Application of supercritical antisolvent method in drug encapsulation: a review

Figures & data

Figure 1 Triple point phase diagram for pure CO₂.^7,14

Note: Adapted with permission from: Ginty PJ, Whitaker MJ, Shakesheff KM, Howdle SM. Drug delivery goes supercritical. Materials Today. 2005;8(8) Suppl 1: 42–48. Copyright 2005 American Chemical Society; and: reprinted from International Journal of Pharmaceutics, vol 364, Are pharmaceutics really going supercritical?, pages 176–187, copyright 2008, with permission from Elsevier.

Figure 2 Schematic diagram of the apparatus for the supercritical antisolvent process.

Table 1 Summary of literature reviews

Compound	Solvent	Polymer	Particle size	Ref
Bupivacaine HCl	DCM/acetonitrile/potassium phosphate and sodium azide	PLGA/PLLA	4–10 μm	^Citation31
Diuron	DCM	PLLA	Needle-like crystals mean length 500 μm	^Citation27
Amoxicillin	NMP	–	0.3–1.2 μm	^Citation26
Europium acetate	DMSO	–	0.2–10 μm	^Citation36
Cilostazol	DCM		Irregular crystals 0.9–4.52 μm	^Citation37
Gadolinium acetate	DMSO	–	0.2–10 μm	^Citation36
Amoxicillin	NMP	–	0.25–1.2 μm	^Citation38
Fluconazole	DCM, acetone and ethanol	–	Needle like crystals several hundred μm	^Citation39
Nalmefene hydrochloride	Ethanol	–	Above the MCP 200–300 nm, near and below the MCP 0.5–2 μm	^Citation40
Zinc acetate	–	–	50 nm	^Citation41
Salbutamol sulphate	DMSO	–	Length 1–3 mm and diameters 0.2–0.35 mm	^Citation43
Tetracycline	NMP	–	Needle-like particles irregular amorphous particles 0.6–0.8 μm 150 nm	^Citation44
Rifampicin	DCM	PLLA	<5 μm	^Citation11
Methylprednisolone acetate	Tetrahydrofuran	–	4–10 μm	^Citation45
Amoxicillin	DMSO	–	Amorphous spherical particles 0.2–1.6 μm	^Citation34
Chlorpropamide	EtAc	–	Platy crystals several tenths μm	^Citation46
Chlorpropamide	Acetone	–	Columnar habit crystals several tenths μm	^Citation46
Sulfathiazole	Acetone	–	Prismatic crystals >750 μm	^Citation46
Sulfathiazole	MeOH	–	Needle-like, tabular crystal habit >750 μm	^Citation46
Ampicillin	NMP	–	Aggregate and separated amorphous spherical particles 0.26 μm	^Citation47
Ampicillin	EtOH	–	Aggregate and separated amorphous spherical particles 1.26 μm	^Citation47
Rifampicin	DMSO	–	Amorphous particles, coalescent nanometric spherical separated icrometric mean 0.4–1 μm 2.5–5 μm	^Citation36
Arbutine	EtOH	–	2.4–4.7 μm	^Citation48
L-PLA	DCM	–	Agglomerate particle <4 μm	^Citation28
Oxeglitizar	EtOH+ CHCl3, EtOH hydrocortisone	PEG/PVP	Needle crystals, polymorphic form A size >50 μm	^Citation35
Oxeglitizar	THF, DCM	PEG/PVP	Needle-like crystals, polymorphic form A, traces form B size >50 μm	^Citation35
Oxeglitizar	EtOH/THF(50:50), EtOH	PEG/PVP	Needle-like crystals, polymorphic form A and form B size >50 μm	^Citation35
Cefonicid	DMSO	–	Spherical submicroparticles and empty shells from 0.2 μm to >50 μm	^Citation29
Sulfamethizole	Acetone	–	Thin platy <56 μm/tabular <220 μm	^Citation49
Silica	–	Eudragit RL100	50 μm	^Citation50
–	DMSO	Dextran	Spherical particles mean 5–100 μm	^Citation38
–	DMSO	HPMA	Spherical particles 100–200 nm	^Citation38
–	DMSO	Inulin	Irregular particles 5–50 mm	^Citation38
–	DCM	L-PLA	Spherical particles mean 1–4 mm	^Citation38
Cyclotrimethylenetrinitramin	DMSO	–	Granular mean size 12.8 μm	^Citation51
RDX	ACN	–	Granular mean size 6.6 μm	^Citation51
RDX	Acetone	–	Rob shaped granular 17.7 μm	^Citation51
RDX	DMF	–	Granular mean size 5.1 μm	^Citation51
Cyclotrimethylenetrinitramin	NMP	–	Irregular mean size 11.4 μm	^Citation51
Cefoperazone	DMSO	–	Submicro particles, micropetric particles, large crystals 0.25–0.5 μm	^Citation52
Cefuroxime	DMSO	–	Submicro particles, wrinkled microparticles, balloons 0.1–0.9 μm, 1–3 μm, 5–20 μm	^Citation52
Trypsin/lysozyme	DMSO	–	Irregular coalescing particles 1–5 μm	^Citation53
Theophylline	EtOH/DCM	–	lamellar crystals and rosette crystals L/d = 5–300 μm/1–100 μm	^Citation54
–	DCM + DMSO	Ethylcellulose/methylcellulose	Spherical coalescing particles 5 μm	^Citation55
–	DCM	L-PLA	Spherical particles or fibers 1–5 μm	^Citation27
–	DCM	L-PLA	Fibers and/or microspheres mean 1–3 μm	^Citation56
–	DCM	L-PLA	Coalescing particles 3–15 μm	^Citation28
Nimesulide	CHCl3, DCM	–	Needle and thin rod-shaped crystals Form I	^Citation57
Nimesulide	Acetone	–	Needle and thin rod-shaped crystals, meta-stable Form II	^Citation57
Rifampicin	DCM	L-PLA	Spherical particle <5 μm	^Citation11

Abbreviations: CHCl₃, chloroform; DCM, di-chloromethane (methylene chloride); PLGA, polylactic-co-glycolic acid; EtAc, ethyl acetate; EtOH, ethanol; MeOH, methanol; PLLA, L poly lactic acid; NMP, N-methyl-2-pyrrolidone; oxeglitazar, (2E, 4E)-5-(7-methoxy-3,3-dimethyl-2,3-dihydro-1-benzoxepin-5-yl)-3-methylpenta-2,4-dienoic acid; DMSO, dimethyl sulfoxide; MCP, melting critical point; THF, tetrahydrofuran; PEG, polyethylene glycol; PVP, polyvinylpyrrolidone; HPMA, N-(2-hydroxypropyl) methacrylamide; L-PLA, L-polylactic acid; ACN, acetonitrile; DMF, dimethylformamide.

Figure 3 Density dependence of CO₂ at various temperatures.¹⁷

Note: Reproduced from Gupta and Kompella with permission from the publisher.

Figure 4 The two mechanisms in competition for particles formation during the supercritical antisolvent process at P > PC and XCO₂ ≥ XMCP.²²

Note: Reprinted from The Journal of Supercritical Fluids, vol 47, Reverchon E, Adami R, Caputo G, De Marco I, Spherical microparticles production by supercritical antisolvent precipitation: interpretation of results, pages 70–84, copyright 2008, with permission from Elsevier.

Figure 5 Coaxial nozzle employed for the simultaneous introduction of the organic solution and the supercritical antisolvent process.³⁴

Note: Reprinted with permission from Kalogiannis CG, Pavlidou E, Panayiotou CG. Production of amoxicillin microparticles by supercritical antisolvent precipitation. Ind Eng Chem Res. 2005;44:9339–9346. Copyright 2005 American Chemical Society.

Abbreviation: SF, supercritical fluid.

Table 2 Effects of the process parameters on the particle size in the supercritical antisolvent (SAS) process

Effects	Ref
Effects of pressure
At higher pressure, obtained smaller particle size. At higher pressure, the deforming pressure forces must be increased to break the droplets into smaller particles. Moreover, particle nucleation and its growth are other important factors affecting particle size. Rapid mass transfer of antisolvent and solvent causes high supersaturations for the solute. High supersaturation results in rapid nucleation and growth of more than one particle per primary droplet.	^Citation56,Citation63,Citation72–Citation73
At lower pressure, obtained smaller particle size. In a situation above the critical condition, reduction in pressure is observed to decrease the solubility which then results in higher maximum supersaturation in the reactor; therefore, smaller particles are produced.	^Citation32,Citation42,Citation45
Pressure variations have no significant effect on particle size because the free intermolecular volume of the polymer will be occupied at the saturation pressure.	^Citation8,Citation41,Citation63
Effects of temperature
At higher temperature, smaller size and more spherical particles obtained. But the temperature must be lower than the Tg of the polymer.	^Citation32,Citation42,Citation63,Citation72,Citation78
At lower temperature, smaller particle size, obtained due to higher volatility.	^Citation32,Citation73
Effects of concentration
At higher concentration, smaller particle size obtained because the increased initial concentration enhances the maximum supersaturation and, therefore, smaller particles will be formed.	^Citation8,Citation32–Citation33
At lower concentration, smaller particle size obtained because supersaturation of the drug occurs very late and therefore, the precipitation delay and nucleation dominate growth, producing smaller particles.	^Citation27,Citation33,Citation36,Citation42,Citation63,Citation72,Citation73,Citation75
Effects of chemical composition of the organic solvent
Particle size decreases with increase in volatility of the solvent.	^Citation27,Citation41
Particle size decreased by using a stronger solvent.	^Citation41
Solubility of the biodegradable polymer in the organic solvent must be higher than the solubility of its drug contents.	^Citation27
Effects of chemical composition of the drug
Lower solubility of the drug in a supercritical fluid enhances rapid precipitation.	^Citation29,Citation60
Enhancement of drug lipophilicity reduces the loading drug efficiency in the SAS process.	^Citation29,Citation59
Effects of chemical composition of the biodegradable polymer
The crystalline polymer forms smaller particle size with narrower particle size distribution.	^Citation7,Citation67–Citation68
Drug stability in amorphous polymers is higher than in crystalline polymers.	^Citation67–Citation68
Effects of the nozzle geometry
A smaller nozzle diameter reduces the particle size and produces more spherical-shaped particles.	^Citation45,Citation63
The effect of the nozzle diameter is not highly significant.	^Citation63
Co-axial nozzle, is especially designed for improvement of the morphology.	^Citation45,Citation63
Effects of flow rates of CO2and liquid phase
Increasing the ratio of CO2 flow rate over the organic solution flow rate reduces particle size.	^Citation72,Citation77

Abbreviation: Tg, glass transition temperature.

Figure 6 Qualitative diagram pressure versus CO₂ molar reaction.²²

Note: Reprinted from The Journal of Supercritical Fluids, vol 47, Reverchon E, Adami R, Caputo G, De Marco I, Spherical microparticles production by supercritical antisolvent precipitation: interpretation of results, pages 70–84, copyright 2008, with permission from Elsevier.

Abbreviation: MCP, melting critical point.

Figure 7 A schematic of a matrix structure (A), and encapsulated structure (B).

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