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SCF Particle Design for Novel DDS Preparations
Yongda Sun*, Haoxi Jiang, Xiuqin Dong, Minhua Zhang
Key Laboratory for Green Chemical Technology of Ministry of Education,
R＆D Center for Petrochemical Technology, Tianjin University, Tianjin 300072, China
*
Corresponding author: ukydsun@hotmail.com; Phone (+86) 22 27404702-8701;Fax (+86) 22 27406119
ABSTRACT
It is an important strategy for pharmaceutical industry to adjust its capacity from API to DDS, providing a short,
less investment, low risk and effective development cycle. Which needs a strong technical support, SCF Particle
Design is such a support. A series of efforts for developing SCF PD have been done. New equipments were
designed and set up, the structure of the high pressure particle formation vessel and the nozzle was modified in
order to control the particle size and to avoid the nozzle blockage, resulting in easily forming nano-particles. It
provides four routes for DDS innovations: (1) Nano or micron particles. The small particles are gaining interest
in enhancing dissolution rate and clinical efficacy of poorly soluble drugs. For example, an insoluble drug,
amoxicilin, was formed uniform nano amorphous particles. (2) Polymorphic particle. Drug can exist in a variety
of distinct solid forms, which deeply influence the bioavailability and other performances of the drug. For
example, tamoxifen citrate, as a targeted therapy to treat and prevent breast cancer, exhibits two forms.
Clinically, form A is better than form B. By our one step processing, form B fully transited form A.
(3).Composite particles. The drug can be dispersed in “matrix” particulate structure with excipient for
controlling the release of drug in a desired quantity and location, increasing the dissolution rate of slightly
water-soluble drug and modifying the surface properties of drug particles. For example, the coated particles of
API with PVP substantially enhanced the dissolution and bioavailability of drug, optimizing release profiles and
improving stability and processing characteristics. (4) Bio-drug particles. Therapeutic protein, polypeptide and
vaccine can be formulated effect, stable dry powder stored at room temperature for long period, In our lab, dry
microspheres of human insulin were produced with good particle size distribution and ideal morphology for
pulmonary delivery.
INTRODUCTION
It is an important strategy for pharmaceutical industry in developing countries to transfer its capacity of API
production to DDS innovation, which provides a short, less investment, low risk, effective and secure
development cycle. Of course, this strategic change must support by new policies and new technologies. SCF
particle design (SCF PD) is one of novel high-tech platforms of DDS innovation since SCF PD can make small
particles of chemical or biological API and smart composite particles incorporating stabilising agents with fine
microstructure.[1]
DDS preparations are the final product, which must be easy administration, proper dosage and enhancement of
the therapeutic efficacy. The design of DDS preparations in nano or micro particles, specific polymorph form or
composite particles have emerged as a new strategy for drug delivery. During the last decades, SCF PD has been
demonstrated unique advantages as a high-tech platform for achieving crystal and particle engineering of drug
substances and DDS preparations.
Our lab has focused on the foundmantal work in the mechanism of SCF particle formation in the pharmaceuticl
application. A new equipment based anti-solvent processing was designed and set up, various preparations of
chemical or biological drug particles were made. In this paper we report on our initial investigations into the
development of nano or micro sized particles, fine powder of specific polymorph, inhaled dry powder and smart
composite particles by performing SCF PD.[2]
MATERIALS AND METHOD
API and chemicals used in this research were purchased from local pharmaceutical suppliers. Solvents and
reagents were of analytical grade. All experiments were carried out using our new SCF PD equipment based
anti-solvent processing. Figure. 1 shows a schematic diagram of this equipment. This nozzle consists of three
channels through which the aqueous solution, drug solution and CO2 separately. The nozzle is designed in such a
way that the CO2 mixes the two solutions just at the moment they leave the nozzle. When this mixture is sprayed
directly into sc- CO2 it is immediately “drying” to particles after mixing. In addition, due to the atomizing CO2,
small droplets are formed, which are therefore dryed almost instantaneously.
API or SCF samples were analyzed by SEM, AFM, XRPD, PSA, TGA, DSC, FTIR and HPLC at the analytic
centres of Tianjin University and China National Academy of Nanotechnology and Engineering.
Figure 1 The photo and the schematic diagram of the new equipment of SCF PD based on SAS
RESULTS AND DISCUSSION
Nano or micron sized particles
The formation of small particles of micrometer or submicrometer size with controlled particle size distribution
(PSD) is gaining interest in the field of DDS design, since particle size (PS) and particle size distribution are
critical parameters that determine the rate of dissolution of the drug in the biological fluids and, hence, have a
significant effect on the bioavailability of those drugs that have poor solubility in water, Current processes such
as spray or freeze drying for the manufacture of drug nanoparticles usually do not allow very accurate control of
the particle size, and so broad particle size distributions are obtained.
Supercritical antisolvent processes have been widely used for for pure API or multi-components to preparate fine
particles, These processes have mostly given products with a high level of purity, suitable PS in the micro or
sub-micrometer range of 100nm-20μm, narrow PSD, smooth surface with low surface enegy, very low residual
solvent, charge and viscosity, and optional solid forms: crystal or amorphous.
Figure 2 SCF PD route for nano or micron sized particles
For exsampl, an insoluble drug, amoxicilin, was formed homogeneous spherical nanoparticles with meant
particle size of 188 nanometer and amophous state, which not only enhance its dissolution rate and also may be
used in transdermal delivery. Amoxicillin (purity ≥97%) and 1-methyl-2-pyrrolidone (NMP) (purity 99.5%)
were bought from Sigma–Aldrich Chemical (Shanghai, China). Carbon dioxide with a minimum purity of
99.8% was supplied by YongLi Chem Co (Tianjin, China). Amoxicillin was soluble in NMP for the fixed
experimental concentration at room temperature. Scanning electron microscope (SEM) pictures of the API and
SCF nano of amoxicillin are shown in Figure. 3.
Figure 3 SEM of API and homogeneous spherical nanoparticles of Amoxicilin
Polymorph screening and separation
APIs can exist in a variety of distinct solid forms, including polymorphs, solvates, hydrates, salts, co-crystals and
amorphous solids. Each form displays unique physicochemical properties that can deeply influence the
bioavailability, stability and other performance characteristics of the drug. Despite more than a century of
research, the fundamental mechanisms that drive crystal form diversity are not well understood. Due to these
limitations, the solid form discovery remains an experimental exercise, where manual screening methods such as
solvent recrystallization and grinding method are employed to explore form diversity of a compound. Therefore,
polymorph screening and separation of drug substances remain a formidable challenge.
The SCF PD technique offers great advantages for polymorph screening and separation of drug substances since
supercritical fluids offer a huge phase space for crystalline packing arrangement with a desired form. For
example, the polymorphs of sulfathiazole have been intensively investigated for almost 70 years. Five
polymorphs of sulfathiazole are well known and clearly described in the literature [3].and an amorphous form of
sulfathiazole is known. Three pure polymorphs and amorphous form of sulfathiazole had been formed by SCF
process. Crystal habit, X-ray diffraction patterns and melting points of SCF crystallized polymorphs of
sulfathiazole were identical to literature values. The SCF PD method proveds a simple and efficient technique
for reproducible and consistent isolation of sulfathiazole polymorphs.[4]
Figure 4 SCF PD route for polymorph screening and separation
Special polymorph form of API is more easily formed by a single step SCF processing. Here, we report on our
initial investigation into the entire polymorph transfer of tamoxifen citrate.
Tamoxifen citrate, clinically used as a targeted therapy to treat and prevent breast cancer, exhibits two
polymorphic forms: form A which exhibits a single band in the 1700-1740 cm-1 region of its infrared spectrum,
and form B which shows two bands in this region. US Pharmacopoeia regulates that only form A enable to use
inclinical therapy.
We successfully demonstrated that the entire polymorph transfer of tamoxifen citrate was fully changed from B
(API, seeing its FTIR, the top in Figure 3) to A (SCF sample, seeing its FTIR, the bottom in Figure 3) by a single
step processing of SCF PD technique. Such polymorph separation and potential discovery of new polymorph
form, provides critically important knowledge and route for pharmaceutical innovations.
Figure 5
SEM and FTIR of tamoxifen citrate polymorphism
Composite particles
Composite particles are produced for many purposes such as controlling the release of drug in a desired quantity
and location, increasing the dissolution rate of slightly water-soluble materials and modifying the surface
properties of particles used in pharmaceutics.
Composite particles are defined as either the dispersion of one or more solid phases in another continuous solid
phase, called matrix structure, or a core of a material coated by another solid phase, called reservoir structure.
For example, composite particles made by two components may have four typical structures (Figure 4): porous,
embedded, coated, dispersed, they offer many potential applications for DDS design.
Figure 6 SCF PD route for composite particles
These composite particles can be produced by different ways. The SCF PD method is the most recent and simple
one. We have extended our work in the use SCF PD techniques for the formation of fine particles and polymer
on the drug core’s surface or into microporous substrates. Particularly, supercritical based routes seem promising
for the surface coating of nanoparticles, owing to the low viscosity and absence of surface tension, which allows
the complete wetting of complex substrates, including the mesoporous internal surface of agglomerates formed
by nanoparticles.
This process was used for the coated particles of API with PVP, which is based on the ability of scCO2 to induce
the precipitation of both the API and PVP dissolved in a suitable solvent when the solution and the scCO2 are
brought into contact. The effective deposition of the PVP film on the surface of the drug core was evidenced in
the SEM picture of sample (Figure 7). With control of the API:PVP mass ratio, the morphology of the composite
particles was changed from crystal to amorphous state, seeing the XRPD and DSC data in Figure 7.
Dissolution of the API/PVP formulations was substantially higher (100% drug release in 60 min) than that of
milled API (~18% drug release in 60 min), the dissolution profile for row or milled API and for both the
API/PVP formulations.
.
Figure 7 The SEM/PXRD/DSC and the dissolution profiles of API or API with PVP
Another example is adsorption of fenofibrate through supercritical CO2 onto silica was for dissolution
enhancement. Fenofibrate (>99% pure, Sigma–Aldrich), S350 porous silicon dioxide (249.7 m2/g surface area,
D0.5 = 3.4μ,Fuji Silysia, Jappan), Eudragit 100-55 (Rohm GmbH, Germany). methanol (>99.9% pure, Fisher
Scientific) were used. After the SCF processing, loadings of up to 30 wt.% drug onto silica are obtained. Since
solvents are not used in the loading process, the fenofibrate/silica formulation is free of any residual solvent, and
carbon dioxide is freely removed upon depressurization. Figure 8 shows the spongy structure of
silica-fenofibrate formulation without any crystals of fenofibrate due to the agglomeration of silica nanoparticles.
Since fenofibrate is adsorbed on to surface of silica, there is no change in morphological structure of silica..
Dissolution of fenofibrate adsorbed onto silica was substantially higher (∼80% drug release in 20 min) than that
of micronized fenofibrate (∼20% drug release in 20 min). Drug dissolution of 90% was obtained in 30 min for
drug-silica formulation, whereas complete (100%) dissolution of fenofibrate was observed within 24 h.
Figure 8
SEM of API/ Eudragit 100/ S350 porous SO2 and SCF sample
Figure 9 SEM and Dissolution profiles of fenofibrate API and the fenofibrate-silica formulation
Biopharmaceutical particles
Bio-macromolecules such as protein and peptide, are usually administered only by injection. Pulmonary drug
delivery provides a direct route to the blood circulation, increasing patient compliance with a minimum of
discomfort and improving drug delivery in several areas such as diabetes, asthma, Chronic obstructive
pulmonary disease (COPD) and pulmonary infection. Preparation of powders suitable for inhalation and loaded
with biomolecules is also of particular interest for gene therapy and vaccination. Multi-dose dry powder inhalers
(DPIs) capable of delivering high dosage loads have rapidly evolved over the last decade. The basic requirement
for inhaled drugs is the dry poeder with narrow particle size distribution (1-5μ), high drug loading, high
structural stability during both processing and high storage effective pulmonary deposition.[5]
Figure 10 SCF PD route for Biopharmaceutical particles
Efficient formulation of the biopharmaceuticals can produced by SCF PD.. An aqueous solution of human
recombinant insulin (HRI) and scCO2 mixed with co-solvent, leading to fine dry powder with good particle size
distribution and near ideal morphology for pulmonary drug delivery. Our experimental results successfully
demonstrated several key points: (1) the new SCF technique is capable of preparing particulate powders of the
HRI from its aqueous solution. (2) The chemical composition of HRI was not effected by selected process
conditions. (3) The moisture content of the SCF processed HRI was consistent with the starting material. (4) The
current stability data suggest that the SCF process does not adversely affect the stability of HRI. (5) The 1-5 μm
fine particles generated with this SCF process are generally spherical, without agglomeration, which fits the
specifications required for inhalation. (6) A stabilized formulation of inhaled dry powder can be obtained and its
potency loss is less than 5% at room temperature when stored for two years.[6]
Figure 10 shows the morphology of the HRI API and HRI microspheres. The PSD of HRI microspheres was
more than 99% within 5 μm, here D10=0.729μm, D50=1.525μm, D90=3.232μm. The XRPD of HRI API and HRI
microspheres, where they are almost a perfect match each other, which indicates that the HRI macromolecular
structure was not changed by SCF processing. Figure 11 shows the typical surface morphology of a HRI
microsphere. It is very clear that its smooth spherical surface with maximum step less than 3 nm, measured by
AFM.
Figure 11
SEM of the HRI microspheres
Figure 12
Surface morphology of HRI microsphere and of HRI API
CONCLUSIONS
SCF PD provides a green effective platform for making fine pharmaceutical powder and DDS innovationMajor
benefits over traditional drug particle formation methods, especially for dry, particulate forms of
biopharmaceuticals with high retained potency, room temperature stable. Also, SCF PD offers huge
opportunities for preparing ‘pure’ pharmaceutical particles and composite particles incorporating stabilising
agents.
REFERENCES
[1] Sun YD, The Drug Delivery & Formulation Development Asia Summit 2011, 2011 62-72
[2] Sun YD, China Powder Industry Chronicle, 2007 182-198
[3] Kruger G. and Gafner G, Acta Cryst. B28 1972 272-283
[4] Kordikowski A, Shekunov T, York P., Pharmaceutical Research, 18 2001 682-688
[5] Chow A, Tong H, Chattopadhyay P and Shekunov B, Pharmaceutical Research, 24 2007 411-437
[6] Sun,YD, Frontiers of Chemical Enginering in China, 4 2010 82-86