Elsevier

Journal of Controlled Release

Volume 102, Issue 2, 2 February 2005, Pages 313-332
Journal of Controlled Release

Review
Microencapsulation by solvent extraction/evaporation: reviewing the state of the art of microsphere preparation process technology

https://doi.org/10.1016/j.jconrel.2004.10.015Get rights and content

Abstract

The therapeutic benefit of microencapsulated drugs and vaccines brought forth the need to prepare such particles in larger quantities and in sufficient quality suitable for clinical trials and commercialisation. Very commonly, microencapsulation processes are based on the principle of so-called “solvent extraction/evaporation”. While initial lab-scale experiments are frequently performed in simple beaker/stirrer setups, clinical trials and market introduction require more sophisticated technologies, allowing for economic, robust, well-controllable and aseptic production of microspheres. To this aim, various technologies have been examined for microsphere preparation, among them are static mixing, extrusion through needles, membranes and microfabricated microchannel devices, dripping using electrostatic forces and ultrasonic jet excitation. This article reviews the current state of the art in solvent extraction/evaporation-based microencapsulation technologies. Its focus is on process-related aspects, as described in the scientific and patent literature. Our findings will be outlined according to the four major substeps of microsphere preparation by solvent extraction/evaporation, namely, (i) incorporation of the bioactive compound, (ii) formation of the microdroplets, (iii) solvent removal and (iv) harvesting and drying the particles. Both, well-established and more advanced technologies will be reviewed.

Introduction

Biodegradable microspheres are widely investigated delivery systems for bioactive compounds such as low molecular weight and macromolecular therapeutics, antigens or DNA. As such they may add substantially to the value of therapies and vaccinations. Considered for parenteral, pulmonary, oral or nasal administration, they are capable of providing sustained and controlled release of the encapsulated bioactive compound, while the nonreleased bioactive material may be protected from degradation and physiological clearance. For vaccines, microspheres may provide additional adjuvancy [1], [2] and allow for direct targeting to professional antigen-presenting cells [3]. Furthermore, they may be surface-modified to target specific cells [4] and tissues [5].

Owing to their excellent biocompatibility, the biodegradable polyesters poly(lactic acid) (PLA) and poly(lactic-co-glycolic acid) (PLGA) are the most frequently used biomaterials for the microencapsulation of therapeutics and antigens [6], [7]. Other materials like proteins [5], polymer blends [8], polysaccharides such as chitosan [9], and lipids [10] have also been studied, although at a lower frequency. A large variety of bioactive compounds have been formulated into microspheres, among them are antineoplastic drugs [11], [12], narcotics [13], anaesthetic agents [14] as well as therapeutic peptides [15], [16] and proteins [17], [18], DNA [19], [20], viruses [21] and bacteria-derived compounds [22], [23]. Preparation technologies capable of producing larger amounts of microspheres in a safe, economic, robust and well-controlled manner are therefore required.

Microspheres have been prepared by various techniques, which feature partly competing, partly complementary characteristics. Many microencapsulation processes are modifications of the three basic techniques: solvent extraction/evaporation, phase separation (coacervation) and spray-drying [24]. Spray-drying is relatively simple and of high throughput but must not be used for highly temperature-sensitive compounds. Moreover, control of the particle size is difficult, and yields for small batches are moderate [25]. Coacervation is frequently impaired by residual solvents and coacervating agents found in the microspheres [26]. Furthermore, it is not well suited for producing microspheres in the low micrometer size range. The use of supercritical gases as phase separating agents was intensively studied to minimise the amount of potentially harmful residues in the microspheres, resulting in processes named, e.g., Precipitation with Compressed Antisolvent (PCA) [27], Gas or Supercritical fluid Anti-Solvent (GAS or SAS) and Aerosol Solvent Extraction System (ASES) [28]. Solvent extraction/evaporation neither requires elevated temperatures nor phase separation-inducing agents. Controlled particle sizes in the nano- to micrometer range can be achieved, but careful selection of encapsulation conditions and materials is needed to yield high encapsulation efficiencies and a low residual solvent content.

Microsphere preparation by solvent extraction/evaporation basically consists of four major steps: (i) dissolution or dispersion of the bioactive compound often in an organic solvent containing the matrix forming material; (ii) emulsification of this organic phase in a second continuous (frequently aqueous) phase immiscible with the first one; (iii) extraction of the solvent from the dispersed phase by the continuous phase, which is optionally accompanied by solvent evaporation, either one transforming the droplets into solid microspheres; (iv) harvesting and drying of the microspheres (Fig. 1).

This article reviews the current state of the art in solvent extraction/evaporation-based microencapsulation technology, with a focus on process-related aspects. Issues like materials, microsphere formulation, choice of appropriate solvents or surfactants are not central aspects of this review, although technology and starting materials are interconnected and can by no means be segregated completely. Both well-established and more advanced technologies will be reviewed.

Section snippets

Incorporation of bioactive compounds

Bioactive compounds may be added to the solution of the matrix material by either codissolution in a common solvent, dispersion of finely pulverised solid material or emulsification of an aqueous solution of the bioactive compound immiscible with the matrix material solution [29]. Codissolution may require a cosolvent to fully dissolve the drug in the matrix-containing solvent. Dispersion of the solid or dissolved bioactive material in the matrix-containing solution may be achieved by

Droplet formation

The droplet formation step determines the size and size distribution of the resulting microspheres. Microsphere size may affect the rate of drug release, drug encapsulation efficiency, product syringeability, in vivo fate in terms of uptake by phagocytic cells and biodistribution of the particles after subcutaneous injection of intranasal administration. In the following, the main procedures used for droplet formation in microsphere production are described. Henceforth, the different types of

Solvent removal

In both solvent extraction and evaporation, the solvent of the disperse phase, i.e., the drug/matrix dispersion, must be slightly soluble in the continuous phase so that partitioning into the continuous phase can occur leading to precipitation of the matrix material. In solvent evaporation, the capacity of the continuous phase is insufficient to dissolve the entire volume of the disperse phase solvent. Therefore, the solvent must evaporate from the surface of the dispersion to yield

Microsphere harvest and drying

Separation of the solidified microspheres from the continuous phase is usually done either by filtration or centrifugation. The particles may then be rinsed with appropriate liquids to remove adhering substances such as dispersion stabilisers or nonencapsulated drugs. Rinsing may involve elevated temperatures or the use of extraction agents to reduce the amount of residual solvent in the microspheres [109]. Finally, the microspheres are dried either at ambient conditions or under reduced

Conclusions

The widespread interest in microencapsulated drugs brought forth the need to prepare such particles in larger quantities and in sufficient quality suitable for clinical trials and commercialisation. The most frequently described solvent extraction/evaporation-based technology using simple beaker/stirrer setup is inappropriate for producing larger amounts of microspheres in an economic, robust and well-controlled manner. Static mixers warrant continuous production and simple scale-up, while the

References (110)

  • P. Couvreur et al.

    Multiple emulsion technology for the design of microspheres containing peptides and oligopeptides

    Adv. Drug Deliv. Rev.

    (1997)
  • L. Meinel et al.

    Stabilizing insulin-like growth factor-I in poly(dl,lactide-co-glycolide) microspheres

    J. Control. Release

    (2001)
  • Y. Capan et al.

    Influence of formulation parameters on the characteristics of poly(d,l-lactide-co-glycolide) microspheres containing poly(l-lysine) complexed plasmid DNA

    J. Control. Release

    (1999)
  • C. Sturesson et al.

    Encapsulation of rotavirus into poly(lactide-co-glycolide) microspheres

    J. Control. Release

    (1999)
  • N. Kofler et al.

    Preparation and characterization of poly-(d,l-lactide-co-glycolide) and poly-(l-lactic acid) microspheres with entrapped pneumotropic bacterial antigens

    J. Immunol. Methods

    (1996)
  • P. Johansen et al.

    Technological considerations related to the up-scaling of protein microencapsulation by spray-drying

    Eur. J. Pharm. Biopharm.

    (2000)
  • J. Jung et al.

    Particle design using supercritical fluids: literature and patent survey

    J. Supercrit. Fluids

    (2001)
  • J. Herrmann et al.

    Biodegradable, somatostatin acetate containing microspheres prepared by various aqueous and non-aqueous solvent evaporation methods

    Eur. J. Pharm. Biopharm.

    (1998)
  • H. Rafati et al.

    Protein-loaded poly(dl-lactide-co-glycolide) microparticles for oral administration: formulation, structural and release characteristics

    J. Control. Release

    (1997)
  • M.J. Blanco Prieto et al.

    Characterization of V3 BRU peptide-loaded small PLGA microspheres prepared by a (w1/o)w2 emulsion solvent evaporation method

    Int. J. Pharm.

    (1994)
  • Y.Y. Yang et al.

    Morphology, drug distribution, and in vitro release profiles of biodegradable polymeric microspheres containing protein fabricated by double emulsion solvent extraction/evaporation method

    Biomaterials

    (2001)
  • H. Sah et al.

    The influence of biodegradable microcapsule formulations on the controlled release of a protein

    J. Control. Release

    (1994)
  • J. Herrmann et al.

    Somatostatin containing biodegradable microspheres prepared by a modified solvent evaporation method based on W/O/W-multiple emulsions

    Int. J. Pharm.

    (1995)
  • Y.Y. Yang et al.

    Effect of preparation conditions on morphology and release profiles of biodegradable polymeric microspheres containing protein fabricated by double-emulsion method

    Chem. Eng. Sci.

    (2000)
  • G. Crotts et al.

    Preparation of porous and nonporous biodegradable polymeric hollow microspheres

    J. Control. Release

    (1995)
  • T. Morita et al.

    Protein encapsulation into biodegradable microspheres by a novel S/O/W emulsion method using poly(ethylene glycol) as a protein micronization adjuvant

    J. Control. Release

    (2000)
  • C. Schugens et al.

    Effect of the emulsion stability on the morphology and porosity of semicrystalline poly l-lactide microparticles prepared by w/o/w double emulsion-evaporation

    J. Control. Release

    (1994)
  • M.J. Blanco Prieto et al.

    Couvreur, Characterization and morphological analysis of cholecystokinin derivative peptide-loaded poly(lactide-co-glycolide) microspheres prepared by a water-in-oil-in-water emulsion solvent evaporation method

    J. Control. Release

    (1997)
  • D. Blanco et al.

    Protein encapsulation and release from poly(lactide-co-glycolide) microspheres: effect of the protein and polymer properties and of co-encapsulation of surfactants

    Eur. J. Pharm. Biopharm.

    (1998)
  • P. Sansdrap et al.

    Influence of manufacturing parameters on the size characteristics and the release profiles of nifedipine from poly(dl-lactide-co-glycolide) microspheres

    Int. J. Pharm.

    (1993)
  • A.G. Coombes et al.

    Resorbable polymeric microspheres for drug delivery-production and simultaneous surface modification using PEO–PPO surfactants

    Biomaterials

    (1994)
  • A. Carrio et al.

    Preparation and degradation of surfactant-free PLAGA microspheres

    J. Control. Release

    (1995)
  • H. Jeffery et al.

    The preparation and characterisation of poly(lactide-co-glycolide) microparticles: I. Oil-in-water emulsion solvent evaporation

    Int. J. Pharm.

    (1991)
  • H. Sah

    Microencapsulation techniques using ethyl acetate as a dispersed solvent: effects of its extraction rate on the characteristics of PLGA microspheres

    J. Control. Release

    (1997)
  • G. Ma et al.

    Preparation of uniform poly(lactide) microspheres by employing the Shirasu Porous Glass (SPG) emulsification technique

    Colloids Surf., A

    (1999)
  • I. Kobayashi et al.

    Microscopic observation of emulsion droplet formation from a polycarbonate membrane

    Colloids Surf., A

    (2002)
  • B.G. Amsden et al.

    An examination of factors affecting the size, distribution and release characteristics of polymer microbeads made using electrostatics

    J. Control. Release

    (1997)
  • C. Berkland et al.

    Fabrication of PLG microspheres with precisely controlled and monodisperse size distributions

    J. Control. Release

    (2001)
  • C. Berkland et al.

    Precise control of PLG microsphere size provides enhanced control of drug release rate

    J. Control. Release

    (2002)
  • G. Brenn

    On the controlled production of sprays with discrete polydisperse drop size spectra

    Chem. Eng. Sci.

    (2000)
  • C. Sturesson et al.

    Preparation of biodegradable poly(lactic-co-glycolic) acid microspheres and their in vitro release of timolol maleate

    Int. J. Pharm.

    (1993)
  • H.T. Wang et al.

    Influence of formulation methods on the in vitro controlled release of protein from poly(ester) microspheres

    J. Control. Release

    (1991)
  • X.M. Deng et al.

    Optimization of preparative conditions for poly-dl-lactide-polyethylene glycol microspheres with entrapped Vibrio Cholera antigens

    J. Control. Release

    (1999)
  • T. Freytag et al.

    Improvement of the encapsulation efficiency of oligonucleotide-containing biodegradable microspheres

    J. Control. Release

    (2000)
  • Y.Y. Yang et al.

    Effect of preparation conditions on morphology and release profiles of biodegradable polymeric microspheres containing protein fabricated by double-emulsion method

    Chem. Eng. Sci.

    (2000)
  • Y.Y. Yang et al.

    Effect of preparation temperature on the characteristics and release profiles of PLGA microspheres containing protein fabricated by double-emulsion solvent extraction/evaporation method

    J. Control. Release

    (2000)
  • S. Faraasen et al.

    Ligand-specific targeting of microspheres to phagocytes by surface modification with poly(l-lysine)–grafted poly(ethylene glycol) conjugate

    Pharm. Res.

    (2003)
  • Y. Kato et al.

    Application of chitin and chitosan derivatives in the pharmaceutical field

    Curr. Pharm. Biotechnol.

    (2003)
  • M. Boisdron-Celle et al.

    Preparation and characterization of 5-fluorouracil-loaded microparticles as biodegradable anticancer drug carriers

    J. Pharm. Pharmacol.

    (1995)
  • R. Verrijk et al.

    Reduction of systemic exposure and toxicity of cisplatin by encapsulation in poly(lactide-co-glycolide)

    Cancer Res.

    (1992)
  • Cited by (797)

    View all citing articles on Scopus
    View full text