microencapsulation-ppt(1).pptx

micro encapsulation appliations

1. Microencapsulation sagar kishor savale 04 / 06 / 16 1 Dr. K. RAJA RAJESWARI ASST PROFESSOR MALLA REDDY COLLEGE OF PHARMACY

2. Introduction Core Material Coating Material Synonyms of Microcapsules Reasons For Microencapsulation Release Mechanisms Different Structures of Microcapsules Types of Microcapsules Application Pharmacological & Physicochemical consideration Classification of Microencapsulation Techniques Applications of Microcapsules and Microspheres Pharmaceutical Applications Evaluation of Microencapsulation Factors Influencing Encapsulation Efficiency Reference Contents 2

3. I n t rod u c tion 3 Definition: “ Microencapsulation may be defined as the process of surrounding or enveloping one substance within another substance on a very small scale, yielding capsules ranging from less than one micron to several hundred microns in size” “It is define has an substance or Pharmaceutical material is encapsulated over the surface of solid, droplet of liquid and dispersion of medium is known has Microencapsulation” It is mean of applying thin coating to small particle of solid or droplet of liquid & dispersion. Particle size: 50-5000 micron. 2 phases: a) Core material b) Coating material Also known as microcapsule, microsphere, coated granules, pellets.

4. Core Material 04 / 06 / 16 4 The material to be coated. It may be liquid or solid or gas. Liquid core may be dissolved or dispersed material. Composition of core material: Drug or active constituent Additive like diluents Stabilizers

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6. Coating Material 04 / 06 / 16 6 Inert substance which coats on core with desired thickness. Composition of coating: Inert polymer Plasticizer Coloring agent Resins, waxes and lipids Release rate enhancers or retardants

7. Synonyms of Microcapsules 04 / 06 / 16 7 Also known as Microcapsule, Microsphere, Microspanules, Microsperules, Microbeads, Microballones, Microgranules, Coated Granules, Pellets, Seeds, Spanules.

8. Reasons For Microencapsulation 04 / 06 / 16 8 For sustained or prolonged drug release. For masking taste and odor of many drugs to improve patient compliance. For converting liquid drugs in a free flowing powder. To reduce toxicity and GI irritation Incompatibility among the drugs can be prevented by microencapsulation. The drugs, which are sensitive to oxygen, moisture or light, can be stabilized by microencapsulation

9. Release Mechanisms 04 / 06 / 16 9 Degradation controlled monolithic system Diffusion controlled monolithic system Diffusion controlled reservoir system Erosion

10. List of coating material 04 / 06 / 16 10 Water soluble resin Water Wax & lipid insoluble resin Enteric resin Gelatin, Gum Arabic, PVP, CMC, Methyl cellulose, Arabinogalactan, Polyvinyl acrylate, Polyacrylic acid. Ethyl cellulose, Polyethylene, P o l y m e t h acry l a t es , Cellulose nitrate, Silicones. Paraffin, Carnauba wax, Bees wax, Stearic acid, Stearyl alcohol. S h e ll ac, Zein, Cellulose acetate phthalate.

11. Stabilization of core material. Inert toward active ingredients. Controlled release under specific conditions. Film-forming, pliable, tasteless, stable. Non-hygroscopic, no high viscosity, economical. Soluble in an aqueous media or solvent, or melting. The coating can be flexible, brittle, hard, thin etc. Coating Material Properties 04 / 06 / 16 11

12. Core Material Characteristic Purpose of Encapsulation Property Final Product Form A s pi r in Slightly water- soluble solid Taste-masking; sustained release; reduced gastric irritation; separation of incompatibles Tablet or capsule Vitamin A Palmitate Nonvolatile liquid Stabilization to oxidation Dry powder Iso s o r b i d e dinitrate Water soluble solid sustained release C a p s u le Table 1: Properties of Some Microencapsulated Core Materials 04 / 06 / 16 12

13. DIFFERENT STUCTURES OF MICROCAPSULES 04 / 06 / 16 13

14. TYPES OF MICROCAPSULES 04 / 06 / 16 14 Simple Microcapsules Enteric coated Microcapsules Mucoadhesive Microcapsules Bioadhesive Microcapsule Floating Microcapsules Magnetic Microcapsules Nanospheres Floating and Effervescent Microcapsules Colonic Microspheres GI Specific Microspheres Intestinal Specific Microspheres

15. Application 04 / 06 / 16 15 Taste masking e.g. acetaminophen. Sustain release e.g. aspirin, iso Sorbide dinitrate. Conversion of liquid to solid e.g. clofibrate Odor masking e.g. castor oil, cysteine. Reducing gastric irritation e.g. phenylbutazone. Stabilization to oxidation e.g. vitamin

16. Pharmacological & Physicochemical consideration 04 / 06 / 16 16

17. Classification of Microencapsulation Techniques: [CAMS 2 P 2 ] 04 / 06 / 16 17 Method Nature S/L Size Range (µ) Coacervation phase separation S & L 2-5000 Air suspension S* 35-5000 Multiorifice centrifugal process S & L 1-5000 Solvent evaporation S & L 5-5000 Spray drying & spray congealing S & L 5-600 Pan coating S 600-5000 Polymerization technique Relatively new Technique

18. Techniques To Manufacture 04 / 06 / 16 18 Physical methods Air-suspension coating Coacervation Process Pan coating Spray–drying Chemical process Solvent Evaporation 2.2. Polymerization

19. Physical or Physico-mechanical methods 04 / 06 / 16 19 ❖ ❖ ❖ ❖ 1. Air-suspension coating [Fluidized Bed Dryer] Inventions of Professor Dale E. Wurster Basically the wurster process consists of the dispersing of solid, particulate core materials in a supporting air stream and the spray-coating of the air suspended particles. Equipment ranging in capacities from one pound to 990 pounds. Micron or submicron particles can be effectively encapsulated by air suspension techniques. [Wurster air suspension Apparatus]

20. Ai r -s u s pen s i o n 04 / 06 / 16 20 The air suspension process offers wide variety of coating material candidates microencapsulation. It consist of dispersing the solid particulate core material in supporting air stream and being coated with coating material (usually polymeric solution) ▪ D i s a d van t ag e - A gg l o m e r a t i on o f the p a rt i c l es to s o m e l ar g e r si ze is no r m a l l y achieved.

21. Processing variables for efficient, effective encapsulation by Air Suspension techniques: Density, surface area, melting point, solubility, friability, volatility, Crystslinity, and flow-ability of core the core material. Coating material concentration (or melting point if not a solution). Coating material application rate. Volume of air required to support and fluidizes the core material. Amount of coating material required. Inlet and outlet operating temperatures. 04 / 06 / 16 21

22. 22 2. Coacervation phase separation The general process consist of 3 steps under continuous agitation: Formation of 3 immiscible chemical phase Deposition of coating Rigidization of coating Step: Three immiscible phases are as: Liquid manufacturing vehicle phase Core material phase Coating material phase Coating material phase formed by utilizing following methods: Temperature change By addition of incompatible polymer By non-solvent addition By salt addition P o 4 / l y 6 m / 1 6 e r -p o l y m e r i n t erac ti o n

23. Core material dispersion in solution of shell polymer; separation of Coacervation from solution; coating of core material by micro droplets of coacervate; Fig: Schematic representation of the Coacervation process. 04 / 06 / 16 23 (d) coalescence of coacervate to form continuous shell around core particles.

24. Temperature change 04 / 06 / 16 24 Core material: N-acetyl p-aminophenol • • • P ol y m er: Solvent: ethyl cellulose cyclohexane Polymer solution + N- EC + Cyclohexane acetyl p-aminophenol (1:2) Gelation & solidification of coating occur Collected by filtration, decantation & centrifugal technique

25. Addition of incompatible polymer 04 / 06 / 16 25 Core material: Coating material: Solvent: Crystalline methylene blue HCl Ethyl cellulose Toluene • • • • Incompatible polymer: Polybutadiene. EC + Toluene mixture + methylene blue HCl (1:4) addition of Polybutadiene EC solidify by adding non-solvent hexane, Collected by titration & drying technique.

26. 26 Addition of Non-solvent Core material: Methyl scopolamine HBr Coating polymer: Cellulose acetate butyrate Solvent: Non-solvent: Methyl ethyl ketone Isopropyl ether. CA butyrate + Methyl ethyl ketone mixture + methyl scopolamine 55 C mixture + isopropyl ether (slowly cool at room temp., collected by centrifugation & drying) 04 / 06 / 16 26

27. Addition of salt addition 04 / 06 / 16 27 Core material: oil soluble vitamin Oil: corn oil Aq. phase: water Polymer: gelatin Salt: sodium sulphate Salt : emulsion ratio is 4:10. Oil soluble vitamin + corn oil mixture + water + sodium sulphate (oil droplet coated uniformly with gelation)

28. polymer-polymer interaction 04 / 06 / 16 28 • • • Core material: Methyl salicylate +ve charge polymer: Gelatin -ve charge polymer: Gum Arabic

29. Oldest industrial procedures for forming small, coated particles or tablets. Solid particle greater than 600 micron size are generally consider for effective coating. It is used for preparation of controlled- release beads. Coating is applied as solution by atomized spray to desired solid core material in coating pan. Usually warm air is passed over the coated material as the coating are being applied in the coating pan. Oldest industrial procedures for forming small, coated particles or tablets. 3. Pan coating 04 / 06 / 16 29 Figure Pan coater

30. Pan coating 04 / 06 / 16 30

31. 4. Spray Drying and Spray Congealing The coating solidification effected by rapid evaporating of solvent in which coating material is dissolved. Spray Congealing: The coating solidification is effected by thermally congealing a molten coating material. The removal of solvent is done by sorption, extraction or evaporation technique. 04 / 06 / 16 31 Spray Drying: Figure Schematic diagram of a Spray Dryer

32. The equipment components of a standard spray dryer include, 1.Air heater, 2.Atomizer, 3.Main spray chamber, 4.Blower or fan, 5.Cyclone and 6.Product collector. 04 / 06 / 16 32

33. ▪ Spray congealing 04 / 06 / 16 33 ▪ ▪ Spray congealing can be accomplished with spray drying equipment when the protective coating is applied as a melt. C o r e m ate r i a l is dispers e d in a coating m aterial m e l t rather than a coating solution. C oati n g solid i f ication (and m icr o e ncapsulation) is acco m plish e d by spraying the hot mixture into a cool air stream.

34. Core material Dissolved Or Dispersed Coating polymer solution With Agitation Liquid Manufacturing Vehicle Phase Heating (If necessary) Evaporation of Polymer solvent Microencapsulation 5. Solvent Evaporation 04 / 06 / 16 34

35. Solvent Evaporation 04 / 06 / 16 35 ❖ ❖ ❖ ❖ In the case in which the core material is dispersed in the polymer solution, polymer shrinks around the core. In the case in which core material is dissolved in the coating polymer solution, a matrix - type microcapsule is formed. The core materials may be either, water - soluble or water - insoluble materials. A variety of film - forming polymers can be used as coatings. Used by companies including the NCR Company, Gavaert Photo - Production NV, and Fuji Photo Film Co., Ltd . Eg. Evaluation of Sucrose Esters as Alternative Surfactants in Microencapsulation of Proteins by the Solvent Evaporation Method.

36. 6. Polymerization 04 / 06 / 16 36 The method involve the reaction of monomeric unit located at the interface existing between a core material substance and continuous phase in which the core material is disperse. The core material supporting phase is usually a liquid or gas, and therefore polymerization reaction occur at liquid-liquid, liquid-gas, solid-liquid, or solid-gas interface. E.g. In the formation of polyamide (Nylon) polymeric reaction occurring at liquid- liquid interface existing between aliphatic diamine & dicarboxylic acid halide.

37. Types of Polymerization Technique: 04 / 06 / 16 37 Interfacial polymer: In Interfacial polymerization, t h e two reac t a n t s i n a polycondensation meet at an interface and react rapidly. I n - si tu po l y m er iz a t i o n : In a few m i cr o enca p s u l a ti o n p r o c e ss e s , t he d ir e ct polymerization of a single monomer is carried out on the particle surface. e.g. Cellulose fibers are encapsulated in polyethylene while immersed in dry toluene. Usual deposition rates are about 0.5μm/min. Coating thickness ranges 0.2-75μm. Matrix polymer: In a number of processes, a core material is imbedded in a polymeric matrix during formation of the particles. Prepares microcapsules containing protein solutions by incorporating the protein in the aqueous diamine phase. National Lead Corporation- utilizing polymerization techniques.

38. 7. Multiorifice - Centrifugal Process 04 / 06 / 16 38 SWRI develop a mechanical process that utilizes centrifugal forces to hurl, a core material particle through an enveloping membrane. The embryonic microcapsule, upon leaving the orifices are hardened, congealed by variety of means. Production rate of 50 to 75 pound/hrs have been achieved with this process.

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40. Applications of Microcapsules and Microspheres 04 / 06 / 16 40 Agricultural Applications Catalysis Food Industry Pharmaceutical Applications Pharmaceutical Applications Potential applications of this drug delivery system are replacement of therapeutic agents (not taken orally today like insulin), gene therapy and in use of vaccines for treating AIDS, tumors, cancer and diabetes. The delivery of corrective gene sequences in the form of plasmid DNA could provide convenient therapy for a number of genetic diseases such as cystic fibrosis and hemophilia.

41. Lupin has already launched in the market worlds first Cephalexin (Ceff-ER) and Cefadroxil (Odoxil OD) antibiotic tablets for treatment of bacterial infections. A spir i n c ontrol l e d rel e as e v ersio n Z O Rpr i n C R t ab l e t s ar e u se d for re l iev i ng ar t hri t is symptoms. Quinidine gluconate CR tablets are used for treating and preventing abnormal heart rhythms. Niaspan CR tablet is used for improving cholesterol levels and thus reducing the risk for a heart attack. Glucotrol (Glipizide SR) is an anti diabetic medicine used to control high blood pressure. Some of the applications of microencapsulation can be described in detail as given below: 1. Prolonged release dosage forms. 2. Prepare enteric-coated dosage forms selectively absorbed in the intestine rather than the stomach. 3. It can be used to mask the taste of bitter drugs. 4. To reduce gastric irritation. . e.g. Nitrofurantoin, Used to aid in the addition of oily medicines to tableted dosage forms. To overcome problems inherent in producing tablets from otherwise tacky granulations. 04 / 06 / 16 41

42. 42 This was accomplished through improved flow properties. Eg. The non-flowable multicomponent solid mixture of niacin, riboflavin, and thiamine hydrochloride and iron phosphate may be encapsulated and made directly into tablets. To protect drugs from environmental hazards such as humidity, light, oxygen or heat. Eg. vitamin A and K have been shown to be protected from moisture and oxygen through microencapsulation. The separations of incompatible substances, Eg. pharmaceutical eutectics. The stability enhancement of incompatible aspirin-chlorpheniramine maleate mixture was accomplished by microencapsulating both of them before mixing. Microencapsulation can be used to decrease the volatility. e.g. Peppermint oil, Methyl salicylate. The hygroscopic properties of many core materials may be reduced by microencapsulation. In the fabrication of multilayered tablet formulations for controlled release of medicament contained in medial layers of tableted particles. Microencapsulation has also been used to decrease potential danger of handling of toxic or n o 4 x /0 i 6 o / u 16 s substances. like pesticides.

43. Evaluation of Microencapsulation 04 / 06 / 16 43 Morphology Drug content Determination of % drug entrapment Bulk density Angle of repose Particle size determination In vitro dissolution studies Diffusion Study Floating Capabilities (only for floating – FLT & TFT) Bioadesion/Mucoadhesion (only for GRDDS) ) In vivo Study – PK & PD (γ-Scintiography - only for GRDDS) Stability studies.

44. CHARACTERIZATION: The characterization of the micro particulate carrier is important, which helps to design a suitable carrier for the proteins, drug or antigen delivery. These microspheres have different microstructures. These microstructures determine the release and the stability of the carrier. PHYSICOCHEMICAL EVALUATION 04 / 06 / 16 44

45. SIEVE ANALYSIS 04 / 06 / 16 45 Separation of the microspheres into various size fractions can be determined by using a mechanical sieve shaker. A series of five standard stainless steel sieves (20, 30, 45, 60 and 80 mesh) are arranged in the order of decreasing aperture size. Five grams of drug loaded microspheres are placed on the upper-most sieve. The sieves are shaken for a period of about 10 min, and then theparticles on the screen are weighed.

46. The surface morphologies of microspheres are examined by a scanning electron microscope. MORPHOLOGY OF MICROSPHERES 04 / 06 / 16 46

47. A Multimode Atomic Force Microscope form Digital Instrument is used to study the surface morphology of the microspheres . ATOMIC FORCE MICROSCOPY (AFM) 04 / 06 / 16 47

48. Particle size determination: Approximately 30 mg microparticles is redisposed in 2–3 ml distilled water, containing 0.1% i nto th e sm a l l volu m e ( m / m ) T w e e n 20 for 3 m i n, using u l tr a s ound. The n t ransferred recirculating unit, operating at 60 ml/ s. The microparticles size can be determined by laser diffractometry. laser diffracto meter PARTICLE SIZE 04 / 06 / 16 48

49. POLYMER SOLUBILITY IN THE SOLVENTS 04 / 06 / 16 49 Solution turbidity is a strong indication of solvent power . The cloud point can be used for the determination of the solubility of the polymer in different organic solvents.

50. The absolute viscosity, kinematic viscosity, and the intrinsic viscosity of the polymer solutions in different solvents can be measured by a U-tube viscometer. The polymer solutions are allowed to stand for 24 h prior to measurement to ensure complète polymère dissolution. VISCOSITY OF THE POLYMER SOLUTIONS 04 / 06 / 16 50

51. DENSITY DETERMINATION 04 / 06 / 16 51 The density of the microspheres can be measured by using a multi volume pychnometer . Accurately weighed sample in a cup is placed into the multi volume pychnometer . Helium is introduced at a constant pressure in the chamber and allowed to expand. This expansion results in a decrease in pressure within the chamber. Two consecutive readings of reduction in pressure at different initial pressure are noted. From two pressure readings the volume and density of the microsphere carrier is determined. Multi volume pychnometer

52. BULK DENSITY 04 / 06 / 16 52 The microspheres fabricated are weighed and transferred to a 10-ml glass graduated cylinder. The cylinder is tapped until the microsphere bed volume is stabilized. The bulk density is estimated by the ratio of microsphere weight to the final volume of the tapped microsphere bed.

53. CAPTURE EFFICIENCY 04 / 06 / 16 53 T he ca p t u re eff i c i e n cy of t h e m i cr o s ph eres or t h e perce n t entr a p m e n t c an b e determined. T he s a m ple is t h e n s ub jec t ed t o the d e t er m i n a t ion o f ac ti v e co n st i t u e n t s as p e r monograph requirement. The percent encapsulation efficiency is calculated using equation: % Entrapment: Actual content/Theoretical content x 100

54. ANGLE OF CONTACT 04 / 06 / 16 54 The angle of contact is measured to determine the wetting property of a micro particulate carrier. T o d e t e r m i n e t h e n a t u re o f m i c r os ph eres i n t e r m s o f h yd r o ph il i c i t y o r hydrophobicity. This thermodynamic property is specific to solid and affected by the presence of the adsorbed component. The angle of contact is measured at the solid/air/water interface. The advancing and receding angle of contact are measured by placing a droplet in a circular cell mounted above objective of inverted microscope.

55. IN VITRO METHODS 04 / 06 / 16 55 release characteristics and There is a need for experimental methods which allow the permeability of a drug through membrane to be determined. For this purpose, a number of in vitro and in vivo techniques have been reported. In vitro drug release studies are employed as a quality control procedure in pharmaceutical production, in product development etc. The influence of technologically defined conditions and difficulty in simulating in vivo conditions has led to development of a number of in vitro release methods for buccal formulations; however no standard in vitro method has yet been developed. Different workers have used apparatus of varying designs and under varying conditions, depending on the shape and application of the dosage form developed.

56. BEAKER METHOD 04 / 06 / 16 56 The dosage form in this method is made to adhere at the bottom of the beaker containing the medium and stirred uniformly using over head stirrer. Volume of the medium used in the literature for the - studies varies from 50- 500 ml -stirrer speed form 60-300 rpm.

57. Standard USP or BP dissolution apparatus have been used to study in vitro release profiles. D i ss o l u ti o n m ed i u m u s ed f o r t h e s tu d y vari e d f r om 1 00 - 50 m l a n d s p eed of rotation from 50-100 rpm. DISSOLUTION APPARATUS 04 / 06 / 16 57

58. ❖ Factors Influencing Encapsulation Efficiency The encapsulation efficiency of the microparticles or microcapsule or microsphere will be affected by different parameters, Fig.5 illustrate the factors influencing encapsulation efficiency. 04 / 06 / 16 58 Figure 5: Factors influencing encapsulation efficiency

59. Solubility of polymer in the organic solvent 04 / 06 / 16 59 Mehta et al., 1996 31 , studied the effect of solubilities of the polymers of different PLGAs in methylene chloride were compared by measuring the methanol cloud point (Cs): Higher Cs meant that the polymer was more soluble in methylene chloride and, thus, required a greater amount of methanol to precipitate from the polymer solution. The PLGA polymer of a relatively high L/G ratio (75/25) had a higher solubility in methylene chloride than the other PLGA (L/G ratio=50/50). A lower molecular weight polymer had a higher solubility in methylene chloride than a higher molecular weight polymer. End- capped polymers, which were more hydrophobic than non-end-capped polymers of the same molecular weight and component ratio, were more soluble in methylene chloride. Diffusion of drugs into the continuous phase mostly occurred during the first 10 minutes of emulsification; therefore, as the time the polymer phase stayed in the non-solidified (semi-solid) state was extended, encapsulation efficiency became relatively low. In Mehta’s study, polymers having relatively high solubilities in methylene chloride took longer to solidify and resulted in low encapsulation efficiencies, and vice versa 31 . Particle size and bulk density also varied according to the polymer. Since polymers having higher solubilities in methylene chloride stayed longer in the semi-solid state, the dispersed phase became more concentrated before it completely solidified, resulting in denser microparticles. Johansen et al., 1998 32 shown that the use of relatively hydrophilic PLGA which carried free carboxylic end groups resulted in a significantly higher encapsulation efficiency compared to that of an end-capped polymer. A similar explanation as above applies to this observation: Hydrophilic PLGA is relatively less soluble in the solvent, methylene chloride, and precipitates more quickly than the end-capped one. High solidification rate might have increased the encapsulation efficiency. On the other hand, the authors attribute the increase to the enhanced interaction between PLGA and the protein through hydrogen bonding and polar interactions 32 . Walter et al 33 . also observed an increased encapsulation efficiency from using relatively hydrophilic PLGA in DNA microencapsulation. The hydrophilicity of the polymer enhanced the stability of the primary emulsion, and it contributed to such an increase.

60. Solubility of organic solvent in water Bodmeier et al 34 . found that methylene chloride resulted in a higher encapsulation efficiency as compared with chloroform or benzene, even though methylene chloride was a better solvent for poly (lactic acid) (PLA) than the others. Methylene chloride is more soluble in water than chloroform or benzene. The ‘high’ solubility allowed relatively fast mass-transfer between the dispersed and the continuous phases and led to fast precipitation of the polymer. The significance of solubility of the organic solvent in water was also confirmed by the fact that the addition of water-miscible co-solvents such as acetone, methanol, ethyl acetate, or dimethyl sulfoxide (DMSO), contributed to increase of the encapsulation efficiency. Knowing that the methanol is a non-solvent for PLA and a water-miscible solvent, it can be assumed that methanol played a dual function in facilitating the polymer precipitation: First, the presence of methanol in the dispersed phase decreased the polymer solubility in the dispersed phase (Jeyanthi et al., 1997) 35 . Second, as a water-miscible solvent, methanol facilitated diffusion of water into the dispersed phase. In order to explain the low encapsulation efficiency obtained with benzene, the authors mention that the benzene required a larger amount of water (non-solvent) than methylene chloride for precipitation of the polymer, and the drug was lost due to the delayed solidification. However, given that benzene is a poorer solvent than methylene chloride for a PLA polymer, this argument does not agree with the widely spread idea that a poor solvent requires a smaller amount of non-solvent to precipitate a polymer. In fact, there could have been a better explanation if they had considered that the delayed solidification was due to the low solubility of benzene in water: As a poor solvent for a PLA polymer, benzene requires only a small amount of non-solvent for complete solidification of the polymer. However, since benzene can dissolve only a tiny fraction of water, it takes much longer to uptake water into the dispersed phase. That is, while solubility of a polymer in an organic solvent governs the quantity of a nonsolvent required in precipitating a polymer, solubility of the organic solvent in the non-solvent limits diffusion of the non-solvent into the polymer phase. Thus, when a cosolvent system is involved, both solubility of a polymer in a solvent and solubility of the solvent in a non-solvent participate in determining the sol id 4/ if i 6 c / a 1 t 6 ion rate of the dispersed phase.

61. Park et al., 1998 36 , lysozyme-loaded PLGA microparticles were prepared using the oil in water (o/w) single emulsion technique. Here, the authors used a co-solvent system, varying the ratio of the component solvents. DMSO was used for solubilization of lysozyme and PLGA, and methylene chloride was used for generation of emulsion drops as well as solubilization of PLGA. Encapsulation efficiency increased, and initial burst decreased as the volume fraction of DMSO in the co-solvent system increased. Particle size increased, and density of the microparticle matrix decreased with increasing DMSO. Overall, these results indicate that the presence of DMSO increased the hydrophilicity of the solvent system and allowed fast extraction of the solvent into the continuous phase, which led to higher encapsulation efficiency and larger particle size. Concentration of the polymer 04 / 06 / 16 61 Encapsulation efficiency increases with increasing polymer concentration (Mehta et al., 1996; Rafati et al., 1997; Li et al., 1999) 31, 37, 38 . For example, the encapsulation efficiency increased from 53.1 to 70.9% when concentration of the polymer increased from 20.0 to 32.5% (Mehta et al., 1996) 31 . High viscosity and fast solidification of the dispersed phase contributed to reducing porosity of the microparticles as well (Schlicher et al., 1997) 39 . The contribution of a high polymer concentration to the encapsulation efficiency can be interpreted in two ways. First, when highly concentrated, the polymer precipitates faster on the surface of the dispersed phase and prevents drug diffusion across the phase boundary (Rafati et al., 1997) 37 . Second, the high concentration increases viscosity of the solution and delays the drug diffusion within the polymer droplets (Bodmeier and McGinity, 1988) 34 .

62. Ratio of dispersed phase to continuous phase (DP/ CP 04 / 06 / 16 62 ratio) Encapsulation efficiency and particle size increase as the volume of the continuous phase increases (Li et al., 1999, Mehta et al., 1996) 38,31 . For example, the encapsulation efficiency increased more than twice as the ratio of the dispersed phase to the continuous phase (DP/CP ratio) decreased from 1/50 to 1/300 (Mehta et al., 1996) 31 . It is likely that a large volume of continuous phase provides a high concentration gradient of the organic solvent across the phase boundary by diluting the solvent, leading to fast solidification of the microparticles. A relevant observation is described in the literature (Sah, 1997) 40 . In this example, which utilized ethyl acetate as a solvent, the formation of microparticles was dependent on the volume of the continuous phase. When 8 mL of PLGA solution (o) was poured into 20 or 50 mL of water phase (w), the polymer solution was well disintegrated into dispersed droplets. On the other hand, when the continuous phase was 80 mL or more, the microspheres hardened quickly and formed irregular precipitates. This is because the large volume of continuous phase provided nearly a sink condition for ethyl acetate and extracted the solvent instantly. Due to the fast solidification of the polymer, particle size increased with increasing volume of the continuous phase. Microparticles generated from a low DP/CP ratio had a lower bulk density (0.561 g/cc at 1/50 vs. 0.357 g/cc at 1/ 300), which the authors interpret as an indication of higher porosity of the polymer matrix (Mehta et al., 1996) 31 . On the other hand, a different example shows that a higher DP/ CP ratio resulted in increased porosity, providing a large specific surface area (measured by the BET method) and the scanning electron microscope (SEM) pictures as evidence (Jeyanthi et al., 1997) 35 . This apparent discrepancy can be explained by the fact that low bulk density (Mehta et al., 1996) 31 is not a true reflection of porosity but a result of large particle size. In fact, porosity increases with increasing DP/CP ratio, i.e., decreasing rate of the polymer precipitation.

63. Rate of solvent removal The method and rate of solvent removal influence the solidification rate of the dispersed phase as well as morphology of the resulting microparticles (Mehta et al., 1994) 41 . In the emulsion-solvent evaporation/extraction method, the solvent can be removed by (i) evaporation, in which the solvent is evaporated around its boiling point or (ii) extraction into the continuous phase. The rate of solvent removal can be controlled by the temperature ramp or the evaporation temperature in the former and by the volume of the dilution medium in the latter. PLGA microparticles containing salmon calcitonin (sCT) were prepared by emulsification, followed by different solvent removal processes (Mehta et al., 1994, Jeyanthi et al., 1996) 41,42 . In the temperature dependent solvent removal process, the solvent (methylene chloride) was removed by increasing the temperature from 15 to 40°C at different rates. The microparticles that resulted from this process had a hollow core and a porous wall. The core size and wall thickness were dependent on the temperature ramp. A rapid rise in temperature resulted in a thin wall and a large hollow core, whereas a stepwise temperature rise (15 to 25, then to 40°C) resulted in a reduced core size. It is believed that the hollow core was due to the rapid expansion of methylene chloride entrapped within the solidified microparticles. In controlled extraction of the solvent, the solvent was removed gradually and slowly by dilution of the continuous phase, which left the microparticles in the soft state for a longer period of time. The resulting microparticles showed a highly porous honeycomb- like internal structure without a hollow core. In the later study, it was noted that the porosity was a function of the amount of water diffused into the dispersed phase from the continuous phase, which could only be allowed before the dispersed phase solidified completely (Li et al., 1995) 43 . In other words, the high porosity of the microparticles was due to the slow solidification of the microparticles. Even though it is generally assumed that fast polymer solidification results in high encapsulation efficiency, this does not apply to the observation of Yang et al. 44 . Here, the encapsulation efficiency was not affected by the solvent evaporation temperature. It may be due to the different processing temperatures influenced not only the rate of polymer solidification but also the diffusivity of the protein and its solubility in water. While the high temperature facilitated solidification of the dispersed phase, it enhanced diffusion of the protein into the continuous phase, compromising the positive effect from the fast solidi f 4 ic / a t 6 i / o 1 n 6 .

64. Interaction between drug and polymer 04 / 06 / 16 64 Interaction between protein and polymer contributes to increasing encapsulation efficiency 45 . Generally, proteins are capable of ionic interactions and are better encapsulated within polymers that carry free carboxylic end groups than the end- capped polymers. On the other hand, if hydrophobic interaction is a dominant force between the protein and the polymer, relatively hydrophobic end-capped polymers are more advantageous in increasing encapsulation efficiency 31 . For example, encapsulation efficiencies of more than 60% were achieved for salmon calcitonin (sCT) microparticles despite the high solubility of sCT in the continuous phase 35 . This is attributed to the strong affinity of sCT to hydrophobic polymers such as PLGA. On the other hand, such interactions between protein and polymer can limit protein release from the microparticles 36,46,47 . In certain cases, a co-encapsulated excipient can mediate the interaction between protein and polymer 32 . Encapsulation efficiency increased when gammahydroxypropylcyclodextrin (g-HPCD) were co-encapsulated with tetanus toxoid in PLGA microparticles. It is supposed that the g-HPCD increased the interaction by accommodating amino acid side groups of the toxoid into its cavity and simultaneously interacting with PLGA through van der Waals and hydrogen bonding forces. Solubility of drug in continuous phase Drug loss into the continuous phase occurs while the dispersed phase stays in a transitional, semi-solid state. If the solubility of the drug in the continuous phase is higher than in the dispersed phase, the drug will easily diffuse into the continuous phase during this stage. For example, the encapsulation efficiency of quinidine sulfate was 40 times higher in the alkaline continuous phase (pH 12, in which quinidine sulfate is insoluble) than in the neutral continuous phase (pH 7, in which quinidine sulfate is very soluble) 34 .

65. Molecular weight of the polymer 04 / 06 / 16 65 X. Fu et al., studied the effect of molecular weight of the polymer on encapsulation efficiency, developed a long-acting injectable huperzine A-PLGA microsphere for the chronic therapy of Alzheimer's disease, the microsphere was prepared by using o/w emulsion solvent extraction evaporation method. The morphology of the microspheres was observed by scanning electron microscopy . The distribution of the drug within microspheres was observed by a confocal laser scanning microscope. The results indicated that the PLGA 15 000 microspheres possessed a smooth and round appearance with average particle size of 50 µm or so. The encapsulation percentages of microspheres prepared from PLGA 15 000, 20 000 and 30 000 were 62.75, 27.52 and 16.63%, respectively . The drug release percentage during the first day decreased from 22.52% of PLGA 30 000 microspheres to 3.97% of PLGA 15 000 microspheres, the complete release could be prolonged to 3 weeks . The initial burst release of microspheres with higher molecular weight PLGA could be explained by the inhomogeneous distribution of drug within microspheres . The encapsulation efficiency of the microspheres improved as the polymer concentration increase in oil phase and PVA concentration decreased in aqueous phase. The burst release could be controlled by reducing the polymer concentration. Evaporation temperature had a large effect on the drug release profiles. It had better be controlled under 30°C. Within a certain range of particle size, encapsulation efficiency decreased and drug release rate increased with the reducing of the particle size 48 .

66. Summary of Factors of Encapsulation Efficiency The techniques reviewed in this article would serve as a forerunner for developing novel drug delivery towards ensuring better therapeutic efficiency. The factors influencing their optimisation provides a clear picture towards developing a suitable technique not only for drug industry but also for other food and cosmetic industry as well. Care full consideration of the above said factors would ensures reproducibility in both lab and production scale.

67. REFERENCE 04 / 06 / 16 67 L e o n, L a c h m an, Her b ert A. L . , J o s e ph , L . K; “ Th e T h e o ry A n d P rac ti ce Of Industrial Pharmacy”, 3rd edition, 1990, Varghese Publishing House,412, 428. Microencapsulation encyclopedia of polymer science and technology, 2005 John Wiley & Sons, 1-3. Mi c r oe n caps u l a ti on : a re v i ew i n t er n a t i o nal j o ur n al o f p ha r m ac e u t i c a l s c i e n c e s review and research volume 1, issue 2, marches – April 2010. Jackson, L. S., Lee. K., (1991-01-01), “Microencapsulation and the food industry” (htm) Lebennsmittel-Wissenschaft Techonologie. Rerrived on 1991-02-02. Youan, B. C., Hussain, A., Nguyen, N.T., “AAPS Pharma Sci.”, 2003, 5(2).