 1427–1454.
[7] N.J. Babu, A. Nangia, Solubility advantage of amorphous drugs and
pharmaceutical cocrystals, Cryst. Growth Des. 11 (2011) 2662–2679.
[8] W. Wu, K. L¨
obmann, T. Rades, H. Grohganz, On the role of salt formation and
structural similarity of co-formers in co-amorphous drug delivery systems, Int. J.
Pharm. 535 (2018) 86–94.
[9] S.V. Bhujbal, B. Mitra, U. Jain, Y. Gong, A. Agrawal, S. Karki, L.S. Taylor, S. Kumar,
Q.i. (Tony) Zhou, Pharmaceutical amorphous solid dispersion: A review of
manufacturing strategies, Acta Pharm. Sin. B. 11 (8) (2021) 2505–2536.
[10] S. Mukesh, P. Joshi, A.K. Bansal, M.C. Kashyap, S.K. Mandal, V. Sathe, A.
T. Sangamwar, Amorphous salts solid dispersions of celecoxib: enhanced
biopharmaceutical performance and physical stability, Mol. Pharm. 18 (2021)
2334–2348.
[11] A.T.M. Serajuddin, Salt formation to improve drug solubility, Adv. Drug Deliv. Rev.
59 (2007) 603–616.
[12] K. Sigfridsson, M. Ahlqvist, M. Lindsj¨
o, S. Paulsson, Salt formation improved the
properties of a candidate drug during early formulation development, Eur. J.
Pharm. Sci. 120 (2018) 162–171.
[13] G.S. Paulekuhn, J.B. Dressman, C. Saal, Trends in active pharmaceutical ingredient
salt selection based on analysis of the orange book database, J. Med. Chem. 50
(2007) 6665–6672.
[14] S.L. Childs, G.P. Stahly, A. Park, The salt−cocrystal continuum: the inuence of
crystal structure on ionization state, Mol. Pharm. 4 (2007) 323–338.
[15] S.S. Bharate, Recent developments in pharmaceutical salts: FDA approvals from
2015 to 2019, Drug Discov. Today 26 (2021) 384–398.
[16] C.S. Towler, L.S. Taylor, Spectroscopic characterization of intermolecular
interactions in solution and their inuence on crystallization outcome, Cryst.
Growth Des. 7 (4) (2007) 633–638.
[17] J.R. Patel, R.A. Carlton, F. Yuniatine, T.E. Needham, L. Wu, F.G. Vogt, Preparation
and structural characterization of amorphous spray-dried dispersions of tenoxicam
with enhanced dissolution, J. Pharm. Sci. 101 (2) (2012) 641–663.
[18] H. Nie, S.R. Byrn, Q. Zhou, Stability of pharmaceutical salts in solid oral dosage
forms, Drug Dev. Ind. Pharm. 43 (8) (2017) 1215–1228.
[19] C.S. Towler, T. Li, H. Wikstr¨
om, D.M. Remick, M.V. Sanchez-Felix, L.S. Taylor, An
investigation into the inuence of counterion on the properties of some amorphous
organic salts, Mol. Pharm. 5 (6) (2008) 946–955.
[20] Y. Gui, E.C. McCann, X. Yao, Y. Li, K.J. Jones, L. Yu, Amorphous drug-polymer salt
with high stability under tropical conditions and fast dissolution: the case of
clofazimine and poly(acrylic acid), Mol. Pharm. 18 (3) (2021) 1364–1372.
[21] D.M. Mudie, S. Buchanan, A.M. Stewart, A. Smith, K.B. Shepard, N. Biswas,
D. Marshall, A. Ekdahl, A. Pluntze, C.D. Craig, M.M. Morgen, J.M. Baumann, D.
T. Vodak, A novel architecture for achieving high drug loading in amorphous spray
dried dispersion tablets, Int. J. Pharm.: X 2 (2020), 100042.
[22] H. Mesallati, A. Umerska, K.J. Paluch, L. Tajber, Amorphous polymeric drug salts
as ionic solid dispersion forms of ciprooxacin, Mol. Pharm. 14 (2017) 2209–2223.
[23] I. Weuts, D. Kempen, G. Verreck, J. Peeters, M. Brewster, N. Blaton, G. Van den
Mooter, Salt formation in solid dispersions consisting of polyacrylic acid as a
carrier and three basic model compounds resulting in very high glass transition
temperatures and constant dissolution properties upon storage, Eur. J. Pharm. Sci.
25 (2005) 387–393.
[24] A. Haser, T. Cao, J.W. Lubach, F. Zhang, In situ salt formation during melt
extrusion for improved chemical stability and dissolution performance of a
meloxicam-copovidone amorphous solid dispersion, Mol. Pharm. 15 (2018)
1226–1237.
[25] X. Liu, L. Zhou, F. Zhang, Reactive melt extrusion to improve the dissolution
performance and physical stability of naproxen amorphous solid dispersions, Mol.
Pharm. 14 (2017) 658–673.
[26] G.A. Ilevbare, L.S. Taylor, Liquid–liquid phase separation in highly supersaturated
aqueous solutions of poorly water-soluble drugs: implications for solubility
enhancing formulations, Cryst. Growth Des. 13 (4) (2013) 1497–1509.
[27] L.S. Taylor, G.G.Z. Zhang, Physical chemistry of supersaturated solutions and
implications for oral absorption, Adv. Drug Deliv. Rev. 101 (2016) 122–142.
[28] G.A. Ilevbare, H. Liu, K.J. Edgar, L.S. Taylor, Maintaining supersaturation in
aqueous drug solutions: impact of different polymers on induction times, Cryst.
Growth Des. 13 (2013) 740–751.
[29] D.P. Elder, D.J. Snodin, Drug substances presented as sulfonic acid salts: overview
of utility, safety and regulation, J. Pharm. Pharmacol. 61 (2009) 269–278.
[30] A. Teasdale, E.J. Delaney, S.C. Eyley, K. Jacq, K. Taylor-Worth, A. Lipczynski,
W. Hoffmann, V. Reif, D.P. Elder, K.L. Facchine, S. Golec, R. Schulte Oestrich,
P. Sandra, F. David, A Detailed study of sulfonate ester formation and solvolysis
reaction rates and application toward establishing sulfonate ester control in
pharmaceutical manufacturing processes, Org. Process Res. Dev. 14 (2010)
999–1007.
[31] D.P. Elder, E. Delaney, A. Teasdale, S. Eyley, V.D. Reif, K. Jacq, K.L. Facchine, R.
S. Oestrich, P. Sandra, F. David, The utility of sulfonate salts in drug development,
J. Pharm. Sci. 99 (2010) 2948–2961.
[32] ChemicalBook, OPC-67683.
[33] ChemSpider, Delamanid.
[34] Y. Dashti, T. Grkovic, R.J. Quinn, Predicting natural product value, an exploration
of anti-TB drug space, Nat. Prod. Rep. 31 (2014) 990–998.
[35] A.L. Sarode, P. Wang, S. Obara, D.R. Worthen, Supersaturation, nucleation, and
crystal growth during single- and biphasic dissolution of amorphous solid
dispersions: Polymer effects and implications for oral bioavailability enhancement
of poorly water soluble drugs, Eur. J. Pharm. Biopharm. 86 (2014) 351–360.
[36] K. Ueda, K. Higashi, M. Kataoka, S. Yamashita, K. Yamamoto, K. Moribe, Inhibition
mechanism of hydroxypropyl methylcellulose acetate succinate on drug
crystallization in gastrointestinal uid and drug permeability from a
supersaturated solution, Eur. J. Pharm. Sci. 62 (2014) 293–300.
[37] K. Ueda, L.S. Taylor, Polymer type impacts amorphous solubility and drug-rich
phase colloidal stability: a mechanistic study using nuclear magnetic resonance
spectroscopy, Mol. Pharm. 17 (2020) 1352–1362.
[38] S.S. Hate, S.M. Reutzel-Edens, L.S. Taylor, Absorptive dissolution testing: an
improved approach to study the impact of residual crystallinity on the performance
of amorphous formulations, J. Pharm. Sci. 109 (2020) 1312–1323.
[39] D.E. Moseson, A.S. Parker, S.P. Beaudoin, L.S. Taylor, Amorphous solid dispersions
containing residual crystallinity: Inuence of seed properties and polymer
adsorption on dissolution performance, Eur. J. Pharm. Sci. 146 (2020), 105276.
[40] W. Thompson, R. Warren, I. Eisdorfer, J. Zarembo, Identication of primary,
secondary, and tertiary pharmaceutical amines by the infrared spectra of their
salts, J. Pharm. Sci. 54 (1965) 1819–1821.
[41] H.L. Lee, J.M. Vasoya, M.d.L. Cirqueira, K.L. Yeh, T. Lee, A.T. Serajuddin,
Continuous preparation of 1: 1 haloperidol–maleic acid salt by a novel solvent-free
method using a twin screw melt extruder, Mol. Pharm. 14 (2017) 1278–1291.
[42] M. Bitencourt, O.M.M.S. Viana, A.L.M. Viana, J.T.J. Freitas, C.C. de Melo, A.
C. Doriguetto, Buclizine crystal forms: First Structural Determinations, counter-ion
stoichiometry, hydration, and physicochemical properties of pharmaceutical
relevance, Int. J. Pharm. 589 (2020), 119840.
[43] I. Eisdorfer, R. Warren, J. Zarembo, Spectroscopy of amines of pharmaceutical
interest, J. Pharm. Sci. 57 (1968) 195–217.
[44] J.D. Damayanti, D.E. Pratama, T. Lee, Green technology for salt formation: slurry
reactive crystallization studies for papaverine HCl and 1: 1 haloperidol-maleic acid
salt, Cryst. Growth Des. 19 (2019) 2881–2891.
[45] P. Guerrieri, A.C. Rumondor, T. Li, L.S. Taylor, Analysis of relationships between
solid-state properties, counterion, and developability of pharmaceutical salts,
AAPS PharmSciTech 11 (2010) 1212–1222.
[46] B. Van Eerdenbrugh, J.A. Baird, L.S. Taylor, Crystallization tendency of active
pharmaceutical ingredients following rapid solvent evaporation—classication
and comparison with crystallization tendency from undercooled melts, J. Pharm.
Sci. 99 (2010) 3826–3838.
[47] S.B. Murdande, M.J. Pikal, R.M. Shanker, R.H. Bogner, Solubility advantage of
amorphous pharmaceuticals: I. A thermodynamic analysis, J. Pharm. Sci. 99
(2010) 1254–1264.
[48] J.D. Hoffman, Thermodynamic driving force in nucleation and growth processes,
J. Chem. Phys. 29 (1958) 1192–1193.
[49] J.X. Wu, M. Yang, F.v.d. Berg, J. Pajander, T. Rades, J. Rantanen, Inuence of
solvent evaporation rate and formulation factors on solid dispersion physical
stability, Eur. J. Pharm. Sci. 44 (2011) 610–620.
[50] V.M. Sonje, L. Kumar, V. Puri, G. Kohli, A.M. Kaushal, A.K. Bansal, Effect of
counterions on the properties of amorphous atorvastatin salts, Eur. J. Pharm. Sci.
44 (2011) 462–470.
[51] T. Van Duong, G. Van den Mooter, The role of the carrier in the formulation of
pharmaceutical solid dispersions. Part II: amorphous carriers, Expert Opin. Drug
Deliv. 13 (12) (2016) 1681–1694.
[52] T. Van Duong, G. Van den Mooter, The role of the carrier in the formulation of
pharmaceutical solid dispersions. Part I: crystalline and semi-crystalline carriers,
Expert Opin. Drug Deliv. 13 (11) (2016) 1583–1594.
[53] V.R. Wilson, X. Lou, D.J. Osterling, D.F. Stolarik, G.J. Jenkins, B.L.B. Nichols,
Y. Dong, K.J. Edgar, G.G.Z. Zhang, L.S. Taylor, Amorphous solid dispersions of
enzalutamide and novel polysaccharide derivatives: investigation of relationships
between polymer structure and performance, Sci. Rep. 10 (2020) 18535.
[54] A.M. Stewart, M.E. Grass, T.J. Brodeur, A.K. Goodwin, M.M. Morgen, D.T. Friesen,
D.T. Vodak, Impact of drug-rich colloids of itraconazole and HPMCAS on
membrane ux in vitro and oral bioavailability in rats, Mol. Pharm. 14 (2017)
2437–2449.
[55] F. Kesisoglou, M. Wang, K. Galipeau, P. Harmon, G. Okoh, W. Xu, Effect of
amorphous nanoparticle size on bioavailability of anacetrapib in dogs, J. Pharm.
Sci. 108 (2019) 2917–2925.
[56] R. Yang, A.K. Mann, T. Van Duong, J.D. Ormes, G.A. Okoh, A. Hermans, L.
S. Taylor, Drug release and nanodroplet formation from amorphous solid
T.V. Duong et al.
European Journal of Pharmaceutics and Biopharmaceutics 174 (2022) 131–143
143
dispersions: insight into the roles of drug physicochemical properties and polymer
selection, Mol. Pharm. 18 (2021) 2066–2081.
[57] H.S. Purohit, N.S. Trasi, D.D. Sun, E.C.Y. Chow, H. Wen, X. Zhang, Y. Gao, L.
S. Taylor, Investigating the impact of drug crystallinity in amorphous tacrolimus
capsules on pharmacokinetics and bioequivalence using discriminatory in vitro
dissolution testing and physiologically based pharmacokinetic modeling and
simulation, J. Pharm. Sci. 107 (2018) 1330–1341.
[58] D.E. Moseson, I.D. Corum, A. Lust, K.J. Altman, T.N. Hiew, A. Eren, Z.K. Nagy, L.
S. Taylor, Amorphous solid dispersions containing residual crystallinity:
competition between dissolution and matrix crystallization, AAPS J. 23 (2021) 69.
T.V. Duong et al.