Solid Dispersions (ASDs) have been widely accepted as a desired solution for
enhancing solubility and bioavailability of poorly soluble drugs.1 With a trend
in increased number of poorly soluble new chemical entities (NCEs), the industry
is adapting non-conventional formulation technologies, exploiting the existing
polymers, and exploring innovative ones to expedite drug development.2 However,
the applicability of those polymers in such technologies has also created new
challenges associated with processing and manufacturing or thermal instability,
such as hot melt extrusion and Kinetisol®, or residual solvents, such as spray
drying and co-precipitation.3-6
number of polymers, including polyvinylpyrrolidone (PVP), copovidone (PVP-VA),
hydroxypropylmethylcellulose (HPMC), hydropropylmethylcellulose acetate
succinate (HPMCAS), amino methacrylate copolymer among others have been used in
ASD formulations.1c However, a clear understanding of factors responsible for
maintaining supersaturation and stability of drug molecules to overcome precipitation
and retardation of dissolution in the gastrointestinal milieu, and their
impacts on the bioavailability of APIs from polymeric ASDs, is still lacking
and thus highly warranted.7-10
a polyethylene glycol, polyvinyl acetate and polyvinylcaprolactame-based graft
copolymer (PVAc-PVCap- PEG), has been studied extensively in ASDs of several investigational,
and model drugs in hot melt extrusion,11-21 spray drying,22-24 high shear
dispersions, Kinetisol,25 electrospinning/electrospraying,26-27 microwave
radiation,28-29 solvent casting,30 solvent evaporation,31-33 ball milling,34
physical/co-milling blends,35-36 and thermal heating38 amongst others.
article is aimed at understanding the in vitro solubilization of a model drug
CBZ, more specifically, at the interplay between achieved supersaturation and
flux of a model drug from Soluplus amorphous dispersions. The mechanisms
underlying the supersaturation and diffusive flux of drug across membrane from
ASDs will also be discussed and postulated.
(BASF, Florham Park, NJ) was used as received. Carbamazepine was extruded with
Soluplus on a 16-mm twin screw extruder (Thermo Fisher) under the processing
conditions as reported previously.38 A miniature device μFLUX™ together with in
situ fiber optic dissolution monitoring system μDISS Profiler™ (Pion, MA,
Figure 1) were used to measure flux of free drug in receiver compartment
separated from the donor by the artificial membrane.39
Solubilization of CBZ
& CBZ-Soluplus Extrudates: Dissolution of CBZ & CBZ Soluplus Dispersions
in SGF & FaSSIF
2A and 2C illustrate the dissolution and solubility of pure crystalline CBZ in
SGF (pH 1.2) and FaSSIF (pH 6.5) buffers. It is clear that as the dissolution progressed,
the CBZ concentration peaked in the first 30 min reaching approx. 200 μg/ml. As
the dissolution continued, the solubility of CBZ declined due to
re-crystallization equilibrating at ~150 μg/ml, and stayed constant for > 16
hours.40 With Soluplus dispersions, on the other hand, CBZ solubility increased
and peaked at >300 μg/ml, and stayed in supersaturation for over 16 hours
without precipitation in both SGF and FaSSIF media (Figures 2B and 2D). The
solubility of CBZ in ASDs was at least 2-fold higher than that in pure CBZ and
was also independent of pH changes. Because the ASD of CBZ was fully dissolved
in this experiment, the solubility enhancement ratio could not be determined.
Flux of CBZ at pH 7.4
further explore the supersaturation,
the solubility of CBZ was investigated
using 2-chamber μFLUX system. The
donor compartment contained pure
drug or ASD formulation (1mg/mL CBZ
load in pH 7.4 Prisma HT buffer),
while the receiver chamber contained
pH 7.4 buffer and a surfactant to
simulate the sink conditions.39 Figures 3A
and 3B show the concentration – time
profile of CBZ in donor and receiver
chambers, respectively. The CBZ concentration
continued to increase in the
receiver with flux changing slightly depending
on the concentration level in the
Soluplus dispersion, CBZ peaked to
maximum concentration of 1 mg/ml, maintaining
the supersaturation over 4 hours
(240 min) as illustrated in Figure 4A.
It ultimately followed a gradual precipitation,
but the CBZ flux in the receiver
chamber continued to stay nearly
constant despite precipitation of CBZ
in the donor (Figure 4B).
data suggests that flux of free CBZ
in the receiver from Soluplus dispersions
was about 3-fold higher than that
from pure CBZ at pH 7.4 in over 4 hours.
The higher concentration of CBZ in
donor resulted in higher flux of CBZ across
the membrane in receiver during all
phases; dissolution, supersaturation, and
precipitation of drug.
5 illustrates curves from dissolution,
supersaturation, and precipitation processes
during the first 200 min from pure
CBZ (Figure 3B) and Soluplus dispersions
(Figure 4B) at pH 7.4 ASB buffer.
Figure 5 illustrates that despite quick
re-precipitation of CBZ, it was
possible to detect differences between
the initial flux of 1.2 μg-min-1•cm-2
(supersaturation region), the flux
during precipitation (0.92
μg•min-1•cm-2), and the flux when the
concentration of CBZ reached equilibrium
concentration (0.85 μg•min-1•cm-2). The flux from CBZ-Soluplus remained nearly constant within a 0.5-
to 3-hour period and was ~3 times
higher than for pure CBZ. Following
the onset of re-precipitation, it decreased
only slightly from 2.7 to 2.4
study describes the application of
Soluplus, a hydrophilic polymeric solubilizer,
in solid dispersions of a model drug
carbamazepine. The scope of this
study is limited to understanding of
hydrophilic polymers and their behaviors
on amorphous dispersions. Therefore,
the studies from other hydrophilic
polymers have been examined in the
context of drug’s solubility,
loading, precipitation, dissolution,
and supersaturation, and also
compared with Soluplus dispersions. Such
comparisons are necessary to help identify the polymers based on a postulated model for achieving the desired supersaturation.
Dispersions With Hydrophilic Polymers
and Lee studied the effects of infusion
of a hydrophilic polymer (PVP K-90)
on supersaturation of model drugs in amorphous dispersions.41 The gradual infusion
of the crystalline inhibitor PVP increased the maximum indomethacin
concentration and attained the supersaturation much longer as opposed to a
faster infusion, suggesting that the hydration of PVP was critical for achieving
and maintaining a higher kinetic solubility. Like PVP, hydrophilic polymers,
such as HPMC, were also effective and maintained the supersaturation of
felodipine and nifedipine from amorphous dispersions.42
and Brewster observed that the addition of hydrophilic polymers PVP (K-30) and
PEG 400 did not help maintain the supersaturation of an investigation compound
(m.p. 300°C), but the addition of polyoxyl hydrogenated 40 castor oil
(Kolliphor® RH40) with PVP K-30 (1:3), resulted in maintaining the supersaturation.43
Addition of Poloxamer 407 in Soluplus dispersions with carbamazepine not only helped
facilitate the extrusion process but also improved the loading and miscibility of
drug in the polymer, and hence, increased the dissolution rate.12 In a recent
study, vitamin E TPGS (Kolliphor® TPGS) when used in copovidone (PVPVA) extrudates
inhibited the precipitation and increased the miscibility and loading of
carbamazepine and fenofibrate (unpublished).
interactions and complexation originating from Hbonding, ionic, and/or van der
Waal’s interactions of hydrophilic polymers with drugs play an important role
in solubilization, stability, and maintaining supersaturation.44 For example,
Soluplus with multiple interaction sites increased the solubility of
albendazole as high as 50% in amorphous dispersions also maintaining the
supersaturation, while, HPMCAS neither enhanced solubility nor resulted in
supersaturation. With other model drugs, such as fenofibrate, the HPMCAS
performed better than Soluplus and/or HPMCE5 and maintained supersaturation,
and significantly improved the bioavailability in rats.45 In other cases,
HPMCAS performed relatively better than copovidone with itraconazole
dispersions, presumably due interactions between an alkaline drug and an acidic
polymer,46 while it performed sluggish as compared with Soluplus dispersion.23 In
cases where drugs are sensitive to acidic or alkaline, changing the
microenvironment pH or counter-ions of ASD might be equally important for
preventing re-crystallization and achieving the supersaturation, and increasing
the kinetic solubility insolution.21 In a recent study, inclusion of Soluplus
in atorvastatin calcium dispersions also prevented recrystallization, and
achieved 3.6-fold higher bioavailability in rats from amorphous dispersions as
compared to physical mixtures.22 In our study, solubilization of CBZ from a
physical mixture was identical to Soluplus amorphous dispersion, suggesting
that drug was likely solubilized in the polymeric micelles, which prevented
recrystallization and maintained the supersaturation (data not shown). Thus, the
lipophilic and solubilizing characteristics of Soluplus are crucial for
complexing with drugs to help not only for maintaining supersaturation in vitro
but also increasing the bioavailability.15,47
et al observed that the solubility and loading of an investigation compound
(BMS-A) was significantly higher in PVP-VA, which led to faster
recrystallization and slower dissolution and lower bioavailability compared to HPMCAS.48
In a study with Soluplus containing 15% itraconazole, the extrudates were
stable over 3 months under accelerated conditions and did not show any signs of
surface recrystallization or retardation of dissolution (unpublished). The
stability of ASDs was also dependent upon the processes used in manufacturing.
For example, when Soluplus, HPMCAS and PVP were used in spray drying and melt extrusion
of felodipine, the dissolution rates were comparable for both spray dried
powders and melt extrudates, but the physical stability of the extrudates was
better than the spray dried powders due, in part, to stronger interactions of
drug and polymer caused by intimate mixing at higher processing temperatures.11
The presence of residual solvents in ASD powders caused phase separation and
formation of local drug domains. Soluplus dispersions with 15% itraconazole
prepared by melt extrusion, and spray dried also behaved identically. Both
formulations maintained supersaturation for an extended period before
also play an important role in influencing the permeation of drugs across the
membranes from solid dispersions. Kanzer et al examined the effects of sorbitan
monolaurate, polyoxyl 40 hydrogenated castor oil and propylene glycol laurate
on permeation of calcein through phospholipid barrier from the melt extrudates
composed of copovidone (PVA-VA) copolymer as a placebo and with two HIV
drugs.49 The surfactants with lower HLB values, for example, propylene glycol
and sorbitan monolaurate (ca. HLB 4-6) did not show any change in permeability
and electrical resistance, and hence, were both compatible with lipid barrier.
In contrast, polyoxyl 40 hydrogenated castor oil (HLB 16) in both API free and API
containing melt extrudates increased permeation of calcein primarily attributed
to leakage of the membrane. This is consistent with an earlier study wherein polyoxyl
35 castor oil (HLB 12-14) was also incompatible, and caused the leakage of
lipid membrane.50 Whentested with CaCo2 cells, the PVPVA/drug dispersions
containing sorbitan monolaurate, the flux of drugs was much higher as compared
to lipid barrier, suggesting that active and passive transports both
interplayed for such increase.53
et al examined the flux of felodipine and nifedipine through a cellulosic
membrane (MWCO of 6-8 K) with HPMC as a crystalline inhibitor in aqueous
solution. The flux of drugs increased linearly in relation to donor
concentration as long as drugs remained in the supersaturation.42 The data from
our studies also suggests that the flux of CBZ through PAMPA membrane from
Soluplus dispersions was 2.5- to 3-fold higher than flux from untreated CBZ.51
data from the Soluplus and carbamazepine
study, and the examples cited in
this article from the literature with hydrophilic
polymers, shed light on understanding
of supersaturation from amorphous
solid dispersions. It also highlights
the factors responsible for drug and
polymer interactions and stability of amorphous
dispersions, to help identify the
physico-chemical characteristics of polymers
relevant to supersaturation. Hence,
three possible scenarios are proposed
to further simplify the supersaturation
phenomenon, and are illustrated in
Curve 6A may arise from polymers possessing
good solubilization and crystalline
inhibitory properties. The combination
of both attributes could lead to
increased kinetic solubility and
maintaining supersaturation, and will
appear as a parachute before precipitation.
Maintaining such behavior could lead
to significantly higher in vitro
trans-membrane flux and meet narrow
therapeutic windows for the
absorption and bioavailability of
Curve 6B may arise from polymers possessing
some degrees of solubilization but
probably lacking a significantly
larger lipophilic characteristic,
thereby, limiting the complexation
with drugs. In such cases, the
desired solubility of drugs can be
achieved, but supersaturation will
be maintained briefly yielding a limited
kinetic solubility and exhibiting a
“spring” behavior, before the
precipitation begins. This trend
could be reversed to a parachute
Curve A by the addition of a
surfactant or solubilizer with higher HLB
values, and/or a hydrophilic polymer
with desired crystalline inhibitory
Curve 6C may arise from polymers possessing
moderate to poor solubilization and
complexation abilities, wherein, the
supersaturation could hardly be
achieved due to precipitation
(limited kinetic solubility),
leading to an immediate drop in the dissolution upon exposure to aqueous solutions. This trend could be reversed by the addition of an appropriate
solubilizer and/or polymers with
desired crystalline inhibitory
properties, and in such cases, Curve C could follow the same trend as Curve B
with limited kinetic solubility, or in a rare case, will follow the Curve A, allowing
to maintain the supersaturation for an extended period.
offers an advantage over many other polymers to study the supersaturation
phenomenon due, in part, to its inherent amphiphilic characteristics derived from
lipophilic and hydrophilic polymeric components. The data from this study
clearly demonstrates that Soluplus possesses all the physicochemical attributes
for improving solubilization, maintaining supersaturation, and preventing the
recrystallization of drugs. Our data demonstrates that Soluplus dispersions maintains
carbamazepine concentrations at least 3-fold higher than pure crystalline drug
and also maintains the supersaturation like the Curve A (Figure 6). The outstanding
in vitro performance of Soluplus dispersions could also help understand the
increased in vivo performances of the extrudates of other model drugs in rats
and beagle dogs.15,22
study showed that the increase of flux of CBZ in the receiver compartment is
lower than the increase in apparent kinetic solubility of the drug from CBZ-Soluplus
ASD, suggesting that the dissolved CBZ is present in both unbound form (free
drug) and CBZ-Soluplus complex (bound form) in donor compartment. Thus, the
dissolution permeability μFLUX™ device can be used to simultaneously monitor
the flux of free drugs in solutions from a complex solid dispersion system.
Additional studies are necessary at molecular levels to understand the
supersaturation and its correlation with thermodynamic and kinetic stability
and flux of drugs in the aqueous and biorelevant solutions.
view this issue and all back issues online, please visit www.drug-dev.com.
(a) F. Qian, J. Huang, and M. A. Hussain, Drug-polymer solubility and miscibility:
Stability consideration and practical challenges in amorphous solid dispersion development,
J. Pharm. Sci., 2010, DOI 10.1002/jps.22074; (b) S. B. Teja, S. P. Patil, G.
Shete, S. Patel, and A. K. Bansal, drug-excipient behavior in polymeric
amorphous solid dispersions, J. Excipients & Food Chem., 2013, 4, 70-94;
(c) C. L-N. Vo, C. Park, and B-J. Lee, Current trends and future perspectives
of solid dispersions containing poorly water-soluble drugs, Eur. J. Pharm.
Biopharm., 2013, 85, 799-813.
(a) D. E. Alonzo, G. G. Z. Zhang, D. Zhou, Y. Gao, and L. S. Tylor, Understanding
the behavior of amorphous pharmaceutical systems during dissolution, Pharm.
Res., 2009, 27, 608-618; (b) A. S. Narang, R-K. Chang, and M. A. Hussain,
Pharmaceutical development and regulatory considerations for nanoparticles and nanoparticulate
drug delivery systems, J. Pharm. Sci., DOI 10.1002/jps.23691.
J. L. Santos, P. Cordeiro, and M. Temtem, Scale-up of spray dried amorphous solid
dispersions, Eur. Indust. Pharm. 2013, 19, 4-8.
B. Li, M. He, W. Li, Z. Luo, Y. Guo, Y. Li, C. Zang, B. Wang, F. Li, S. Li and
P. Ji, Dissolution and pharmacokinetics of baicalin–polyvinylpyrrolidone coprecipitate,
J. Pharm. Pharmacol., 2013, 65, 1670-1678.
J. R. Hughey, J. M. Kean, D. A. Miller, C. Brough, J. W. McGinity, Preparation
and characterization of fusion processed solid dispersions containing a viscous
thermally labile polymeric carrier, Int. J. Pharm. 2012, 438, 11-19.
D. A. Miller, J. C. DeNunzio, J. R. Hughey, R. O. Williams III, and J. W.
McGinity, Kinetisol: A new processing paradigm for amorphous solid dispersion system,
Drug Development & Delivery, 2012, 30-39.
N. Kohri, Y. Yamayoshi, H. Xin, K. Iseki, N. Sato, S. Todo, K. Miyazaki, Improving
the oral bioavailability of albendazole in rabbits by solid dispersion
technique, J. Pharm. Pharmacol., 1999, 51, 159-164.
N. Newa, K. H. Bhandari, D. X. Li, T. Kwon, J. A. Kim, B. K. Yoo, J. S. Woo, W.
S. Lyoo, C. S. Yong, H. G. Choi, Preparation, characterization and in vivo
evaluation of ibuprofen binary solid dispersions with poloxamer 188, Int. J.
Pharm. 2007, 343, 228-237.
(a) Six et al., Clinical study of solid dispersions of itraconazole prepared by
hot stage extrusion, Eur. J. Pharm. Sci., 2005, 24, 179-186; (b). K. Six, G.
Verreck, J. Peeters, M. Brewster, and G. V. den Mooter, Increased physical
stability and improved dissolution properties of itraconazole, a Class II drug,
by solid dispersions that combine fast- and slow-dissolving polymers, J. Pharm.
Sci., 2004, 93, 124-131.
N. Shah, R. M. Iyer, H-J. Mair, D. S. Choi, H. Tian, R. Diodone, K. Fahnrich,
A. Pabst-Ravot, K. Tang, E. Scheubel, J. F. Grippo, S. A. Moreira, Z. Go, J. Mousakountakis,
T. Louie, P. N. Ibrahim, H. Sandhu, L. Rubia, H. Chokshi, D. Singhal, and W.
Malick, Improved human bioavailability of vemurafenib, a practically insoluble
drug, using an amorphous polymerstabilized solid dispersion prepared by a
solvent controlled co-precipitation, J. Pharm. Sci., 2013, 102, 967-981.
Y. Tian, V. Caron, D. S. Jones, A-M. Healy, and G. P. Andrews, Using
Flory-Huggins phase diagrams as a preformulation tool for the production of
amorphous solid dispersions: a comparison between hot-melt extrusion and spray
drying, J. Pharm. Pharmacol., 2013, 66, 256-274.
J. Djuris, N. Ionnis, S. Ibric, Z. Djuric and K. Kachrimanis, Effect of composition
in the development of carbamazepine hot melt extruded solid dispersions by application
of mixture experimental design, J. Pharm. Pharmacol., 2013, 66, 232-243.
I. Durate, M. Temtem, J. F. Pinto, M. Gil and F. Gaspar, Screening methodology
for the development of amorphous solid dispersions, PBP World Meeting.
L. Sambath, A. K. Mathu, M. A. Kumar, K. Phaneendra, and Shalini, Physicochemical
characterization and in vitro dissolution behavior of gliclazide-Soluplus solid
dispersions, Int. J. Pharm. Pharmaceutical Sci., 2013, 5, 204-210.
M. Linn, E-M. Collnot, D. Djuric, K. Hempel, E. Fabian, K. Kolter, and C-M.
Lehr, Soluplus as an effective absorption enhancer of poorly soluble drugs in vitro
and in vivo, Eur. J. Pharm. Sci., 2012, 45, 336-343.
R. Rajeswari and A. K. Sudhakar, Development, characterization and solubility
study of solid dispersion of valsartan, J. Chem. Pharm. Res. 2011, 3, 180-187.
R. Fule and P. Amin, Development and evaluation of lafuthidine solid dispersion
via hot melt extrusion: Investigating drug-polymer miscibility with advanced characterization,
Asian J. Pharm. Sci., 2014, 9, 92-106.
R. A. Fule, T. S. Meer, A. R. Sav, and P. D. Amin, Artether-Soluplus hot melt
extrudate solid dispersion systems for solubility and dissolution rate
enhancement with amorphous state characteristics, J. Pharm., Volume 2013,
Article ID 151432, 15 pages.
A. K. Mehata, V. Suryadevara, S. R. Lankapalli, A. M. Deshmukh, and L. P.
Sambath, Indonesian J. Pharm., 2013, 24, 206-214.
S. Chavan, K. Patel, D. Shelar, and P. Vavia, Preparation of oxcarbazepine
solid dispersion by hot melt extrusion for enhanced dissolution: downstream processing
to tablets, Am. J. Pharm. Res., 2013, 3, 557-569.
C. Kulkarni, A. Kelly, T. Gough, and A. Paradkar, Stability study of artemisinin-Soluplus
solid dispersion (www. Pharmaceutical-engineering.brad.ac.uk).
E-S. Ha, I-H. Baek, W. cho, S-J. Hwang, and M-S. Kim, Preparation and evalulation
of solid dispersion of atorvastatin calcium with Soluplus® by spray drying technique,
Chem. Pharm. Bull., 2014, 62, 545-551.
D. Smithey, J. Fennewald, J. Gautschi, M. Crew, S. Ali, Y. Lan, and N. Langley,
evaluation of the polymer Soluplus for spray dried dispersions of poorly
soluble compounds, AAPS poster 2010.
B. Rashmika, V. Veena, S. Kachhwaha, and D. V. R. N. Bhikshapathi, Der Pharmacia
Lettre, 2013, 5, 73-82.
R. Hughey, J. M. Keen, D. A. Miller, K. Kolter, N. Langley, and J. W. McGinity,
The use of inorganic salts to improve the dissolution characteristics of
tablets containing Soluplus-based solid dispersions, Eur. J. Pharm. Sci., 2013,
U. Paaver, I. Tamm, I. Laidmäe, A. Lust, K. Kirsimae, P. Veski, K. Kogermänn,
and J. Hein ämääki, Soluplus graft copolymer- Potential novel carrier polymer
in electrospinning of nanofibrous delivery systems for wounds therapy, Biomed.
Res. International, 2014,2014, 1-7.
Z. K. Nagy, A. Balogh, B. Vajna, A. Farkas, G. Patyi, A. Kramarics, and G.
Marosi, Comparison of electrospun and extruded Soluplus- based solid dosage forms
of improved dissolution, J. Pharm. Sci, 2011; DOI 10.1002/jps.22731.
M. Sharma, R. Garg, and G. D. Gupta, Formulation and development of solid dispersion
of atorvastatin calcium, J. Pharm. Sci. Innovation, 2013, 2, 73-81.
A. Hussain, I. Ermolina, N. I. Bhkhari, K. A. Khan, and G. Smith, Milling and
co-milling with various excipients for the improvement of intrinsic dissolution
rate of ibuprofen, UKPharmSci, 2013, Edinburgh, Sept. 2-4.
M. M. Pandey, G. K. Kumar, R. Ramakrishan and S. Chardet, Solubility enhancement
of felodipine by solid dispersions with novel polymeric solubilizer Soluplus,
J. Bioequi. Availab, 2012, 4(3), 146.
A. Homayouni, F. Sadeghi, J. Varhosaz, and H. Garekani, Soluplus: a novel
excipient to improve dissolution rate of poorly water soluble drug, celecoxib,
Res. Pharm. Sci., 2012, 7(5), S386.
G. Jyothirmal and V. V. N. Rao, Solubility enhancement of gliclazide by solid dispersion
technique, Int. J. Inv. Pharm. Sci., 2013, 1, 542-553.
C. Mendiratta, V. Kadam, and V. Pakharkar, Lansoprazole solid dispersion using
a novel amphiphilic polymer Soluplus, J. Chem. Pharm. Res., 2011, 3, 536-543.
V. Caron, Y. Hu, L. Tajber, A. Erxleben, O. I. Corrigan, P. McArdle, and A. M. Healy,
Amorphous solid dispersions of sulfonamide/Soluplus and sulfonamide/PVP
prepared by ball milling, AAPS PharmSciTech, 2013, 14, 464-474.
K. R. Shankar and K. P. R. Chowdary, Formulation development of efavirenz tablets
employing b-cyclodextrin, Soluplus and PVP K30: factorial study, Int. Res. J.
Pharm. App. Sci., 2013, 3, 110-115.
N. A. Khetrapal, A. R. Sav, L. Rao, and P. D. Amin, Formulation development of
stable solid oral dosage form of valproic acid using colloidal silica, Int. J.
Drug Del., 2012, 4, 266-274.
G. Vamkas, Q. Fang and A. Fatmi, Improved dissolution profile of API BCS Class
IV drugs using solubility enhancement technologies, AAPS Poster 2011.
H. Hardung, D. Djuric, and S. Ali, Combining HME and solubilization: Soluplus®
–The solid solution, Drug Del. Tech., 2010, 10, 20-27.
(a) A. Avdeef, and O. Tsinman, PAMPA -A drug absorption in vitro model 13. Chemical
selectivity due to membrane hydrogen bonding: In combo comparisons of HDM-,DOPC-,
and DS-PAMPA models, Eur. J. Pharm. Sci., 2006, 28, 43-50; (b). A Avdeef,
Absorption and Drug Development. Solubility, Permeability and Charge State. John
K. Tsinman, O. Tsinman, N. Langley, and S. Ali, Soluplus maintains the supersaturation
of carbamazepine from amorphous solid dispersions, AAPS poster, 2012.
D. D. Sun and P. I. Lee, Evolution of supersaturation of amorphous pharmaceuticals:
The effect of rate of supersaturation generation, Mol. Pharm. 2013, 10, 4330-4346.
S. A. Raina, G. G. Z. Zhang, D. E. Alonzo, J. Wu, D. Zhu, N. D. Carton, Y. Gao,
and L S. Tylor, Enhancements and limits in drug membrane transport using supersaturated
solutions of poorly soluble drugs, J. Pharm. Sci., 2013; DOI 10.1002/jps.23826.
G. Verreck, J. Peeters, and M. Brewster, Dissolution optimization and solid dispersion
feasibility approaches for an anti-HIV drug candidate, CRS Poster, 2014.
(a) L. A. Wegiel, L. J. Mauer, K. J. Edger, ad L. Tylor, Midinfrared spectroscopy
as a polymer selection tool for formulating amorphous solid dispersions, J.
Pharm. Pharmacol., 2013, 66, 244-255; (b) Y. Li, H. Pang, Z. Guo, L. Lin, Y.
Dong, G. Li, M. Lu and C. Wu, Interactions between drugs and polymers
influencing hot melt extrusion, J. Pharm. Pharmacol, 2013, 66, 148-166.
M. Zhang, H. Li, B. Lang, K. O’Donnell, H. Zhang, Z. Wang, Y. Dong, C. Wu, and
R. O. William III, Formulation and delivery of improved amorphous fenofibrate
solid dispersions prepared by thin film freezing, Eur. J. Pharm. Biopharm.,
2012, 82, 534-544.
P. Gao, B. D. Rush, W. P. Pfund, T. Huang, J. M. Bauer, W. Morozowich, M. S.
Kuo, and M J. Hageman, Development of a supersaturable SEDDS (S-SEDDS) formulation
of paclitaxel with improved bioavailability, J. Pharm. Sci., 2003, 92,
S. Ali, N. Langley, D. Djuric and K. Kolter, Soluplus, Tablets & Capsules -
Eye on Excipients, 2010, 8, #7.
F. Qian , J. Wang, R. Hartley, J. Tao, R. Haddadin, N. Mathias, and M. Hussain,
Solution behavior of PVP–VA and HPMC–AS-based amorphous solid dispersions and their
bioavailability implications. Pharm Res 2012, 29,2765–2776.
J. Kanzer, I. Tho, G. E. Flaten, M. Magerlein, P. Holig, G. Fricker, and M.
Brandl, In-vitro permeability screening of melt extrudate formulations containing
poorly water-soluble drug compounds using the phospholipid vesicle-based barrier,
J. Pharm. Pharmacol., 2010, 62, 1591-1598.
G. E. Flaten, K. Luthman, T. Vasskog, and M. Brandl, Drug permeability across a
phospholipid vesicle-based barrier: 4. The effects of tensides, co-solvents and
pH changes on barrier integrity and on drug permeability, Eur. J. Pharm. Sci.,
2008, 34, 173-180.
K. Tsinman and O. Tsinman, Dissolution-permeability apparatus with integrated in
situ concentration monitoring of both donor and received compartments, AAPS
Ms. Oksana Tsinman is a Senior Scientist and a Manager of the
Research and Analytical Laboratory at Pion Inc. She earned her Master’s in
Biochemistry in the Ukraine in 1990. Ms. Tsinman joined Pion in 2002 and
quickly became an integral part of Pion’s research team working on R&D projects
that included among others optimization of high throughput
solubility-permeability measurements, developing early stage formulation screening
techniques and applying in situ UV fiber-optic measurements to preformulation
screening. Her research in artificial membrane permeability measurements that
would predict blood-brain-barrier transport was a basis for Pion receiving
Phase I and II grant from the NIH. Her experimental skills and attention to the
details made her a key part of multiple collaborative research projects with
scientists from the pharmaceutical industry and academic institutions. She has
co-authored more than 15 articles presented at international conferences and
published in primary scientific journals
Dr. Konstantin Tsinman is the Director of Science and Research at
Pion Inc. He joined the company in 1998 as principal developer of the very
first commercial Parallel Artificial Membrane Permeability Assay (PAMPA)
instrument and subsequently the high-throughput method for measuring solubility
- pH profiles. He has been participating in numerous studies expanding the
scope of applications for in situ UV fiber-optic instrumentation and utilization
of derivative spectroscopy techniques for real-time concentration analysis of
complex formulations in turbid solutions. Dr. Tsinman has been involved in
multiple collaborative research projects with scientists from the
pharmaceutical industry and academic institutions. He has co-authored more than
25 articles published in primary scientific journals and holds several patents.
He earned his PhD in Physics in 1994 from the Institute for Metal Physics,
Dr. Shaukat Ali has over 20 years of experience in the pharmaceutical
industry, including 10 years at BASF, where he supports the solubilization
platform and APIs. He serves the USP panel of experts for General Chapters-Physical
Analysis. He is also a member of the editorial boards of American Pharmaceutical
reviews, Contract Pharma, Drug Development & Delivery, Biopharma Asia (UK),
and International Journal of Pharmaceutical Investigation. He has authored over
25 scientific articles and is inventor/co-inventor in 14 US patents. He earned
his PhD in Chemistry from the City University of New York and pursued his
postdoctoral interest at the University of Minnesota and Cornell University.
Dr. Ali’s areas of expertise include drug solubilization, liposome drug
delivery, controlled release, and film development technologies.